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Heritability and genome-wide association study of benign prostatic hyperplasia (BPH) in the eMERGE network.
Hellwege JN, Stallings S, Torstenson ES, Carroll R, Borthwick KM, Brilliant MH, Crosslin D, Gordon A, Hripcsak G, Jarvik GP, Linneman JG, Devi P, Peissig PL, Sleiman PAM, Hakonarson H, Ritchie MD, Verma SS, Shang N, Denny JC, Roden DM, Velez Edwards DR, Edwards TL
(2019) Sci Rep 9: 6077
MeSH Terms: Aged, Aged, 80 and over, Biomarkers, Case-Control Studies, Electronic Health Records, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, Inheritance Patterns, Male, Middle Aged, Polymorphism, Single Nucleotide, Prostate, Prostatic Hyperplasia
Show Abstract · Added March 3, 2020
Benign prostatic hyperplasia (BPH) results in a significant public health burden due to the morbidity caused by the disease and many of the available remedies. As much as 70% of men over 70 will develop BPH. Few studies have been conducted to discover the genetic determinants of BPH risk. Understanding the biological basis for this condition may provide necessary insight for development of novel pharmaceutical therapies or risk prediction. We have evaluated SNP-based heritability of BPH in two cohorts and conducted a genome-wide association study (GWAS) of BPH risk using 2,656 cases and 7,763 controls identified from the Electronic Medical Records and Genomics (eMERGE) network. SNP-based heritability estimates suggest that roughly 60% of the phenotypic variation in BPH is accounted for by genetic factors. We used logistic regression to model BPH risk as a function of principal components of ancestry, age, and imputed genotype data, with meta-analysis performed using METAL. The top result was on chromosome 22 in SYN3 at rs2710383 (p-value = 4.6 × 10; Odds Ratio = 0.69, 95% confidence interval = 0.55-0.83). Other suggestive signals were near genes GLGC, UNCA13, SORCS1 and between BTBD3 and SPTLC3. We also evaluated genetically-predicted gene expression in prostate tissue. The most significant result was with increasing predicted expression of ETV4 (chr17; p-value = 0.0015). Overexpression of this gene has been associated with poor prognosis in prostate cancer. In conclusion, although there were no genome-wide significant variants identified for BPH susceptibility, we present evidence supporting the heritability of this phenotype, have identified suggestive signals, and evaluated the association between BPH and genetically-predicted gene expression in prostate.
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16 MeSH Terms
A case study evaluating the portability of an executable computable phenotype algorithm across multiple institutions and electronic health record environments.
Pacheco JA, Rasmussen LV, Kiefer RC, Campion TR, Speltz P, Carroll RJ, Stallings SC, Mo H, Ahuja M, Jiang G, LaRose ER, Peissig PL, Shang N, Benoit B, Gainer VS, Borthwick K, Jackson KL, Sharma A, Wu AY, Kho AN, Roden DM, Pathak J, Denny JC, Thompson WK
(2018) J Am Med Inform Assoc 25: 1540-1546
MeSH Terms: Algorithms, Data Warehousing, Databases, Factual, Electronic Health Records, Genomics, Humans, Male, Organizational Case Studies, Phenotype, Prostatic Hyperplasia
Show Abstract · Added March 24, 2020
Electronic health record (EHR) algorithms for defining patient cohorts are commonly shared as free-text descriptions that require human intervention both to interpret and implement. We developed the Phenotype Execution and Modeling Architecture (PhEMA, http://projectphema.org) to author and execute standardized computable phenotype algorithms. With PhEMA, we converted an algorithm for benign prostatic hyperplasia, developed for the electronic Medical Records and Genomics network (eMERGE), into a standards-based computable format. Eight sites (7 within eMERGE) received the computable algorithm, and 6 successfully executed it against local data warehouses and/or i2b2 instances. Blinded random chart review of cases selected by the computable algorithm shows PPV ≥90%, and 3 out of 5 sites had >90% overlap of selected cases when comparing the computable algorithm to their original eMERGE implementation. This case study demonstrates potential use of PhEMA computable representations to automate phenotyping across different EHR systems, but also highlights some ongoing challenges.
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MeSH Terms
MAGI-2 Is a Sensitive and Specific Marker of Prostatic Adenocarcinoma:  A Comparison With AMACR.
Goldstein J, Goyal R, Roland JT, Gellert LL, Clark PE, Hameed O, Giannico GA
(2016) Am J Clin Pathol 146: 294-302
MeSH Terms: Adaptor Proteins, Signal Transducing, Adenocarcinoma, Biomarkers, Tumor, Carrier Proteins, Diagnosis, Differential, Guanylate Kinases, Humans, Male, Prostate, Prostatectomy, Prostatic Hyperplasia, Prostatic Intraepithelial Neoplasia, Prostatic Neoplasms, Racemases and Epimerases, Sensitivity and Specificity, Tissue Array Analysis
Show Abstract · Added June 27, 2017
OBJECTIVES - We compared the utility of membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI-2) and α-methylacyl CoA (AMACR) by immunohistochemistry in diagnosing prostatic adenocarcinoma.
METHODS - Seventy-eight radical prostatectomies were used to construct three tissue microarrays with 512 cores, including benign prostatic tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma. AMACR and MAGI-2 immunohistochemistry were evaluated by visual and image analysis.
RESULTS - MAGI-2 and AMACR were significantly higher in adenocarcinoma and HGPIN compared with benign tissue. At H-score cutoffs of 300 and 200, MAGI-2 was more accurate in distinguishing benign from malignant glands than AMACR. Areas under the curve by image and visual analysis were 0.846 and 0.818 for MAGI-2 and 0.937 and 0.924 for AMACR, respectively. The accuracy of MAGI-2 in distinguishing benign from malignant glands on the same core was higher (95% vs 88%).
CONCLUSIONS - MAGI-2 could represent a useful adjunct for diagnosis of prostatic adenocarcinoma, especially when AMACR is not discriminatory.
© American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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16 MeSH Terms
NF-κB and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance.
Austin DC, Strand DW, Love HL, Franco OE, Grabowska MM, Miller NL, Hameed O, Clark PE, Matusik RJ, Jin RJ, Hayward SW
(2016) Prostate 76: 1004-18
MeSH Terms: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, 5-alpha Reductase Inhibitors, Animals, Apoptosis, Drug Resistance, Gene Expression, Gene Knockdown Techniques, Humans, Isoenzymes, Lower Urinary Tract Symptoms, Male, Membrane Proteins, Mice, Mice, Nude, NF-kappa B, Orchiectomy, Prostate, Prostatic Hyperplasia, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Testosterone, Treatment Failure, Up-Regulation
Show Abstract · Added April 18, 2017
BACKGROUND - Benign prostatic hyperplasia (BPH) is treated with 5α-reductase inhibitors (5ARI). These drugs inhibit the conversion of testosterone to dihydrotestosterone resulting in apoptosis and prostate shrinkage. Most patients initially respond to 5ARIs; however, failure is common especially in inflamed prostates, and often results in surgery. This communication examines a link between activation of NF-κB and increased expression of SRD5A2 as a potential mechanism by which patients fail 5ARI therapy.
METHODS - Tissue was collected from "Surgical" patients, treated specifically for lower urinary tract symptoms secondary to advanced BPH; and, cancer free transition zone from "Incidental" patients treated for low grade, localized peripheral zone prostate cancer. Clinical, molecular and histopathological profiles were analyzed. Human prostatic stromal and epithelial cell lines were genetically modified to regulate NF-κB activity, androgen receptor (AR) full length (AR-FL), and AR variant 7 (AR-V7) expression.
RESULTS - SRD5A2 is upregulated in advanced BPH. SRD5A2 was significantly associated with prostate volume determined by Transrectal Ultrasound (TRUS), and with more severe lower urinary tract symptoms (LUTS) determined by American Urological Association Symptom Score (AUASS). Synthesis of androgens was seen in cells in which NF-κB was activated. AR-FL and AR-V7 expression increased SRD5A2 expression while forced activation of NF-κB increased all three SRD5A isoforms. Knockdown of SRD5A2 in the epithelial cells resulted in significant reduction in proliferation, AR target gene expression, and response to testosterone (T). In tissue recombinants, canonical NF-κB activation in prostatic epithelium elevated all three SRD5A isoforms and resulted in in vivo growth under castrated conditions.
CONCLUSION - Increased BPH severity in patients correlates with SRD5A2 expression. We demonstrate that NF-κB and AR-V7 upregulate SRD5A expression providing a mechanism to explain failure of 5ARI therapy in BPH patients. Prostate 76:1004-1018, 2016. © 2016 Wiley Periodicals, Inc.
© 2016 Wiley Periodicals, Inc.
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23 MeSH Terms
MAGI-2 in prostate cancer: an immunohistochemical study.
Goldstein J, Borowsky AD, Goyal R, Roland JT, Arnold SA, Gellert LL, Clark PE, Hameed O, Giannico GA
(2016) Hum Pathol 52: 83-91
MeSH Terms: Adaptor Proteins, Signal Transducing, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Area Under Curve, Biomarkers, Tumor, Biopsy, Carrier Proteins, Guanylate Kinases, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Male, Middle Aged, Neoplasm Grading, PTEN Phosphohydrolase, Predictive Value of Tests, Prostatic Hyperplasia, Prostatic Intraepithelial Neoplasia, Prostatic Neoplasms, ROC Curve, Tissue Array Analysis, Transcription Factors, Tumor Suppressor Proteins, Up-Regulation
Show Abstract · Added April 18, 2017
Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI-2) is a scaffolding protein that links cell adhesion molecules, receptors, and signaling molecules to the cytoskeleton and maintains the architecture of cell junctions. MAGI-2 gene rearrangements have recently been described in prostate cancer. We studied the immunohistochemical expression of MAGI-2 protein in prostate tissue. Seventy-eight radical prostatectomies were used to construct 3 tissue microarrays consisting of 512 cores, including benign tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma, Gleason patterns 3 to 5. Immunohistochemistry for phosphatase and tensin homologue (PTEN) and double-stain MAGI-2/p63 was performed and analyzed by visual and image analysis, the latter as percent of analyzed area (%AREA), and mean optical density multiplied by %AREA (STAIN). By visual and image analysis, MAGI-2 was significantly higher in adenocarcinoma and HGPIN compared with benign (benign versus HGPIN P < .001; benign versus adenocarcinoma, P < .001). HGPIN and adenocarcinoma did not significantly differ by either modality. Using visual intensity to distinguish benign tissue and adenocarcinoma, a receiver operating curve yielded an area under the curve of 0.902. A STAIN threshold of 1470 yielded a sensitivity of 0.66 and specificity of 0.96. There was a significant correlation between PTEN and MAGI-2 staining for normal and benign prostatic hyperplasia, but this was lost in HGPIN and cancer. We conclude that MAGI-2 immunoreactivity is elevated in prostate cancer and HGPIN compared with normal tissue, and suggest that MAGI-2 may contribute to prostate carcinogenesis. This is the first report of MAGI-2 staining by immunohistochemistry in prostate cancer.
Copyright © 2016 Elsevier Inc. All rights reserved.
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26 MeSH Terms
NF-κB and androgen receptor variant expression correlate with human BPH progression.
Austin DC, Strand DW, Love HL, Franco OE, Jang A, Grabowska MM, Miller NL, Hameed O, Clark PE, Fowke JH, Matusik RJ, Jin RJ, Hayward SW
(2016) Prostate 76: 491-511
MeSH Terms: Aged, Cell Line, Tumor, Cell Survival, Disease Progression, Humans, Male, Middle Aged, NF-kappa B, Prostate, Prostatic Hyperplasia, Receptors, Androgen, Signal Transduction
Show Abstract · Added April 18, 2017
BACKGROUND - Benign prostatic hyperplasia (BPH) is a common, chronic progressive disease. Inflammation is associated with prostatic enlargement and resistance to 5α-reductase inhibitor (5ARI) therapy. Activation of the nuclear factor-kappa B (NF-κB) pathway is linked to both inflammation and ligand-independent prostate cancer progression.
METHODS - NF-κB activation and androgen receptor variant (AR-V) expression were quantified in transition zone tissue samples from patients with a wide range of AUASS from incidental BPH in patients treated for low grade, localized peripheral zone prostate cancer to advanced disease requiring surgical intervention. To further investigate these pathways, human prostatic stromal and epithelial cell lines were transduced with constitutively active or kinase dead forms of IKK2 to regulate canonical NF-κB activity. The effects on AR full length (AR-FL) and androgen-independent AR-V expression as well as cellular growth and differentiation were assessed.
RESULTS - Canonical NF-κB signaling was found to be upregulated in late versus early stage BPH, and to be strongly associated with non-insulin dependent diabetes mellitus. Elevated expression of AR-variant 7 (AR-V7), but not other AR variants, was found in advanced BPH samples. Expression of AR-V7 significantly correlated with the patient AUASS and TRUS volume. Forced activation of canonical NF-κB in human prostatic epithelial and stromal cells resulted in elevated expression of both AR-FL and AR-V7, with concomitant ligand-independent activation of AR reporters. Activation of NF-κB and over expression of AR-V7 in human prostatic epithelial cells maintained cell viability in the face of 5ARI treatment.
CONCLUSION - Activation of NF-κB and AR-V7 in the prostate is associated with increased disease severity. AR-V7 expression is inducible in human prostate cells by forced activation of NF-κB resulting in resistance to 5ARI treatment, suggesting a potential mechanism by which patients may become resistant to 5ARI therapy.
© 2015 Wiley Periodicals, Inc.
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12 MeSH Terms
Nfib Regulates Transcriptional Networks That Control the Development of Prostatic Hyperplasia.
Grabowska MM, Kelly SM, Reese AL, Cates JM, Case TC, Zhang J, DeGraff DJ, Strand DW, Miller NL, Clark PE, Hayward SW, Gronostajski RM, Anderson PD, Matusik RJ
(2016) Endocrinology 157: 1094-109
MeSH Terms: Animals, Cell Line, Tumor, Cell Proliferation, Chromatin Immunoprecipitation, Fluorescent Antibody Technique, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Gene Regulatory Networks, Hepatocyte Nuclear Factor 3-alpha, Humans, Immunohistochemistry, Male, Mice, Mice, Knockout, NFI Transcription Factors, Prostate, Prostatic Hyperplasia, Prostatic Neoplasms, Receptors, Androgen, Sequence Analysis, DNA, Sequence Analysis, RNA
Show Abstract · Added February 15, 2016
A functional complex consisting of androgen receptor (AR) and forkhead box A1 (FOXA1) proteins supports prostatic development, differentiation, and disease. In addition, the interaction of FOXA1 with cofactors such as nuclear factor I (NFI) family members modulates AR target gene expression. However, the global role of specific NFI family members has yet to be described in the prostate. In these studies, chromatin immunoprecipitation followed by DNA sequencing in androgen-dependent LNCaP prostate cancer cells demonstrated that 64.3% of NFIB binding sites are associated with AR and FOXA1 binding sites. Interrogation of published data revealed that genes associated with NFIB binding sites are predominantly induced after dihydrotestosterone treatment of LNCaP cells, whereas NFIB knockdown studies demonstrated that loss of NFIB drives increased AR expression and superinduction of a subset of AR target genes. Notably, genes bound by NFIB only are associated with cell division and cell cycle. To define the role of NFIB in vivo, mouse Nfib knockout prostatic tissue was rescued via renal capsule engraftment. Loss of Nfib expression resulted in prostatic hyperplasia, which did not resolve in response to castration, and an expansion of an intermediate cell population in a small subset of grafts. In human benign prostatic hyperplasia, luminal NFIB loss correlated with more severe disease. Finally, some areas of intermediate cell expansion were also associated with NFIB loss. Taken together, these results show a fundamental role for NFIB as a coregulator of AR action in the prostate and in controlling prostatic hyperplasia.
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22 MeSH Terms
Genetic Determinants of Metabolism and Benign Prostate Enlargement: Associations with Prostate Volume.
Giri A, Edwards TL, Motley SS, Byerly SH, Fowke JH
(2015) PLoS One 10: e0132028
MeSH Terms: Adult, Aged, Collagen Type IV, Genetic Loci, Genotype, Humans, Linear Models, Male, Middle Aged, Nerve Tissue Proteins, Obesity, Organ Size, Polymorphism, Single Nucleotide, Prostate, Prostatic Hyperplasia, Prostatic Neoplasms, Ribosomal Proteins, Sodium Channels, Symporters, Ultrasonography
Show Abstract · Added February 22, 2016
Prostate enlargement leading to clinical benign prostatic hyperplasia (BPH) is associated with metabolic dysregulation and obesity. The genetic basis of this association is unclear. Our objective was to evaluate whether single nucleotide polymorphisms (SNPs) previously associated with metabolic disorders are also associated with prostate volume (PV). Participants included 876 men referred for prostate biopsy and found to be prostate cancer free. PV was measured by transrectal ultrasound. Samples were genotyped using the Illumina Cardio-MetaboChip platform. Multivariable adjusted linear regression models were used to evaluate SNPs (additive coding) in relation to natural-log transformed (log) PV. We compared SNP-PV results from biopsy-negative men to 442 men with low-grade prostate cancer with similar levels of obesity and PV. Beta-coefficients from the discovery and replication samples were then aggregated with fixed effects inverse variance weighted meta-analysis. SNP rs11736129 (near the pseudo-gene LOC100131429) was significantly associated with log-PV (beta: 0.16, p-value 1.16x10(-8)) after adjusting for multiple testing. Other noteworthy SNPs that were nominally associated (p-value < 1x10(-4)) with log-PV included rs9583484 (intronic SNP in COL4A2), rs10146527 (intronic SNP in NRXN3), rs9909466 (SNP near RPL32P31), and rs2241606 (synonymous SNP in SLC12A7). We found several SNPs in metabolic loci associated with PV. Further studies are needed to confirm our results and elucidate the mechanism between these genetic loci, PV, and clinical BPH.
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20 MeSH Terms
SOX2 expression in the developing, adult, as well as, diseased prostate.
Yu X, Cates JM, Morrissey C, You C, Grabowska MM, Zhang J, DeGraff DJ, Strand DW, Franco OE, Lin-Tsai O, Hayward SW, Matusik RJ
(2014) Prostate Cancer Prostatic Dis 17: 301-9
MeSH Terms: Animals, Blotting, Western, Heterografts, Humans, Immunohistochemistry, Male, Mice, Mice, Transgenic, Neuroendocrine Tumors, Prostate, Prostatic Hyperplasia, Prostatic Neoplasms, SOXB1 Transcription Factors, Tissue Array Analysis
Show Abstract · Added January 20, 2015
BACKGROUND - SOX2 is a member of SOX (SRY-related high mobility group box) family of transcription factors.
METHODS - In this study, we examined the expression of SOX2 in murine and human prostatic specimens by immunohistochemistry.
RESULTS - We found that SOX2 was expressed in murine prostates during budding morphogenesis and in neuroendocrine (NE) prostate cancer (PCa) murine models. Expression of SOX2 was also examined in human prostatic tissue. We found that SOX2 was expressed in 26 of the 30 BPH specimens. In these BPH samples, expression of SOX2 was limited to basal epithelial cells. In contrast, 24 of the 25 primary PCa specimens were negative for SOX2. The only positive primary PCa was the prostatic NE tumor, which also showed co-expression of synaptophysin. Additionally, the expression of SOX2 was detected in all prostatic NE tumor xenograft lines. Furthermore, we have examined the expression of SOX2 on a set of tissue microarrays consisting of metastatic PCa tissues. Expression of SOX2 was detected in at least one metastatic site in 15 of the 24 patients with metastatic castration-resistant PCa; and the expression of SOX2 was correlated with synaptophysin.
CONCLUSIONS - SOX2 was expressed in developing prostates, basal cells of BPH, as well as prostatic NE tumors.
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14 MeSH Terms
FOXA1 deletion in luminal epithelium causes prostatic hyperplasia and alteration of differentiated phenotype.
DeGraff DJ, Grabowska MM, Case TC, Yu X, Herrick MK, Hayward WJ, Strand DW, Cates JM, Hayward SW, Gao N, Walter MA, Buttyan R, Yi Y, Kaestner KH, Matusik RJ
(2014) Lab Invest 94: 726-39
MeSH Terms: Animals, Cell Differentiation, Epithelium, Hepatocyte Nuclear Factor 3-alpha, Immunohistochemistry, Integrases, Male, Mice, Mice, Knockout, Mice, Transgenic, Microscopy, Fluorescence, Oligonucleotide Array Sequence Analysis, Prostate, Prostatic Hyperplasia, Reverse Transcriptase Polymerase Chain Reaction, Seminal Vesicles, Transcriptome
Show Abstract · Added May 27, 2014
The forkhead box (Fox) superfamily of transcription factors has essential roles in organogenesis and tissue differentiation. Foxa1 and Foxa2 are expressed during prostate budding and ductal morphogenesis, whereas Foxa1 expression is retained in adult prostate epithelium. Previous characterization of prostatic tissue rescued from embryonic Foxa1 knockout mice revealed Foxa1 to be essential for ductal morphogenesis and epithelial maturation. However, it is unknown whether Foxa1 is required to maintain the differentiated status in adult prostate epithelium. Here, we employed the PBCre4 transgenic system and determined the impact of prostate-specific Foxa1 deletion in adult murine epithelium. PBCre4/Foxa1(loxp/loxp) mouse prostates showed progressive florid hyperplasia with extensive cribriform patterning, with the anterior prostate being most affected. Immunohistochemistry studies show mosaic Foxa1 KO consistent with PBCre4 activity, with Foxa1 KO epithelial cells specifically exhibiting altered cell morphology, increased proliferation, and elevated expression of basal cell markers. Castration studies showed that, while PBCre4/Foxa1(loxp/loxp) prostates did not exhibit altered sensitivity in response to hormone ablation compared with control prostates, the number of Foxa1-positive cells in mosaic Foxa1 KO prostates was significantly reduced compared with Foxa1-negative cells following castration. Unexpectedly, gene expression profile analyses revealed that Foxa1 deletion caused abnormal expression of seminal vesicle-associated genes in KO prostates. In summary, these results indicate Foxa1 expression is required for the maintenance of prostatic cellular differentiation.
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17 MeSH Terms