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/)

Paxillin binding to the cytoplasmic domain of CD103 promotes cell adhesion and effector functions for CD8+ resident memory T cells in tumors

International audienc

Selection of tumor‑resistant variants following sustained natural killer cell‑mediated immune stress

International audienceResistance of tumor cells to cell‑mediated cytotoxicity remains an obstacle to the immunotherapy of cancer and its molecular basis is poorly understood. To investigate the acquisition of tumor resistance to cell‑mediated cytotoxicity, resistant variants were selected following long‑term natural killer (NK) cell selection pressure. It was observed that these variants were resistant to NK cell‑mediated lysis, but were sensitive to autologous cytotoxic T lymphocytes or cytotoxic drugs. This resistance appeared to be dependent, at least partly, on an alteration of target cell recognition by NK effector cells, but did not appear to involve any alterations in the expression of KIR, DNAM1 or NKG2D ligands on resistant cells, nor the induction of protective autophagy. In the present study, in order to gain further insight into the molecular mechanisms underlying the acquired tumor resistance to NK cell‑mediated cytotoxicity, a comprehensive analysis of the variant transcriptome was conducted. Comparative analysis identified an expression profile of genes that best distinguished resistant variants from parental sensitive cancer cells, with candidate genes putatively involved in NK cell‑mediated lysis resistance, but also in adhesion, migration and invasiveness, including upregulated genes, such as POT1, L1CAM or ECM1, and downregulated genes, such as B7‑H6 or UCHL1. Consequently, the selected variants were not only resistant to NK cell‑mediated lysis, but also displayed more aggressive properties. The findings of the present study emphasized that the role of NK cells may span far beyond the mere killing of malignant cells, and NK cells may be important effectors during cancer immunoediting

Regulation of Melanoma Progression through the TCF4/miR-125b/NEDD9 Cascade

Melanoma progression from a primary lesion to a distant metastasis is a complex process associated with genetic alterations, epigenetic modifications, and phenotypic switches. Elucidation of these phenomena may indicate how to interfere with this fatal disease. The role of microRNAs as key negative regulators of gene expression, controlling all cellular processes including cell migration and invasion, is now being recognized. Here, we used in silico analysis of microRNA expression profiles of primary and metastatic melanomas and functional experiments to show that microRNA-125b (miR-125b) is a determinant candidate of melanoma progression: (i) miR-125b is more strongly expressed in aggressive metastatic than primary melanomas, (ii) there is an inverse correlation between the amount of miR-125b and overall patient survival, (iii) invasion/migration potentials in vitro are inversely correlated with the amount of miR-125b in a series of human melanoma cell lines, and (iv) inhibition of miR-125b reduces migratory and invasive potentials without affecting cell proliferation in vitro. Furthermore, we show that neural precursor cell expressed developmentally down-regulated protein 9 (i.e., NEDD9) is a direct target of miR-125b and is involved in modulating melanoma cell migration and invasion. Also, transcription factor 4, associated with epithelial-mesenchymal transition and invasion, induces the transcription of miR-125b-1. In conclusion, the transcription factor 4/miR-125b/NEDD9 cascade promotes melanoma cell migration/invasion.publisher: Elsevier articletitle: Regulation of Melanoma Progression through the TCF4/miR-125b/NEDD9 Cascade journaltitle: Journal of Investigative Dermatology articlelink: http://dx.doi.org/10.1016/j.jid.2016.02.803 content_type: article copyright: © 2016 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.status: publishe

TGF-β signaling intersects with CD103 integrin signaling to promote T lymphocyte accumulation and antitumor activity in the lung tumor microenvironment

International audienceHoming of CD8+ T lymphocytes to the tumor microenvironment is an important step for mounting a robust antitumor immune response. TGF-β is responsible for CD103 (αEβ7) integrin induction in activated intraepithelial CD8+ T lymphocytes. However, the interplay between TGF-β and CD103 and their contribution to T-cell infiltration and antitumor activity remain unknown. Here, we used viable human lung tumor slices and autologous tumor antigen-specific T-lymphocyte clones to provide evidence that CD103 is directly involved in T-lymphocyte recruitment within epithelial tumor islets and intratumoral early T-cell signaling. Moreover, TGF-β enhanced CD103-dependent T-cell adhesion and signaling, whereas it inhibited leukocyte function-associated antigen (LFA)-1 (αLβ2) integrin expression and LFA-1-mediated T-lymphocyte functions. Mechanistic investigations revealed that TGF-β bound to its receptors (TGFBR), which promoted the recruitment and phosphorylation of integrin-linked kinase (ILK) by TGFBR1. We further show that ILK interacted with the CD103 intracellular domain, resulting in protein kinase B (PKB)/AKT activation thereby initiating integrin inside-out signaling. Collectively, our findings suggest that the abundance of TGF-β in the tumor microenvironment may in fact engage with integrin signaling pathways to promote T-lymphocyte antitumor functions, with potential implications for T-cell-based immunotherapies for cance