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Use of the q-Gaussian mutation in evolutionary algorithms

TINOS, Renato; YANG, Shengxiang
Fonte: SPRINGER Publicador: SPRINGER
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
36.32%
This paper proposes the use of the q-Gaussian mutation with self-adaptation of the shape of the mutation distribution in evolutionary algorithms. The shape of the q-Gaussian mutation distribution is controlled by a real parameter q. In the proposed method, the real parameter q of the q-Gaussian mutation is encoded in the chromosome of individuals and hence is allowed to evolve during the evolutionary process. In order to test the new mutation operator, evolution strategy and evolutionary programming algorithms with self-adapted q-Gaussian mutation generated from anisotropic and isotropic distributions are presented. The theoretical analysis of the q-Gaussian mutation is also provided. In the experimental study, the q-Gaussian mutation is compared to Gaussian and Cauchy mutations in the optimization of a set of test functions. Experimental results show the efficiency of the proposed method of self-adapting the mutation distribution in evolutionary algorithms.; FAPESP; CNPq in Brazil; Engineering and Physical Sciences Research Council (EPSRC) of the UK[EP/E060722/1]; Engineering and Physical Sciences Research Council (EPSRC) of the UK[EP/E060722/2]

Experimental evaluation of SDL and One-Op mutation for C

Delamaro, Márcio Eduardo; Deng, Lin; Durelli, Vinicius Humberto Serapilha; Li, Nan; Offutt, Jeff
Fonte: IEEE Computer Society; Cleveland, Ohio Publicador: IEEE Computer Society; Cleveland, Ohio
Tipo: Conferência ou Objeto de Conferência
ENG
Relevância na Pesquisa
36.34%
Mutation analysis modifies a program by applying syntactic rules, called mutation operators, systematically to create many versions of the program (mutants) that differ in small ways. Testers then design tests to cause the mutants to behave differently from the original program. Mutation testing is widely considered to result in very effective tests, however, it is also quite costly. Cost comes from the many mutants that are created, the number of tests that are needed to kill the mutants, and the difficulty of deciding whether mutants behave equivalently to the original program. One-op mutation theorizes that cost can be reduced by using a single, very powerful, mutation operator that leads to tests that are almost as effective as if all operators are used. Previous research proposed the statement deletion operator (SDL) and found promising results. This paper investigates the use of SDL-mutation in a new context, the language C, and poses additional empirical questions, including whether other operators can be used. We carried out a controlled experiment in which cost and effectiveness of each individual C mutation operator were collected for 39 different subject programs. Experimental data are used to define a cost-effectiveness metric to choose the best single operator for one-op mutation.; FAPESP (número processo 2012/16950-5)

Designing deletion mutation operators

Delamaro, Márcio Eduardo; Offutt, Jeff; Ammann, Paul
Fonte: IEEE Computer Society; Cleveland, Ohio Publicador: IEEE Computer Society; Cleveland, Ohio
Tipo: Conferência ou Objeto de Conferência
ENG
Relevância na Pesquisa
36.34%
Mutation analysis modifies a program by applying syntactic rules, called mutation operators, systematically to create many versions of the program (mutants) that differ in small ways. Testers then design tests to cause the mutants to behave differently from the original program. Mutation testing is widely considered to result in very effective tests, however, it is also quite costly. Cost comes from the many mutants that are created, the number of tests that are needed to kill the mutants, and the difficulty of deciding whether mutants behave equivalently to the original program. One-op mutation theorizes that cost can be reduced by using a single, very powerful, mutation operator that leads to tests that are almost as effective as if all operators are used. Previous research proposed the statement deletion operator (SDL) and found promising results. This paper investigates the use of SDL-mutation in a new context, the language C, and poses additional empirical questions, including whether other operators can be used. We carried out a controlled experiment in which cost and effectiveness of each individual C mutation operator were collected for 39 different subject programs. Experimental data are used to define a cost-effectiveness metric to choose the best single operator for one-op mutation.; FAPESP (número processo 2012/16950-5)

Características biológicas e vocais durante o desenvolvimento vocal masculino nos períodos pré, peri e pós muda vocal; Biological and vocal characteristics during vocal male development in vocal premutation, mutation and postmutation

Oliveira, Cristiane Ferraz 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 02/10/2007 PT
Relevância na Pesquisa
36.33%
As grandes mudanças ocorridas na voz masculina durante a puberdade fazem com que o estudo do desenvolvimento vocal masculino normal seja bastante interessante, entretanto pouco estudado. Assim, este trabalho teve como objetivo verificar as características biológicas e vocais durante desenvolvimento vocal masculino nos períodos pré, peri e pós muda vocal. Participaram deste estudo 85 indivíduos do sexo masculino, com idades entre 8 e 18 anos ('X BARRA' = 14 anos '+ OU -' 32 meses), divididos de acordo com o desenvolvimento vocal nos grupos "pré-muda", "muda", "final muda" e "pós-muda". Foram realizadas entrevista, medida de estatura e peso, auto-avaliação da maturação sexual, avaliação perceptivo-auditiva da voz falada (escala GIRBAS), medidas da freqüência fundamental habitual e fonetografia computadorizada. Com os resultados observou-se durante o desenvolvimento vocal: aumento significante da estatura e do peso; desenvolvimento gradativo dos genitais e dos pêlos pubianos, axilares e faciais; pequena porcentagem de alteração vocal discreta em todos os grupos, sendo maior no período da muda vocal ("muda" e "final muda"); diminuição significante da freqüência fundamental habitual em aproximadamente uma oitava; diminuição significante das freqüências mínima e máxima da fonetografia (11st e 7st respectivamente); aumento significante da extensão vocal e deslocamento desta em direção às freqüências mais graves; ocorrência significante de quebras de freqüência...

Mutação de interface: um critério Interprocedimental para o teste de integração; Interface mutation: an interprocedural adequacy criterion for integration testing

Delamaro, Márcio Eduardo
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 17/06/1997 PT
Relevância na Pesquisa
36.36%
Um dos pontos fundamentais na atividade de teste de software é o projeto de casos de teste. Diversos critérios de adequação têm sido propostos com o objetivo de fornecer meios que permitam que a avaliação e elaboração de casos de teste sejam feitas de maneira sistemática e fundamentadas teoricamente. Infelizmente, a maioria dos critérios de adequação de casos de teste definidos tem seu uso restrito ao teste de unidade. Para fases posteriores da atividade de teste, em particular para o teste de integração, nota-se a ausência de critérios de adequação, principalmente porque os critérios propostos definem requisitos de teste que se restringem aos limites de uma única unidade, não exercitando de maneira efetiva as interações entre as unidades, que devem ser alvo principal no teste de integração. Com exceção de alguns poucos trabalhos que procuram estender critérios estruturais para o nível interprocedimental, tem-se utilizado nessa fase de teste, quase que exclusivamente, critérios funcionais. Dada essa ausência de critérios e salientando ainda o caráter complementar entre as diferentes técnicas de teste, esta tese apresenta um critério de teste interprocedimental baseado em defeitos chamado de Mutação de Interface. Esse critério busca exercitar as interações entre as unidades através da seleção de casos de teste que distingam mutantes criados pela introdução de defeitos típicos e que...

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 PT
Relevância na Pesquisa
36.38%
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...

Caracterização do fenótipo e rastreamento gênico em famílias com neoplasia endócrina múltipla tipo 2A devido à nova dupla mutação germinativa C634Y/Y791F no proto-oncogene RET; Phenotype characterization and genetic screening in multiple endocrine neoplasia type 2A families associated with the new double germline mutation C634Y/Y791F in the RET proto-oncogene

Coutinho, Flávia Lima
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 25/04/2013 PT
Relevância na Pesquisa
36.32%
INTRODUÇÃO: A imensa maioria dos casos com Neoplasia Endócrina Múltipla Tipo 2 (NEM2) é causada por uma única mutação germinativa no proto-oncogene RET. Entretanto, há alguns poucos casos descritos na literatura (~16) que apresentam duplas mutações/polimorfismos no gene RET, geralmente associados a fenótipos atípicos. OBJETIVOS: Os objetivos deste projeto são: a) caracterizar os aspectos clínicos de pacientes advindos de cinco famílias não relacionadas com diagnóstico de NEM2A, nas quais se documentou a presença de uma nova dupla mutação germinativa RET nos códons 634 e 791 e b) realizar rastreamento gênico familiar dos casos sob-risco com a finalidade de identificarmos possíveis casos com esta nova mutação. PACIENTES: Cinco casos-índice foram recentemente descobertos albergando a dupla mutação germinativa RET C634Y/Y791F. Nestas famílias há relato de 208 parentes, potencialmente, sob-risco (~50%) de serem portadores desta mutação. Dentre estes 208 indivíduos, 81 (38,9%) aceitaram participar do rastreamento gênico. MÉTODOS: O estudo foi realizado na Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. O DNA do sangue periférico dos pacientes e de seus parentes sob- risco foi obtido após a obtenção do consentimento livre e esclarecido. Após PCR...

The frequency of 844ins68 mutation in the cystathionine β-synthase gene is not increased in patients with venous thrombosis

Franco, Rendrik; Maffei, Francisco; Lourenço, Dayse; Piccinato, Carlos; Morelli, Vânia; Thomazini, Isolete; Zago, Marco
Fonte: Universidade Estadual Paulista Publicador: Universidade Estadual Paulista
Tipo: Artigo de Revista Científica Formato: 1006-1008
ENG
Relevância na Pesquisa
36.32%
Background and Objectives. A frequent mutation in the cystathionine β- synthase (CBS) gene (844ins68, a 68-bp insertion in the coding region of exon 8) was recently discovered. In the present study we investigated this mutation as a candidate risk factor for venous thrombosis. Design and Methods. The prevalence of the 844ins68 CBS mutation was determined in 101 patients with objectively diagnosed deep venous thrombosis and in 101 healthy controls matched for age, sex and race. PCR amplification of a DNA fragment containing exon 8 of the CBS gene was employed to determine the genotypes. Additionally, Bsrl restriction enzyme digestion of the PCR products was performed in all samples from carriers of the insertion, to test for concurrent presence of a second mutation (T833C) in the CBS gene. Results. The insertion was found in 21 out of 101 patients (20.8%; allele frequency 0.109) and in 20 out of 101 controls (19.8%; allele frequency 0.114), yielding a relative risk for venous thrombosis related to the 844ins68 CBS mutation close to 1.0. In addition, the T833C CBS mutation was detected in all alleles carrying the 844ins68 CBS insertion, confirming the co- inheritance of the two mutations. Interpretation and Conclusions. Our findings do not support the hypothesis that the 844ins68 mutation in the CBS gene is a genetic risk factor for venous thrombosis.

Espectro tumoral e alterações moleculares associadas à tumorigênese em portadores da mutação TP53 R337H; Tumor spectrum and molecular changes associated to tumorigenesis in carriers of TP53 R337H mutation

Ana Luiza Ongaro Seidinger Conte
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 27/03/2012 PT
Relevância na Pesquisa
36.32%
O gene supressor de tumor TP53 é um dos mais bem caracterizados genes cujo papel na etiologia é conhecido tanto em tumores hereditários como esporádicos. Mutações germinativas neste gene normalmente estão associadas à Síndrome de Li-Fraumeni, uma síndrome de predisposição ao câncer cujos portadores apresentam alto risco de desenvolvimento de uma variedade de tumores ao longo da vida. Uma mutação específica deste gene é altamente prevalente na população brasileira, chegando a estar presente em 0.3% da população saudável. Esta mutação, a R337H, não foi descrita como uma mutação associada a um amplo espectro tumoral e, sim, como uma mutação tecido-específica associada somente ao desenvolvimento do tumor do córtex da adrenal (TCA). Entretanto, algumas evidências indicavam que ela poderia contribuir para a etiologia de outros tumores, além do TCA. A R337H foi encontrada em 06 famílias com Síndrome de Li- Fraumeni like e em 2.4% de pacientes diagnosticadas com câncer de mama. Com o objetivo de obter maiores evidências sobre a contribuição da R337H na etiologia de outros tumores além do TCA, investigamos a prevalência desta mutação em 493 pacientes diagnosticados com diferentes tumores pediátricos. Além disto...

Prevalência da mutação germinativa TP53 p.R337H na região metropolitana de Campinas e cidades circunvizinhas; Prevalence of germline TP53 p.R337H mutation at metropolitan area of Campinas and surrounding cities

Isabel Pereira Caminha
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 24/02/2015 PT
Relevância na Pesquisa
36.32%
A mutação germinativa p.R337H do gene TP53 está associada à alta incidência de tumores do córtex da adrenal (TCA) em regiões Sul e Sudeste do Brasil, onde as evidências indicam a ocorrência de efeito fundador. A alta frequência de relatos desta mutação no Sul do Brasil nos encorajou a desenvolver um método adequado para a detecção de mutações em larga escala, com o objetivo de determinar a incidência da p.R337H em uma população de São Paulo, o Estado mais populoso do Brasil. Um novo método foi desenvolvido a fim de detectar a mutação p.R337H em amostras armazenadas em papel filtro, utilizando PCR em tempo real. Amostras de DNA genômico de 34.344 recém-nascidos de uma região específica do Estado de São Paulo foram selecionadas para detectar a frequência desta mutação germinativa. PCR Alelo-específico e Nested-PCR foram utilizados para verificar a presença do haplótipo fundador brasileiro em recém-nascidos portadores da mutação. Entre as 34.344 amostras triadas, 75 foram identificadas como portadores da mutação p.R337H. Esta frequência (0,21%) é semelhante à encontrada na região Sul do Brasil. O haplótipo fundador brasileiro foi identificado em todos os pacientes em que a amostra foi adequada para esta análise. A distribuição da mutação mostrou-se heterogênea...

Detection of hepatitis B virus A1762T/G1764A mutant by amplification refractory mutation system

Wang,Yong-Zhong; Zhu,Zhen; Zhang,Hong-Yu; Zhu,Min-Zhi; Xu,Xin; Chen,Chun-Hua; Liu,Long-Gen
Fonte: Brazilian Society of Infectious Diseases Publicador: Brazilian Society of Infectious Diseases
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2014 EN
Relevância na Pesquisa
36.35%
OBJECTIVE: To study the role of hepatitis B virus with A1762T/G1764A double mutation in liver cirrhosis and hepatocellular carcinoma, and create a sensitive, fast, accurate assay for detection of A1762T/G1764A double mutation. METHODS: We developed an accurate and fast real-time amplification refractory mutation system to detect A1762T/G1764A double mutation. Cloned hepatitis B virus genome was used as a control. Assay sensitivity was determined by serial dilution and mixed template experiments. Specificity was determined by cross experiments with wild and mutant hepatitis B virus. Fifty clinical samples were tested by the real-time amplification refractory mutation system and the results were compared with sequencing. RESULTS: The real-time amplification refractory mutation system had a sensitivity of 100 copies of virus with these mutations, and 0.1% weak population virus with double mutation could be found in mixtures. A total of 50 randomly collected clinical samples were detected by real-time amplification refractory mutation system, and the results were consistent with those by DNA sequencing. Hepatitis B virus genotype C was more prevalent in 39 of 50 samples than genotype B (11 samples), and about 75% of genotype C carried a double mutation compared to 45% of genotype B. However...

Determination of microsatellite DNA mutation rates , mutation models and mutation bias in four main felidae lineages (european wild cat , felis silvestris ; ocelot , leopardus pardalis ; puma , puma concolor ; jaguar , panthera onca); Molecular Population Genetics, Evolutionary Biology and Biological Conservation of Neotropical Carnivores

Ruiz García, Manuel; García Perea, Rosa; Corrales, Carolina; Murillo, Andrea; Alvarez, Diana; Pinedo Castro, Myreya; Shostell, Joseph Mark
Fonte: Nova Science Pub Inc Publicador: Nova Science Pub Inc
Formato: 1-720
Relevância na Pesquisa
36.34%
We analyzed for 12 nuclear DNA microsatellites in 4 wild cat species (European wild cat, ocelot, puma, and jaguar) representing four different phylogenetics felid lineages. The objective of our study, using these species and molecular markers, was to obtain more data about the molecular evolution of microsatellites. The main findings of this study are: 1- From the measurements of diverse genetics variables and statistics in the four species, we determined that the ocelot showed the highest number of alleles, number of repeats, allele range and levels of heterozygosity. However, no significant differences were observed among the average microsatellite mutation rates observed in the four species of felids studied. 2- We estimated two independent average mutation rates (3.116 x 10-5 and 5.353 x 10-5) using two different phylogenetics strategies. However, there was no significant difference between these two estimates. 3- We found the observed mutation model to be basically a uni-step mutation model or a two-phase mutation model. The four felid species showed an average stepwise mutation model for 92-94 % of the uni-step mutations. 4- The regression models we applied among different genetic diversity statistics, samples sizes and other variables showed: a- the allele range was clearly more correlated with the allele number at the microsatellites studied than to the allele dispersion...

Determination of Microsatellite DNA Mutation Rates, Mutation Models and Mutation Bias in four main Felidae Lineages (European wild cat , Felis silvestris; Ocelot, Leopardus pardalis; Puma, Puma concolor; Jaguar, Panthera onca); Molecular Population Genetics, Evolutionary Biology, and Biological Conservation of Neotropical Carnivores

Ruiz-García, Manuel; García-Perea, Rosa; Corrales, Carolina; Murillo, Andrea; Alvarez, Diana; Pinedo-Castro, Myreya; Shostell, Joseph Mark
Fonte: Nova Science Publishers, Inc. Publicador: Nova Science Publishers, Inc.
Formato: 1-79
Relevância na Pesquisa
36.35%
We analyzed for 12 nuclear DNA microsatellites in 4 wild cat species (European wild cat, ocelot, puma, and jaguar) representing four different phylogenetics felid lineages. The objective of our study, using these species and molecular markers, was to obtain more data about the molecular evolution of microsatellites. The main findings of this study are: 1- From the measurements of diverse genetics variables and statistics in the four species, we determined that the ocelot showed the highest number of alleles, number of repeats, allele range and levels of heterozygosity. However, no significant differences were observed among the average microsatellite mutation rates observed in the four species of felids studied. 2- We estimated two independent average mutation rates (3.116 x 10-5 and 5.353 x 10-5) using two different phylogenetics strategies. However, there was no significant difference between these two estimates. 3- We found the observed mutation model to be basically a uni -step mutation model or a two-phase mutation model. The four felid species showed an average stepwise mutation model for 92-94 % of the uni-step mutations. 4- The regression models we applied among different genetic diversity statistics...

Differential effects of FGFR2 mutation in ophthalmic findings in Apert syndrome

Khong, J.; Anderson, P.; Hammerton, M.; Roscioli, T.; Selva-Nayagam, D.; David, D.
Fonte: Lippincott Williams & Wilkins Publicador: Lippincott Williams & Wilkins
Tipo: Artigo de Revista Científica
Publicado em //2007 EN
Relevância na Pesquisa
36.34%
Apert syndrome is mostly caused by one of the two specific point mutations in the fibroblast growth factor receptor 2 (FGFR2). The objective of this study was to determine whether there were any differences in the prevalence of ophthalmic features in Apert syndrome when comparing the Ser252Trp and Pro253Arg mutations in FGFR2. This was a retrospective study of patients with Apert syndrome with genotype analysis. The prevalence of five ophthalmic features, visual impairment, amblyopia, strabismus, corneal abnormality, and pale optic discs, were compared between the two FGFR2 genotypes. There were 25 (74%) cases with Ser252Trp mutation, and 9 (26%) cases with the Pro253Arg mutation in FGFR2. Ophthalmic findings in 20 cases of FGFR2 Ser252Trp and 9 cases of Pro253Arg mutation were compared. Visual acuity worse than 6/12 in at least one eye was present in 60% patients with FGFR2 Ser252Trp mutation compared with 12.5% patients with Pro253Arg mutation (P < 0.05). Forty percent of eyes with FGFR2 Ser252Trp mutation compared with 12.5% eyes with Pro253Arg mutation were worse than 6/12. There was a trend of more frequent amblyopia and strabismus in FGFR2 Ser252Trp mutation and more frequent optic disc pallor in the FGFR2 Pro253Arg mutation. There was a differential effect of FGFR2 mutations in ophthalmic findings in patients with Apert syndrome...

Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX Trial of capecitabine alone or in combination with Bevacizumab and Mitomycin in advanced colorectal cancer

Price, T.; Hardingham, J.; Lee, C.; Weickhardt, A.; Townsend, A.; Wrin, J.; Chua, A.; Shivasami, A.; Cummins, M.; Murone, C.; Tebbutt, N.
Fonte: Amer Soc Clinical Oncology Publicador: Amer Soc Clinical Oncology
Tipo: Artigo de Revista Científica
Publicado em //2011 EN
Relevância na Pesquisa
36.32%
Purpose: Mutations affecting the KRAS gene are established predictive markers of outcome with anti–epithelial growth factor receptor (EGFR) antibodies in advanced colorectal cancer (CRC). The relevance of these markers for anti–vascular endothelial growth factor (VEGF) therapy is controversial. This analysis was performed to assess the predictive and prognostic impact of KRAS and BRAF gene mutation status in patients receiving capecitabine with bevacizumab (CG) or capecitabine without bevacizumab in the phase III AGITG MAX (Australasian Gastrointestinal Trials Group MAX) study. Patients and Methods: Mutation status was determined for 315 (66.9%) of the original 471 patients. Mutation status was correlated with efficacy outcomes (response rate, progression-free survival [PFS], and overall survival [OS]), and a predictive analyses was undertaken. Results: Mutations in KRAS and BRAF genes were observed in 28.8% and 10.6% of patients, respectively. KRAS gene mutation status (wild type [WT] v mutated [MT]) had no prognostic impact for PFS (hazard ratio [HR], 0.89; CI, 0.69 to 1.14) or OS (HR, 0.97; CI, 0.73 to 1.28). BRAF mutation status (WT v MT) was not prognostic for PFS (HR, 0.80; CI, 0.54 to 1.18) but was prognostic for OS (HR...

Die Mutation Y1206S steigert die Affinität des Sulfonylharnstoffrezeptors SUR2A für Glibenclamid und unterstützt den Einfluß der Koexpression mit KIR6.2; The mutation Y1206S increases the affinity of the sulfonalurea receptor SUR2A for glibenclamide and enhances the effects of coexpression with KIR6.2

Stauß, Eva
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
DE_DE
Relevância na Pesquisa
36.33%
ATP-empfindliche Kaliumkanäle (KATP-Kanäle) kommen in allen erregbaren Zellen vor und sind vor allem bekannt als Ansatzpunkt der Sulfonylharnstoffe und Glinide, die durch Hemmung der Aktivität des Kanals in der ß-Zelle der Pankreas die Insulinsekretion fördern. KATP-Kanäle setzen sich aus vier schwach einwärtsgleichrichtenden Kaliumkanaluntereinheiten der Familie KIR6.x und vier Sulfonylharnstoffrezeptoren (SUR) zusammen. SUR übernimmt die Steuerung der Kanalaktivität und enthält die Bindungsstellen der Sulfonylharnstoffe und der KATP-Kanalöffner. Die KIR6.x-Familie besteht aus zwei Mitgliedern: KIR6.1 kommt in Gefäßmuskelzellen und KIR6.2 in allen anderen erregbaren Zellen vor. Die SUR-Subtypen umfassen unter anderem SUR1 (B-Zelle, Gehirn), SUR2A (Herz- und Skelettmuskel) und SUR2B (glatte Muskelzellen). Beide Isoformen zeigen im Vergleich zu SUR1 eine geringere Affinität gegenüber Glibenclamid (GBC), dem bekanntesten Sulfonylharnstoff. In SUR1 wurde der Aminosäurerest Serin 1237 als wichtig für die GBC-Affinität erkannt, bei SUR2 ist dieser Rest durch Tyrosin 1206 ersetzt. Die Punktmutation Y1206S in SUR2B, bei welcher Tyrosin im SUR2B der Ratte durch Serin aus SUR1 ersetzt wurde, erhöht die Affinität des Rezeptors für GBC um einen Faktor 5-10 (Hambrock et al....

Glutaminsynthetase- und Cytochrom P450-Expression in soliden Tumoren des Kindesalters mit CTNNB1 (beta-Catenin)-Mutation; Glutamine synthetase and cytochrome p 450 expression in solid childhood tumors with CTNNB1 (beta-catenin) mutation

Schmidt, Andreas
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
DE_DE
Relevância na Pesquisa
36.34%
Hintergrund: Mutationen im ß-Catenin (CTNNB1)-Gen und damit ein veränderter Wnt-Signalweg sind in unterschiedlichsten Tumorarten zu finden, darunter Hepatoblastome (HB) und Wilms-Tumore (WT). Das GS- und das CYP-Gen sind Zielgene des Wnt/ß-Catenin (CTNNB1)-Signalwegs. Ziel dieser Arbeit war, solide Tumore des Kindesalters auf ß-Catenin (CTNNB1)-Mutationen und auf die Expression der GS und von CYP-Isoformen zu untersuchen. Material und Methoden: Tumorproben von 85 Patienten mit unterschiedlichen soliden Tumoren des Kindesalters (HB [10], WT [12], Neuroblastome [35], Rhabdomyosarkome [16] und andere Weichteilsarkome [12]) wurden anhand DNA-Sequenzierung auf Mutationen im ß-Catenin (CTNNB1)-Gen untersucht. Mittels Immunhistochemie, Western-Blot und Real Time PCR wurde das Expressionsverhalten der GS und verschiedener CYP-Isoformen beurteilt. Um spezielle histologische Fragestellungen zu klären, kam die Methode der Mikrodissektion zum Einsatz. Ergebnisse: Von den untersuchten Tumoren wiesen nur HB (8/10) und WT (4/12) Mutationen im ß-Catenin (CTNNB1)-Gen auf. Die GS-Expression war in allen HB mit ß-Catenin (CTNNB1)-Mutation erhöht und in 3 von 4 WT mit ß-Catenin (CTNNB1)-Mutation. Epithelial-fetale HB vom hellzelligen Subtyp (5) zeigten eine erhöhte GS-Expression vor allem am Rand des Tumors in direkter Nachbarschaft zum Stroma. Epithelial-embryonale HB (3) exprimierten die GS homogen. Alle Tumore mit ß-Catenin (CTNNB1)-Mutation zeigten auch eine erhöhte Expression für mindestens eine CYP-Isoform. Schlussfolgerung: Zwischen Tumoren mit ß-Catenin (CTNNB1)-Mutation und der Expression des GS-Gens war eine positive Korrelation festzustellen. Zudem exprimierten ß-Catenin (CTNNB1)-mutierte Tumore verstärkt verschiedene CYP-Isoformen. Eine klinische Relevanz dieser Ergebnisse könnte sich aus einem veränderten Medikamentenmetabolismus durch vermehrte Aktivität der CYP-Isoformen ergeben. GS-positive Tumore könnten zudem ein Selektionsvorteil durch Unabhängigkeit von externer Glutamin-Zufuhr besitzen.; Background: Glutamine synthetase (GS) is a target of the Wnt/beta-catenin pathway in the liver. A linkage of the glutamine pathway to hepatocarcinogenesis has been demonstrated. Mutation of beta-catenin gene is frequent in different kind of tumors...

Molecular Evolution and Mutation Accumulation Lines in the Nematode Pristionchus pacificus; Molekulare Evolution und Mutations-Anhäufungs-Linien in der Nematode Pristionchus pacificus

Molnar, Ruxandra
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
EN
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36.35%
The nematode Pristionchus pacificus has been established as a model system for modern evolutionary studies. Evolutionary reconstruction of the natural history of organisms requires knowledge about the development, ecology, and phylogeny of species. Mutations are the source of natural variation, hence studies of mutational processes improve the understanding of the natural history of an organism. Mutation accumulation (MA) lines experiments facilitate the study of spontaneous mutation rates over many generations and offer the possibility of inferring calibrated phylogenies for taxa that lack fossil records. In this study, we used the MA lines setup to calculate mutation rates at the level of the mitochondrial genome and microsatellite loci of the nuclear genome of P. pacificus. Mitochondrial DNA (mtDNA) evolves rapidly in populations, is usually transmitted maternally without intermolecular recombination and has therefore been intensively used for phylogeographic studies. The P. pacificus mtDNA is 15; 955 bp in length and contains all the known mitochondrial genes. In the 142nd generation of the 82 MA lines, we found an overall mutation rate of 7.6e-8 per site per generation. The unusual presence of a suppressor transfer RNA for the codon UAA has...

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
DE_DE
Relevância na Pesquisa
36.38%
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...

Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification

Parsons, M.T.; Buchanan, D.D.; Thompson, B.; Young, J.P.; Spurdle, A.B.
Fonte: BMJ Publishing Group Publicador: BMJ Publishing Group
Tipo: Artigo de Revista Científica
Publicado em //2012 EN
Relevância na Pesquisa
36.37%
Colorectal cancer (CRC) that demonstrates microsatellite instability (MSI) is caused by either germline mismatch repair (MMR) gene mutations, or 'sporadic' somatic tumour MLH1 promoter methylation. MLH1 promoter methylation is reportedly correlated with tumour BRAF V600E mutation status. No systematic review has been undertaken to assess the value of BRAF V600E mutation and MLH1 promoter methylation tumour markers as negative predictors of germline MMR mutation status. A literature review of CRC cohorts tested for MMR mutations, and tumour BRAF V600E mutation and/or MLH1 promoter methylation was conducted using PubMed. Studies were assessed for tumour features, stratified by tumour MMR status based on immunohistochemistry or MSI where possible. Pooled frequencies and 95% CIs were calculated using a random effects model. BRAF V600E results for 4562 tumours from 35 studies, and MLH1 promoter methylation results for 2975 tumours from 43 studies, were assessed. In 550 MMR mutation carriers, the BRAF V600E mutation frequency was 1.40% (95% CI 0.06% to 3%). In MMR mutation-negative cases, the BRAF V600E mutation frequency was 5.00% (95% CI 4% to 7%) in 1623 microsatellite stable (MSS) cases and 63.50% (95% CI 47% to 79%) in 332 cases demonstrating MLH1 methylation or MLH1 expression loss. MLH1 promoter methylation of the 'A region' was reported more frequently than the 'C region' in MSS CRCs (17% vs 0.06%...