38 research outputs found

    The macrophage in HIV-1 infection: From activation to deactivation?

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    Macrophages play a crucial role in innate and adaptative immunity in response to microorganisms and are an important cellular target during HIV-1 infection. Recently, the heterogeneity of the macrophage population has been highlighted. Classically activated or type 1 macrophages (M1) induced in particular by IFN-Îł display a pro-inflammatory profile. The alternatively activated or type 2 macrophages (M2) induced by Th-2 cytokines, such as IL-4 and IL-13 express anti-inflammatory and tissue repair properties. Finally IL-10 has been described as the prototypic cytokine involved in the deactivation of macrophages (dM). Since the capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines, this review shows how modulation of macrophage activation by cytokines impacts the capacity to support productive HIV-1 infection. Based on the activation status of macrophages we propose a model starting with M1 classically activated macrophages with accelerated formation of viral reservoirs in a context of Th1 and proinflammatory cytokines. Then IL-4/IL-13 alternatively activated M2 macrophages will enter into the game that will stop the expansion of the HIV-1 reservoir. Finally IL-10 deactivation of macrophages will lead to immune failure observed at the very late stages of the HIV-1 disease

    The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

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    Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

    Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

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    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3â€Č-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

    Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

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    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/)

    A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

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    Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

    Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

    Get PDF
    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

    A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

    Get PDF
    Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

    La sophistication de l’intermĂ©diation au sein des industries crĂ©atives Ă  travers le studio de crĂ©ation digitale Femme Fatale Studio

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    This thesis questions the principle of cultural intermediation within the cinematographic and audiovisual branch. There are a multitude of actors who collaborate and participate in the creation of content within the various cultural production chains, from the conception until the distribution. Mainly composed of small agencies and creative studios, these actors contribute on a daily basis to the enhancement of the culture field by bringing innovation and flexibility, which makes their role difficult to substitute. Hence the necessity of studying how they operate and their position as providers, which often remains in the margins because of some more institutional and traditional actors in the sector.Ce mĂ©moire interroge le principe d’intermĂ©diation culturelle au sein de la filiĂšre cinĂ©matographique et audiovisuelle. Il existe, au sein des diffĂ©rentes chaĂźnes de production culturelle, une multitude d’acteurs qui collaborent et participent Ă  une crĂ©ation de contenu, de leur conception Ă  leur diffusion. Ces acteurs prennent majoritairement la forme de petites agences ou de studios de crĂ©ation et participent indĂ©niablement Ă  un enrichissement du secteur culturel en apportant innovation et flexibilitĂ©, ce qui rend leur rĂŽle difficilement substituable. Il est alors nĂ©cessaire d’étudier leur fonctionnement et position de prestataire, qui reste aujourd’hui souvent en marge de certains acteurs plus institutionnels et traditionnels de lafiliĂšre

    Delayed Horner's syndrome during a continuous infraclavicular brachial plexus block

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    Horner's syndrome is a potential, albeit rare, feature of continuous infraclavicular brachial plexus local anesthetics infusion, mainly the result of anatomical considerations. Horner's syndrome may be described as an "unpleasant side effect" because it has no clinical consequences in itself. Nevertheless, patient discomfort and anxiety may reduce acceptance of the analgesic technique. Reassurance and close clinical monitoring of the patient are essential to enhance patient's safety and acceptance of the technique. © 2007 Elsevier Inc. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

    Imagination olfactive en IRMf : Evaluation de supports visuels facilitateurs

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    National audienceObjectifs : L’imagination olfactive est sollicitĂ©e dans divers protocoles cliniques et expĂ©rimentaux, tant pour identifier des pertes sensorielles (NCT03979716) que pour tenter de rĂ©duire certains Ă©tats d’inconfort notamment induits par immersion virtuelle (NCT05308433). ParticuliĂšrement complexe, cette capacitĂ© cognitive est couramment facilitĂ©e par la prĂ©sentation de supports visuels (mots, couleurs, images...). Cependant, l’absence de comparaison directe dans la littĂ©rature entre les diffĂ©rents types de supports visuels questionne l’implication de certaines aires corticales lors de l’imagination olfactive [1]. L’objectif de cette Ă©tude Ă©tait de comparer en IRM fonctionnelle (IRMf) les activations centrales induites par l’imagination olfactive facilitĂ©e par diffĂ©rents types de supports visuels.MatĂ©riels et MĂ©thodes : Vingt-cinq volontaires sains (dont 10 femmes, Ăąge moyen = 22,6 ans) capables de bien imaginer des odeurs [2] ont eu pour consigne de se concentrer sur les odeurs Ă©voquĂ©es par 4 types de supports visuels projetĂ©s sur un Ă©cran. Deux acquisitions IRMf ont Ă©tĂ© rĂ©alisĂ©es, comprenant chacune 7 cycles composĂ©s d’une phase d’activation (14x5s) suivie d’une phase contrĂŽle (15s). Lors de chaque acquisition, 2 types de supports visuels ont Ă©tĂ© prĂ©sentĂ©s pendant les phases d’activation (acquisition 1 : couleurs unies et mosaĂŻques colorĂ©es abstraites ; acquisition 2 : images et mots d’objets odorants). Les images ont Ă©tĂ© acquises sur une IRM 3T Siemens Prisma avec une antenne tĂȘte 64 canaux et traitĂ©es sur le logiciel SPM12. Pour chaque type de support visuel, une analyse par rĂ©gion d’intĂ©rĂȘt a Ă©tĂ© effectuĂ©e en ciblant les rĂ©gions olfactives et non-olfactives reconnues comme Ă©tant impliquĂ©es dans l’imagination olfactive.RĂ©sultats : Au niveau du groupe, seule l’utilisation des images et des mots lors de l’imagination olfactive est associĂ©e Ă  des clusters d’activation significatifs (p<0.001 ; k=10) au niveau du cortex orbitofrontal (rĂ©gion reconnue dans les associations visuo-olfactives et considĂ©rĂ©e comme le cortex olfactif secondaire). Une activation significative au niveau de l’insula et de l’aire motrice supplĂ©mentaire a Ă©tĂ© observĂ©e pour tous les types de supports, alors qu’aucune activation du cortex piriforme (cortex olfactif primaire) n’a Ă©tĂ© rĂ©vĂ©lĂ©e.Conclusion : Nos rĂ©sultats suggĂšrent un phĂ©nomĂšne d’activation cĂ©rĂ©brale support-dĂ©pendante. Ainsi, le type support visuel utilisĂ© pour Ă©voquer des odeurs doit ĂȘtre pris en compte lors de l’interprĂ©tation des rĂ©sultats issus de paradigmes de neuroimagerie. Le couplage des acquisitions IRMf avec des mesures psychomĂ©triques fait actuellement l’objet de travaux (NCT05308433) afin de dĂ©terminer quel type de support facilite le plus l’imagination olfactive
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