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Sequencing of the invasive E. coli strain BEN2908 isolated from poultry: A comparative investigation of genomic regions shared with intestinal and extraintestinal model E. coli strains
No full textInternational audienceExtraintestinal pathogenic Escherichia coli (ExPEC) cause disease outside the gut and include avian pathogenic E. coli (APEC), a leading cause of bacterial infections in poultry. Among their highly diverse types, strain BEN2908 stands out for its significant invasive ability across various human and avian cell types. Aiming to investigate further aspects of this strain and its plasmid, we sequenced and assembled the complete genome of BEN2908 and compared it to 22 E. coli strains, including other invasive strains such as adherent and invasive E. coli (AIEC) LF82 and NRG857c, by constructing a phylogenetic tree and using web-based characterization software.With these results, we selected eight strains closely related to BEN2908 to perform a ring comparison, including two APEC (APEC O1 and IMT5155), two neonatal meningitis E. coli (NMEC; RS218 and IHE3034), two uropathogenic E. coli (UPEC; 78-Pyelo and CFT073), one commensal E. coli (MG1655) and one adherent-invasive E. coli (AIEC; LF82). This revealed 20 genomic regions (GRs) of interest which were then analysed by CD-Search, BLASTp and KEGG Pathway databases. Many of the genes in these GRs had no previous description but showed similarity to known genes involved in sugar uptake, nitrogen metabolism, and dicarboxylate transport and processing, among other functions. These results were tabulated and used to infer possible pathways that could be involved in ExPEC pathogenesis, highlighting candidate genes that have been overlooked in ExPEC research
Enhanced Lysosomal Glycogen Breakdown is associated with Liver Tumorigenesis in Glycogen Storage Disease Type III
No full textInternational audienceBackground & Aims: Glycogen storage disease type III (GSDIII) is a rare metabolic disorder caused by mutations in the glycogen debranching enzyme (AGL), leading to hepatic glycogen accumulation, fibrosis and increased hepatocellular carcinoma (HCC) risk. This study investigates the metabolic mechanisms driving liver tumorigenesis in an Agl-/- model of GSDIII. Methods: Liver and tumor samples from 14-month-old Agl-/- and Agl+/+ mice, and liver biopsies from GSDIII patients (n=4), were analyzed using histological, biochemical and molecular approaches. Results: Agl-/- mice recapitulated key features of GSDIII, including a 3.5-fold hepatic glycogen overload (p<0.001), and chronic liver disease. More than 30% of the animals developed liver tumors, associated to a 2.5-fold increase in α-fetoprotein levels (p<0.005). Despite marked reductions in glucose (7.5-fold, p<0.0001), glucose-6 phosphate (6.2-fold, p<0.0001), lactate (8-fold, p<0.005), cholesterol (1.9-fold, p<0.001) and triglyceride levels (6.2-fold, p<0.001) in the liver, glycaemia was maintained at around 87.0±9.6 mg/dl after 6h of fasting, through activated extrahepatic, but not hepatic, gluconeogenesis. Intriguingly, most tumors exhibited lower glycogen content than surrounding tissue (3.3-fold decrease, p<0.0001), associated with increased lysosomal α-acid glucosidase activity (19.5±5.5 in tumor vs 9.9±2.0 mmol/h/mg in Agl -/-liver; p<0.0005) and the presence of glycophagosomes. PAS-negative staining in GSDIII patient HCCs supported these observations. Although YAP nuclear staining varied between tumors, overall increased YAP nuclear localization and CTGF expression suggest that Hippo/YAP pathway inhibition could contribute to tumorigenesis in GSDIII hepatocytes.Conclusions: In GSDIII, liver metabolism is characterized by the accumulation of structurally abnormal glycogen and a significant reduction of key energy substrates. In this metabolic context, enhanced lysosomal glycogen degradation may support tumor growth, highlighting a mechanistic link between glycogen metabolism and the development of liver cancer
Commentary on Seersholm Et al.: Yersinia pestis Infection Is Not Synonymous With Deadly Plague in Neolithic Scandinavia
No full textInternational audienceABSTRACT Objectives Emerging genomic evidence has identified ancestral strains of Yersinia pestis in ancient human populations, which has sparked debates about its pathogenic role in later Neolithic societies. Here, we review published evidence linking anthropological and biological data reflecting the past natural history of Y. pestis infection. Materials and Methods Review of reported ancient Y. pestis genomes, paleomicrobiological, archaeological, and ecological data related to ancient plague. Results and Discussion While some researchers attributed the Scandinavian Neolithic population decline to plague epidemics, we argue that early Y. pestis strains were more likely associated with outbreaks of food‐borne enteritis rather than flea‐borne plague. This hypothesis is supported by genetic, archaeological, and ecological analyses, which indicate that Y. pestis evolved key flea‐borne transmission mechanisms only later in its history
ERAP2 inhibitor −incorporated nanofibers: Characterization and biological assessment
No full textInternational audienceERAP2 is an enzyme essential in the preparation of mature antigen from peptide precursors. Inhibitors of this enzyme can find applications in immuno-oncology and in the treatment of autoimmune diseases including psoriasis and ankylosing spondylitis. In recent years, electrospinning has attracted considerable interest in the field of drug delivery. The potential applications of electrospun fibers in the treatment of skin and arthritis diseases are significant. This can be attributed to the fibers' structural similarity to the extracellular matrix, in addition to their capacity to encapsulate disease-modifying anti-inflammatory agents. Electrospun fibrous mats are also used as drug delivery systems for loading potential anticancer drugs, with the aim of killing cancer cells. This allows for enhanced tumour penetration, increased drug retention, and higher drug delivery.The objective of this project was to evaluate the production of meshes using electrospun poly(ε-Caprolactone) (PCL), and poly-(vinyl alcohol) (PVA) fibrous patches, loaded with an ERAP2 inhibitor, with or without liposomes. An examination was conducted to ascertain the physicochemical properties, including morphology and structure. The loading, release and stability of the inhibitor was studied by both UV-Vis and MS spectroscopy. The cytotoxic assay demonstrated the biocompatibility of the fabricated nanomats of PVA and PVA-liposome (PVA-L) formulations. In vitro assays demonstrated the compatibility of meshes with cell growth, ERAP2 engagement and antigen presentation. The results of the study validated the potential for future applications in the specified therapeutic areas
Prévalence et tendances des prescriptions d’antibiotiques dans les hôpitaux de Conakry, Guinée : une enquête multicentrique transversale
No full textInternational audienceBackground Inappropriate use of antibiotics is a major driver of antimicrobial resistance (AMR), particularly in low- and middle-income countries. Understanding antibiotic use and patterns in hospital settings is essential for promoting rational use and optimizing antimicrobial stewardship (AMS). This study aims to assess the extent of antibiotic prescribing in secondary and tertiary hospitals in Conakry, Guinea, and to evaluate the appropriateness of these prescriptions on the basis of WHO recommendations via the Access, Watch, Reserve (AWaRe) classification of antibiotics. Methods A multicentre cross-sectional survey was conducted from June to October 2024 to assess patient antibiotic use levels across six hospital wards in Conakry, capital of Guinea. The prevalence of antibiotic prescriptions, with 95% confidence intervals (CI), was compared across patient, prescriber and ward variables. Antibiotic use was categorized by Anatomic Therapeutic Chemical and AWaRe classifications. Associations between categorical variables were assessed using the Chi-square or Fisher's exact test. Univariate and multivariate logistic regression were used to analyse factors associated with antibiotic prescription. Results Of 1482 patients surveyed, the overall prevalence of antibiotic prescriptions was 35.0% (95% CI: 32.6–37.5), with significant differences between inpatients (83.4%, 95% CI: 78.1–87.6) and outpatients (25.1%, 95% CI: 22.7–27.6). The total number of antibiotics prescribed was 669, and the most commonly prescribed antibiotics were beta-lactams/beta-lactamase inhibitors (24.2%), followed by third-generation cephalosporins (21.7%), imidazoles (18.5%), and penicillins (13.6%). Almost all antibiotic courses (99.4%) were started empirically, without microbiological testing to guide choice. Regarding the AWaRe classification of all prescribed antibiotics, Access antibiotics accounted for 64.3% (430/669), and 33.3% (223/669) were from the Watch group. Conclusions The results of this study, conducted in six hospital departments, provide an overview of antibiotic prescriptions in Conakry hospitals, with a high prevalence of antibiotic prescription, particularly among inpatients and almost all courses were initiated empirically without microbiological guidance. These findings underscore the urgent need for AMS programs and interventions.ContexteL’utilisation inappropriée d’antibiotiques est un facteur majeur de la résistance aux antimicrobiens (RAM), en particulier dans les pays à revenu faible et intermédiaire. Comprendre l’utilisation et les habitudes des antibiotiques en milieu hospitalier est essentiel pour promouvoir une utilisation rationnelle et optimiser la gestion des antimicrobiens (AMS). Cette étude vise à évaluer l’étendue de la prescription d’antibiotiques dans les hôpitaux secondaires et tertiaires de Conakry, en Guinée, et à évaluer la pertinence de ces prescriptions sur la base des recommandations de l’OMS via la classification Access, Watch, Reserve (AWaRe) des antibiotiques.MéthodeUne enquête multicentrique transversale a été menée de juin à octobre 2024 pour évaluer les niveaux d’utilisation d’antibiotiques chez les patients dans six services hospitaliers de Conakry, capitale de la Guinée. La prévalence des prescriptions d’antibiotiques, avec des intervalles de confiance (IC) de 95 %, a été comparée entre les variables patient, prescripteur et service. L’utilisation d’antibiotiques était classée par classification anatomique, thérapeutique chimique et AWaRe. Les associations entre variables catégorielles ont été évaluées à l’aide du test du chi-carré ou du test exact de Fisher. La régression logistique univariée et multivariée a été utilisée pour analyser les facteurs associés à la prescription d’antibiotiques.RésultatsParmi les 1482 patients interrogés, la prévalence globale des prescriptions d’antibiotiques était de 35,0 % (IC 95 % : 32,6–37,5), avec des différences significatives entre les patients hospitalisés (83,4 %, IC 95 % : 78,1–87,6) et les patients ambulatoires (25,1 %, IC 95 % : 22,7–27,6). Le nombre total d’antibiotiques prescrits était de 669, et les antibiotiques les plus couramment prescrits étaient les inhibiteurs bêta-lactames/bêta-lactamase (24,2 %), suivis des céphalosporines de troisième génération (21,7 %), des imidazoles (18,5 %) et des pénicillines (13,6 %). Presque toutes les cures d’antibiotiques (99,4 %) ont été commencées empiriquement, sans tests microbiologiques pour guider le choix. Concernant la classification AWaRe de tous les antibiotiques prescrits, les antibiotiques d’accès représentaient 64,3 % (430/669), et 33,3 % (223/669) provenaient du groupe Watch.ConclusionsLes résultats de cette étude, menée dans six services hospitaliers, offrent un aperçu des prescriptions d’antibiotiques dans les hôpitaux de Conakry, avec une forte prévalence de prescriptions d’antibiotiques, en particulier chez les patients hospitalisés, et presque tous les traitements ont été initiés empiriquement sans guidance microbiologique. Ces résultats soulignent l’urgence de programmes et d’interventions AMS
Contribution of the immune bone marrow microenvironment to tumor growth and bone deconstruction: implications for improving immunotherapeutic strategies in bone metastasis
No full textInternational audienceBone metastases are frequent complications of many solid tumors, leading to painful skeletal morbidities and increasing mortality for patients with advanced cancer. Once in bone, cancer cells deregulate bone homeostasis, altering the functions of bone-forming (osteoblasts) and bone-resorbing (osteoclasts) cells, which results in skeletal deconstruction. Aside from bone cells, cancer cells in the bone marrow interact with other cell populations, including immune cells that also play an integral part in the regulation of bone homeostasis. In this respect, immune checkpoint inhibitors (ICIs) have become a standard of care in immunotherapy for the treatment of patients with advanced cancer. Strikingly, however, those with bone metastases have a shorter survival when treated with ICIs than ICI-treated cancer patients without bone metastases. In this Review, after presenting the immune cells involved in bone metastasis, we review preclinical and clinical findings assessing ICI efficacy both in bone and extraosseous metastases, and we discuss the clinical utility of using bone-targeted agents —including denosumab and bisphosphonates— to improve anti-tumoral efficacy of ICI treatments in patients with cancer and bone metastases
Clinical Presentation and Mid-Term Results of Mitral Valve Surgery for Calcified Mitral Valve Disease - The MITRACURE registry
No full textInternational audienceBackgroundCalcified mitral valve disease (CMVD) is an increasingly recognized condition associated with specific management challenges. MITRACURE, a large multicenter observational registry conducted in France and Canada, provides real-world insights into the characteristics and outcomes of patients with CMVD undergoing MV surgery.MethodsAmong the 3,522 patients included in MITRACURE, patients identified with CMVD were matched 4:1 for age, sex, and concomitant procedures with patients with myxomatous MV disease.ResultsSixty patients (2%) with CMVD were matched to 240 with myxomatous MV disease. Compared to the myxomatous cohort, CMVD patients had a greater burden of cardiovascular risk-factors, more comorbidities, and a more advanced presentation, with 70% vs. 52% in NYHA class III–IV (P=0.01). In-hospital mortality and major complication rates (composite of death, cardiogenic shock/low cardiac output requiring inotropes, acute renal failure requiring dialysis, and stroke or transient ischemic attack) were significantly higher in CMVD than myxomatous patients (20% vs. 4%, and 38% vs. 20%, both P<0.01). Median EuroSCORE II was slightly higher in CMVD patients (3.5 [IQR 2.2-5.7]) compared with those with myxomatous disease (2.6 [IQR 1.5-4.2], P<0.01). However, the observed mortality in the CMVD group was three to four times higher than predicted, whereas in the myxomatous group it was consistent with predicted values.ConclusionCMVD defines a high-risk surgical population with substantial baseline cardiovascular morbidity and markedly elevated postoperative mortality and complication rates that were substantially underestimated by EuroSCORE II emphasizing the need for refined risk prediction models and individualized management strategies in this subset of patients
Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells
No full textInternational audienceNon-small cell lung cancers (NSCLCs) treated with tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) almost invariably relapse in the long term, due to the emergence of subpopulations of resistant cells. Through a DNA barcoding approach, we show that the clinically approved drug sorafenib specifically abolishes the selective advantage of EGFR-TKI-resistant cells, while preserving the response of EGFR-TKI-sensitive cells. Sorafenib is active against multiple mechanisms of resistance/tolerance to EGFR-TKIs and its effects depend on early inhibition of MAPK-interacting kinase (MKNK) activity and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and later down-regulation of MCL1 and EGFR. Using different xenograft and allograft models, we show that the sorafenib-EGFR-TKI combination can delay tumor growth and promote the recruitment of inflammatory cells. Together, our findings indicate that sorafenib can prolong the response to EGFR-TKIs by targeting NSCLC capacity to adapt to treatment through the emergence of resistant cells
In vitro morphological profiling of T cells predicts clinical response to natalizumab therapy in patients with multiple sclerosis
No full textInternational audienceDespite the efficacy of natalizumab, which targets the integrin VLA-4, in treating multiple sclerosis (MS), approximately 35% patients with MS present evidence of disease activity two years after treatment initiation. Individual heterogeneity of leukocyte response to VLA-4 on natalizumab-mediated blockade may underlie disparities in treatment efficacy. Here we use a high-content cell imaging (HCI) pipeline to profile the in vitro effects of natalizumab on VLA-4-stimulated PBMCs from MS patients prior to natalizumab treatment. Unsupervised clustering of image data partially discriminates non-responder MS patients based on morphology, F-actin organization and signaling-related features in CD8+ T cells. Furthermore, through a random forest approach, treatment response can be predicted with a performance of 92% for a discovery cohort and 88% for a validation cohort. Unfavorable treatment response is associated with a distinct actin remodeling response of natalizumab-exposed CD8+ T cells and a residual ability of these cells to spread on VCAM-1. Our study thus unveils that CD8+ T cells from individual MS patients display heterogeneous susceptibility to natalizumab in vitro and highlights the potential of HCI-based pretreatment monitoring to assist individualized treatment prescription