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10.1093/neuonc/nou208.9 http://scihub22266oqcxt.onion/10.1093/neuonc/nou208.9 C4144621/?report=reader!4144621!C4144621     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Neuro+Oncol 2014 ; 16 (Suppl 3): iii25 Nephropedia Template TP {{tp|p=C4144621|t=2014. EPIGENETIC TARGETING OF HEDGEHOG PATHWAY TRANSCRIPTIONAL OUTPUT |pdf=|usr=}}{{C4144621}} gab.com Text EPIGENETIC TARGETING OF HEDGEHOG PATHWAY TRANSCRIPTIONAL OUTPUT JO: Neuro Oncol http://www.kidney.de/pget.php?&tw=1&pmid=C4144621 #FOAvip BACKGROUND: (blind field) METHODS: We used ligand and genetic activation of the Hedgehog pathway to study the effects of BET bromodomain inhibition on Hedgehog pathway transcriptional output. Furthermore, we studied the in vitro and in vivo efficacy of BET bromodomain inhibitors using tumor cells generated from genetically engineered mouse (GEM) and patient derived xenograft models of Hedgehog driven tumors, including a panel of tumors resistant to the current FDA-approved Smoothened antagonists. RESULTS: We show that knockdown of BRD4 or treatment with the BET bromodomain inhibitor, JQ1, dramatically inhibits transcription of GLI1, GLI2 and other Hedgehog target genes upon ligand-mediated or genetic activation of the Hedgehog pathway. We confirm the inhibitory effect of JQ1 occurs downstream of SMO and SUFU and verify by chromatin immunoprecipitation that BRD4 directly occupies the GLI1 and GLI2 promoters with a substantial decrease in the engagement of these genomic sites upon treatment with JQ1. We observe a corresponding downregulation of genes associated with medulloblastoma-specific GLI1 binding sites upon exposure to JQ1, confirming the direct regulation of GLI1 by BET bromodomain proteins. Finally, in patient- and GEM-derived cells of Hedgehog-driven cancer (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor), we show that JQ1 decreases Hh pathway output and proliferation, even in cells resistant to Smoothened inhibitors. CONCLUSIONS: These results expand the role of BET bromodomain inhibitors to targeting Hedgehog-driven cancers and highlight a strategy that overcomes the limitation of Hedgehog pathway inhibitors currently in clinical use. SECONDARY CATEGORY: Pediatrics. Twit Text FOAVip EPIGENETIC TARGETING OF HEDGEHOG PATHWAY TRANSCRIPTIONAL OUTPUT ????Neuro Oncol http://www.kidney.de/pget.php?&tw=1&pmid=C4144621 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=C4144621 #FOAvip English Wikipedia <ref>{{Cite pmid|C4144621}}</ref> EPIGENETIC TARGETING OF HEDGEHOG PATHWAY TRANSCRIPTIONAL OUTPUT #MMPMIDC4144621 Cho YJ; Tang Y; Schubert S; Willardson M; Bandopadhayay P; Bergthold G; Nguyen B; Masoud S; Vue N; Balansay B; Gholamin S; Cheshier SH; Atwood SX; Whitson RJ; Lee A; Tang JY; Qi J; Beroukhim R; Wechsler-Reya R; Oro AE; Link B; Bradner JE; Cho YJ Neuro Oncol 2014[Jul]; 16 (Suppl 3): iii25 PMIDC4144621show ga BACKGROUND: (blind field) METHODS: We used ligand and genetic activation of the Hedgehog pathway to study the effects of BET bromodomain inhibition on Hedgehog pathway transcriptional output. Furthermore, we studied the in vitro and in vivo efficacy of BET bromodomain inhibitors using tumor cells generated from genetically engineered mouse (GEM) and patient derived xenograft models of Hedgehog driven tumors, including a panel of tumors resistant to the current FDA-approved Smoothened antagonists. RESULTS: We show that knockdown of BRD4 or treatment with the BET bromodomain inhibitor, JQ1, dramatically inhibits transcription of GLI1, GLI2 and other Hedgehog target genes upon ligand-mediated or genetic activation of the Hedgehog pathway. We confirm the inhibitory effect of JQ1 occurs downstream of SMO and SUFU and verify by chromatin immunoprecipitation that BRD4 directly occupies the GLI1 and GLI2 promoters with a substantial decrease in the engagement of these genomic sites upon treatment with JQ1. We observe a corresponding downregulation of genes associated with medulloblastoma-specific GLI1 binding sites upon exposure to JQ1, confirming the direct regulation of GLI1 by BET bromodomain proteins. Finally, in patient- and GEM-derived cells of Hedgehog-driven cancer (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor), we show that JQ1 decreases Hh pathway output and proliferation, even in cells resistant to Smoothened inhibitors. CONCLUSIONS: These results expand the role of BET bromodomain inhibitors to targeting Hedgehog-driven cancers and highlight a strategy that overcomes the limitation of Hedgehog pathway inhibitors currently in clinical use. SECONDARY CATEGORY: Pediatrics. äEPIGENETIC TARGETING OF HEDGEHOG PATHWAY TRANSCRIPTIONAL OUTPUT (epmc).pdf DeepDyve Pubget Overpricing