Epigenomic heterogeneity as a source of tumour evolution.

In the past decade, remarkable progress in cancer medicine has been achieved by the development of treatments that target DNA sequence variants. However, a purely genetic approach to treatment selection is hampered by the fact that diverse cell states can emerge from the same genotype. In multicellular organisms, cell-state heterogeneity is driven by epigenetic processes that regulate DNA-based functions such as transcription; disruption of these processes is a hallmark of cancer that enables the emergence of defective cell states.

Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells.

DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion.

A novel bioinformatic approach reveals cooperation between Cancer/Testis genes in basal-like breast tumors.

Breast cancer is the most prevalent type of cancer in women worldwide. Within breast tumors, the basal-like subtype has the worst prognosis, prompting the need for new tools to understand, detect, and treat these tumors. Certain germline-restricted genes show aberrant expression in tumors and are known as Cancer/Testis genes; their misexpression has diagnostic and therapeutic applications.

A genome-wide screen reveals new regulators of the 2-cell-like cell state.

In mammals, only the zygote and blastomeres of the early embryo are totipotent. This totipotency is mirrored in vitro by mouse '2-cell-like cells' (2CLCs), which appear at low frequency in cultures of embryonic stem cells (ESCs). Because totipotency is not completely understood, we carried out a genome-wide CRISPR knockout screen in mouse ESCs, searching for mutants that reactivate the expression of Dazl, a gene expressed in 2CLCs.

OP2113, a new drug for chronic hypoxia-induced pulmonary hypertension treatment in rat.

Background And Purpose: Pulmonary hypertension (PH) is a cardiovascular disease characterised by an increase in pulmonary arterial (PA) resistance leading to right ventricular (RV) failure. Reactive oxygen species (ROS) play a major role in PH. OP2113 is a drug with beneficial effects on cardiac injuries that targets mitochondrial ROS.

Endothelial DLL4 Is an Adipose Depot-Specific Fasting Sensor Regulating Fatty Acid Fluxes.

Background: Adaptation of fat depots to change in fuel availability is critical for metabolic flexibility and cardiometabolic health. The mechanisms responsible for fat depot-specific lipid sensing and shuttling remain elusive. Adipose tissue microvascular endothelial cells (AT-EC) regulates bidirectional fatty acid fluxes depending on fed or fasted state.

MYO10-filopodia support basement membranes at pre-invasive tumor boundaries.

Ductal carcinoma in situ (DCIS) is a pre-invasive stage of breast cancer. During invasion, the encapsulating DCIS basement membrane (BM) is compromised, and tumor cells invade the surrounding stroma. The mechanisms that regulate functional epithelial BMs in vivo are poorly understood.

Design, synthesis and biological evaluation of quinoline-2-carbonitrile-based hydroxamic acids as dual tubulin polymerization and histone deacetylases inhibitors.

A series of quinoline and quinazoline analogs were designed and synthesized as new tubulin polymerization (TP) and histone deacetylases (HDAC) inhibitors. Compounds 12a and 12d showed the best cytotoxicity activities against a panel of human cancer cell lines with an averaged IC value of 0.6 and 0.

Characterization of Microtubule Destabilizing Drugs: A Quantitative Cell-Based Assay That Bridges the Gap between Tubulin Based- and Cytotoxicity Assays.

(1) Background: Microtubule depolymerizing agents (MDAs) are commonly used for cancer treatment. However, the therapeutic use of such microtubule inhibitors is limited by their toxicity and the emergence of resistance. Thus, there is still a sustained effort to develop new MDAs.

Cyclic bridged analogs of isoCA-4: Design, synthesis and biological evaluation.

In this work, a series of cyclic bridged analogs of isocombretastatin A-4 (isoCA-4) with phenyl or pyridine linkers were designed and synthesized. The synthesis of the desired analogs was performed by the formation of nitro-vinyl intermediates, followed by a Cadogan cyclization. Structure activity relationship (SAR) study demonstrates the critical role of the combination of quinaldine as ring A, pyridine as the linker, and indole as ring B in the same molecule, for the cytotoxic activity.

Genetic screens reveal mechanisms for the transcriptional regulation of tissue-specific genes in normal cells and tumors.

The proper tissue-specific regulation of gene expression is essential for development and homeostasis in metazoans. However, the illegitimate expression of normally tissue-restricted genes-like testis- or placenta-specific genes-is frequently observed in tumors; this promotes transformation, but also allows immunotherapy. Two important questions are: how is the expression of these genes controlled in healthy cells? And how is this altered in cancer? To address these questions, we used an unbiased approach to test the ability of 350 distinct genetic or epigenetic perturbations to induce the illegitimate expression of over 40 tissue-restricted genes in primary human cells.

Mechanisms of DNA Methyltransferase Recruitment in Mammals.

DNA methylation is an essential epigenetic mark in mammals. The proper distribution of this mark depends on accurate deposition and maintenance mechanisms, and underpins its functional role. This, in turn, depends on the precise recruitment and activation of de novo and maintenance DNA methyltransferases (DNMTs).

Local and systemic innate immune response to secondary human peritonitis.

Introduction: Our aim was to describe inflammatory cytokines response in the peritoneum and plasma of patients with peritonitis. We also tested the hypothesis that scenarios associated with worse outcome would result in different cytokine release patterns. Therefore, we compared cytokine responses according to the occurrence of septic shock, mortality, type of peritonitis and peritoneal microbiology.

Predictive factors of advanced interventional procedures in a multicentre severe postpartum haemorrhage study.

Purpose: Severe postpartum haemorrhage (SPPH) is the leading cause of peripartum hysterectomy and maternal death. There are no easily measurable parameters that indicate the failure of medical therapy and the need for an advanced interventional procedure (AIP) to stop genital tract bleeding. The aim of the study was to define factors predictive of the need for an AIP in the management of emergent PPH.

Factors associated with septic shock and mortality in generalized peritonitis: comparison between community-acquired and postoperative peritonitis.

Introduction: The risk factors associated with poor outcome in generalized peritonitis are still debated. Our aim was to analyze clinical and bacteriological factors associated with the occurrence of shock and mortality in patients with secondary generalized peritonitis.

Methods: This was a prospective observational study involving 180 consecutive patients with secondary generalized peritonitis (community-acquired and postoperative) at a single center.

Diastolic arterial blood pressure: a reliable early predictor of survival in human septic shock.

Background: Emphasis in therapy of human septic shock is shifting towards reliable end points and predictors of survival. Rationale is to study whether the evolution of cardiovascular reactivity in view of the administered doses of norepinephrine is an early predictor of in-hospital survival and to determine the optimal threshold of norepinephrine therapy and its consequences on renal function.

Methods: Observational study of a prospective cohort of patients in septic shock, hospitalized in intensive care unit at least 24 hours before requiring norepinephrine.

Adrenal response in patients with septic shock of abdominal origin: relationship to survival.

Objective: To evaluate the prognostic value of adrenocortical response to corticotropin in septic shock patients operated on exclusively for an intra-abdominal source of infection.

Design And Setting: Prospective, observational, single-center study in a surgical intensive care unit of a university hospital

Patients: 118 consecutive septic shock patients undergoing laparotomy or drainage for intra-abdominal infection.

Measurements And Results: Baseline cortisol (t (0)) and cortisol response to corticotropin test (Delta) were measured during the first 24 h following onset of shock.

[Diagnostic and therapeutic strategy in duodenal diverticular bleeding: report of two cases and review of the literature].

Host of the duodenal diverticulum are asymptomatic and located on the second part of the duodenum; these diverticula may induce major haemorrhage on rare occasions. We report on two patients who presented with massive upper gastrointestinal bleeding originating from a duodenal diverticulum. One patient was successfully treated by endoscopy and the other patient required diverticulectomy with successful outcome.

Inflammatory cytokines, C reactive protein, and procalcitonin as early predictors of necrosis infection in acute necrotizing pancreatitis.

Background: Infection of necrosis is a major risk factor in patients with acute pancreatitis. Systematic use of broad spectrum antibiotics has been recommended in these patients but may induce serious side effects. To better target patients in whom antibiotic prophylaxis could be beneficial, we evaluated whether early serum profiles of interleukin 6 (IL-6), tumor necrosis factor (TNF-alpha, C reactive protein (CRP) and procalcitonin (PCT) help to discriminate between patients who eventually develop infection of necrosis and those who do not.

[Audit of preoperative antibiotic prophylaxis in a surgical site infections surveillance network].

Objective: To evaluate the preoperative antibiotic prophylaxis (PAP) prescriptions in a surgical site infection (SSI) surveillance network.

Study Design: Auto-evaluative audit in a prospective multicenter cohort included in a surveillance system.

Patients And Methods: Since 1997, surgical wards in volunteer centers monitored all surgery patients each year during a period of two months.