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1.
Nat Commun ; 12(1): 1236, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33623038

RESUMO

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.

2.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33450964

RESUMO

In 2020, approximately 191,930 new prostate cancer (PCa) cases are estimated in the United States (US). Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. This study aims to assess methylation patterns between aggressive and indolent PCa including DNA repair genes along with ancestry proportions. Prostate tumors classified as aggressive (n = 11) and indolent (n = 13) on the basis of the Gleason score were collected. Tumor and adjacent normal tissue were annotated on H&E (Haemotoxylin and Eosin) slides and extracted by macro-dissection. Methylation patterns were assessed using the Illumina 850K DNA methylation platform. Raw data were processed using the Bioconductor package. Global ancestry proportions were estimated using ADMIXTURE (k = 3). One hundred eight genes including AOX1 were differentially methylated in tumor samples. Regarding the PCa aggressiveness, six hypermethylated genes (RREB1, FAM71F2, JMJD1C, COL5A3, RAE1, and GABRQ) and 11 hypomethylated genes (COL9A2, FAM179A, SLC17A2, PDE10A, PLEKHS1, TNNI2, OR51A4, RNF169, SPNS2, ADAMTSL5, and CYP4F12) were identified. Two significant differentially methylated DNA repair genes, JMJD1C and RNF169, were found. Ancestry proportion results for African, European, and Indigenous American were 24.1%, 64.2%, and 11.7%, respectively. The identification of DNA methylation patterns related to PCa in H/L men along with specific patterns related to aggressiveness and DNA repair constitutes a pivotal effort for the understanding of PCa in this population.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33420416

RESUMO

BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

4.
Int J Cancer ; 148(1): 99-105, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32930425

RESUMO

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.

5.
Cancers (Basel) ; 12(11)2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33158149

RESUMO

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

6.
Prostate ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33141952

RESUMO

BACKGROUND: In prostate cancer (PCa), lack of androgen receptor (AR) regulated TMPRSS2-ETS-related gene (ERG) gene fusion (ERGnegative ) status has been associated with African American race; however, the implications of ERG status for the location of dominant tumors within the prostate remains understudied. METHODS: An African American-enriched multiinstitutional cohort of 726 PCa patients consisting of both African American men (AAM; n = 254) and European American men (EAM; n = 472) was used in the analyses. Methods of categorical analysis were used. Messenger RNA (mRNA) expression differences between anterior and posterior tumor lesions were analyzed using Wilcoxon rank-sum tests with multiple comparison corrections. RESULTS: Anti-ERG immunohistochemistry staining showed that the association between ERG status and anterior tumors is independent of race and is consistently robust for both AAM (ERGnegative 81.4% vs. ERGpositive 18.6%; p = .005) and EAM (ERGnegative 60.4% vs. ERGpositive 39.6%; p < .001). In a multivariable model, anterior tumors were more likely to be IHC-ERGnegative (odds ratio [OR]: 3.20; 95% confidence interval [CI]: 2.14-4.78; p < .001). IHC-ERGnegative were also more likely to have high-grade tumors (OR: 1.73; 95% CI: 1.06-2.82; p = .02). In the exploratory genomic analysis, mRNA expression of location-dependent genes is highly influenced by ERG status and African American race. However, tumor location did not impact the expression of AR or the major canonical AR-target genes (KLK3, AMACR, and MYC). CONCLUSIONS: ERGnegative tumor status is the strongest predictor of anterior prostate tumors, regardless of race. Furthermore, AR expression and canonical AR signaling do not impact tumor location.

7.
Clin Cancer Res ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037017

RESUMO

PURPOSE: The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME). EXPERIMENTAL DESIGN: A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis. RESULTS: AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial-mesenchymal transition. AAM TME has higher total immune content score (ICSHIGH) compared with 0 (37.8% vs. 21.9%, P = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. IFITM3 (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HRAAM = 2.30; 95% confidence interval (CI), 1.21-4.34; P = 0.01] and validation (HRAAM = 2.42; 95% CI, 1.52-3.86; P = 0.0001) but not in EAM. CONCLUSIONS: Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.

8.
Cancer Med ; 9(22): 8662-8675, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32986937

RESUMO

Approximately 10%-20% of patients with clinically localized clear cell renal cell carcinoma (ccRCC) at time of surgery will subsequently experience metastatic progression. Although considerable progression was seen in the systemic treatment of metastatic ccRCC in last 20 years, once ccRCC spreads beyond the confines of the kidney, 5-year survival is less than 10%. Therefore, significant clinical advances are urgently needed to improve overall survival and patient care to manage the growing number of patients with localized ccRCC. We comprehensively evaluated expression of 388 candidate genes related with survival of ccRCC by using TCGA RNAseq (n = 515), Total Cancer Care (TCC) expression array data (n = 298), and a well characterized Moffitt RCC cohort (n = 248). We initially evaluated all 388 genes for association with overall survival using TCGA and TCC data. Eighty-one genes were selected for further analysis and tested on Moffitt RCC cohort using NanoString expression analysis. Expression of nine genes (AURKA, AURKB, BIRC5, CCNE1, MK167, MMP9, PLOD2, SAA1, and TOP2A) was validated as being associated with poor survival. Survival prognostic models showed that expression of the nine genes and clinical factors predicted the survival in ccRCC patients with AUC value: 0.776, 0.821 and 0.873 for TCGA, TCC and Moffitt data set, respectively. Some of these genes have not been previously implicated in ccRCC survival and thus potentially offer insight into novel therapeutic targets. Future studies are warranted to validate these identified genes, determine their biological mechanisms and evaluate their therapeutic potential in preclinical studies.

9.
Nat Commun ; 11(1): 3905, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764609

RESUMO

It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA/genética , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Ilhas de CpG , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Modelos Genéticos , Fatores de Risco
10.
Sci Rep ; 10(1): 10597, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32606331

RESUMO

Transforming growth factor-ß (TGF-ß) promotes tumor invasion and metastasis by inducing epithelial-mesenchymal transition (EMT). EMT is often related with acquisition of stemness characteristics. The objective of this study was to determine whether EMT and stemness characteristics induced by TGF-ß might be associated with epigenetic regulation in lung cancer. A human normal lung epithelial cell line and four lung cancer cell lines were treated with TGF-ß. Transcriptome analysis of BEAS-2B and A549 cells incubated with TGF-ß were analyzed through next-generation sequencing (NGS). Western blotting was carried out to investigate expression levels of epithelial and mesenchymal markers. Wound healing and Matrigel invasion assay, sphere formation assay, and in vivo mice tumor model were performed to evaluate functional characteristics of EMT and stemness acquisition. To investigate whether activation of EMT and stem cell markers might be involved in epigenetic regulation of lung cancer, experiment using a DNA methyltransferase inhibitor (5-azacytidine, AZA), methylation-specific PCR (MSP) and bisulfite sequencing were performed. NGS revealed changes in expression levels of EMT markers (E-cadherin, N-cadherin, fibronectin, vimentin, slug and snail) and stem cell markers (CD44 and CD87) in both BEAS-2B and A549 cells. Functional analysis revealed increased migration, invasion, sphere formation, and tumor development in mice after TGF-ß treatment. Expression of slug and CD87 genes was activated following treatment with AZA and TGF-ß. MSP and bisulfite sequencing indicated DNA demethylation of slug and CD87 genes. These results suggest that TGF-ß induced EMT and cancer stemness acquisition could be associated with activation of slug and CD87 gene by their promoter demethylation.

11.
Eur J Hum Genet ; 28(10): 1467-1475, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32514134

RESUMO

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

12.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1731-1738, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32581112

RESUMO

BACKGROUND: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. METHODS: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. RESULTS: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. CONCLUSIONS: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. IMPACT: Personalized genetic risk assessments could inform prostate cancer screening decisions.

13.
Eur Urol ; 78(3): 316-320, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32409115

RESUMO

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

14.
Am J Mens Health ; 14(3): 1557988320919626, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32436757

RESUMO

The number of cases of aggressive prostate cancer is increasing. Differentiating between aggressive and indolent cases has resulted in increased difficulty for the physician and patient to decide on the best treatment option. Due to this challenge, efforts are underway to profile genetic risk for prostate cancer aggressiveness, which may help physicians and patients at risk for developing aggressive prostate cancer to select an appropriate treatment option. This study explores patients' interest in receiving genetic results, preference for how genetic risk information should be communicated, and willingness to share results with adult male first-degree relatives (FDRs). A nine-item survey was adapted to assess their beliefs and attitudes about genetic testing for prostate cancer aggressiveness. In addition, participants (n = 50) responded to hypothetical scenarios and questions associated with perceived importance of risk disclosure, preferences for receiving genetic risk information, and sharing of results with FDRs. As the hypothetical risk estimate for aggressive prostate cancer increased, patients' willingness to receive genetic risk information increased. This study found that most patients preferred receiving genetic risk education in the form of a DVD (76%), one-page informational sheet (75%), or educational booklet (70%). Almost all patients (98%) reported that they would be willing to share their test results with FDRs. The results of this study highlight prostate cancer patients' desire to receive and share genetic risk information. Future research should focus on assessing the long-term benefits of receiving genetic information for prostate cancer patients and implications of sharing this information with FDRs.

15.
Sci Rep ; 10(1): 5167, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198489

RESUMO

Prostate cancer (PCa) is one of the most common cancers to affect men worldwide. Androgen receptor (AR) signaling is central to PCa and PCa therapy. MicroRNAs (miRNAs) play crucial roles in the regulation of prostate cancer through modulation of signaling pathways. In the present study, we illustrate the functional significance and therapeutic benefit of miR-299-3p, an AR targeting microRNA, in PCa progression. We noted loss of expression of miR-299-3p in prostate tumors compared to noncancerous prostate tissues. Replenishment of miR-299-3p in C4-2B, 22Rv-1 and PC-3 cells contributed to cell cycle arrest, reduced proliferation, migration and increased expression of apoptotic markers. Additionally, overexpression of miR-299-3p induced a reduction of AR, PSA and VEGFA expression. AGO-RNA pulldown experiment showed enrichment of AR, VEGFA and miR-299-3p in C4-2B cells overexpressing miR-299-3p. miR-299-3p overexpression also inhibited epithelial mesenchymal transition, expression of Slug, TGF-ß3, phospho-AKT and phospho-PRAS40, but increased expression of E-cadherin. Furthermore, miR-299 overexpression resulted in reduced tumor growth in xenograft models and increased drug sensitivity. Overall, this study has identified novel mechanisms of antitumor and antimigration function of miR-299-3p through modulation of AR and VEGFA signaling pathways which lead to improved drug sensitivity of PCa.

16.
Cancer Epidemiol Biomarkers Prev ; 29(1): 246-253, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31757784

RESUMO

BACKGROUND: Commercial gene expression signatures of prostate cancer prognosis were developed and validated in cohorts of predominantly European American men (EAM). Limited research exists on the value of such signatures in African American men (AAM), who have poor prostate cancer outcomes. We explored differences in gene expression between EAM and AAM for three commercially available panels recommended by the National Comprehensive Cancer Network for prostate cancer prognosis. METHODS: A total of 232 EAM and 95 AAM patients provided radical prostatectomy specimens. Gene expression was quantified using NanoString for 60 genes spanning the Oncotype DX Prostate, Prolaris, and Decipher panels. A continuous expression-based risk score was approximated for each. Differential expression, intrapanel coexpression, and risk by race were assessed. RESULTS: Clinical and pathologic features were similar between AAM and EAM. Differential expression by race was observed for 48% of genes measured, although the magnitudes of expression differences were small. Coexpression patterns were more strongly preserved by race group for Oncotype DX and Decipher than Prolaris. Poorer prognosis was estimated in EAM versus AAM for Oncotype DX (P < 0.001), whereas negligible prognostic differences were predicted between AAM and EAM using Prolaris or Decipher (P > 0.05). CONCLUSIONS: Because of observed racial differences across three commercial gene expression panels for prostate cancer prognosis, caution is warranted when applying these panels in clinical decision-making in AAM. IMPACT: Differences in gene expression by race for three commercial panels for prostate cancer prognosis indicate that further study of their effectiveness in AAM with long-term follow-up is warranted.


Assuntos
Afro-Americanos/genética , Biomarcadores Tumorais/genética , Grupo com Ancestrais do Continente Europeu/genética , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , Transcriptoma , Humanos , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Neoplasias da Próstata/patologia , Fatores Raciais
17.
Methods Mol Biol ; 2054: 223-241, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31482459

RESUMO

Cell-SELEX is a live cell-based in vitro selection method that generates functional oligonucleotides, or aptamers. Often referenced as the chemist's antibody, aptamers bind to select targets with high affinity and can be utilized in a number of applications, including biomedicine, bioimaging, and biosensing. Here we describe the cell-SELEX technique and discuss this methodology's unique merit(s)-namely the ability to isolate highly selective aptamer panels with no prior knowledge of cellular signatures. This strategy thus presents as a technology that has the potential to enhance the precision of molecular medicine and targeted therapeutics.


Assuntos
Aptâmeros de Nucleotídeos/isolamento & purificação , DNA de Cadeia Simples/isolamento & purificação , Técnica de Seleção de Aptâmeros/métodos , Aptâmeros de Nucleotídeos/genética , Aptâmeros de Nucleotídeos/farmacologia , Técnicas de Cultura de Células/métodos , Linhagem Celular , DNA de Cadeia Simples/genética , DNA de Cadeia Simples/farmacologia , Humanos , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Técnica de Seleção de Aptâmeros/instrumentação , Nanomedicina Teranóstica/métodos
18.
Eur J Cancer Prev ; 28(5): 397-412, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31386635

RESUMO

Gastric cancer is one of the most common causes of cancer-related mortality worldwide. The objective of this article is to review the epidemiology and biology of gastric cancer risk. This literature review explores the biological, clinical, and environmental factors that influence the rates of this disease and discuss the different intervention methods that may not only increase the awareness of gastric cancer but also increase screening in efforts to reduce the risk of gastric cancer. Helicobacter pylori infection is the primary risk factor for gastric cancer. Additional risk factors include geographical location, age, sex, smoking, socioeconomic status, dietary intake, and genetics. Primary and secondary prevention strategies such as dietary modifications and screenings are important measures for reducing the risk of gastric cancer. Interventions, such as H. pylori eradication through chemoprevention trials, have shown some potential as a preventative strategy. Although knowledge about gastric cancer risk has greatly increased, future research is warranted on the differentiation of gastric cancer epidemiology by subsite and exploring the interactions between H. pylori infection, genetics, and environmental factors. Better understanding of these relationships can help researchers determine the most effective intervention strategies for reducing the risk of this disease.


Assuntos
Mucosa Gástrica/patologia , Infecções por Helicobacter/epidemiologia , Helicobacter pylori/patogenicidade , Fumar/epidemiologia , Neoplasias Gástricas/epidemiologia , Fatores Etários , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Antibacterianos/uso terapêutico , Quimioprevenção/métodos , Comportamento Alimentar/fisiologia , Mucosa Gástrica/microbiologia , Predisposição Genética para Doença , Geografia , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Humanos , Metaplasia/epidemiologia , Metaplasia/microbiologia , Metaplasia/patologia , Metaplasia/prevenção & controle , Inibidores da Bomba de Prótons/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Fatores Sexuais , Fumar/efeitos adversos , Classe Social , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/prevenção & controle , Resultado do Tratamento
19.
PLoS One ; 14(8): e0220864, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31425527

RESUMO

There has been marked improvement in leukemia survival, particularly among children in recent time. However, the long-term trends in survival among adult leukemia patients and the associated sex and racial survival disparities are not well understood. We, therefore, evaluated the secular trends in survival improvement of leukemia patients from 1973 through 2014, using Surveillance Epidemiology and End-Result Survey Program (SEER) data. ICD-O-3 morphology codes were used to group leukemia into four types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML). Survival analysis for each leukemia type stratified by race/ethnicity, age, sex was performed to generate relative survival probability estimates for the baseline time period of 1973 through 1979. Hazard ratios (HR) and respective 95% confidence intervals (CIs) for survival within subsequent 10-year time periods by race, age and sex were calculated using Cox proportional hazard models. Of the 83,255 leukemia patients for the current analysis, the 5-year survival of patients with ALL, AML, CLL, and CML during 1973-1979 were 42.0%, 6.5%, 66.5%, and 20.9%, respectively. Compared to the baseline, there were substantial improvements of leukemia-specific survival in 2010-2014 among African-American (81.0%) and Asian (80.0%) patients with CML and among 20-49 year of age with CLL (96.0%). African-American patients, those with AML and those older than 75 years of age had the lowest survival improvements. Asians experienced some of the largest survival improvements during the study period. Others, including African-American and the elderly, have not benefited as much from advances in leukemia treatment.


Assuntos
Leucemia/epidemiologia , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Fatores Sexuais , Análise de Sobrevida , Estados Unidos/epidemiologia , Adulto Jovem
20.
J Morphol ; 280(10): 1485-1491, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31313859

RESUMO

The Korean shuttles mudskipper Periophthalmus modestus has paired olfactory organs on its snout, consisting of anterior and posterior nostrils, a single olfactory canal with sensory and nonsensory epithelia, and a single accessory nasal sac. Its sensory epithelium consists of numerous islets forming a pseudostratified layer and contains various cells: olfactory receptor neurons, supporting cells, basal cells, lymphatic cells (LCs), and axon bundles. The sensory epithelium is a stratified squamous layer comprising stratified epithelial cells, mucous cells (MCs) with glycogen, flattened cells (FCs), LCs, and unidentified cells. Specific structures are as follows: (a) a tubular anterior nostril projecting outward, (b) a slit posterior nostril, (c) an elongated olfactory canal, (d) an ethmoidal accessory nasal sac, (e) axon bundles found only in the basal layer of the sensory epithelium, (f) FCs only at the top of the nonsensory epithelium, and (g) glycogen-containing MCs. Such structures seem to be unique in that they have not been observed in most teleost fishes spending their whole life in water.


Assuntos
Peixes/anatomia & histologia , Mucosa Olfatória/citologia , Animais , Peixes/metabolismo , Cavidade Nasal/anatomia & histologia , Mucosa Olfatória/metabolismo
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