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1.94 Å structure of synthetic α-synuclein fibrils seeding MSA neuropathology
No full textInternational audienceMultiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown etiology, typically affecting individuals aged 50-60 and leading to patient death within a decade 1-3 . Characterized by the presence of oligodendroglial intracellular aggregates (GCIs) primarily composed of fibrillar alpha-synuclein (aSyn) 4-8 , formation of MSA neuropathology presents similarities to prion propagation 9,10 . While previous investigations have scrutinized fibrils extracted from MSA brains 11 , their "protein-only" replication was questioned 12 and their capacity to induce GCIs in animal models was not explored. Conversely, the synthetic fibril strain 1B 13,14 assembled from recombinant human aSyn self-replicates autonomously in vitro and induces GCIs in mice 15 , suggesting relevance to MSA. Here we report the high-resolution structural analysis of the 1B fibrils revealing similarities with human brain extracted MSA aSyn filaments, particularly the lack of a specific Thioflavin T (ThT) binding pocket 16 . In addition, 1B causes sustained intracerebral GCI spread over the years, prompt lethality in transgenic mice, and transmission of inclusion pathology to wild-type animals after crude brain homogenate inoculation. This points to an underlying prion-like seeding process which we demonstrate in situ using correlative light-electron microscopy. Our findings underscore structural features of aSyn fibrils pivotal for MSA pathogenesis and provide insights for therapeutic development
Second primary cancers and hormonal therapies for prostate cancer: A nested case–control study
No full textInternational audienceIntroduction: (Pre-)clinical studies have not ruled out a potential risk of second primary cancer (SCP) under the effect of some new androgen receptor pathway inhibitors (ARPIs), especially enzalutamide (ENZ).Methods: Using the French health reimbursement claims database (Système National des Données de Santé), we designed a case-control study nested in a 2013-2020 cohort of new users of androgen-deprivation therapy. The cases were patients with a first diagnosis of SPC, identified beyond 12 months following cohort entry and up to December 31st, 2021; up to 10 controls were matched per case, based on age and cohort entry date. The main analysis focused on patients who had not switched to a different ARPI. Applying a one-year lag time, we determined the most frequent and longest cumulative exposure patterns to abiraterone (ABI) or ENZ and estimated the odds ratios.Results: The cohort comprised 147 092 patients, including 7928 cases and 78 554 controls eligible for analysis. The SPCs mainly involve the digestive organs, the urinary tract, or the lungs. Recent and short exposure to ENZ was associated with SPC: OR 1.7, 95% CI [1.2-2.4]. Recent one full year of exposure to ABI, as well as full-year plus part of the second year, was associated with SPC: OR 1.8 [1.2-2.7] and 2.3 [1.3-4.0], respectively.Discussion/conclusion: SPC cases were mainly observed among recently exposed patients, which could be linked to a detection bias. The insufficient number of patients exposed over many years means that no definitive conclusions can be drawn
Unlocking the Gates: A Novel Diagnostic Molecule for Quantifying Efflux Levels in Gram‐Positive Bacteria
No full textInternational audienceAbstract Efflux‐mediated antibiotic resistance poses a significant global threat, affecting diverse bacterial species. Clinicians recognize the danger of efflux mechanisms during antibiotic treatment, yet precise diagnostic tools remain unavailable. The antibiogram currently infers abnormal efflux pump activity in clinical isolates, which is subsequently confirmed through transcriptomic or genomic analysis. This study harnesses the colorimetric, fluorescence, and solubility properties of phenazinium derivatives to develop a rapid protocol for detecting bacterial efflux. Among several synthesized phenazinium compounds, the compound demonstrating differential MIC in Staphylococcus efflux mutants and exhibiting appropriate physicochemical properties is selected. A diagnostic protocol is developed using the selected compound to assess efflux levels, categorized as no, weak, or strong, through colorimetry and spectroscopy techniques. Testing on Gram‐positive efflux mutants and clinical Staphylococcus isolates further validates the approach. In‐silico docking analysis confirms the interaction between the chosen compound and the NorA efflux pump in S. aureus . Flow cytometry is employed to re‐evaluate the detection assays. The developed molecule and protocol represent the first known method to evaluate efflux levels in any Gram‐positive species through a streamlined and user‐friendly process. This pioneering test significantly advances the epidemiological analysis of efflux mechanisms and enables more informed therapeutic decision‐making, leading to more effective treatment
Structural Variety in Calcium Metal-Organic Frameworks with a Tetratopic Carboxylate Ligand
No full textInternational audienceThe solvothermal synthesis of three new calcium-based metal-organic frameworks (MOFs) employing the tetratopic carboxylate ligand, 4,4′,4″,4‴-(naphthalene-2,3,6,7-tetrayl)tetrabenzoate (NTTB) is reported. 1:These have distinct structures and compositions depending on the solvent used in synthesis. The crystal structures of the materials were elucidated through single-crystal X-ray diffraction (SC-XRD) analysis, along with a solvate of the acid form of the ligand. Sample purity was confirmed via powder XRD (PXRD), and thermal stability was assessed using thermogravimetric analysis (TGA). The resulting crystal architectures were analysed in detail with respect to the ligand binding modes, the connectivity of the calcium centres, the ligand conformation and hydrogen bonding. Notably, a solventdependent structural connectivity was observed: while the structures all contain six-coordinate Ca, substituting DMA with ethanol in synthesis induced a change in the MOF building units from discrete calcium nodes in 1 to infinite chains in 2 and interrupted chains in 3.</div
A Randomized clinical trial evaluating the impact on survival and quality of life of 177Lutetium[Lu]-edotreotide versus everolimus in patients with neuroendocrine tumors of the lung and thymus: the LEVEL study (GETNE T-2217)
No full textInternational audienceBackground: Everolimus is the only approved therapy for patients with advanced neuroendocrine tumors (NET) of lung and thymus and new treatment options are urgently needed. Expression of somatostatin receptor 2 (SSTR2) is frequently seen in functional imaging in lung-NETs opening the opportunity to treat SSTR2 positive patients with radioligand therapies (RLT). Retrospective data suggest a potential meaningful benefit of RLT directed to SSTR2 in lung-NET patients.Methods: The LEVEL trial is a randomized, open-label, phase III international trial of 177Lu-edotreotide versus everolimus in patients with progressive, locally advanced or metastatic, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin. Patients could be treatment-naïve or have progressed (PD) on somatostatin analogues or ≤ 2 additional systemic treatments. Prior RLT or mTOR inhibitors are not permitted. Eligible patients are randomly assigned 3:2 to 6 cycles of 177Lu-edotreotide (total administered activity 7.5 ± 0.7 GBq / cycle) or to oral everolimus 10 mg once daily until PD or unacceptable toxicity. Only patients with positivity in somatostatin receptor imaging will be included. CT or MRI scans are performed every 12 weeks until PD. Blood samples are analyzed at baseline, at 1st tumor assessment, and at PD for pharmacodynamic endpoints. Archival tumor tissue samples will be analyzed for ancillary studies. The primary endpoint is progression-free survival (PFS) according to RECIST v1.1 based on local investigator assessment. Secondary endpoints include overall survival, overall response rate, safety, and quality of life (EORTC QLQ-C30). The expected sample size is 120 patients to demonstrate statistical significant risk reduction of 46.4% (HR = 0.536) in PFS with the experimental treatment using an overall 5% two-sided alpha error with 80% power. An interim PFS analysis was included using the Lan-DeMets with O'Brian-Fleming-like boundaries.Discussion: The LEVEL trial will investigate if 177Lu-edotreotide has the potential to be incorporated as a standard treatment option for patients with NETs from the lung and Thymus
« Procédure disciplinaire conventionnelle et maintien de la référence à la notion de garantie de fond : un premier indice »
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« Présomption du caractère professionnel des SMS envoyés depuis un téléphone mis à disposition par l’employeur »
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Droit de la peine. Concours - Combinaison de mécanismes de réduction au maximum légal et de confusion facultative de peine (Cass. crim., 14 nov. 2024, n° 23-85.703, B : JurisData n° 2024-020228)
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Life cycle assessment of an innovative process assisted by pressurized CO2 for direct recycling of lithium-ion battery positive electrode production scraps
No full text"ADC - Accord Couperin / American Chemical Society (2024-2026)"International audienceWith global lithium-ion battery (LIB) production on the rise, production scraps, constituting 5 to 30 wt % of the total manufacturing output are expected to remain a major waste stream until at least 2030. These scraps present a significant recycling challenge, necessitating the development of effective and sustainable solutions. In this study, we conduct a life cycle assessment (LCA) of an innovative CO2-assisted direct recycling process for LIB-positive electrode production scraps. Using NMC622 (LiNi0.6Mn0.2Co0.2O2) positive electrode material as a case study, this paper describes the environmental benefits and impacts of the recovery of this material with direct recycling compared to other conventional treatments (incineration, pyrometallurgy, and hydrometallurgy). Lab-scale modeling identifies energy consumption and solvent usage as key environmental hotspots. A scale-up framework is applied to provide valuable insights and guide the sustainable development of this emerging technology. Eco-design strategies and benchmarking indicate that direct recycling has the potential to reduce environmental impacts; however, advancements in process energy efficiency and material recovery rates are necessary to ensure its competitiveness with existing recycling methods and its ability to meet industry quality standards