Enhanced Lysosomal Glycogen Breakdown is associated with Liver Tumorigenesis in Glycogen Storage Disease Type III

International 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

Long non-coding RNA UCA1 affects chromatin remodeling via SMARCA2-containing SWI/SNF complex in human colorectal cancer

Summary Differential lncRNA expression has been correlated to clinical characteristics of colorectal cancers (CRC), which are the second leading cause of cancer-related deaths. LncRNA UCA1 plays a role in epigenetic gene regulation in diverse cancers. We studied CRC cell properties in CRISPR/Cas9 HT29-derived models and, interestingly, UCA1-depleted HT29 cells presented an increased stem-cell phenotype. We show that loss of UCA1 affected SWI/SNF chromatin remodeling complexes, which are previously shown to be involved in maintaining stem-cell properties. Not only was UCA1 permissive for induced SWI/SNF subunit SMARCA2 (BRM) expression upon chemo-drug treatment, but it also affected subunit compositions of SWI/SNF complexes by direct interaction of UCA1 with both ATP helicase BRM and BRG1. UCA1 is known to stimulate proliferation and decrease apoptosis, and we here show that it can restrain cells from a stem cell phenotype. The dual action of UCA1 revealed in this study highlights the complex actions of lncRNAs in cancer

Culturable macroplastic-associated potential human pathogens in coral reef lagoons, Madagascar

International 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 (Atsimo-Andrefana 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 misinterpretation

A new chemotype that opens the S2∗ pocket of the 3CL protease exhibits antiviral activity against SARS-CoV-2

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The STRAT clinical risk score to predict early ischaemic stroke post-TAVI: The FRANCE-TAVI registry

International 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

Mitral Annulus Calcification: Pathophysiology, Outcome, and Imaging Evaluation

International audienceMitral annulus calcification (MAC) is a chronic, degenerative process characterized by calcium deposition in the mitral annulus. It is commonly observed in elderly individuals and those with chronic kidney disease, hypertension, and metabolic disorders. MAC has been increasingly recognized as a marker of cardiovascular disease and is associated with adverse clinical outcomes, including mitral valve dysfunction, arrhythmias, and increased cardiovascular mortality. The pathophysiology of MAC involves endothelial dysfunction, chronic inflammation, and osteogenic differentiation of valvular interstitial cells, driven by risk factors such as aging, chronic kidney disease, diabetes mellitus, and hypertension. Imaging modalities, including echocardiography and computed tomography (CT) play a crucial role in the diagnosis, assessment, and risk stratification of MAC. The presence of MAC complicates mitral valve interventions, making surgical and transcatheter approaches challenging. Despite advancements in imaging and therapeutic strategies, MAC remains a significant challenge in cardiovascular medicine, necessitating further research into its pathophysiology, optimal management strategies, and long-term outcomes

Health-related quality of life in nondialysis CKD patients: a comprehensive description of five-year trajectories among the CKD–REIN cohort

International audienceBackground Few studies have analyzed the quality-of-life trajectories of CKD patients not receiving kidney replacement therapy, and the results are inconsistent. This study aimed to identify subgroups of long-term trajectories of the physical (PCS) and mental components summary (MCS) of the KDQOL-36 in patients with CKD stages 3-5 and to describe their associations with patient characteristics. MethodsWe used a joint latent class-mixed model to identify the PCS and MCS trajectories of 2716 patients with CKD stages 3-5 enrolled in the CKD-Renal Epidemiology and Information Network (CKD-REIN) cohort study. Qualityof-life was assessed annually using the Kidney Disease Quality-of-life-36. All the participants had scores for at least one-time point. ResultsDuring a median follow-up of 5.56 (4.77-6.16) years, 664 participants started KRT, and 465 died before KRT. We identified three profiles of PCS: a "High and declining PCS trajectory" which included 5.89% of patients, characterized by a higher initial score and a decline of more than 10 points over three years; a "High and stable PCS trajectory" in 50.96%, characterized by a higher initial score that remained stable; and a "Low and stable PCS trajectory" in 43.15%, characterized by a lower initial score that remained stable. For MCS, we identified a single, stable mean trajectory over time. A decline in eGFR was faster in participants with a "High and declining PCS trajectory" (-4.30 mL/min per years). Patients in the high and stable trajectory had a more favorable clinical and biological profile at baseline. The evolution of the specific dimensions of CKD within each PCS trajectory followed a pattern similar to that of the PCS itself. Conclusions The study highlights substantial heterogeneity in PCS evolution in patients with CKD, which contrasts with the stability of that for MCS.</div

Socioeconomic and nutritional determinants outweigh gut microbiota influence on neurodevelopment in young children from Antananarivo, Madagascar

International audienceIn 2024, stunted child growth affected 150 million children under the age of five years, underscoring its critical impact on global health. Stunting has also been associated with neurodevelopmental delays. This study explores the relationship between stunting, the fecal microbiota, and neurodevelopment in 2–5-year-old children from the Afribiota cross-sectional study in Madagascar. Children were assessed using the Ages and Stages Questionnaire (ASQ-3), covering five developmental domains (communication, personal-social, problem-solving, fine and gross motor). Fecal samples were analyzed via 16S rRNA gene amplicon sequencing. Classical bi- and multivariate analysis was combined with Structural Equation Modelling to evaluate direct and indirect associations between different clinical factors, the microbiota and neurodevelopment. Our study shows that stunting and low socioeconomic status are consistently linked to poorer neurodevelopmental outcomes, while low branched-chain amino acids and hemoglobin levels are associated with stunting. Furthermore, a higher microbial diversity within individuals (α-diversity—specifically the Shannon index-) was directly linked to improved neurodevelopment scores in one of the tested models, while gut microbiota variation between individuals (β-diversity) was not associated with neurodevelopment. These findings support the hypothesis of neurodevelopment being primarily influenced by nutritional and social factors, with a more limited role for microbiota diversity

Unmasking the hidden catalyst: how infections trigger Alzheimer's disease

International audienceFor years, the understanding of Alzheimer's disease (AD) has been shaped by the amyloid hypothesis, which suggests that pathological markers like amyloid-beta (Aβ) and phosphorylated Tau are the primary drivers of the disease. This hypothesis has guided the development of major treatment strategies, including monoclonal antibodies targeting Aβ.However, most of these treatments have failed to produce clinically significant results, highlighting the urgent need for a new therapeutic approach. It is now evident that AD is a complex, multifactorial disease that develops over decades, ultimately leading to Aβ and Tau accumulation. Therefore, addressing the underlying causes of these depositions is crucial. One well-supported yet underrecognized theory is the infection hypothesis, which links infections to AD pathology. Despite substantial scientific evidence, this perspective has faced significant resistance. In this review, we describe how chronic infections contribute to AD by triggering neuroinflammation and Aβ accumulation. We also explore the barriers to accepting the infection hypothesis and the steps necessary for its integration into drug development and early-stage treatment strategies. Persisting with an amyloid-centric approach will only exacerbate the societal burden. Embracing the infection hypothesis could transform AD research, diagnosis, and treatment, bringing new hope to millions.</div

Green gold of the Pacific: unlocking compounds from terrestrial flora for antitumor and immunomodulatory drug discovery

International audienceCovering up to 2025Natural products (NPs) from the terrestrial biodiversity play a key role in oncology drug discovery. While historically identified through bioactivity-guided fractionation, recent advances in high-content screening (HCS) assays, metabolomics, and in silico modeling have significantly enhanced the potential and attractiveness of flora-derived NPs for the development of anticancer therapeutics. This includes immunomodulatory molecules that are able to target the tumor microenvironment to promote immune-mediated clearance of the tumor, thereby improving patient response. This review highlights the untapped potential of molecules extracted from the South Pacific's terrestrial flora in the search for novel antitumor and immunomodulatory compounds. The unique biodiversity of Oceania, including Australia, New Zealand, and Pacific Island Countries and Territories (PICTs) across Micronesia, Melanesia and Polynesia, offers a promising yet largely unexplored reservoir for discovering plant-derived molecules with antitumor and immunomodulatory activities. Herein, we examine the recent pharmacological advances in this field and highlight the need for sustainable and collaborative research. Leveraging cutting-edge technologies could help overcome the challenge of NP-based drug discovery on these geographically isolated islands, unlocking the region's vast potential for plant-derived cancer therapeutics