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1.
Am Heart J ; 215: 41-51, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31277053

RESUMO

BACKGROUND: The incretin hormone glucagon-like peptide 1 (GLP-1) has been shown to protect against lethal ischemia-reperfusion injury in animal models and against nonlethal ischemia reperfusion injury in humans. Furthermore, GLP-1 receptor agonists have been shown to reduce major adverse cardiovascular and cerebrovascular events (MACCE) in large-scale studies. We sought to investigate whether GLP-1 reduced percutaneous coronary intervention (PCI)-associated myocardial infarction (PMI) during elective PCI. METHODS: The study was a randomized, double-blind controlled trial in which patients undergoing elective PCI received an intravenous infusion of either GLP-1 at 1.2 pmol/kg/min or matched 0.9% saline placebo before and during the procedure. Randomization was performed in 1:1 fashion, with stratification for diabetes mellitus. Six-hour cardiac troponin I (cTnI) was measured with a primary end point of PMI defined as rise ≫×5 upper limit of normal (280 ng/L). Secondary end points included cTnI rise and MACCE at 12 months. RESULTS: A total of 192 patients were randomized with 152 (79%) male and a mean age of 68.1 ±â€¯8.9 years. No significant differences in patient demographics were noted between the groups. There was no difference in the rate of PMI between GLP-1 and placebo (9 [9.8%] vs 8 [8.3%], P = 1.0) or in the secondary end points of difference in median cTnI between groups (9.5 [0-88.5] vs 20 [0-58.5] ng/L, P = .25) and MACCE at 12 months (7 [7.3%] vs 9 [9.4%], P = .61). CONCLUSIONS: In this randomized, placebo-controlled trial, GLP-1 did not reduce the low incidence of PMI or abrogate biomarker rise during elective PCI, nor did it influence the 12-month MACCE rate which also remained low. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov Number: NCT02127996https://clinicaltrials.gov/ct2/show/NCT02127996.


Assuntos
Procedimentos Cirúrgicos Eletivos/métodos , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fragmentos de Peptídeos/administração & dosagem , Intervenção Coronária Percutânea/métodos , Idoso , Biomarcadores/sangue , Angiografia Coronária , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Período Pré-Operatório , Estudos Retrospectivos , Resultado do Tratamento , Troponina I/sangue
2.
Nat Genet ; 39(8): 984-8, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17618284

RESUMO

Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Idoso , Cromossomos Humanos Par 8 , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
3.
Prenat Diagn ; 33(6): 555-62, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23592512

RESUMO

Recently, we have witnessed the rapid translation into clinical practice of non-invasive prenatal testing for the common aneuploidies, most notably within the United States and China. This represents a lucrative market with testing being driven by companies developing and offering their services. These tests are currently aimed at women with high/medium-risk pregnancies identified by serum screening and/or ultrasound scanning. Uptake has been impressive, albeit limited to the commercial sector. However, non-invasive prenatal diagnosis (NIPD) for single-gene disorders has attracted less interest, no doubt because this represents a much smaller market opportunity and in the majority of cases has to be provided on a bespoke, patient or disease-specific basis. The methods and workflows are labour-intensive and not readily scalable. Nonetheless, there exists a significant need for NIPD of single-gene disorders, and the continuing advances in technology and data analysis should facilitate the expansion of the NIPD test repertoire. Here, we review the progress that has been made to date, the different methods and platform technologies, the technical challenges, and assess how new developments may be applied to extend testing to a wider range of genetic disorders.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/métodos , Diagnóstico Pré-Natal/métodos , DNA/sangue , DNA/metabolismo , Feminino , Feto/metabolismo , Doenças Genéticas Inatas/sangue , Humanos , Gravidez
4.
Cardiovasc Res ; 118(3): 872-882, 2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-33783498

RESUMO

AIMS: In pre-clinical models of acute myocardial infarction (MI), mature B cells mobilize inflammatory monocytes into the heart, leading to increased infarct size and deterioration of cardiac function, whilst anti-CD20 antibody-mediated depletion of B cells limits myocardial injury and improves cardiac function. Rituximab is a monoclonal anti-CD20 antibody targeted against human B cells. However, its use in cardiovascular disease is untested and is currently contraindicated. Therefore, we assessed the safety, feasibility, and pharmacodynamic effect of rituximab given to patients with acute ST-elevation MI (STEMI). METHODS AND RESULTS: Rituximab in patients with acute ST-elevation myocardial infarction (RITA-MI) was a prospective, open-label, dose-escalation, single-arm, phase 1/2a clinical trial, which tested rituximab administered as a single intravenous dose in patients with STEMI within 48 h of symptom onset. Four escalating doses (200, 500, 700, and 1000 mg) were used. The primary endpoint was safety, whilst secondary endpoints were changes in circulating immune cell subsets including B cells, and cardiac and inflammatory biomarkers. A total of 24 patients were dosed. Rituximab appeared well tolerated. Seven serious adverse events were reported, none of which were assessed as being related to the rituximab infusion. Rituximab caused a mean 96.3% (95% confidence interval 93.8-98.8%) depletion of circulating B cells within 30 min of starting the infusion. Maximal B-cell depletion was seen at Day 6, which was significantly lower than baseline for all doses (P < 0.001). B-cell repopulation at 6 months was dose-dependent, with modulation of returning B-cell subsets. Immunoglobulin (IgG, IgM, and IgA) levels were not affected during the 6 months of follow-up. CONCLUSIONS: A single infusion of rituximab appears safe when given in the acute STEMI setting and substantially alters circulating B-cell subsets. We provide important new insight into the feasibility and pharmacodynamics of rituximab in acute STEMI, which will inform further clinical translation of this potential therapy. CLINICAL TRIAL REGISTRATION: NCT03072199 at https://www.clinicaltrials.gov/.


Assuntos
Pesquisa Biomédica , Infarto do Miocárdio , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Estudos Prospectivos , Rituximab/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Resultado do Tratamento
5.
Hum Mol Genet ; 17(23): 3720-7, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18753146

RESUMO

The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19; 95% CI: 1.15-1.23; P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.


Assuntos
Cromossomos Humanos Par 11/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Variação Genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Fatores de Risco
6.
J Food Prot ; 69(12): 3031-6, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17186676

RESUMO

Listeria monocytogenes encounters numerous stresses both in the food environment and during infection of the host. The ability to survive and tolerate bile and low pH conditions, which are two major stresses, is of particular importance for survival within the host. The uvrA gene in other bacteria is involved in the repair of acid-induced DNA damage and in adaptation to low pH. Thus, a uvrA in-frame deletion mutant was constructed to identify the role of uvrA in the growth and survival of L. monocytogenes under various environmental conditions. The uvrA mutant was highly sensitive to UV radiation. Growth under normal laboratory conditions was impaired during the exponential phase, and the time to reach the exponential phase of growth, TV(max), was significantly delayed (P < 0.05). Growth of the uvrA mutant in acidic medium (pH 5) was slightly impaired, and the TV(max) was significantly delayed (P < 0.05). Growth and the TV(max) of the mutant in the presence of 0.3% bile salts also were significantly impaired (P < 0.05). These results suggest that uvrA is needed for optimal growth and survival of L. monocytogenes under various stressful environmental conditions.


Assuntos
Proteínas de Bactérias/genética , Ácidos e Sais Biliares/farmacologia , Irradiação de Alimentos , Genes Bacterianos , Listeria monocytogenes/crescimento & desenvolvimento , Listeria monocytogenes/genética , Contagem de Colônia Microbiana , Qualidade de Produtos para o Consumidor , Reparo do DNA , Microbiologia de Alimentos , Humanos , Concentração de Íons de Hidrogênio , Listeria monocytogenes/efeitos da radiação , Mutação , Tolerância a Radiação , Fatores de Tempo , Raios Ultravioleta
7.
Genome Res ; 19(6): 987-93, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19395656

RESUMO

Recent genome-wide scans for colorectal cancer (CRC) have revealed the SMAD7 (mothers against decapentaplegic homolog 7) gene as a locus associated with a modest, but highly significant increase in CRC risk. To identify the causal basis of the association between 18q21 variation and CRC, we resequenced the 17-kb region of linkage disequilibrium and evaluated all variants in 2532 CRC cases and 2607 controls. A novel C to G single nucleotide polymorphism (SNP) at 44,703,563 bp was maximally associated with CRC risk (P = 5.98 x 10(-7); > or =1.5-fold more likely to be causal than other variants). Using transgenic assays in Xenopus laevis as a functional model, we demonstrate that the G risk allele leads to reduced reporter gene expression in the colorectum (P = 5.4 x 10(-3)). Electrophoretic mobility shift assays provided evidence for the role of Novel 1 in transcription factor binding. We propose that the novel SNP we have identified is the functional change leading to CRC predisposition through differential SMAD7 expression and, hence, aberrant TGF-beta signaling.


Assuntos
Cromossomos Humanos Par 18/genética , Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único , Proteína Smad7/genética , Idoso , Alelos , Animais , Linhagem Celular Tumoral , Mapeamento Cromossômico , Neoplasias Colorretais/patologia , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença/genética , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Ligação Proteica , Fatores de Risco , Análise de Sequência de DNA , Proteína Smad7/metabolismo , Xenopus laevis/embriologia , Xenopus laevis/genética
8.
Leuk Lymphoma ; 49(2): 271-2, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18231913

RESUMO

Linkage has implicated variation in 18q24 in genetic susceptibility to chronic lymphocytic leukemia (CLL). 18q24 harbors mothers against decapentaplegic homolog 7 (SMAD7), an intracellular antagonist of TGF-beta signaling which participates in a negative feedback loop controlling growth arrest and apoptosis of B-cells. Recently we have demonstrated variation in SMAD7, defined by the single nucleotide polymorphism rs12953717, to be strongly associated with risk of colorectal cancer. Given that many polymorphic variants have pleiotropic effects we explore the relationship between polymorphic variation at rs12953717 and CLL we compared the frequency of genotypes in 984 cases and 4831 healthy controls. There was therefore no evidence for an association between rs12953717 genotype and CLL; P = 0.40 (allelic test) with ORs of 0.99 (95% CI: 0.85 - 1.16) and 0.91 (95% CI: 0.74 - 1.11) for heterozygotes and TT homozygotes, respectively. These data suggests variation at SMAD7 does not significantly contribute to an inherited susceptibility to CLL.


Assuntos
Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Proteína Smad7/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 18 , Frequência do Gene , Genótipo , Humanos , Leucemia Linfocítica Crônica de Células B/etiologia
9.
Leuk Lymphoma ; 49(1): 130-3, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18203022

RESUMO

While familial predisposition to B-cell chronic lymphocytic leukemia (CLL) is well recognized no gene which when mutated in the germline has been unambiguously shown to confer susceptibility to the disease. An approach based on mutation screening methods targeted to coding regions of candidate genes offers an attractive strategy for the identification of rare disease-causing alleles. The RAD genes participate in the cellular response to DNA double strand breaks, detecting DNA damage, activating cell cycle checkpoints and apoptosis. Defects in members of these genes are linked to increased chromosomal instability and in lymphoma predisposition, thereby representing strong candidate susceptibility genes a priori. To examine this proposition we screened 75 familial CLL probands for germline mutations in this set of genes. No overt pathogenic mutations were identified. These findings indicate that germline mutations in RAD51, RAD51AP1, RAD51L1, RAD51L3, RAD52 and RAD54L are unlikely to be causal of an inherited predisposition to CLL.


Assuntos
Mutação em Linhagem Germinativa , Leucemia Linfocítica Crônica de Células B/genética , Proteínas Nucleares/genética , Rad51 Recombinase/genética , Proteína Rad52 de Recombinação e Reparo de DNA/genética , DNA Helicases , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Humanos , Leucemia Linfocítica Crônica de Células B/etiologia , Proteínas de Ligação a RNA
10.
Nat Genet ; 40(5): 623-30, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18372905

RESUMO

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.


Assuntos
Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 8/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Genoma Humano , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Fator de Iniciação 3 em Eucariotos/genética , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
11.
Nat Genet ; 39(11): 1315-7, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17934461

RESUMO

To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 individuals with familial colorectal tumor (627 CRC, 313 advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication sample sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-beta and Wnt signaling) associated with CRC. Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant (P(trend) = 1.0 x 10(-12)).


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Genoma Humano , Proteína Smad7/genética , Alelos , Estudos de Casos e Controles , Ligação Genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
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