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1.
BMC Genet ; 20(1): 85, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718536

RESUMO

BACKGROUND: Over the relatively short history of Genome Wide Association Studies (GWASs), hundreds of GWASs have been published and thousands of disease risk-associated SNPs have been identified. Summary statistics from the conducted GWASs are often available and can be used to identify SNP features associated with the level of GWAS statistical significance. Those features could be used to select SNPs from gray zones (SNPs that are nominally significant but do not reach the genome-wide level of significance) for targeted analyses. METHODS: We used summary statistics from recently published breast and lung cancer and scleroderma GWASs to explore the association between the level of the GWAS statistical significance and the expression quantitative trait loci (eQTL) status of the SNP. Data from the Genotype-Tissue Expression Project (GTEx) were used to identify eQTL SNPs. RESULTS: We found that SNPs reported as eQTLs were more significant in GWAS (higher -log10p) regardless of the tissue specificity of the eQTL. Pan-tissue eQTLs (those reported as eQTLs in multiple tissues) tended to be more significant in the GWAS compared to those reported as eQTL in only one tissue type. eQTL density in the ±5 kb adjacent region of a given SNP was also positively associated with the level of GWAS statistical significance regardless of the eQTL status of the SNP. We found that SNPs located in the regions of high eQTL density were more likely to be located in regulatory elements (transcription factor or miRNA binding sites). When SNPs were stratified by the level of statistical significance, the proportion of eQTLs was positively associated with the mean level of statistical significance in the group. The association curve reaches a plateau around -log10p ≈ 5. The observed associations suggest that quasi-significant SNPs (10- 5 < p < 5 × 10- 8) and SNPs at the genome wide level of statistical significance (p < 5 × 10- 8) may have a similar proportions of risk associated SNPs. CONCLUSIONS: The results of this study indicate that the SNP's eQTL status, as well as eQTL density in the adjacent region are positively associated with the level of statistical significance of the SNP in GWAS.

2.
Food Sci Nutr ; 7(8): 2731-2739, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31428361

RESUMO

The article presents a technology developed for the production of synbiotic Yoghurt with new bioactive filler based on natural components. The Yoghurt has prebiotic and sorption properties. A higher consumer appeal of the product developed has been substantiated; its characteristics compared with the Yoghurt of traditional production technology have been presented. The brittle, containing peeled walnuts, as well as barley, wheat, rye, oatmeal and buckwheat flakes, sugar, and water, was used as a filler. Optimum time and temperature regimes of boiling caramel mixtures and brewing raw walnut-cereal mass in the brittle have been selected. The formulation developed enables increasing the nutritional and biological values of the finished product. The research studies of the finished product involved an analysis of organoleptic, physicochemical, and microbiological points. When performing the tasks, the approved regulatory and technical documentation (GOST) was applied. Each measurement was carried out in triplicate. The physicochemical characteristics of the samples developed were compared with the requirements for the quality of fermented milk products. The nutritional and biological values were calculated. The increase in consumer properties, and nutritional and biological values of the finished dairy product was scientifically substantiated and experimentally confirmed.

3.
J Thorac Oncol ; 14(8): 1360-1369, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31009812

RESUMO

INTRODUCTION: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. METHODS: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. RESULTS: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. CONCLUSIONS: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.

4.
Oncotarget ; 10(19): 1760-1774, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30956756

RESUMO

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

5.
Cancer Genet ; 231-232: 67-79, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30803560

RESUMO

BACKGROUND: Usually, genes with a higher-than-expected number of somatic mutations in tumor samples are assumed to be cancer related. We identified genes with a fewer-than-expected number of somatic mutations - "untouchable genes". METHODS: To predict the expected number of somatic mutations, we used a linear regression model with the number of mutations in the gene as an outcome, and gene characteristics, including gene size, nucleotide composition, level of evolutionary conservation, expression level and others, as predictors. Analysis of residuals from the regression model was used to compare the observed and predicted number of mutations. RESULTS: We have identified 19 genes with a less-than-expected number of loss-off-function (nonsense, frameshift or pathogenic missense) mutations - i.e., untouchable genes. The number of silent or neutral missense mutations in untouchable genes was equal or higher than the expected number. Many mucins, including MUC16, MUC17, MUC6, MUC5AC, MUC5B, and MUC12, are untouchable. We hypothesized that untouchable mucins help tumor cells to avoid immune response by providing a protective coat that prevents direct contact between effector immune cells, e.g., cytotoxic T-cells, and tumor cells. Survival analysis of available TCGA data demonstrated that overall survival of patients with low (below the median) expression of untouchable mucins was better compared to patients with high expression of untouchable mucins. Aside from mucins, we have identified a number of other untouchable genes. CONCLUSIONS: Untouchable genes may be ideal targets for cancer treatment since suppression of untouchable genes is expected to inhibit survival of tumor cells.


Assuntos
Genes Neoplásicos , Genoma Humano , Neoplasias/genética , Neoplasias/terapia , Códon sem Sentido/genética , Mutação da Fase de Leitura/genética , Humanos , Modelos Lineares , Mutação com Perda de Função/genética , Mucinas/genética , Mutação de Sentido Incorreto/genética , Análise de Sobrevida
6.
Probiotics Antimicrob Proteins ; 11(4): 1324-1329, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30674007

RESUMO

A promising approach for slowing down the rate of reproductive aging is the use of probiotic bacteria as a feed additive. In the current study was investigated the influence of the intake of a potential probiotic on the follicle content and expression of vitellogenin genes (vtg1, vtg2, vtg3) in aged hens. RNA was isolated from liver samples collected from 570-day-old laying hens and gene expression levels were measured using RT-PCR. Bacillus subtilis KATMIRA1933 supplementation had a positive effect on the number of formed follicles in hens and also triggered a significant increase in the relative expression levels of vtg1, vtg2, and vtg3. A Bacillus amyloliquefaciens B-1895 enriched diet or a combination of the two strains had a modest effect on both the number of follicles and the expression of vitellogenin genes. Additionally, the study demonstrates that vitellogenin mRNA expression levels can be considered as a biomarker in a convenient approach for analyzing the hen's egg-laying ability.

7.
Probiotics Antimicrob Proteins ; 11(2): 588-593, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29974408

RESUMO

In the current study, we performed in vivo investigation of probiotic intake influence on nuclear and mitochondrial DNA damage of hens, using quantitative PCR techniques. The probiotic supplementation to the diet of Hisex Brown hens had no significant effect on the rate of telomere shortening. After prolonged probiotic intake (225 and 445 days), the 18-21% decrease in the mtDNA lesions was detected. Since avian mitochondrial DNA damage investigations are rare, the current study of the probiotic-enriched diet's impact on the damage of the hen mitochondrial DNA is novel and highly important. The decrease of mtDNA damage is a beneficial property, which could positively affect the reproductive aging of hens. The positive impact of probiotic supplementation on hens' performance traits such as hen-day egg production, egg weight and mass, and feed conversion ratio was observed.

8.
Mol Cancer Res ; 17(1): 109-119, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30171176

RESUMO

Melanoma is the most aggressive type of skin cancer in the United States with an increasing incidence. Melanoma lesions often exhibit high immunogenicity, with infiltrating immune cells playing important roles in regression of tumors occurring spontaneously or caused by therapeutic treatment. Computational and experimental methods have been used to estimate the abundance of immune cells in tumors, but their applications are limited by the requirement of large gene sets or multiple antibodies. Although the prognostic role of immune cells has been appreciated, a systematic investigation of their association with clinical factors, genomic features, prognosis and treatment response in melanoma is still lacking. This study, identifies a 25-gene signature based on RNA-seq data from The Cancer Genome Atlas (TCGA)-Skin Cutaneous Melanoma (TCGA-SKCM) dataset. This signature was used to calculate sample-specific Leukocyte Infiltration Scores (LIS) in six independent melanoma microarray datasets and scores were found to vary substantially between different melanoma lesion sites and molecular subtypes. For metastatic melanoma, LIS was prognostic in all datasets with high LIS being associated with good survival. The current approach provided additional prognostic information over established clinical factors, including age, tumor stage, and gender. In addition, LIS was predictive of patient survival in stage III melanoma, and treatment efficacy of tumor-specific antigen vaccine. IMPLICATIONS: This study identifies a 25-gene signature that effectively estimates the level of immune cell infiltration in melanoma, which provides a robust biomarker for predicting patient prognosis.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica/métodos , Leucócitos/metabolismo , Melanoma/genética , Neoplasias Cutâneas/genética , Feminino , Humanos , Masculino , Melanoma/patologia , Prognóstico , Neoplasias Cutâneas/patologia
9.
BMC Bioinformatics ; 19(1): 430, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30453881

RESUMO

BACKGROUND: Because driver mutations provide selective advantage to the mutant clone, they tend to occur at a higher frequency in tumor samples compared to selectively neutral (passenger) mutations. However, mutation frequency alone is insufficient to identify cancer genes because mutability is influenced by many gene characteristics, such as size, nucleotide composition, etc. The goal of this study was to identify gene characteristics associated with the frequency of somatic mutations in the gene in tumor samples. RESULTS: We used data on somatic mutations detected by genome wide screens from the Catalog of Somatic Mutations in Cancer (COSMIC). Gene size, nucleotide composition, expression level of the gene, relative replication time in the cell cycle, level of evolutionary conservation and other gene characteristics (totaling 11) were used as predictors of the number of somatic mutations. We applied stepwise multiple linear regression to predict the number of mutations per gene. Because missense, nonsense, and frameshift mutations are associated with different sets of gene characteristics, they were modeled separately. Gene characteristics explain 88% of the variation in the number of missense, 40% of nonsense, and 23% of frameshift mutations. Comparisons of the observed and expected numbers of mutations identified genes with a higher than expected number of mutations- positive outliers. Many of these are known driver genes. A number of novel candidate driver genes was also identified. CONCLUSIONS: By comparing the observed and predicted number of mutations in a gene, we have identified known cancer-associated genes as well as 111 novel cancer associated genes. We also showed that adding the number of silent mutations per gene reported by genome/exome wide screens across all cancer type (COSMIC data) as a predictor substantially exceeds predicting accuracy of the most popular cancer gene predicting tool - MutsigCV.


Assuntos
Códon sem Sentido , Mutação da Fase de Leitura , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Neoplasias/genética , Humanos , Taxa de Mutação
10.
Nat Commun ; 9(1): 3221, 2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-30104567

RESUMO

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.


Assuntos
Cromossomos Humanos Par 15/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes , Fatores de Risco , Fumar/efeitos adversos , Adulto Jovem
11.
Melanoma Res ; 28(5): 380-389, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29975213

RESUMO

Factors influencing melanoma survival include sex, age, clinical stage, lymph node involvement, as well as Breslow thickness, presence of tumor-infiltrating lymphocytes based on histological analysis of primary melanoma, mitotic rate, and ulceration. Identification of genes whose expression in primary tumors is associated with these key tumor/patient characteristics can shed light on molecular mechanisms of melanoma survival. Here, we show results from a gene expression analysis of formalin-fixed paraffin-embedded primary melanomas with extensive clinical annotation. The Cancer Genome Atlas data on primary melanomas were used for validation of nominally significant associations. We identified five genes that were significantly associated with the presence of tumor-infiltrating lymphocytes in the joint analysis after adjustment for multiple testing: IL1R2, PPL, PLA2G3, RASAL1, and SGK2. We also identified two genes significantly associated with melanoma metastasis to the regional lymph nodes (PIK3CG and IL2RA), and two genes significantly associated with sex (KDM5C and KDM6A). We found that LEF1 was significantly associated with Breslow thickness and CCNA2 and UBE2T with mitosis. RAD50 was the gene most significantly associated with survival, with a higher level of expression associated with worse survival.


Assuntos
Expressão Gênica/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Melanoma/mortalidade , Melanoma/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida
13.
J Med Entomol ; 55(5): 1160-1169, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-29733384

RESUMO

The Simulium aureum group (Diptera: Simuliidae), also known as subgenus Eusimulium Roubaud, is a monophyletic, Holarctic taxon of bird-feeding black flies with a reduced chromosome number of two and remarkably similar external structure in all life stages. We analyzed the banding patterns of the polytene chromosomes to understand the composition of this species group along the northern coast of the Black Sea where two little-known nominal species have their type localities. Our analyses link the names Simulium krymense (Rubtsov) and Simulium maritimum (Rubtsov) with unique chromosomal characters, indicate that both are male chiasmate, and reveal the presence of Simulium angustipes Edwards along the northern coast of the Black Sea for the first time. We show that S. krymense has a banding sequence most similar to the hypothesized ancestral form of the S. aureum group, and that the entire group is derived from within the Simulium vernum group, rendering the latter group and its encompassing subgenus, Nevermannia Enderlein, paraphyletic.


Assuntos
Cariótipo , Filogenia , Cromossomos Politênicos , Simuliidae/genética , Animais , Mar Negro , Feminino , Masculino
14.
PLoS One ; 13(1): e0189498, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29293537

RESUMO

Gene-level analysis of ImmunoChip or genome-wide association studies (GWAS) data has not been previously reported for systemic sclerosis (SSc, scleroderma). The objective of this study was to analyze genetic susceptibility loci in SSc at the gene level and to determine if the detected associations were shared in African-American and White populations, using data from ImmunoChip and GWAS genotyping studies. The White sample included 1833 cases and 3466 controls (956 cases and 2741 controls from the US and 877 cases and 725 controls from Spain) and the African American sample, 291 cases and 260 controls. In both Whites and African Americans, we performed a gene-level analysis that integrates association statistics in a gene possibly harboring multiple SNPs with weak effect on disease risk, using Versatile Gene-based Association Study (VEGAS) software. The SNP-level analysis was performed using PLINK v.1.07. We identified 4 novel candidate genes (STAT1, FCGR2C, NIPSNAP3B, and SCT) significantly associated and 4 genes (SERBP1, PINX1, TMEM175 and EXOC2) suggestively associated with SSc in the gene level analysis in White patients. As an exploratory analysis we compared the results on Whites with those from African Americans. Of previously established susceptibility genes identified in Whites, only TNFAIP3 was significant at the nominal level (p = 6.13x10-3) in African Americans in the gene-level analysis of the ImmunoChip data. Among the top suggestive novel genes identified in Whites based on the ImmunoChip data, FCGR2C and PINX1 were only nominally significant in African Americans (p = 0.016 and p = 0.028, respectively), while among the top novel genes identified in the gene-level analysis in African Americans, UNC5C (p = 5.57x10-4) and CLEC16A (p = 0.0463) were also nominally significant in Whites. We also present the gene-level analysis of SSc clinical and autoantibody phenotypes among Whites. Our findings need to be validated by independent studies, particularly due to the limited sample size of African Americans.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Escleroderma Sistêmico/genética , Humanos , Polimorfismo de Nucleotídeo Único
15.
Probiotics Antimicrob Proteins ; 10(2): 367-373, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29238921

RESUMO

The study aims at elucidating the effect of bacilli probiotic preparations on the physiology of laying hens and roosters. Probiotic formulations were prepared as soybean products fermented by Bacillus subtilis KATMIRA1933 and Bacillus amyloliquefaciens B-1895. In this study, groups of male and female chickens were used. These groups received a probiotic preparation based on either B. subtilis KATMIRA1933 or B. amyloliquefaciens B-1895, or of a mixture of strains, from the first day to the age of 39 weeks. These preparations positively affected egg production, quality of sperm production, and quality and hatchery of eggs. Considering the simplicity and cost effectiveness of the soy-based probiotic preparation, these formulations should be considered as advantageous in modern livestock production.


Assuntos
Bacillus amyloliquefaciens/metabolismo , Bacillus subtilis/metabolismo , Galinhas/fisiologia , Suplementos Nutricionais/análise , Probióticos/administração & dosagem , Soja/microbiologia , Ração Animal/análise , Ração Animal/microbiologia , Fenômenos Fisiológicos da Nutrição Animal , Animais , Galinhas/crescimento & desenvolvimento , Dieta/veterinária , Feminino , Fermentação , Masculino , Oviposição , Óvulo/fisiologia , Probióticos/metabolismo , Soja/metabolismo , Espermatozoides/fisiologia
16.
BMC Genomics ; 18(1): 789, 2017 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-29037167

RESUMO

BACKGROUND: Accurate inference of genetic ancestry is of fundamental interest to many biomedical, forensic, and anthropological research areas. Genetic ancestry memberships may relate to genetic disease risks. In a genome association study, failing to account for differences in genetic ancestry between cases and controls may also lead to false-positive results. Although a number of strategies for inferring and taking into account the confounding effects of genetic ancestry are available, applying them to large studies (tens thousands samples) is challenging. The goal of this study is to develop an approach for inferring genetic ancestry of samples with unknown ancestry among closely related populations and to provide accurate estimates of ancestry for application to large-scale studies. METHODS: In this study we developed a novel distance-based approach, Ancestry Inference using Principal component analysis and Spatial analysis (AIPS) that incorporates an Inverse Distance Weighted (IDW) interpolation method from spatial analysis to assign individuals to population memberships. RESULTS: We demonstrate the benefits of AIPS in analyzing population substructure, specifically related to the four most commonly used tools EIGENSTRAT, STRUCTURE, fastSTRUCTURE, and ADMIXTURE using genotype data from various intra-European panels and European-Americans. While the aforementioned commonly used tools performed poorly in inferring ancestry from a large number of subpopulations, AIPS accurately distinguished variations between and within subpopulations. CONCLUSIONS: Our results show that AIPS can be applied to large-scale data sets to discriminate the modest variability among intra-continental populations as well as for characterizing inter-continental variation. The method we developed will protect against spurious associations when mapping the genetic basis of a disease. Our approach is more accurate and computationally efficient method for inferring genetic ancestry in the large-scale genetic studies.


Assuntos
Genética Populacional/métodos , Europa (Continente) , Genoma Humano/genética , Humanos , Filogenia , Análise de Componente Principal
17.
Hum Mol Genet ; 26(8): 1465-1471, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28334950

RESUMO

Genome-wide association studies (GWASs) identified over 500 single nucleotide polymorphisms (SNPs) influencing cancer risk. It is logical to expect the cancer-associated genes to cluster in pathways directly involved in carcinogenesis, e.g. cell cycle. Nevertheless, analyses of the GWAS-detected cancer risk genes usually show no or weak enrichment by known cancer genes.We hypothesized that GWAS-detected cancer risk-associated genes function as upstream regulators of the genes directly involved in carcinogenesis. We have analyzed four common cancers: breast, colon, lung, and prostate. To identify downstream targets of GWAS-detected cancer risk genes we used MedScan, which is a text mining tool offered by PathwayStudio. We also used data on protein/protein interactions reported by BioGRID database. Among all identified targets we have selected common downstream targets. A gene was considered a common downstream target if it was a downstream target for at least three GWAS-detected genes for a given cancer type. Common downstream targets were identified separately for each cancer type. We found that common downstream targets for all four cancer types were enriched by cell cycle genes, more specifically, the genes involved in G1/S transition. Common downstream targets for bipolar disorder, Crohn's disease, and type 2 diabetes did not show G1/S transition enrichment.The results of this analysis suggest that many cancer risk genes function as upstream regulators of the genes directly involved in G1/S transition and exert their risk effects by reducing threshold for G1/S transition, elevating the background level of cell proliferation and cancer risk.


Assuntos
Carcinogênese/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas de Neoplasias/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
18.
EBioMedicine ; 7: 85-93, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27322462

RESUMO

BACKGROUND: In the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride. METHODS: From 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5mg finasteride or placebo daily in a double-blind study during the 4-6weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERß, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers. FINDINGS: We found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups. INTERPRETATION: We showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT.


Assuntos
Finasterida/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Administração Oral , Idoso , Apoptose , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Método Duplo-Cego , Finasterida/farmacologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/metabolismo , Resultado do Tratamento
19.
J Robot Surg ; 10(4): 343-346, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27263110

RESUMO

While robotic-assisted laparoscopic radical prostatectomy (RALRP) is an effective treatment for localized prostate cancer, the risk of complications in older patients can be a deterrent to surgery. We evaluated the rate of medical complications following RALRP in a national dataset of safety events, and assessed whether age is an independent risk factor for these complications. Retrospective analysis of patients undergoing RALRP between 2009 and 2012 in the prospectively maintained American College of Surgeons National Surgical Quality Improvement (ACS-NSQIP) database was performed. Demographic and comorbid data were collated, medical complications occurring during the 30-day post-operative period were identified. We identified age-related comorbidities, and complications associated with these comorbidities. A binary logistic regression model with age and age-related comorbidities as predictors and specific complication as outcome, was used to evaluate whether age is an independent risk factor for these complications. 12,123 patients underwent RALRP between 2009 and 2012, with a mean age of 62 (22-92). Post-operative medical complications included urinary tract infection (UTI) (1.77 %), deep venous thrombosis (DVT) (0.67 %), pulmonary embolism (PE) (0.45 %), pneumonia (PNA) (0.27 %), myocardial infarction (MI) (0.12 %), and cerebrovascular accident (CVA) (0.01 %). Nine comorbidities were positively correlated with age (p < 0.05). Four medical complications were associated with these age-related comorbidities: MI, CVA, PNA, and UTI. On multivariate analysis, age was an independent risk factor for post-operative PNA (p < 0.05), but not for MI (p = 0.09), UTI (p = 0.3) or CVA (p = 0.2). Patient age was independently associated with post-operative pneumonia only. These data suggest that RALRP can be considered as a treatment option in selected older patients with minimal increased risk for post-operative complications.


Assuntos
Laparoscopia/métodos , Complicações Pós-Operatórias/etiologia , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/complicações , Hemorragia/complicações , Humanos , Laparoscopia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Prostatectomia/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/complicações , Melhoria de Qualidade , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Infecções Urinárias/complicações , Adulto Jovem
20.
BMC Bioinformatics ; 17: 122, 2016 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-26961892

RESUMO

BACKGROUND: Identifying subpopulations within a study and inferring intercontinental ancestry of the samples are important steps in genome wide association studies. Two software packages are widely used in analysis of substructure: Structure and Eigenstrat. Structure assigns each individual to a population by using a Bayesian method with multiple tuning parameters. It requires considerable computational time when dealing with thousands of samples and lacks the ability to create scores that could be used as covariates. Eigenstrat uses a principal component analysis method to model all sources of sampling variation. However, it does not readily provide information directly relevant to ancestral origin; the eigenvectors generated by Eigenstrat are sample specific and thus cannot be generalized to other individuals. RESULTS: We developed FastPop, an efficient R package that fills the gap between Structure and Eigenstrat. It can: 1, generate PCA scores that identify ancestral origins and can be used for multiple studies; 2, infer ancestry information for data arising from two or more intercontinental origins. We demonstrate the use of FastPop using 2318 SNP markers selected from the genome based on high variability among European, Asian and West African (African) populations. We conducted an analysis of 505 Hapmap samples with European, African or Asian ancestry along with 19661 additional samples of unknown ancestry. The results from FastPop are highly consistent with those obtained by Structure across the 19661 samples we studied. The correlations of the results between FastPop and Structure are 0.99, 0.97 and 0.99 for European, African and Asian ancestry scores, respectively. Compared with Structure, FastPop is more efficient as it finished ancestry inference for 19661 samples in 16 min compared with 21-24 h required by Structure. FastPop also provided scores based on SNP weights so the scores of reference population can be applied to other studies provided the same set of markers are used. We also present application of the method for studying four continental populations (European, Asian, African, and Native American). CONCLUSIONS: We developed an algorithm that can infer ancestries on data involving two or more intercontinental origins. It is efficient for analyzing large datasets. Additionally the PCA derived scores can be applied to multiple data sets to ensure the same ancestry analysis is applied to all studies.


Assuntos
Algoritmos , Grupos de Populações Continentais/genética , Grupos Étnicos/genética , Genética Populacional , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal , Software , Teorema de Bayes , Genótipo , Projeto HapMap , Humanos
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