Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy

Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy.Peer reviewe

PRISE EN CHARGE DIAGNOSTIQUE ET THERAPEUTIQUE DES CALCULS URETERAUX

ANGERS-BU Médecine-Pharmacie (490072105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Evaluation rétrospective de la radiothérapie adjuvante à la prostatectomie radicale, dans le traitement des adénocarcinomes prostatiques localement avancés (à propos de 146 cas)

La prise en charge de l'adénocarcinome de prostate localement avancé traité initialement par prostatectomie radicale n'est pas consensuelle. L'enjeu est cependant considérable du fait d'un taux de récidive biologique à 10 ans avoisinant 80%, avec prés de 40% de patients métastatiques . L'analyse de nos pratiques et de nos résultats était donc nécessaire. Matériel et Méthode: 146 patients pT3a et pT3b opérés dans le Maine et Loire entre 1995 et 2001 ont été étudiés de façon rétrospective. Une irradiation de la loge de prostatectomie pouvait être proposée en traitement adjuvant à la chirurgie. Résultats: 29 patients ont eu une irradiation conformationnelle adjuvante de 56 Gy en moyenne. Le suivi médian était de 103 mois. La survie sans récidive biologique à 10 ans des patients irradiés de façon adjuvante (52,9%) était significativement différente de celle des 117 patients non irradiés en adjuvant (28,5%). La survie sans métastase et la survie spécifique n'étaient pas différentes statistiquement. Conclusion: Ce travail avait pour but d étudier les résultats de la radiothérapie adjuvante dans notre pratique quotidienne et de contribuer au débat, en confirmant sur une étude de petite taille mais de longue durée, le bénéfice net de l irradiation adjuvante en terme de survie sans récidive biologique sans amélioration de la survie sans métastase ou de la survie spécifique. Aujourd hui l irradiation adjuvante devrait être proposée aux patients marges positives et être optionnelle pour les patients marges négatives , en fonction d autres facteurs prédictifs de récidive tels que l atteinte des vésicules séminales et le score de Gleason supérieur à 7.ANGERS-BU Médecine-Pharmacie (490072105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Impact of retrograde flexible ureteroscopy and intracorporeal lithotripsy on kidney functional outcomes

ABSTRACT Objective: The aim of the study was to evaluate renal function and to identify factors associated with renal function deterioration after retrograde intrarenal surgery (RIRS) for kidney stones. Materials and Methods: We retrospectively analyzed patients with renal stones treated by RIRS between January 2010 and June 2013 at a single institute. We used the National Kidney Foundation classification of chronic kidney disease (CKD) to classify Glomerular Filtration Rate (GFR) in 5 groups. The baseline creatinine level was systematically pre-operatively and post-operatively evaluated. All patients had a creatinine blood measurement in June 2013. A change toward a less or a more favorable GFR group following RIRS was considered significant. Results: We included 163 patients. There were 86 males (52.8%) and 77 females (47.3%) with a mean age of 52.8±17 years. After a mean follow-up of 15.5±11.5 months, median GFR was not significantly changed from 84.3±26.2 to 84.9±24.5 mL/min (p=0.675). Significant renal function deterioration occurred in 8 cases (4.9%) and significant renal function amelioration occurred in 23 cases (14.1%). In univariate analysis, multiple procedures (p=0.023; HR: 5.4) and preoperative CKD (p=0.011; HR: 6.8) were associated with decreased renal function. In multivariate analysis these factors did not remain as predictive factors. Conclusion: Stone management with RIRS seems to have favorable outcomes on kidney function; however, special attention should be given to patients with multiple procedures and preoperative chronic kidney disease

Different dose rate-dependent responses of human melanoma cells and fibroblasts to low dose fast neutrons.

PURPOSE: To analyze the dose rate influence in hyper-radiosensitivity (HRS) of human melanoma cells to very low doses of fast neutrons and to compare to the behaviour of normal human skin fibroblasts. MATERIALS AND METHODS: We explored different neutron dose rates as well as possible implication of DNA double-strand breaks (DSB), apoptosis, and energy-provider adenosine-triphosphate (ATP) levels during HRS. RESULTS: HRS in melanoma cells appears only at a very low dose rate (VLDR), while a high dose rate (HDR) induces an initial cell-radioresistance (ICRR). HRS does not seem to be due either to DSB or to apoptosis. Both phenomena (HRS and ICRR) appear to be related to ATP availability for triggering cell repair. Fibroblast survival after neutron irradiation is also dose rate-dependent but without HRS. CONCLUSIONS: Melanoma cells or fibroblasts exert their own survival behaviour at very low doses of neutrons, suggesting that in some cases there is a differential between cancer and normal cells radiation responses. Only the survival of fibroblasts at HDR fits the linear no-threshold model. This new insight into human cell responses to very low doses of neutrons, concerns natural radiations, surroundings of accelerators, proton-therapy devices, flights at high altitude. Furthermore, ATP inhibitors could increase HRS during high-linear energy transfer (high-LET) irradiation

Prognostic value of renal vein and inferior vena cava involvement in renal cell carcinoma.

International audienceBACKGROUND: The prognostic significance of venous tumor thrombus extension in patients with renal cell carcinoma (RCC) is a matter of many controversies in the current literature. OBJECTIVE: To evaluate the prognostic role of inferior vena cava (IVC) involvement in a large series of pT3b and pT3c RCCs. DESIGN, SETTING, AND PARTICIPANTS: A total of 1192 patients from 13 European institutions underwent a radical nephrectomy for pT3b and pT3c RCC between 1982 and 2003. The patients were evaluated in a retrospective manner. Age, gender, clinical symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, TNM stage, tumor size, adrenal invasion, perinephric fat invasion, histological type, and Fuhrman grade were reviewed. The log-rank and Cox uni- and multivariate regression analyses were used to evaluate prognostic factors for overall survival. MEASUREMENTS: Overall survival and prognostic factors for overall survival in patients with RCC extending to the renal vein (RV) or to the IVC. RESULTS AND LIMITATIONS: The median follow-up was 61.4 mo (56.3-66.5 mo). The mean age was 63.2 yr. The mean tumor size was 8.9 cm. Group 1 (Gr 1) included 933 patients with a renal vein tumor thrombus (78.3%), Group 2 (Gr 2) included 196 patients with a subdiaphragmatic IVC tumor thrombus (16.4%), and Group 3 (Gr 3) included 63 patients with a supradiaphragmatic IVC tumor thrombus (5.3%). Median survival was 52 mo for Gr 1, 25.8 mo for Gr 2, and 18 mo for Gr 3. In univariate analysis, Gr 1 had a significantly better overall survival than Gr 2 (p<0.001) and Gr 3 (

Age at diagnosis is a determinant factor of renal cell carcinoma-specific survival in patients treated with nephrectomy.

International audienceOBJECTIVE: Based on combined data for 4880 patients, 2 previous studies reported that advanced age is a predictor of increased renal cell carcinoma-specific mortality (RCC-SM). We explored the effect of age in cubic spline analyses to identify the age groups with the most elevated risk for renal cell carcinoma (RCC). METHODS: Our study included 3595 patients from 14 European centres who had partial or radical nephrectomies. We used the Kaplan-Meier method to compile life tables, and we performed Cox regression analyses to assess RCC-SM. Covariates included age at diagnosis, sex, TNM (tumour, node, metastasis) stage, tumour size, Fuhrman grade, symptom classification and histological subtype. RESULTS: Age ranged from 10 to 89 (mean 63, median 67) years. The median duration of follow-up was 2.9 years. The median survival for the cohort was 13.4 years. Stage distribution was as follows: 1915 patients (53.3%) had stage I disease, 388 (10.8%) had stage II, 895 (24.9%) had stage III and 397 (11.0%) had stage IV disease. In multivariate analyses, we coded age at diagnosis as a cubic spline, and it achieved independent predictor status (p < 0.001). The risk of RCC-SM was lowest among patients younger than 50 years. We observed an increase in RCC-SM until the age of 50, at which point the level of risk reached a plateau. We observed a second increase among patients aged 75-89 years. We found similar patterns when we stratified patients according to the 2002 American Joint Committee on Cancer (AJCC) stages. CONCLUSION: The effect of age shows prognostic significance and indicates that follow-up and possibly secondary treatments might need to be adjusted according to the age of the patient