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Cross-talk between hematopoietic stem cells (HSCs) and bone marrow stromal cells (BMSCs) is essential for HSCs regulation and leukemogenesis. Studying bone marrow of myelodysplasia patients, a pre-leukemic condition, we found mRNA overexpression of vascular endothelial growth factor A (VEGFA) in CD34 + HSCs and semaphorin 3A (SEMA3A) in BMSCs. To better understand the role of VEGFA and SEMA3A in leukemogenesis, we recruited 30 myelodysplastic syndrome (MDS) patients, 29 acute myeloid leukemia (6 secondary to MDS) patients and 12 controls. We found higher VEGFA expression in de novo AML patients (without prior MDS) group (p=0.0073) and higher SEMA3A expression in all BMSCs patient's samples compared to control group. We then overexpressed VEGFA in an acute myelogenous leukemia cell line, KG1 cells, and in normal CD34 + cells. This overexpression increased KG1 (p=0.045) and CD34 + cell (p=0.042) viability and KG1 (p=0.042) and CD34 + cell (p=0.047) proliferation. Moreover, KG1 and CD34 + cells overexpressing VEGFA also had increased proliferation when co-cultured with human marrow stromal HS5 cells (p=0.045 and p=0.02, respectively). However, co-culture of these transformed cells with HS5 cells overexpressing SEMA3A reduced KG1 (p=0.004) and CD34 + (p=0.009) proliferation. Co-culture of KG1 transformed cells with HS27 cells overexpressing SEMA3A reduced KG1 proliferation as well (p=0.01). To investigate whether the dominant SEMA3A effect over VEGFA could be due to competition for neuropilin1 receptor (NRP1), we performed immunoprecipitation with anti-NRP1 antibody of cell extracts of co-cultured KG1 and HS5 cells, induced or not by VEGFA and SEMA3A recombinant proteins. Results showed a preferential association of NRP1 with SEMA3A, suggesting that SEMA3A can partially reverse the effects caused by the VEGFA preventing its binding with the NRP1 receptor. Since both hematopoietic cells, leukemic and normal, showed similar behavior, we suppose that the attempt to reversion of VEGF effects by SEMA3A is a homeostatic phenomenon in the hematopoietic niche. Finally, we conclude that VEGFA overexpression confers AML cell advantages and SEMA3A may partially reverse this effect; thus, SEMA3A protein combined with VEGFA inhibitors could be beneficial for AML treatment., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: 1) To synthesize the current observational evidence for the association between sedentary behavior and health outcomes using information from systematic reviews. 2) To assess the methodological quality of the systematic reviews found., Methodology/principal Findings: Medline; Excerpta Medica (Embase); PsycINFO; and Web of Science were searched for reviews published up to September 2013. Additional publications were provided by Sedentary Behaviour Research Network members. The methodological quality of the systematic reviews was evaluated using recommended standard criteria from AMSTAR. For each review, improper use of causal language in the description of their main results/conclusion was evaluated. Altogether, 1,044 review titles were identified, 144 were read in their entirety, and 27 were included. Based on the systematic reviews with the best methodological quality, we found in children and adolescents, strong evidence of a relationship between time spent in sedentary behavior and obesity. Moreover, moderate evidence was observed for blood pressure and total cholesterol, self-esteem, social behavior problems, physical fitness and academic achievement. In adults, we found strong evidence of a relationship between sedentary behavior and all-cause mortality, fatal and non-fatal cardiovascular disease, type 2 diabetes and metabolic syndrome. In addition, there is moderate evidence for incidence rates of ovarian, colon and endometrial cancers., Conclusions: This overview based on the best available systematics reviews, shows that sedentary behavior may be an important determinant of health, independently of physical activity. However, the relationship is complex because it depends on the type of sedentary behavior and the age group studied. The relationship between sedentary behavior and many health outcomes remains uncertain; thus, further studies are warranted.