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1.
Anticancer Res ; 40(1): 27-34, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892550

RESUMO

BACKGROUND/AIM: Even though prostate cancer (PCa) has good prognosis, there is a discrepancy in the risk among ethnic groups, with high morbidity in African American men. Single nucleotide polymorphisms (SNPs) in interleukin 10 (IL-10) have been associated with inflammation and cancer risk. We investigated the association of five SNPs in the IL-10 promoter with clinical features such as Gleason score and smoking. MATERIALS AND METHODS: A total of 413 DNA samples were obtained from a nested case-control study of African American males who were genotyped for 5 SNPs utilizing pyrosequencing. Multiple and binary logistic regression models were applied to analyze the clinical and genotypic data. RESULTS: rs12122923 and rs1800871 were associated with PCa risk. Smoking was also found to increase the risk of PCa by 1.6-fold. rs1800893 was found to be associated with lower grades for prostate cancer. CONCLUSION: IL-10 promoter polymorphisms might be a risk factor for PCa development in smoking subjects and PCa progression.


Assuntos
Afro-Americanos/genética , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Neoplasias da Próstata/etiologia , Fumar/efeitos adversos , Idoso , Alelos , Biomarcadores , Estudos de Casos e Controles , Suscetibilidade a Doenças , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Medição de Risco , Fatores de Risco
2.
Cancer Genomics Proteomics ; 15(3): 185-191, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29695400

RESUMO

BACKGROUND/AIM: Prostate cancer is the most common malignancy in US males. African American men have higher incidence and mortality rates than European Americans. Five single nucleotide polymorphisms are associated with PCa. We hypothesized haplotypes inferred from these SNPs are also associated with PCa. PATIENTS AND METHODS: We genotyped SNPs in a case-control admixture mapping study. SNP haplotypes inferred for 157 PCa cases and 150 controls were used in the regression analysis. RESULTS: We found an association between "GTCCC", "ATTCT", and "ACCCC" haplotypes and PCa after ancestry adjustment (OR=3.62, 95%CI=1.42-9.21, p=0.0070; OR=7.89, 95%CI=2.36-26.31, p=0.0008; OR=4.34, 95%CI=1.75-10.78, p=0.0016). The rs615382 variant disrupts the recombination signal binding protein with immunoglobulin kappa J binding site in Rac GTPase activating protein 1 (RACGAP1). CONCLUSION: Disruption of notch 1 mediated-repression of RACGAP1 may contribute to PCa in African Americans.


Assuntos
Afro-Americanos/genética , Mapeamento Cromossômico/métodos , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Receptor Notch1/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Idoso , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/patologia
3.
Clin Cancer Res ; 24(2): 306-315, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29113986

RESUMO

Purpose: MuscadinePlus (MPX), a commercial preparation of pulverized muscadine grape skin, was evaluated as a therapeutic option for men with biochemically recurrent (BCR) prostate cancer wishing to defer androgen deprivation therapy.Experimental Design: This was a 12-month, multicenter, placebo-controlled, two-dose, double-blinded trial of MPX in 125 men with BCR prostate cancer, powered to detect a PSA doubling time (PSADT) difference of 6 months (low dose) and 12 months (high dose) relative to placebo. Participants were stratified (baseline PSADT, Gleason score) and randomly assigned 1:2:2 to receive placebo, 500 mg MPX (low), or 4,000 mg MPX (high) daily. Correlates included superoxide dismutase-2 (SOD2) genotype, lipid peroxidation, and polyphenol pharmacokinetics.Results: The evaluable population included 112 patients, all treated for at least 6 months and 62% treated for 12 months. No significant difference was found in PSADT change between control and treatment arms (P = 0.81): control 0.9 months (n = 20; range, 6.7-83.1), low dose 1.5 months (n = 52; range, 10.3-87.2), high dose 0.9 months (n = 40; range, 27.3-88.1). One high-dose patient experienced objective response. No drug-related CTCAE grade 3-4 adverse events were seen. In a preplanned exploratory analysis, PSADT pre-to-post increase was significant in the 27 (26%) genotyped patients with SOD2 Alanine/Alanine genotype (rs4880 T>C polymorphism) on MPX (pooled treatment arms; 6.4 months, P = 0.02), but not in control (1.8 months, P = 0.25).Conclusions: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses. Exploratory analysis revealed a patient population with potential benefit that would require further study. Clin Cancer Res; 24(2); 306-15. ©2017 AACR.


Assuntos
Extratos Vegetais/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Vitis/química , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Estudos de Casos e Controles , Genótipo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Extratos Vegetais/química , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Recidiva , Superóxido Dismutase/genética
4.
Genes (Basel) ; 8(11)2017 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-29120399

RESUMO

Increasing evidence suggests a role of the gut microbiota in colorectal carcinogenesis (CRC). To detect bacterial markers of colorectal cancer in African Americans a metabolomic analysis was performed on fecal water extracts. DNA from stool samples of adenoma and healthy subjects and from colon cancer and matched normal tissues was analyzed to determine the microbiota composition (using 16S rDNA) and genomic content (metagenomics). Metagenomic functions with discriminative power between healthy and neoplastic specimens were established. Quantitative Polymerase Chain Reaction (q-PCR) using primers and probes specific to Streptococcus sp. VT_162 were used to validate this bacterium association with neoplastic transformation in stool samples from two independent cohorts of African Americans and Chinese patients with colorectal lesions. The metabolomic analysis of adenomas revealed low amino acids content. The microbiota in both cancer vs. normal tissues and adenoma vs. normal stool samples were different at the 16S rRNA gene level. Cross-mapping of metagenomic data led to 9 markers with significant discriminative power between normal and diseased specimens. These markers identified with Streptococcus sp. VT_162. Q-PCR data showed a statistically significant presence of this bacterium in advanced adenoma and cancer samples in an independent cohort of CRC patients. We defined metagenomic functions from Streptococcus sp. VT_162 with discriminative power among cancers vs. matched normal and adenomas vs. healthy subjects' stools. Streptococcus sp. VT_162 specific 16S rDNA was validated in an independent cohort. These findings might facilitate non-invasive screening for colorectal cancer.

5.
Ethn Dis ; 27(2): 169-178, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28439188

RESUMO

BACKGROUND: Variants of unknown significance (VUSs) have been identified in BRCA1 and BRCA2 and account for the majority of all identified sequence alterations. Notably, VUSs occur disproportionately in people of African descent hampering breast cancer (BCa) management and prevention efforts in the population. Our study sought to identify and characterize mutations associated with increased risk of BCa at young age. METHODS: In our study, the spectrum of mutations in BRCA1 and BRCA2 was enumerated in a cohort of 31 African American women of early age at onset breast cancer, with a family history of breast or cancer in general and/or with triple negative breast cancer. To improve the characterization of the BRCA1 and BRCA2 variants, bioinformatics tools were utilized to predict the potential function of each of the variants. RESULTS: Using next generation sequencing methods and in silico analysis of variants, a total of 197 BRCA1 and 266 BRCA2 variants comprising 77 unique variants were identified in 31 patients. Of the 77 unique variants, one (1.3%) was a pathogenic frameshift mutation (rs80359304; BRCA2 Met591Ile), 13 (16.9%) were possibly pathogenic, 34 (44.2%) were benign, and 29 (37.7%) were VUSs. Genetic epidemiological approaches were used to determine the association with variant, haplotype, and phenotypes, such as age at diagnosis, family history of cancer and family history of breast cancer. There were 5 BRCA1 SNPs associated with age at diagnosis; rs1799966 (P=.045; Log Additive model), rs16942 (P=.033; Log Additive model), rs1799949 (P=.058; Log Additive model), rs373413425 (P=.040 and .023; Dominant and Log Additive models, respectively) and rs3765640 (P=.033 Log Additive model). Additionally, a haplotype composed of all 5 SNPs was found to be significantly associated with younger age at diagnosis using linear regression modeling (P=.023). Specifically, the haplotype containing all the variant alleles was associated with older age at diagnosis (OR= 5.03 95% CI=.91-9.14). CONCLUSIONS: Knowing a patient's BRCA mutation status is important for prevention and treatment decision-making. Improving the characterization of mutations will lead to better management, treatment, and BCa prevention efforts in African Americans who are disproportionately affected with aggressive BCa and may inform future precision medicine genomic-based clinical studies.


Assuntos
Afro-Americanos , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , DNA de Neoplasias/genética , Mutação , Adulto , Idade de Início , Alelos , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Neoplasias da Mama/etnologia , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Prevalência , Estados Unidos/epidemiologia , Adulto Jovem
6.
Autoimmune Infect Dis ; 2(3)2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27559544

RESUMO

AIM: To examine the association of TLR4 Asp299Gly and MICA exon 5 microsatellites polymorphisms with severity of trachoma in a sub-Saharan East Africa population of Tanzanian villagers. METHODS: The samples were genotyped for MICA exon 5 microsatellites and the TLR4 299 A/G polymorphism by Restriction Fragment Length Polymorphism (RFLP), and GeneScan®, respectively. The association of TLR4 Asp299Gly and MICA exon 5 microsatellites with inflammatory trachoma (TI) and trichiasis (TI) were examined. RESULTS: The results showed an association between TLR4 and MICA polymorphisms and trachoma disease severity, as well as with protection. TLR4 an allele was significantly associated with inflammatory trachoma (p=0.0410), while the G allele (p=0.0410) was associated with protection. CONCLUSION: TLR4 and MICA may modulate the risk of severity to trachoma disease by modulating the immune response to Ct. In addition; the increased frequency of MICA-A9 heterozygote in controls may suggest a positive selection of these alleles in adaptation to environments where Ct is endemic.

7.
Bioorg Med Chem ; 24(16): 3849-55, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27345756

RESUMO

Chagas disease, also called American trypanosomiasis, is a parasitic disease caused by Trypanosoma cruzi (T. cruzi). Recent findings have underscored the abundance of the causative organism, (T. cruzi), especially in the southern tier states of the US and the risk burden for the rural farming communities there. Due to a lack of safe and effective drugs, there is an urgent need for novel therapeutic options for treating Chagas disease. We report here our first scientific effort to pursue a novel drug design for treating Chagas disease via the targeting of T. cruzi tubulin. First, the anti T. cruzi tubulin activities of five naphthoquinone derivatives were determined and correlated to their anti-trypanosomal activities. The correlation between the ligand activities against the T. cruzi organism and their tubulin inhibitory activities was very strong with a Pearson's r value of 0.88 (P value <0.05), indicating that this class of compounds could inhibit the activity of the trypanosome organism via T. cruzi tubulin polymerization inhibition. Subsequent molecular modeling studies were carried out to understand the mechanisms of the anti-tubulin activities, wherein, the homology model of T. cruzi tubulin dimer was generated and the putative binding site of naphthoquinone derivatives was predicted. The correlation coefficient for ligand anti-tubulin activities and their binding energies at the putative pocket was found to be r=0.79, a high correlation efficiency that was not replicated in contiguous candidate pockets. The homology model of T. cruzi tubulin and the identification of its putative binding site lay a solid ground for further structure based drug design, including molecular docking and pharmacophore analysis. This study presents a new opportunity for designing potent and selective drugs for Chagas disease.


Assuntos
Doença de Chagas/tratamento farmacológico , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Tubulina (Proteína)/efeitos dos fármacos , Sequência de Aminoácidos , Desenho de Drogas , Humanos , Polimerização , Homologia de Sequência de Aminoácidos , Tripanossomicidas/uso terapêutico , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo
8.
Anticancer Res ; 35(7): 3811-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26124326

RESUMO

BACKGROUND/AIM: Several studies reported that patients with benign prostatic hyperplasia (BPH) experienced a 10% increased incidence of prostate cancer (PCa) after the first 5 years of diagnosis. We investigated the association between single nucleotide polymorphisms (SNPs) in the promoter of Serine Protease Inhibitor Kazal Type 1 (SPINK1) and the increased risk of BPH and PCa. MATERIALS AND METHODS: We genotyped three SNPs in a cases-control study, including BPH and PCa cases. Multiple logistic regression models were applied to analyze clinical and genotypic data. RESULTS: We found an inverse association between SNP rs10035432 and BPH under the log-additive (p=0.007) model. No association was found between these SNPs and PCa risk. However, we observed a possible association between rs1432982 and lower-grade PCa (p=0.05) under the recessive model. CONCLUSION: SPINK1 promoter variants are likely to be associated with the risk of BPH.


Assuntos
Proteínas de Transporte/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/genética , Risco , Inibidor da Tripsina Pancreática de Kazal
9.
Anticancer Res ; 35(3): 1549-58, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25750310

RESUMO

BACKGROUND/AIM: Several studies have revealed an association between single nucleotide polymorphisms (SNPs) in the VDR gene and prostate cancer (PCa) risk in European and Asian populations. To investigate whether VDR SNPs are associated with PCa risk in African-American (AA) men, nine VDR SNPs were analyzed in a case-control study. MATERIALS AND METHODS: Multiple and binary logistic regression models were applied to analyze the clinical and genotypic data. RESULTS: rs731236 and rs7975232 were significantly associated with PCa risk (p<0.05). In the analysis of clinical phenotypes, rs731236, rs1544410 and rs3782905 were strongly associated with high PSA level (p<0.05), whereas rs1544410 and rs2239185 showed a statistically significant association with high Gleason score (p<0.05). Haplotype analysis revealed several VDR haplotypes associated with PCa risk. Additionally, a trend existed, where as the number of risk alleles increased in the haplotype, the greater was the association with risk (p-trend=0.01). CONCLUSION: These results suggest that the VDR SNPs may be associated with PCa risk and other clinical phenotypes of PCa in AA men.


Assuntos
Afro-Americanos/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/genética , Receptores de Calcitriol/genética , Idoso , Estudos de Casos e Controles , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Risco
10.
Bol Asoc Med P R ; 105(1): 18-23, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23767380

RESUMO

Multiple Sclerosis (MS) is a complex disease where genetic and environmental factors have been implicated. The onset of symptoms occurs in individuals from twenty to fifty years of age, producing a progressive impairment of motor, sensory and cognitive functions. MS is more frequent in females than in males with a ratio of 4:1. The prevalence of the MS varies among ethnics groups such as Europeans, Africans and Caucasians. The estimated prevalence of MS in Puerto Rico is 42 for each 100,000 habitants, which is more than the prevalence reported for Central America and the Caribbean. In spite of this prevalence, the genetic component of MS has not been explored in order to know the alleles' expression of Puerto Rican MS patients and compare it with the allele expression in other ethnic groups. Thirty-five patients and 31 control subjects were genotyped. The allele frequencies expressed in this sample were similar to those expressed for Puerto Ricans in the National Marrow Donor Program Registry (n = 3,149). The most prevalent alleles for MS patients were HLA-DRB1*01 and *03. HLA-DQB1*04 was the most frequent in the control group and HLA-A*30, in MS patients. These findings are in agreement with published data. HLA-DQB1*04 was a marginal protector in this sample and this role has not been described before. The accuracy of the results is limited due to the sample size. After performing a statistical power analysis it showed that by increasing the sample the values would be significant.


Assuntos
Genes MHC da Classe II/genética , Genes MHC Classe I/genética , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Adulto , Alelos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Porto Rico
11.
Arch Pharm Res ; 35(1): 27-33, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22297740

RESUMO

The antitrypanosomal activities, cytotoxicity, and selectivity indices of eleven imido-substituted 1,4-naphthoquinone derivatives and nifurtimox have been studied. Compared to nifurtimox (IC(50) = 10.67 µM), all the imido-naphthoquinone analogs (IMDNQ1-IMDNQ11) are more potent on Trypanosoma cruzi with IC50 values ranging from 0.7 µM to 6.1 µM (p < 0.05). Studies of the cytotoxic activities of these compounds on a Balb/C 3T3 mouse fibroblast cell line revealed that four of these compounds, IMDNQ1, IMDNQ2, IMDNQ3, and IMDNQ10 displayed selectivity indices of 60.25, 53.97, 31.83, and 275.3, respectively, rendering them significantly (p < 0.05) more selective in inhibiting the parasite growth than nifurtimox (selectivity index = 10.86).


Assuntos
Citotoxinas/farmacologia , Naftoquinonas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Citotoxinas/química , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Naftoquinonas/química , Tripanossomicidas/química
12.
Invest Ophthalmol Vis Sci ; 50(4): 1734-8, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18824733

RESUMO

PURPOSE: Trachoma remains the leading preventable infectious cause of blindness in developing countries. Human leukocyte antigen (HLA) associations with ocular disease severity and persistent Chlamydia trachomatis infection of Tanzanians living in trachoma-endemic villages were examined to determine possible protective candidate allotypes for vaccine development. METHODS: Buccal swab scrapes were taken from subjects in the Trichiasis Study Group (TSG), which studied females only, and the Family Trachoma Study (FTS), which compared persistently infected probands who had severe disease with disease-free siblings and parents. DNA was purified for polymerase chain reaction sequence-specific oligonucleotide identification of HLA-DRB1, DQB1, and B allotypes. Infection was detected from conjunctival scrapes using a C. trachomatis-specific PCR-enzyme immunoassay for the MOMP-1 gene. RESULTS: In the TSG, DR*B11 (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.26-0.90; P=0.02) was significantly associated with lack of trichiasis, whereas HLA-B*07 (OR, 3.26; 95% CI, 1.42-7.49; P=0.004) and HLA-B*08 (OR, 5.12; 95% CI, 1.74-15.05; P=0.001) were associated with trichiasis. In addition, HLA-B*14 was significantly associated with inflammatory trachoma + follicular trachoma (OR, 3.76; 95% CI, 1.70-8.33; P=0.04). There were no significant allele frequencies for the FTS. CONCLUSIONS: The data suggest that HLA-DRB*11 may offer protection from trichiasis in trachoma hyperendemic villages. Complete allotype identification and designation of its respective protective CD4(+) T-cell antigens could provide a testable candidate vaccine for blindness prevention. Additionally, buccal swab DNA was sufficiently stable when acquired under harsh field conditions and stored long term in the freezer for low-resolution HLA typing.


Assuntos
Alelos , Doenças Endêmicas , Antígenos HLA-B/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Tracoma/genética , Tracoma/prevenção & controle , Adolescente , Adulto , Chlamydia trachomatis/patogenicidade , DNA Bacteriano/análise , Feminino , Citometria de Fluxo , Frequência do Gene , Genótipo , Cadeias beta de HLA-DQ , Cadeias HLA-DRB1 , Teste de Histocompatibilidade , Humanos , Mucosa Bucal , Hibridização de Ácido Nucleico , Porinas/genética , População Rural , Tanzânia/epidemiologia , Tracoma/epidemiologia
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