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10.1038/s41419-017-0256-4 http://scihub22266oqcxt.onion/10.1038/s41419-017-0256-4 C5833553!5833553 !29472557     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\29472557 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Cell+Death+Dis 2018 ; 9 (3 ): 311 Nephropedia Template TP {{tp|p=29472557 |t=2018. Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms |pdf=|usr=}}{{29472557 }} gab.com Text Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms JO: Cell Death Dis http://www.kidney.de/pget.php?&tw=1&pmid=29472557 #FOAvip The recurrent gain-of-function JAK2(V617F) mutation confers growth factor-independent proliferation for hematopoietic cells and is a major contributor to the pathogenesis of myeloproliferative neoplasms (MPN). The lack of complete response in most patients treated with the JAK1/2 inhibitor ruxolitinib indicates the need for identifying novel therapeutic strategies. Metformin is a biguanide that exerts selective antineoplastic activity in hematological malignancies. In the present study, we investigate and compare effects of metformin and ruxolitinib alone and in combination on cell signaling and cellular functions in JAK2(V617F)-positive cells. In JAK2(V617F)-expressing cell lines, metformin treatment significantly reduced cell viability, cell proliferation, clonogenicity, and cellular oxygen consumption and delayed cell cycle progression. Metformin reduced cyclin D1 expression and RB, STAT3, STAT5, ERK1/2 and p70S6K phosphorylation. Metformin plus ruxolitinib demonstrated more intense reduction of cell viability and induction of apoptosis compared to monotherapy. Notably, metformin reduced Ba/F3 JAK2(V617F) tumor burden and splenomegaly in Jak2(V617F) knock-in-induced MPN mice and spontaneous erythroid colony formation in primary cells from polycythemia vera patients. In conclusion, metformin exerts multitarget antileukemia activity in MPN: downregulation of JAK2/STAT signaling and mitochondrial activity. Our exploratory study establishes novel molecular mechanisms of metformin and ruxolitinib action and provides insights for development of alternative/complementary therapeutic strategies for MPN. Twit Text FOAVip Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms ????Cell Death Dis http://www.kidney.de/pget.php?&tw=1&pmid=29472557 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=29472557 #FOAvip English Wikipedia <ref>{{Cite pmid|29472557 }}</ref> Metformin exerts multitarget antileukemia activity in JAK2(V617F)-positive myeloproliferative neoplasms #MMPMID29472557 Machado-Neto JA ; Fenerich BA ; Scopim-Ribeiro R ; Eide CA ; Coelho-Silva JL ; Dechandt CRP ; Fernandes JC ; Rodrigues Alves APN ; Scheucher PS ; Simões BP ; Alberici LC ; de Figueiredo Pontes LL ; Tognon CE ; Druker BJ ; Rego EM ; Traina F Cell Death Dis 2018[Feb]; 9 (3 ): 311 PMID29472557 show ga The recurrent gain-of-function JAK2(V617F) mutation confers growth factor-independent proliferation for hematopoietic cells and is a major contributor to the pathogenesis of myeloproliferative neoplasms (MPN). The lack of complete response in most patients treated with the JAK1/2 inhibitor ruxolitinib indicates the need for identifying novel therapeutic strategies. Metformin is a biguanide that exerts selective antineoplastic activity in hematological malignancies. In the present study, we investigate and compare effects of metformin and ruxolitinib alone and in combination on cell signaling and cellular functions in JAK2(V617F)-positive cells. In JAK2(V617F)-expressing cell lines, metformin treatment significantly reduced cell viability, cell proliferation, clonogenicity, and cellular oxygen consumption and delayed cell cycle progression. Metformin reduced cyclin D1 expression and RB, STAT3, STAT5, ERK1/2 and p70S6K phosphorylation. Metformin plus ruxolitinib demonstrated more intense reduction of cell viability and induction of apoptosis compared to monotherapy. Notably, metformin reduced Ba/F3 JAK2(V617F) tumor burden and splenomegaly in Jak2(V617F) knock-in-induced MPN mice and spontaneous erythroid colony formation in primary cells from polycythemia vera patients. In conclusion, metformin exerts multitarget antileukemia activity in MPN: downregulation of JAK2/STAT signaling and mitochondrial activity. Our exploratory study establishes novel molecular mechanisms of metformin and ruxolitinib action and provides insights for development of alternative/complementary therapeutic strategies for MPN. |Animals [MESH] |Antineoplastic Agents/*administration & dosage [MESH] |Cell Cycle/drug effects [MESH] |Cell Proliferation/drug effects [MESH] |Cell Survival/drug effects [MESH] |Cyclin D1/genetics/metabolism [MESH] |Female [MESH] |Gene Knock-In Techniques [MESH] |Humans [MESH] |Janus Kinase 2/genetics/*metabolism [MESH] |Metformin/*administration & dosage [MESH] |Mice [MESH] |Mice, Inbred NOD [MESH] |Mutation, Missense [MESH] |Myeloproliferative Disorders/*drug therapy/genetics/metabolism/physiopathology [MESH] |Phosphorylation/drug effects [MESH] |STAT3 Transcription Factor/genetics/metabolism [MESH]Metformin exerts multitarget antileukemia activity in JAK2(V617F)-posi(epmc).pdf DeepDyve Pubget Overpricing