520 research outputs found
IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in jak2v617f-positive myeloproliferative neoplasms
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)The recurrent V617F mutation in JAK2 (JAK2(V617F)) has emerged as the primary contributor to the pathogenesis of myeloproliferative neoplasms (MPN). However, the lack of complete response in most patients treated with the JAK1/2 inhibitor, ruxolitinib, indicates the need for identifying pathways that cooperate with JAK2. Activated JAK2 was found to be associated with the insulin receptor substrate 2 (IRS2) in non-hematological cells. We identified JAK2/IRS2 binding in JAK2(V617F) HEL cells, but not in the JAK2(WT) U937 cell line. In HEL cells, IRS2 silencing decreased STAT5 phosphorylation, reduced cell viability and increased apoptosis; these effects were enhanced when IRS2 silencing was combined with ruxolitinib. In U937 cells, IRS2 silencing neither reduced cell viability nor induced apoptosis. IRS1/2 pharmacological inhibition in primary MPN samples reduced cell viability in JAK2(V617F)-positive but not JAK2(WT) specimens; combination with ruxolitinib had additive effects. IRS2 expression was significantly higher in CD34(+) cells from essential thrombocythemia patients compared to healthy donors, and in JAK2(V617F) MPN patients when compared to JAK2(WT). Our data indicate that IRS2 is a binding partner of JAK2(V617F) in MPN. IRS2 contributes to increased cell viability and reduced apoptosis in JAK2-mutated cells. Combined pharmacological inhibition of IRS2 and JAK2 may have a potential clinical application in MPN.The recurrent V617F mutation in JAK2 (JAK2V617F) has emerged as the primary contributor to the pathogenesis of myeloproliferative neoplasms (MPN). However, the lack of complete response in most patients treated with the JAK1/2 inhibitor, ruxolitinib, indi7669486959sem informaçãoConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)sem informaçã
The role of Background Independence for Asymptotic Safety in Quantum Einstein Gravity
We discuss various basic conceptual issues related to coarse graining flows
in quantum gravity. In particular the requirement of background independence is
shown to lead to renormalization group (RG) flows which are significantly
different from their analogs on a rigid background spacetime. The importance of
these findings for the asymptotic safety approach to Quantum Einstein Gravity
(QEG) is demonstrated in a simplified setting where only the conformal factor
is quantized. We identify background independence as a (the ?) key prerequisite
for the existence of a non-Gaussian RG fixed point and the renormalizability of
QEG.Comment: 2 figures. Talk given by M.R. at the WE-Heraeus-Seminar "Quantum
Gravity: Challenges and Perspectives", Bad Honnef, April 14-16, 2008; to
appear in General Relativity and Gravitatio
New Approach to GUTs
We introduce a new string-inspired approach to the subject of grand
unification which allows the GUT scale to be small, \lesssim 200 TeV, so that
it is within the reach of {\em conceivable} laboratory accelerated colliding
beam devices. The key ingredient is a novel use of the heterotic string
symmetry group physics ideas to render baryon number violating effects small
enough to have escaped detection to date. This part of the approach involves
new unknown parameters to be tested experimentally. A possible hint at the
existence of these new parameters may already exist in the EW precision data
comparisons with the SM expectations.Comment: 8 pages; improved text and references, note added; extended text, 1
figure added; extended text for publication in Eur. Phys. Journal
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