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))