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1.
Anim Biotechnol ; : 1-14, 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33325302

RESUMO

The effects of inclusion of powdered seeds of black cumin (B) (Nigella sativa L.) and fenugreek (F) (Trigonella foenum-graecum L.) on productive traits, selected blood constituents, microbiota and immunity of broilers were studied. A total of 648 day-old chicks were randomly assigned to nine treatments, with four pen replicates, each with 18 birds, including three levels of B seed powder (BSP; 0, 5 or 10 g/kg) and three levels of F seed powder (FSP; 0, 5 or 10 g/kg) in a 3 × 3 factorial arrangement. Neither powder affected feed intake. The FSP increased (p = 0.048) feed conversion ratio (FCR), but decreased daily BW gain (p = 0.02) between days 0 and 21, while BSP increased daily gain between days 22 and 42 and overall (both p = 0.005). Abdominal fat was decreased (p = 0.003) by BSP. Blood constituents were unaffected by either powder, but ileal Escherichia coli were decreased (p = 0.039) at day 42. The BSP increased a range of immunological titers, where BSP affected positively the measured variables. The interactions between BSP and FSP, specifically on broiler carcass cuts, suggested that where BSP is included at 10 g/kg, the inclusion of FSP at the same level may provide no additional benefit. Thus, while either powder could be included separately, the co-inclusion of both at 10 g/kg is not recommended.

2.
J Clin Endocrinol Metab ; 105(12)2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32785663

RESUMO

CONTEXT: Lower dehydroepiandrosterone-sulfate (DHEA-S) levels have been inconsistently associated with coronary heart disease (CHD) and mortality. Data are limited for heart failure (HF) and association between DHEA-S change and events. OBJECTIVE: Assess associations between low DHEA-S/DHEA-S change and incident HF hospitalization, CHD, and mortality in older adults. DESIGN: DHEA-S was measured in stored plasma from visits 4 (1996-1998) and 5 (2011-2013) of the Atherosclerosis Risk in Communities study. Follow-up for incident events: 18 years for DHEA-S level; 5.5 years for DHEA-S change. SETTING: General community. PARTICIPANTS: Individuals without prevalent cardiovascular disease (n = 8143, mean age 63 years). MAIN OUTCOME MEASURE: Associations between DHEA-S and incident HF hospitalization, CHD, or mortality; associations between 15-year change in DHEA-S (n = 3706) and cardiovascular events. RESULTS: DHEA-S below the 15th sex-specific percentile of the study population (men: 55.4 µg/dL; women: 27.4 µg/dL) was associated with increased HF hospitalization (men: hazard ratio [HR] 1.30, 95% confidence interval [CI], 1.07-1.58; women: HR 1.42, 95% CI, 1.13-1.79); DHEA-S below the 25th sex-specific percentile (men: 70.0 µg/dL; women: 37.1 µg/dL) was associated with increased death (men: HR 1.12, 95% CI, 1.01-1.25; women: HR 1.19, 95% CI, 1.03-1.37). In men, but not women, greater percentage decrease in DHEA-S was associated with increased HF hospitalization (HR 1.94, 95% CI, 1.11-3.39). Low DHEA-S and change in DHEA-S were not associated with incident CHD. CONCLUSIONS: Low DHEA-S is associated with increased risk for HF and mortality but not CHD. Further investigation is warranted to evaluate mechanisms underlying these associations.

3.
Hum Mutat ; 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32643855

RESUMO

We hypothesized that human genes differ by their sensitivity to ultraviolet (UV) exposure. We used somatic mutations detected by genome-wide screens in melanoma and reported in the Catalog Of Somatic Mutations In Cancer. As a measure of UV sensitivity, we used the number of silent mutations generated by C>T transitions in pyrimidine dimers of a given transcript divided by the number of potential sites for this type of mutations in the transcript. We found that human genes varied by UV sensitivity by two orders of magnitude. We noted that the melanoma-associated tumor suppressor gene CDKN2A was among the top five most UV-sensitive genes in the human genome. Melanoma driver genes have a higher UV-sensitivity compared with other genes in the human genome. The difference was more prominent for tumor suppressors compared with oncogene. The results of this study suggest that differential sensitivity of human transcripts to UV light may explain melanoma specificity of some driver genes. Practical significance of the study relates to the fact that differences in UV sensitivity among human genes need to be taken into consideration whereas predicting melanoma-associated genes by the number of somatic mutations detected in a given gene.

4.
Pract Lab Med ; 21: e00174, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32613070

RESUMO

Matching of actionable tumor mutations with targeted therapy increases response rates and prolongs survival in lung cancer patients. Drug development and trials targeting genetic alterations are expanding rapidly. We describe the role of a Molecular Tumor Board (MTB) in the design of molecularly informed treatment strategies in our lung cancer patient population. Tumor DNA was sequenced using a 50-gene targeted next-generation sequencing panel. Cases were evaluated by a multidisciplinary MTB who suggested a course of treatment based on each patient's molecular findings. During a three-year period, 21 lung cancer patients were presented at the MTB. All patients lacked common activating EGFR mutations and ALK rearrangements. One patient had Stage IIIb disease; all others were Stage IV; 18 patients had received ≥1 prior line of therapy (range 0-5). Suggestions for treatment with a targeted therapy were made for 19/21 (90.5%) patients, and four patients (21%) underwent treatment with a targeted agent, two as part of a clinical trial. Identified barriers to treatment with targeted therapy included: ineligibility for clinical trials (n â€‹= â€‹2), lack of interest in study/distance to travel (n â€‹= â€‹2), lack of disease progression (n â€‹= â€‹2), poor performance status (n â€‹= â€‹5), decision to treat next with immunotherapy (n â€‹= â€‹3), and unknown (n â€‹= â€‹1). For the majority of lung cancer patients, the MTB provided recommendations based on tumor genetic profiles. Identified barriers to treatment suggest that presentation to the MTB at earlier stages of disease may increase the number of patients eligible for treatment with a genetically informed targeted agent.

5.
Carcinogenesis ; 41(10): 1353-1362, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32681635

RESUMO

We hypothesized that a joint analysis of cancer risk-associated single-nucleotide polymorphism (SNP) and somatic mutations in tumor samples can predict functional and potentially causal SNPs from GWASs. We used mutations reported in the Catalog of Somatic Mutations in Cancer (COSMIC). Confirmed somatic mutations were subdivided into two groups: (1) mutations reported as SNPs, which we call mutational/SNPs and (2) somatic mutations that are not reported as SNPs, which we call mutational/noSNPs. It is generally accepted that the number of times a somatic mutation is reported in COSMIC correlates with its selective advantage to tumors, with more frequently reported mutations being more functional and providing a stronger selective advantage to the tumor cell. We found that mutations reported ≥10 times in COSMIC-frequent mutational/SNPs (fmSNPs) are likely to be functional. We identified 12 cancer risk-associated SNPs reported in the Catalog of published GWASs at least 10 times as confirmed somatic mutations and therefore deemed to be functional. Additionally, we have identified 42 SNPs that are tightly linked (R2 ≥ 0.8) to SNPs reported in the Catalog of published GWASs as cancer risk associated and that are also reported as fmSNPs. As a result, 54 candidate functional/potentially causal cancer risk associated SNPs were identified. We found that fmSNPs are more likely to be located in evolutionarily conserved regions compared with cancer risk associated SNPs that are not fmSNPs. We also found that fmSNPs also underwent positive selection, which can explain why they exist as population polymorphisms.

6.
Nat Commun ; 11(1): 2220, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393777

RESUMO

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.


Assuntos
Adenocarcinoma/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias Pulmonares/genética , Idoso , Alelos , Bases de Dados Genéticas , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Judeus/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , RNA-Seq , Fatores de Risco
7.
Cancer Epidemiol Biomarkers Prev ; 29(7): 1423-1429, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32277007

RESUMO

BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project. RESULTS: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 × 10-6). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 × 10-3). CONCLUSIONS: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility. IMPACT: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.

8.
J Adv Vet Anim Res ; 7(1): 51-55, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32219109

RESUMO

Objective: This study aims to investigate the callipyge gene (CLPG) polymorphism in sheep of Edilbay, Volgograd, and Kalmyk breeds. Materials and Methods: The analysis was performed by the polymerase chain reaction-restriction fragment length polymorphisms method. The objects of the study were Edilbay fat-tailed sheep (n = 500) at the breeding plant Volgograd-Edilbay (Volgograd region), Volgograd fine-wool sheep (n = 500) at the breeding plant Romashkovskiy (Volgograd region), and Kalmyk fat-tailed sheep (n = 500) at the breeding plant Kirovsky (the Republic of Kalmykia, Yashkul rayon). To conduct the research, tissue samples of 1 cm² from sheep of Kalmyk and Edilbay breeds were taken from the auricle. Results: The allelic CLPG gene variants have been determined and genotypes of representative sampling of the three breeds of livestock grown in the steppe zone of Russia. The presented results of the CLPG gene polymorphism in these sheep breeds grown in Russia were obtained for the first time. The research study has revealed that in terms of the CLPG gene, the Edilbay, Volgograd, and Kalmyk sheep breeds have only a homozygous form. Conclusion: The results obtained expand the current understanding of the molecular markers that characterize the meat qualities of sheep.

9.
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.


Assuntos
Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla/métodos , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Escleroderma Sistêmico/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Modelos Estatísticos , Especificidade de Órgãos , Elementos Reguladores de Transcrição
10.
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.

11.
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.

12.
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.


Assuntos
Cromossomos Humanos Par 5 , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Telomerase/genética , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
13.
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
14.
Probiotics Antimicrob Proteins ; 11(4): 1324-1329, 2019 12.
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.


Assuntos
Proteínas Aviárias/genética , Galinhas/genética , Probióticos/administração & dosagem , Vitelogeninas/genética , Ração Animal/análise , Animais , Proteínas Aviárias/metabolismo , Bacillus amyloliquefaciens/fisiologia , Bacillus subtilis/fisiologia , Galinhas/crescimento & desenvolvimento , Galinhas/fisiologia , Suplementos Nutricionais/análise , Feminino , Expressão Gênica/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Vitelogeninas/metabolismo
15.
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
16.
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.


Assuntos
Bacillus subtilis , Galinhas/genética , Dano ao DNA , DNA Mitocondrial/genética , Probióticos/administração & dosagem , Telômero , Animais , Suplementos Nutricionais , Ovos , Feminino
17.
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
18.
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
19.
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
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