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Optimization of freezing and thawing protocols for human ovarian tissue cryopreservation through thermophysical characterisation of freezing medium by Differential Scanning Calorimetry
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LXR pathway drives hormonal response intensity in polycystic ovary syndrome
No full textInternational audienceGonadotropin injections used to stimulate oocyte production during assisted reproductive technology (ART) procedures are associated with the risk of an abnormal response in predisposed patients suffering polycystic ovary syndrome (PCOS). Liver X receptors (LXR) pathway has been identified as key regulators during this process. This study explores the integration of the hormonal signals, cellular networks and molecular mechanisms linking sterol signaling with inflammation and immune infiltration. Pharmacological activation of LXR in a wild-type context protects against gonadotropin hyperstimulation mirroring the effect observed in LXR-deficient mice. Ovarian stimulation leads to immune cell infiltration orchestrated by granulosa cells in absence of LXR, resulting in an altered granulosa cell response to gonadotropin and enhanced inflammation. LXR controls inflammasome activity by regulating Thioredoxin Interacting Protein (TXNIP) gene expression in mural granulosa cells, thereby modulating IL1β production. This immune cell infiltration persists throughout ovulation in PCOS patients and is observed in cumulus oocytes complexes, highlighting the pivotal role of LXR path in regulating inflammatory processes during hormonal stimulation in ART procedures
Use of Disease-Modifying Therapies in Patients With Late-Onset Multiple Sclerosis
No full textInternational audienceBackground and objectives: The therapeutic strategy in patients with late-onset MS (LOMS) remains poorly defined. In this study, we aimed to evaluate both clinical and MRI outcomes between 2 cohorts of patients with relapsing-remitting LOMS treated or not yet treated.Methods: Patients with relapsing-remitting MS were included for the analysis if disease onset occurred after 55 years and if they had at least one follow-up visit. The primary outcome was time to first relapse between 2 matched groups of patients with LOMS (treated and not yet treated). Secondary outcomes were as follows: (1) time to first confirmed disability progression (CDP), (2) time to first progression independent of relapse activity (PIRA) event, (3) time to secondary progression (SPMS), (4) time to first MRI activity, and (5) serious infection incidence rates (IIRs). For the comparative analyses, we adopted a time-dependent propensity score matching approach.Results: A total of 881 patients fulfilled the inclusion criteria. The mean (SD) age at onset was 59.9 (4.43) years. After applying propensity score matching, 436 patients were matched. The mean (SD) follow-up duration was 5.2 (4.27) years in the treated group and 5.0 (3.86) years in the not-yet-treated group. Mean (SD) time to first relapse was significantly longer in the treated group compared with the not-yet-treated group (7.0 years [0.33] vs 5.4 years [0.33]; p = 0.001). Mean (SD) time to first MRI activity was significantly longer in the treated group (5.9 years [0.33] vs 5.0 years [0.33]; p = 0.049). However, the mean time to CDP, PIRA, or SPMS was not different between the 2 groups (difference = 0.32 years; p = 0.585 for CDP; difference = 0.40 years; p = 0.442 for PIRA; difference = -0.02 years; p = 0.952 for SPMS). No increase in serious IIRs was observed with an incidence rate ratio of 0.38 (95% CI 0.07-2.10, p = 0.265) in the never-treated group compared with the treated one.Discussion: This study demonstrates a beneficial effect of disease-modifying therapy (DMT) on disease activity in patients with LOMS but without significant impact on disability progression. Main limitations are linked to the challenge of data collection and to the baseline imbalances between the 2 groups.Classification of evidence: This study provides Class III evidence that in patients with LOMS, treatment with DMTs is associated with a longer time to first relapse compared with those not treated with DMTs
FLOT chemotherapy treatment affects adipocyte’s lipid metabolism: an in vitro study
No full textInternational audienceCachexia is a complex syndrome that is often associated with cancer. Chemotherapy, one of the main cancer treatments, worsens weight loss in cancer-induced cachexia. In this context, it is thought that fat loss precedes muscle loss, and that alterations in adipose tissue are associated with tumours. However, the effect of cancer treatment on adipose tissue is not well understood. This study aimed to evaluate the impact of chemotherapy alone on mature 3T3-L1 adipocytes to identify the mechanisms contributing to adipose tissue alteration. The murine cell line 3T3-L1, a model of mature adipocytes, was used in this study. After differentiation, cells were treated for 48 h with a chemotherapy cocktail called FLOT composed of 5-fluorouracil, leucovorin, oxaliplatin and docetaxel at two concentrations (FLOT 1X and 0.1X). The control group was treated with the vehicle of the chemotherapy cocktail. Viability, mitochondrial function and dynamics, lipid metabolism, and cellular stress were also evaluated. FLOT 1X chemotherapy significantly reduced viability of mature 3T3-L1 cells and inhibited lipid accumulation. Interestingly, while FLOT 1X treatment downregulated lipogenesis markers, FLOT 0.1X treatment upregulated some of them. Although, the treatment showed no effect on mitochondrial respiration or density, it significantly increased expression of oxidative stress and inflammation markers in adipocytes.This in vitro study provides the first evidence of FLOT chemotherapy's direct effects on healthy mature adipocytes. The results demonstrate significant treatment-induced reductions in cell viability along with dysregulation of both lipogenic and lipolytic pathways. These findings elucidate previously unrecognized mechanisms underlying adipose tissue dysfunction in cancer cachexia
Is leg-length discrepancy after total hip arthroplasty corrected accurately after revision? : functional outcomes and complication rate in 57 patients.
No full textInternational audienceAimsThe results of revision surgery to correct leg-length discrepancy (LLD) after total hip arthroplasty (THA) are not clear. Only two previous small series have been published dealing with this issue. The aim of this retrospective study of revision THAs for LLD was to determine the postoperative change in LLD, the functional outcomes, and whether obtaining equal leg lengths influenced function, as well as to report the complication rate and survival.MethodsThis multicentre study included 57 patients: 42 revisions for limb shortening and 15 for limb lengthening. LLD was measured on conventional radiographs. The Oxford Hip Score (OHS) and Forgotten Joint Score (FJS) were collected, along with the number of patients achieving the minimal clinically important difference (MCID) for the OHS.ResultsRevisions were carried out at a mean of 2.8 years after the initial THA. The median LLD decreased significantly from 7.5 mm (IQR 5 to 12) to 1 mm (IQR 0.5 to 2.5) at a mean follow-up of two years (SD 2.4) (p < 0.001). A total of 55 patients (96%) had < 5 mm LLD at follow-up and 12 (21%) had equal leg lengths. The complication rate was 26%. There were 13 mechanical complications (eight periprosthetic femoral fractures, two stem loosenings, two acetabular loosenings and one dislocation), and one periprosthetic infection. Patient satisfaction was high, with a median FJS of 79% (IQR 64 to 98), and 37/48 patients (77%) reached the OHS MCID. Lengthening procedures had significantly worse function postoperatively than shortening procedures (38% vs 91% of patients achieving the OHS MCID (p < 0.001)). Survival was 85% (95% CI 77.9 to 92.5) at two years and 77% (95% CI 66.3 to 87.1) at 4.6 years using re-revision as the endpoint.ConclusionWhen LLD after THA remains symptomatic after conservative management, revision THA should be considered. Revision THA for LLD improved the medium-term functional outcomes with a high patient satisfaction rate, especially for shortening procedures. However, the complication rate, particularly of periprosthetic femoral fracture, was high
Anti-CD19 CAR T-cell therapy for patients with Richter transformation: A LYSA study from the DESCAR-T registry
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Impaired cytotoxic function and exhausted phenotype of natural killer cells in VEXAS syndrome
No full textInternational audienceVEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an autoinflammatory disorder caused by acquired somatic UBA1 mutations in hematopoietic stem cells, affecting peripheral myeloid and natural killer (NK) cells. Given the high rate of severe infections observed in VEXAS patients, we hypothesized that NK cell dysfunction contributes to this increased susceptibility. We conducted a comprehensive immune characterization of peripheral NK cells in patients with VEXAS (n=40), patients with autoinflammatory diseases without UBA1 mutations (n=22), and elderly gender-matched healthy controls (HCs) (n=16). Multiparameter phenotyping was performed using CyTOF, scRNAseq, whole blood stimulation assays and in vitro NK cell cytotoxic assay. Peripheral NK cells in VEXAS were quantitatively and qualitatively impaired. Mass cytometry revealed reduced frequencies of mature cytotoxic CD56dim NK cells and an expansion of the CD56high CD16dim subset. NK cells exhibited features of exhaustion, including increased PD-1 expression, and reduced levels of cytotoxic markers such as NKp46 and CD8α. scRNAseq analysis showed decreased signatures of cytotoxicity and IL-2 and IFN-γ production, alongside increased inflammatory signatures. Whole blood stimulation assays confirmed impaired IL-2, IFN-γ, and granzyme B production following TLR3, TLR4, and TLR7/TLR8 agonist stimulation. Extended NK phenotyping by flow cytometry confirmed reduced activating receptors' expression and impaired IFN-γ production in VEXAS. Moreover, in vitro UBA1 inhibitors impaired NK cell cytotoxic capacity and promote cell death. Finally, reduced NK cell frequencies were independently associated with an increased risk of severe infections. These findings suggest that NK cell dysfunction in VEXAS syndrome contributes to increased susceptibility to severe infections
Corticosteroids in immunocompromised ICU patients with severe COVID-19: a multicenter retrospective study
No full textInternational audienceImmunocompromised patients were excluded most of the time from trials testing corticosteroids in COVID-19. This study aimed to assess the associations between early corticosteroid use and (1) mortality at day 60, and (2) the occurrence of nosocomial infections in immunocompromised patients with severe COVID-19 admitted to the ICU. It was a multicentre retrospective study, achieved in French ICUs of the Outcomerea™ network and medical ICUs of 4 other hospitals in France. This study included immunocompromised patients admitted to an ICU between January 1, 2020, and August 31, 2022, for severe COVID-19, with an ICU stay of more than 2 days. Patients were classified as receiving early corticosteroid therapy if they were given steroids within the first 5 days following ICU admission. Each patient was categorized into one of four immunosuppression subgroups: ‘corticosteroid therapy,’ ‘monocytic alteration,’ ‘cellular immunosuppression,’ or ‘humoral immunosuppression.’ Survival analyses were performed, and confounding by indication was addressed using propensity score weighting with overlap. 383 patients were included, 50 were into the no-early-corticosteroids group and 333 in the early-corticosteroids group. In the overlap cohort, 118 were included (46 in the non-early-corticosteroids and 72 in the early-corticosteroids group). There was no association with day-60 mortality (IPTWoverlapHR = 0.97, 95% CI [0.51; 1.85], p = 0.92). There was also no association with the occurrence of nosocomial infections (IPTWoverlapSubHR = 2.59, CI 95% [0.77; 8.7], p = 0.13). We report that steroids had no benefit on mortality in immunocompromised patients admitted to ICU for severe COVID-19
Avis de l'Anses relatif à l’évaluation des effets indésirables liés à la consommation de compléments alimentaires contenant du « Garcinia cambogia »
No full textCitation suggéréeAnses (2025). Avis relatif à l’évaluation des effets indésirables liés à la consommation de compléments alimentaires contenant du « Garcinia cambogia » (saisine 2020-SA-0047). Maisons-Alfort : Anses, 69 p.L’Anses s’est autosaisie le 31 mars 2020 pour évaluer les risques liés à la consommation de compléments alimentaires contenant du « Garcinia cambogia ».CONTEXTE ET OBJET DE LA SAISINEGarcinia cambogia Desr. est une plante traditionnellement utilisée en Asie en tant que condiment dans des préparations culinaires et pour des usages médicinaux. Cette plante est autorisée dans les compléments alimentaires dans plusieurs pays de l’Union européenne.En France, l’utilisation de plantes dans les compléments alimentaires est encadrée par le décret n°2006-352 du 20 mars 2006 relatif aux compléments alimentaires et par l’arrêté du 24 juin 2014 établissant la liste des plantes, autres que les champignons, autorisées dans les compléments alimentaires et les conditions de leur emploi, ci-après dénommé « arrêté plantes » [1]. Garcinia cambogia Desr. ne figure pas sur cette liste mais elle est inscrite, du fait de la reconnaissance mutuelle entre les Etats membres au titre de l’article 16 du décret n°2006-352, sous le nom erronéde Garcinia gummi-gutta (L.) Roxb [2], sur la liste consolidée par la Direction générale de la concurrence, de la consommation et de la répression des fraudes (DGCCRF) [3] et publiée en janvier 2019 ainsi que sur le site Compl'Alim mis en place par la Direction générale de l’alimentation (DGAL) en 2024 [4].Les extraits de Garcinia cambogia Desr. sont présents dans des compléments alimentaires visant la perte de poids. Ses propriétés amaigrissantes sont attribuées à l’acide (-)-hydroxycitrique (AHC) présent dans le péricarpe du fruit. Cette substance fait actuellement l’objet d’une évaluation par l’Autorité européenne de sécurité des aliments (Efsa) dans le cadre de la procédure prévue à l’article 8 du règlement 1925/2006 du parlement et du conseil du 20 décembre 2006 concernant l'adjonction de vitamines, de minéraux et de certaines autres substances aux denrées alimentaires.Dans le cadre de son dispositif de nutrivigilance, l’Anses a reçu en 2019, le signalement d’un cas d’hépatite fulminante mortelle associée à la consommation du complément alimentaire Slim Metabol®, contenant notamment du Garcinia cambogia Desr. Au vu de la sévérité des effets indésirables et de l’imputabilité très vraisemblable de ce produit, ce signalement a été publié sur le site de l’Anses5. La revue bibliographique menée à l’occasion de l’expertise de ce cas, a mis en évidence l’implication majeure de Garcinia cambogia Desr. dans la survenue d’hépatites fulminantes similaires à partir de 2005.Depuis la mise en place du dispositif de nutrivigilance en 2009, trente-huit signalements d’effets indésirables susceptibles d’être liés à la consommation de compléments alimentaires contenant du Garcinia cambogia Desr. ont été portés à la connaissance de l’Anses.Aux États-Unis et au Canada, des signalements d’atteintes hépatiques, musculaires, cardiaques et neurologiques parfois graves ont été rapportés quelques années après la commercialisation de produits multi-ingrédients contenant du Garcinia cambogia Desr.. Cela a d’ailleurs conduit, en 2009, la Food and Drug Administration (FDA) à demander le retrait de Garcinia cambogia Desr. de la composition de ces produits. En France, l’Agence nationale de sécurité du médicament et des produits de santé (ANSM) a interdit en 2012 « l’importation, la préparation, la prescription et la délivrance de préparations magistrales, officinales et hospitalières composées de Garciniacambogia, ainsi que la prescription, la délivrance et l’administration à l’homme de la plante Garcinia cambogia ».Au vu de ces données, l’Anses et compte tenu de la mission de nutrivigilance qui lui a été confiée par la loi du 21 juillet 20096, l’agence a décidé de s’autosaisir afin de dresser un état des lieux des connaissances relatives aux propriétés physico-chimiques de Garcinia cambogia Desr. ainsi qu’une analyse des cas cliniques publiés dans la littérature ou rapportés dans le cadre de dispositifs de vigilance, afin de tirer les conclusions de cet ensemble de signaux.[1] Arrêté du 24 juin 2014 établissant la liste des plantes, autres que les champignons, autorisées dans les complémentsalimentaires et les conditions de leur emploi : https://www.legifrance.gouv.fr/loda/id/JORFTEXT000029254516[2] Cette désignation erronée ne correspond à aucune plante[3]https://www.economie.gouv.fr/files/files/directions_services/dgccrf/securite/produits_alimentaires/Complement_alimentaire/CA_Liste_PlantesAutres_janvier2019.pdf?[4] https://compl-alim.beta.gouv.fr/entreprise
Coarse-Grained Insights into Insulin Aspart Adsorption on Plasticized Poly(vinyl chloride) (PVC) Surfaces
No full textInternational audienceInsulin aspart, a biomacromolecule essential for diabetes treatment, is known to interact with polymer-based drug delivery systems. Plasticized polyvinyl chloride (PVC) materials, widely used in medical infusion tubing, contribute significantly to insulin aspart loss due to adsorption. However, experimental studies alone cannot distinguish the individual contributions of plasticizers and the PVC matrix in this process. To address this, we employed coarse-grained molecular dynamics (Martini 3) simulations to investigate protein-surface interactions over extended timescales, providing deeper insights into adsorption mechanisms. Our results revealed a strong preference for insulin aspart adsorption onto PVC regions rather than plasticizers, explaining the experimentally observed lack of adsorption differences between plasticized and non-plasticized PVC surfaces. Additionally, we explored the formation of the insulin aspart adsorption layer for both monomeric and hexameric forms, further characterizing the thermodynamics of the adsorption process