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Improved prediction of MAPKi response duration in melanoma patients using genomic data and machine learning
No full textInternational audienceBaseline genomic data have not demonstrated significant value for predicting the response duration to MAPK inhibitors (MAPKi) in patients with advanced BRAF V600 -mutated melanoma. We used machine learning algorithms and pre-processed genomic data to test whether they could contain useful information to improve the progression-free survival (PFS) prediction. This exploratory analysis compared the predictive performance of a dataset that contained clinical features alone and supplemented with baseline genomic data. In the evaluation set (two cohorts, n = 111), the cross-validated model performance improved when pre-processed genomic data, such as mutation rates, were added to the clinical features. In the validation dataset (two cohorts, n = 73), the best model with genomic data outperformed the best model with clinical features alone. Finally, our best model outperformed with baseline genomic data, increasing the number of patients with a correctly predicted relapse by between +12% and +28%. In our models, baseline genomic data improved the prediction of response duration and could be incorporated into the development of predictive models of MAPKi treatment in melanoma
Unsupervised Machine Learning Analysis to Enhance Risk Stratification in Patients with Asymptomatic Aortic Stenosis
No full textInternational audienceAims: There is a lack of studies investigating the pathophysiologic and phenotypic distinctiveness of aortic stenosis (AS). This heterogeneity has important implications for identifying optimal intervention timing and potential medical management. This study seeks to identify phenogroups of AS using unsupervised machine learning to improve risk stratification. Methods and results: A total of 349 patients with asymptomatic AS from the PROGRESSA study were included in this analysis. Echocardiographic, clinical and blood sample data were used in the unsupervised clustering process. Longitudinal echocardiographic data were used to evaluate AS progression. Five clusters of patients were revealed using 18 variables selected by an unsupervised machine learning algorithm. Amongst them, aortic valvular phenotype, mean gradient, peak jet velocity (Vpeak), and left ventricle stroke volume were selected as discriminatory variables. Following the clustering process, characteristics differed between clusters, including age, body mass index, and sex ratio (all P < 0.001). Of note, cluster 1 showed higher AS severity at baseline with significantly higher initial Vpeak (344 [314; 376] cm/s) and calcium score (1257 [806; 1837] UA) (P < 0.001). Patients from cluster 1 had a faster AS progression (progression of Vpeak = 22 [9; 39] cm/s/year), and calcium score (213 [111; 307] UA/year) (P < 0.001). Cluster 1 was also associated with a higher composite risk of mortality and aortic valve replacement when adjusted for age, sex, and baseline AS severity (P < 0.001).Conclusion: Artificial intelligence-guided phenotypic classification revealed 5 distinct groups and enhanced risk stratification of patientswith AS. This approach may be useful to optimize and individualize medical and interventional management of AS
From visualization to education: the role of 3D-Printed and virtual kidney models in training for renal cancer surgery, a systematic review
No full textInternational audienceObjectives: This systematic review on novel 3D technologies aims to discuss the current evidence on the usefulness of 3D printing, virtual reality (VR) and augmented reality (AR) simulators in the education and training of young urologists for kidney cancer surgery, highlighting the modalities employed, their educational impact, and areas for future development.Materials and Methods: We performed a comprehensive literature search limited to the last 10 years across PubMed and Embase libraries, identifying studies evaluating the use of 3D technologies as educational tools in urologist training for kidney cancer surgery. The review followed PRISMA guidelines, and two reviewers independently screened eligible studies. We extracted data on study designs and on urologists' education outcomes, through different subcategories.Results: Seventeen studies were included, mostly small-scale validation or descriptive investigations. Twelve investigated 3D-printed models and five VR/AR platforms. Simulations focused on laparoscopic and robot-assisted partial nephrectomy, often using patient-specific models for rehearsal and skill development. Training outcomes included improved spatial anatomy understanding, increased technical performance, greater procedural confidence, and enhanced familiarity with complex surgical steps. However, considerable heterogeneity in methodology and limited sample sizes across studies underscore the need for standardized evaluation of these educational tools.Conclusion: 3D technologies, including 3D-printed models and VR/AR platforms, show promise in enhancing surgical training for renal cancer by improving anatomical understanding and procedural skills. These technologies demonstrate good precision and can help assess trainee surgical skill. However, evidence remains limited, and further research is needed to validate their effectiveness, cost-efficiency, and integration into standardized urological training curricula
Increasing Evidence Supports the Benefits of Rapid Uptitration of the Neurohormonal Blockade in HFmrEF/HFpEF Patients With AHF
No full textInternational audienceNo abstract availabl
Évaluation des inhibiteurs des histones déacétylases pour augmenter la restauration de la dystrophine dans la dystrophie musculaire de Duchenne après saut d'exon
No full textDuchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by mutations in the DMD gene, leading to a loss of functional dystrophin. Among the therapeutic approaches under development, exon skipping using antisense oligonucleotides (ASOs) represents a promising strategy. However, the low dystrophin restoration efficiency observed in clinical trials has limited their therapeutic impact. In this context, our work aimed to improve exon skipping efficacy through combined treatments involving ASOs and histone deacetylase inhibitors (HDACi), in order to modulate the epigenetic environment and enhance DMD transcript availability.We first evaluated a 12-week combination therapy with valproic acid (VPA) and a tcDNA-ASO targeting exon 23 in the mdx mouse model. The dual treatment led to a 50% increase in exon skipping and up to 70% more dystrophin restoration in skeletal muscles, with cardiac dystrophin levels reaching 25% of wild-type. This molecular improvement translated into significant gains in muscle strength, coordination, and resistance to eccentric contractions, alongside improved biomarker profiles and overall functional recovery. However, no correction of the Dmd transcriptional imbalance was observed, and mild renal toxicity was detected with long-term VPA treatment.We then extended our approach to the mdx52 mouse model, which carries a deletion of exon 52 and more closely resembles patient mutations. After characterizing a more pronounced 5'-3' transcriptional imbalance in this model, we screened three HDACi and identified givinostat as the most effective compound for enhancing exon 51 skipping. In vivo, the combination of givinostat and tcDNA-ASO significantly improved dystrophin restoration, muscle fiber maturation, mitochondrial integrity, and reduced fibrosis. This resulted in enhanced muscle function with no observed toxicity.Finally, we compared the efficacy of VPA in mdx versus mdx52 models. Contrary to its benefits in mdx mice, the VPA+ASO combination failed to improve exon skipping, dystrophin expression, or muscle function in mdx52. In addition, it was associated with elevated muscle damage biomarkers and no correction of the transcriptional imbalance.Overall, our findings support the development of combined therapeutic strategies to enhance ASO efficacy in DMD and demonstrate that the response to adjuvants such as HDAC inhibitors may depend strongly on the mutation context and transcriptomic profile. Givinostat, in particular, emerges as a strong candidate for synergistic combination with exon-skipping ASOs in clinically relevant DMD models.La dystrophie musculaire de Duchenne (DMD) est une maladie neuromusculaire liée à l'X, causée par des mutations du gène DMD entraînant l'absence de dystrophine fonctionnelle. Parmi les approches thérapeutiques en développement, le saut d'exon induit par des oligonucléotides antisens (ASO) constitue une stratégie prometteuse. Toutefois, la faible efficacité de restauration de la dystrophine observée en clinique limite actuellement son impact thérapeutique. Dans ce contexte, nos travaux visent à améliorer l'efficacité du saut d'exon par des thérapies combinées associant ASO et inhibiteurs d'histone désacétylases (HDACi), afin de moduler l'environnement épigénétique et d'augmenter la disponibilité des transcrits DMD.Nous avons d'abord évalué une bi-thérapie de 12 semaines associant l'acide valproïque (VPA) et un ASO de type tcDNA ciblant l'exon 23 dans le modèle murin mdx. Ce traitement combiné a permis une augmentation de 50 % du saut d'exon et jusqu'à 70 % de restauration supplémentaire de la dystrophine dans les muscles squelettiques, avec un niveau de restauration cardiaque atteignant 25 % du niveau physiologique. Ces effets moléculaires se sont traduits par une amélioration significative de la force musculaire, de la coordination motrice et de la résistance aux contractions excentriques, accompagnée de profils biomarqueurs améliorés. En revanche, aucun rééquilibrage du déséquilibre transcriptionnel du gène Dmd n'a été observé, et une toxicité rénale modérée a été détectée à long terme sous VPA.Nous avons ensuite appliqué cette approche au modèle murin mdx52, porteur d'une délétion de l'exon 52, plus représentatif des mutations cliniques. Après avoir caractérisé un déséquilibre transcriptionnel 5'-3' encore plus marqué dans ce modèle, nous avons réalisé un criblage de trois HDACi et identifié le givinostat comme le plus efficace pour améliorer le saut de l'exon 51. In vivo, l'association givinostat + ASO a permis une augmentation significative de la restauration de la dystrophine, une meilleure maturation des fibres musculaires, une intégrité mitochondriale préservée, ainsi qu'une réduction de la fibrose, avec à la clé une amélioration de la fonction musculaire sans effet toxique observé.Enfin, nous avons comparé l'efficacité du VPA entre les modèles mdx et mdx52. Contrairement à ses bénéfices dans le modèle mdx, la combinaison VPA+ASO n'a pas permis d'améliorer le saut d'exon, la restauration de la dystrophine ni les performances musculaires dans le modèle mdx52. Elle était même associée à une élévation des biomarqueurs de dommages musculaires et n'a pas corrigé le déséquilibre transcriptionnel.En conclusion, nos résultats soutiennent le développement de stratégies combinées visant à renforcer l'efficacité des ASO dans la DMD. Ils montrent également que la réponse aux adjuvants tels que les inhibiteurs d'HDAC dépend fortement du contexte mutationnel et transcriptionnel. Le givinostat apparaît comme un candidat de choix pour une combinaison synergique avec des ASO dans des modèles précliniques cliniquement pertinents
Acceptabilité et potentiel de mise en œuvre d'une intervention visant à améliorer la littératie en santé afin d'augmenter le dépistage du cancer colorectal dans les zones défavorisées : une étude qualitative menée auprès de patients et de médecins généralistes participant à un essai contrôlé randomisé en clusters
No full textInternational audienceBackground Colorectal cancer (CCR) is one of the leading causes of death worldwide. Early detection remains a highly effective strategy for curing this disease. In France, despite a free organised screening programme for people aged between 50 and 74, participation rates remain suboptimal. Socioeconomic position and health literacy levels exacerbate the situation, with the lowest screening rates observed in the most socially disadvantaged areas. This study assessed patients’ and General Practitioners’ (GP) views on the acceptability of an intervention to increase screening uptake using a simple brochure and video on the importance and process of CCR screening. Method We conducted a cross-sectional qualitative study using semi-structured interviews with patients (n = 24) and GPs (n = 22) who used or participated in the DECODE project intervention. The interviews were conducted by telephone or videoconference and analysed thematically using Nvivo software and dual independent coding. Results 95% of GPs expressed a clear preference for the video over the brochure. Patients had varied results with 50% preferring the video, as it demonstrated how to do the test, versus the brochure. The humorous and de-dramatising aspects of the video were the two key factors highlighted by interviewees. However, support from healthcare staff (GPs, nurses, etc.) is still essential, in supporting patients in prevention. This presents a challenge for GPs, who are frequently constrained by time limitations during consultations. Conclusion Our findings emphasize the need to tailor promotional materials for both patients and healthcare professionals to improve CCR screening uptake, balancing digital efficiency with maintaining core human relationships in healthcare. Such intervention can be integrated into different workflows. The addition of video into national CRC screening programs might also help. Targeting CRC screening interventions at provider-patient interactions, ensuring they are tailored, accessible, and engaging, is key to reducing disparities
STARDEV Study: Neurodevelopmental Trajectory and Long‐Term Outcomes of Patients with Startle Disease/Hyperekplexia
No full textInternational audienceBackground Although initial clinical presentation of hyperekplexia/startle disease is well known, data regarding long‐term clinical outcomes is lacking. Objectives We provide a long‐term evaluation from clinical and pharmacological perspectives, focusing on neurodevelopmental trajectory. Methods Twenty‐eight patients from nine French hospitals were included based on clinical diagnosis criteria. Adaptive abilities were assessed using VABS‐II. Results VABS‐II showed preserved adaptive abilities, except in motor skills. Early development was marked by neurodevelopmental delay in 53% of patients, with 57% developing neurodevelopmental disorders, primarily specific learning disorders. Intellectual disability and/or autism spectrum disorder were present in five patients. Symptoms were most frequent during the first 3 years of life, with persistence of exaggerated startle reflex and falls. One‐quarter of the patients discontinued clonazepam. A genetic variant was found in 85% of patients, involving one of the three main genes GLRA1 , SLC6A5 , or GLRB . Conclusions Our findings highlight preserved adaptive abilities, frequent neurodevelopmental disorders and long‐term pharmacodependence
Controversy: in heart failure patients with a reduced ejection fraction and left bundle branch block, conduction system pacing can be a valid alternative to biventricular pacing—pro and contra
No full textInternational audienceFor patients with heart failure (HF) and bundle branch block, cardiac resynchronization therapy (CRT) by biventricular pacing (BiVP) has been found effective and has been widely used for around 20 years. The effects of BiVP are well documented in a row of large randomized controlled trials (RCTs) with long-term follow-up to include prolonged survival, less HF hospitalizations, and better quality of life for the patients. More recently, conduction system pacing (CSP) as His bundle pacing or left bundle branch area pacing has been introduced for CRT and shown to in best cases establish a normal or near-to-normal electrical activation of the left ventricular myocardium. Data from large RCTs documenting the beneficial effects of CSP are awaited. Currently, the question is to what extent the contemporary literature supports a transition from BiVP to CSP for CRT in patients with HF and bundle branch block. This Europace Controversy article presents opposing viewpoints on this topic. H.B., M.J., and J.J. argue in favour of CSP being superior to BiVP. Conversely, C.L., N.B., and J.C.D. advocate for BiVP still being the first choice for CRT. This Controversy aims to present data and their interpretation from different expert perspectives on an important topic in CRT for HF
HTRF-based identification of small molecules targeting SARS-CoV-2 E protein interaction with ZO-1 PDZ2
No full textInternational audienceThe SARS-CoV-2 E protein through its C-terminal PDZ-binding motif (PBM) interacts with several host PDZ-containing proteins, including Zonula occludens-1 (ZO-1) protein via its PDZ2 domain, thereby contributing to viral pathogenesis. Targeting this interaction represents a potential therapeutic strategy. In this study, we determined the X-ray structure of the E PBM peptide in complex with the ZO-1 PDZ2 domain at 1.7 Å resolution. The structure revealed a domain-swapped dimer conformation of ZO-1 PDZ2, with the E PBM peptide conventionally bound within the PDZ domain’s canonical binding groove, exhibiting key interactions characteristic of type II PBM/PDZ interactions. To identify potential inhibitors of the E PBM/ZO-1 PDZ2 interaction, we performed a Homogeneous Time-Resolved Fluorescence (HTRF) screening using a protein-protein interaction-focused library of 1000 compounds. This led to the identification of 36 hits that disrupted this interaction. Subsequent cytotoxicity and dose-response assays narrowed the selection to 14 promising compounds. Docking simulations showed that some compounds bind within or near the PBM-binding pocket, supporting a competitive mechanism of interaction inhibition, while others bind at a central interface between the two PDZ monomers, suggesting an inhibition of dimerization, which in turn prevents PBM binding. Thus, the E PBM/ZO-1 PDZ2 interaction can be inhibited through both direct and indirect mechanisms. Finally, antiviral assays using a NanoLuciferase-expressing recombinant SARS-CoV-2 demonstrated that one compound, C19, significantly reduced viral replication, highlighting its potential as a candidate for further therapeutic development
Le rôle des lipases de l'adipocyte, HSL et ATGL, dans le métabolisme glucido-lipidique
No full textObesity is a major global public health concern and represents a significant risk factor for the development of various metabolic disorders, including insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular diseases. A common early feature of these conditions is the ectopic accumulation of lipids in multiple tissues, often associated with adipocyte dysfunction, excessive adipose tissue lipolysis, and elevated circulating lipid levels.In this context, a better understanding of the physiological and pathological roles of adipocyte lipolysis-primarily mediated by the enzymes ATGL (adipose triglyceride lipase) and HSL (hormone-sensitive lipase)-is essential for elucidating the mechanisms underlying the metabolic dysregulation observed in obesity. My thesis addresses this issue by investigating the specific roles of ATGL and HSL in regulating adipose tissue function and systemic energy metabolism.By generating adipose tissue-specific knockout mouse models for these lipases, my work demonstrates that complete inhibition of adipocyte lipolysis exerts context-dependent effects on metabolism. Specifically, it markedly reduces energy expenditure during prolonged fasting, improves metabolic parameters in a diet-induced obesity model, and alleviates hyperglycemia and hyperketonemia in a murine model of type 1 diabetes.Furthermore, this research highlights a critical metabolic crosstalk between adipose tissue and the pancreas, mediated by lipolysis-derived fatty acids. Disruption of this pathway impairs insulin secretion, a defect that can be rescued by exogenous supplementation of free fatty acids. These fatty acids regulate insulin secretion both directly, through activation of the GPR40 receptor on pancreatic β-cells, and indirectly, via modulation of somatostatin release. This mechanism is preserved under obese conditions, underscoring the pivotal role of adipocyte lipolysis in ensuring proper insulin secretion and maintaining metabolic homeostasis.L'obésité représente une problématique majeure de santé publique à l'échelle mondiale et constitue un facteur de risque important pour le développement de plusieurs pathologies métaboliques, telles que la résistance à l'insuline, le diabète de type 2, la stéatose hépatique non alcoolique et les maladies cardiovasculaires. Un dénominateur commun précoce à ces affections est l'accumulation ectopique de lipides au sein de divers tissus, souvent associée à un dysfonctionnement des adipocytes, une lipolyse excessive du tissu adipeux et une élévation des concentrations lipidiques circulantes.Dans ce contexte, une meilleure compréhension des fonctions physiologiques et pathologiques de la lipolyse adipocytaire, principalement médiée par les enzymes ATGL (adipose triglyceride lipase) et HSL (hormone-sensitive lipase), apparaît essentielle pour appréhender les mécanismes impliqués dans la dérégulation métabolique associée à l'obésité. Ma thèse s'inscrit dans cette problématique et vise à caractériser le rôle spécifique d'ATGL et HSL dans la régulation de la fonction adipocytaire et dans le contrôle du métabolisme énergétique à l'échelle de l'organisme.Grâce au développement de modèles murins à invalidation spécifique de ces lipases dans le tissu adipeux, mes travaux ont permis de démontrer que l'abolition complète de la lipolyse adipocytaire exerce des effets contextuels sur le métabolisme : elle induit une réduction marquée du métabolisme énergétique en condition de jeûne prolongé, améliore les paramètres métaboliques dans un modèle d'obésité induite par un régime riche en graisses, et atténue l'hyperglycémie ainsi que l'hypercétonémie dans un modèle murin de diabète de type 1.Par ailleurs, ces travaux ont révélé l'existence d'un dialogue métabolique étroit entre le tissu adipeux et le pancréas, reposant sur la libération d'acides gras issus de la lipolyse. L'invalidation de cette voie entraîne un défaut de sécrétion d'insuline, qui peut être restauré par l'apport exogène d'acides gras libres. Ces derniers régulent la sécrétion d'insuline à la fois par une action directe sur le récepteur GPR40 des cellules β pancréatiques et indirectement via la modulation de la sécrétion de somatostatine. Ce mécanisme est conservé en situation d'obésité, soulignant le rôle central de la lipolyse adipocytaire dans le maintien d'une sécrétion insulinique adéquate et de l'homéostasie métabolique