The Tumor Coagulome as a Transcriptional Target and a Potential Effector of Glucocorticoids in Human Cancers

Background: The coagulome, defined as the repertoire of genes that locally regulate coagulation and fibrinolysis, is a key determinant of vascular thromboembolic complications of cancer. In addition to vascular complications, the coagulome may also regulate the tumor microenvironment (TME). Glucocorticoids are key hormones that mediate cellular responses to various stresses and exert anti-inflammatory effects. We addressed the effects of glucocorticoids on the coagulome of human tumors by investigating interactions with Oral Squamous Cell Carcinoma, Lung Adenocarcinoma, and Pancreatic Adenocarcinoma tumor types. Methods: We analyzed the regulation of three essential coagulome components, i.e., the tissue factor (TF), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1) in cancer cell lines exposed to specific agonists of the glucocorticoid receptor (GR) (dexamethasone and hydrocortisone). We used QPCR, immunoblots, small-interfering RNA, Chromatin immunoprecipitation sequencing (ChIPseq) and genomic data from whole tumor and single-cell analyses. Results: Glucocorticoids modulate the coagulome of cancer cells through a combination of indirect and direct transcriptional effects. Dexamethasone directly increased PAI-1 expression in a GR-dependent manner. We confirmed the relevance of these findings in human tumors, where high GR activity/high SERPINE1 expression corresponded to a TME enriched in active fibroblasts and with a high TGF-β response. Conclusion: The transcriptional regulation of the coagulome by glucocorticoids that we report may have vascular consequences and account for some of the effects of glucocorticoids on the TME.</p

Seismic noise-based methods for soft-rock landslide characterization

International audienceIn order to better understand the mechanics and dynamic of landslides, it is of primary interest to image correctly their internal structure. Several active geophysical methods are able to provide the geometry of a given landslide, but were rarely applied in 3 dimensions in the past. The main disadvantages of methods like seismic reflection or electrical tomographies are that there are heavy to set up, require for some heavy processing tools to implement, and consequently are expensive and time consuming. Moreover, in the particular case of soft-rock landslides, their respective sensitivity and resolution are not always adequate to locate the potential slip surfaces. The passive methods, which require lighter instrumentation and easier processing tools, can represent an interesting alternative, particularly for difficult accessible landslides. Among them, the seismic noise based methods have shown increasing applications and developments, in particular for seismic hazard mapping in urban environment. In this paper, we present seismic noise investigations carried out on two different sites, a mudslide and a translational clayey landslide where independent measurements (geotechnical and geophysical tests) were performed earlier. Our investigations were composed of H/V measurements, which are fast and easy to perform in the field, in order to image shear wave contrasts (slip surfaces), and seismic noise array method, which is heavier to apply and interpret, but provides S-waves velocity profile versus depth. The comparisons between geophysical investigations and geotechnical information proved the applicability of such passive methods in 3D complexes, but also some limitations. Indeed interpretation of these measurements can be tricky in rough and non-homogeneous terrains

An Image-Based High-Content Screening Assay for Compounds Targeting Intracellular Leishmania donovani Amastigotes in Human Macrophages

Leishmaniasis is a tropical disease threatening 350 million people from endemic regions. The available drugs for treatment are inadequate, with limitations such as serious side effects, parasite resistance or high cost. Driven by this need for new drugs, we developed a high-content, high-throughput image-based screening assay targeting the intracellular amastigote stage of different species of Leishmania in infected human macrophages. The in vitro infection protocol was adapted to a 384-well-plate format, enabling acquisition of a large amount of readouts by automated confocal microscopy. The reading method was based on DNA staining and required the development of a customized algorithm to analyze the images, which enabled the use of non-modified parasites. The automated analysis generated parameters used to quantify compound activity, including infection ratio as well as the number of intracellular amastigote parasites and yielded cytotoxicity information based on the number of host cells. Comparison of this assay with one that used the promastigote form to screen 26,500 compounds showed that 50% of the hits selected against the intracellular amastigote were not selected in the promastigote screening. These data corroborate the idea that the intracellular amastigote form of the parasite is the most appropriate to be used in primary screening assay for Leishmania

Need for a Standardized Translational Drug Development Platform: Lessons Learned from the Repurposing of Drugs for COVID-19

In the absence of drugs to treat or prevent COVID-19, drug repurposing can be a valuable strategy. Despite a substantial number of clinical trials, drug repurposing did not deliver on its promise. While success was observed with some repurposed drugs (e.g., remdesivir, dexamethasone, tocilizumab, baricitinib), others failed to show clinical efficacy. One reason is the lack of clear translational processes based on adequate preclinical profiling before clinical evaluation. Combined with limitations of existing in vitro and in vivo models, there is a need for a systematic approach to urgent antiviral drug development in the context of a global pandemic. We implemented a methodology to test repurposed and experimental drugs to generate robust preclinical evidence for further clinical development. This translational drug development platform comprises in vitro, ex vivo, and in vivo models of SARS-CoV-2, along with pharmacokinetic modeling and simulation approaches to evaluate exposure levels in plasma and target organs. Here, we provide examples of identified repurposed antiviral drugs tested within our multidisciplinary collaboration to highlight lessons learned in urgent antiviral drug development during the COVID-19 pandemic. Our data confirm the importance of assessing in vitro and in vivo potency in multiple assays to boost the translatability of pre-clinical data. The value of pharmacokinetic modeling and simulations for compound prioritization is also discussed. We advocate the need for a standardized translational drug development platform for mild-to-moderate COVID-19 to generate preclinical evidence in support of clinical trials. We propose clear prerequisites for progression of drug candidates for repurposing into clinical trials. Further research is needed to gain a deeper understanding of the scope and limitations of the presented translational drug development platform

Modello, dessin de présentation ou riccordo : à propos de quelques dessins « très finis » de Jean-Baptiste Greuze

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Jean-Baptiste Greuze à Rome (1755-1757). Quelques remarques sur son activité de dessinateur

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La représentation du jeune dessinateur. Un motif de la France des Lumières

International audiencePopularisée par les peintres Jean Siméon Chardin, Nicolas-Bernard Lépicié et François-Hubert Drouais, la représentation du jeune dessinateur se développe particulièrement durant la seconde moitié du 18e siècle. Cette étude propose de comprendre l’exceptionnelle fortune de ce motif, de son origine à son appropriation par une élite lettrée, sensible aux idées de Rousseau et au goût nouveau pour la pratique artistique. Il convient en effet de replacer cette iconographie au regard des problématiques du siècle des Lumières tout en essayant de déterminer son genre au sein d’une hiérarchie qui tend à s’estomper. Ce motif s’inscrit dans les autres représentations de l’enfance et de la jeunesse contemporaines, mais il diffère par l’attention portée au dessin et renforce ainsi la spécificité française

Représenter le père : ambivalence du sentiment paternel chez Jean-Baptiste Greuze

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La représentation du jeune dessinateur. Un motif de la France des Lumières

International audiencePopularisée par les peintres Jean Siméon Chardin, Nicolas-Bernard Lépicié et François-Hubert Drouais, la représentation du jeune dessinateur se développe particulièrement durant la seconde moitié du 18e siècle. Cette étude propose de comprendre l’exceptionnelle fortune de ce motif, de son origine à son appropriation par une élite lettrée, sensible aux idées de Rousseau et au goût nouveau pour la pratique artistique. Il convient en effet de replacer cette iconographie au regard des problématiques du siècle des Lumières tout en essayant de déterminer son genre au sein d’une hiérarchie qui tend à s’estomper. Ce motif s’inscrit dans les autres représentations de l’enfance et de la jeunesse contemporaines, mais il diffère par l’attention portée au dessin et renforce ainsi la spécificité française