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‣ Subsídios para o estabelecimento de estratégias de teste baseadas na técnica de mutação.; Subsidies for the establishment of testing strategy based on mutation technique.

Vincenzi, Auri Marcelo Rizzo
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 06/11/1998 Português
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Para sistematizar os testes e contornar as restrições de tempo e custo associadas à atividade de teste, diversas técnicas, critérios e ferramentas têm sido desenvolvidas. Além disso, visando ao estabelecimento de uma estratégia de teste incremental, que apresente baixo custo de aplicação e alta eficácia em revelar a presença de erros, estudos teóricos e empíricos vêm sendo conduzidos pela comunidade de teste. O presente trabalho está inserido nesse contexto e tem como objetivo a realização de estudos empíricos para comparar a adequação entre os critérios baseados em erros - Análise de Mutantes (teste de unidade) e Mutação de Interface (teste de integração) - visando ao estabelecimento de estratégias de teste de baixo custo e eficazes, que englobem todo o ciclo de desenvolvimento de software. Nessa perspectiva, algumas estratégias incrementais de aplicação dos operadores de mutação de unidade e de integração são definidas, explorando o aspecto complementar dos critérios baseados em mutação, reduzindo com isso os custos da atividade de teste durante as fases do teste de unidade e de integração, sem comprometer sua qualidade. Ainda, um conjunto essencial de operadores de mutação para o critério Mutação de Interface é apresentado.; Techniques...

‣ Detecção da mutação T1799A do gene BRAF em células de carcinoma papilífero obtidas por punção aspirativa com agulha fina; Detection of BRAF gene mutation T1799A in papillary carcinoma cells obtained by fine needle aspiration

Lima, Erika Urbano de
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 17/08/2012 Português
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O câncer da tireoide é a neoplasia endócrina mais comum, sendo responsável por cerca de 1 a 2% das neoplasias malignas da tireoide. Atualmente, a patogênese molecular do carcinoma papilífero da tireoide (CPT) tem sido relacionada à ativação aberrante da via de sinalização MAPK, desencadeada por mutações em diversos oncogenes. Destas, a mutação p.V600E do gene BRAF é a mais freqüente, sendo observada em 30%-80% dos casos. Numerosos estudos têm demonstrado que a presença dessa mutação está relacionada a uma maior agressividade do tumor e, conseqüentemente, a um prognóstico menos favorável, tornando-a um marcado importante no CPT. Contudo, poucos métodos utilizados na análise do gene BRAF em amostras de punção de nódulos tireoidianos foram satisfatórios em relação ao custo-tempo e sensibilidade do teste. Os objetivos deste estudo foram padronizar a extração de DNA a partir de amostras obtidas de PAAF guiada por ultrassom de nódulos tireoidianos; validar e determinar a eficiência e a relação custo-tempo da técnica de genotipagem por PCR em tempo real na detecção da mutação p.V600E do gene BRAF em amostras de PAAF de nódulos tireoidianos; analisar a prevalência da mutação p.V600E em pacientes com CPT; correlacionar à presença da mutação p.V600E com características clínicas e histopatológicas de maior agressividade e por fim analisar a sensibilidade...

‣ Análise de mutantes no contexto de sistemas reativos : uma contribuição para o estabelecimento de estratégias de teste e validação; The Mutation analysis in the context of reactive systems : uma contribuição para o estabelecimento de estratégias de teste e validação testing and validation

Fabbri, Sandra Camargo Pinto Ferraz
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 21/10/1996 Português
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Este trabalho propõe a extensão do critério Análise de Mutantes, originalmente desenvolvido para o teste de programas, para sua aplicação no teste de especificações do aspecto comportamental de Sistemas Reativos. Esses sistemas constituem hoje um componente fundamental em várias atividades humanas e, em geral, falhas nos mesmos podem envolver grandes riscos a vida ou ao patrimônio. Isso toma imprescindível um maior rigor no processo de desenvolvimento e, em particular, na atividade de teste, que é fundamentalmente baseada em simulação, não fornecendo critério que avalie essa atividade de forma quantitativa. A proposta aborda a aplicação da Análise de Mutantes na validação de especificações de Sistemas Reativos baseadas em três técnicas formais, que possuem apoio gráfico, mais utilizadas para este fim: Máquinas de Estados Finitos, Redes de Petri e Statecharts. Para a aplicação do critério nesse contexto, estabeleceu-se um paralelo entre os níveis de programa e de especificação, quanto as suas hipóteses básicas do programador competente e do efeito de acoplamento. Foram definidos os operadores de mutação para cada uma das três técnicas consideradas, além de critérios de mutação alternativa que visam a minimização no custo de aplicação do critério. Foram realizados...

‣ Analises de mutações e de seus efeitos na expressão do gene SRY em casos de disgenesia gonadal XY; SRY gene mutation analysis and functional effects in cases of XY gonadal dysgenesis

Jose Luiz Rosenberis Cunha Junior
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 25/02/2010 Português
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A expressão do gene SRY (Sex Determining Region in chromosome Y) é responsável por desencadear a determinação testicular durante o desenvolvimento embrionário, a partir das gônadas ainda indiferenciadas. Mutações nesse gene são encontradas em muitos casos de anomalias do desenvolvimento gonadal. O projeto teve por objetivo principal a análise funcional do efeito de uma mutação na região promotora do gene SRY, sendo que essa mutação consiste em uma deleção de 3 pares de base em um dos sítios consenso de ligação do fator de transcrição Sp1 ao promotor do gene. O portador dessa mutação é um indivíduo com disgenesia gonadal pura 46,XY, sendo que outros membros da família apresentavam ambiguidade genital e o pai, também portador da mutação, possuía grave hipospadia ao nascimento. Para tentar esclarecer os efeitos desta mutação nos mecanismos moleculares de regulação da expressão do gene SRY, este trabalho primeiramente analisou a interação da proteína Sp1 com os sítios localizados na região promotora de SRY e o efeito da mutação nesta interação, através de ensaios de EMSA (Electrophoretic Mobility Shift Assay). Concluiu-se que os sítios Sp1A e Sp1B se ligam a duas moléculas de Sp1 e que a mutação no Sp1A praticamente abole esta ligação. Possivelmente a ausência dessa ligação impediu a formação de um complexo de transcrição...

‣ Comparison of KRAS Mutation Analysis and FISH for Detecting Pancreatobiliary Tract Cancer in Cytology Specimens Collected During Endoscopic Retrograde Cholangiopancreatography

Kipp, Benjamin R.; Barr Fritcher, Emily G.; Clayton, Amy C.; Gores, Gregory J.; Roberts, Lewis R.; Zhang, Jun; Levy, Michael J.; Halling, Kevin C.
Fonte: American Society for Investigative Pathology Publicador: American Society for Investigative Pathology
Tipo: Artigo de Revista Científica
Publicado em /11/2010 Português
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Pancreatobiliary tract strictures result either from malignancies of the biliary tract and pancreas or from nonmalignant etiopathogenesis. The goal of this study was to determine whether KRAS mutations could be identified in residual pancreatobiliary stricture brushings and to compare the performance characteristics of KRAS mutation analysis to cytology and fluorescence in situ hybridization (FISH) for the detection of carcinoma. Residual brushing cytology cell pellets were retrieved from 132 patients with subsequent clinicopathologic follow-up of cholangiocarcinoma (n = 41), pancreatic adenocarcinoma (n = 35), gallbladder cancer (n = 2), and nonmalignant strictures (n = 54). All specimens had a prior cytology and FISH UroVysion results as part of clinical practice. KRAS mutation analysis was performed using the quantitative PCR DxS KRAS Mutation Test Kit. KRAS mutation analysis was successful in 130 of 132 specimens. KRAS mutations and polysomic (ie, positive) FISH results were identified in 24 (69%) and 22 (63%) pancreatic adenocarcinoma specimens, respectively, with a combined sensitivity of 86% (30/35). KRAS mutations and polysomic FISH results were identified in 12 (29%) and 17 (41%) cholangiocarcinoma specimens, with a combined sensitivity of 54% (22/41). KRAS mutations were identified in two patients with primary sclerosing cholangitis...

‣ Direct mutation analysis by high-throughput sequencing: from germline to low-abundant, somatic variants

Gundry, Michael; Vijg, Jan
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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DNA mutations are the source of genetic variation within populations. The majority of mutations with observable effects are deleterious. In humans mutations in the germ line can cause genetic disease. In somatic cells multiple rounds of mutations and selection lead to cancer. The study of genetic variation has progressed rapidly since the completion of the draft sequence of the human genome. Recent advances in sequencing technology, most importantly the introduction of massively parallel sequencing (MPS), have resulted in more than a hundred-fold reduction in the time and cost required for sequencing nucleic acids. These improvements have greatly expanded the use of sequencing as a practical tool for mutation analysis. While in the past the high cost of sequencing limited mutation analysis to selectable markers or small forward mutation targets assumed to be representative for the genome overall, current platforms allow whole genome sequencing for less than $5,000. This has already given rise to direct estimates of germline mutation rates in multiple organisms including humans by comparing whole genome sequences between parents and offspring. Here we present a brief history of the field of mutation research, with a focus on classical tools for the measurement of mutation rates. We then review MPS...

‣ Plasma epidermal growth factor receptor mutation analysis and possible clinical applications in pulmonary adenocarcinoma patients treated with erlotinib

CHEN, YUH-MIN; FAN, WEN-CHIEN; TSENG, PEI-CHUN; TSAI, CHUN-MING; CHOU, TEH-YING; WU, CHIEH-HUNG; CHOU, KUN-TA; LEE, YU-CHIN; PERNG, REURY-PERNG; WHANG-PENG, JACQUELINE
Fonte: D.A. Spandidos Publicador: D.A. Spandidos
Tipo: Artigo de Revista Científica
Português
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Tumor epidermal growth factor receptor (EGFR) mutation analysis is significant for making treatment decisions for metastatic pulmonary adenocarcinoma. However, less than half of patients have adequate tumor samples for mutation analysis. Patients with adenocarcinoma of the lungs who were due to receive erlotinib treatment were included in the present study. Tumor EGFR mutation status was analyzed using DNA sequencing. Plasma specimens from the patients were collected prior to erlotinib treatment. The plasma-free DNA EGFR mutation status was analyzed using the PCR clamp method. A total of 54 consecutive patients were included in the study. The plasma-free DNA EGFR mutation status of the 54 patients was analyzed. Only 30 patients had adequate tumor samples for EGFR analysis, including 15 with activating mutations (exon 19 deletions or L858R). EGFR-activating mutations were detected in the plasma-free DNA in 25 of 54 patients. The response rate was 86.7 and 33.3% in patients with and without tumor activating mutations, respectively (p=0.002). The response rate was 68 and 31% based on the patients’ plasma-free DNA EGFR mutation status, respectively (p=0.013). No significant difference in progression-free survival (PFS) was observed between patients with and without EGFR-activating mutations...

‣ Mutation Analysis in Chinese Patients with Cornelia de Lange Syndrome

Zhong, Qiulian; Liang, Desheng; Liu, Jing; Xue, Jinjie; Wu, Lingqian
Fonte: Mary Ann Liebert, Inc. Publicador: Mary Ann Liebert, Inc.
Tipo: Artigo de Revista Científica
Publicado em /09/2012 Português
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Aims: Cornelia de Lange syndrome (CdLS) is a dominant multisystem developmental disorder and related to mutations of the NIPBL, SMC1A, and SMC3 genes. So far, there has been no report of a mutation analysis in Chinese patients with CdLS, while 12 cases have been clinically described. In the present study, we tried to search for pathogenic mutations of the NIPBL, SMC1A, and SMC3 genes in four patients with CdLS from four unrelated Chinese families. Results: The mutational analysis of the NIPBL, SMC1A, and SMC3 genes by direct sequencing revealed a heterozygous splice-site mutation c.4321G>T(p.V1441L) at exon 20 of NIPBL in proband 2 and a novel heterozygous splice-site mutation c.6589+5G>C at intron 38 of NIPBL in proband 3, which was showed by reverse transcription polymerase chain reaction to generate both the full-length and an alternatively spliced transcript with an exon 38 deletion. Conclusions: This is the first report of the mutation analysis of NIPBL in China and our findings both expand the mutation spectrum of NIPBL and provide data for further understanding of the diverse and variable effects of NIPBL mutations.

‣ Mutation Analysis in Glycogen Storage Disease Type III Patients in the Netherlands: Novel Genotype-Phenotype Relationships and Five Novel Mutations in the AGL Gene

Sentner, Christiaan P; Vos, Yvonne J; Niezen-Koning, Klary N; Mol, Bart; Smit, G Peter A.
Fonte: Springer Berlin Heidelberg Publicador: Springer Berlin Heidelberg
Tipo: Artigo de Revista Científica
Publicado em 16/03/2012 Português
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Glycogen Storage Disease type III (GSD III) is an autosomal recessive disorder in which a mutation in the AGL gene causes deficiency of the glycogen debranching enzyme. In childhood, it is characterized by hepatomegaly, keto-hypoglycemic episodes after short periods of fasting, and hyperlipidemia. In adulthood, myopathy, cardiomyopathy, and liver cirrhosis are the main complications. To determine the genotype of the GSD III patients (n = 14) diagnosed and treated in our center, mutation analysis was performed by either denaturing gradient gel electrophoresis or full gene sequencing. We developed, validated and applied both methods, and in all patients a mutation was identified on both alleles. Five novel pathogenic mutations were identified in seven patients, including four missense mutations (c.643G>A, p.Asp215Asn; c.655A>G, p.Asn219Asp; c.1027C>T, p.Arg343Trp; c.1877A>G, p.His626Arg) and one frameshift mutation (c.3911delA, p.Asn1304fs). The c.643G>A, p.Asp215Asn mutation is related with type IIIa, as this mutation was found homozygously in two type IIIa patients. In addition to five novel mutations, we present new genotype–phenotype relationships for c.2039G>A, p.Trp680X; c.753_756delCAGA, p.Asp251fs; and the intron 32 c.4260-12A>G splice site mutation. The p.Trp680X mutation was found homozygously in four patients...

‣ A single center analysis of nucleophosmin in acute myeloid leukemia: value of combining immunohistochemistry with molecular mutation analysis

Woolthuis, Carolien M.; Mulder, André B.; Verkaik-Schakel, Rikst Nynke; Rosati, Stefano; Diepstra, Arjan; van den Berg, Eva; Schuringa, Jan Jacob; Vellenga, Edo; Kluin, Philip M.; Huls, Gerwin
Fonte: Ferrata Storti Foundation Publicador: Ferrata Storti Foundation
Tipo: Artigo de Revista Científica
Publicado em /10/2013 Português
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Mutations of nucleophosmin 1 are frequently found in acute myeloid leukemia and lead to aberrant cytoplasmic accumulation of nucleophosmin protein. Immunohistochemical staining is therefore recommended as the technique of choice in front-line screening. In this study, we assessed the sensitivity and specificity of immunohistochemistry on formalin-fixed bone marrow biopsies compared with gold standard molecular analysis to predict nucleophosmin 1 mutation status in 119 patients with acute myeloid leukemia. Discrepant cases were further characterized by gene expression analyses and fluorescence in situ hybridization. A large overlap between both methods was observed. Nevertheless, nine patients demonstrated discordant results at initial screening. Five cases demonstrated nuclear staining of nucleophosmin 1 by immunohistochemistry, but a nucleophosmin 1 mutation by molecular analysis. In two cases this could be attributed to technical issues and in three cases minor subpopulations of myeloblasts had not been discovered initially. All tested cases exhibited the characteristic nucleophosmin-mutated gene expression pattern. Four cases had cytoplasmic nucleophosmin 1 staining and a nucleophosmin-mutated gene expression pattern without a detectable nucleophosmin 1 mutation. In two of these cases we found the chromosomal translocation t(3;5)(q25;q35) encoding the NPM-MLF1 fusion protein. In the other discrepant cases the aberrant cytoplasmic nucleophosmin staining and gene expression could not be explained. In total six patients (5%) had true discordant results between immunohistochemistry and mutation analysis. We conclude that cytoplasmic nucleophosmin localization is not always caused by a conventional nucleophosmin 1 mutation and that in the screening for nucleophosmin 1 abnormalities...

‣ Mutation Analysis of the BRCA1 and BRCA2 Genes in the Belgian Patient Population and Identification of a Belgian Founder Mutation BRCA1 IVS5+3A>G

Claes, Kathleen; Machackova, Eva; De Vos, Michel; Poppe, Bruce; De Paepe, Anne; Messiaen, Ludwine
Fonte: IOS Press Publicador: IOS Press
Tipo: Artigo de Revista Científica
Português
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Since the identification of the BRCA1 and BRCA2 genes, several hundred different germline mutations in both genes have been reported. Recurrent mutations are rare and mainly due to founder effects. As the mutational spectrum of the BRCA1 and BRCA2 genes in the Belgian patient population is largely unknown, we initiated mutation analysis for the complete coding sequence of both genes in Belgian families with multiple breast and/or ovarian cancer patients and in “sporadic” patients with early onset disease. We completed the analysis in 49 families and in 19 “sporadic” female patients with early onset breast and/or ovarian cancer. In 15 families we identified a mutation (12 mutations in BRCA1 and 3 mutations in BRCA2). In 5 apparently unrelated families the same splice site mutation was identified (BRCA1 IVS5+3A>G). Haplotype analysis revealed a common haplotype immediately flanking the mutation in all families suggesting that disease alleles are identical by descent. In none of the 19 sporadic patients was a mutation found.

‣ Um benchmark para avaliação de técnicas de busca no contexto de análise de Mutantes sql; A benchmark to evaluation of search techniques in the context of sql mutation analysis

Queiroz, Leonardo Teixeira
Fonte: Universidade Federal de Goiás; Brasil; UFG; Programa de Pós-graduação em Ciência da Computação (INF); Instituto de Informática - INF (RG) Publicador: Universidade Federal de Goiás; Brasil; UFG; Programa de Pós-graduação em Ciência da Computação (INF); Instituto de Informática - INF (RG)
Tipo: Dissertação Formato: application/pdf
Português
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One of the concerns in test Applications Database (ADB) is to keep the operating and computational costs low. In the context of the ADB, one way to collaborate with this assumption is ensuring that the Test Databases (TDB) are small, but effective in revealing defects of SQL statements. Such bases can be constructed or obtained by the reduction of Production Databases (PDB). In the reductions case, there are combinatorial aspects involved that require the use of a specific technique for their implementation. In this context, in response to a deficiency identified in the literature, this work aims to build and provide a benchmark to enable performance evaluation, using SQL Mutation Analysis, any search technique that intends to conduct databases reductions. Therefore, to exercise the search techniques, the benchmark was built with two scenarios where each one is composed of a PDB and a set of SQL statements. In addition, as a reference for search techniques, it also contains performance of data database randomly reduced. As a secondary objective of this work, from the experiments conducted in the construction of the benchmark, analyses were made with the results obtained to answer important questions about what factors are involved in the complexity of SQL statements in the context of Test Mutation. A key finding in this regard was on the restrictiveness of SQL commands...

‣ Uma abordagem evolucionária para o teste de instruções select SQL com o uso da análise de mutantes; An evolutionary approach to test SQL select statements using the mutation analysis

Monção, Ana Claudia Bastos Loureiro
Fonte: Universidade Federal de Goiás; Brasil; UFG; Programa de Pós-graduação em Ciência da Computação (INF); Instituto de Informática - INF (RG) Publicador: Universidade Federal de Goiás; Brasil; UFG; Programa de Pós-graduação em Ciência da Computação (INF); Instituto de Informática - INF (RG)
Tipo: Dissertação Formato: application/pdf
Português
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Software Testing is an important area of Software Engineering to ensuring the software quality. It consists of activities that involve long time and high costs, but need to be made throughout the process of building software. As in other areas of software engineering, there are problems in the activities of Software Testing whose solution is not trivial. For these problems, several techniques of optimization and search have been explored trying to find an optimal solution or near optimal, giving rise to lines of research textit Search-Based Software Engineering (SBSE) and textit Search-Based Software Testing (SBST). This work is part of this context and aims to solve the problem of selecting test data for test execution in SQL statements. Given the number of potential solutions to this problem, the proposed approach combines techniques Mutation Analysis for SQL with Evolutionary Computation to find a reduced data set, that be able to detect a large number of defects in SQL statements of a particular application. Based on a heuristic perspective, the proposal uses Genetic Algorithms (GA) to select tuples from a existing database (from production environment) trying to reduce it to a set of data relevant and effective. During the evolutionary process...

‣ Mutation analysis of the Fanconi anaemia A gene in breast tumours with loss of heterozygosity at 16q24.3

Cleton-Jansen, A.M.; Moerland, E.; Pronk, J.; Van Berkel, C.; Apostolou, S.; Crawford, J.; Savoia, A.; Auerbach, A.; Callen, D.; Cornelisse, C.
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em //1999 Português
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The recently identified Fanconi anaemia A (FAA) gene is located on chromosomal band 16q24.3 within a region that has been frequently reported to show loss of heterozygosity (LOH) in breast cancer. FAA mutation analysis of 19 breast tumours with specific LOH at 16q24.3 was performed. Single-stranded conformational polymorphism (SSCP) analysis on cDNA and genomic DNA, and Southern blotting failed to identify any tumour-specific mutations. Five polymorphisms were identified, but frequencies of occurrence did not deviate from those in a normal control population. Therefore, the FAA gene is not the gene targeted by LOH at 16q24.3 in breast cancer. Another tumour suppressor gene in this chromosomal region remains to be identified.; A-M Cleton-Jansen, EW Moerland, JC Pronk, CGM van Berkel, S Apostolou, J Crawford, A Savoia, AD Auerbach, CG Mathew, DF Callen and CJ Cornelisse; Article no. bjoc.1998.0168

‣ MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression

Frints, S.; Lenzer, S.; Bauters, M.; Jensen, L.R.; Van Esch, H.; des Portes, V.; Moog, U.; Macville, M.; Roozendaal, K.; Schrander-Stumpel, C.; Tzschach, A.; Marynen, P.; Fryns, J.P.; Hamel, B.; van Bokhoven, H.; Chelly, J.; Beldjord, C.; Turner, G.; Gecz
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em //2008 Português
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Mutations in the thyroid monocarboxylate transporter 8 gene (MCT8/SLC16A2) have been reported to result in X-linked mental retardation (XLMR) in patients with clinical features of the Allan–Herndon–Dudley syndrome (AHDS). We performed MCT8 mutation analysis including 13 XLMR families with LOD scores >2.0, 401 male MR sibships and 47 sporadic male patients with AHDS-like clinical features. One nonsense mutation (c.629insA) and two missense changes (c.1A>T and c.1673G>A) were identified. Consistent with previous reports on MCT8 missense changes, the patient with c.1673G>A showed elevated serum T3 level. The c.1A>T change in another patient affects a putative translation start codon, but the same change was present in his healthy brother. In addition normal serum T3 levels were present, suggesting that the c.1A>T (NM_006517) variation is not responsible for the MR phenotype but indicates that MCT8 translation likely starts with a methionine at position p.75. Moreover, we characterized a de novo translocation t(X;9)(q13.2;p24) in a female patient with full blown AHDS clinical features including elevated serum T3 levels. The MCT8 gene was disrupted at the X-breakpoint. A complete loss of MCT8 expression was observed in a fibroblast cell-line derived from this patient because of unfavorable nonrandom X-inactivation. Taken together...

‣ Mutationsanalyse des Prop-1-Gens bei Kindern mit hypoplastischer Adenohypophyse und ektoper Neurohypophyse; Mutation analysis of the Prop-1- gene on children with hypoplastic adenohypophysis and ectopic neurohypophysis

Schywalsky, Sofia
Fonte: Universität Tübingen Publicador: Universität Tübingen
Tipo: Dissertation; info:eu-repo/semantics/doctoralThesis
Português
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Molekulargenetische Untersuchungen der letzten 2 Jahrzehnte erbrachten weitreichende Einsichten in die Genese der hypophysären Insuffizienz, die sowohl als isolierter Wachstumshormonmangel, wie auch als kombinierter hypophysärer Hormonausfall auftreten kann. Isoliert wurden Transkriptionsfaktoren, die zeitlich während der Embryonalentwicklung der Hypophyse exprimiert werden und sowohl bei der Morphogenese und Organogenese der Hypophyse, als auch an der Differenzierung und Proliferation der hypohysären Zellreihen eine wesentliche Rolle spielen. Genetische Defekte im Bereich dieser Transkriptionsfaktoren können allerdings nicht nur zum endokrinen Phänotyp des hypophysären Hormonausfalls führen, sondern auch zum klinischen Bild der missgebildeten Hypophyse mit einer hypoplastischen Adenohypophyse und insbesondere einer ektopen Neurohypophyse. Die wichtigsten bisher bekannten Transkriptionsfaktoren sind HESX-1, LHX-1, LHX-4, Prop-1 und Pit-1. In unserer Studie führten wir eine molekulargenetische Mutationsanalyse des Prop-1-Gens bei Patienten mit einer Ektopie der Neurohypophyse und einer hypophysären Insuffizienz durch. Wir postulierten einen ursächlichen Zusammenhang zwischen eines möglichen Gendefektes im Bereich der Prop-1- Sequenz und der ektopen Neurohypophyse. Dafür amplifizierten wir die Prop1-Sequenz aller Patienten mittels PCR und unterzogen die Amplifikate einer SSCP-Analyse. Alle dort auffälligen Sequenzen und die gesamte Homöodomäne aller Patienten wurden im weiteren Verlauf sequenziert. Überraschenderweise konnte eine Mutation der Prop-1-Sequenz bei keiner der untersuchten Personen nachgewiesen werden. Auch in vorausgegangenen Studien konnten bei Patienten mit einem nachgewiesenen Prop-1-Defekt normale...

‣ Mutationsanalyse des VHL-Tumorsuppressorgens vor dem Hintergrund der erblichen VHL-Erkrankung und Karzinogenexposition beim sporadischen Nierenzellkarzinom; Mutation analysis of the VHL-tumor suppressor gene with respect to the hereditary VHL-disease and carcinogen-induced sporadic renal cell carcinoma

Klein, Bettina
Fonte: Universität Tübingen Publicador: Universität Tübingen
Tipo: Dissertation; info:eu-repo/semantics/doctoralThesis
Português
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Das von Hippel-Lindau-Tumorsuppressorgen (VHL) ist ursächlich an der Entstehung der erblichen von Hippel-Lindau-Erkrankung (VHL), einem Multi-Tumor-Syndrom beteiligt. Mutationen in diesem Gen können die Funktion des Genprodukts (pVHL) modulieren, dessen Rolle beim kontrollierten Proteinabbau im Proteasom am besten erforscht ist. Für die Etablierung von aussagefähigen Genotyp-Phänotyp-Korrelationen sind zunehmend moderne Verfahren zur kostengünstigen, schnellen und verlässlichen VHL-Mutationsdetektion in Blut-DNA gefragt, wie z.B. DHPLC- und Sequenzieranalysen. Aus diesem Grund wurde im ersten Teil der vorliegenden Arbeit eine PCR- und DHPLC-basierte Nachweismethode für bereits bekannte VHL-Keimbahnmutationen etabliert. Diese Methode wurde anschließend für den Nachweis von Mutationen bei VHL-Verdachtspatienten angewandt. Im Rahmen der Aufklärung der komplexen Genotyp-Phänotyp-Zusammenhänge beim VHL-Syndrom konnten zwei kosegregierende VHL-Mutationen, 454 C>T (Pro81Ser) und 775 C>G (Leu188Val), dem VHL2C-Phänotyp zugeordnet werden. Zunächst war davon ausgegangen worden, dass dieser minimale VHL-Phänotyp durch eine Leu188Val-Mutation in der alpha-Domäne des pVHL hervorgerufen wird und so die Interaktion mit dem Protein Elongin C stört. In dieser Arbeit wurde erstmalig gezeigt...

‣ A Leri-Weill dyschondrosteosis patient confirmed by mutation analysis of SHOX gene

Choi, Won Bok; Seo, Seung Hyeon; Yoo, Woo Hyun; Kim, Su Young; Kwak, Min Jung
Fonte: The Korean Society of Pediatric Endocrinology Publicador: The Korean Society of Pediatric Endocrinology
Tipo: Artigo de Revista Científica
Português
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46.80722%
Leri-Weill dyschondrosteosis is characterized by SHOX deficiency, Madelung deformity, and mesomelic short stature. In addition, SHOX deficiency is associated with idiopathic short stature, Turner syndrome, and Langer mesomelic dysplasia. We report the first case of a Leri-Weill dyschondrosteosis patient confirmed by SHOX gene mutation analysis in Korea. The patient, who was a 7-year-old female, showed short stature. Her height and weight were 108.9 cm (<3rd percentile) and 19.7 kg (5th-10th percentile), respectively. Her arm span, height of trunk, leg length, and sitting length were 100.5 cm, 58 cm, 50.9 cm, and 62.5 cm, respectively. Her body proportion was 1.13:1. Extremities to trunk ratio was 2.61. Her hand radiograph showed Madelung deformity. And the growth hormone stimulation test showed a normal response. Furthermore, because of Madelung deformity with idiopathic short stature, she was suspected of SHOX deficiency. We performed SHOX gene mutation analysis and found a c.491G>A (p.W164X) mutation of the SHOX gene. Accordingly, this patient was diagnosed with Leri-Weill dyschondrosteosis. Recently, many mutations have been reported in the SHOX gene. However, to date, mutation analysis of the SHOX gene for Leri-Weill dyschondrosteosis has not been reported in Korea as yet. We report the first case of a Leri-Weill dyschondrosteosis patient confirmed by mutation analysis of the SHOX gene.

‣ Strategy for mutation analysis in the autosomal recessive limb-girdle muscular dystrophies

Pogue, Robert; Anderson, Louise V.B.; Pyle, Angela; Sewry, Caroline; Pollitt, Christine; Johnson, Margaret A.; Davison, Keith; Moss, Jennifer A.; Mercuri, Eugenio; Muntoni, Francesco; Bushby, Katherine M.D.
Fonte: Universidade Católica de Brasília Publicador: Universidade Católica de Brasília
Tipo: Artigo de Revista Científica Formato: Texto
Português
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We describe a strategy for molecular diagnosis in the autosomal recessive limb-girdle muscular dystrophies, a highly heterogeneous group of inherited muscle-wasting diseases. Genetic mutation analysis is directed by immunoanalysis of muscle biopsies using antibodies against a panel of muscular dystrophy-associated proteins. Performing the molecular analysis in this way greatly increases the chance that mutations will be found in the ®rst gene examined. The use of this strategy can signi®cantly decrease the time involved in determining the genetic fault in a patient with a clinical diagnosis of recessive limb-girdle muscular dystrophy, as well as having a feedback effect, which is useful in helping clinicians to identify subtle clinical differences between the subtypes of the disease. The use of this approach has so far helped us to identify mutations in ten sarcoglycanopathy (limb-girdle muscular dystrophy 2C±2F) patients, and seven calpainopathy (limb-girdle muscular dystrophy 2A) patients.

‣ Value of TIRADS, BSRTC and FNA-BRAFV600E mutation analysis in differentiating high-risk thyroid nodules

Zhang, Yu-zhi; Xu, Ting; Cui, Dai; Li, Xiao; Yao, Qing; Gong, Hai-yan; Liu, Xiao-yun; Chen, Huan-huan; Jiang, Lin; Ye, Xin-hua; Zhang, Zhi-hong; Shen, Mei-ping; Duan, Yu; Yang, Tao; Wu, Xiao-hong
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em 24/11/2015 Português
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The thyroid imaging reporting and data system (TIRADS) and Bethesda system for reporting thyroid cytopathology (BSRTC) have been used for interpretation of ultrasound and fine-needle aspiration cytology (FNAC) results of thyroid nodules. BRAFV600E mutation analysis is a molecular tool in diagnosing thyroid carcinoma. Our objective was to compare the diagnostic value of these methods in differentiating high-risk thyroid nodules. Total 220 patients with high-risk thyroid nodules were recruited in this prospective study. They all underwent ultrasound, FNAC and BRAFV600E mutation analysis. The sensitivity and specificity of TIRADS were 73.1% and 88.4%. BSRTC had higher specificity (97.7%) and similar sensitivity (77.6%) compared with TIRADS. The sensitivity and specificity of BRAFV600E mutation (85.1%, 100%) were the highest. The combination of BSRTC and BRAFV600E mutation analysis significantly increased the efficiency, with 97.8% sensitivity, 97.7% specificity. In patients with BSRTC I-III, the mutation rate of BRAFV600E was 64.5% in nodules with TIRADS 4B compared with 8.4% in nodules with TIRADS 3 or 4A (P < 0.001). Our study indicated that combination of BSRTC and BRAFV600E mutation analysis bears a great value in differentiating high-risk thyroid nodules. The TIRADS is useful in selecting high-risk patients for FNAB and patients with BSRTC I-III for BRAFV600E mutation analysis.