GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients

International audienceGenetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46x10-12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16x10-11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors

Epstein-Barr Virus genome deletions in Epstein-Barr Virus-positive T/NK cell lymphoproliferative diseases

The main target cells for Epstein-Barr virus (EBV) infection and persistence are B lymphocytes, although T and NK cells can also become infected. In this paper, we characterize the EBV present in 21 pediatric and adult patients who were treated in France for a range of diseases that involve infection of T or NK cells. Of these 21 cases, 5 pediatric patients (21%) and 11 adult patients (52%) were of Caucasian origin. In about 30% of the cases, some of the EBV genomes contain a large deletion. The deletions are different in every patient but tend to cluster near the BART region of the viral genome. Detailed investigation of a family in which several members have persistent T or NK cell infection by EBV indicates that the virus genome deletions arise or are selected independently in each individual patient. Genome sequence polymorphisms in the EBV in these T or NK cell diseases reflect the geographic origin of the patient and not a distinct type of EBV (the 21 cases studied included examples of both type 1 and type 2 EBV infection). Using virus produced from type 1 or type 2 EBV genomes cloned in bacterial artificial chromosome (BAC) vectors, we demonstrate infection of T cells in cord blood from healthy donors. Our results are consistent with transient infection of some T cells being part of normal asymptomatic infection by EBV in young children. IMPORTANCE EBV contributes to several types of human cancer. Some cancers and nonmalignant lymphoproliferative diseases involving T or NK cells contain EBV. These diseases are relatively frequent in Japan and China and have been shown sometimes to have deletions in the EBV genome in the disease cells. We identify further examples of deletions within the EBV genome associated with T or NK cell diseases, and we provide evidence that the virus genomes with these deletions are most likely selected in the individual cases, rather than being transmitted between people during infection. We demonstrate EBV infection of cord blood T cells by highly characterized, cloned EBV genomes and suggest that transient infection of T cells may be part of normal asymptomatic infection by EBV in young children

LE RECEPTEUR TYROSINE KINASE RET (DEREGULATION DES MECANISMES DE SIGNALISATION DANS LA MALADIE DE HIRSCHSPRUNG ET ETUDE DES VOIES DE TRANSDUCTION ACTIVEES PAR LE LIGAND GDNF)

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Signaux moléculaires de tri des protéines dans les cellules épithéliales : implication du domaine transmembranaire et des processus de maturation post-traductionnels

Le tri des protéines dans les cellules épithéliales représente le processus fondamental de la mise en place et du maintien de la polarité fonctionnelle des cellules épithéliales. Des processus nombreux et interdépendants sont mis en oeuvre pour réaliser ces étapes spécialisées du trafic intracellulaire. Les dernières données de la littérature sur les composantes de ces voies de trafic seront présentées et discutées dans la première partie de cet article. Les signaux portés par les protéines pour spécifier leur destination représentent l’un des éléments majeurs de l’adressage. Les signaux basolatéraux sont pour l’essentiel connus et relativement univoques, alors que les signaux apicaux sont quant à eux discutés et multiples en terme de nature moléculaire. Le cas des signaux portés par la dipeptidyl peptidase IV (DPP IV/CD26) est particulièrement intéressant à aborder, car cette protéine rejoint le pôle apical des cellules épithéliales selon des voies qui varient avec le type cellulaire considéré. Ces voies de trafic variables et complexes qui conduisent à des localisations temporaires de la DPP IV autres que la bordure en brosse apicale sont associées à des fonctions diverses : digestion enzymatique, liaison de protéines circulantes, interaction avec la matrice extracellulaire. Nous avons entrepris l’étude de ces signaux et nous décrirons ici le rôle potentiel de la glycosylation et celui du domaine transmembranaire dans l’adressage apical de la DPP IV, en insistant sur les capacités des différentes machineries cellulaires à interpréter ces signaux

Antibody-coated microbiota in nasopharynx of healthy individuals and hypogammaglobulinemia patients.

We show that nasopharyngeal microbiota are coated by different immunoglobulin isotypes in healthy individuals and with IgG in X-linked agammaglobulinemia (XLA) patients treated with immunoglobulin replacement therapy

Loss of RASGRP 1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility

International audienceInherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T-lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein-Barr virus (EBV) infection. RASGRP1 is a T-lymphocyte-specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in RASGRP1 leading to the loss RASGRP1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin lymphoma. RASGRP1-deficient T cells exhibited defective MAPK activation and impaired proliferation that was restored by expression of wild-type RASGRP1. Similar defects were observed in T cells from healthy individuals when RASGRP1 was downregulated. RASGRP1-deficient T cells also exhibited decreased CD27-dependent proliferation toward CD70-expressing EBV-transformed B cells, a crucial pathway required for expansion of antigen-specific T cells during anti-EBV immunity. Furthermore, RASGRP1-deficient T cells failed to upregulate CTPS1, an important enzyme involved in DNA synthesis. These results show that RASGRP1 deficiency leads to susceptibility to EBV infection and demonstrate the key role of RASGRP1 at the crossroad of pathways required for the expansion of activated T lymphocytes

Hsp70 negatively controls rotavirus protein bioavailability in caco-2 cells infected by the rotavirus RF strain

International audiencePrevious studies demonstrated that the induction of the heat shock protein Hsp70 in response to viral infection is highly specific and differs from one cell to another and for a given virus type. However, no clear consensus exists so far to explain the likely reasons for Hsp70 induction within host cells during viral infection. We show here that upon rotavirus infection of intestinal cells, Hsp70 is indeed rapidly, specifically, and transiently induced. Using small interfering RNA-Hsp70-transfected Caco-2 cells, we observed that Hsp70 silencing was associated with an increased virus protein level and enhanced progeny virus production. Upon Hsp70 silencing, we observed that the ubiquitination of the main rotavirus structural proteins was strongly reduced. In addition, the use of proteasome inhibitors in infected Caco-2 cells was shown to induce an accumulation of structural viral proteins. Together, these results are consistent with a role of Hsp70 in the control of the bioavailability of viral proteins within cells for virus morphogenesis

How Water Fosters a Remarkable 5-Fold Increase in Low-Pressure CO2 Uptake within Mesoporous MIL-100(Fe)

International audienceThe uptake and adsorption enthalpy of carbon dioxide at 0.2 bar have been studied in three different topical porous MOF samples, HKUST-1, UiO-66(Zr), and MIL-100(Fe), after having been pre-equilibrated under different relative humidities (3, 10, 20, 40%) of water vapor. If in the case of microporous UiO-66, CO2 uptake remained similar whatever the relative humidity, and correlations were difficult for microporous HKUST-1 due to its relative instability toward water vapor. In the case of MIL-100(Fe), a remarkable 5-fold increase in CO2 uptake was observed with increasing RH, up to 105 mg g(-1) CO2 at 40% RH, in parallel with a large decrease in enthalpy measured. Cycling measurements show slight differences for the initial three cycles and complete reversibility with further cycles. These results suggest an enhanced solubility of CO2 in the water-filled mesopores of MIL-100(Fe)