Agir Pour les Maladies Chroniques

Chimeric antigen receptor (CAR)-T-cell therapy is a revolutionary approach in immunotherapy that has shown remarkable success in the treatment of blood cancers. Many preclinical studies are currently underway worldwide to extend the CAR-T-cell therapy benefits to a broad spectrum of cancers, using rodent models. Alternative in vivo platforms are essential for overcoming the drawbacks associated with rodent models, including immunodeficiency in humanized models, ethical concerns, extended time requirements, and cost. In this work, we used the chicken chorioallantoic membrane (CAM) assay to evaluate the in vivo efficacy of cluster-of-differentiation 19 (CD19)-targeting CAR-T cells expressing a second-generation CAR construct against human lymphoma derived from the Raji cell line. Our results confirm the efficacy of selected CAR-T cells on tumor growth, metastasis, and angiogenesis. Further, the chicken embryo has an intrinsic active immune system. Therefore, the dialog between CAR-T cells and endogenous immune cells, as well as their participation in the tumor challenge, has also been studied. In conclusion, our study demonstrates that the chicken CAM assay provides a relevant in vivo, 3Rs (Replacement, Reduction and Refinement)-compliant new approach methodology (NAM), which is well-suited for the current needs of preclinical research on CAR-T-cell therapy.

Salvage brachytherapy (BT) after definitive irradiation for prostate cancer is gaining increasing interest, although many areas of uncertainty remain. We established a large national retrospective cohort including all patients treated with salvage prostate BT for isolated prostatic local relapse after definitive radiotherapy between 2006 and 2022 in seven French expert centers. A total of 266 patients were included. At initial diagnosis, 42% of patients presented with high-risk disease. Primary irradiation consisted of external beam radiotherapy (EBRT) in 78% of cases, most commonly delivered with a 3D conformal technique (51%), with a median dose of 74Gy. Median PSA at relapse was 3.7ng/mL. Salvage BT was performed using low-dose-rate (LDR) permanent iodine seed implantation in 63% of patients and high-dose-rate (HDR) brachytherapy in 37%. Seventy percent of patients were treated with whole-gland irradiation, while the remainder received a focal approach. In 34.5% of cases, androgen deprivation therapy (ADT) was combined with salvage BT. After a median follow-up of 60.1months, 135 (50.7%) of patients experienced biochemical relapse. Median biochemical progression-free survival (bPFS) was 40.0months. On multivariate analysis, initial risk group (high-risk: HR=1.64, 95% CI [1.13-2.37], p=0.008), BT technique (HDR: HR=2.14, 95% CI [1.41-3.26], p=0.0004), and treated volume (focal vs. whole-gland: HR=2.14, 95% CI [1.23-3.73], p=0.007) were significantly associated with bPFS. Late grade 3 gastrointestinal and genitourinary toxicities occurred in 3% and 14% of patients, respectively. Salvage BT provides encouraging disease control with an acceptable toxicity profile. Careful patient selection remains essential.

The study reports the initial experience in transarterial embolization (TAE) using an ethiodized oil-based emulsion for patients with refractory shoulder pain, focusing on safety, pain reduction, and functional improvement. This is a retrospective, multicenter study including 23 patients treated with TAE using an ethiodized oil-based emulsion between April 2021 and May 2024. Clinical outcomes were assessed using visual analog scale (VAS) scores for pain (0-100mm) and QuickDASH (0-100) scores (Disability of the Arm, Shoulder and Hand) for functionality. Adverse events were recorded and classified. The primary etiology of shoulder pain was adhesive capsulitis (61%), followed by bursitis (39%). Median follow-up was 87days (range: 27-1088days). Mean VAS score decreased from 65mm (± 22) at rest, and 82mm (± 13) during mobilization to 30mm (± 27) at rest, and 36mm (± 24) during mobilization at the last follow-up (p < 0.05). Mean QuickDASH score improved from 67 (± 17) pre-procedure to 43 (± 25) post-procedure (p < 0.05). No major complications occurred, and minor adverse events included one radial artery thrombosis (4%) and one puncture site hematoma (4%). TAE of the shoulder using an ethiodized oil-based emulsion is safe and effective, warranting further investigation in larger studies.

BackgroundThe appropriate antithrombotic regimen for patients with chronic coronary syndrome who are at high atherothrombotic risk and receiving long-term oral anticoagulation remains unknown.MethodsWe conducted a multicenter, double-blind, randomized, placebo-controlled trial in France involving patients with chronic coronary syndrome who had undergone a previous stent implantation (>6 months before enrollment) and were at high atherothrombotic risk and currently receiving long-term oral anticoagulation. The patients were randomly assigned in a 1:1 ratio to receive aspirin (100 mg once daily) or placebo; all the patients continued to receive their current oral anticoagulation therapy. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularization, or acute limb ischemia. The key safety outcome was major bleeding.ResultsA total of 872 patients underwent randomization; 433 were assigned to the aspirin group, and 439 to the placebo group. The trial was stopped early at the advice of the independent data and safety monitoring board after a median follow-up of 2.2 years because of an excess of deaths from any cause in the aspirin group. A primary efficacy outcome event occurred in 73 patients (16.9%) in the aspirin group and in 53 patients (12.1%) in the placebo group (adjusted hazard ratio, 1.53; 95% confidence interval [CI], 1.07 to 2.18; P=0.02). Death from any cause occurred in 58 patients (13.4%) in the aspirin group and in 37 (8.4%) in the placebo group (adjusted hazard ratio, 1.72; 95% CI, 1.14 to 2.58; P=0.01). Major bleeding occurred in 44 patients (10.2%) in the aspirin group and in 15 patients (3.4%) in the placebo group (adjusted hazard ratio, 3.35; 95% CI, 1.87 to 6.00; P<0.001). A total of 467 and 395 serious adverse events were reported in the aspirin group and placebo group, respectively.ConclusionsAmong patients with chronic coronary syndrome at high atherothrombotic risk who were receiving an oral anticoagulant, the addition of aspirin led to a higher risk of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularization, or acute limb ischemia than placebo, as well as higher risks of death from any cause and major bleeding. (Funded by the French Ministry of Health and Bayer Healthcare; ClinicalTrials.gov number, NCT04217447.)

Abstract Tissue wounding causes rapid mechanical changes in the epithelium, but how these changes affect intracellular organization remains unclear. Using the Drosophila embryonic epidermis, we show that wounding induces a fast, transient compaction of chromatin and its detachment (“dewetting”) from the nuclear lamina in about half of the wound-edge cells. Within minutes, chromatin in these cells re-expands and re-associates with the lamina (“re-wetting”). This reversible chromatin–lamina dewetting is mechanosensitive, requiring both the LINC complex and intracellular calcium. During compaction, calcium is stored within chromatin and is later released during ATR-mediated expansion and lamina re-wetting. Chromatin re-expansion then triggers actomyosin contraction and promotes tissue repair through Jun kinase activation, straightening of the wound edge, and supracellular actin ring formation. Together, our findings reveal a multiscale mechanosensitive mechanism by which tissue-scale mechanical changes induce a reversible chromatin-lamina dewetting, leading to cellular contraction and initiation of tissue repair.

BackgroundObstructive sleep apnea (OSA) pathogenesis, clinical manifestations, and consequences vary markedly among patients. Yet OSA heterogeneity goes largely unaddressed in current management pathways, which are characterized by high treatment failure rates of ∼50%. Growing knowledge of OSA pathogenesis has stimulated new lines of investigation for therapies targeted to specific underlying mechanisms or “endotypes.” OSA endotypes include the primary anatomic predisposition to pharyngeal collapse, as well as “nonanatomic” mechanisms of low arousal threshold, unstable control of breathing (high loop gain), and impaired pharyngeal dilator muscle function. Identification of interindividual differences in OSA endotypes and disease expression, or “OSA phenotypes,” offers promise for a more targeted approach to OSA management in which appropriate treatments are tailored to individual needs. However, these concepts have largely been limited to the research setting, and more evidence is needed to support clinical translation.GoalsTo outline the rationale for clinical use, challenges, and key research priorities required to translate OSA endophenotyping for delivery of a more tailored approach to improve patient care and outcomes.MethodsAn international multidisciplinary working group with expertise in OSA epidemiology, pathophysiology, diagnostics, and treatments was convened. The group met at the American Thoracic Society 2024 International Conference to discuss the current state of OSA endophenotyping and required research objectives. This research statement, authored with input from all members, summarizes the group discussion, identified key areas, and research priorities.ResultsThe working group identified research priorities that cover the spectrum from discovery to translation/implementation, including technical standards, validation, establishment of clinical cutoffs and minimal clinically important differences, generalizability across diverse populations, stability and reproducibility of measurement, prospective study design and conduct, clinical utility, and impact analysis.ConclusionsThis research statement provides a road map of the opportunities and key steps required to generate the evidence necessary to translate OSA endophenotyping concepts into clinical care at scale.