Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy.

The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers, and their therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS mutants with bivalent histone H3 lysine 27 trimethylation (H3K27me3) and Polycomb repressive complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1, and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS mutants. Coincident with bivalent reprogramming, the increased expression of pro-metastatic and melanocyte-specific cell-identity genes is associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS mutant melanoma patients

Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma.

Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways, including glycolysis. KMT2D deficiency aberrantly upregulates glycolysis enzymes, intermediate metabolites, and glucose consumption rates. Mechanistically, KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states. Enhancer loss and subsequent repression of IGFBP5 activates IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. Pharmacological inhibition of glycolysis and insulin growth factor (IGF) signaling reduce proliferation and tumorigenesis preferentially in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating an increased use of the glycolysis pathway for enhanced biomass needs via enhancer reprogramming, thus presenting an opportunity for therapeutic intervention through glycolysis or IGF pathway inhibitors

Management of intra-abdominal infections : recommendations by the WSES 2016 consensus conference

This paper reports on the consensus conference on the management of intra-abdominal infections (IAIs) which was held on July 23, 2016, in Dublin, Ireland, as a part of the annual World Society of Emergency Surgery (WSES) meeting. This document covers all aspects of the management of IAIs. The Grading of Recommendations Assessment, Development and Evaluation recommendation is used, and this document represents the executive summary of the consensus conference findings.Peer reviewe

Effects of the COVID-19 pandemic on lifestyle among Iranian population: A multicenter cross-sectional study

Background: Quarantine, an unpleasant experience, was implemented in many countries to limit the spread of Coronavirus disease 2019 (COVID-19), which it could associated whit lifestyle changes. The present study aimed to determine the changes in Iranian's lifestyle during COVID-19 pandemic. Materials and Methods: In the present cross-sectional study, 2710 Iranian people completed an online researcher-made questionnaire asking lifestyle regarding COVID-19, which includes five sections about physical activity, stress and anxiety, nutrition habit, sleep disorders, and interpersonal relationship in addition to demographic data from January to February 2021, using the multistage cluster sampling method. Results: The participants' mean age was 33.78 ± 11.50 years and 68.3 of them were female. Traveling, sightseeing, and family visits have been eliminated from 91, 83.5, and 77.5 of participants' lives, respectively. There were increase in stress level (P < 0.001), weight of the participants (P < 0.001), sleep problems (P < 0.001), and healthier foods (P < 0.001) but decrease in interpersonal communication (P < 0.001) and the amount of physical activity (P < 0.001). Conclusion: In summary, this study indicates some changes in lifestyle of Iranian people, including changes in some eating practices, physical activity, social communication, and sleeping habits during the pandemic. However, as the COVID-19 pandemic is ongoing, a comprehensive understanding of these behaviors and habits can help develop interventions to mitigate the negative lifestyle behaviors during COVID-19 pandemic. © 2022 EDP Sciences. All rights reserved