Phenotypic and genomic characterization as predictors of DMD 45 to 55 multi-exon skipping therapy

International audienceDuchenne and Becker muscular dystrophy (DMD and BMD) are X-linked myopathies characterized by a progressive muscular dystrophy with or without cardiomyopathy. As described in literature, 63% of DMD patients are eligible to a multi-exon skipping therapy, thus becoming BMD patients with exons 45 to 55 deletion (BMDdel45-55). Precision medicine approaches are currently in development and/or clinical testing. Interestingly, emerging regulatory actors as long non-coding RNA (lncRNA) are localized in 44 and 55 introns (Bovolenta et al., 2012). The specific neo-introns of each BMDdel45-55 patient could create or modify the lncRNA and/or RNA non-coding sequences and result in a various clinical outcome. Here we present a population of 54 "skip-equivalent" BMDdel45-55 patients. The objective is to identify modifier factors involved in phenotypic variability in these patients. We performed first a phenotypic characterization showing that 100% patients have BMD phenotype. Interestingly, 67% display the first signs age <16 y.o. The most disabling complains are the walking/running difficulties (65 %) and in 16 patients 50% have dilatative cardiomyopathy. Then we established the profile of lncRNA presence in 38/54 patients at genomic level in healthy subjects, muscle biopsies of BMDdel45-55 and DMD patients and human immortalized myoblasts displaying a deletion of 45-52 exons in DMD gene (Myo-45-52). We identified one cluster associating a smaller number of lncRNAs with a "milder" phenotype. In addition, in Myo-45-52 the profile of lncRNA expression underlined two lacking lncRNA. The WGS in 19/54 patients allowed precise identification of the deletion breakpoints underling specific sequence different for all analyzed patients. This study allowed us to describe phenotypic and genomic profile in the largest reported cohort of BMDdel45-55 patients. Genomic data profiling would have a favorable contribution in the design of these therapeutic approaches

Evaluation and parameterization of ATCOR3 topographic correction method for forest cover mapping in mountain areas

A topographic correction of optical remote sensing data is necessary to improve the quality of quantitative forest cover change analyses in mountainous terrain. The implementation of semi-empirical correction methods requires the calibration of model parameters that are empirically defined. This study develops a method to improve the performance of topographic corrections for forest cover change detection in mountainous terrain through an iterative tuning method of model parameters based on a systematic evaluation of the performance of the correction. The latter was based on: (i) the general matching of reflectances between sunlit and shaded slopes and (ii) the occurrence of abnormal reflectance values, qualified as statistical outliers, in very low illuminated areas. The method was tested on Landsat ETM+ data for rough (Ecuadorian Andes) and very rough mountainous terrain (Bhutan Himalayas). Compared to a reference level (no topographic correction), the ATCOR3 semi-empirical correction method resulted in a considerable reduction of dissimilarities between reflectance values of forested sites in different topographic orientations. Our results indicate that optimal parameter combinations are depending on the site, sun elevation and azimuth and spectral conditions. We demonstrate that the results of relatively simple topographic correction methods can be greatly improved through a feedback loop between parameter tuning and evaluation of the performance of the correction model. ⺠Method improving performance of topographic corrections for forest change detection. ⺠Test of the method on Landsat ETM+ data for Ecuadorian Andes and Bhutan Himalayas. ⺠Iterative tuning method of correction model parameters based on two criteria. ⺠Analysis of reflectance matching between sunlit and shaded slopes. ⺠Consideration of abnormal reflectance values occuring in very low illuminated areas

Surgical treatment of locally advanced, non-metastatic, gastrointestinal stromal tumours after treatment with imatinib

Item does not contain fulltextAIMS: Patients with locally advanced gastrointestinal stromal tumours (GISTs) have a high risk of tumour perforation, incomplete tumour resections and often require multivisceral resections. Long-term disease-free and overall survival is usually impaired in this group of patients. Induction therapy with imatinib followed by surgery seems to be beneficial in terms of improved surgical results and long-term outcome. We report on a large cohort of locally advanced GIST patients who have been treated in four centres in the Netherlands specialized in the treatment of sarcomas. METHODS: Between August 2001 and June 2011, 57 patients underwent surgery for locally advanced GISTs after imatinib treatment. Data of all patients were retrospectively collected. Endpoints were progression-free and overall survival. RESULTS: The patients underwent surgery after a median of 8 (range 1-55) months of imatinib treatment. Median tumour size before treatment was 12.2 (range 5.2-30) cm and reduced to 6.2 (range 1-20) cm before surgery. No tumour perforation occurred and a surgical complete (R0) resection was achieved in 48 (84%) patients. Five-year PFS and OS were 77% and 88%. Eight patients had recurrent/metastatic disease. CONCLUSIONS: Imatinib in locally advanced GIST is feasible and enables a high complete resection rate without tumour rupture. The combination of imatinib and surgery in patients with locally advanced GIST seems to improve PFS and OS