Diabetes mellitus in older men
In: The aging male: the official journal of the International Society for the Study of the Aging Male, Band 9, Heft 3, S. 139-147
ISSN: 1473-0790
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In: The aging male: the official journal of the International Society for the Study of the Aging Male, Band 9, Heft 3, S. 139-147
ISSN: 1473-0790
In May 2012, a Sarcopenia Consensus Summit was convened by the Foundation of the National Institutes of Health (FNIH), National Institute of Aging (NIA), and the U.S. Food and Drug Administration (FDA); and co-sponsored by five pharmaceutical companies. At this summit, sarcopenia experts from around the world worked to develop agreement on a working definition of sarcopenia, building on the work of previous efforts to generate a consensus. With the ultimate goal of improving function and independence in individuals with sarcopenia, the Task Force focused its attention on people at greatly increased risk of muscle atrophy as a consequence of hip fracture. The rationale for looking at this population is that since hip fracture is a recognized condition, there is a clear regulatory path forward for developing interventions. Moreover, patients with hip fracture may provide an appropriate population to advance understanding of sarcopenia, for example helping to define diagnostic criteria, develop biomarkers, understand the mechanisms that underlie the age-related loss of muscle mass and strength, and identify endpoints for clinical trials that are reliable, objective, and clinically meaningful. Task Force members agreed that progress in treating sarcopenia will require strengthening of partnerships between academia, industry, and government agencies, and across continents to reach consensus on diagnostic criteria, optimization of clinical trials design, and identification of improved treatment and preventive strategies. In this report, the main results of the Task Force discussion are presented.
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Son of Sevenless 1 (SOS1) is a dual guanine nucleotide exchange factor (GEF) that activates the small GTPases RAC and RAS. Although the molecular mechanisms of RAS GEF catalysis have been unveiled, how SOS1 acquires RAC GEF activity and what is the physio-pathological relevance of this activity is much less understood. Here we show that SOS1 is tyrosine phosphorylated on Y1196 by ABL. Phosphorylation of Y1196 controls SOS1 inter-molecular interaction, is required to promote the exchange of nucleotides on RAC in vitro and for platelet-derived growth factor (PDGF) activation of RAC- and RAC-dependent actin remodeling and cell migration. SOS1 is also phosphorylated on Y1196 by BCR-ABL in chronic myelogenous leukemic cells. Importantly, in these cells, SOS1 is required for BCR-ABL-mediated activation of RAC, cell proliferation and transformation in vitro and in a xenograft mouse model. Finally, genetic removal of Sos1 in the bone marrow-derived cells (BMDCs) from Sos1 fl/fl mice and infected with BCR-ABL causes a significant delay in the onset of leukemogenesis once BMDCs are injected into recipient, lethally irradiated mice. Thus, SOS1 is required for full transformation and critically contribute to the leukemogenic potential of BCR-ABL. ; This work has been supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC 10168 and 18621), the Italian Ministries of Education- University-Research (MIUR-PRIN-2009X23L78), the International Association For Cancer Research (AICR-09-0582 and 14-0335), the CARIPLO Foundation (2010-0737) and the European Research Council (Advanced-ERC268836). ALI was supported by a Grant from der German Jose Carreras Stiftung (DJCLS R14/22) and a Grant from the Government Baden-Württemberg (MWK). CM was supported form a AECC fellowship, Spain. ; Peer Reviewed
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