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10.1056/NEJMoa1412098 http://scihub22266oqcxt.onion/10.1056/NEJMoa1412098 C4660033!4660033!25671252     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       N+Engl+J+Med 2015 ; 372 (7): 601-12 Nephropedia Template TP {{tp|p=25671252|t=2015. Effect of Mutation Order on Myeloproliferative Neoplasms |pdf=|usr=}}{{25671252}} gab.com Text Effect of Mutation Order on Myeloproliferative Neoplasms JO: N Engl J Med http://www.kidney.de/pget.php?&tw=1&pmid=25671252 #FOAvip BACKGROUND: Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect the sum of these mutations. However, little is known about the effect of the order in which mutations are acquired. METHODS: We determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. RESULTS: The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 mutation was acquired first (hereafter referred to as ?TET2-first patients?), patients in whom the Janus kinase 2 (JAK2) mutation was acquired first (?JAK2-first patients?) had a greater likelihood of presenting with polycythemia vera than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2?TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from up-regulating genes associated with proliferation. CONCLUSIONS: The order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. (Funded by Leukemia and Lymphoma Research and others.) Twit Text FOAVip Effect of Mutation Order on Myeloproliferative Neoplasms ????N Engl J Med http://www.kidney.de/pget.php?&tw=1&pmid=25671252 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=25671252 #FOAvip English Wikipedia <ref>{{Cite pmid|25671252}}</ref> Effect of Mutation Order on Myeloproliferative Neoplasms #MMPMID25671252 Ortmann CA; Kent DG; Nangalia J; Silber Y; Wedge DC; Grinfeld J; Baxter EJ; Massie CE; Papaemmanuil E; Menon S; Godfrey AL; Dimitropoulou D; Guglielmelli P; Bellosillo B; Besses C; Döhner K; Harrison CN; Vassiliou GS; Vannucchi A; Campbell PJ; Green AR N Engl J Med 2015[Feb]; 372 (7): 601-12 PMID25671252show ga BACKGROUND: Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect the sum of these mutations. However, little is known about the effect of the order in which mutations are acquired. METHODS: We determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. RESULTS: The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 mutation was acquired first (hereafter referred to as ?TET2-first patients?), patients in whom the Janus kinase 2 (JAK2) mutation was acquired first (?JAK2-first patients?) had a greater likelihood of presenting with polycythemia vera than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2?TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from up-regulating genes associated with proliferation. CONCLUSIONS: The order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. (Funded by Leukemia and Lymphoma Research and others.) äEffect of Mutation Order on Myeloproliferative Neoplasms (epmc).pdf DeepDyve Pubget Overpricing