Evaluation of the dystrophin carboxy-terminal domain for micro-dystrophin gene therapy in cardiac and skeletal muscles in the DMDmdx rat model

Duchenne muscular dystrophy (DMD) is a muscle wasting disorder caused by mutations in the gene encoding dystrophin. Gene therapy using micro-dystrophin (MD) transgenes and recombinant adeno-associated virus (rAAV) vectors hold great promise. To overcome the limited packaging capacity of rAAV vectors, most MD do not include dystrophin carboxy-terminal (CT) domain. Yet, the CT domain is known to recruit α1- and β1-syntrophins and α-dystrobrevin, a part of the dystrophin-associated protein complex (DAPC), which is a signaling and structural mediator of muscle cells. In this study, we explored the impact of inclusion of the dystrophin CT domain on ΔR4-23/ΔCT MD (MD1), in DMDmdx rats, which allows for relevant evaluations at muscular and cardiac levels. We showed by LC-MS/MS that MD1 expression is sufficient to restore the interactions at a physiological level of most DAPC partners in skeletal and cardiac muscles, and that inclusion of the CT domain increases the recruitment of some DAPC partners at supra-physiological levels. In parallel, we demonstrated that inclusion of the CT domain does not improve MD1 therapeutic efficacy on DMD muscle and cardiac pathologies. Our work highlights new evidences of the therapeutic potential of MD1 and strengthens the relevance of this candidate for gene therapy of DMD

Impact de la tomoscintigraphie myocardique à la tétrofosmine synchronisée à l'électrocardiogramme sur le diagnostic de la maladie coronaire chez les patients obèses (résultats du centre caennais au sein de l'étude TECOPO)

CAEN-BU Médecine pharmacie (141182102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Influence of CA 15-3 blood level and doubling time on diagnostic performances of 18F-FDG PET in breast cancer patients with occult recurrence

International audienc

Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model

International audienceCharacterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat mode

Incidental uptake of 18F-fluorocholine (FCH) in the head or in the neck of patients with prostate cancer

Background. Positron emission tomography-computed tomography (PET/CT) with 18F-fluorocholine (FCH) is routinely performed in patients with prostate cancer. In this clinical context, foci of FCH uptake in the head or in the neck were considered as incidentalomas, except for those suggestive of multiple bone metastases

F-18 FDG PET/CT Findings in Pulmonary Necrotizing Sarcoid Granulomatosis.

Necrotizing sarcoid granulomatosis (NSG) is a rare systemic disease that was described by Liebow in 1973. Dyspnea and chest pain may be present, as in our first patient; however, 25% of patients are asymptomatic, as our second patient. The typical radiographic findings are nonspecific: single or multiple lung opacities, with common involvement of the pleura. To the best of our knowledge, fluorodeoxyglucose (FDG) PET has only been reported in one case of NSG, which was atypical as it occurred in an adolescent. We report 2 cases, confirming that the lesions of NSG are FDG positive, showing a typical pattern of multiple bilateral lung nodules (imaged with PET/CT in 1 case). FDG imaging has a potential role when this distribution is observed on CT, to guide the surgical biopsy and show the actual extent of the disease

Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents

International audienceEmerging knowledge regarding B cells in organ transplantation has demonstrated that these cells can no longer be taken as mere generators of deleterious Abs but can also act as beneficial players. We previously demonstrated in a rat model of cardiac allograft tolerance induced by short-term immunosuppression an accumulation in the blood of B cells overexpressing inhibitory molecules, a phenotype also observed in the blood of patients that spontaneously develop graft tolerance. In this study, we demonstrated the presence in the spleen of regulatory B cells enriched in the CD24intCD38+CD27+IgD2IgM+/low subpopulation, which are able to transfer donor-specific tolerance via IL-10 and TGF-b1–dependent mechanisms and to suppress in vitro TNF-a secretion. Following anti-CD40 stimulation, IgD2IgM+/low B cells were blocked in their plasma cell differentiation pathway, maintained high expression of the inhibitory molecules CD23 and Bank1, and upregulated Granzyme B and Irf4, two molecules described as highly expressed by regulatory B cells. Interestingly, these B cells recognized specifically a dominant donor Ag, suggesting restricted specificity that could lead to a particular B cell response. Regulatory B cells were not required for induction of tolerance and appeared following Foxp3+CD4+CD25+ regulatory T cells, suggesting cooperation with regulatory T cells for their expansion. Nevertheless, following transfer to new recipients, these B cells migrated to the allograft, kept their regulatory profile, and promoted local accumulation of Foxp3+CD4+CD25+ regulatory T cells. Mechanisms of regulatory B cells and their cell therapy potential are important to decipher in experimental models to pave the way for future developments in the clinic

18F-fluorocholine PET/CT in patients with occult biochemical recurrence of prostate cancer: Detection rate, impact on management and adequacy of impact. A prospective multicentre study.

To prospectively evaluate the clinical impact and the diagnostic performance of FCH-PET/CT in patients with occult biochemical recurrence of prostate cancer (PCa).Results of 179 patients (mean PSA = 7.5ng/mL) with negative/inconclusive results of pelvic-MRI and of bone-scintigraphy were analysed. To determine the impact of FCH-PET/CT on diagnostic thinking and on patient management, the referring physicians prospectively filled-in a 1st and 2nd questionnaire related to patient's planned management before and after FCH-PET/CT. Based on data from a 6-month follow-up after FCH-PET/CT, an independent assessor blinded to results of FCH-PET/CT determined the adequacy of management changes motivated by FCH-PET/CT.FCH-PET/CT localised foci evocative of recurrent PCa in 59% (105/179) of patients. Results of FCH-PET/CT motivated a change in scheduled patient management in 56% (100/179) of patients; which was considered as adequate in 89% (89/100) of patients. FCH-PET/CT also led to the detection of lung cancer in two patients.FCH PET/CT is a powerful tool to localise the sites of occult biochemical recurrence of PCa, leading to an adequate management change in half of patients