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1.
Cancer Res ; 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653773

RESUMO

Lung carcinogenesis is a complex and stepwise process involving accumulation of genetic mutations in signaling and oncogenic pathways via interactions with environmental factors and host susceptibility. Tobacco exposure is the leading cause of lung cancer, but its relationship to clinically relevant mutations and the composite tumor mutation burden (TMB) has not been fully elucidated. In this study, we investigated the dose-response relationship in a retrospective observational study of 931 patients treated for advanced stage non-small cell lung cancer (NSCLC) between April 2013 and February 2020 at the Dana Farber Cancer Institute and Brigham and Women's Hospital. Doubling smoking pack-years was associated with increased KRASG12C mutations and less frequent EGFRdel19 and EGFRL858R mutations, while doubling smoking-free months was associated with more frequent EGFRL858R. In advanced lung adenocarcinoma, doubling smoking pack-years was associated with an increase in TMB, while doubling smoking-free months was associated with a decrease in TMB, after controlling for age, gender and stage. There is a significant dose-response association of smoking history with genetic alterations in cancer-related pathways and tumor mutation burden in advanced lung adenocarcinoma.

3.
Hum Genet ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33170346

RESUMO

Page 4: In the "Results-Genetic correlation between AD and metabolic traits" section, the sentence "We also observed that HDL had a significant genetic correlation with AD (Rg = -0.137, P = 0.0436)" should be "We also observed that HDL had a significant genetic correlation with AD (Rg = 0.322, P = 0.017)".

4.
Genet Epidemiol ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924180

RESUMO

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1ß pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

5.
Nat Genet ; 52(9): 969-983, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32839606

RESUMO

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Genoma/genética , LDL-Colesterol/genética , Simulação por Computador , Estudo de Associação Genômica Ampla/métodos , Humanos , Modelos Genéticos , Anotação de Sequência Molecular/métodos , Fenótipo , Sequenciamento Completo do Genoma/métodos
6.
Respir Res ; 20(1): 64, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940143

RESUMO

BACKGROUND: A growing number of studies clearly demonstrate a substantial association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD), although little is known about the shared genetics that contribute to this association. METHODS: We conducted a large-scale cross-trait genome-wide association study to investigate genetic overlap between COPD (Ncase = 12,550, Ncontrol = 46,368) from the International COPD Genetics Consortium and four primary cardiac traits: resting heart rate (RHR) (N = 458,969), high blood pressure (HBP) (Ncase = 144,793, Ncontrol = 313,761), coronary artery disease (CAD)(Ncase = 60,801, Ncontrol = 123,504), and stroke (Ncase = 40,585, Ncontrol = 406,111) from UK Biobank, CARDIoGRAMplusC4D Consortium, and International Stroke Genetics Consortium data. RESULTS: RHR and HBP had modest genetic correlation, and CAD had borderline evidence with COPD at a genome-wide level. We found evidence of local genetic correlation with particular regions of the genome. Cross-trait meta-analysis of COPD identified 21 loci jointly associated with RHR, 22 loci with HBP, and 3 loci with CAD. Functional analysis revealed that shared genes were enriched in smoking-related pathways and in cardiovascular, nervous, and immune system tissues. An examination of smoking-related genetic variants identified SNPs located in 15q25.1 region associated with cigarettes per day, with effects on RHR and CAD. A Mendelian randomization analysis showed a significant positive causal effect of COPD on RHR (causal estimate = 0.1374, P = 0.008). CONCLUSION: In a set of large-scale GWAS, we identify evidence of shared genetics between COPD and cardiac traits.


Assuntos
Doenças Cardiovasculares/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Doença Pulmonar Obstrutiva Crônica/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Bases de Dados Genéticas/tendências , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Característica Quantitativa Herdável
7.
Am J Hum Genet ; 104(5): 802-814, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982610

RESUMO

Whole-genome sequencing (WGS) studies are being widely conducted in order to identify rare variants associated with human diseases and disease-related traits. Classical single-marker association analyses for rare variants have limited power, and variant-set-based analyses are commonly used by researchers for analyzing rare variants. However, existing variant-set-based approaches need to pre-specify genetic regions for analysis; hence, they are not directly applicable to WGS data because of the large number of intergenic and intron regions that consist of a massive number of non-coding variants. The commonly used sliding-window method requires the pre-specification of fixed window sizes, which are often unknown as a priori, are difficult to specify in practice, and are subject to limitations given that the sizes of genetic-association regions are likely to vary across the genome and phenotypes. We propose a computationally efficient and dynamic scan-statistic method (Scan the Genome [SCANG]) for analyzing WGS data; this method flexibly detects the sizes and the locations of rare-variant association regions without the need to specify a prior, fixed window size. The proposed method controls for the genome-wise type I error rate and accounts for the linkage disequilibrium among genetic variants. It allows the detected sizes of rare-variant association regions to vary across the genome. Through extensive simulated studies that consider a wide variety of scenarios, we show that SCANG substantially outperforms several alternative methods for detecting rare-variant-associations while controlling for the genome-wise type I error rates. We illustrate SCANG by analyzing the WGS lipids data from the Atherosclerosis Risk in Communities (ARIC) study.


Assuntos
Algoritmos , Biologia Computacional/métodos , Variação Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Sequenciamento Completo do Genoma/métodos , Humanos , Desequilíbrio de Ligação , Modelos Genéticos
8.
J Environ Manage ; 237: 569-575, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30826638

RESUMO

BACKGROUND: China and other developing countries in Asia follow similar economic growth patterns described by the flying geese (FG) model, which explains the "catching-up" process of industrialization in latecomer economies. Japan, newly industrialized economies, and China have followed this path, with similar economic development trajectories. Based on the FG model, we postulated a "flying S" hypothesis stating that if a country is located within an FG region and its energy matrix is relatively constant, its per capita CO2 emission curve will mirror that of "leading geese" countries in the same FG group. METHOD: Historical CO2 emissions data were obtained from literature review and national reports and were calculated using bottom-up methods. A sigmoid-shaped, non-linear mixed effect model was applied to examine ex post data with 1000 simulated predictions to construct 95% empirical bands from these fits. By multiplying by estimated population, we predicted total emissions of selected FG countries. RESULTS: Per capita CO2 emissions from the same FG group mirror each other, especially among second and third industrial sectors. We estimated an annual 18,252.24 million tons of CO2 emissions (MtCO2) (95% CI = 9458.88-23,972.88) in China and 8281.76 MtCO2 (95% CI = 2765.68-14,959.12) in India in 2030. CONCLUSION: This study bridges the macroeconomic FG paradigm to study climate change and proposes a "flying S" hypothesis to predict greenhouse gas emissions in East Asia. By applying our theory to empirical data, we provide an alternative framework to predict CO2 emissions in 2030 and beyond.


Assuntos
Dióxido de Carbono , Carbono , Ásia , China , Índia , Japão
9.
Hum Genet ; 138(3): 271-285, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30805717

RESUMO

A growing number of studies clearly demonstrate a substantial link between metabolic dysfunction and the risk of Alzheimer's disease (AD), especially glucose-related dysfunction; one hypothesis for this comorbidity is the presence of a common genetic etiology. We conducted a large-scale cross-trait GWAS to investigate the genetic overlap between AD and ten metabolic traits. Among all the metabolic traits, fasting glucose, fasting insulin and HDL were found to be genetically associated with AD. Local genetic covariance analysis found that 19q13 region had strong local genetic correlation between AD and T2D (P = 6.78 × 10- 22), LDL (P = 1.74 × 10- 253) and HDL (P = 7.94 × 10- 18). Cross-trait meta-analysis identified 4 loci that were associated with AD and fasting glucose, 3 loci that were associated with AD and fasting insulin, and 20 loci that were associated with AD and HDL (Pmeta < 1.6 × 10- 8, single trait P < 0.05). Functional analysis revealed that the shared genes are enriched in amyloid metabolic process, lipoprotein remodeling and other related biological pathways; also in pancreas, liver, blood and other tissues. Our work identifies common genetic architectures shared between AD and fasting glucose, fasting insulin and HDL, and sheds light on molecular mechanisms underlying the association between metabolic dysregulation and AD.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Metabolismo Energético/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Característica Quantitativa Herdável , Doença de Alzheimer/metabolismo , Glicemia , Jejum , Estudos de Associação Genética , Humanos , Insulina/sangue , Desequilíbrio de Ligação , Redes e Vias Metabólicas , Fenótipo , Locos de Características Quantitativas
10.
Hum Genet ; 137(1): 15-30, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29288389

RESUMO

Over a decade of genome-wide association, studies have made great strides toward the detection of genes and genetic mechanisms underlying complex traits. However, the majority of associated loci reside in non-coding regions that are functionally uncharacterized in general. Now, the availability of large-scale tissue and cell type-specific transcriptome and epigenome data enables us to elucidate how non-coding genetic variants can affect gene expressions and are associated with phenotypic changes. Here, we provide an overview of this emerging field in human genomics, summarizing available data resources and state-of-the-art analytic methods to facilitate in-silico prioritization of non-coding regulatory mutations. We also highlight the limitations of current approaches and discuss the direction of much-needed future research.


Assuntos
Redes Reguladoras de Genes , Variação Genética , Genoma Humano , Genômica , Estudos de Associação Genética , Loci Gênicos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação
11.
Int J Pharm ; 303(1-2): 113-24, 2005 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-16139453

RESUMO

Perphenazine (a potent antiemetic) was aerosolized using capillary aerosol generator to generate respirable condensation aerosols from drug in propylene glycol (PG) solutions, by pumping the liquids through a heated capillary tube. The study characterized the stability of perphenazine during and following aerosol generation. The stability-indicating HPLC method (C-8 column with a mobile phase of 52% 0.01 M pH 3.0 acetate buffer+48% acetonitrile) also enabled the study of perphenazine stability in solution under acidic, basic, oxidizing and photolysing conditions. An LC-MS (ESI+) method was used to characterize the degradation products. Perphenazine was found to be stable in acidic and basic conditions, while perphenazine sulfoxide was the major product formed in dilute peroxide solutions. Two photo-degradation products were formed in PG that were tentatively identified by LC-MS; one of these was synthesized and confirmed to be 2-[4-(3-phenothiazin-10-yl-propyl)-piperazino]-ethanol. Both photolysis products showed that aromatic dechlorination had occurred and one appeared to also result from interaction with the solvent. Within an aerosolization energy window of 84-95 J, fine particle aerosols were generated from perphenazine PG formulations with no significant degradation. Small amounts of degradation products were produced in all samples during aerosolization at elevated (non-optimal) energies. These were largely consistent with those seen to result from oxidation and photolysis in solution, showing that oxidation and dehalogenation appeared to be the main degradation pathways followed when the CAG system was overheated.


Assuntos
Antieméticos/química , Nebulizadores e Vaporizadores , Perfenazina/química , Aerossóis , Antieméticos/análise , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Temperatura Alta , Peróxido de Hidrogênio , Concentração de Íons de Hidrogênio , Luz , Espectrometria de Massas , Oxirredução , Tamanho da Partícula , Perfenazina/análise , Propilenoglicol , Reprodutibilidade dos Testes , Soluções , Fatores de Tempo
12.
Zhongguo Zhong Yao Za Zhi ; 29(5): 390-4, 2004 May.
Artigo em Chinês | MEDLINE | ID: mdl-15706883

RESUMO

The chemical constituents and pharmacological activities on the genus of Symplocos were reviewed. Their constituents mainly included triterpenes and triterpenoid saponins, flavonoids, iridoids, lignans, alkaloids, polysaccharides and ellagic acids. A number of species among them have been used as folk medicine for the treatment of fever, detoxifying, acesodyne and hemostasis.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/isolamento & purificação , Magnoliopsida/química , Plantas Medicinais/química , Triterpenos/isolamento & purificação , Alcaloides/química , Alcaloides/isolamento & purificação , Fármacos Anti-HIV/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Flavonoides/química , Lignanas/química , Lignanas/isolamento & purificação , Estrutura Molecular , Triterpenos/química
13.
J Asian Nat Prod Res ; 5(1): 49-56, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12608639

RESUMO

A new triterpenoid, 2beta,3beta,19alpha,24-tetrahydroxy-23-norurs-12-en-28-oic acid (4), together with three known triterpenoids 3-oxo-19alpha,23,24-trihydroxyurs-12-en-28-oic acid (1), 2alpha,3beta,19alpha,23-tetrahydroxyurs-12-en-28-oic acid (2), 2alpha,3alpha,19alpha,23-tetrahydroxyurs-12-en-28-oic acid (3), was isolated from the roots of Symplocos chinensis. The new triterpenoid shows significant cytotoxic activity against B16 and BGC-823 cells.


Assuntos
Antineoplásicos/farmacologia , Asteraceae , Fitoterapia , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Raízes de Plantas , Triterpenos/administração & dosagem , Triterpenos/uso terapêutico , Células Tumorais Cultivadas/efeitos dos fármacos
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