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2.
Comput Methods Biomech Biomed Engin ; 22(15): 1219-1228, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31441330

RESUMO

When designing any rehabilitation, sportswear or exoskeleton device the mechanical behaviour of the body segment must be known, specifically the skin, because an excessive tissue strain may lead to ulceration and bedsores. To date, it is not known if the kinematic variability between subjects have an effect on the skin strain field, and therefore, in the design and manufacturing of rehabilitation products, such as orthoses. Several studies have analysed the skin deformation during human motion, nevertheless, the comparison between the skin strain field in different subjects during normal or pathological gait has not been reported yet. This work presents a comparison of skin strain analysis for different gait patterns to study the differences between people and, specifically, if it is possible to standardize the orthotic design between subjects with the same gait disorder. Moreover, the areas with relatively minimum strain during the ankle-foot motion are compared to improve the design of structural parts of rehabilitation devices. In this case, a validated 3D digital image correlation system has been used for this purpose combined with strain ellipse theory. The results demonstrate variations in the skin strain field between subjects with the same pathology and similarities between subjects with normal gait. However, more studies and experiments are necessaries to validate this hypothesis and also to test it between different gait pathologies.

3.
Nat Rev Genet ; 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455890

RESUMO

Human genomics is undergoing a step change from being a predominantly research-driven activity to one driven through health care as many countries in Europe now have nascent precision medicine programmes. To maximize the value of the genomic data generated, these data will need to be shared between institutions and across countries. In recognition of this challenge, 21 European countries recently signed a declaration to transnationally share data on at least 1 million human genomes by 2022. In this Roadmap, we identify the challenges of data sharing across borders and demonstrate that European research infrastructures are well-positioned to support the rapid implementation of widespread genomic data access.

5.
Nat Commun ; 10(1): 1929, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028265

RESUMO

Genetically modified mice have advanced our understanding of valve development and disease. Yet, human pathophysiological valvulogenesis remains poorly understood. Here we report that, by combining single cell sequencing and in vivo approaches, a population of human pre-valvular endocardial cells (HPVCs) can be derived from pluripotent stem cells. HPVCs express gene patterns conforming to the E9.0 mouse atrio-ventricular canal (AVC) endocardium signature. HPVCs treated with BMP2, cultured on mouse AVC cushions, or transplanted into the AVC of embryonic mouse hearts, undergo endothelial-to-mesenchymal transition and express markers of valve interstitial cells of different valvular layers, demonstrating cell specificity. Extending this model to patient-specific induced pluripotent stem cells recapitulates features of mitral valve prolapse and identified dysregulation of the SHH pathway. Concurrently increased ECM secretion can be rescued by SHH inhibition, thus providing a putative therapeutic target. In summary, we report a human cell model of valvulogenesis that faithfully recapitulates valve disease in a dish.


Assuntos
Células Endoteliais/patologia , Proteínas Hedgehog/genética , Prolapso da Valva Mitral/patologia , Valva Mitral/patologia , Células-Tronco Pluripotentes/patologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Proteína Morfogenética Óssea 2/farmacologia , Caderinas/genética , Caderinas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Embrião de Mamíferos , Endocárdio/metabolismo , Endocárdio/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/transplante , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator de Transcrição GATA5/genética , Fator de Transcrição GATA5/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Valva Mitral/metabolismo , Prolapso da Valva Mitral/genética , Prolapso da Valva Mitral/metabolismo , Prolapso da Valva Mitral/terapia , Modelos Biológicos , Células-Tronco Pluripotentes/efeitos dos fármacos , Células-Tronco Pluripotentes/metabolismo , Cultura Primária de Células , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Proteína Wnt3A/farmacologia
7.
Nucleic Acids Res ; 46(W1): W545-W553, 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29860484

RESUMO

With the rapidly developing high-throughput sequencing technologies known as next generation sequencing or NGS, our approach to gene hunting and diagnosis has drastically changed. In <10 years, these technologies have moved from gene panel to whole genome sequencing and from an exclusively research context to clinical practice. Today, the limit is not the sequencing of one, many or all genes but rather the data analysis. Consequently, the challenge is to rapidly and efficiently identify disease-causing mutations within millions of variants. To do so, we developed the VarAFT software to annotate and pinpoint human disease-causing mutations through access to multiple layers of information. VarAFT was designed both for research and clinical contexts and is accessible to all scientists, regardless of bioinformatics training. Data from multiple samples may be combined to address all Mendelian inheritance modes, cancers or population genetics. Optimized filtration parameters can be stored and re-applied to large datasets. In addition to classical annotations from dbNSFP, VarAFT contains unique features at the disease (OMIM), phenotypic (HPO), gene (Gene Ontology, pathways) and variation levels (predictions from UMD-Predictor and Human Splicing Finder) that can be combined to optimally select candidate pathogenic mutations. VarAFT is freely available at: http://varaft.eu.

9.
J Neuromuscul Dis ; 4(4): 293-306, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29125504

RESUMO

BACKGROUND: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. OBJECTIVE: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. METHODS: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. RESULTS: Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. CONCLUSIONS: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field.

10.
Bull Cancer ; 104(7-8): 602-607, 2017 Jul - Aug.
Artigo em Francês | MEDLINE | ID: mdl-28689638

RESUMO

INTRODUCTION: Oncogenetics is a long-term process, which requires a close relation between patients and medical teams, good familial links allowing lifetime follow-up. Numerous documents are exchanged in between the medical team, which has to frequently interact. We present here a new tool that has been conceived specifically for this management. METHODS: The tool has been developed according to a model-view-controler approach with the relational system PostgreSQL 9.3. The web site used PHP 5.3, HTML5 and CSS3 languages, completed with JavaScript and jQuery-AJAX functions and two additional modules, FPDF and PHPMailer. RESULTS: The tool allows multiple interactions, clinical data management, mailing and emailing, follow-up plannings. Requests are able to follow all patients and planning automatically, to send information to a large number of patients or physicians, and to report activity. DISCUSSION: The tool has been designed for oncogenetics and adapted to its different aspects. The CNIL delivered an authorization for use. Secured web access allows the management at a regional level. Its simple concept makes it evolutive according to the constant updates of genetic and clinical management of patients.


Assuntos
Bases de Dados Factuais , Correio Eletrônico , Gestão da Informação em Saúde/métodos , Internet , Neoplasias/genética , Neoplasias/terapia , Relações Profissional-Paciente , Software , Humanos
11.
Haematologica ; 102(10): 1758-1766, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28751561

RESUMO

Splenic diffuse red pulp lymphoma is an indolent small B-cell lymphoma recognized as a provisional entity in the World Health Organization 2008 classification. Its precise relationship to other related splenic B-cell lymphomas with frequent leukemic involvement or other lymphoproliferative disorders remains undetermined. We performed whole-exome sequencing to explore the genetic landscape of ten cases of splenic diffuse red pulp lymphoma using paired tumor and normal samples. A selection of 109 somatic mutations was then evaluated in a cohort including 42 samples of splenic diffuse red pulp lymphoma and compared to those identified in 46 samples of splenic marginal zone lymphoma and eight samples of hairy-cell leukemia. Recurrent mutations or losses in BCOR (the gene encoding the BCL6 corepressor) - frameshift (n=3), nonsense (n=2), splicing site (n=1), and copy number loss (n=4) - were identified in 10/42 samples of splenic diffuse red pulp lymphoma (24%), whereas only one frameshift mutation was identified in 46 cases of splenic marginal zone lymphoma (2%). Inversely, KLF2, TNFAIP3 and MYD88, common mutations in splenic marginal zone lymphoma, were rare (one KLF2 mutant in 42 samples; 2%) or absent (TNFAIP3 and MYD88) in splenic diffuse red pulp lymphoma. These findings define an original genetic profile of splenic diffuse red pulp lymphoma and suggest that the mechanisms of pathogenesis of this lymphoma are distinct from those of splenic marginal zone lymphoma and hairy-cell leukemia.


Assuntos
Biomarcadores Tumorais , Variação Genética , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Neoplasias Esplênicas/diagnóstico , Neoplasias Esplênicas/genética , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Feminino , Humanos , Fatores de Transcrição Kruppel-Like/genética , Leucemia de Células Pilosas/diagnóstico , Leucemia de Células Pilosas/genética , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/genética , Pessoa de Meia-Idade , Mutação , Fator 88 de Diferenciação Mieloide/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Sequenciamento Completo do Exoma
12.
PLoS One ; 12(5): e0175998, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28481884

RESUMO

BACKGROUND: Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine. METHODS: Two-hundred forty-three patients were analysed (88.5% capecitabine monotherapy). Grade 3 and grade 4 capecitabine-related digestive and/or neurologic and/or hemato-toxicities were observed in 10.3% and 2.1% of patients, respectively. DPYD exome, along with flanking intronic regions 3'UTR and 5'UTR, were sequenced on MiSeq Illumina. DPD phenotype was assessed by pre-treatment plasma uracil (U) and dihydrouracil (UH2) measurement. RESULTS: Among the 48 SNPs identified, 19 were located in coding regions, including 3 novel variations, each observed in a single patient (among which, F100L and A26T, both pathogenic in silico). Combined analysis of deleterious variants *2A, I560S (*13) and D949V showed significant association with grade 3-4 toxicity (sensitivity 16.7%, positive predictive value (PPV) 71.4%, relative risk (RR) 6.7, p<0.001) but not with grade 4 toxicity. Considering additional deleterious coding variants D342G, S492L, R592W and F100L increased the sensitivity to 26.7% for grade 3-4 toxicity (PPV 72.7%, RR 7.6, p<0.001), and was significantly associated with grade 4 toxicity (sensitivity 60%, PPV 27.3%, RR 31.4, p = 0.001), suggesting the clinical relevance of extended targeted DPYD genotyping. As compared to extended genotype, combining genotyping (7 variants) and phenotyping (U>16 ng/ml) did not substantially increase the sensitivity, while impairing PPV and RR. CONCLUSIONS: Exploring an extended set of deleterious DPYD variants improves the performance of DPYD genotyping for predicting both grade 3-4 and grade 4 toxicities (digestive and/or neurologic and/or hematotoxicities) related to capecitabine, as compared to conventional genotyping restricted to consensual variants *2A, *13 and D949V.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Capecitabina/efeitos adversos , Di-Hidrouracila Desidrogenase (NADP)/genética , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Capecitabina/uso terapêutico , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
13.
Eur Respir J ; 49(5)2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28495692

RESUMO

Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53-6.12; p=9.45×10-4). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10-2).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença , Doenças Pulmonares Intersticiais/genética , Fibrose Pulmonar/genética , Adulto , Idoso , Artrite Reumatoide/complicações , Estudos de Casos e Controles , DNA Helicases/genética , Europa (Continente) , Exoma , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Doenças Pulmonares Intersticiais/complicações , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Fibrose Pulmonar/complicações , Fatores de Risco , Análise de Sequência de DNA , Software , Telomerase/genética
14.
Hum Mutat ; 37(12): 1318-1328, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27633797

RESUMO

As next-generation sequencing increases access to human genetic variation, the challenge of determining clinical significance of variants becomes ever more acute. Germline variants in the BRCA1 and BRCA2 genes can confer substantial lifetime risk of breast and ovarian cancer. Assessment of variant pathogenicity is a vital part of clinical genetic testing for these genes. A database of clinical observations of BRCA variants is a critical resource in that process. This article describes BRCA Share™, a database created by a unique international alliance of academic centers and commercial testing laboratories. By integrating the content of the Universal Mutation Database generated by the French Unicancer Genetic Group with the testing results of two large commercial laboratories, Quest Diagnostics and Laboratory Corporation of America (LabCorp), BRCA Share™ has assembled one of the largest publicly accessible collections of BRCA variants currently available. Although access is available to academic researchers without charge, commercial participants in the project are required to pay a support fee and contribute their data. The fees fund the ongoing curation effort, as well as planned experiments to functionally characterize variants of uncertain significance. BRCA Share™ databases can therefore be considered as models of successful data sharing between private companies and the academic world.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Bases de Dados Factuais , Neoplasias Ovarianas/genética , Curadoria de Dados , Bases de Dados Factuais/economia , Feminino , Predisposição Genética para Doença , Humanos , Mutação
15.
Artigo em Inglês | MEDLINE | ID: mdl-27589961

RESUMO

Fully automated text mining (TM) systems promote efficient literature searching, retrieval, and review but are not sufficient to produce ready-to-consume curated documents. These systems are not meant to replace biocurators, but instead to assist them in one or more literature curation steps. To do so, the user interface is an important aspect that needs to be considered for tool adoption. The BioCreative Interactive task (IAT) is a track designed for exploring user-system interactions, promoting development of useful TM tools, and providing a communication channel between the biocuration and the TM communities. In BioCreative V, the IAT track followed a format similar to previous interactive tracks, where the utility and usability of TM tools, as well as the generation of use cases, have been the focal points. The proposed curation tasks are user-centric and formally evaluated by biocurators. In BioCreative V IAT, seven TM systems and 43 biocurators participated. Two levels of user participation were offered to broaden curator involvement and obtain more feedback on usability aspects. The full level participation involved training on the system, curation of a set of documents with and without TM assistance, tracking of time-on-task, and completion of a user survey. The partial level participation was designed to focus on usability aspects of the interface and not the performance per se In this case, biocurators navigated the system by performing pre-designed tasks and then were asked whether they were able to achieve the task and the level of difficulty in completing the task. In this manuscript, we describe the development of the interactive task, from planning to execution and discuss major findings for the systems tested.Database URL: http://www.biocreative.org.


Assuntos
Curadoria de Dados/métodos , Mineração de Dados/métodos , Processamento Eletrônico de Dados/métodos
16.
Hum Mutat ; 37(12): 1272-1282, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27599893

RESUMO

High-throughput sequencing technologies have become fundamental for the identification of disease-causing mutations in human genetic diseases both in research and clinical testing contexts. The cumulative number of genes linked to rare diseases is now close to 3,500 with more than 1,000 genes identified between 2010 and 2014 because of the early adoption of Exome Sequencing technologies. However, despite these encouraging figures, the success rate of clinical exome diagnosis remains low due to several factors including wrong variant annotation and nonoptimal filtration practices, which may lead to misinterpretation of disease-causing mutations. In this review, we describe the critical steps of variant annotation and filtration processes to highlight a handful of potential disease-causing mutations for downstream analysis. We report the key annotation elements to gather at multiple levels for each mutation, and which systems are designed to help in collecting this mandatory information. We describe the filtration options, their efficiency, and limits and provide a generic filtration workflow and highlight potential pitfalls through a use case.


Assuntos
Anotação de Sequência Molecular/métodos , Mutação , Exoma , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Análise de Sequência de DNA/métodos , Software
17.
Hum Mutat ; 37(12): 1299-1307, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27600092

RESUMO

Adoption of next-generation sequencing (NGS) in a diagnostic context raises numerous questions with regard to identification and reports of secondary variants (SVs) in actionable genes. To better understand the whys and wherefores of these questioning, it is necessary to understand how they are selected during the filtering process and how their proportion can be estimated. It is likely that SVs are underestimated and that our capacity to label all true SVs can be improved. In this context, Locus-specific databases (LSDBs) can be key by providing a wealth of information and enabling classifying variants. We illustrate this issue by analyzing 318 SVs in 23 actionable genes involved in cancer susceptibility syndromes identified through sequencing of 572 participants selected for a range of atherosclerosis phenotypes. Among these 318 SVs, only 43.4% are reported in Human Gene Mutation Database (HGMD) Professional versus 71.4% in LSDB. In addition, 23.9% of HGMD Professional variants are reported as pathogenic versus 4.8% for LSDB. These data underline the benefits of LSDBs to annotate SVs and minimize overinterpretation of mutations thanks to their efficient curation process and collection of unpublished data.


Assuntos
Aterosclerose/genética , Bases de Dados Genéticas , Neoplasias/genética , Biologia Computacional , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Anotação de Sequência Molecular , Mutação , Software
18.
Hum Mutat ; 37(12): 1308-1317, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27647783

RESUMO

High-throughput next-generation sequencing such as whole-exome and whole-genome sequencing are being rapidly integrated into clinical practice. The use of these techniques leads to the identification of secondary variants for which decisions about the reporting or not to the patient need to be made. The American College of Medical Genetics and Genomics recently published recommendations for the reporting of these variants in clinical practice for 56 "actionable" genes. Among these, seven are involved in Marfan Syndrome And Related Disorders (MSARD) resulting from mutations of the FBN1, TGFBR1 and 2, ACTA2, SMAD3, MYH11 and MYLK genes. Here, we show that mutations collected in UMD databases for MSARD genes (UMD-MSARD) are rarely reported, including the most frequent ones, in global scale initiatives for variant annotation such as the NHLBI GO Exome Sequencing Project (ESP), the Exome Aggregation Consortium (ExAC), and ClinVar. The predicted pathogenic mutations reported in global scale initiatives but absent in locus-specific databases (LSDBs) mainly correspond to rare events. UMD-MSARD databases are therefore the only resources providing access to the full spectrum of known pathogenic mutations. They are the most comprehensive resources for clinicians and geneticists to interpret MSARD-related variations not only primary variants but also secondary variants.


Assuntos
Doenças Cardiovasculares/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Exoma , Predisposição Genética para Doença , Genoma Humano , Genômica/métodos , Humanos , Bases de Conhecimento
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