Abstract Chronic inflammation represents a central component in the pathogenesis of Alzheimer's disease (AD). Recent work suggests that breaking immune tolerance by Programmed cell Death‐1 (PD1) checkpoint inhibition produces an IFN‐γ‐dependent systemic immune response, with infiltration of the brain by peripheral myeloid cells and neuropathological as well as functional improvements even in mice with advanced amyloid pathology (Baruch et al., ( ): Nature Medicine, 22:135–137). Immune checkpoint inhibition was therefore suggested as potential treatment for neurodegenerative disorders when activation of the immune system is appropriate. Because a xenogeneic rat antibody (mAb) was used in the study, whether the effect was specific to PD1 target engagement was uncertain. In the present study we examined whether PD1 immunotherapy can lower amyloid‐β pathology in a range of different amyloid transgenic models performed at three pharmaceutical companies with the exact same anti‐PD1 isotype and two mouse chimeric variants. Although PD1 immunotherapy stimulated systemic activation of the peripheral immune system, monocyte‐derived macrophage infiltration into the brain was not detected, and progression of brain amyloid pathology was not altered. Similar negative results of the effect of PD1 immunotherapy on amyloid brain pathology were obtained in two additional models in two separate institutions. These results show that inhibition of PD1 checkpoint signaling by itself is not sufficient to reduce amyloid pathology and that additional factors might have contributed to previously published results (Baruch et al., ( ): Nature Medicine, 22:135–137). Until such factors are elucidated, animal model data do not support further evaluation of PD1 checkpoint inhibition as a therapeutic modality for Alzheimer's disease.
Rural, a vocation agricole et industrielle, Bresse-Revermont-Val de Saone est un territoire qui se periurbanise sous l'effet du desserrement de Mâcon. L'habitat individuel domine, avec des risques d'emiettement. La situation de l'emploi demeure favorable malgre la crise. Face a l'attractivite residentielle, les principaux enjeux sont le renforcement de l'activite (notamment agricole), la preservation du cadre de vie et le developpement des equipements.
En 2015, en Auvergne-Rhone-Alpes, 172 000 personnes âgees sont en situation de perte d’autonomie. Si les tendances se poursuivaient, elles seraient 187 000 en 2020 puis 215 000 en 2030. Actuellement, 109 000 emplois (en equivalent temps plein) permettent d’aider les personnes âgees en perte d’autonomie dans leur vie quotidienne, qu’elles vivent a leur domicile ou soient hebergees en institution. Les lois recentes donnent encore plus la priorite au maintien a domicile. Ainsi, 12 000 emplois supplementaires seraient necessaires a l’horizon 2020.
Recently, new sensitive methods have been proposed to determine hyaluronic acid in serum, either by radioimmunoassay I or by an irnmunoenzyrnoassay.' The immunoenzymoassay was based on the specific binding of a glycoprotein, hyaluronectin, to hyaluronic acid. Other glycosaminoglycans were shown not to interfere in the assay. The blocking of hyaluronectin binding to hyaluronic acid coated plates by soluble hyaluronic acid allowed the quantitation of hyaluronic acid in biological fluids. The validity of that method for pleural and ascitic fluids was demonstrated by testing 53 samples (49 pleural fluids and four ascitic fluids) including four pleural and one peritoneal mesotheliomas. Their hyaluronic acid content was determined by the immunoenzymoassay as well as by the electrophoretic method routinely used for the diagnosis of mesothelioma. The electrophoretic method required a 72 hour proteolytic digest of 10 mL sample (pronase, streptomyces griseus, Sigma, St Louis, Missouri, USA, type XIV, O' 5 mg/rnl, in Tris 0·1 M, CaCI2 0·4 mM, pH 8'6) before dialysis against running water for 8 hours. The hyaluronic acid was then precipitated by three volumes of a mixture of sodium acetate/ethanol (1/3 v/v) at 4°C overnight. The precipitate was collected by centrifugation, dried and dissolved in distilled water. The recovery of hyaluronic acid extraction was 79%. Quantitation of hyaluronic acid was performed by electrophoresis, as previously descri bed. ] Immunoenzymoassay was performed as previously described? except that incubation of samples with hyaluronectin was carried out in plates at 37°C. As shown previously, incubation at 37°C lowers the hyaluronectin-hyaluronic acid affinity, thus permitting measurement of hyaluronic acid at higher concentrations without
Les inegalites entre hommes et femmes s’observent en premier lieu dans le domaine de l’education. D’une maniere generale, les performances scolaires des filles sont meilleures que celles des garcons. Independamment de ces resultats, les orientations different dans le sens ou les filles s’engagent moins souvent dans les filieres professionnelles. Sur le marche du travail, les femmes sont de plus en plus presentes. L’augmentation du niveau de diplome leur permet egalement d’etre de plus en plus representees parmi les cadres, quel que soit le secteur d’activite. Si certains metiers restent typiquement feminins, les femmes integrent petit a petit des secteurs d’ou elles etaient absentes, comme celui du bâtiment.
Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, accounting for 30-40% of newly diagnosed non-Hodgkin lymphomas. Historically, DLBCL has been thought to involve recurrent translocations of the immunoglobulin heavy (IGH) locus and the deregulation of rearranged oncogenes. Whole exome sequencing (WES) of more than 200 DLBCLs has completely redefined the genetic landscape of the disease by identifying recurrent single nucleotide variants and providing new therapeutic opportunities in DLBCL molecular subtypes. Some of these somatic mutations target genes that play a crucial role in B-cell function (B cell receptor [BCR] signaling, nuclear factor κB [NF-κB] pathway, Toll-like receptor [TLR] signaling and phosphatidylinositol 3-kinase [PI3K] pathway), immunity, cell cycle/apoptosis or chromatin modification. In this review, following an overview of the somatic mutations reported in DLBCL, we focus on activating and clustered mutations targeting genes including MYD88, CD79A/B, EZH2 and CARD11 and discuss their clinical and therapeutic relevance in the precision medicine era.
