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‣ Relationships between gene polymorphisms of folate-related proteins and vitamins and metabolites in pregnant women and neonates

LOPREATO, Fernanda R.; STABLER, Sally P.; CARVALHO, Felipe R.; HIRATA, Rosario D. C.; HIRATA, Mario H.; ROBI, Dbora L.; SARNPAIO-NETO, Luiz F.; ALLEN, Robert H.; GUERRA-SHINOHARA, Elvira M.
Fonte: ELSEVIER SCIENCE BV Publicador: ELSEVIER SCIENCE BV
Tipo: Artigo de Revista Científica
Português
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Background: The methylenetetrahydrofolate reductase (MTHFR), glutamate carboxypeptidase II (GCPII) and reduced folate carrier (RFC1) gene polymorphisms were associated with folate status. We investigated the effects of these polymorphisms on serum folate (SF) and folate-related metabolites in mothers and their neonates. Methods: Cobalamin (Cbl), SF, total homocysteine (tHcy), methylmalonic acid (MMA), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) were measured in 275 healthy women and their neonates. MTHFR C677T, GCPII C1561T and RFC1 A80G polymorphisms were determined by PCR-RFLP. Results: Maternal tHcy was affected individually by MTHFR C677T and GCPII C1561T polymorphisms and by combined genotypes MTHFR 677TT/GCPII 1561CC and MTHFR 677TT/RFC1 80AG. The MTHFR and RFC1 polymorphisms were not associated with variations in vitamins or SAM, SAH and MMA in neonates. Neonatal tHcy was predicted directly by maternal tHcy and inversely by maternal SF, neonatal Cbl and neonatal RFC1 80G allele (AG+GG genotypes). Maternal MMA and SAM/SAH were predicted by creatinine and Cbl, respectively. Neonatal MMA was predicted by maternal MMA and GCPII 1561T allele (CT+TT genotypes) and by neonatal Cbl. Conclusions: Maternal tHcy was affected by MTHFR C677T...

‣ Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women

BARBOSA, P. R.; STABLER, S. P.; MACHADO, A. L. K.; BRAGA, R. C.; HIRATA, R. D. C.; HIRATA, M. H.; SAMPAIO-NETO, L. F.; ALLEN, R. H.; GUERRA-SHINOHARA, E. M.
Fonte: NATURE PUBLISHING GROUP Publicador: NATURE PUBLISHING GROUP
Tipo: Artigo de Revista Científica
Português
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Objectives: To examine the association between methylenetetrahydrofolate reductase (MTHFR) (C677T and A1298C), methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G gene polymorphisms and total homocysteine (tHcy), methylmalonic acid (MMA) and S-adenosylmethionine/ S-adenosylhomocysteine (SAM/SAH) levels; and to evaluate the potential interactions with folate or cobalamin (Cbl) status. Subjects/ Methods: Two hundred seventy-five healthy women at labor who delivered full-term normal babies. Cbl, folate, tHcy, MMA, SAM and SAH were measured in serum specimens. The genotypes for polymorphisms were determined by PCR-restriction fragment length polymorphism ( RFLP). Results: Serum folate, MTHFR 677T allele and MTR 2756AA genotypes were the predictors of tHcy levels in pregnant women. Serum Cbl and creatinine were the predictors of SAM/SAH ratio and MMA levels, respectively. The gene polymorphisms were not determinants for MMA levels and SAM/SAH ratios. Low levels of serum folate were associated with elevated tHcy in pregnant women, independently of the gene polymorphisms. In pregnant women carrying MTHFR 677T allele, or MTHFR 1298AA or MTRR 66AA genotypes, lower Cbl levels were associated with higher levels of tHcy. Lower SAM/SAH ratio was found in MTHFR 677CC or MTRR A2756AA genotypes carriers when Cbl levels were lower than 142 pmol/l. Conclusions: Serum folate and MTHFR C677T and MTR A2576G gene polymorphisms were the determinants for tHcy levels. The interaction between low levels of serum Cbl and MTHFR (C677T or A1298C) or MTRR A66G gene polymorphisms was associated with increased tHcy.

‣ Meta-analysis of the association of 4 angiotensinogen polymorphisms with essential hypertension - A role beyond M235T?

PEREIRA, Tiago Veiga; NUNES, Ane C. F.; RUDNICKI, Martina; YAMADA, Yoshiji; PEREIRA, Alexandre Costa; KRIEGER, Jose E.
Fonte: LIPPINCOTT WILLIAMS & WILKINS Publicador: LIPPINCOTT WILLIAMS & WILKINS
Tipo: Artigo de Revista Científica
Português
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Angiotensinogen (AGT) gene polymorphisms have been linked to increased risk of hypertension, but the data remain controversial. In this study we review the most commonly investigated polymorphisms at the AGT locus (other than M235T) and provide summary estimates regarding their association with essential hypertension, while addressing heterogeneity, as well as publication biases. Data on 26 818 subjects from 46 studies for the 4 most-studied AGT variants (T174M in exon 2 and 3 promoter variants: A-6G, A-20C, and G-217A) were meta-analyzed. Statistically significant associations with hypertension were identified for the T174M ( odds ratio [OR]: 1.19; 95% CI: 1.07 to 1.33; P = 0.002) and G-217A (OR: 1.37; 95% CI: 1.17 to 1.59; P = 0.00006) polymorphisms. A dual but consistent effect was observed for the -20C allele, which was associated with a decreased risk of hypertension in populations of mixed and European ancestries (OR: 0.64; 95% CI: 0.44 to 0.92; P = 0.02 and OR: 0.77; 95% CI: 0.65 to 0.91; P = 0.003, respectively), but with a 24% increase in the odds of hypertension in Asian subjects (OR: 1.24; 95% CI: 1.04 to 1.48; P = 0.02). No association of the A-6G variant with hypertension was detected. Current studies support the notion that single variants at the AGT might modulate the risk of hypertension but indicate caution in interpreting these results because of the putative presence of publication bias and gene-environment interactions.

‣ European ancestry and polymorphisms in DNA repair genes modify the risk of melanoma: A case-control study in a high UV index region in Brazil

GONCALVES, Fernanda T.; FRANCISCO, Guilherme; SOUZA, Sonia P. de; LUIZ, Olinda C.; FESTA-NETO, Cyro; SANCHES, Jose A.; CHAMMAS, Roger; GATTAS, Gilka J. F.; ELUF-NETO, Jose
Fonte: ELSEVIER IRELAND LTD Publicador: ELSEVIER IRELAND LTD
Tipo: Artigo de Revista Científica
Português
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Background: UV radiation is the major environmental factor related to development of cutaneous melanoma. Besides sun exposure and the influence of latitude, some host characteristics such as skin phototype and hair and eye color are also risk factors for melanoma. Polymorphisms in DNA repair genes could be good candidates for susceptibility genes, mainly in geographical regions exposed to high solar radiation. Objective: Evaluate the role of host characteristic.; and DNA repair polymorphism in melanoma risk in Brazil. Methods: We carried out a hospital-based case-control study in Brazil to evaluate the contribution of host factors and polymorphisms in DNA repair to melanoma risk. A total of 412 patients (202 with melanoma and 210 controls) were analyzed regarding host characteristics for melanoma risk as well as for 11 polymorphisms in DNA repair genes. Results: We found an association of host characteristics with melanoma development, such as eye and hair color, fair skin, history of pigmented lesions removed, sunburns in childhood and adolescence, and also European ancestry. Regarding DNA repair gene polymorphisms, we found protection for the XPG 1104 His/His genotype (OR 0.32; 95% CI 0.13-0.75), and increased risk for three polymorphisms in the XPC gene (PAT+; IV-6A and 939Gln)...

‣ Better CD4+T Cell Recovery in Brazilian HIV-Infected Individuals Under HAART Due to Cumulative Carriage of SDF-1-3`A, CCR2-V64I, CCR5-D32 and CCR5-Promoter 59029A/G Polymorphisms

RIGATO, Paula O.; HONG, Marisa A.; CASSEB, Jorge; UEDA, Mirthes; CASTRO, Isac de; BENARD, Gil; DUARTE, Alberto J. S.
Fonte: BENTHAM SCIENCE PUBL LTD Publicador: BENTHAM SCIENCE PUBL LTD
Tipo: Artigo de Revista Científica
Português
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Polymorphisms of chemokines and chemokine-receptors genes have been shown to influence the rate of progression to AIDS; however, their influence on response to HAART remains unclear. We investigated the frequency of the SDF-1-3`A, CCR2-64I, CCR5-D32 and CCR5-Promoter-59029-A/G polymorphisms in Brazilian HIV-1-infected and uninfected individuals and their influence on CD4+ T-cell evolution HIV-1 infected individuals before and during HAART. Polymorphism detection was done in a transversal study of 200 HIV-1-infected and 82 uninfected individuals. The rate of CD4+ T cell increase or decrease was studied in a cohort of 155 HIV-1 infected individuals on pre and post-HAART. Polymorphisms were determined by PCR associated with RFLP. The rate of CD4+ T-cell decline or increase was also determined. HIV-1 infected and uninfected subjects showed, respectively, frequencies of 0.193 and 0.220 for SDF-1-3`A, of 0.140 and 0.110 for CCR2-V64I, of 0.038 and 0.055 for CCR5-D32, and of 0.442 and 0.390 for CCR5-P-59029-A/G. HIV-1-infected subjects carrying one, two or three of these four polymorphisms showed better CD4+ T-cell recovery than HIV-1-infected subjects carrying the four wild-type alleles (+2.7, +1.6, +3.5, and -0.9 lymphocytes/mu l/month...

‣ CYP1A2*1C, CYP2E1*5B, and GSTM1 polymorphisms are predictors of risk and poor outcome in head and neck squamous cell carcinoma patients

OLIVIERI, Eloisa Helena Ribeiro; SILVA, Sabrina Daniela da; MENDONCA, Fernando Fernandes; URATA, Yuri Nagamine; VIDAL, Daniel Onofre; FARIA, Marcilia de Araujo Medrado; NISHIMOTO, Ines Nobuko; RAINHO, Claudia Aparecida; KOWALSKI, Luiz Paulo; ROGATTO, Silv
Fonte: ELSEVIER SCIENCE BV Publicador: ELSEVIER SCIENCE BV
Tipo: Artigo de Revista Científica
Português
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Head and neck squamous cell carcinoma (HNSCC) is associated with environmental factors, especially tobacco and alcohol consumption. Most of the carcinogens present in tobacco smoke are converted into DNA-reactive metabolites by cytochrome P450 (CYPs) enzymes and detoxification of these substances is performed by glutathione S-transferases (GSTs). It has been suggested that genetic alterations, such as polymorphisms, play an important role in tumorigenesis and HNSCC progression. The aim of this study was to investigate CYP1A1, CYP1A2, CYP2E1, GSTM1, and GSTT1 polymorphisms as risk factors in HNSCC and their association with clinicopathologic data. The patients comprised 153 individuals with HNSCC (cases) and 145 with no current or previous diagnosis of cancer (controls). Genotyping of the single nucleotide polymorphisms (SNPs) of the CYP1A1, CYP1A2, and CYP2E1 genes was performed by PCR-RFLP and the GSTM1 and GSTT1 copy number polymorphisms (CNPs) were analyzed by PCR-multiplex. As expected, a significant difference was detected for tobacco and alcohol consumption between cases and controls (P < 0.001). It was observed that the CYP1A2*1D (OR = 16.24) variant and GSTM1 null alleles (OR = 0.02) confer increased risk of HNSCC development (P < 0.001). In addition...

‣ Human leukocyte antigen (HLA) and single nucleotide polymorphisms (SNPs) tumor necrosis factor (TNF)-alpha-238 and-308 as genetic markers of susceptibility to psoriasis and severity of the disease in a long-term follow-up Brazilian study

MAGALHAES, Renata Ferreira; BIRAL, Ana Cristina; PANCOTO, Joao Alexandre Tres; DONADI, Eduardo Antonio; MENDES-JUNIOR, Celso Texeira; MAGNA, Luis Antonio; KRAEMER, Maria Helena
Fonte: WILEY-BLACKWELL Publicador: WILEY-BLACKWELL
Tipo: Artigo de Revista Científica
Português
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Background The strongest genetic marker for psoriasis is Cw*06. Polymorphisms in the tumor necrosis factor (TNF)-alpha promoter region, especially replacement of guanine with adenine in positions -238 and -308 are related to higher TNF-alpha production and higher risk for psoriasis in Caucasoid populations, not found in Asians. We performed a case-control study of 69 patients with psoriasis type I and 70 controls, characterized clinical progression along 10-years of follow-up in mild or severe disease and determined HLA class I, II, and TNF single nucleotide polymorphisms (SNPs) -238 and -308 polymorphisms to demonstrate whether these polymorphisms may be genetic risk for susceptibility to psoriasis or severity of the disease in Brazilians. Methods Polymorphisms were identified using PCR/SSP. Alleles, genotypes, and haplotypes frequencies were compared using Fisher`s test. Results More severe disease was found in male patients. It may be suggested that alleles B*37, Cw*06, Cw*12, and DRB1*07 were associated with severe disease course, while B*57 with mild disease. No statistical difference was found between the patients and controls regarding polymorphisms frequencies in TNF SNPs. This study pointed to a higher TNF-238 G/G genotype frequency (OR: 3.21; CI: 1.06-9.71; P = 0.04) in the group with severe disease. Conclusions Polymorphisms in the TNF-alpha SNPs do not seem to be a more important genetic risk factor for psoriasis than the already known Cw*06 in Brazilian patients...

‣ Frequency distribution of XbaIG > T and HaeIIIT > C GLUT1 polymorphisms among different Brazilian ethnic groups

COSTA, G. C. S.; ALCANTARA, L. C. J.; AZEVEDO, R.; MURICY, G.; KASHIMA, S. H.; COVAS, D. T.; GALVAO-CASTRO, B.; GADELHA, S. R.
Fonte: SPRINGER Publicador: SPRINGER
Tipo: Artigo de Revista Científica
Português
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GLUT is the major glucose transporter in mammalian cells. Single nucleotide polymorphisms (SNP) at GLUT1 promoter and regulatory regions have been associated to the risk of developing nephropathy in different type 1 and type 2 diabetic populations. It has been demonstrated that differences in allelic and genotypic frequencies of GLUT1 gene (SLC2A1) polymorphisms occur among different populations. Therefore, ethnic differences in distribution of GLUT1 gene polymorphisms may be an important factor in determining gene-disease association. In this study, we investigated the XbaIG > T and HaeIIIT > C polymorphisms in six different Brazilian populations: 102 individuals from Salvador population (Northern Brazil), 56 European descendants from Joinville (South Brazil), 85 Indians from Tiryi tribe (North Brazil) and 127 samples from Southern Brazil: 44 from European descendants, 42 from African descendants and 41 from Japanese descendants. Genotype frequencies from both sites did not differ significantly from those expected under the Hardy-Weinberg equilibrium. We verified that the allele frequencies of both polymorphisms were heterogeneous in these six Brazilian ethnic groups.; Fundacao de Amparo a Pesquisa do Estado da Bahia (FAPESB)

‣ Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia

ROCHA, V.; PORCHER, R.; FERNANDES, J. F.; FILION, A.; BITTENCOURT, H.; SILVA JR., W.; VILELA, G.; ZANETTE, D. L.; FERRY, C.; LARGHERO, J.; DEVERGIE, A.; RIBAUD, P.; SKVORTSOVA, Y.; TAMOUZA, R.; GLUCKMAN, E.; SOCIE, G.; ZAGO, M. A.
Fonte: NATURE PUBLISHING GROUP Publicador: NATURE PUBLISHING GROUP
Tipo: Artigo de Revista Científica
Português
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Individual differences in drug efficacy or toxicity can be influenced by genetic factors. We investigated whether polymorphisms of pharmacogenes that interfere with metabolism of drugs used in conditioning regimen and graft-versus-host disease (GvHD) prophylaxis could be associated with outcomes after HLA-identical hematopoietic stem cell transplantation (HSCT). Pharmacogenes and their polymorphisms were studied in 107 donors and patients with leukemia receiving HSCT. Candidate genes were: P450 cytochrome family (CYP2B6), glutathione-S-transferase family (GST), multidrug-resistance gene, methylenetetrahydrofolate reductase (MTHFR) and vitamin D receptor (VDR). The end points studied were oral mucositis (OM), hemorrhagic cystitis (HC), toxicity and venoocclusive disease of the liver (VOD), GvHD, transplantation-related mortality (TRM) and survival. Multivariate analyses, using death as a competing event, were performed adjusting for clinical factors. Among other clinical and genetic factors, polymorphisms of CYP2B6 genes that interfere with cyclophosphamide metabolism were associated with OM (recipient CYP2B6*4; P=0.0067), HC (recipient CYP2B6*2; P=0.03) and VOD (donor CYP2B6*6; P=0.03). Recipient MTHFR polymorphisms (C677T) were associated with acute GvHD (P=0.03)...

‣ TNF-alpha polymorphisms are associated with obsessive-compulsive disorder

HOUNIE, Ana Gabriela; CAPPI, Carolina; CORDEIRO, Quirino; SAMPAIO, Aline Santos; MORAES, Ivanil; ROSARIO, Maria Conceicao do; PALACIOS, Selma A.; GOLDBERG, Anna Carla; VALLADA, Homero Pinto; MACHADO-LIMA, Ariane; NAKANO, Eduardo; KALIL, Jorge; PAULS, Davi
Fonte: ELSEVIER IRELAND LTD Publicador: ELSEVIER IRELAND LTD
Tipo: Artigo de Revista Científica
Português
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Introduction: Several lines of evidence support an immunologic involvement in obsessive-compulsive disorder (OCD): the increased prevalence of OCD in patients with rheumatic fever (RF), and the aggregation of obsessive-compulsive spectrum disorders among relatives of RF probands. Tumor necrosis factor alpha is a proinflammatory cytokine involved in RF and other autoimmune diseases. Polymorphisms in the promoter region of the TNFA gene have been associated with RE Given the association between OCD and RF, the goal of the present study was to investigate a possible association between polymorphisms within the promoter region of TNFA and OCD. Materials and methods: Two polymorphisms were investigated: -308 G/A and -238 G/A. The allelic and genotypic frequencies of these polymorphisms were examined in 111 patients who fulfilled DSM-IV criteria for OCD and compared with the frequencies in 250 controls. Results: Significant associations were observed between both polymorphisms and OCD. For -238 G/A, an association between the A allele and OCD was observed (X-2 = 12.05, p = 0.0005). A significant association was also observed between the A allele of the -308 G/A polymorphism and OCD (X-2 = 7.09, p = 0.007). Finally, a haplotype consisting of genotypes of these two markers was also examined. Significant association was observed for the A-A haplotype (p = 0.0099 after correcting for multiple testing). Discussion: There is association between the -308 G/A and -238 G/A TNFA polymorphisms and OCD in our Brazilian sample. However...

‣ Polimorfismos genéticos, susceptibilidade e resposta ao tratamento em crianças portadoras de leucemia linfoblástica aguda; Genetic polymorphisms, susceptibility and treatment outcome in children with acute lymphoblastic leukemia

Andrade, Vanessa da Silva Silveira
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 04/08/2006 Português
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As leucemias constituem o câncer mais comum da infância, representando 30% de todas as neoplasias infantis. Dentre elas, a leucemia linfoblástica aguda (LLA) é a mais freqüente, atingindo 75% dos casos pediátricos de leucemias. A ocorrência da LLA tem sido relacionada com a exposição a alguns fatores ambientais (químico, físico e biológicos) e maternos (uso de drogas e dieta) tanto no desenvolvimento intra-útero como após o nascimento. No entanto, o processo de leucemogênese, particularmente com relação à importância da susceptibilidade genética herdade e fatores ambientais, ainda não foi elucidado. As enzimas do citocromo P450 (CYP), assim como outras enzimas das fases I e II do metabolismo estão envolvidas na biotransformação de uma variedade de xenobióticos presentes na alimentação, no cigarro, nas drogas, nas bebidas alcoólicas e nos poluentes ambientais. Polimorfismos em genes responsáveis por codificar essas enzimas de metabolismo têm sido associados com um aumento na susceptibilidade a diferentes tipos de câncer e a doenças hematológicas em adultos e crianças. Similarmente, a capacidade diferencial de crianças portadoras de leucemia aguda para metabolizar carcinógenos e drogas quimioterápicas...

‣ Polimorfismos genéticos de invasão e metástase, inflamação e reparo de DNA e prognóstico de tumores de laringe ; Influence of genetic polymorphisms related with invasion and metastasis, inflammation and repair of DNA and prognosis of laryngeal squamous cell carcinoma

Mendoza López, Rossana Verónica
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 26/06/2007 Português
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Introdução: O prognóstico dos carcinomas epidermóides de laringe é limitado e a taxa de sobrevida em cinco anos é menor que 70%. A relação de características clínicas e epidemiológicas tem sido investigada na sobrevida de pacientes com tumores de laringe, mas pouco se conhece sobre o efeito dos polimorfismos genéticos no prognóstico da doença. Objetivo: Estudar o papel dos polimorfismos genéticos de genes relacionados aos processos de invasão e metástase (MMP1 e MMP3), de inflamação (Interleucina 2, Interleucina 6, LTA) e reparo de DNA(XRCC1) no prognóstico do carcinoma epidermóide de laringe. Material e métodos: Coorte com 170 pacientes com carcinoma epidermóide de laringe,confirmados por exame anátomo-patológico. Os casos tiveram origem em estudo caso-controle conduzido em cinco hospitais de São Paulo, um hospital em Porto Alegre e outro em Goiânia. As informações sobre o status vital dos pacientes foram levantadas dos prontuários médicos e dos bancos de óbitos municipais e estaduais. A extração do DNA das amostras de sangue dos pacientes foi realizada pelo Instituto de Medicina Tropical da USP e a genotipagem dos polimorfismos genéticos pela Fundação Hemocentro de Ribeirão Preto da Faculdade de Medicina da USP. Resultados: Os polimorfismos genéticos estudados (MMP1 1607...

‣ Polimorfismos nos Genes CYP17, CYP1B1, CYP1A1 e COMT e as Lesões Genômicas Espontâneas em Pacientes com Câncer de Mama; CYP17, CYP1B1, CYP1A1 and COMT Polymorphisms and the Spontaneous Genomic Lesions in Breast Cancer Women

Santos, Raquel Alves dos
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 22/02/2008 Português
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O Câncer de Mama (CM) é o segundo tipo mais freqüente de câncer no mundo e a doença maligna mais comum entre as mulheres. Apesar do câncer ser considerado uma típica doença do envelhecimento, o CM apresenta algumas características distintas no que diz respeito às taxas de incidência. Os fatores de risco para o CM incluem idade da menarca precoce e menopausa tardia, terapias hormonais, exposição aos poluentes ambientais, tabagismo e etilismo, no entanto, a exposição prolongada aos estrógenos representa o fator de risco mais importante. A biossíntese e a metabolização dos estrógenos requerem um grande número de vias que são reguladas por uma série de genes cujos polimorfismos têm sido descritos em associação com o CM. Também se sabe que os estrógenos podem danificar a molécula de DNA por aumentar a formação de aductos ou ainda por induzir a 8-hidroxilação de purinas e as quebras de fita simples e duplas do DNA. Dessa forma, o objetivo do presente do presente trabalho foi investigar os níveis de danos no DNA de pacientes com CM antes da quimioterapia ou da radioterapia, a possível associação entre os polimorfismos dos genes metabolizadores de estrógeno CYP17, CYP1B1, CYP1A1 and COMT e o risco ao CM e também a possível influência desses polimorfismos nos níveis espontâneos de danos no DNA. Os linfócitos do sangue periférico de 45 mulheres com diagnóstico para Carcinoma Ductal "in situ" ou invasorl e 85 mulheres sadias (controles) foram utilizados para avaliação de danos espontâneos no DNA pelo teste do micronúcleo e Ensaio Cometa. Os resultados mostraram que as freqüências de micronúcleos (MNs) e os danos no DNA detectados pelo Ensaio Cometa foram significativamente maiores no grupo de pacientes do CM do que no grupo controle. Os níveis de danos no DNA foram similares entre fumantes e não-fumantes e a idade não influenciou as freqüências de MNs observadas em pacientes com CM e controles. Para a abordagem molecular a casuística foi de 131 mulheres controles saudáveis e 104 mulheres também com diagnóstico para Carcinoma ductal "in situ" ou invasor. A comparação da ocorrência dos polimorfismos estudados nos genes CYP17...

‣ Estudo de polimorfismos genéticos na susceptibilidade e na resposta à sepse; Study of genetic polymorphisms in the susceptibility and in the response to sepsis

Carregaro, Fernanda
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 10/04/2008 Português
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Polimorfismos em genes codificando proteínas envolvidas no reconhecimento de microrganismos e na resposta imune contra patógenos podem influenciar na quantidade ou na função da proteína produzida em resposta ao estímulo bacteriano. Existem evidências de que alguns destes polimorfismos genéticos modificam a resposta do paciente à sepse. No presente estudo, foram estudados polimorfismos presentes em genes que, sabidamente ou supostamente, apresentam um efeito biológico importante na sepse com o objetivo de identificar marcadores associados com a sepse e com a evolução clínica favorável ou com a morte. Entre esses polimorfismos estão aqueles presentes nos genes TNF_, TNFß, IL1RN, HSP70, IL6, IL10, CD14, TLR4, TLR2. As técnicas utilizadas compreenderam PCR em tempo real usando sondas com marcação fluorescente (VIC e FAM), PCR usual, digestão com enzimas de restrição e eletroforese. Os 97 pacientes com sepse, sepse grave e choque séptico estudados foram tratados na UTI do Hospital de Base de São José do Rio Preto. Também foram estudadas amostras de 207 indivíduos saudáveis coletadas no Hemocentro do mesmo hospital. Os polimorfismos IL6-597, HSP70-2 e o haplótipo do gene IL6 apresentaram valores estatisticamente significativos. Os dados obtidos sugerem que os polimorfismos IL6-597 e o haplótipo IL6 -174/-1753/- 2954/-597 estão associados com a evolução clínica da sepse...

‣ Estudo de polimorfismos de MTOR e PPP3CA em receptores de transplante renal e sua relação com a resposta a imunossupressores; Study of MTOR and PPP3CA polymorphisms in renal transplant recipients and its relationship with the response to immunosuppressive agents.

Salgado, Patricia de Cássia
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 26/10/2012 Português
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Os imunossupressores tacrolimo (Tac) e sirolimo (Srl) são amplamente utilizados no transplante renal. Estes medicamentos apresentam estreita faixa terapêutica e estão associados a uma vasta gama de efeitos colaterais. Polimorfismos de nucleotídeo único (SNP) parecem ter um impacto significativo sobre a farmacocinética dos imunossupressores. Com o objetivo de avaliar a associação de SNP nos genes PPP3CA e MTOR com a resposta farmacológica dos imunossupressores tacrolimo e sirolimo foram selecionados 156 indivíduos indicados para transplante renal entre os pacientes atendidos no Hospital do Rim e Hipertensão da UNIFESP. Esses indivíduos foram tratados com esquema imunossupressor baseado em tacrolimo ou convertido para sirolimo. Amostras de sangue foram coletadas antes do transplante para extração de DNA. As determinações das concentrações sanguíneas de Tac foram determinadas por chemiluminescent microparticle immunoassay (CMIA) e as concentrações sanguíneas de Srl foram obtidas pela técnica de HPLC (High- Performance Liquid Chromatography). Os polimorfismos do MTOR (c.1437T>C, T c.2997C>T e c.4731G>A) e PPP3CA (c.249G>A) foram identificados por PCR em tempo real. O polimorfismo PPP3CA c.246G>A não foi associado à dose diária de tacrolimo ou sirolimo. Já a concentração sanguínea de tacrolimo foi menor nos portadores do alelo A no terceiro dia e terceiro mês de estudo. Os polimorfismos do MTOR foram relacionados à concentração sanguínea corrigida pela dose de tacrolimo. Os portadores dos alelos raros G...

‣ Profiles of gene polymorphisms in cytokines and toll-like receptors with higher risk for gastric cancer

De Oliveira, Juliana Garcia; Rossi, Ana Flávia Teixeira; Nizato, Daniela Manchini; Miyasaki, Kenji; Silva, Ana Elizabete
Fonte: Universidade Estadual Paulista Publicador: Universidade Estadual Paulista
Tipo: Artigo de Revista Científica Formato: 978-988
Português
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Background: Chronic inflammation and gastric carcinogenesis show a close association, so gene polymorphisms that modify the intensity of the inflammatory response may contribute to variations in gastric cancer risk. Aims: The purpose of this study was to investigate the combined effect of the pro- and anti-inflammatory cytokines and toll-like receptors polymorphisms on the chronic gastritis and gastric cancer risk in a Brazilian population sample. Methods: We evaluated 669 DNA samples (200 of gastric cancer [GC], 229 of chronic gastritis [CG], and 240 of healthy individuals [C]). Ten polymorphisms were genotyped: IL-1RN and TLR2 -196 to -174 del using the allele-specific PCR method and TNF-A (rs1800629; rs1799724), TNF-B (rs909253), IL-8 (rs4073; rs2227532), IL-10 (rs1800872) and TLR4 (rs4986790; rs4986791) using PCR-RFLP. Results: Polymorphisms TNF-A-308G/A, IL-8-251A/T, TNF-B + 252A/G and TLR4 + 1196C/T were not associated with risk of any gastric lesion. However, an association with increased risk for GC was observed for polymorphisms IL-1RNL/2 (p < 0.001), TNF-A-857C/T (p = 0.022), IL-8-845T/C (p < 0.001), IL-10-592C/A (p < 0.001), TLR2ins/del (p < 0.001), and TLR4 + 896A/G (p = 0.033). In CG, an association was observed only with polymorphisms IL-1RNL/2 and IL-10-592A/C (p < 0.001 for both). A combined analysis of these six polymorphisms associated with GC revealed a profile with two to four combined genotypes which confer a higher risk of gastric carcinogenesis...

‣ Investigação de polimorfismos em genes do sistema imune inato em uma população com diabetes tipo 2; Toll-like receptor 4 (TLR-4) and inducible nitric oxide synthase (iNOS) gene polymorphisms are associated with type 2 diabetes

Renata Alvares Bagarolli
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 16/02/2009 Português
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Atualmente, o DM2 constitui-se como um grande problema de saúde pública mundial devido à sua elevada prevalência, morbimortalidade, além do impacto que apresenta nos custos públicos com a saúde. Os mecanismos fisiopatológicos desta doença têm se tornado cada vez mais evidentes, estando relacionados com o envolvimento exclusivo de células, receptores e mediadores do sistema imune inato. Dentre estes compostos destacam-se o TLR4, um receptor de antígenos deste sistema, responsável por ativar a transcrição de citocinas pró-inflamatórias, e a iNOS, uma enzima cálcio independente, que produz elevadas concentrações de NO. Ambas as proteínas estão envolvidas no desenvolvimento de resistência à insulina. Por esta razão, este presente trabalho investigou se 2 polimorfismos no promotor do gene da iNOS (NOS2) (deleção / inserção AAAT e (CCTTT)n) e 2 polimorfismos na seqüência codificadora do gene do TLR4 (TLR4) (Asp299Gly e Thr399Ile), tanto isolados como em conjunto, possuíam alguma associação com a susceptibilidade de desenvolvimento DM2. Além disso, também foi avaliado se os polimorfismos estavam associados com fatores de risco para a resistência à insulina e características clínicas do DM2. Foram coletadas amostras de sangue de 411 indivíduos...

‣ Angiogenesis regulating gene polymorphisms in adverse pregnancy outcomes.

Andraweera, Prabha Hemamali
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2012 Português
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Introduction: Both placental vascular defects and a genetic contribution are documented in pregnancies complicated by preeclampsia, small-for-gestational-age infants (SGA) and spontaneous preterm birth (sPTB). Our primary aim was to investigate the association between polymorphisms in genes regulating placental vascular integrity including vascular endothelial growth factor (VEGFA), placenta growth factor (PGF), kinase insert domain receptor (KDR), fms-like tyrosine kinase 1 receptor (FLT1), angiopoietin 1 (ANGPT1) and thrombospondin 1 (TSP1) and these pregnancy complications in a Caucasian cohort. The secondary aims were to investigate the association between these polymorphisms and (1) preeclampsia in Sri Lankan women (2) first trimester placental gene expression (3) abnormal uterine and umbilical artery Doppler (4) environment and lifestyle interactions that modify the risk of pregnancy complications and to (5) compare term placental angiogenic gene mRNA expression in complicated pregnancy with uncomplicated pregnancy. Methods: Nulliparous pregnant women, their partners and infants (3234 trios) were recruited to a prospective multicenter cohort study (SCOPE study) in Adelaide, Australia and Auckland, New Zealand. Pregnancy outcomes were classified using international guidelines. Uterine and umbilical artery Doppler was performed at 20 weeks gestation. Mean uterine or umbilical artery resistance indices (RI) above the 90th percentile or the presence of bilateral notching of the uterine artery waveform were considered abnormal. A second Sri Lankan cohort comprised 175 nulliparous preeclamptic women and 171 matched controls. The polymorphisms in the Caucasian parent-infant trios...

‣ Metabolism and gene polymorphisms of the folate pathway in Brazilian women with history of recurrent abortion

Boas,Wendell Vilas; Gonçalves,Rozana Oliveira; Costa,Olívia Lúcia Nunes; Goncalves,Marilda Souza
Fonte: Federação Brasileira das Sociedades de Ginecologia e Obstetrícia Publicador: Federação Brasileira das Sociedades de Ginecologia e Obstetrícia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/02/2015 Português
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PURPOSE: To investigate the association between polymorphisms in genes that encode enzymes involved in folate- and vitamin B12-dependent homocysteine metabolism and recurrent spontaneous abortion (RSA). METHODS: We investigated the C677T and A1298C polymorphisms of the methylenetetrahydrofalate reductase gene (MTHFR), the A2756G polymorphism of the methionine synthase gene (MS) and the 844ins68 insertion of the cystathionine beta synthetase gene (CBS). The PCR technique followed by RFLP was used to assess the polymorphisms; the serum levels of homocysteine, vitamin B12 and folate were investigated by chemiluminescence. The EPI Info Software version 6.04 was used for statistical analysis. Parametric variables were compared by Student's t-test and nonparametric variables by the Wilcoxon rank sum test. RESULTS: The frequencies of gene polymorphisms in 89 women with a history of idiopathic recurrent miscarriage and 150 controls were 19.1 and 19.6% for the C677T, insertion, 20.8 and 26% for the A1298C insertion, 14.2 and 21.9% for the A2756G insertion, and 16.4 and 18% for the 844ins68 insertion, respectively. There were no significant differences between case and control groups in any of the gene polymorphisms investigated. However, the frequency of the 844ins68 insertion in the CBS gene was higher among women with a history of loss during the third trimester of pregnancy (p=0.003). Serum homocysteine...

‣ Dysfunctional Crohn's disease-associated NOD2 polymorphisms cannot be reliably predicted on the basis of RIPK2-binding or membrane association

Parkhouse, Rhiannon; Monie, Tom P.
Fonte: Frontiers Publicador: Frontiers
Tipo: Article; published version
Português
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This is the final version of the article. It first appeared from Frontiers via http://dx.doi.org/10.3389/fimmu.2015.00521; Polymorphisms in NOD2 represent the single greatest genetic risk factor for the development of Crohn's disease. Three different non-synonomous NOD2 polymorphisms - R702W, G908R, L1007fsincC - account for roughly 80 % of all NOD2-associated cases of Crohn's disease and are reported to result in a loss of receptor function in response to muramyl dipeptide stimulation. Loss of NOD2 signalling can result from a failure to detect ligand; alterations in cellular localization; and changes in protein interactions, such as an inability to interact with downstream adaptor protein RIPK2. Using an overexpression system we analysed approximately 50 NOD2 polymorphisms reportedly connected to Crohn's disease to determine if they also displayed loss of function and if this could be related to alterations in protein localization and/or association with RIPK2. Just under half the polymorphisms displayed a significant reduction in signalling capacity following ligand stimulation, with nine of them showing near complete ablation. Only two polymorphisms, R38M and R138Q, lost the ability to interact with RIPK2. However, both these polymorphisms still associated with cellular membranes. In contrast...