Inhibition of Chk1 Kills Tetraploid Tumor Cells through a p53-Dependent Pathway

Tetraploidy constitutes an adaptation to stress and an intermediate step between euploidy and aneuploidy in oncogenesis. Tetraploid cells are particularly resistant against genotoxic stress including radiotherapy and chemotherapy. Here, we designed a strategy to preferentially kill tetraploid tumor cells. Depletion of checkpoint kinase-1 (Chk1) by siRNAs, transfection with dominant-negative Chk1 mutants or pharmacological Chk1 inhibition killed tetraploid colon cancer cells yet had minor effects on their diploid counterparts. Chk1 inhibition abolished the spindle assembly checkpoint and caused premature and abnormal mitoses that led to p53 activation and cell death at a higher frequency in tetraploid than in diploid cells. Similarly, abolition of the spindle checkpoint by knockdown of Bub1, BubR1 or Mad2 induced p53-dependent apoptosis of tetraploid cells. Chk1 inhibition reversed the cisplatin resistance of tetraploid cells in vitro and in vivo, in xenografted human cancers. Chk1 inhibition activated p53-regulated transcripts including Puma/BBC3 in tetraploid but not in diploid tumor cells. Altogether, our results demonstrate that, in tetraploid tumor cells, the inhibition of Chk1 sequentially triggers aberrant mitosis, p53 activation and Puma/BBC3-dependent mitochondrial apoptosis

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Synthèse et caractérisation de composés hydrurables dérivés de LaNi5+x pour accumulateurs NiMH

Les matériaux hydrurables dérivés du composé sur-stoechiométrique LaNi5+x sont utilises dans les électrodes négatives des accumulateurs NiMH. Ce travail concerne la caractérisation des propriétés d alliages dérivés de la formule MmNi4.07Mn0.63Al0.2Co0.4 (Mm=mélange de terre rare) utilisés industriellement et contenant 5% massique de cobalt. Dans une première partie, il a été montré que la limite de sur-stoechiométrie de ce composé est supérieure à 7 hors équilibre thermodynamique (refroidissement par hypertrempe) alors quelle est de à l équilibre. Une méthode originale pour faire précipiter une seconde phase a été utilisée. Dans une seconde partie, le cobalt a été partiellement ou totalement remplacé par du Ni, Mn, Al, Fe, Cu dans le but d évaluer l effet de chaque élément sur les propriétés thermodynamiques et électrochimiques. Des composés sans cobalt présentant de bonnes propriétés électrochimiques ont été obtenus et sont potentiellement utilisables dans les accumulateurs NiMH.Hydride-forming alloys derived from non-stoichiometric LaNi5+x compound are used as negative electrode material in NiMH batteries. This work is based on compositions derived from MmNi4.07Mn0.63Al0.2Co0.4 (Mm=rare earth mixture) used in industry and containing 5 wt % cobalt. In a first part, it has been shown that non-stoichiometry upper limit is higher than 7 out of thermodynamic equilibrium (rapid cooling) whereas this limit is about 5.5 at thermodynamic equilibrium. An original method for precipitating a second phase has been set up. In a second part, cobalt has been partially or totally replaced by Ni, Mn, Al, Fe, Cu in order to evaluate the effect of each element on the thermodynamic and electrochemical properties. Cobalt-free compounds with good electrochemical properties have been obtained and could potentially be used in NiMH batteries.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocPARIS12-THIAIS CNRS ICMPE (940732301) / SudocSudocFranceF

Géographies des enfants et des jeunes

Introduction au numéro spécialno abstrac

Géographies des enfants et des jeunes

no abstrac

"Géographie des enfants et de jeunes" : numéro spécial de la revue Les Carnets de Géographes

no abstrac

Multipolar mitosis of tetraploid cells: inhibition by p53 and dependency on Mos.

Tetraploidy can constitute a metastable intermediate between normal diploidy and oncogenic aneuploidy. Here, we show that the absence of p53 is not only permissive for the survival but also for multipolar asymmetric divisions of tetraploid cells, which lead to the generation of aneuploid cells with a near-to-diploid chromosome content. Multipolar mitoses (which reduce the tetraploid genome to a sub-tetraploid state) are more frequent when p53 is downregulated and the product of the Mos oncogene is upregulated. Mos inhibits the coalescence of supernumerary centrosomes that allow for normal bipolar mitoses of tetraploid cells. In the absence of p53, Mos knockdown prevents multipolar mitoses and exerts genome-stabilizing effects. These results elucidate the mechanisms through which asymmetric cell division drives chromosomal instability in tetraploid cells