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Whole‐exome sequencing in families from Lifou Island (New Caledonia) reveals candidate variants involved in gout pathogenesis
No full textInternational audienceBackground Gout, which manifests as severe inflammation caused by excessive serum urate levels and monosodium urate deposits in the joints, is associated with multiple genomic loci in Europeans. In this exploratory work, we aimed to identify additional gene variants in Melanesian families from New Caledonia, a population in which the disease is highly prevalent. Methods Two families from Lifou Island (New Caledonia) in which multiple members were diagnosed with gout were selected. Whole exome sequencing and/or targeted sequencing of a panel of genes involved in immunity was performed in patients and their healthy relatives. Rare variants in Melanesian populations were selected using an autosomal dominant segregation model. Results Several variants were identified in genes not previously involved in immune diseases or hyperuricemia, several of which were not observed in control individuals from Remote Oceania. Conclusion This work highlights new candidate susceptibility loci for gout in New Caledonians, an underrepresented population in genomic studies, and suggests that novel pathways are likely involved in gout pathogenesis
Disease-free survival as surrogate for overall survival in esophageal cancer: An individual patient data meta-analysis of neoadjuvant chemotherapy and chemoradiotherapy
No full textInternational audienceBackground: The use of surrogate endpoints may expedite the reporting of study outcomes of clinical trials. The validity of disease-free survival (DFS) as a surrogate for overall survival (OS) in the neoadjuvant treatment of esophageal (E) or gastroesophageal junctional (GEJ) carcinomas remains uncertain.Objective:To evaluate DFS as a surrogate end-point for OS in E/GEJ using the meta-analytical approachDesign, setting, and participantsindividual patient data from an international meta-analysis on operable locally advanced E/GEJ, which including randomized trials comparing at least two of the neo-adjuvant treatment strategies: upfront surgery (S), chemotherapy followed by surgery (CS), and/or chemoradiotherapy followed by surgery (CRS).Main outcomes and measures: Individual (Kendall’s tau) and trial-level (R2) correlations between DFS and OS were estimated using a Clayton copula.Results: DFS and OS data were available for a total of 4518 pts: 2222 pts included in CS vs S, 1908 pts in CRS vs S, and 388 in CS vs CRS comparisons. 3440 patients had a DFS event and 3303 patients died. Kendall’s tau was 0.73 [95 % CI 0.71 – 0.75] and R2 trial-level correlation was 0.95 [0.84 – 0.99] for CS vs S, Kendall’s tau was 0.76 [0.74 – 0.77] and R2 was 0.96 [0.87 – 0.99] for CRS vs S, Kendall’s tau was 0.87 [0.78 – 0.92] and R2 was 0.93 [0.43 – 1] for CRS vs CS. In a multistate model, the median time in the recurrence state was shorter in older vs more recent trials: mean time of 10.8 [10.2 – 11.4] vs 16.5 months [15.4–17.6].Conclusions and relevance: DFS is a validated surrogate endpoint for OS in trials evaluating neoadjuvant chemotherapy or chemoradiotherapy in E/GEJ. DFS may be more useful as an endpoint when delays between recurrences and death become larger
Real-world efficacy of the dabrafenib-trametinib (D-T) combination in BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC): Results from the IFCT-2004 BLaDE cohort
No full textInternational audienceBRAF V600E mutations occur in 2-5 % of advanced non-small cell lung cancer (NSCLC) patients. The dabrafenib-trametinib (D-T) combination was associated with improved and durable OS in patients in phase II. This study (IFCT-2004 BLaDE study) reported the efficacy of D-T combination in a large retrospective French real-world multicenter cohort of patients with advanced BRAF V600E-mutated NSCLC
Immunoglobulins G from Patients with Systemic Sclerosis Modify the Molecular Signatures of Endothelial Cells
No full textInternational audienceObjective: Antinuclear antibodies (ANA) are powerful biomarkers in systemic sclerosis (SSc). Functional antibodies (FA) might be implicated in vasculopathy, in which endothelial cells (EC) are key players. We aimed to explore the effect of purified IgG from patients with SSc on omics signatures of EC and examine the influence of ANA serotypes and FA.Methods: EC were cultured in the presence of purified IgG from patients with SSc, patients with systemic lupus erythematosus (SLE) or healthy controls (HC). EC omics profiles were analysed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and RNA sequencing. EC proteome induced by IgG from patients with SSc was confirmed with an external validation cohort.Results: In the derivation cohort, principal component analysis (PCA) using proteomics data showed three distinct groups of subjects: a first one including mostly anti-topoisomerase-I positive patients (ATA+), a second one including mostly anti-centromere positive patients and a third group comprising anti-RNA polymerase-III positive patients, SLE and HC. In transcriptomics, PCA distinguished one group composed of ATA+patients only from a second group mixing ATA+patients with other individuals. The validation cohort confirmed the existence of two groups of distinct EC proteome profiles and clinical severity in ATA+patients. In both SSc cohorts, no association between FA presence and proteomic profiles was observed. Quantitative proteomics measured the most discriminant proteins in EC exposed to purified IgG.Conclusion: Purified IgG from patients with SSc can modify EC proteome and transcriptome. The observed changes closely associate with ANA serotype
Integrative metagenomics and metabolomics reveal age-associated gut microbiota and metabolite alterations in a hamster model of COVID-19
No full textInternational audienceAging is a key contributor of morbidity and mortality during acute viral pneumonia. The potential role of age-associated dysbiosis on disease outcomes is still elusive. In the current study, we used high-resolution shotgun metagenomics and targeted metabolomics to characterize SARS-CoV-2-associated changes in the gut microbiota from young (2-month-old) and aged (22-month-old) hamsters, a valuable model of COVID-19. We show that age-related dysfunctions in the gut microbiota are linked to disease severity and long-term sequelae in older hamsters. Our data also reveal age-specific changes in the composition and metabolic activity of the gut microbiota during both the acute phase (day 7 post-infection, D7) and the recovery phase (D22) of infection. Aged hamsters exhibited the most notable shifts in gut microbiota composition and plasma metabolic profiles. Through an integrative analysis of metagenomics, metabolomics, and clinical data, we identified significant associations between bacterial taxa, metabolites and disease markers in the aged group. On D7 (high viral load and lung epithelial damage) and D22 (body weight loss and fibrosis), numerous amino acids, amino acid-related molecules, and indole derivatives were found to correlate with disease markers. In particular, a persistent decrease in phenylalanine, tryptophan, glutamic acid, and indoleacetic acid in aged animals positively correlated with poor recovery of body weight and/or lung fibrosis by D22. In younger hamsters, several bacterial taxa (Eubacterium, Oscillospiraceae, Lawsonibacter) and plasma metabolites (carnosine and cis-aconitic acid) were associated with mild disease outcomes. These findings support the need for age-specific microbiome-targeting strategies to more effectively manage acute viral pneumonia and long-term disease outcomes
LmCen−/− based vaccine is protective against canine visceral leishmaniasis following three natural exposures in Tunisia
No full textInternational audienc
Proteomic profiling of the serological response to a chemically-inactivated nodavirus vaccine in European sea bass Dicentrarchus labrax
No full textInternational audienceThese viruses are among the most significant viral pathogens of finfish, causing viral nervous necrosis (VNN) or viral encephalopathy and retinopathy (VER), which represents a crucial bottleneck for the development of mariculture in several countries (Toffan et al. 2017). Sea bass (D. labrax) is exposed to various pathogens during its life production cycle, including the VNN virus, particularly the red-spotted grouper nervous necrosis virus (RGNNV) genotype (Toffan et al. 2017). All stages of sea Viruses of the Betanodavirus genus are highly pathogenic, capable of evading the host's protective systems, and can either replicate and invade other cells or remain latent
Synthesis, crystal structure, computational and solution studies of a new phosphotetradecavanadate salt. Assessment of its effect on U87 glioblastoma cells
No full textInternational audienceThe new benzylammonium (C 7 H 10 N) salt of the phosphotetradecavanadate (PV14) anion PV 14 O 42 9-, (C 7 H 10 N) 6 [H 3 PV 14 O 42 ]•7H 2 O (1), is synthesized under mild conditions and characterized by a combination of physicochemical techniques such as Fourier transform infrared spectroscopy, powder X-ray diffraction, elemental analyses and cyclic voltammetry. As evaluated by 51 V NMR spectroscopy, at milimolar concentrations and pH ~2.5 the PV14 anions decompose slowly, thus demonstrating kinetic stability, but at pH ~7 this process takes place much faster. However, in the presence of human serum albumin, the 51 V NMR peaks of PV14 anions broaden significantly and their decomposition becomes much slower, this being due to a direct interaction between both components. The structure of 1 is elucidated by single-crystal X-ray diffraction and reveals the presence of three-fold protonated, bicapped Keggin type [H 3 PV 14 O 42 ] 6-anions. The supramolecular interactions governing the crystal packing are further studied using the Hirshfeld surface analysis. Computational studies using density functional theory were effective in determining the electronic and protonation states of PV14 clusters, as well as the multi-electron redox behavior of compound 1 in acidic aqueous solutions. Molecular dynamics calculations confirm the high hydrophilicity and absence of aggregation between protonated PV14 anions in aqueous medium. Notably, this compound shows high inhibitory effect on the viability of the U87 glioblastoma cell line with IC 50 values of 3.2 ± 0.6 μM and 1.10 ± 0.04 μM after 24 h and 72 h treatments. The mode of action of compound 1 is mediated by the pro-apoptotic process. These data provide evidence on the potential therapeutic use of PV14 compounds against glioblastoma
SARS-CoV-2 excretion and genetic evolution in nasopharyngeal and stool samples from primary immunodeficiency and immunocompetent pediatric patients
No full textInternational audienceBackground Primary Immunodeficiency disorders (PID) can increase the risk of severe COVID-19 and prolonged infection. This study investigates the duration of SARS-CoV-2 excretion and the genetic evolution of the virus in pediatric PID patients as compared to immunocompetent (IC) patients.Materials and methods A total of 40 nasopharyngeal and 24 stool samples were obtained from five PID and ten IC children. RNA detection was performed using RT-qPCR, and whole-genome sequencing was conducted with the NexSeq 1000 platform. Data analysis used the nextflow/viralrecon pipeline. Hotspot amino acid frequencies were investigated using GraphPad Prism v10. Phylodynamic analysis was conducted with BEAST software.ResultsIn IC children, the viral excretion period lasted up to 14 days in nasopharyngeal swabs, with an average duration of 7 days, and ranged from 7 to 14 days in stool samples. In PID patients, the viral RNA was detected in nasopharyngeal for periods between 7 and 28 days, with an average duration of 15 days, and up to 28 days in stool samples. Two SARS-CoV-2 variants were detected in PID patients: Delta (AY.122) and Omicron (BA.1.1). Patients with antibody and combined deficiencies, exhibited the most prolonged shedding periods in both nasopharyngeal and stool samples and one patient presented complications and fatal outcome. Specific Hotspot amino acid changes were detected in PID: A2821V and R550H (ORF1ab).ConclusionOur findings underscore the prolonged excretion of SARS-CoV-2 RNA in patients with antibody and combined deficiencies. Thus, specialized care is essential for effectively managing PID patients
One Health : une stratégie pour faire face aux maladies de demain
No full textArticle co-rédigé par les scientifiques et la rédaction sur la thématique One Health à l'Université de Perpignan avec l'exemple de deux projets de recherche du laboratoire IHP