Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) beyond SMARCA4 Mutations: A Comprehensive Genomic Analysis.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive malignancy that occurs in young women, is characterized by recurrent loss-of-function mutations in the SMARCA4 gene, and for which effective treatments options are lacking. The aim of this study was to broaden the knowledge on this rare malignancy by reporting a comprehensive molecular analysis of an independent cohort of SCCOHT cases. We conducted Whole Exome Sequencing in six SCCOHT, and RNA-sequencing and array comparative genomic hybridization in eight SCCOHT. Additional immunohistochemical, Sanger sequencing and functional data are also provided. SCCOHTs showed remarkable genomic stability, with diploid profiles and low mutation load (mean, 5.43 mutations/Mb), including in the three chemotherapy-exposed tumors. All but one SCCOHT cases exhibited 19p13.2-3 copy-neutral LOH. SMARCA4 deleterious mutations were recurrent and accompanied by loss of expression of the SMARCA2 paralog. Variants in a few other genes located in 19p13.2-3 (e.g., PLK5) were detected. Putative therapeutic targets, including MAGEA4, AURKB and CLDN6, were found to be overexpressed in SCCOHT by RNA-seq as compared to benign ovarian tissue. Lastly, we provide additional evidence for sensitivity of SCCOHT to HDAC, DNMT and EZH2 inhibitors. Despite their aggressive clinical course, SCCOHT show remarkable inter-tumor homogeneity and display genomic stability, low mutation burden and few somatic copy number alterations. These findings and preliminary functional data support further exploration of epigenetic therapies in this lethal disease

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/)

Etudes fonctionnelles de gènes impliqués dans la différenciation gonadique précoce chez la souris (Foxl2/Rspo1 et SRY/sry)

Chez les vertébrés, avant la différenciation sexuelle, les futures gonades sont bipotentielles. Chez le mâle, la présence du gène SRY induit la différenciation testiculaire. En absence de celui-ci, ou si sa protéine est non fonctionnelle, des ovaires se forment. Ce travail traite de la différenciation sexuelle précoce et se divise en deux parties traitant respectivement de la voie femelle et mâle. La première partie de cette thèse traite de la différenciation ovarienne précoce. Cette étude se focalise sur le rôle de deux gènes femelles : Foxl2 et Rspondin-1 (Rspo1). Les souris XX Foxl2-/- sont infertiles, quant aux Rspo1-/-, elles développent des ovo-testicules. L étude des gonades de souris XX Foxl2-/-/Rspo1-/- démontre une masculinisation des gonades ainsi que du tractus. Ceci serait dû à la présence ectopique de cellules stéroïdogènes fœtales. Nos résultats tendent à conclure que Foxl2 et Rspo1, par deux voies de signalisation distinctes, qui réprimeraient la voie mâle, via entre autre, l inhibition de la stéroïdogénèse fœtale. La seconde partie traite de différenciation testiculaire et plus particulièrement de la caractérisation de lignées de souris transgéniques pour SRY caprin (SRYg). Chez les mammifères, SRY est exprimé lors de la différenciation sexuelle, jusqu à l âge adulte, sauf chez la souris où il s éteint rapidement. Il existe un site de fixation de la protéine SOX9 sur le promoteur SRY, absent chez la souris, qui active l expression de SRY in vitro. Grâce à l étude de nouvelles lignées de souris transgéniques pour SRYg, dont le site SOX9 a été muté, nos résultats démontrent que ce site n est pas le seul responsable de l expression continue du gène SRYg.In vertebrates, before sexual differentiation, future gonads are bipotential. In males, presence of the testis-determining factor, SRY gene, induces testis differentiation. In its absence or if SRY protein is not functional, ovaries are formed. This work is about early sexual differentiation and is divided into two parts dealing with female or male pathway. The first part is about early ovarian differentiation. This study focuses on the role of two genes, Foxl2 and Rspondin-1 (Rspo1). In XX mice, invalidation of Foxl2 and Rspo1 lead respectively to infertility and ovo-testis formation. Our results show masculinization of XX Foxl2-/-/Rspo1-/- gonads in mice, apparently du to the presence of ectopic steroidogenic fetal cells. Our results tend to conclude that Foxl2 and Rspo1 belong to two distinct signalling pathways that suppress testicular differentiation, via for example, inhibition of fetal steroidogenesis in female. The second part is about testicular differentiation and especially characterization of transgenic mouse lines for SRY goat (SRYg). In mammals, SRY gene is expressed during sexual differentiation, until adulthood, except in mice where expression rapidly switches off. A SOX9 binding site localised on SRY promoter has been described as inducing SRY gene expression in vitro. Thanks to new SRYg transgenic mouse lines studies, whose SOX9 binding site was deleted, our results do not demonstrate any crucial regulatory effect of this binding site on SRYg expression. Therefore, this SOX9 binding site is not responsible alone for continuous expression of the gene SRYg.VERSAILLES-BU Sciences et IUT (786462101) / SudocSudocFranceF

Data from: The highs and lows of dispersal: how connectivity and initial population size jointly shape establishment dynamics in discrete landscapes

Identifying the main factors driving introduced populations to establishment is a major challenge of invasion biology. Due to their small initial size, introduced populations are most vulnerable to extinction because of demographic stochasticity or Allee effects. While an increase in initial population size is known to increase establishment success, much remains to be understood regarding its interplay with connectivity in spatially structured environments. In order to better understand how demographic mechanisms interact at such spatial scale, we developed a stochastic model of population dynamics in discrete space to investigate the effect of connectivity and initial population size on establishment. The predictions derived from the model were then tested using experimental introductions of an insect parasitoid (Trichogramma chilonis) in spatially structured laboratory microcosms. Both theoretical and experimental results demonstrated that the connectivity of the introduction site had 1) a deleterious effect in the first generation when the introduced population was small and 2) a beneficial impact brought about by metapopulation effects in the subsequent generations. Interestingly, populations displayed a weakly pushed invasion pattern promoting early establishment, which was mainly underpinned by dispersal stochasticity and the discrete nature of the landscape. These results shed light on the critical influence of landscape connectivity on establishment dynamics

The highs and lows of dispersal: how connectivity and initial population size jointly shape establishment dynamics in discrete landscapes

article sous presseInternational audienc

High-efficiency, simple setup for pulse cleaning at the millijoule level by nonlinear induced birefringence

International audienceNonlinear elliptical polarization rotation is used to improve the contrast of femtosecond pulses by several orders of magnitude. Using nonlinear induced birefringence in air, we produced cleaned pulses with an energy of a few hundreds of microjoules. This technique presents several major advantages, such as convenience and stability of the setup. We investigated the phase profile required for obtaining high-energy pulses. No phase distortion is observed, and the spatial quality of the beam is preserved

The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells.

International audienceFOXL2 is a lineage determining transcription factor in the ovary, but its direct targets and modes of action are not fully characterized. In this study, we explore the targets of FOXL2 and five nuclear receptors in murine primary follicular cells. We found that FOXL2 is required for normal gene regulation by steroid receptors, and we show that estrogen receptor beta (ESR2) is the main vector of estradiol signaling in these cells. Moreover, we found that FOXL2 directly modulates Esr2 expression through a newly identified intronic element. Interestingly, we found that FOXL2 repressed the testis-determining gene Sox9 both independently of estrogen signaling and through the activation of ESR2 expression. Altogether, we show that FOXL2 mobilizes estrogen signaling to establish a coherent feed-forward loop repressing Sox9. This sheds a new light on the role of FOXL2 in ovarian maintenance and function