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Clémence Cardon-Quint, L’argent de l’école. Histoire du budget de l’Éducation nationale depuis 1945.
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Phase I(b) study evaluating the safety and efficacy of intratumoral agonistic anti-CD40 (selicrelumab) in combination with anti-PD-L1 (atezolizumab) in patients with refractory or relapsed B-cell lymphoma (ITSELF trial)
No full textInternational audienceBACKGROUND: The efficacy of immune checkpoint blockade therapy requires pre-existing antitumor immunity. Defective antigen presentation during the priming phase can reduce the generation of tumor-specific T cells, which are necessary during the effector phase and subsequent tumor elimination. We propose an in situ immunization strategy to enhance direct tumor antigen presentation by the lymphoma B cells via cluster of differentiation (CD)40 stimulation in order to sensitize B-cell lymphoma to programmed cell death protein 1/programmed death-ligand 1 (PD-L1) blockade therapy.MATERIALS AND METHODS: ITSELF is a multicenter, open-label, dose-escalation phase Ib trial of intratumoral selicrelumab, an agonistic anti-CD40 monoclonal antibody, every 3 weeks for three cycles in combination with intravenous atezolizumab, an antagonistic anti-PD-L1 monoclonal antibody, at 1200 mg every 3 weeks for three cycles followed by intravenous atezolizumab monotherapy for a total of 12 months in patients with relapsed/refractory B-cell lymphoma. RESULTS: Two patients with follicular lymphoma and two patients with diffuse large B-cell lymphoma were enrolled at the first dose level of 1 mg intratumoral selicrelumab. Those four patients received the three cycles of intratumoral selicrelumab in combination with intravenous atezolizumab. Patients did not develop severe adverse events related to the drugs or the intratumoral procedures. No or low-grade adverse events were reported and related to atezolizumab or to the combination therapy. All patients discontinued the treatment because of disease progression according to Lugano 2014 criteria on their first positron emission tomography scan disease evaluation at the end of cycle 3 (week 9). The trial was stopped prematurely because of issues with selicrelumab drug supply.CONCLUSION: The combination of 1 mg of intratumoral selicrelumab and 1200 mg of intravenous atezolizumab was safe for patients with relapsed/refractory B-cell lymphoma and led to some tumor stabilization or regression, although it did not result in objective tumor response
Version [2.0]-[NeoCoMM: Neocortical neuro-inspired computational model for realistic microscale simulations]
No full textInternational audienceIn this new version of the NeoCoMM (Neocortical Computational Microscale Model) software, we present an updated neuroinspired computational model of the cortical column that includes neuroplasticity and a transcranial Electric Stimulation (tES) modeling platform. The neuroplasticity update consists of three types of long- term plasticity models based on the calcium dynamics that are incorporated into the principal cells (PCs) of the network. For tES, a new panel in the GUI was added to simulate the electric field parameters allowing the user to simulate the impact of both Direct (tDCS) and Alternating (tACS) Current Stimulation on the network dynamics
Chemical fate in vitro: A physiological biokinetic (PBK) model for cell-based assays
No full textInternational audienceIn vitro toxicology assays are widely used in the context of toxicology to study in vivo outcomes and to improve mechanistic understanding of toxic responses. For this purpose, a better characterization of actual exposure and the fate of chemicals within the cellular test system is required. The present study aimed to develop a novel model, INSIGHT (In Silico Guide for Harmonized in vitro Testing), that integrates physiological and physi-cochemical parameters to better describe chemical fate in vitro and to guide assay design. The newly devel-oped model, integrating the dynamic features of the Virtual Cell Based Assay model with the partitioning framework of the Virtual In Vitro Distribution model, was calibrated using both a large literature dataset and original experimental data, comprising a total of 42 chemicals and 7 commonly used cell lines: HepaRG, HepG2, 3T3 Balb/c, PC12, MCF-7, RTgill-W1, and HEK293. These cell lines were selected for their diverse tissue and species origins, metabolic capacities, and potential for functional transport mechanisms, known to influence chemical kinetics. The INSIGHT model demonstrated flexibility and robustness across a range of cell lines when the parameters driving their metabolic activity or functional transport were informed. The present study underscores the pivotal function of logPow determination and the necessity for accurate calibration of partition coefficients, permeability, and metabolic processes to account for variability across cell lines and tested chemicals. This approach supports and facilitates enhanced experimental design and advancing quan-titative in vitro-to-in vivo extrapolation (qIVIVE) in toxicology and strengthens next generation risk assessment (NGRA) workflows
Clinical Phenotypes of Critically Ill Patients with COVID-19 Infected with Omicron: A Nationwide Prospective Cohort Study
No full textInternational audienceINTRODUCTION: The clinical presentation of critically ill patients with coronavirus disease 2019 (COVID-19) has evolved significantly with the emergence of the Omicron variant. Current intensive care unit (ICU) admissions involve patients with diverse comorbidities and immune statuses, highlighting the need to redefine homogeneous phenotypic subgroups within this population. This study aimed to characterize distinct clinical phenotypes among critically ill patients with COVID-19 and acute respiratory failure. METHODS: This multicenter prospective substudy of the SEVARVIR cohort included adult patients from 39 French ICUs between December 2021 and October 2024 with acute respiratory failure and infected with the Omicron variant. Clustering analysis was conducted using Kohonen’s self-organizing maps (SOMs) and validated with ClinTrajan, two unsupervised clustering methods, to identify homogeneous patient phenotypes. RESULTS: During the study period, 777 patients with Omicron infection were included, and 7 distinct clinical clusters were identified. Clusters 1 and 2 included patients with metabolic and cardiovascular comorbidities. Cluster 3 featured younger, mildly ill patients with isolated chronic respiratory failure, while cluster 4 comprised older male patients with isolated respiratory failure. Cluster 5 included patients with isolated hematologic malignancies, cluster 6 patients with multiorgan failure, and cluster 7 organ transplant recipients, with high severity scores and impaired renal function. ICU management varied substantially across clusters. Patients in clusters 5 and 7 had the highest requirements for organ support, with frequent use of invasive mechanical ventilation, vasopressors (cluster 6), and renal replacement therapy (cluster 7). Dexamethasone and tocilizumab were most commonly prescribed in cluster 4 (91.3% and 30.2%, respectively). Mortality at day 28 varied significantly across clusters, ranging from 13.1% in cluster 3 to 41.1% in cluster 6. CONCLUSIONS: This clustering analysis highlights, for the first time, the clinical heterogeneity of critically ill patients infected with Omicron, identifying seven distinct clusters with varying clinical presentations, management strategies and outcomes. These findings underscore the relevance of a phenotype-driven approach to support personalized treatment strategies and guide future clinical trials. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05162508. A Graphical Abstract is available for this article
Helicene-Azulene Conjugates: Synthesis, Photophysical Properties and Proton-Induced Chiroptical Switching
No full textInternational audienceThe synthesis of 4,13-dimethoxy-carbo[6]helicene derivatives substituted at positions 2,15 by either 2-azulene (H-2-azu) or 6-azulene (H-6-azu) units is presented. The photophysical and chiroptical properties of these new helicene-azulene derivatives have been examined in details. Both helical constitutional isomers H-2-azu and H-6-azu exhibit strong electronic circular dichroic responses in the azulene absorption region and reversible chiroptical switching upon protonation/deprotonation. Furthermore, although very weak, emission was also observed and was analyzed as originating from the S(1) excited state, i.e., obeying the Kasha rule, which is not common in azulene derivatives. Theoretical calculations helped confirm these observations. Finally, these systems revealed efficient chemical acid-base triggered chiroptical switching activity, showing notably a strong red shift upon protonation
Long-term Survival of Midurethral Mesh Slings for Women with Stress Urinary Incontinence
No full textInternational audienceBACKGROUND AND OBJECTIVE: Midurethral sling (MUS) use for stress urinary incontinence (SUI) has declined because of controversies. However, there is little evidence on the long-term prevalence of MUS reoperation. The aim of this study was to examine long-term removal and reoperation rates among women with MUS. METHODS: This national retrospective cohort study included all female patients aged ≥18 yr with a first MUS insertion for SUI in all French public hospitals and private practices between January 1, 2013, and September 30, 2022. Patients were followed until January 1, 2023. The primary outcome was the MUS removal rate. Secondary outcomes were new MUS insertion and any other surgery for SUI. Cox regression models were used to assess potential factors associated with MUS removal. KEY FINDINGS AND LIMITATIONS: The study included 217 326 women with a first MUS insertion. There were 5851 MUS removals and 9521 new MUS insertions. Most removals occurred within the first year (58%). The MUS removal rate was 2.7% at 10 yr. There were fewer removals after transoboturator insertion than after retropubic insertion. Alcohol consumption, smoking, and obesity were associated with MUS reoperation. At 10 yr, the rate of new MUS insertions was 4.5% and the rate of any other surgeries was 2.8%. CONCLUSIONS AND CLINICAL IMPLICATIONS: These findings may help in counseling patients on decision-making for SUI treatment. PATIENT SUMMARY: One treatment option for stress urinary incontinence (SUI) in women is insertion of a mesh sling. We looked at the rates of sling removal and reoperation among women treated for SUI in the French population. We found that after 10 years, only 2.7% of cases needed sling removal, 4.5% needed a new sling inserted without removal of the previous sling, and 2.8% needed another type of surgery. These results will help patients in choosing the correct treatment for SUI
Professionnels des transformations pédagogiques dans l'enseignement supérieur : contexte, enjeux, perspectives
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From Show Programmes to Data: Designing a Workflow to Make Performing Arts Ephemera Accessible Through Language Models
No full textMany heritage institutions hold extensive collections of theatre programmes, which remain largely underused due to their complex layouts and lack of structured metadata. In this paper, we present a workflow for transforming such documents into structured data using a combination of multimodal large language models (LLMs), an ontology-based reasoning model, and a custom extension of the Linked Art framework. We show how vision-language models can accurately parse and transcribe born-digital and digitised programmes, achieving over 98% of correct extraction. To overcome the challenges of semantic annotation, we train a reasoning model (POntAvignon) using reinforcement learning with both formal and semantic rewards. This approach enables automated RDF triple generation and supports alignment with existing knowledge graphs. Through a case study based on the Festival d'Avignon corpus, we demonstrate the potential for large-scale, ontology-driven analysis of performing arts data. Our results open new possibilities for interoperable, explainable, and sustainable computational theatre historiography
Design, synthesis, structural and theoretical investigation of novel aminonaphthol-based Betti derivatives with antioxidant activity
No full textInternational audienceIn this study, three new Betti-base derivatives were synthesized via a green and efficient one-pot multicomponent reaction under solvent-free conditions. The compounds were structurally characterized by spectroscopic techniques (FT-IR, NMR, HRMS), single-crystal X-ray diffraction, and supported by DFT calculations. Their antioxidant potential was evaluated using DPPH, ABTS, and ferric-phenanthroline assays. Crystallographic analysis revealed significant non-covalent interactions contributing to crystal packing stability, while theoretical investigations provided insights into electronic descriptors (HOMO-LUMO gap, electrophilicity, chemical hardness) and radical stabilization mechanisms through bond dissociation energy (BDE) and Fukui functions. Among the synthesized aminonaphthol derivatives, compound (1) exhibited promising antioxidant properties, correlating with its favorable electronic and structural parameters. This work demonstrates the synergy between green synthesis, crystallography, and quantum chemistry in the development of potential bioactive agents