Statins reduce intratumor cholesterol affecting adrenocortical cancer growth

Mitotane causes hypercholesterolemia in ACC patients. We suppose that cholesterol increases within the tumor and can be used to activate proliferative pathways. In this study, we used statins to decrease intratumor cholesterol and investigated the effects on ACC growth related to ER\u3b1 action at the nuclear and mitochondrial levels. We first used microarray to investigate mitotane effect on genes involved in cholesterol homeostasis and evaluated their relationship with patients' survival in ACC TCGA. We then blocked cholesterol synthesis with simvastatin and determined the effects on H295R cell proliferation, estradiol production and ER\u3b1 activity in vitro and in xenograft tumors. We found that mitotane increases intratumor cholesterol content and expression of genes involved in cholesterol homeostasis, among them INSIG, whose expression affects patients' survival. Treatment of H295R cells with simvastatin to block cholesterol synthesis decreased cellular cholesterol content and this affected cell viability. Simvastatin reduced estradiol production and decreased nuclear and mitochondrial ER\u3b1 function. A mitochondrial target of ER\u3b1, the respiratory complex IV (COX IV) was reduced after simvastatin treatment, which profoundly affected mitochondrial respiration activating apoptosis. In vivo experiments confirmed the ability of simvastatin to reduce tumor volume and weight of grafted H295R cells, intratumor cholesterol content, Ki-67 and ER\u3b1, COX IV expression and activity and increase TUNEL positive cells. Collectively these data demonstrate that a reduction in intratumor cholesterol content prevents estradiol production, inhibits mitochondrial respiratory chain inducing apoptosis in ACC cells. Inhibition of mitochondrial respiration by simvastatin represents a novel strategy to counteract ACC growth

Author Correction: WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Genome-wide associations for birth weight and correlations with adult disease

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW ($\textit{P}$  < 5 × 10$^{-8}$). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure ($\textit{R}$ $_{g}$ = -0.22, $\textit{P}$  = 5.5 × 10$^{-13}$), T2D ($\textit{R}$ $_{g}$ = -0.27, $\textit{P}$  = 1.1 × 10$^{-6}$) and coronary artery disease ($\textit{R}$ $_{g}$ = -0.30, $\textit{P}$  = 6.5 × 10$^{-9}$). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions ($\textit{P}$ = 1.9 × 10$^{-4}$). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.For a full list of the funders pelase visit the publisher's website and look at the supplemetary material provided. Some of the funders are: British Heart Foundation, Cancer Research UK, Medical Research Council, National Institutes of Health, Royal Society and Wellcome Trust

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe

The fuction of Autoimmune Regulator (Aire) gene in the control of adhesion between medullary thymic epithelial cells with thymocytes

O crosstalk entre timócitos e células epiteliais tímicas é crucial para o desenvolvimento das células T e estabelecimento da tolerância central. Células tímicas epiteliais medulares (mTECs) contribuem para a autotolerância por meio da expressão ectópica de antígenos restritos aos tecidos (TRAs). A expressão de TRAs em mTECs é altamente dependente do gene Autoimmune Regulator (Aire). Por meio do reconhecimento de TRAs com alta afinidade, células T autoreativas são selecionadas negativamente do pool de timócitos em desenvolvimento. Apesar do papel de Aire na indução da tolerância central ser bem conhecido, os mecanismos celulares e moleculares precisos do processo permanecem obscuros. Nesse estudo, hipotetizamos que perturbações na expressão do gene Aire influenciam a adesão entre mTECs e timócitos, o que poderia resultar em um desequilíbrio na imunotolerância a antígenos próprios. Um ensaio funcional realizado com timócitos frescos, extraídos de um timo normal de camundongo e cocultivados com células epiteliais tímicas medulares da linhagem mTEC 3.10, demonstrou que a inibição do gene Aire por meio de RNA de interferência reduziu significativamente a capacidade das mTECs de promover a adesão dos timócitos. Análises por microarray revelaram que o silenciamento do gene Aire nas células mTEC 3.10 causou a modulação de mais de 1000 genes, alguns que codificam TRAs, outros que codificam proteínas envolvidas na adesão celular, como VCAM-1, e também outros que codificam moléculas coestimuladoras como CD80. Esses resultados contribuem para uma melhor compreensão do papel de Aire no controle da adesão mTEC-timócitos, a qual constitui um processo essencial para a seleção negativa de timócitos autoreativosThe crosstalk between thymocytes and thymic epithelial cells is critical for T cell development and the establishment of central tolerance. Medullary thymic epithelial cells (mTECs) contribute to self-tolerance through the ectopic expression of tissuerestricted antigens (TRAs) in the thymus. TRAs expression in mTECs is largely dependent on Autoimmune Regulator (Aire) gene. Through the recognition of TRAs with high affinity, developing autoreactive T cells are negatively select from the pool of developing thymocytes. Although the role of Aire in the induction of central tolerance is well known, the precise cellular and molecular mechanisms remain unclear. In this study, we hypothesize that disturbance in Aire gene expression influences adhesion between mTECs and thymocytes, which could result in an imbalance in immune-tolerance to self-antigens. A functional assay performed with fresh thymocytes dissociated from a normal mouse thymus and co-cultured with a medullary thymic epithelial cell line named mTEC 3.10, demonstrated that Aire RNAi knockdown significantly decreased the ability of mTECs to promote thymocyte adhesion. Microarray analysis revealed that Aire knockdown of the murine mTEC 3.10 cell line led to the modulation of more than 1000 genes, some of them coding for TRAs, others for proteins involved in cell adhesion like VCAM-1 and also for costimulatory molecules like CD80. These results contribute to a better understanding of the role of Aire in the control of mTEC-thymocyte adhesion, which is an essential process for negative selection of autoreactive thymocyte