HAL - RIIP
Not a member yet
17635 research outputs found
Sort by
Genomic risk model to implement precision prostate cancer screening in clinical care: the ProGRESS study
No full textInternational audiencePrecision healthcare aims to tailor disease prevention and early detection to individual risk. Prostate cancer screening may benefit from genomics-informed approaches. We developed and validated the P-CARE model, a prostate cancer risk prediction tool combining a polygenic score, family history and genetic ancestry, using data from over 585,000 male participants in the Million Veteran Program. The model was externally validated in diverse cohorts and implemented via a blended genome-exome assay for clinical use. Here we show that the P-CARE model identifies clinically meaningful gradients of prostate cancer risk among men, with higher scores associated with increased risk of any, metastatic and fatal prostate cancer. The model is now being used in a clinical trial of precision prostate cancer screening. This work demonstrates the potential for genomics-enabled health systems to improve prostate cancer screening and prevention in men. ClinicalTrials.gov registration: NCT0592610
Selective eIF4E–eIF4G Pairing and Cap-4 Recognition Mechanisms in Trypanosomatids: Insights From EIF4E5–EIF4G1 and EIF4E6–EIF4G5 Complexes
No full textInternational audienceTargeting epigenetics is a new strategy to treat cancer and develop novel epigenetic drugs with anti-tumor activity. DNA methyltransferases transfer the methyl group from S-adenosyl-L-methionine (SAM) to the cytosine residue in a CpG island, leading to the transcription silencing of the gene. Hypermethylation can frequently be observed in several tumor types. Hence, the inhibition of DNMT1 has become a novel approach to cure cancer. In this study, virtual screening and molecular docking were performed for more than 11,000 ligands from the ZINC15 database to discover new hypomethylation agents. Four candidate compounds were further tested for their effects on DNMT1 in silico and in vitro. Compounds 2 and 4 showed the best DNMT1 inhibitory activity, but only compound 4 was able to inhibit the growth of several cancer cell lines. The hypomethylation of the luciferase gene by compound 4 was verified by a CMV- luciferase assay using KG-1 cells. Additionally, compound 4 suppressed cell migration in a dose- and time-dependent manner in the wound healing assay. Moreover, cell cycle analyses demonstrated that compound 4 arrested CCRF-CEM cells and MDA-MB-468 cells in the G0/G1 phase. Also, compound 4 significantly induced early and late apoptosis in a dose-dependent manner. In conclusion, we introduce compound 4 as a novel DNMT1 inhibitor with anticancer activity
Rational and design of EACVI-MMVD study: an international registry on multimodality imaging for mixed and multiple valvular heart disease
No full textInternational audienceAims Multiple and mixed valvular heart disease (MMVD) are frequent situations in clinical practice. Despite a high prevalence, comprehensive insights into their clinical presentation, management strategies, impact of multimodality imaging, and outcomes are not well established, due to a lack of dedicated studies. Methods and results The ‘EACVI-MMVD Study’ will be a large prospective, multicentre, observational cohort study led by the Heart Imagers of Tomorrow of the European Association of Cardiovascular Imaging (EACVI). It will assess the proportion, management, and prognosis of MMVD over a 1-year period of follow-up. All consecutive patients diagnosed with MMVD using transthoracic echocardiography will be recruited over a 6-month recruitment period in 88 centres from 24 different countries. Baseline evaluation will be determined by physicians and encompass the whole spectrum of multimodality imaging including transthoracic and transoesophageal echocardiography, stress echocardiography, computed tomography, and cardiovascular magnetic resonance. Centres will have the opportunity to send cardiovascular imaging data for core laboratory analysis and to extend recruitment throughout a 5-year follow-up period. Conclusion The EACVI-MMVD study will be the largest international multicentre study evaluating the prevalence of MMVD in clinical routine and determining the impact of multimodality cardiovascular imaging in MMVD patients. Clinical Trial Registration: NCT06235385 URL: https://classic.clinicaltrials.gov/ct2/show/NCT0623538
Relationship between amyloid choroidopathy and neurological involvement severity scores in transthyretin amyloidosis
No full textInternational audienceBackground: Transthyretin amyloidosis (ATTR) is a disorder characterized by amyloid fibril deposits in various tissues, leading to dysfunction of one or multiple organs. Ocular manifestations include keratoconjunctivitis, secondary glaucoma, vitreous deposits, and amyloid choroidopathy. This study aims to describe the angiographic findings in 40 patients with either hereditary (ATTRv) or wild-type (ATTRwt) transthyretin amyloidosis, analyze the 3-year progression of choroidal involvement, and correlate these findings with neurological and cardiac involvement.Patients and methods: We retrospectively analyzed 79 eyes of 40 patients who underwent a comprehensive ophthalmological examination, including fluorescein angiography and indocyanine green angiography (ICGA), between 2018 and 2021. A neurological assessment (SFN-SIQ questionnaire, PND, FAP, and NIS scores) and cardiology evaluation (NYHA, LVEF) were systematically performed.Results: A total of 25 men and 15 women with a mean age of 65.8±16.8 years were included. Seventy-five percent had ATTRv, mostly with the Val30Met (p.Val50Met) mutation (35%). In 61.1% of cases, hyperfluorescent lesions were observed on ICGA. Only Val30Met (p.Val50Met) patients exhibited firework-like patterns on ICGA. There was no progression of choroidal involvement over 3 years. Ninety-five percent of patients showed neurological involvement. Diffuse choroidal involvement is associated with higher SFN-SIQ questionnaire value (P=0.02), FAP score (P=0.017) and NIS score (P=0.046). In contrast, no relationship was found between cardiac involvement and choroidal involvement.Conclusion: ICG may be used as a marker for neural components of the choroid in this disease. A prospective longitudinal study is needed to evaluate the progression of hyperfluorescent lesions on ICGA in choroidal neuropathy under treatment over time in ATTR
First evidence of human borreliosis local transmission in Cambodia
No full textInternational audienceWe report the first cases of confirmed human local transmission of borreliosis in Cambodia. Four patients, including cases with no travel history, presented typical clinical signs and tested positive for Borrelia burgdorferi antibodies. These findings confirm the presence, circulation, and local transmission of Borrelia in Cambodia. These results are important to convince for the need and the development of surveillance of tick-borne diseases in Southeast Asia
Culturable macroplastic-associated potential human pathogens in coral reef lagoons, Madagascar
No full textInternational audiencePotentially human pathogenic bacteria (PHPBs) have been detected in plastic-associated marine microbiomes, primarily through DNA-based methods. However, data on their culturability and concentrations on plastics remain limited, yet are essential to assess actual health risks. To address this gap, 70 floating macroplastic and 20 seawater samples were collected from two human-impacted reef lagoons in southwestern Madagascar (AtsimoAndrefana region). PHPBs were cultured from their microbiomes using selective media and quantified. Macroplastics were predominantly polypropylene (34 %) and polyamide (31 %). In increasing order of concentration, four culturable PHPBs, Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, and Vibrio Harveyi clade species, were identified on both macroplastics and in seawater, across all sites and polymer types. Notably, 52 % of macroplastic samples harbored two PHPB species simultaneously, while only 7 % were PHPB-free. Concentrations of all PHPBs were consistently and significantly higher on macroplastics than in seawater, regardless of the measurement unit or polymer type, with the Vibrio Harveyi clade being the most abundant. No significant correlations were observed among PHPB species concentrations, suggesting limited interaction and independent colonization. These findings indicate that floating macroplastics may serve as reservoirs and fomites for viable PHPBs. However, their potential impacts on ecosystems and human health should be interpreted cautiously. We emphasize the need to contextualize PHPB concentration data by considering factors such as exposure pathways, environmental persistence, and bacterial virulence, rather than relying solely on concentration-based comparisons, which may lead to misinterpretatio
Immune dysregulation through longitudinal lymphocyte trajectories and their clinical determinants in hospitalized COVID-19 patients
No full textInternational audienceAbstractObjective Immune dysregulation plays a pivotal role in the pathophysiology of sepsis and COVID-19, with lymphopenia emerging as a consistent marker of severity and poor prognosis. However, most existing studies have assessed lymphocyte counts at isolated time points, limiting insights into their temporal behavior and prognostic value. The dynamics of lymphocyte recovery or persistence of lymphopenia remain largely unexplored in large populations, as well as the impact of adjunctive therapies such as corticosteroids. We hypothesized that the persistence or recovery of lymphopenia may be key to understanding disease progression and predicting outcomes. Using the multinational ISARIC cohort, we investigated longitudinal lymphocyte trajectories in hospitalized patients and the clinical determinants associated with their evolution over time. Methods We conducted a multinational prospective observational cohort study using data from the ISARIC-WHO Clinical Characterization Protocol. Patients with confirmed SARS-CoV-2 infection and at least four lymphocyte measurements during the first 28 days of hospitalization were included. We analyzed lymphocyte trajectories, Cox regression survival analyses and multivariable linear regression modelling. We also applied multistate models and joint modeling to assess the association between lymphocyte trajectories and 28-day mortality, incorporating corticosteroid use as a time-varying covariate. Results Of 945,317 screened patients, 231,933 hospitalized adults with confirmed COVID-19 and sufficient lymphocyte data were included, with 56.6% classified as lymphopenic. Lymphopenia was independently associated with higher rates of ICU admission, organ support, and in-hospital mortality (OR = 1.52, 95% CI 1.48–1.55), and lower absolute lymphocyte counts were strongly linked to worse survival in adjusted Cox models (HR = 1.33 per 1 × 10⁹ cells/L decrease, 95% CI 1.28–1.38). Multistate modeling revealed that lymphopenic patients had a significantly higher daily transition rate to death and a shorter duration in that immune state, while corticosteroid exposure was associated with an increased likelihood of entering and remaining in lymphopenia. Joint modeling identified age, sex, and corticosteroid use as significant predictors of lower lymphocyte trajectories over time, with distinct dynamics between survivors and non-survivors.Conclusion Lymphopenia was common and strongly associated with worse outcomes in hospitalized COVID-19 patients, with impaired recovery particularly evident in those receiving corticosteroids. These findings highlight the value of lymphocyte monitoring to inform tailored immunomodulatory strategies in sepsis and severe viral infections
The STRAT clinical risk score to predict early ischaemic stroke post-TAVI: The FRANCE-TAVI registry
No full textInternational audienceBackgroundPractitioners recommending transcatheter aortic valve implantation (TAVI) currently lack reliable tools to predict periprocedural risk of ischaemic stroke.AimsWe aimed to develop and internally validate a clinical risk score to accurately stratify this risk.MethodsUsing data from the nationwide, multicentre FRANCE-TAVI registry, we developed a clinical predictive risk score for 30-day ischaemic stroke post-TAVI using multivariable logistic regression analysis. The model was internally validated through cross-validation techniques.ResultsAmong 62,747 patients, 1712 (2.7%) experienced ischaemic stroke within 30 days. Nine clinical predictors were identified: female sex, age > 85 years, weight < 60 kg, symptomatic status, history of stroke or transient ischaemic attack, multiple (i.e. > 1) episodes of acute heart failure, severe mobility reduction, diabetes and creatinine clearance < 60 mL/min. The resulting scoring model demonstrated good accuracy (Brier score 0.18), moderate discrimination (C-index 0.63) and excellent calibration as assessed by calibration plots, calibration-in-the-large and calibration slope. The score categorized patients into low – (90.2% of the population), intermediate – (8.0%) and high-risk (1.8%) groups. Observed stroke rates increased progressively across these groups, from 2.25% in the low-risk group to 6.51% in the intermediate-risk group and 10.10% in the high-risk group.ConclusionsThis newly developed STRAT score is a clinical, practical and effective tool for predicting early ischaemic stroke in patients undergoing TAVI. It was derived and internally validated in the FRANCE-TAVI registry and may help tailor preventive strategies. Further studies are necessary to externally validate this score and evaluate its impact on clinical decision-making
Intracellular Membrane Repair Dysregulation and Accumulation of Mature Myostatin Protein are Novel Markers of Muscle Pathophysiology in Pompe Disease
No full textInternational audiencePompe disease is an autosomal recessive metabolic disorder caused by acid alphaglucosidase deficiency, characterized by progressive skeletal muscle weakness and respiratory insufficiency. Affected muscles exhibit glycogen-filled lysosomes, autophagic build-up, and mitochondrial abnormalities. Despite global myofibrillar disorganization, satellite cells (SCs) fail to activate, due to mechanisms that remain unclear. This study sought to comprehensively characterize the phenotypic features of affected muscles in Pompe disease, focusing in particular on membrane repair processes, as membrane damage is a primary trigger for SC activation. Longitudinal transcriptomic analysis of muscle from a Pompe disease mouse model, combined with immunohistochemical and biochemical analyses, showed early and sustained overexpression of dysferlin (DYSF), annexin A2 (ANXA2), and AHNAK2, proteins involved in membrane repair. Abnormal localization of these proteins was observed throughout the disease course, as evidenced by sarcoplasmic accumulation at lysosomes, autophagosomes, and T-tubules, respectively. These alterations suggest a compensatory mechanism to preserve the integrity of intracellular structures. Analysis of muscle biopsies from patients with lateonset Pompe disease (LOPD) suggested sarcoplasmic localization of DYSF, ANXA2 and AHNAK2 that correlated with the severity of the histological phenotype. Moreover, in the mouse model, we observed persistent post-transcriptional accumulation of mature myostatin, a key negative regulator of muscle growth, which may contribute to impaired SC activation and the absence of muscle regeneration despite extensive tissue damage. In conclusion, our findings identified differential expression of proteins associated with intracellular membrane repair and dysregulation of myostatin as key markers in the course of Pompe disease. These insights provide new perspectives on the underlying pathophysiology and point to novel therapeutic avenues for limiting disease-associated damage
EMBO Workshop Host–Parasite Relationship 2025: Cutting-edge science from the shores of Les Embiez
No full textInternational audienceThe EMBO-funded workshop 'Host–Parasite Relationship: from mechanism to control strategies' took place in Les Embiez, France, on 5–8 October 2025. It was supported by the LabEx ParaFrap community and organized by Lucy Glover and Benoit Gamain. After a hiatus of 3 years, this biannual conference series is consolidating its role as the flagship parasitology meeting within Europe, where scientists meet to share their breakthroughs and to discuss new ideas in the beautiful shores of Les Embiez Island. The workshop had an outstanding line-up of invited speakers, exciting reports from selected speakers, flash talk presenters, a panel discussion for Young Investigators in Parasitology (YIP), and two vibrant poster sessions. In this TrendsTalk, we invited early career researchers to summarize the highlights of the meeting