Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Aneuploidy is the leading cause of miscarriage and congenital birth defects, and a hallmark of cancer. Despite this strong association with human disease, the genetic causes of aneuploidy remain largely unknown. Through exome sequencing of patients with constitutional mosaic aneuploidy, we identified biallelic truncating mutations in CENATAC (CCDC84). We show that CENATAC is a novel component of the minor (U12-dependent) spliceosome that promotes splicing of a specific, rare minor intron subtype. This subtype is characterized by AT-AN splice sites and relatively high basal levels of intron retention. CENATAC depletion or expression of disease mutants resulted in excessive retention of AT-AN minor introns in similar to 100 genes enriched for nucleocytoplasmic transport and cell cycle regulators, and caused chromosome segregation errors. Our findings reveal selectivity in minor intron splicing and suggest a link between minor spliceosome defects and constitutional aneuploidy in humans.Peer reviewe

The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0 % were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5 %). The diagnosis was deep-vein thrombosis (DVT) in 59.5 % and pulmonary embolism (PE) in 40.5 %. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5 %), hypertension (42.3 %) and dyslipidaemia (21.1 %). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2 %), almost half received a vitamin K antagonist (48.7 %) and nearly a quarter received a DOAC (24.5 %). Almost a quarter of all presentations were for recurrent VTE, with >80 % of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes

Dépister la dénutrition de l'enfant en pratique courante = Malnutrition screening in clinical practice

La dénutrition protéino-énergétique (DPE) est l'état pathologique résultant d'une inadéquation entre les besoins et les apports protéino-énergétiques. Elle est délétère par ses conséquences fonctionnelles et structurelles (perte tissulaire) et peut entraîner une augmentation de la morbidité, voire de la mortalité d_une éventuelle pathologie sous-jacente. Le Comité de nutrition de la Société française de pédiatrie (SFP) recommande de peser et de mesurer tout enfant quel que soit le contexte de visite ou d_hospitalisation. En l'absence d_information sur la cinétique de la croissance, l'indice de masse corporelle (IMC) doit être calculé et interprété en fonction des courbes de référence figurant dans le carnet de santé. Pour tout IMC < 3e percentile pour l'âge et le sexe, il est recommandé d'examiner l'enfant à la recherche de signes cliniques de dénutrition ou de signes orientant vers son origine et de tracer l'évolution de la croissance staturopondérale (IMC et taille). Toute dénutrition, qu'elle soit identifiée en pédiatrie communautaire ou en milieu hospitalier, nécessite d'établir une stratégie nutritionnelle intégrée à la prise en charge globale de l'enfant. Elle suppose de définir le poids cible et d'adapter les apports protéino-énergétiques en termes de niveaux, de composition et de modalités d'administration (orale, entérale, parentérale). Dans tous les cas cette attitude sera évaluée et adaptée selon l'effet obtenu. Protein energy malnutrition (PEM) occurs when energy and protein intake do not meet requirements. It has a functional and structural impact and increases both morbidity and mortality of a given disease. The Nutrition Committee of the French Pediatric Society recommends weighing and measuring any child when hospitalized or seen in consultation. The body mass index (BMI) must be calculated and analyzed according to references any time growth kinetics cannot be analyzed. Any child with a BMI below the third centile or -2 standard deviations for age and sex needs to be examined looking for clinical signs of malnutrition and signs orienting toward an etiology and requires having his BMI and height dynamics plotted on a chart. PEM warrants drawing up a nutritional strategy along with the overall care plan. A target weight needs to be determined as well as the quantitative and qualitative nutritional care including its implementation. This plan must be evaluated afterwards in order to adapt the nutritional therapy

Chromosomal instability by mutations in the novel minor spliceosome component CENATAC

Aneuploidy is the leading cause of miscarriage and congenital birth defects, and a hallmark of cancer. Despite this strong association with human disease, the genetic causes of aneuploidy remain largely unknown. Through exome sequencing of patients with constitutional mosaic aneuploidy, we identified biallelic truncating mutations in CENATAC (CCDC84). We show that CENATAC is a novel component of the minor (U12-dependent) spliceosome that promotes splicing of a specific, rare minor intron subtype. This subtype is characterized by AT-AN splice sites and relatively high basal levels of intron retention. CENATAC depletion or expression of disease mutants resulted in excessive retention of AT-AN minor introns in ˜ 100 genes enriched for nucleocytoplasmic transport and cell cycle regulators, and caused chromosome segregation errors. Our findings reveal selectivity in minor intron splicing and suggest a link between minor spliceosome defects and constitutional aneuploidy in humans

New chondrosarcoma cell lines and mouse models to study the link between chondrogenesis and chemoresistance

Chondrosarcomas are cartilage-forming, poorly vascularized tumors. They represent the second malignant primary bone tumor of adults after osteosarcoma, but in contrast to osteosarcoma they are resistant to chemotherapy and radiotherapy, surgical excision remaining the only therapeutic option. Few cell lines and animal models are available, and the mechanisms behind their chemoresistance remain largely unknown. Our goal was to establish new cell lines and animal cancer models from human chondrosarcoma biopsies to study their chemoresistance. Between 2007 and 2012, 10 chondrosarcoma biopsies were collected and used for cell culture and transplantation into nude mice. Only one transplanted biopsy and one injected cell line has engrafted successfully leading to conventional central high-grade chondrosarcoma similar to the original biopsies. In culture, two new stable cell lines were obtained, one from a dedifferentiated and one from a grade III conventional central chondrosarcoma biopsy. Their genetic characterization revealed triploid karyotypes, mutations in IDH1, IDH2, and TP53, deletion in CDKN2A and/or MDM2 amplification. These cell lines expressed mesenchymal membrane markers (CD44, 73, 90, 105) and were able to produce a hyaline cartilaginous matrix when cultured in chondrogenic three-dimensional (3D) pellets. Using a high-throughput quantitative RT-PCR approach, we observed that cell lines cultured in monolayer had lost expression of several genes implicated in cartilage development (COL2A1, COMP, ACAN) but restored their expression in 3D cultures. Chondrosarcoma cells in monolayer were sensitive to several conventional chemotherapeutic agents but became resistant to low doses of mafosfamide or doxorubicin when cultured in 3D pellets, in parallel with an altered nucleic accumulation of the drug. Our results indicate that the cartilaginous matrix produced by chondrosarcoma cells may impair diffusion of several drugs and thus contribute to chemoresistance. Therefore, 3D chondrogenic cell pellets constitute a more relevant model to study chondrosarcoma chemoresistance and may be a valuable alternative to animal experimentations