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Etude de la superfamille du TGFβ durant le développement de la thyroïde
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Year: 2012 Publisher: Bruxelles: UCL,

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Identification de facteurs de transcription qui interagissent avec les protéines SMADs dans les lymphocytes T. Humains
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Year: 2014 Publisher: Bruxelles: UCL. Faculté de pharmacie et des sciences biomédicales,

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Le TGF-P est une cytokine aux effets immunosuppresseurs puissants. Le TGF-P inhibe notamment la prolifération des lymphocytes T. Chez les patients cancéreux, l'effet cytostatique du TGF-P sur les lymphocytes T pourrait contribuer à l'inhibition des réponses immunes anti-tumorales et empêcher le rejet des tumeurs.La voie canonique de transduction du signal par le TGF-P passe par les facteurs de transcription SMADs. Le TGF-P régule l'expression d'un grand nombre de gènes, grâce à l'association des SMADs à d'autres facteurs de transcription dont la nature dépend du contexte cellulaire. Les mécanismes conduisant à l'effet cytostatique du TGF-P ont été bien décrits dans les cellules épithéliales. Cependant, des analyses préliminaires réalisées au laboratoire semblent indiquer que les mécanismes opérants dans les lymphocytes T sont différents de ceux opérant dans les cellules épithéliales. L'objectif de mon travail est d'identifier les cofacteurs qui s'associent aux SMADs et qui participent à l'effet cytostatique du TGF-P dans les lymphocytes T.Dans un premier temps, nous avons utilisé le programme TfactS afin d'identifier des facteurs de transcription dont l'activité est régulée par le TGF-P dans les lymphocytes T. Nous avons obtenu une liste de 37 candidats. Nous avons tenté de vérifier expérimentalement si nos candidats interagissaient avec les SMADs par deux techniques indépendantes : d'une part, par co-immunoprécipitation , et d'autre part, par Proximity Ligation Assay (PLA). Nous avons tout d'abord validé ces deux approches dans les lymphocytes T à l'aide d'un contrôle positif, à savoir l'interaction entre SMAD2/3 et SMAD4 induite par un signal TGF-p. Nous avons ensuite appliqué ces deux techniques à une série de candidats que nous avions sélectionnés dans notre liste de 37 cofacteurs. Après une première série d'analyses, deux candidats semblent montrer une interaction avec SMAD2/3 : il s'agit des facteurs de transcription c-Rel et FoxO1.Enfin, nous avons voulu déterminer à l'aide d'un test de prolifération le rôle de ces deux facteurs de transcription dans l'effet cytostatique du TGF-p. Pour ce faire, nous avons électroporé un clone de lymphocyte T CD4+ avec des ARN interférants ciblant soit le gène REL, soit le gène FOXO 1. Cependant, les ARN interférants utilisés n'étaient pas assez efficaces et nous n'avons pas pu observer de diminution de l'effet cytostatique du TGF-P dans ces cellules. De nouvelles expériences utilisant des ARN interférants plus efficaces seront donc nécessaires afin de conclure au rôle de ces 2 facteurs de transcription dans l'effet cytostatique du TGF-P dans les lymphocytes T. Identification of the transcription factors interacting with the SMADs in human T lymphocytesTGF-P is a cytokine with patent immunosuppressive effects. Notably, TGF-P inhibits the proliferation of T cells. In cancer patients, the cytostatic effect of TGF-P on T cells could contribute to the inhibition of anti-tumor immune responses and prevent tumor rejection.Signal transduction upon TGF-P stimulation involves the SMAD transcription factors. SMADs associate to other transcription factors, whose identity depends on cell type and context. As a consequence, which genes are regulated in response to TGF-P signais is also dependent on cell type and context. SMAD cofactors and TGF-P target genes responsible for the cytostatic effect of TGF-P have been well characterized in epithelial cells. However, preliminary analyses in our laboratory suggest that the mechanisms at play in T cells are different from the ones operating in epithelial cells. The aim of my work is to identify cofactors that associate with SMADs and participate to the cytostatic effect of TGF-P in human T cells.We used the TfactS program to identify transcription factors whose activity appears to be regulated in response to TGF-P in human T cells. We obtained a list of 37 candidates.We tried to verify experimentally if some of the candidates interact with SMADs, using two independent techniques, namely co-immunoprecipitation and Proximity Ligation Assay. We validated these two approaches in human T cells using the known interaction between SMAD2/3 and SMAD4 as a positive contrai. We then applied these techniques to 6 of the 37 candidates. Our results indicate that two candidates, namely c-Rel and Foxü l, interact with SMAD2/3.Finally, we attempted to test if these two transcription factors play a role in the cytostatic effect of TGF-P on human T cells. We electroporated a human CD4+ T cell clone with siRNAs targeting the REL or the FOXOJ gene. Unfortunately, the siRNAs did not efficiently decrease REL and FOXOJ mRNA levels, and we observed no decrease in the cytostatic effect of TGF-P in these cells. Further experiments, using for example more patent siRNAs, are required to conclude about the role of these two transcription factors in the cytostatic effect of TGF- p in human T cells.


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Renal Cell Carcinoma
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ISBN: 3039286390 3039286382 Year: 2020 Publisher: MDPI - Multidisciplinary Digital Publishing Institute

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Renal cancer is a health problem of major concern worldwide. Although tyrosine kinase inhibitors and immune check-point blockade treatments, alone or in combination, are giving promising results, failures are quite frequent due to intratumor heterogeneity and to the acquisition of drug resistance. The spectrum of renal cell carcinoma subtypes is wide. Up to 70–80% of renal tumors are clear cell renal cell carcinomas, a clinically aggressive tumor subtype linked to VHL gene inactivation. Next in frequency, the papillary renal cell carcinoma category encompasses an intricate puzzle of classic and newly described entities with poorly defined limits, some of them pending definite clarification. Likewise, the chromophobe–oncocytoma duality, the so-called hybrid tumors and oncocytic neoplasms, remain to be well profiled. Finally, a growing list of very uncommon renal tumors linked to specific molecular signatures fulfill the current portrait of renal cell neoplasia. This Special Issue of Cancers regards RCC from very different perspectives, from the intimate basic mechanisms governing this disease to the clinical practice principles of their diagnoses and treatments. The interested reader will have the opportunity to contact with some of the most recent findings and will be updated with excellent reviews.

Keywords

Renal cell carcinoma. --- Kidneys --- Cancer. --- Adenocarcinoma of kidney --- Clear cell carcinoma --- Grawitz tumor --- Grawitz's tumor --- Hypernephroid carcinoma --- Hypernephroma --- Renal adenocarcinoma --- Renal cell adenocarcinoma --- Cancer --- N-glycomapping --- n/a --- SMAD proteins --- patient survival --- pro-IL-1? --- survival prediction --- inflammation markers --- tumor migration --- prognostic factors --- practical approach --- circular RNAs in a clinico-genomic predictive model --- glycomarkers --- review --- nephrectomy --- uric acid --- VEGF inhibitors --- metabolic reprogramming --- collecting duct carcinoma --- curcumin --- metabolome profiling --- identification of circular RNAs --- IL-2 --- experimental validation of circular RNA --- Raf/MEK/ERK --- HOT --- PI3K/Akt/mTOR --- pentose phosphate pathway --- kidney cancer --- LOT --- mutation --- RCC --- polybromo-1 --- pale cell --- MMP-9 --- gene expression --- recurrence free survival --- chromosomal loss --- IL-1? --- chronic kidney disease --- glutathione transferase omega 2 --- label-free --- glutathione transferase omega 1 --- emerging entity --- copy number alteration --- FOXO3 --- predictive role --- tumor slice culture --- tyrosine kinase inhibitors --- PPP --- ESC --- CDKN1A expression --- metastasis --- PD-L1 --- diagnostic and prognostic markers --- EVI1 --- copy number loss --- RNA sequencing --- NK cells --- glutathione metabolism --- clear cell renal cell carcinoma --- renal cell cancer --- proliferation --- eosinophilic variant --- Xp11 translocation renal cell carcinoma --- prognosis --- invasion --- immune infiltration --- IL4R? --- FISH --- 11) translocation renal cell carcinoma --- tumor microenvironment --- metabolome --- hyperosmolality --- toxicity --- ALK --- drug sensitivity --- t(6 --- copy number analysis --- urine --- genetic association --- polymorphism --- solute carrier proteins --- kidney --- metastatic ccRCC --- molecular genetic features --- recurrence-free survival --- chromophobe renal cell carcinoma --- unclassified renal tumor --- overall survival --- mTOR inhibitors --- mTOR --- JAK2 --- von Hippel–Lindau --- miR-155-5p --- glycoproteomics --- PBRM1 --- miR-133b --- survival --- TFE3 --- TFEB --- oncocytic renal tumor --- immune checkpoint inhibitors --- biomarker --- MMP10 --- TCGA --- ghrelin --- EMT like --- checkpoint inhibitors --- MiT family translocation renal cell carcinoma --- gene signature --- sarcomatoid --- transforming growth factor beta --- clear cell Renal Cell Carcinoma --- tumor adhesion --- renal cancer --- unclassified renal cell carcinoma --- Papillary renal cell carcinoma (pRCC) --- miR-146a-5p --- renal cell --- everolimus --- integrins --- cytoreductive nephrectomy --- immunotherapy --- predictive factors --- immunohistochemistry --- MTA2 --- IL13R?1 --- targeted therapy --- intratumour heterogeneity --- aurora A --- TCA cycle --- AMP-activated protein kinases --- cancer-specific survival --- programmed death-ligand 1 --- efficacy --- renal cell carcinoma --- anaplastic lymphoma kinase rearrangement --- TFEB-amplified renal cell carcinoma --- statins --- cancer immunotherapy --- microRNA --- new entity --- proteome profiling --- von Hippel-Lindau

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