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Validation en vie réelle d'un modèle prédictif du besoin de nutrition entérale prophylactique avant une radiothérapie pour un cancer de la tête et du cou
No full textThe current roles of artificial intelligence in radiotherapy involve the automation of certain technical tasks. The main goal is to streamline workflow. Artificial intelligence as clinical decision support is still in the proof-of-concept stage. Indeed, the routine clinical use of an AI- based algorithm to guide patient management qualifies the algorithm as a medical device and assumes the prediction of a clinically relevant event, with good predictive performance obtained on an external, prospective validation cohort that is representative of the target population. A systematic literature review has identified that despite a consensus on the definition of malnutrition, the rate of malnutrition during radiotherapy for head and neck cancer has been reported very heterogeneously, making it complex to evaluate the causes and consequences of malnutrition during ENT radiotherapy, as malnutrition definitions were too heterogeneous. However, a number of parameters were consistently associated with malnutrition regardless of the definition used. We have developed a model based on Xgboost to predict the need for a patient to require a gastrostomy during radiotherapy. This model was validated on a multicentric real-world data cohort prospectively collected through structured data queries within the radiotherapy management software. This model yielded an area under the curve of 0.81 with true negative and true positive rates of 78% and 76% respectively across the entire cohort. The clinical benefit of this model remains to be established, with a proposed clinical trial first to verify predictive performance and compare it to that of a physician, and secondly to conduct randomization between the use by a physician of the predictive model versus non-use of this algorithm to decide on preventive gastrostomy. The nutritional and oncological benefits would then be evaluated during and after radiotherapy. This would be one of the first clinically evaluated clinical decision support models.Les usages actuels de l’intelligence artificielle en radiothérapie concernent principalement l’automatisation de certaines tâches techniques. Le but est de fluidifier le flux de travail. Les applications de l’intelligence artificielle comme aide à la décision pour prescrire restent encore à l’état de preuve de concept. En effet l’utilisation en routine clinique d’un algorithme fondé sur l’intelligence artificielle (IA) pour guider la prise en charge d’un patient qualifie l’algorithme comme dispositif médical, et suppose la prédiction d’un évènement cliniquement pertinent, avec de bonnes performances obtenues sur une cohorte de validation externe et prospective de l’algorithme sur une cohorte représentative de la population cible. Une revue systématique de la littérature a identifié que malgré un consensus sur la définition de la dénutrition, le taux de dénutrition pendant la radiothérapie pour un cancer de la tête et du cou a été rapporté de manière très hétérogène et qu’il était donc complexe d’évaluer les causes et les conséquences de la dénutrition pendant une radiothérapie ORL, puisque les définitions de la dénutrition étaient trop hétérogènes. Cependant un certain nombre de paramètres étaient associés à la dénutrition de manière récurrente quelle que soit la définition utilisée. Nous avons développé un modèle basé sur Xgboost pour établir une prédiction du besoin pour un patient de requérir une gastrostomie pendant la radiothérapie. Ce modèle a été validé sur une cohorte de données de vie réelle multicentrique recueillie prospectivement, et obtenue par des requêtes de données structurées collectée au sein du logiciel métier de radiothérapie. Ce modèle a permis d’obtenir une aire sous la courbe à 0.81 avec un taux de vrais négatifs de 78% et de vrais positifs de 76% sur l’ensemble de la cohorte. Le bénéfice clinique de ce modèle reste à être établi, avec une proposition d’essai clinique permettant dans un premier temps de vérifier la performance prédictive et de la confronter à celle d’un médecin, et dans un second temps de réaliser une randomisation entre l’utilisation par un médecin du modèle prédictif vs. la non-utilisation de cet algorithme pour décider d’une gastrostomie préventive. Le bénéfice nutritionnel et oncologique serait alors évalué au décours et à distance de la radiothérapie. Il s’agirait alors de l’un des premiers modèles d’aide décisionnelle clinique évalué cliniquement
Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer
No full textInternational audienceHigh-grade serous ovarian cancer (HGSOC) remains an urgent unmet clinical need, with more than 70% of patients presenting with metastatic disease. Many patients develop large volumes of ascites, which promotes metastasis and is associated with poor therapeutic response and survival. Immunotherapy trials have shown limited success, highlighting the need to better understand HGSOC immunology. Here, we analyzed cytotoxic lymphocytes [natural killer (NK), T, and innate T cells] from patients with HGSOC and observed widespread dysfunction across primary and metastatic sites. Although nutrient rich, ascites was immunosuppressive for all lymphocyte subsets. NK cell dysfunction was driven by uptake of polar lipids, with associated dysregulation in lipid storage. Phosphatidylcholine was a key immunosuppressive metabolite, disrupting NK cell membrane order and cytotoxicity. Blocking lipid uptake through SR-B1 protected NK cell antitumor functions in ascites. These findings offer insights into immune suppression in HGSOC and have important implications for the design of future immunotherapies
Electrification of catalytic processes with induction heating: The possible hidden role of non-thermal magnetic fields
No full textInternational audienceThe electrification of the chemical industry is a crucial step toward moving away from fossil fuels and achieving a more sustainable energy future. In this context, induction heating has emerged as a promising strategy to enhance catalytic performance in both metal-free carbon catalysts and metal-supported systems. This perspective emphasizes its strong potential, showing that induction heating improves performance not only through localized thermal effects but also through possible non-thermal contributions from alternating current magnetic fields. These fields can influence radical lifetimes, spin states, adsorption-desorption equilibria, and defect reactivity, thereby enabling reaction pathways and selectivities that remain inaccessible under conventional heating. Coupling carbon and supported metal catalysts with induction heating also offers an effective way to mitigate deactivation, as defect sites can act as adsorption centers that, under magnetic field stimulation, promote targeted transformations. Direct evidence for non-thermal contributions to catalytic performance remains scarce, mainly due to the limited availability of operando investigations. Nevertheless, the substantial gains in activity and selectivity observed under induction heating cannot be explained solely by localized thermal effects, suggesting an additional non-thermal influence. These findings point toward new opportunities for designing nextgeneration catalysts with improved operability and stability. In addition, the combined evidence of localized thermal effects, non-thermal field interactions, and the advantages of carbon-based catalysts shows that the synergy between advanced material design and induction heating provides a powerful pathway for electricitydriven catalysis, with significant implications for decarbonizing the chemical industry and advancing the energy transition
Dialysis preparedness and access to the transplant waitlist: evidence from a national United States cohort study
No full textInternational audienceBackgroundIndividuals who initiate dialysis for kidney failure do so with different levels of preparedness. Whether this has downstream effects for access to kidney transplant is unknown.MethodsWe identified adults (≥18 years) initiating dialysis between 2015 and 2019 from the United States Renal Data System, and followed them until waitlisting, death, or end of follow-up (December 31, 2021), whichever occurred first. We grouped dialysis initiation context as: group 1 initiated peritoneal dialysis (PD) or hemodialysis (HD) with mature arteriovenous access (AVA); group 2 initiated HD with a catheter and maturing AVA; group 3 initiated HD with a catheter and without a maturing AVA; and group 4 lacked pre-dialysis nephrology care. Fine-Gray sub-distribution hazard models assessed the association between dialysis initiation context and waitlisting, adjusted for clinical and non-clinical factors, and stratified by age, sex, race, and insurance status.ResultsAmong 541,861 adults initiating dialysis, 26.9%, 14.9%, 29.8% and 28.4% were in groups 1, 2, 3 and 4, respectively. Compared to group 1, individuals in groups 2, 3 and 4 were 40% (adjusted Hazard Ratio: 0.60 [95%CI 0.59-0.62]), 45% (0.55 [0.54-0.56]) and 58% (0.42 [0.41-0.43]) less likely to be waitlisted. The relative impact of no pre-dialysis nephrology care was most pronounced among older, Black, female and Medicare insured patients.ConclusionA large proportion (∼60%) of adults in the US initiate dialysis with no AVA or pre-dialysis nephrology care, with detrimental consequences for downstream transplant access
Epithelial to Mesenchymal Transition Transcriptional Regulator ZEB1 in Liver Cancer: Oncogenic Roles and Therapeutic Potential
No full textInternational audienceZinc finger E-box binding homeobox 1 (ZEB1) is a member of the zinc finger homeodomain transcription factor family, with a pivotal role in regulating the epithelial to mesenchymal transition (EMT) process. Increasing evidence suggests that ZEB1 is overexpressed in liver tumors, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), and it correlates with advanced disease features and reduced overall survival. Here, we examine ZEB1 molecular functions, regulatory networks and contribution to tumorigenesis. We also discuss the emerging therapeutic strategies and future research directions aimed at targeting the ZEB1 molecular network to improve the outcome of liver cancer patients
The Combined Expression Profiles of Epigenetic Biomarkers Reveal Heterogeneity in Normospermic Human Sperm Samples
No full textInternational audienceBackground: Male infertility is evaluated using standard semen parameters. However, these criteria offer limited insight into sperm functionality and poorly predict natural fertility or assisted reproductive technology (ART) outcomes. Methods: In this study, the expression levels of three genes (AURKA, HDAC4, and CARHSP1) involved in mitosis regulation, epigenetic modulation and early embryonic development, were measured by RT-qPCR in sperm samples (training dataset). For each gene, thresholds of normal and reduced expression were established by biostatistical modeling and combined with the number of motile spermatozoa to develop the Spermatozoa Function Index (SFI). Results: The ROC analysis was used to interpret the SFI values: SFI > 320 (normal), 290-320 (intermediate), and <290 (low). Then, this index was validated using 627 fresh semen samples from 25-to 60-year-old men at our ART center. Based on the World Health Organization criteria, 54.5% of the 627 sperm samples were normospermic, 8.8% showed oligo-astheno-teratospermia, and 36.6% had one or two abnormal parameters. According to the SFI values, 41% of sperm samples displayed normal expression, 55.9% low expression, and 4.1% intermediate expression. Only 57% of the 342 normospermic samples had normal SFI values and 37% had low SFI values. Among the 81 samples with stringent normal criteria (≥50 million/mL, ≥50% total motility, ≥14% normal morphology), 67.9% displayed normal SFI and 22.2% low SFI values. These findings suggest that even sperm with normal parameters may harbor dysfunctions. Conclusions: Our data highlight a gene signature with strong discriminatory power and promising diagnostic value for detecting subclinical sperm defects and improving male infertility assessment
Dévelοppement de stratégies thérapeutiques et diagnοstiques ciblant l’unité neurοvasculaire après une expοsitiοn à des agents οrganοphοsphοrés
No full textOP exposure, whether caused by organophosphate pesticides or nerve agents, represent a major public health concern due to their high toxicity and the lack of effective countermeasures to prevent long-term brain damage. These compounds irreversibly inhibit AChE, leading to excessive accumulation of ACh and cholinergic hyperactivation. This initial dysregulation triggers a cascade of secondary events involving the glutamatergic system, notably the overactivation of NMDAR, resulting in excitotoxicity, neuroinflammation, and persistent neurovascular alterations. Although currently recommended antidotes, such as atropine and oximes, reduce acute lethality, they fail to prevent the persistent neurological sequelae observed in exposed individuals.The aim of this thesis was to characterize the early and long-lasting mechanisms underlying OP-induced brain injuries and to evaluate innovative therapeutic approaches targeting alterations of the NVU. Using murine models exposed to low, non-convulsive OP doses, we demonstrate that even in the absence of overt clinical signs, OP exposure induces sustained disturbances in neuronal dynamics, increased BBB permeability, and impaired NVC. Our findings identify the tPA–NMDAR interaction as a key mechanism linking endothelial activation to neurovascular and functional impairments. Furthermore, we show that Glunomab, a monoclonal antibody selectively blocking the deleterious interaction between tPA and NMDAR, prevents early NVU alterations, restores cerebral hemodynamic regulation, and limits neuroinflammatory damage.Overall, these results propose a paradigm shift in the understanding of OP-induced brain injuries by revealing the NVU as a central target of OP toxicity. They pave the way for the development of innovative therapeutic strategies complementary to current treatments and highlight the translational potential of targeting the tPA–NMDAR pathway to mitigate long-term neurological sequelae.L’exposition aux OP, qu’ils soient utilisés comme POP ou comme NOP, constitue un problème majeur de santé publique en raison de leur forte toxicité et de l’absence de contremesures efficaces pour prévenir les atteintes cérébrales à long terme. Ces composés inhibent de manière irréversible l’AChE, ce qui entraîne une accumulation excessive d’ACh et une hyperactivation cholinergique. Cette dérégulation initiale induit une cascade d’événements secondaires impliquant le système glutamatergique, notamment une suractivation des NMDAR, responsable d’une excitotoxicité, d’une neuroinflammation et d’altérations neurovasculaires durables. Les antidotes actuellement recommandés, tels que l’atropine et les oximes, réduisent la létalité aiguë mais restent insuffisants pour prévenir les séquelles neurologiques persistantes observées chez les sujets exposés.L’objectif de ce travail de thèse était de caractériser les mécanismes précoces et durables impliqués dans les atteintes cérébrales induites par les OP et d’évaluer de nouvelles approches thérapeutiques ciblant les altérations de l’UNV. En utilisant des modèles murins exposés à de faibles doses d’OP, nous avons montré que, y compris en l’absence de signes convulsifs, l’exposition entraîne des perturbations prolongées de la dynamique neuronale, une augmentation de la perméabilité de la BHE et un dysfonctionnement du CNV. Nos travaux démontrent que l’interaction tPA–NMDAR constitue un mécanisme clé reliant l’activation endothéliale aux perturbations neurovasculaires et fonctionnelles. De plus, nous montrons que le Glunomab, un anticorps monoclonal bloquant spécifiquement l’interaction délétère entre le tPA et les NMDAR, prévient les altérations précoces de l’UNV, restaure la régulation hémodynamique cérébrale et limite les lésions neuro-inflammatoires.Dans l’ensemble, ces résultats proposent un changement de paradigme dans la compréhension des atteintes cérébrales induites par les OP en identifiant l’UNV comme une cible majeure de cette toxicité. Ils ouvrent la voie au développement de stratégies thérapeutiques innovantes, complémentaires des traitements actuels, et mettent en lumière l’intérêt translationnel de cibler la voie tPA–NMDAR pour limiter les séquelles neurologiques à long terme
Determination of the diastereomeric excesses of chiral flavonoids in organs of with two-dimensional supercritical fluid chromatography
No full textInternational audienceCitrus aurantium (bitter orange), is widely used in culinary preparations, food supplements, cosmetics and traditional medicine. Its bioactivity is mainly associated to two major glycosylated flavanones, naringin and neohesperidin, each comprising two diastereoisomers having different bioactivities. To possibly relate bioactivity to stereoisomeric composition, an analytical method was necessary.A two-dimensional supercritical fluid chromatography (SFC) method was used to measure diastereomeric excesses of the flavonoids in bitter orange organs, including flowers, leaves and fruits at different stages of maturity. The extracts were prepared with supercritical fluid extraction (SFE) with CO2, ethanol and water. SFE conditions were defined following a 3-factor Box-Behnken design of experiments. While neohesperidin was highly stable, with circa 100 % stereomeric excess in all samples, naringin was prone to racemization, especially in mature fruits.This study also examined the importance of using a sufficient mass of sample to obtain accurate and meaningful measurements, particularly when stereoisomers are concerne
Fréquences d’exposition aux principaux facteurs de risque biomécaniques d’usure professionnelle chez les femmes et les hommes dans la cohorte CONSTANCES
No full textInternational audienceIntroduction:As part of the 2023 pension reform in France, a fund for the prevention of occupational wear and tear (fonds pour la prévention de l'usure professionnelle, FIPU) was set up to prevent premature aging and musculoskeletal disorders. In accordance with French law, the FIPU takes into consideration exposure to three biomechanical criteria: manual handling of loads, painful positions at work, and mechanical vibrations. The aim of our study was to identify the occupational categories most exposed to the three FIPU criteria, as well as to another biomechanical risk factor for musculoskeletal disorders: repetitive work. Methods:The analyses are based on cross-sectional data from the French CONSTANCES cohort (Consultants des centres d'examens de santé). Exposure to the three FIPU criteria and to repetitive work were described according to occupational categories (based on the French nomenaculture for occupational groups [Familles professionnelles, FAPs]).Results: Among men, the FAPs most exposed to at least one of the three FIPU criteria were skilled construction workers (structural and finishing work: 95.8% and 88.1%) and metal workers (86.0%). Among women, the FAPs most impacted were home help personnel and cleaners (80.3%), assistant nurses (79.2%), and childcare assistants (77.1%). Adding the repetitive work factor increased the proportion of exposed workers, particularly among women, and highlighted new occupations, not obtained with the FIPU criteria alone. Discussion: This study provides precise quantitative data on exposure to biomechanical risk factors in France, differentiated by gender. In this sense, it helps to better identify the factors to consider for the prevention of occupational wear and tear.Introduction : Dans le cadre de la réforme des retraites de 2023 en France, un fonds pour la prévention de l’usure professionnelle (FIPU) a été créé pour limiter les expositions à trois critères : les manutentions manuelles de charges, les postures pénibles et les vibrations mécaniques. Cette étude vise à identifier les familles professionnelles les plus exposées aux trois critères du FIPU ainsi qu’à l’ajout d’un facteur de risque biomécanique supplémentaire (répétitivité). Méthode : Les analyses sont basées sur des données transversales de la cohorte CONSTANCES (Consultants des centres d’examens de santé). Les expositions aux trois critères du FIPU et à la répétitivité ont été décrites selon les familles professionnelles (FAP).Résultats : Les FAP les plus exposées à au moins un des trois critères du FIPU, chez les hommes, sont les ouvriers qualifiés du bâtiment (gros et second oeuvre : 95,8 % et 88,1 %) et du formage de métal (86,0 %). Chez les femmes, les FAP les plus touchées sont les aides à domicile/aides ménagères (80,3 %), les aides-soignantes (79,2 %) et les assistances maternelles (77,1 %). L’ajout du facteur répétitivité augmente la proportion d’exposés, notamment chez les femmes, et fait ressortir de nouveaux métiers comparativement à ceux obtenus avec les critères du FIPU.Discussion : Cette étude apporte un enrichissement en fournissant des données quantitatives précises sur l’exposition aux facteurs de risque biomécaniques en France, avec une différentiation selon le sexe. En ce sens, elle permet de mieux orienter les facteurs à considérer pour la prévention de l’usure professionnelle
Association of early doses of diuretics and nitrates in acute heart failure with 30 days outcomes: ancillary analysis of ELISABETH study
No full textInternational audienceAims The optimal dose of diuretics and nitrates for acute heart failure treatment remains uncertain. This study aimed to assess the association between intravenous nitrates and loop diuretics doses within the initial 4 h of emergency department presentation and the number of days alive and out of hospital (NDAOH) through 30 days. Methods This was an ancillary study of the ELISABETH stepped-wedge cluster randomized trial that included 502 acute heart failure patients 75 years or older in 15 French emergency departments. The primary endpoint was the NDAOH at 30 days. The total dose of intravenous nitrates and loop diuretics administered in the initial 4 h were each categorized into three classes: ‘no nitrate’, ‘> 0–16’, and ‘> 16 mg’ for nitrates and ‘< 60’, ‘60’, and ‘> 60 mg’ for diuretics. Secondary endpoints included 30-day mortality, 30-day hospital readmission, and hospital length of stay in patients alive at 30 days. Generalized linear mixed models were used to examine associations with the endpoints. Results Of 502 patients, the median age was 87 years, with 59% women. The median administered dose within the initial 4 h was 16 mg (5.0; 40.0) for nitrates and 40 mg (40.0; 80.0) for diuretics. The median NDAOH at 30 days was 19 (0.0–24.0). The adjusted ratios of the NDAOH were 0.88 [95% confidence interval (CI): 0.63–1.23] and 0.76 (95% CI: 0.58–1.00) for patients that received 60 and > 60 mg, respectively, compared with patients that received 40 mg or less of diuretics. Compared with patients who did not receive nitrates, the adjusted ratios of the NDAOH were 1.17 (95% CI: 0.82–1.67) and 1.45 (95% CI: 0.90–2.33) for patients who received 1–16 and > 16 mg, respectively. There was no significant association with any of the secondary endpoints. Conclusion In this ancillary analysis, there was no significant association between different doses of diuretics and nitrates with the NDAOH at 30 days. Point estimates and CIs may suggest that the optimal doses are less than 60 mg of diuretics, and more than 16 mg of nitrates in the first 4 h