Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 100
Filtrar
1.
Int J Equity Health ; 20(1): 68, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648504

RESUMO

BACKGROUND: Indigenous people tend to exhibit a higher burden of disability than their non-Indigenous counterparts, and are often underserved by disability services. Engaging appropriately with Indigenous communities, families and individuals in the initial stages of disability assessment and planning is crucial in order to build trust and understanding of disability service models and ensure that Indigenous people receive support that is tailored to their needs and cultural realities. This article aims to identify key elements of culturally competent communication in Indigenous disability assessment and planning, and provide recommendations for strengthening capacity in this area. METHODS: This qualitative research was designed to involve Aboriginal and Torres Strait Islander people at all stages and to reflect the views of Aboriginal and Torres Strait Islander researchers, people and families affected by disability and the community-controlled health sector. Semi-structured individual interviews were undertaken with staff implementing the National Disability Insurance Scheme (NDIS) (n = 4), NDIS participants (n = 24), disability support providers and organisational partners (n = 19) and Community Connectors (n = 8) in Queensland and the Northern Territory of Australia. Key themes derived from thematic analysis included appropriate and adequate engagement of individuals with disability and their families, the role of trusted relationships, and culturally safe and appropriate communication during planning meetings. RESULTS: Overall, the research findings highlight that a low level of cultural competence in the initial stages of the disability assessment and planning process exacerbated participant confusion and distrust towards assessment staff and the NDIS. Given difficulties in communication, participant understanding of the NDIS was generally limited. The necessity of culturally safe and appropriate use of interpreters was stressed, as was the role of trusted individuals, including existing service providers, Community Connectors and family members in providing a solid base for participant understanding of the NDIS. CONCLUSIONS: Cultural competence in disability assessment and planning can be strengthened through multi-level engagement with the Aboriginal community-controlled sector and community leaders. Implementing mechanisms to enable the involvement of families, trusted service providers and Community Connectors can support a more meaningful understanding of individuals' needs within their cultural context and in relation to their cultural roles.

2.
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.

3.
J Dent Hyg ; 94(5): 44-52, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33008949

RESUMO

Purpose: Examining the long-term outcomes of education programs delivered online can help assess the impact of the program on graduates and the value of the delivery format. The purpose of this study was to measure the overall outcomes of an online dental hygiene degree completion program and identify key alumni outcomes.Methods: A 35 item electronic survey was delivered via email to all graduates (2009-2017) of an online degree completion program based in Ann Arbor, Michigan, two years following program completion. Survey items included Likert scale, closed and open-ended questions focusing on career characteristics, leadership, scholarly activities, evidence- and community-based practices, professional confidence, and transformative learning. Descriptive and inferential statistics were used to analyze the data.Results: Of the nine alumni cohorts (n=75), 50 graduates participated in the survey for a response rate of 67%. Eighty-two percent of respondents felt they had more career options after graduation and reported post-degree career activities that included dental hygiene instruction (36%), public health (32%), and administration (14%). There was a statistically significant increase in the instructor/educator role of the participants post-graduation (p = 0.000). The majority (94%) indicated the program improved their competency in areas of leadership and evidence-based practice and all (100%) indicated a greater responsibility to use their professional skills to address oral health disparities in their communitiesConclusion: Graduates of the online degree completion program reported ongoing activities in key areas of leadership, evidence- and community-based practice. Future research should focus on ensuring that program goals reflect the evolving dental hygiene profession and program delivery practices meet the needs of the working professional student.


Assuntos
Higienistas Dentários , Higiene Bucal , Humanos , Estudos Longitudinais , Michigan , Inquéritos e Questionários
4.
Pathology ; 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32967771

RESUMO

ANXA2 (Annexin A2 or Annexin II) is a calcium dependent phospholipid binding protein with diverse cellular functions. While ANXA2 is either absent or expressed focally in the prostate epithelium of well and moderately differentiated tumours, it is highly expressed in a subset of poorly differentiated tumours. Here we examined the association between ANXA2 expression and tumour progression, with consideration of ERG expression status and patient race (Caucasian American and African American). We evaluated ANXA2 and ERG expression in index tumours by immunohistochemistry of whole mounted prostate sections and tissue microarrays derived from radical prostatectomies of 176 patients, matched for long term post-radical prostatectomy follow-up of up to 22 years (median 12.6 years), race and pathological stage. Expression of ERG and ANXA2 was analysed for correlation with grade group (GG), and pathological T (pT) stage. Kaplan-Meier estimation curves were used to examine associations between ANXA2 or ERG expression and biochemical recurrence (BCR) free survival, and distant metastasis free survival. Significant associations were found between ANXA2(+) index tumours and poorest grade groups (GG 4-5, p=0.0037), and worse pathological stage (pT 3-4, p=0.0142). Patients with ANXA2(+) prostate tumours showed trends towards earlier BCR and metastatic progression. ANXA2(+)/ERG(-) tumours were found to be associated with GG 4-5; ANXA2(-)/ERG(+) tumours, with GG 1-2 (p=0.0036). ANXA2 expression was not associated with patient race. The association between high ANXA2 expression and prostate tumours of higher grade (GG 4-5) and stage (pT 3-4) suggests a potential use for ANXA2 as a prognostic biomarker of aggressive prostate cancer.

5.
J Urol ; : 101097JU0000000000001374, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32945736

RESUMO

PURPOSE: Prostate cancer is predominantly indolent at diagnosis with a small fraction (15-25%) representing aggressive subtype [Gleason score (GS) 7-10], which is prone to metastatic progression. It is critical to explore non-invasive assays for the early detection of this aggressive subtype, when it still can be treated effectively. Additionally, there is an emerging need to develop markers that perform equally well across races, as racial differences in the prevalence and mortality of prostate cancer has become evident. MATERIALS AND METHODS: First-catch, non-DRE urine specimens were collected from patients undergoing diagnostic biopsy. Total RNA was extracted from urinary exosomes and a quantitative expression assay protocol using droplet digital PCR was developed for detection of candidate genes in exosomal mRNAs from urine. Clinical performance for the gene expression assay was evaluated to predict high grade cancer (GS 7-10) from low grade cancer (GS 6) and cancer negative cases at biopsy. Assay performance was examined in combination with standard of care (SOC) to determine improvement in model prediction. RESULTS: In a racially diverse patient cohort a two-gene panel (PCA3, PCGEM1), in combination with SOC variables, significantly improved the prediction of high-grade cancer at diagnosis compared to SOC variables alone (AUC=0.88 versus AUC=0.80, respectively, p= 0.016). Decision curve analysis showed that there is a benefit of adopting the gene panel for detection of high-grade cancer compared to SOC alone. CONCLUSIONS: This study highlights the potential for developing broadly applicable CaP diagnostic biomarker panels for aggressive prostate cancer using our novel gene expression assay platform.

6.
Urology ; 143: 103-111, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32525077

RESUMO

OBJECTIVES: To evaluate the association of the Genomic Prostate Score (GPS) assay result with biochemical recurrence (BCR), distant metastases (DM), and prostate-specific death (PCD) in unfavorable intermediate (UFI) risk prostate cancer patients. The GPS assay is used to help guide management decisions for newly diagnosed low and favorable intermediate (FI) risk disease. METHODS: GPS results from 2 studies (Center for Prostate Disease Research [CPDR]; Kaiser Permanente Northern California [KPNC]) in men treated with radical prostatectomy were analyzed to determine associations of the GPS result with BCR, DM, and PCD in UFI risk disease. Analyses included 299 intermediate risk prostate patients, 175 of whom had UFI risk disease (KPNC = 103; CPDR = 72). RESULTS: The GPS result as a dichotomous value (≤40 vs >40) was a significant predictor of BCR in UFI patients in multivariate analyses (hazard ratio [HR] 6.0; 95% confidence interval [CI] 2.0-22.4; P = .0035; CPDR). The GPS result was a strong predictor of all 3 endpoints in multivariate analyses (BCR HR 7.1; 95% CI 5.7-8.8; P < .0001; DM HR 5.4; 95% CI 3.8-7.8; P < .0001; PCD HR 3.4; 95% CI 1.5-8.9; P = .006; KPNC). UFI patients with GPS >40 had outcomes consistent with high-risk disease, whereas UFI patients with GPS ≤40 had outcomes similar to FI risk patients (CPDR/KPNC). CONCLUSIONS: The GPS result was a strong independent predictor of BCR, DM, and PCD in intermediate risk prostate cancer. UFI patients with GPS >40 have a poor prognosis and may benefit from additional therapeutic options.

7.
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.

8.
Cancers (Basel) ; 12(5)2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32429558

RESUMO

Although ~40% of screen-detected prostate cancers (PCa) are indolent, advanced-stage PCa is a lethal disease with 5-year survival rates around 29%. Identification of biomarkers for early detection of aggressive disease is a key challenge. Starting with 52 candidate biomarkers, selected from existing PCa genomics datasets and known PCa driver genes, we used targeted mass spectrometry to quantify proteins that significantly differed in primary tumors from PCa patients treated with radical prostatectomy (RP) across three study outcomes: (i) metastasis ≥1-year post-RP, (ii) biochemical recurrence ≥1-year post-RP, and (iii) no progression after ≥10 years post-RP. Sixteen proteins that differed significantly in an initial set of 105 samples were evaluated in the entire cohort (n = 338). A five-protein classifier which combined FOLH1, KLK3, TGFB1, SPARC, and CAMKK2 with existing clinical and pathological standard of care variables demonstrated significant improvement in predicting distant metastasis, achieving an area under the receiver-operating characteristic curve of 0.92 (0.86, 0.99, p = 0.001) and a negative predictive value of 92% in the training/testing analysis. This classifier has the potential to stratify patients based on risk of aggressive, metastatic PCa that will require early intervention compared to low risk patients who could be managed through active surveillance.

9.
Oncotarget ; 11(15): 1321-1333, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32341752

RESUMO

INTRODUCTION: Oncogenic activation of ERG resulting from TMPRSS2-ERG gene fusion is a key molecular genetic alteration in prostate cancer (CaP). The frequency of ERG fusion is variable by race; however, there are limited data available on germline polymorphisms associating with ERG fusion status. The goal of this study is to identify the inherited risk variants associating with ERG status of CaP. MATERIALS AND METHODS: SNP genotyping was performed on the Illumina platform using Infinium Oncoarray SNP chip on blood derived genomic DNA samples from 400 patients treated by radical prostatectomy at a single military institution. ERG status was determined in whole mounted prostate specimens by immuno-histochemistry (IHC) for ERG protein expression. Data analysis approaches included association analyses based on EMMAX and imputation by IMPUTE2. Imputed SNPs were validated by ddPCR. RESULTS: SNP genotyping analysis using imputation identified rs34349373 (p 4.68 × 10 -8 ) and rs2055272 (p 5.62 × 10-8) in TBC1D22B to be significantly associated with ERG fusion status in index tumor and non-index tumor foci. Imputed SNP rs2055272 was further experimentally validated by ddPCR with 98.04% (100/102) concordance. Initial discovery analysis based on SNPs on Oncoarray SNP chip, showed significant (p 10-5) association for SNPs (rs6698333, rs1889877, rs3798999, rs10215144, rs3818136, rs9380660 and rs1792695) with ERG fusion status. The study also replicated two previously known ERG fusion associated SNPs (rs11704416 in chromsome 22; rs16901979 in chromosome 8). CONCLUSIONS: This study identified SNPs associated with ERG status of CaP. IMPACT: The findings may contribute towards defining the underlying genetics of ERG positive and ERG negative CaP patients.

10.
Urol Oncol ; 38(10): 794.e1-794.e9, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32139288

RESUMO

INTRODUCTION: Combined radiotherapy and hormonal treatment are recommended for intermediate- and high-risk prostate cancer (CaP). This study compared the long-term effects on health-related quality of life (HRQoL) of intermediate- and high-risk CaP patients managed with radiation therapy (RT) with vs. without hormone therapy (HT). METHODS: Patients with intermediate- and high-risk CaP enrolled in the Center for Prostate Disease Research diagnosed from 2007 to 2017 were included. EPIC and SF-36 questionnaires were completed and HRQoL scores were compared for patients receiving RT vs. RT + HT at baseline (pretreatment), 6, 12, 24, 36, 48, and 60 months after CaP diagnosis. Longitudinal patterns of change in HRQoL were modeled using linear regression models, adjusting for baseline HRQoL, age at CaP diagnosis, race, comorbidities, National Comprehensive Cancer Network (NCCN) risk stratum, time to treatment, and follow-up time. RESULTS: Of 164 patients, 93 (56.7%) received RT alone and 71 (43.3%) received RT + HT. Both groups reported comparable baseline HRQoL. Patients receiving RT+HT were more likely to be NCCN high risk as compared to those receiving only RT. The RT + HT patients experienced worse sexual function, hormonal function, and hormonal bother than those who only received RT; however, HRQoL recovered over time for the RT + HT group. No significant differences were observed between groups in urinary and bowel domains or SF-36 mental and physical scores. CONCLUSION: Combined RT + HT treatment was associated with temporary lower scores in sexual and hormonal HRQoL compared with RT only. Intermediate- and high-risk CaP patients should be counseled about the possible declines in HRQoL associated with HT.

11.
Oncotarget ; 11(4): 362-377, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32064040

RESUMO

Prostate cancer is a disease with heterogeneity of multiple gene transcriptomes and biological signaling pathways involved in tumor development. The prostate transmembrane protein, androgen induced 1 (PMEPA1), a multifunctional protein played critical roles in prostate tumorigenesis. The pleiotropic nature of PMEPA1 in modulating androgen and TGF-ß signaling as well as splice variants mechanisms for functional regulations of cancer-associated genes prompted us to investigate the biological roles of PMEPA1 isoforms in prostate cancer. In addition to 4 reported PMEPA1 isoforms (a, b, c and d), one novel isoform PMEPA1-e was identified with RNA Seq analysis of hormone responsive VCaP, LNCaP cells and human prostate cancer samples from The Cancer Genome Atlas (TCGA) dataset. We analyzed the structures, expressions, biological functions and clinical relevance of PMEPA1-e isoform and less characterized isoforms c and d in the context of prostate cancer and AR/TGF-ß signaling. The expression of PMEPA1-e was induced by androgen and AR. In contrast, PMEPA1-d was responsive to TGF-ß and inhibited TGF-ß signaling. Both PMEPA1-d and PMPEA1-e promoted the growth of androgen independent prostate cancer cells. Although PMEPA1-c was responsive to TGF-ß, it was found to have no impacts on cell growth and androgen/TGF-ß signaling. The TCGA data analysis from 499 patients showed higher expression ratios of PMEAP1-b versus -d or -e strongly associated with enhanced Gleason score. Taken together, our findings first time defined the prostate tumorigenesis mediated by PMEPA1-d and -e isoforms, providing novel insights into the new strategies for prognostic evaluation and therapeutics of prostate tumor.

12.
Cancer Med ; 9(6): 2235-2242, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31965751

RESUMO

BACKGROUND: The relationship between race, prostate tumor location, and BCR-free survival is inconclusive. This study examined the independent and joint roles of patient race and tumor location on biochemical recurrence-free (BCR) survival. METHODS: A retrospective cohort study was conducted among men with newly diagnosed, biopsy-confirmed, NCCN-defined low risk CaP who underwent radical prostatectomy (RP) at the Walter Reed National Military Medical Center from 1996 to 2008. BCR-free survival was modeled using Kaplan-Meier estimation curves and multivariable Cox proportional hazards (PH) analyses. RESULTS: There were 539 eligible patients with low-risk CaP (25% African American, AA; 75% Caucasian American, CA). Median age at CaP diagnosis and post-RP follow-up time was 59.2 and 8.1 years, respectively. Kaplan-Meier analyses showed no significant association between race (P = .52) or predominant tumor location (P = .98) on BCR-free survival. In Cox PH multivariable analysis, neither race (HR = 1.18; 95% CI = 0.68-2.02; P = .56) nor predominant tumor location (HR = 1.13; 95% CI = 0.59-2.15; P = .71) was an independent predictor of BCR-free survival. CONCLUSIONS: Neither race nor predominant tumor location was associated with adverse oncologic outcome.

13.
J Transl Med ; 18(1): 10, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910880

RESUMO

BACKGROUND: Predicting the clinical course of prostate cancer is challenging due to the wide biological spectrum of the disease. The objective of our study was to identify prostate cancer prognostic markers in patients 'sera using a multi-omics discovery platform. METHODS: Pre-surgical serum samples collected from a longitudinal, racially diverse, prostate cancer patient cohort (N = 382) were examined. Linear Regression and Bayesian computational approaches integrated with multi-omics, were used to select markers to predict biochemical recurrence (BCR). BCR-free survival was modeled using unadjusted Kaplan-Meier estimation curves and multivariable Cox proportional hazards analysis, adjusted for key pathologic variables. Receiver operating characteristic (ROC) curve statistics were used to examine the predictive value of markers in discriminating BCR events from non-events. The findings were further validated by creating a training set (N = 267) and testing set (N = 115) from the cohort. RESULTS: Among 382 patients, 72 (19%) experienced a BCR event in a median follow-up time of 6.9 years. Two proteins-Tenascin C (TNC) and Apolipoprotein A1V (Apo-AIV), one metabolite-1-Methyladenosine (1-MA) and one phospholipid molecular species phosphatidic acid (PA) 18:0-22:0 showed a cumulative predictive performance of AUC = 0.78 [OR (95% CI) = 6.56 (2.98-14.40), P < 0.05], in differentiating patients with and without BCR event. In the validation set all four metabolites consistently reproduced an equivalent performance with high negative predictive value (NPV; > 80%) for BCR. The combination of pTstage and Gleason score with the analytes, further increased the sensitivity [AUC = 0.89, 95% (CI) = 4.45-32.05, P < 0.05], with an increased NPV (0.96) and OR (12.4) for BCR. The panel of markers combined with the pathological parameters demonstrated a more accurate prediction of BCR than the pathological parameters alone in prostate cancer. CONCLUSIONS: In this study, a panel of serum analytes were identified that complemented pathologic patient features in predicting prostate cancer progression. This panel offers a new opportunity to complement current prognostic markers and to monitor the potential impact of primary treatment versus surveillance on patient oncological outcome.

14.
Eur Urol ; 77(2): 158-166, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31420248

RESUMO

BACKGROUND: Elderly patients (≥65yr) with advanced prostate cancer and cardiovascular disease (CVD) conditions are often excluded from clinical trials of abiraterone acetate (AA) or enzalutamide (ENZ). Consequently, little is known about the effects of these medications on these vulnerable patients. OBJECTIVE: To assess the short-term outcomes of AA and ENZ in patients with pre-existing CVDs. DESIGN, SETTING, AND PARTICIPANTS: A population-based retrospective study. The Surveillance, Epidemiology, and End Results-Medicare-linked database was used to identify prostate cancer patients using AA or ENZ. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was 6-mo all-cause mortality, analyzed using modified Poisson regression modeling of relative risk (RR) adjusted for confounders and comorbidities. RESULTS AND LIMITATIONS: Among eligible patients (2845 with AA and 1031 with ENZ), 67% had at least one pre-existing CVD. Compared with those without pre-existing CVDs, having one to two pre-existing CVDs was associated with 16% higher 6-mo mortality (RR=1.16, 95% confidence interval [CI]: 1.00-1.36), and the risk increased further among those having three or more CVDs (RR=1.56, 95% CI: 1.29-1.88). Most of the differences in survival of patients with pre-existing CVD condition occurred within the first 6mo of treatment. CONCLUSIONS: After treatment with AA or ENZ, elderly prostate cancer patients with pre-existing CVDs experienced higher short-term mortality than otherwise similar patients without CVDs. Mortality associated with CVDs did not depend on having received AA versus ENZ. PATIENT SUMMARY: Patients with pre-existing cardiovascular diseases (CVDs) experienced higher short-term mortality after abiraterone acetate or enzalutamide than those without pre-existing CVDs. It is recommended that a multidisciplinary team, including a cardiologist, evaluate patients having pre-existing CVDs in the process of making treatment decisions and monitoring potential side effects.

15.
J Urol ; : 101097JU0000000000001484, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33493001

RESUMO

PURPOSE: Adoption of prognostic molecular assays for prostate cancer requires evidence of robust performance in different racial groups. Retrospective analysis was conducted to assess the performance of the Oncotype DX® Genomic Prostate Score® test in Black and White men with surgically treated prostate cancer. MATERIALS AND METHODS: We compared the assay results (scale 0-100) and the 4 gene group scores in biopsy specimens from 201 Black and 1,144 White men with clinically localized prostate cancer in 6 cohorts. Adverse pathology was defined as high grade (primary Gleason pattern 4 or any pattern 5) and/or nonorgan-confined disease (≥pT3). Binary logistic regression models were used for adverse pathology. Biochemical recurrence was defined as 2 successive prostate specific antigen levels >0.2 ng/ml or initiation of salvage therapy after radical prostatectomy. Cox proportional hazards models evaluated the association of the assay result or racial group with time to biochemical recurrence. RESULTS: Each cohort had different clinical risk distributions and percentages of Blacks, although median and interquartile ranges of the assay results and gene group scores were similar between both racial groups. In a multivariable model with the assay and pathological/clinical features including race, the assay was significantly associated with adverse pathology (p ≤0.004) and biochemical recurrence (p <0.001). Race was not a significant predictor of either end point. CONCLUSIONS: The assay is similarly predictive of outcomes in Black and White patients, and improves risk stratification in men with newly diagnosed prostate cancer from both racial groups.

16.
Genes Cancer ; 10(5-6): 150-159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798767

RESUMO

Tenascin C (TNC), an extra-cellular matrix (ECM) family gene, is expressed in several cancer tissues of breast, lung, colon, and gastrointestinal tract leading to proliferation, migration, invasion, angiogenesis and metastasis, but its role in tumorigenesis of prostate cancer is poorly understood. We took a meta-analysis approach to characterize the alterations of TNC gene in prostate cancer using publicly available databases (cBioportal Version 2.2.0, http://www.cBioportal.org/index.do). The analysis identified TNC alterations (gene amplification) significantly in the neuroendocrine prostate cancer dataset (Trento/Broad/Cornell, N = 114), which was further validated in other prostate cancer datasets, including The Cancer Genome Atlas (TCGA) prostate cancer (2015). In the TCGA prostate cancer dataset (N = 498), high TNC (alteration frequency, 36%) revealed a strong association with high diagnostic Gleason score. Genomic alterations of TNC was also significantly associated (P < 0.05) with expression level of genes from NOTCH, SOX and WNT family, implicating a link between TNC and poorly differentiated aggressive phenotype in NEPC. TCGA prostate adenocarcinoma cases with TNC alteration also demonstrated prominent decrease in disease-free survival (P = 0.0637). These findings indicate a possible association of TNC to the aggressive subtype of prostate cancer and warrant further functional studies to evident the involvement of TNC in prostate cancer progression.

17.
Cancers (Basel) ; 11(12)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842254

RESUMO

Dysfunctions of androgen/TGF-ß signaling play important roles in prostate tumorigenesis. Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) inhibits androgen and TGF-ß signaling via a negative feedback loop. The loss of PMEPA1 confers resistance to androgen signaling inhibitors and promotes bone metastasis. Conflicting reports on the expression and biological functions of PMEPA1 in prostate and other cancers propelled us to investigate isoform specific functions in prostate cancer (PCa). One hundred and twenty laser capture micro-dissection matched normal prostate and prostate tumor tissues were analyzed for correlations between quantitative expression of PMEPA1 isoforms and clinical outcomes with Q-RT-PCR, and further validated with a The Cancer Genome Atlas (TCGA) RNA-Seq dataset of 499 PCa. Cell proliferation was assessed with cell counting, plating efficiency and soft agar assay in androgen responsive LNCaP and TGF-ß responsive PC3 cells. TGF-ß signaling was measured by SMAD dual-luciferase reporter assay. Higher PMEPA1-a mRNA levels indicated biochemical recurrence (p = 0.0183) and lower PMEPA1-b expression associated with metastasis (p = 0.0173). Further, lower PMEPA1-b and a higher ratio of PMEPA1-a vs. -b were correlated to higher Gleason scores and lower progression free survival rate (p < 0.01). TGF-ß-responsive PMEPA1-a promoted PCa cell growth, and androgen-responsive PMEPA1-b inhibited cancer cell proliferation. PMEPA1 isoforms -a and -b were shown to be promising candidate biomarkers indicating PCa aggressiveness including earlier biochemical relapse and lower disease specific life expectancy via interrupting androgen/TGF-ß signaling.

18.
Oncotarget ; 10(60): 6466-6483, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31741711

RESUMO

BACKGROUND: As a major cause of morbidity and mortality among men, prostate cancer is a heterogenous disease, with a vast heterogeneity in the biology of the disease and in clinical outcome. While it often runs an indolent course, local progression or metastasis may eventually develop, even among patients considered "low risk" at diagnosis. Therefore, biomarkers that can discriminate aggressive from indolent disease at an early stage would greatly benefit patients. We hypothesized that tissue specimens from early stage prostate cancers may harbor predictive signatures for disease progression. METHODS: We used a cohort of radical prostatectomy patients with longitudinal follow-up, who had tumors with low grade and stage that revealed no signs of future disease progression at surgery. During the follow-up period, some patients either remained indolent (non-BCR) or progressed to biochemical recurrence (BCR). Total RNA was extracted from tumor, and adjacent normal epithelium of formalin-fixed-paraffin-embedded (FFPE) specimens. Differential gene expression in tumors, and in tumor versus normal tissues between BCR and non-BCR patients were analyzed by NanoString using a customized CodeSet of 151 probes. RESULTS: After controlling for false discovery rates, we identified a panel of eight genes (ERG, GGT1, HDAC1, KLK2, MYO6, PLA2G7, BICD1 and CACNAID) that distinguished BCR from non-BCR patients. We found a clear association of ERG expression with non-BCR, which was further corroborated by quantitative RT-PCR and immunohistochemistry assays. CONCLUSIONS: Our results identified ERG as the strongest predictor for BCR and showed that potential prognostic prostate cancer biomarkers can be identified from FFPE tumor specimens.

19.
Int J Mol Sci ; 20(19)2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31581661

RESUMO

The androgen receptor is one of the key targets for prostate cancer treatment. Despite its less satisfactory effects, chemotherapy is the most common treatment option for metastatic and/or castration-resistant patients. There are constant needs for novel anti-prostate cancer therapeutic/prevention agents. Curcumin, a known chemo-preventive agent, was shown to inhibit prostate cancer cell growth. This study aimed to unravel the inhibitory effect of curcumin in prostate cancer through analyzing the alterations of expressions of curcumin targeting genes clusters in androgen-dependent LNCaP cells and androgen-independent metastatic C4-2B cells. Hierarchical clustering showed the highest number of differentially expressed genes at 12 h post treatment in both cells, suggesting that the androgen-dependent/independent manner of curcumin impacts on prostate cancer cells. Evaluation of significantly regulated top canonical pathways highlighted that Transforming growth factor beta (TGF-ß), Wingless-related integration site (Wnt), Phosphoinositide 3-kinase/Protein Kinase B/ mammalian target of rapamycin (PIK3/AKT(PKB)/mTOR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling were primarily inhibited, and Phosphatase and tensin homolog (PTEN) dependent cell cycle arrest and apoptosis pathways were elevated with curcumin treatment. The short term (3-24 h) and long term (48 h) effect of curcumin treatment revealed 31 and four genes modulated in both cell lines. TGF-ß signaling, including the androgen/TGF-ß inhibitor Prostate transmembrane protein androgen-induced 1 (PMEPA1), was the only pathway impacted by curcumin treatment after 48 h. Our findings also established that MYC Proto-Oncogene, basic helix-loop-helix (bHLH) Transcription Factor (MYC) signaling was down-regulated in curcumin-treated cell lines. This study established, for the first time, novel gene-networks and signaling pathways confirming the chemo-preventive and cancer-growth inhibitory nature of curcumin as a natural anti-prostate cancer compound.


Assuntos
Antineoplásicos/farmacologia , Curcumina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios/metabolismo , Androgênios/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Transdução de Sinais/efeitos dos fármacos
20.
Clin Genitourin Cancer ; 17(6): 470-475.e1, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31530439

RESUMO

INTRODUCTION: The aim of this study was to investigate the association of prostate-specific antigen (PSA) values on metastasis-free survival (MFS) in men with biochemically recurrent prostate cancer (BRPC) and PSA doubling time (PSADT) < 12 months. This dataset also reflects an update with longer follow-up of our prior publications on the natural history of BRPC in the absence of treatment. MATERIALS AND METHODS: In this report, we combined databases from the Center for Prostate Disease Research and Johns Hopkins University (CPDR/JHU). In the CPDR/JHU radical prostatectomy database (30,936 total patients), 656 men with BRPC (> 0.2 ng/mL) after prostatectomy and PSADT < 12 months, who received no adjuvant/salvage androgen deprivation and/or radiation therapy, were prospectively followed until radiologic evidence of metastasis and are included in this analysis. RESULTS: Metastasis occurred in 250 of 656 patients with BRPC (median follow-up, 5 years). PSADT < 7.5 months and Gleason score were independent risk factors for distant metastasis in multivariable analysis. Risk of metastasis increased for PSADT 6.01 to 7.50, 4.51 to 6.0, 3.01 to 4.50, and ≤ 3.0 months, after adjusting for Gleason score. A PSA value ≥ 0.5 ng/mL significantly and independently increased risk of metastasis in patients with PSADT < 12 months (hazard ratio, 2.79; 95% confidence interval, 1.47-5.29; P = .001). CONCLUSIONS: In men with PSADT < 12 months, PSADT ≤ 7.5 months, PSA ≥ 0.5 ng/mL, and Gleason score are independent predictors of MFS on multivariable analysis.


Assuntos
Recidiva Local de Neoplasia/diagnóstico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Idoso , Estudos de Coortes , Bases de Dados Factuais , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Prostatectomia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/cirurgia , Terapia de Salvação , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...