Delivery of Anticancer Drugs Using Microbubble-Assisted Ultrasound in a 3D Spheroid Model.

Tumor spheroids are promising three-dimensional (3D) in vitro tumor models for the evaluation of drug delivery methods. The design of noninvasive and targeted drug methods is required to improve the intratumoral bioavailability of chemotherapeutic drugs and reduce their adverse off-target effects. Among such methods, microbubble-assisted ultrasound (MB-assisted US) is an innovative modality for noninvasive targeted drug delivery. The aim of the present study is to evaluate the efficacy of this US modality for the delivery of bleomycin, doxorubicin, and irinotecan in colorectal cancer (CRC) spheroids. MB-assisted US permeabilized the CRC spheroids to propidium iodide, which was used as a drug model without affecting their growth and viability. Histological analysis and electron microscopy revealed that MB-assisted US affected only the peripheral layer of the CRC spheroids. The acoustically mediated bleomycin delivery induced a significant decrease in CRC spheroid growth in comparison to spheroids treated with bleomycin alone. However, this US modality did not improve the therapeutic efficacy of doxorubicin and irinotecan on CRC spheroids. In conclusion, this study demonstrates that tumor spheroids are a relevant approach to evaluate the efficacy of MB-assisted US for the delivery of chemotherapeutics.

Reform of the first year of medical studies and diversification of student profiles in France: an unmet need?

OBJECTIVES: To determine whether the reform of the first year of medical studies implemented in September 2020 in France met its objective of diversifying the profiles of students admitted to second year at the faculty of medicine at the University of Tours. METHODS: Single-centered, retrospective study, covering students who passed the first year of medical studies between 2018 and 2022. Student profiles originating from three different entry gateways (PACES, PASS and L.AS) to the second year of medical studies were compared. RESULTS: One thousand four hundred and seventy-nine students over five promotions were included (806 in PACES, 329 in PASS, 198 in L.AS). The ratio of students who had obtained a baccalaureate with high or highest honors was significantly higher in PACES (85%) and PASS (96%) compared to L.AS (66%; p < 0.001). These differences were related to increased student intake via a standard pass in L.AS (21% compared to 3.2% in PACES and 0.9% in PASS) (p < 0.001). In terms of geographical origin, the proportion of students residing in regions outside the University City area increased significantly in L.AS (11%) compared to PACES (1.7%) and PASS (3.3%) (p < 0.001). The mean number of parents from the white-collar and knowledge professional category was significantly higher in PACES (0.91) and PASS (1.06) compared to L.AS (0.80; p < 0.001). CONCLUSION: Students with a scientific background and who obtained highest honors in their high school diploma, remain the standard in PACES and PASS. Diversification of student profiles was achieved only within the L.AS gateway, which represented 42% of total second year admissions during the post-reform year. Student profile diversification was therefore a partially achieved objective and follow up studies of future promotions is needed to assess the medium and long-term impact of the reform. Particular attention should be paid to the future of these students who have different profiles between L.AS and PASS to determine whether these changes will have any impact in the quality of healthcare for the French population.

The Conserved YPX3L Motif in the BK Polyomavirus VP1 Protein Is Important for Viral Particle Assembly but Not for Its Secretion into Extracellular Vesicles.

The BK polyomavirus (BKPyV) is a small DNA non-enveloped virus whose infection is asymptomatic in most of the world's adult population. However, in cases of immunosuppression, the reactivation of the virus can cause various complications, and in particular, nephropathies in kidney transplant recipients or hemorrhagic cystitis in bone marrow transplant recipients. Recently, it was demonstrated that BKPyV virions can use extracellular vesicles to collectively traffic in and out of cells, thus exiting producing cells without cell lysis and entering target cells by diversified entry routes. By a comparison to other naked viruses, we investigated the possibility that BKPyV virions recruit the Endosomal-Sorting Complexes Required for Transport (ESCRT) machinery through late domains in order to hijack extracellular vesicles. We identified a single potential late domain in the BKPyV structural proteins, a YPX3L motif in the VP1 protein, and used pseudovirions to study the effect of point mutations found in a BKPyV clinical isolate or known to ablate the interaction of such a domain with the ESCRT machinery. Our results suggest that this domain is not involved in BKPyV association with extracellular vesicles but is crucial for capsomere interaction and thus viral particle assembly.