HAL Université de Tours
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Human papillomavirus infection is a favorable prognostic factor for patients with stage I-IVA esophageal squamous cell carcinoma but not adenocarcinoma
No full textInternational audienceWith its two distinct histological subtypes [squamous cell carcinoma (SCC) and adenocarcinoma (ADC)], its rising incidence in both high- and low-income countries and its elevated 5-year mortality rate, esophageal cancer still represents a significant global health challenge. While the implication of high-risk human papillomaviruses (HPV) in both anogenital and head and neck carcinogenesis is well established, the association between these mucosotropic viruses and esophageal cancers has been a subject of debate for nearly two decades. In an effort to resolve this unclear situation and advance precision medicine, a large cohort of 378 patients diagnosed with locally advanced esophageal carcinoma [SCC (n=226) and ADC (n=152)] over a 20-year period was collected and thoroughly characterized (at clinical, histopathologic, immunologic and virologic levels). In total, about one third (48/152, 31.58%) of ADC were positive for high-risk HPV DNA, but a transcriptionally active infection was only detected in 17.76% of samples. Surprisingly, only a minority of malignant cells (typically less than 20%) showed viral transcripts, and HPV positivity had no prognostic significance for patients with esophageal ADC. Regarding SCC, 12.39% (28/226) of tissue specimens were HPV positive, with viral/transcriptional activity observed in virtually 100% of neoplastic cells. These HPV-positive neoplasms more frequently exhibited basaloid differentiation, non-aberrant p53 expression, and were significantly less associated with tobacco/alcohol use than their virus-negative counterparts. Importantly, uni-multivariate analyses indicated that HPV positivity was a reliable predictor of improved progression-free survival in patients with esophageal SCC. Taken together, our findings indicate that, unlike in ADC where testing for HPV is unnecessary, a dual classification system for esophageal SCC based on HPV status could/should be considered, with potential implications for personalized and optimized treatment strategies
Magnetic resonance imaging as a readout of CLN5 gene therapy efficacy in sheep
No full textInternational audiencePurpose Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of rare inherited neurodegenerative disorders caused by mutations in one of 13 ceroid lipofuscinosis neuronal ( CLN ) genes. The diseases share a common set of symptoms, including motor and cognitive dysfunction, progressive loss of vision, and seizure activity. A naturally occurring model of CLN5 NCL exists in New Zealand Borderdale sheep, which exhibit similar clinical disease and post‐mortem pathology to the human disease. Recent trials of concurrent intracerebroventricular and intravitreal gene therapy in sheep with CLN5 disease confirmed the therapeutic efficacy of this approach. Given the documented natural history of brain volume changes, detected by MRI, in sheep with CLN5 disease, the current study sought to utilize MRI as both a longitudinal readout and cross‐sectional measure of therapeutic efficacy in treated sheep. Method Sheep treated at a pre‐symptomatic timepoint underwent five T1‐weighted structural MRI scans between 5 and 18 months of age. Sheep treated at early and advanced symptomatic disease stages underwent a single MRI at 18 months of age. All scans from treated sheep were compared to historical healthy control and affected untreated sheep at each age. Finding Pre‐symptomatic treated sheep showed growth in intracranial volume at a comparable rate to healthy control sheep over the course of the study. Whilst grey matter volume decreased and cerebrospinal fluid volume increased in treated sheep, this was to a much smaller degree than in untreated affected sheep. The majority of the cortical regions assessed showed stable volumes over the course of the study, with the notable exception of the cerebellum. Both early and advanced symptomatic treated sheep showed intracranial volumes comparable to untreated affected sheep at 18 months of age. However, when individual tissue types were assessed, grey and white matter were significantly larger, and cerebrospinal fluid was significantly smaller in early symptomatic sheep compared to untreated affected sheep, while the same volumes in advanced symptomatic treated sheep were comparable to untreated affected sheep. Cortical regions assessed showed an age‐at‐treatment and dose effect. Conclusion This study has demonstrated that MRI, a clinically relevant outcome measure, can be successfully utilized to assess therapeutic efficacy in a large animal model of CLN5 NCL, both in a longitudinal study and a cross‐sectional study when robust natural history data is available for comparison
Optimization of Adcitmer, a Monomethyl-Auristatin E bearing antibody-drug conjugate for the treatment of CD56-expressing cancers
No full textInternational audienceThe cell adhesion protein CD56 has been identified as a potential therapeutic target in several solid tumors and hematological malignancies. Recently, we developed a CD56-directed antibody-drug conjugate (ADC), called Adcitmer and demonstrated its antitumor properties in preclinical models of the rare and aggressive skin cancer Merkel cell carcinoma (MCC). The present study aims to further optimize Adcitmer to overcome the therapeutic limitations observed with previously evaluated CD56-targeting ADCs, which were partially related to toxic effects on leukocytes. To this end, we aimed to avoid interaction of Adcitmer with immune cells via Fc gamma receptor (FcγR) binding. Since glycosylation is essential for FcγR binding, an aglycosylated form of Adcitmer was generated and evaluated on human leukocytes and MCC cell lines using cell death (annexin V/ 7-aminoactinomycine D ) and proliferation (2,3-Bis-(2-methoxy-4Nitro-5-sulfophenyl)-2H-tetrazolium-5carboxanilide) assays. Finally, the therapeutic performance of Adcitmer and its aglycosylated form was assessed in an MCC xenograft mouse model. Investigating the Adcitmer interaction with immune cells demonstrated that it is mostly mediated by Fc recognition. Accordingly, Adcitmer aglycosylation led to reduced immune cell toxicity and strikingly also to improved therapeutic performance even in an MCC xenograft model using immunodeficient mice. Our study suggests that aglycosylated Adcitmer should be considered as a therapeutic option in patients with advanced MCC or other CD56-positive tumors
Atypical Homogeneous Rheology of a High-Entropy Metallic Glass Challenges Standard Free Volume Models
No full textInternational audienceMetallic glasses (MGs) exhibit exceptional mechanical properties but their application is often limited by brittleness. At elevated temperatures near the glass transition (T), they undergo homogeneous viscoplastic deformation, a regime commonly described using free volume (FV) theory. Despite its prevalence, the quantitative accuracy and applicability of FV models, particularly for transient behaviors, remain subjects of investigation. This study examines the homogeneous rheology of a LaCeYNiAl High-Entropy MG (HEMG) between 475 K and 490 K, and critically assesses the relevance of two prominent FV model formulations. Experimental characterization included dynamic mechanical analysis and uniaxial tensile tests across various strain rates. The tensile data were subsequently analyzed using two elasto-viscoplastic constitutive frameworks incorporating distinct FV evolution kinetics: Spaepen’s original formulation (Model 1) and the bimolecular annihilation kinetics proposed by Van den Beukel/Sietsma (Model 2). Our analysis reveals that Model 1, when applied to steady-state flow, yields physically inconsistent negative parameters, questioning its validity for homogeneous deformation. Model 2 demonstrates better qualitative agreement with experimental stress-strain curves but fails to accurately reproduce stress overshoot features. Furthermore, fitting Model 2 necessitates unphysically low Young’s modulus values and results in unusual negative apparent activation energies for key kinetic parameters, suggesting limitations in the model structure (e.g., neglecting explicit viscoelasticity) or potentially unique behavior in HEMGs. These findings highlight significant shortcomings of standard FV models in quantitatively capturing the homogeneous deformation of this HEMG, particularly transient effects, and underscore the need for more refined constitutive descriptions
Review - Restricted access to pasture and inadequate grazing in ruminants and equines
No full textThis review summarises the knowledge on the benefits and the risks associated with pasture access in ruminants and equines from a welfare point of view. The consequences of preventing pasture access are also described along with recommandations to ensure adequate pasture access
Targeted metabolite analysis: comparison of DBS and serum by LC-MRM
No full textInternational audienceLes échantillons de type Dried Blood Spot (DBS) constituent une méthode d’échantillonnage et de conservation à la fois pratique et polyvalente. Cette matrice est devenue un outil incontournable dans de nombreuses applications telles que le dépistage néonatal, les tests de maladies infectieuses, l’analyse génétique, etc. Le DBS est désormais largement utilisé comme alternative au prélèvement sanguin, en raison de son caractère peu invasif, de sa facilité de transport et de son coût réduit. La plateforme dispose d’une méthode métabolomique ciblée validée pour l’analyse du sérum humain. Face à l’intérêt croissant de l’utilisation de la matrice DBS, nous prévoyons d’adapter et de mettre en œuvre une méthode, transférée depuis la plateforme de Tours, afin d’élargir le catalogue d’analyses disponibles sur la plateforme. Nous proposons une méthode analytique permettant de quantifier plusieurs familles de métabolites : les acides aminés, dérivés du tryptophane, acides organiques et acides biliaires. Les échantillons sont préparés sur des plaques 96 puits comprenant deux dérivatisations distinctes. L’analyse est ensuite réalisée par LC-MRM à l’aide d’un système Agilent 6495d fonctionnant en mode positif pour les acides aminés et les dérivés du tryptophane, et en mode négatif pour les acides organiques et les acides biliaires. Le traitement de données est assuré par le logiciel Skyline.Cette étude va permettre de comparer les profils métaboliques ciblés et quantitatifs obtenus à partir des matrices DBS et sérum, afin d’identifier leurs différences et similitudes pour chacune des quatre familles de composés analysées. Les résultats détaillés de cette comparaison seront présentés sur le poster
Adapting to climate change: example of the use of the Explore2 ensemble of climate and hydrological projections in assessing the vulnerability to climate change at local scale
No full textInternational audienceTo be effective, measures to adapt to climate change must consider both present and future local specificities. However, the scale on which climate and hydrological models are produced does not correspond to the scales used by managers and operators. In 2023, the Agence de l’eau Rhône Méditerranée Corse (AE-RMC) updated its Basin Plan for Adaptation to Climate Change. This work was an opportunity to illustrate how climate and hydrological projections can be integrated into public policies for adaptation to climate change at local level. An evaluation of vulnerability to climate change was carried out for all AE-RMC subbasins. Four issues were studied: soil drying, resource availability, resource quality and biodiversity of aquatic environments. For each issue, vulnerability was assessed by combining climate and/or hydrological projection data (exposure factor) with data describing the current state (sensitivity factor) of the watersheds to provide a vulnerability score. Exposure factors were estimated for 2050 using 11 climate models and 2 hydrological models from the project Explore2. As a result, all but two subbasins are highly to very highly vulnerable for at least 1 issue, and 55% of the sub-basins are highly to very highly vulnerable for 3 or more issues. This work is one of the possible uses for operational purposes of the Explore2 results and shows how climate and hydrological projection data can be used to drive public policies for adapting to climate change.Pour être efficaces, les mesures d’adaptation au changement climatique doivent tenir compte des spécificités locales tantactuelles qu’à venir. Cependant l’échelle de rendu des modélisations climatiques et hydrologiques ne correspond pas auxéchelles employées par les gestionnaires. En 2023, l’Agence de l’eau Rhône Méditerranée Corse (AERMC) a actualisé son Plan de Bassin d’Adaptation au Changement Climatique. Ces travaux ont été l’occasion d’illustrer comment les données de projections climatiques peuvent être intégrer dans la conduite des politiques publiques d’adaptation au changement climatique à l’échelle locale. Un diagnostic de vulnérabilité au changement climatique a été réalisé sur l’ensemble des bassins versants du SDAGE de l’AERMC. Quatre enjeux ont été étudiés : l’assèchement des sols, la disponibilité de la ressource, la qualité de la ressource et la biodiversité des milieux aquatiques. Pour chaque enjeu, la vulnérabilité a été évaluée en croisant des données de projections climatiques et/ou hydrologiques (facteur d’exposition) issues de 11 modèles climatiques et de 2 modèles hydrologiques du projet EXPLORE2 à l’horizon 2050 et des données décrivant l’état actuel (facteur de sensibilité) des bassins versants pour fournir un score de vulnérabilité variant de 1 (peu vulnérable) à 5 (très vulnérable). Ce travail est une des exploitations possibles à des fins opérationnelles des premiers résultats d’EXPLORE2 disponibles en 2023 et montre comment des données de projections climatiques et hydrologiques peuvent être exploitées pour conduire des politiques publiques d’adaptation au changement climatique
