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BackgroundBiopsies performed for elevated serum PSA often show inflammatory infiltrates. However, the influence of intraprostatic inflammation on serum PSA in men without biopsy indication and negative for prostate cancer has not been described in detail.MethodsWe studied 224 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) who underwent end-of-study biopsy per trial protocol, had PSA 0 to ≤0.8, >0.8 to ≤1.5 and >1.5 to

Precancer or intraepithelial neoplasia (IEN) is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and that predicts for a substantial likelihood of developing invasive cancer. The AACR Task Force on the Treatment and prevention of IEN has delineated the relationship between IEN and cancer risk as well as the clinical benefit that can be derived from reducing IEN burden. Although several effective endoscopic and surgical treatments for IEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk. The incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population, and the rapid advancement of imaging and molecular diagnostics is bringing to light precancers that were heretofore clinically silent. There is therefore an urgent need to rapidly develop new treatment and prevention agents for IEN. The AACR IEN Task Force recommends focusing on established precancers as the target for new agent development because of the close association between dysplasia and invasive cancer and because a convincing reduction in IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive interventions. The IEN Task Force proposes several clinical trial designs that provide practical and feasible approaches to the rapid development of new agents to treat and prevent precancer.

Precancer or intraepithelial neoplasia (IEN) is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and that predicts for a substantial likelihood of developing invasive cancer. The AACR Task Force on the Treatment and prevention of IEN has delineated the relationship between IEN and cancer risk as well as the clinical benefit that can be derived from reducing IEN burden. Although several effective endoscopic and surgical treatments for IEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk. The incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population, and the rapid advancement of imaging and molecular diagnostics is bringing to light precancers that were heretofore clinically silent. There is therefore an urgent need to rapidly develop new treatment and prevention agents for IEN. The AACR IEN Task Force recommends focusing on established precancers as the target for new agent development because of the close association between dysplasia and invasive cancer and because a convincing reduction in IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive interventions. The IEN Task Force proposes several clinical trial designs that provide practical and feasible approaches to the rapid development of new agents to treat and prevent precancer.

Prostate cancer chemoprevention represents a relatively new and promising strategy for reducing the immense public health burden of this devastating cancer of men in the United States and Western societies. Chemoprevention is defined as the administration of agents (drugs, biologics, and natural products) that modulate (inhibit) one or more steps in the multistage carcinogenesis process culminating in invasive adenocarcinoma of the prostate. In 2000, there were an estimated 170,000 new cases of prostate cancer and 31,000 deaths in the United States. During the past decade, the National Cancer Institute (NCI) organized the chemoprevention research program and began testing the first generation of promising agents (eg, 4-(hydroxy)-fenretinide [4-HPR], difluoromethylornithine [DFMO], antiandrogens) in high-risk cohorts and launched the first-large scale US phase 3 primary prevention trial, known as Prostate Cancer Prevention Trial (PCPT-1), in 18,000 average-risk men (age more than 55 years and prostate-specific antigen [PSA] less than 3 ng/mL) treated for 7 years with finasteride or placebo. In the summer of 1998, the NCI Prostate Cancer Progress Review Group (PRG) Report to the director of NCI was published in response to the leadership of the prostate cancer advocacy community in conjunction with Congress. To further elucidate and address critical issues identified in this report and to develop a research agenda for the newly created Prostate and Urologic Cancer Research Group in the Division of Cancer Prevention at NCI, the NCI organized the workshop "New Clinical Trial Strategies for Prostate Cancer Chemoprevention." The major objectives were to promote understanding and cooperation among the NCI, US Food and Drug Administration (FDA), academia, pharmaceutical industry, and the public regarding new opportunities for clinical prevention trials for prostate cancer. The workshop was divided into three concurrent breakout panels and a fourth joint integrative panel. The workshop addressed multiple key areas identified in the PRG report in the following panels: (1) Molecular Targets and Promising Agents in Clinical Development; (2) Intermediate Endpoint Biomarkers for Prevention Trials; (3) High-Risk Study Populations for Prevention Trials, and (4) Preventive Clinical Trial Designs and Regulatory Issues. Expert panelists were drawn from leading academic, pharmaceutical, and government scientists in basic research and clinical investigation. Key pharmaceutical, biotechnology, academic, and National Institutes of Health scientists presented overviews of their new agents and products in clinical development (representing the next generation of promising agents). Senior FDA physicians from the Center for Drugs and Center for Biologics presented on current standards for new drug and biologic approval for chemoprevention efficacy. Some of the key topics included recent advances in the state of knowledge of promising agents in the clinic based on molecular targets as well as bottlenecks in drug development for pharmaceutical sponsors; strategic modulable biomarkers that can serve as primary endpoints in phase 1/2 trials to assess preventive efficacy; high-risk cohorts with precancer (high-grade prostatic intraepithelial neoplasia) and representative clinical trial designs that are ready for immediate translation into efficient prevention trials, such as Bayesian sequential monitoring for early assessment of biologic activity and factorial designs for assessment of multiagent combinations. Finally, each expert panel generated recommendations for areas of future research emphasizing opportunities and infrastructure needs.

Purpose: To investigate serologic evidence of infection by cytomegalovirus (CMV), a herpesvirus with known oncogenic potential that has been detected in malignant prostate tissue, in relation to prostate cancer (PCa) risk in a large case-control study nested in the Prostate Cancer Prevention Trial (PCPT).Methods: Cases were men with a confirmed diagnosis of PCa after visit 2 (n = 614), and controls were men not diagnosed with PCa during the trial who also had a negative end-of-study biopsy (n = 616). Controls were frequency-matched to cases by age, treatment arm, and family history of PCa. Sera from visit 2 were tested for CMV IgG antibodies.Results: No association was observed between CMV serostatus and PCa risk (adjusted CMV seroprevalence = 67.9 % for cases and 65.2 % for controls, odds ratio = 1.13, 95 % CI 0.89-1.45).Conclusions: Considering our null findings in the context of the full CMV literature, CMV infection, as measured by serostatus, does not appear to increase PCa risk. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Low levels of androgens in men may play a role in the development of diabetes; however, few studies have examined the association between androgen concentration and diabetes in men in the general population. The objective of this study is to test the hypothesis that low normal levels of total, free, and bioavailable testosterone are associated with prevalent diabetes in men. RESEARCH DESIGN AND METHODS: The study sample included 1,413 adult men aged >/=20 years who participated in the morning session of the first phase of the Third National Health and Nutrition Examination Survey, a cross-sectional survey of the civilian, noninstitutionalized population of the U.S. Bioavailable and free testosterone levels were calculated from serum total testosterone, sex hormone-binding globulin, and albumin concentrations. RESULTS: In multivariable models adjusted for age, race/ethnicity, and adiposity, men in the first tertile (lowest) of free testosterone level were four times more likely to have prevalent diabetes compared with men in the third tertile (odds ratio 4.12 [95% CI 1.25-13.55]). Similarly, men in the first tertile of bioavailable testosterone also were approximately four times as likely to have prevalent diabetes compared wth men in the third tertile (3.93 [1.39-11.13]). These associations persisted even after excluding men with clinically abnormal testosterone concentrations defined as total testosterone <3.25 ng/ml or free testosterone <0.07 ng/ml. No clear association was observed for total testosterone after multivariable adjustment (P for trend across tertiles = 0.27). CONCLUSIONS: Low free and bioavailable testosterone concentrations in the normal range were associated with diabetes, independent of adiposity. These data suggest that low androgen levels may be a risk factor for diabetes in men. [ABSTRACT FROM AUTHOR]

Cancer researchers tend to be well-versed in communicating research and research results to scientific audiences. To maintain momentum and progress against cancer, they must acquire and nurture skills allowing for better engagement with the lay public., Competing Interests: Declaration of interests I serve as the Editor-in-Chief of Cancer Today, a magazine published by the American Association for Cancer Research (AACR) that is focused on lay communication and education around topics in cancer research and cancer care., (Copyright © 2024 Elsevier Inc. All rights reserved.)

How prostate cancer cells and their precursors mediate changes in the tumor microenvironment (TME) to drive prostate cancer progression is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we perform extensive single-cell RNA-sequencing (scRNA-seq) and molecular pathology of the comparative biology between human prostate cancer and key stages in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues reveal that cancer cell-intrinsic activation of MYC signaling is a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Cell communication network and pathway analyses in GEMMs show that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogram the TME during carcinogenesis, leading to a convergence of cell state alterations in neighboring epithelial, immune, and fibroblast cell types that parallel key findings in human prostate cancer., (© 2024. The Author(s).)

The stromal component of the tumour microenvironment in primary and metastatic prostate cancer can influence and promote disease progression. Within the prostatic stroma, fibroblasts are one of the most prevalent cell types associated with precancerous and cancerous lesions; they have a vital role in the structural composition, organization and integrity of the extracellular matrix. Fibroblasts within the tumour microenvironment can undergo cellular senescence, which is a stable arrest of cell growth and a phenomenon that is emerging as a recognized hallmark of cancer. Supporting the idea that cellular senescence has a pro-tumorigenic role, a subset of senescent cells exhibits a senescence-associated secretory phenotype (SASP), which, along with increased inflammation, can promote prostate cancer cell growth and survival. These cellular characteristics make targeting senescent cells and/or modulating SASP attractive as a potential preventive or therapeutic option for prostate cancer., (© 2023. Springer Nature Limited.)

Importance: The National Cancer Institute comprehensive cancer centers (CCCs) lack spatial and temporal evaluation of their self-designated catchment areas., Objective: To identify disparities in cancer stage at diagnosis within and outside a CCC's catchment area across a 10-year period using spatial and statistical analyses., Design, Setting, and Participants: This cross-sectional, population-based study conducted between 2010 and 2019 utilized cancer registry data for the Johns Hopkins Sidney Kimmel CCC (SKCCC). Eligible participants included patients with cancer in the contiguous US who received treatment for cancer, a diagnosis of cancer, or both at SKCCC. Patients were geocoded to zip code tabulation areas (ZCTAs). Individual-level variables included sociodemographic characteristics, smoking and alcohol use, treatment type, cancer site, and insurance type. Data analysis was performed between March and July 2023., Exposures: Distance between SKCCC and ZCTAs were computed to generate a catchment area of the closest 75% of patients and outer zones in 5% increments for comparison., Main Outcomes and Measures: The primary outcome was cancer stage at diagnosis, defined as early-stage, late-stage, or unknown stage. Multinomial logistic regression was used to determine associations of catchment area with stage at diagnosis., Results: This study had a total of 94 007 participants (46 009 male [48.94%] and 47 998 female [51.06%]; 30 195 aged 22-45 years [32.12%]; 4209 Asian [4.48%]; 2408 Hispanic [2.56%]; 16 004 non-Hispanic Black [17.02%]; 69 052 non-Hispanic White [73.45%]; and 2334 with other or unknown race or ethnicity [2.48%]), including 47 245 patients (50.26%) who received a diagnosis of early-stage cancer, 19 491 (20.73%) who received a diagnosis of late-stage cancer , and 27 271 (29.01%) with unknown stage. Living outside the main catchment area was associated with higher odds of late-stage cancers for those who received only a diagnosis (odds ratio [OR], 1.50; 95% CI, 1.10-2.05) or only treatment (OR, 1.44; 95% CI, 1.28-1.61) at SKCCC. Non-Hispanic Black patients (OR, 1.16; 95% CI, 1.10-1.23) and those with Medicaid (OR, 1.65; 95% CI, 1.46-1.86) and no insurance at time of treatment (OR, 2.12; 95% CI, 1.79-2.51) also had higher odds of receiving a late-stage cancer diagnosis., Conclusions and Relevance: In this cross-sectional study of CCC data from 2010 to 2019, patients residing outside the main catchment area, non-Hispanic Black patients, and patients with Medicaid or no insurance had higher odds of late-stage diagnoses. These findings suggest that disadvantaged populations and those living outside of the main catchment area of a CCC may face barriers to screening and treatment. Care-sharing agreements among CCCs could address these issues.

Glutathione S-transferase pi 1 (GSTP1) is lowly expressed in normal prostate luminal cells and becomes induced in most proliferative inflammatory atrophy (PIA) lesions. GSTP1 becomes silenced in prostatic intraepithelial neoplasia (PIN) and prostate adenocarcinoma (CaP) via cytosine-phospho-guanine (CpG) island promoter hypermethylation. However, GSTP1 methylation patterns in PIA and PIN, and their relationship to patterns in CaP are poorly understood. We used bisulfite genomic sequencing to examine patterns of GSTP1 promoter CpG island methylation in laser capture microdissected benign, PIA, PIN, and CaP regions from 32 subjects that underwent radical prostatectomy. We analyzed 908 sequence clones across 24 normal epithelium, 37 PIA, 18 PIN, and 23 CaP regions, allowing assessment of 34,863 CpG sites with allelic phasing. Normal and PIA lesions were mostly unmethylated with 0.52 and 1.3% of total CpG sites methylated, respectively. PIN and CaP lesions had greater methylation with 24% and 51% of total CpG sites methylated, respectively. The degree of GSTP1 methylation showed progression from PIA << PIN < CaP. PIN lesions showed more partial methylation compared with CaP lesions. Partially methylated lesions were enriched for methylation changes at AP1 and SP1 transcription factor binding sites. These results demonstrate that methylation density in the GSTP1 CpG island in PIN was intermediate relative to that in normal prostate epithelium/PIA and CaP lesions. These results are consistent with gradual spreading of DNA methylation centered at the SP1/AP1 transcription factor binding sites in precursor lesions, with subsequent spreading of methylation across the entire CpG island in transition to CaP., Prevention Relevance: DNA hypermethylation at the GSTP1 promoter progressively spreads from being unmethylated in normal prostate to intermediate levels in precursor lesions to extensive methylation in cancer. This molecular progression of GSTP1 promoter methylation patterns in early prostate carcinogenesis could be useful for identification and interception of prostate cancer precursors., (©2023 American Association for Cancer Research.)

Background: Evaluating the complex interplay of cell types in the tissue microenvironment is critical to understanding the origin and progression of diseases in the prostate and potential opportunities for intervention. Mouse models are an essential tool to investigate the molecular and cell-type-specific contributions of prostate disease at an organismal level. While there are well-documented differences in the extent, timing, and nature of disease development in various genetically engineered and exposure-based mouse models in different mouse strains and prostate lobes within each mouse strain, the underlying molecular phenotypic differences in cell types across mouse strains and prostate lobes are incompletely understood., Methods: In this study, we used single-cell RNA-sequencing (scRNA-seq) methods to assess the single-cell transcriptomes of 6-month-old mouse prostates from two commonly used mouse strains, friend virus B/NIH jackson (FVB/NJ) (N = 2) and C57BL/6J (N = 3). For each mouse, the lobes of the prostate were dissected (anterior, dorsal, lateral, and ventral), and individual scRNA-seq libraries were generated. In situ and pathological analyses were used to explore the spatial and anatomical distributions of novel cell types and molecular markers defining these cell types., Results: Data dimensionality reduction and clustering analysis of scRNA-seq data revealed that basal and luminal cells possessed strain-specific transcriptomic differences, with luminal cells also displaying marked lobe-specific differences. Gene set enrichment analysis comparing luminal cells by strain showed enrichment of proto-Oncogene targets in FVB/NJ mice. Additionally, three rare populations of epithelial cells clustered independently of strain and lobe: one population of luminal cells expressing Foxi1 and components of the vacuolar ATPase proton pump (Atp6v0d2 and Atp6v1g3), another population expressing Psca and other stem cell-associated genes (Ly6a/Sca-1, Tacstd2/Trop-2), and a neuroendocrine population expressing Chga, Chgb, and Syp. In contrast, stromal cell clusters, including fibroblasts, smooth muscle cells, endothelial cells, pericytes, and immune cell types, were conserved across strain and lobe, clustering largely by cell type and not by strain or lobe. One notable exception to this was the identification of two distinct fibroblast populations that we term subglandular fibroblasts and interstitial fibroblasts based on their strikingly distinct spatial distribution in the mouse prostate., Conclusions: Altogether, these data provide a practical reference of the transcriptional profiles of mouse prostate from two commonly used mouse strains and across all four prostate lobes., (© 2022 Wiley Periodicals LLC.)

Basal cell carcinoma (BCC) of the prostate is a rare tumor. Compared with the more common acinar adenocarcinoma (AAC) of the prostate, BCCs show features of basal cell differentiation and are thought to be biologically distinct from AAC. The spectrum of molecular alterations of BCC has not been comprehensively described, and genomic studies are lacking. Herein, whole genome sequencing was performed on archival formalin-fixed, paraffin-embedded specimens of two cases with BCC. Prostatic BCCs were characterized by an overall low copy number and mutational burden. Recurrent copy number loss of chromosome 16 was observed. In addition, putative driver gene alterations in KIT, DENND3, PTPRU, MGA, and CYLD were identified. Mechanistically, depletion of the CYLD protein resulted in increased proliferation of prostatic basal cells in vitro. Collectively, these studies show that prostatic BCC displays distinct genomic alterations from AAC and highlight a potential role for loss of chromosome 16 in the pathogenesis of this rare tumor type., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

A limited number of cell lines have fueled the majority of preclinical prostate cancer research, but their genomes remain incompletely characterized. Here, we utilized whole-genome linked-read sequencing for comprehensive characterization of phased mutations and rearrangements in the most commonly used cell lines in prostate cancer research including PC3, LNCaP, DU145, CWR22Rv1, VCaP, LAPC4, MDA-PCa-2b, RWPE-1, and four derivative castrate-resistant (CR) cell lines LNCaP&#95;Abl, LNCaP&#95;C42b, VCaP-CR, and LAPC4-CR. Phasing of mutations allowed determination of "gene-level haplotype" to assess whether genes harbored heterozygous mutations in one or both alleles. Phased structural variant analysis allowed identification of complex rearrangement chains consistent with chromothripsis and chromoplexy. In addition, comparison of parental and derivative CR lines revealed previously known and novel genomic alterations associated with the CR phenotype., Implications: This study therefore comprehensively characterized phased genomic alterations in the commonly used prostate cancer cell lines, providing a useful resource for future prostate cancer research., (©2022 The Authors; Published by the American Association for Cancer Research.)

Purpose: Pathways involving sex hormones and insulin-like growth factors (IGFs) have been proposed to explain, in part, the lower risk of prostate cancer among men with diabetes. To gain insights into potential biological mechanisms we explored differences in serum concentrations of sex hormones and IGFs across the trajectory from normoglycemia to prediabetes to poorly controlled diabetes., Methods: Using cross-sectional data from the National Health and Nutrition Examination Survey III we examined differences in levels of circulating sex hormones, sex hormone-binding globulin (SHBG), IGF-1, and IFG-binding protein 3 (IGFBP-3), according to diabetes status: no diabetes [n = 648], prediabetes [n = 578], undiagnosed diabetes [n = 106], well-controlled diabetes [n = 42], and poorly controlled diabetes [n = 56]. Adjusted geometric mean concentrations were derived using multivariable linear regression, adjusted for age, race, and other lifestyle factors., Results: Total testosterone concentrations were lower among prediabetics (4.89 ng/mL, 95% confidence interval (CI) 4.95-5.21) than men without prediabetes/diabetes (5.29 ng/mL, 95% CI 5.06-5.53) but did not reduce further across diabetes groups. Concentrations of estradiol, estimated free testosterone, SHGB, IGF-1, and IGFBP-3 did not differ. While the ratio of IGF-1 to IGFBP-3 was lower among men with prediabetics and undiagnosed diabetes than men without prediabetes/diabetes, there was no trend across groups. A positive trend for the ratio of estradiol-to-testosterone levels was observed across groups (p trend = 0.045)., Conclusion: Our findings do not provide clear support for either an androgen driven or IGF-driven pathway for the inverse association between diabetes and prostate cancer risk., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Prostate cancer exerts a greater toll on African American men than on White men of European descent (hereafter referred to as European American men): the disparity in incidence and mortality is greater than that of any other common cancer. The disproportionate impact of prostate cancer on Black men has been attributed to the genetics of African ancestry, to diet and lifestyle risk factors, and to unequal access to quality health care. In this Review, all of these influences are considered in the context of the evolving understanding that chronic or recurrent inflammatory processes drive prostatic carcinogenesis. Studies of inherited susceptibility highlight the contributions of genes involved in prostate cell and tissue repair (BRCA1/2, ATM) and regeneration (HOXB13 and MYC). Social determinants of health appear to accentuate these genetic influences by fueling prostate inflammation and associated cell and genome damage. Molecular characterization of the prostate cancers that arise in Black versus White men further implicates this inflammatory microenvironment in disease behavior. Yet, when Black and White men with similar grade and stage of prostate cancer are treated equally, they exhibit equivalent outcomes. The central role of prostate inflammation in prostate cancer development and progression augments the impact of the social determinants of health on disease pathogenesis. And, when coupled with poorer access to high-quality treatment, these inequities result in a disparate burden of prostate cancer on African American men.

Non-supplemental carotenoids and retinol may potentiate antioxidant and anti-inflammatory mechanisms. Chronic intraprostatic inflammation is linked to prostate carcinogenesis. We investigated the association of circulating carotenoids and retinol with intraprostatic inflammation in benign tissue. We included 235 men from the Prostate Cancer Prevention Trial placebo arm who had a negative end-of-study biopsy, most (92.8%) done without clinical indication. α-carotene, β-carotene, β-cryptoxanthin, lycopene, and retinol were assessed by high-performance liquid chromatography using pooled year 1 and 4 serum. Presence and extent of intraprostatic inflammation in benign tissue was assessed in 3 (of 6-10) biopsy cores. Logistic (any core with inflammation vs none) and polytomous logistic (some or all cores with inflammation vs none) regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of intraprostatic inflammation by concentration tertile adjusting for age, race, prostate cancer family history, and serum cholesterol. None of the carotenoids or retinol was associated with intraprostatic inflammation, except β-cryptoxanthin, which appeared to be positively associated with any core with inflammation [vs none, T2: OR (95% CI) = 2.67 (1.19, 5.99); T3: 1.80 (0.84, 3.82), P -trend = 0.12]. These findings suggest that common circulating carotenoids and retinol are not useful dietary intervention targets for preventing prostate cancer via modulating intraprostatic inflammation.

Background: Resistance to androgen deprivation therapies is a major driver of mortality in advanced prostate cancer. Therefore, there is a need to develop new preclinical models that allow the investigation of resistance mechanisms and the assessment of drugs for the treatment of castration-resistant prostate cancer., Methods: We generated two novel cell line models (LAPC4-CR and VCaP-CR) which were derived by passaging LAPC4 and VCaP cells in vivo and in vitro under castrate conditions. We performed detailed transcriptomic (RNA-seq) and proteomic analyses (SWATH-MS) to delineate expression differences between castration-sensitive and castration-resistant cell lines. Furthermore, we characterized the in vivo and in vitro growth characteristics of these novel cell line models., Results: The two cell line derivatives LAPC4-CR and VCaP-CR showed castration-resistant growth in vitro and in vivo which was only minimally inhibited by AR antagonists, enzalutamide, and bicalutamide. High-dose androgen treatment resulted in significant growth arrest of VCaP-CR but not in LAPC4-CR cells. Both cell lines maintained AR expression, but exhibited distinct expression changes on the mRNA and protein level. Integrated analyses including data from LNCaP and the previously described castration-resistant LNCaP-abl cells revealed an expression signature of castration resistance., Conclusions: The two novel cell line models LAPC4-CR and VCaP-CR and their comprehensive characterization on the RNA and protein level represent important resources to study the molecular mechanisms of castration resistance., (© 2021 Wiley Periodicals LLC.)

The epigenomic regulation of transcriptional programs in metastatic prostate cancer is poorly understood. We studied the epigenomic landscape of prostate cancer drivers using transcriptional profiling and ChIP-seq in four clonal metastatic tumors derived from a single prostate cancer patient. Our epigenomic analyses focused on androgen receptor (AR), which is a key oncogenic driver in prostate cancer, the AR pioneer factor FOXA1, chromatin insulator CCCTC-Binding Factor, as well as for modified histones H3K27ac and H3K27me3. The vast majority of AR binding sites were shared among healthy prostate, primary prostate cancer, and metastatic tumor samples, signifying core AR-driven transcriptional regulation within the prostate cell lineage. Genes associated with core AR-binding events were significantly enriched for essential genes in prostate cancer cell proliferation. Remarkably, the metastasis-specific active AR binding sites showed no differential transcriptional output, indicating a robust transcriptional program across metastatic samples. Combined, our data reveal a core transcriptional program in clonal metastatic prostate cancer, despite epigenomic differences in the AR cistrome., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

GSTP1 is a member of the Glutathione-S-transferase (GST) family silenced by CpG island DNA hypermethylation in 90-95% of prostate cancers. However, prostate cancers expressing GSTP1 have not been well characterized. We used immunohistochemistry against GSTP1 to examine 1673 primary prostatic adenocarcinomas on tissue microarrays (TMAs) with redundant sampling from the index tumor from prostatectomies. GSTP1 protein was positive in at least one TMA core in 7.7% of cases and in all TMA cores in 4.4% of cases. The percentage of adenocarcinomas from Black patients who had any GSTP1 positive TMA cores was 14.9%, which was 2.5 times higher than the percentage from White patients (5.9%; P < 0.001). Further, the percentages of tumors from Black patients who had all TMA spots positive for GSTP1 (9.5%) was 3-fold higher than the percentage from White patients (3.2%; P<0.001). In terms of association with other molecular alterations, GSTP1 positivity was enriched in ERG positive cancers among Black men. By in situ hybridization, GSTP1 mRNA expression was concordant with protein staining, supporting the lack of silencing of at least some GSTP1 alleles in GSTP1-positive tumor cells. This is the first report revealing that GSTP1-positive prostate cancers are substantially over-represented among prostate cancers from Black compared to White men. This observation should prompt additional studies to determine whether GSTP1 positive cases represent a distinct molecular subtype of prostate cancer and whether GSTP1 expression could provide a biological underpinning for the observed disparate outcomes for Black men., Competing Interests: Conflicts of interest: S.Y., W.G.N., and A.M.D. are paid consultants to Cepheid LLC, with whom they are developing epigenetic tests for prostate cancer. S.Y. has received sponsored research support from Cepheid for development and testing of prostate cancer epigenetic biomarkers. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Resistance to AR signaling inhibitors (ARSis) in a subset of metastatic castration-resistant prostate cancers (mCRPCs) occurs with the emergence of AR- neuroendocrine prostate cancer (NEPC) coupled with mutations/deletions in PTEN, TP53, and RB1 and the overexpression of DNMTs, EZH2, and/or SOX2. To resolve whether the lack of AR is the driving factor for the emergence of the NE phenotype, molecular, cell, and tumor biology analyses were performed on 23 xenografts derived from patients with PC, recapitulating the full spectrum of genetic alterations proposed to drive NE differentiation. Additionally, phenotypic response to CRISPR/Cas9-mediated AR KO in AR+ CRPC cells was evaluated. These analyses document that (a) ARSi-resistant NEPC developed without androgen deprivation treatment; (b) ARS in ARSi-resistant AR+/NE+ double-positive "amphicrine" mCRPCs did not suppress NE differentiation; (c) the lack of AR expression did not necessitate acquiring a NE phenotype, despite concomitant mutations/deletions in PTEN and TP53, and the loss of RB1 but occurred via emergence of an AR-/NE- double-negative PC (DNPC); (d) despite DNPC cells having homogeneous genetic driver mutations, they were phenotypically heterogeneous, expressing basal lineage markers alone or in combination with luminal lineage markers; and (e) AR loss was associated with AR promoter hypermethylation in NEPCs but not in DNPCs.

From a clinical, morphological and molecular perspective, prostate cancer is a heterogeneous disease. Primary prostate cancers are often multifocal, having topographically and morphologically distinct tumour foci. Sequencing studies have revealed that individual tumour foci can arise as clonally distinct lesions with no shared driver gene alterations. This finding demonstrates that multiple genomically and phenotypically distinct primary prostate cancers can be present in an individual patient. Lethal metastatic prostate cancer seems to arise from a single clone in the primary tumour but can exhibit subclonal heterogeneity at the genomic, epigenetic and phenotypic levels. Collectively, this complex heterogeneous constellation of molecular alterations poses obstacles for the diagnosis and treatment of prostate cancer. However, advances in our understanding of intra-tumoural heterogeneity and the development of novel technologies will allow us to navigate these challenges, refine approaches for translational research and ultimately improve patient care.

Background & Aims: This study aimed to analyse the association of sex hormone levels with liver enzyme levels and non-alcoholic fatty liver disease (NAFLD) in a nationally representative sample of men., Methods: A total of 919 men from the US National Health and Nutrition Examination Study (NHANES) III were included in this cross-sectional analysis of data from 1988 to 1991. We used existing data on serum total and free testosterone, total and free estradiol, androstanediol glucuronide (AAG) and sex steroid-binding globulin (SHBG), and estimated their associations with aspartate aminotransferase (AST), and alanine aminotransferase (ALT) and NAFLD, as determined using ultrasound, after adjusting for possible confounders including age, race, smoking, alcohol, physical activity, waist circumference and steroid hormones., Results: Lower total testosterone (TT) and higher free estradiol were associated with higher odds of NAFLD after adjusting for confounders including the other sex hormones. Lower TT was associated with higher odds of elevated AST, but not ALT. Free testosterone, total estradiol, SHBG and AAG were not associated with NAFLD or liver enzymes., Conclusions: This study supports an inverse association between TT concentration and NAFLD in men independent of other sex hormones (SHBG, AAG and estradiol) and known risk factors, such as obesity, age and lifestyle. Exploration of whether TT might be a non-invasive marker for NAFLD diagnosis is warranted., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Epidemiology, clinical and experimental animal studies suggest high fructose diets are detrimental to metabolic status and may contribute to tumor development. This due to increased obesity and metabolic syndrome, known risk factors for many types of cancer. We compared tumor development in N-methyl-N-nitrosourea (MNU)-treated rats fed either a high (60%)-fructose diet (HFD) or a standard diet (SD). Female Sprague-Dawley rats at 43 days of age (DOA) were fed a SD or HFD followed by administration of MNU at 50 DOA. Rats were palpated weekly and sacrificed at 190 DOA. MNU-treated rats on HFD exhibited decreased tumor latency and roughly a two-fold increase in tumor multiplicity. RNA-Seq on frozen tumors (SD vs. HFD rats) showed altered expression of approximately 10% of genes (P < 0.05). When examined by Ingenuity Pathway Analysis, multiple highly significant pathways were identified including A) mechanisms of cancer, B) Wnt pathway, C) immune response ( e.g. , "Th1 and Th2 activation" and "antigen presentation") and D) LXR/RXR nuclear receptor. These generalized pathways were indirectly confirmed by alterations of various interrelated disease pathways (epithelial cancers, T cell numbers and apoptosis). In a second study, serum was collected from rats on the HFD or SD pre-MNU and at the time of sacrifice. Metabolomics revealed that the HFD yielded: A) increased levels of fructose, B) increases of various monoglycerols, C) reduced levels of various diacylglycerols and oxygenated inflammatory lipids (9 and 13 HODE and 12,13 DHOME) and D) increased levels of secondary bile acids (hyodeoxycholate and 6-oxolithocholate), which may reflect microbiome changes. These metabolomic changes, which are distinct from those on a high-fat diet, may prove relevant when examining individuals who consume higher levels of fructose.

Background: In cancers, maintenance of telomeres often occurs through activation of the catalytic subunit of telomerase, encoded by TERT. Yet, most cancers show only modest levels of TERT gene expression, even in the context of activating hotspot promoter mutations (C228T and C250T). The role of epigenetic mechanisms, including DNA methylation, in regulating TERT gene expression in cancer cells is as yet not fully understood., Methods: Here, we have carried out the most comprehensive characterization to date of TERT promoter methylation using ultra-deep bisulfite sequencing spanning the CpG island surrounding the core TERT promoter in 96 different human cell lines, including primary, immortalized and cancer cell types, as well as in control and reference samples., Results: In general, we observed that immortalized and cancer cell lines were hypermethylated in a region upstream of the recurrent C228T and C250T TERT promoter mutations, while non-malignant primary cells were comparatively hypomethylated in this region. However, at the allele-level, we generally found that hypermethylation of promoter sequences in cancer cells is associated with repressed expression, and the remaining unmethylated alleles marked with open chromatin are largely responsible for the observed TERT expression in cancer cells., Conclusions: Our findings suggest that hypermethylation of the TERT promoter alleles signals transcriptional repression of those alleles, leading to attenuation of TERT activation in cancer cells. This type of fine tuning of TERT expression may account for the modest activation of TERT expression in most cancers.

Aspirin and statin use may lower the risk of advanced/fatal prostate cancer, possibly by reducing intraprostatic inflammation. To test this hypothesis, we investigated the association of aspirin and statin use with the presence and extent of intraprostatic inflammation, and the abundance of specific immune cell types, in benign prostate tissue from a subset of men from the placebo arm of the Prostate Cancer Prevention Trial. Men were classified as aspirin or statin users if they reported use at baseline or during the 7-year trial. Presence and extent of inflammation were assessed, and markers of specific immune cell types (CD4, CD8, FoxP3, CD68, and c-KIT) were scored, in slides from end-of-study prostate biopsies taken irrespective of clinical indication, per trial protocol. Logistic regression was used to estimate associations between medication use and inflammation measures, adjusted for potential confounders. Of 357 men included, 61% reported aspirin use and 32% reported statin use. Prevalence and extent of inflammation were not associated with medication use. However, aspirin users were more likely to have low FoxP3, a T regulatory cell marker [OR, 5.60; 95% confidence interval (CI), 1.16-27.07], and statin users were more likely to have low CD68, a macrophage marker (OR, 1.63; 95% CI, 0.81-3.27). If confirmed, these results suggest that these medications may alter the immune milieu of the prostate, which could potentially mediate effects of these medications on advanced/fatal prostate cancer risk., (©2020 American Association for Cancer Research.)

Background: Intraprostatic inflammation is an emerging prostate cancer risk factor. Estrogens are pro-inflammatory while androgens are anti-inflammatory. Thus, we investigated whether serum sex steroid hormone concentrations are associated with intraprostatic inflammation to inform mechanistic links among hormones, inflammation, and prostate cancer., Methods: We conducted a cross-sectional study among 247 men in the placebo arm of the Prostate Cancer Prevention Trial who had a negative end-of-study biopsy, most (92.7%) performed without clinical indication per trial protocol. Serum estradiol, estrone, and testosterone were previously measured by immunoassay in pooled baseline and Year 3 serum. Free estradiol and free testosterone were calculated. Inflammation was visually assessed (median of three prostate biopsy cores per man). Polytomous or logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of some or all cores inflamed (both vs none) or any core inflamed (vs none) by hormone tertile, adjusting for age, race, and family history. We evaluated effect modification by waist circumference and body mass index (BMI)., Results: In all, 51.4% had some and 26.3% had all cores inflamed. Free (P-trend = .11) but not total estradiol was suggestively inversely associated with all cores inflamed. In men with waist circumference greater than or equal to 102 cm (P-trend = .021) and BMI ≥ 27.09 kg/m 2 (P-trend = .0037) free estradiol was inversely associated with any core inflamed. Estrone was inversely associated with all cores inflamed (T3: OR = 0.36, 95% CI 0.14-0.95, P-trend = .036). Total (T3: OR = 1.91, 95% CI 0.91-4.02, P-trend = .11) and free (T3: OR = 2.19, 95% CI 1.01-4.74, P-trend = .05) testosterone were positively associated with any core inflamed, especially free testosterone in men with waist circumference less than 102 cm (T3: OR = 3.51, 95% CI 1.03-12.11, P-trend = .05)., Conclusions: In this first study in men without prostate cancer and irrespective of clinical indication for biopsy, contrary to the hypothesis, circulating estrogens appeared to be inversely associated, especially in heavy men, whereas androgens appeared to be positively associated with intraprostatic inflammation., (© 2020 Wiley Periodicals LLC.)

Organic carbon content of sediments, whether directly or indirectly assessed, has often been used as an indicator of marine benthic community condition both in site-specific and regional scale condition assessment studies. The conceptual framework underlying use of this indicator was developed based primarily on site-specific studies. A quantitative analysis of literature data on sediment organic matter impacts in marine systems was conducted to determine whether biotic metrics respond to abiotic indicators of sediment organic content, as predicted by conceptual models, at larger spatial scales. The ability to detect predicted decreases in community metrics (abundance, species richness, species diversity index H', biomass) varied among metrics, with best performance by species richness and H'. There was significant added variation both between and within analytical approaches (loss on ignition, total organic carbon methods), emphasizing the need for careful cross calibration and quality control in studies with multiple laboratory partners. High levels of variability for biotic metrics versus organic carbon metrics appear typical for large scale studies, and organic matter source, site depth, and individual estuarine system differences were important sources of variation. Covariation of organic matter content with percent fine sediments is another known source of variation, but various normalization methods may be inadequate due to inherent sources of variation at estuary level. While likely still useful for point-source studies, multiple major sources of variation appear to limit the usefulness of sediment organic content as a benthic condition indicator at larger spatial scales.

Background: The protist Trichomonas vaginalis causes a common, sexually transmitted infection and has been proposed to contribute to the development of chronic prostate conditions, including benign prostatic hyperplasia and prostate cancer. However, few studies have investigated the extent to which it involves the prostate in the current antimicrobial era. We addressed this question by investigating the relation between T. vaginalis antibody serostatus and serum prostate-specific antigen (PSA) concentration, a marker of prostate infection, inflammation, and/or cell damage, in young, male, US military members., Methods: We measured T. vaginalis serum IgG antibodies and serum total PSA concentration in a random sample of 732 young, male US active duty military members. Associations between T. vaginalis serostatus and PSA were investigated by linear regression., Results: Of the 732 participants, 341 (46.6%) had a low T. vaginalis seropositive score and 198 (27.0%) had a high score, with the remainder seronegative. No significant differences were observed in the distribution of PSA by T. vaginalis serostatus. However, slightly greater, nonsignificant differences were observed when men with high T. vaginalis seropositive scores were compared with seronegative men, and when higher PSA concentrations were examined (≥0.70 ng/mL). Specifically, 42.5% of men with high seropositive scores had a PSA concentration greater than or equal to 0.70 ng/mL compared with 33.2% of seronegative men (adjusted P = .125)., Conclusions: Overall, our findings do not provide strong support for prostate involvement during T. vaginalis infection, although our suggestive positive findings for higher PSA concentrations do not rule out this possibility entirely. These suggestive findings may be relevant for prostate condition development because higher early- to mid-life PSA concentrations have been found to predict greater prostate cancer risk later in life., (© 2019 Wiley Periodicals, Inc.)

Background: To evaluate the association of liver fibrosis scores with PSA level among U.S. adult men overall and by race/ethnicity., Methods: Data from the National Health and Nutrition Examination Survey (NHANES), 2001-2010, were used. Males ages ≥40 years without a prostate cancer diagnosis and who had serum PSA, liver enzymes, albumin, and platelet counts measured as part of NHANES protocol were included. Liver fibrosis was measured using three scores: aspartate aminotransferase to platelet ratio index (APRI), fibrosis 4 index (FIB-4), and NAFLD fibrosis score (NFS). We assessed overall and race/ethnicity-stratified geometric mean PSA by fibrosis score using predictive margins by linear regression, and the association of abnormal fibrosis scores (APRI > 1, FIB-4 > 2.67, NFS > 0.676) and elevated PSA (>4 ng/mL) by logistic regression., Results: A total of 6,705 men were included. Abnormal liver fibrosis scores were present in 2.1% (APRI), 3.6% (FIB-4), and 5.6% (NFS). Men with higher fibrosis scores had lower geometric mean PSA (all P trend < 0.02). Men with abnormal APRI had a lower odds of PSA > 4 ng/mL [adjusted OR (aOR) = 0.33; 95% confidence interval (CI), 0.11-0.96]. Compared with men with 0 abnormal scores, those with 2 or 3 abnormal fibrosis scores had a lower odds of PSA > 4 ng/mL (aOR = 0.55; 95% CI, 0.33-0.91). The patterns were similar by race/ethnicity., Conclusions: Men of all race/ethnicities with higher liver fibrosis scores had lower serum PSA, and men with advanced fibrosis scores had a lower odds of an elevated PSA., Impact: These findings support further research to inform the likelihood of delay in prostate cancer detection in men with abnormal liver function., (©2019 American Association for Cancer Research.)

Purpose: To report age-specific serum estradiol concentration in nonsmoking, lean US men without comorbidities. We provide concentrations from 30 and 15 to 20 years ago given previously described declines in serum estradiol in US men over time., Methods: We used data from the Third National Health and Nutrition Examination Survey (NHANES III; 1988 to 1991) and continuous NHANES (1999 to 2004). Serum estradiol and SHBG were previously measured by competitive electrochemiluminescence immunoassays. Free estradiol was estimated from estradiol, SHBG, and albumin. By age, we calculated median concentrations overall and for nonsmoking, lean (body mass index <25 kg/m 2 and waist <102 cm) men without diabetes, cardiovascular disease, or cancer., Results: Overall, respective total estradiol medians for men ages 20 to 39, 40 to 59, and ≥60 years old were 37.0, 33.9, and 33.5 pg/mL in NHANES III and 31.3, 30.5, and 27.0 pg/mL in continuous NHANES. In nonsmoking, lean men without comorbidities, respective total estradiol medians were 32.0, 32.1, and 32.0 pg/mL in NHANES III and 29.1, 22.7, and 26.1 pg/mL in continuous NHANES. Overall, respective free estradiol medians were 0.82, 0.72, and 0.64 pg/mL in NHANES III and 0.67, 0.61, and 0.47 pg/mL in continuous NHANES. In nonsmoking, lean men without comorbidities, respective free estradiol medians were 0.64, 0.67, and 0.62 pg/mL in NHANES III and 0.58, 0.42, and 0.40 pg/mL continuous NHANES., Conclusion: We report US nationally representative serum estradiol concentrations in healthy men, which could be used for targeting estradiol during testosterone supplementation and for general good health.

Context: Testosterone deficiency prevalence increases with age, comorbidities, and obesity., Objective: To inform clinical guidelines for testosterone deficiency management and development of targets for nonpharmacologic intervention trials for these men, we determined serum testosterone in never-smoking, lean men without select comorbidities in nationally representative surveys., Design Setting Participants: We used cross-sectional data for never-smoking, lean men ≥20 years without diabetes, myocardial infarction, congestive heart failure, stroke, or cancer, without use of hormone-influencing medications, and participated in morning sessions of National Health and Nutrition Examination Survey (NHANES) III (phase I 1988-1991) or continuous NHANES (1999-2004). By age, we determined median total testosterone (ng/mL) measured previously by a Food and Drug Administration-approved immunoassay and median estimated free testosterone concentration., Results: In NHANES III, in never-smoking, lean men without comorbidities, median (25th, 75th percentile) testosterone was 4% to 9% higher than all men-20 to 39 years: 6.24 (5.16, 7.51), 40 to 59: 5.37 (3.83, 6.49), and ≥60: 4.61 (4.01, 5.18). In continuous NHANES, in never-smoking, lean men without comorbidities, levels were 13% to 24% higher than all men-20 to 39 years: 6.26 (5.32, 7.27), 40 to 59: 5.86 (4.91, 6.55), and ≥60: 4.22 (3.74, 5.73). In never-smoking, lean men without comorbidities, median estimated free testosterone was similar to (NHANES III) or slightly higher than (continuous NHANES) in all men., Conclusions: These nationally representative data document testosterone levels (immunoassay) in never-smoking, lean men without select comorbidities 30 and 15 to 20 years ago. This information can be incorporated into guidelines for testosterone deficiency management and used to develop targets for nonpharmacologic intervention trials for testosterone deficiency., Competing Interests: Disclosure Summary: E.A.P. was a volunteer member of the guideline panel for the 2018 American Urological Association’s (AUA) Evaluation and Management of Testosterone Deficiency. The submitted paper was not commissioned by or done under the direction of the AUA. E.A.P. is a member of the Scientific Advisory Committee of the Cancer Section, Division of Research, Kaiser Permanente Northern California, an arrangement that has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. The remaining authors have nothing to disclose. Data Availability: NHANES data are publicly available. Data generated or analyzed during this study are included in this published article or in the data repositories listed in the references.

DNA methylation can mediate epigenetic silencing of tumor suppressor and cancer protective genes. The protein ubiquitin-like containing PHD and ring finger domains 1 (UHRF1) is an essential component in cells for DNA methylation maintenance. The SET- and RING-associated (SRA) domain of UHRF1 can bind hemimethylated DNA, and mediate recruitment of DNA methyltransferases to copy the methylation pattern to the newly synthesized daughter strand. Loss of UHRF1 function can lead to demethylation and re-expression of epigenetically silenced tumor suppressor genes and can reduce cancer cell growth and survival. We created a high-throughput time-resolved fluorescence resonance energy transfer (TR-FRET) assay to screen for inhibitors capable of disrupting the interaction between the UHRF1-SRA domain and hemimethylated DNA. Using this assay (Z' factor of 0.74 in 384-well format) we screened the Library of Pharmacologically Active Compounds (LOPAC) for UHRF1-SRA inhibitors, and validated 7 hit compounds. These compounds included the anthracycline derivatives idarubicin and mitoxantrone, which are commonly used chemotherapeutic drugs known to mediate cytotoxicity by acting as class II topoisomerase (TOP2) poisons. In a panel of additional known topoisomerase poisons, only the anthracycline derivatives showed dose responsive inhibition of UHRF1-SRA. Additionally, mitoxantrone and doxorubicin showed dose-responsive global DNA demethylation and demonstrated a synergistic growth inhibition of multiple cancer cell lines when combined with the DNA methyltransferase (DNMT) inhibitor decitabine. These data validate a novel TR-FRET assay for identification of UHRF1 inhibitors, and revealed unexpected epigenetic properties of commonly used chemotherapeutic drugs that showed synergistic cytotoxicity of cancer cells when combined with a demethylating agent., Competing Interests: CONFLICTS OF INTEREST Celgene provides sponsored research support through the Johns Hopkins Technology Ventures office for work carried out in the laboratories of W.G.N. and S.Y. Additionally, W.G.N. and S.Y. are co-founders of Brahm Astra Therapeutics (BA), focused on development of epigenetic therapeutic strategies. Celgene and BA did not provide funding for any of the work presented in this study.

A level of epigenetic programming, encoded by complex sets of chemical marks on DNA and histones, and by context-specific DNA, RNA, protein interactions, that all regulate the structure, organization, and function of the genome, is critical to establish both normal and neoplastic cell identities and functions. This structure-function relationship of the genome encoded by the epigenetic programming can be thought of as an epigenetic cityscape that is built on the underlying genetic landscape. Alterations in the epigenetic cityscape of prostate cancer cells compared with normal prostate tissues have a complex interplay with genetic alterations to drive prostate cancer initiation and progression. Indeed, mutations in genes encoding epigenetic enzymes are often observed in human cancers including prostate cancer. Interestingly, alterations in the prostate cancer epigenetic cityscape can be highly recurrent, a facet that can be exploited for development of biomarkers and potentially as therapeutic targets., (Copyright © 2019 Cold Spring Harbor Laboratory Press; all rights reserved.)

A better understanding of the early stages of prostate cancer initiation, potentially arising from precursor lesions, may fuel development of powerful approaches for prostate cancer prevention or interception. The best-known candidate for such a precursor lesion has been referred to as high-grade prostatic intraepithelial neoplasia (HGPIN). Although there is significant evidence supporting the notion that such HGPIN lesions can give rise to invasive adenocarcinomas of the prostate, there are also numerous complicating considerations and evidence that cloud the picture in many instances. Notably, recent evidence has suggested that some fraction of such lesions that are morphologically consistent with HGPIN may actually be invasive carcinomas masquerading as HGPIN-a state that we term "postinvasive intraepithelial carcinoma" (PIC). Although the prevalence of such PIC lesions is not fully understood, this and other factors can confound the potential of identifying prostate precursors that can be targeted for disease prevention, interception, or treatment. Here, we review our current understanding of the morphological and molecular pathological features of prostate cancer precursor lesions., (Copyright © 2019 Cold Spring Harbor Laboratory Press; all rights reserved.)

Background: Given the recent findings from pooled studies about a potential inverse association between selenium levels and prostate cancer risk, this cross-sectional study aimed to investigate the association between serum selenium and serum concentrations of sex steroid hormones including estradiol in a nationally representative sample of U.S. men to investigate one mechanism by which selenium may influence prostate cancer risk., Methods: The study included 1,420 men ages 20 years or older who participated in the Third National Health and Nutrition Examination Survey between 1988 and 1994. We calculated age/race-ethnicity-adjusted and multivariable-adjusted geometric mean serum concentrations of total and estimated free testosterone and estradiol, androstanediol glucuronide, and sex hormone binding globulin, and compared them across quartiles of serum selenium., Results: Adjusting for age, race/ethnicity, smoking status, serum cotinine, household income, physical activity, alcohol consumption, and percent body fat, mean total estradiol [e.g., Q1, 38.00 pg/mL (95% confidence interval (CI), 36.03-40.08) vs. Q4, 35.29 pg/mL (95% CI, 33.53-37.14); P trend = 0.050] and free estradiol [e.g., Q1, 0.96 pg/mL (95% CI, 0.92-1.01) vs. Q4, 0.90 (95% CI, 0.85-0.95); P trend = 0.065] concentrations decreased over quartiles of selenium. Stratification by smoking and alcohol consumption, showed that the latter observation was stronger for never smokers ( P interaction = 0.073) and those with limited alcohol intake ( P interaction = 0.017). No associations were observed for the other sex steroid hormones studied., Conclusions: Our findings suggests that a possible mechanism by which selenium may be protective for prostate cancer is related to estrogen., Impact: Further studies of longitudinal measurements of serum and toenail selenium in relation to serum measurements of sex steroid hormones are needed., (©2018 American Association for Cancer Research.)

Antibodies are employed ubiquitously in biomedical sciences, including for diagnostics and therapeutics. One of the most important uses is for immunohistochemical (IHC) staining, a process that has been improving and evolving over decades. IHC is useful when properly employed, yet misuse of the method is widespread and contributes to the "reproducibility crisis" in science. We report some of the common problems encountered with IHC assays, and direct readers to a wealth of literature documenting and providing some solutions to this problem. We also describe a series of vignettes that include our approach to analytical validation of antibodies and IHC assays that have facilitated a number of biological insights into prostate cancer and the refutation of a controversial association of a viral etiology in gliomas. We postulate that a great deal of the problem with lack of accuracy in IHC assays stems from the lack of awareness by researchers for the critical necessity for end-users to validate IHC antibodies and assays in their laboratories, regardless of manufacturer claims or past publications. We suggest that one reason for the pervasive lack of end-user validation for research antibodies is that researchers fail to realize that there are two general classes of antibodies employed in IHC. First, there are antibodies that are "clinical grade" reagents used by pathologists to help render diagnoses that influence patient treatment. Such diagnostic antibodies, which tend to be highly validated prior to clinical implementation, are in the vast minority ( e.g.  < 500). The other main class of antibodies are "research grade" antibodies (now numbering >3 800 000), which are often not extensively validated prior to commercialization. Given increased awareness of the problem, both the United States, National Institutes of Health and some journals are requiring investigators to provide evidence of specificity of their antibody-based assays.

Background: To extend our previous observation of a short-term rise in prostate-specific antigen (PSA) concentration, a marker of prostate inflammation and cell damage, during and immediately following sexually transmitted and systemic infections, we examined the longer-term influence of these infections, both individually and cumulatively, on PSA over a mean of 10 years of follow-up in young active duty U.S. servicemen., Methods: We measured PSA in serum specimens collected in 1995-7 (baseline) and 2004-6 (follow-up) from 265 men diagnosed with chlamydia (CT), 72 with gonorrhea (GC), 37 with non-chlamydial, non-gonococcal urethritis (NCNGU), 58 with infectious mononucleosis (IM), 91 with other systemic or non-genitourinary infections such as varicella; and 125-258 men with no infectious disease diagnoses in their medical record during follow-up (controls). We examined the influence of these infections on PSA change between baseline and follow-up., Results: The proportion of men with any increase in PSA (>0 ng/mL) over the 10-year average follow-up was significantly higher in men with histories of sexually transmitted infections (CT, GC, and NCNGU; 67.7% vs 60.8%, P = 0.043), systemic infections (66.7% vs 54.4%, P = 0.047), or any infections (all cases combined; 68.5% vs 54.4%, P = 0.003) in their military medical record compared to controls., Conclusions: While PSA has been previously shown to rise during acute infection, these findings demonstrate that PSA remains elevated over a longer period. Additionally, the overall infection burden, rather than solely genitourinary-specific infection burden, contributed to these long-term changes, possibly implying a role for the cumulative burden of infections in prostate cancer risk., (© 2018 Wiley Periodicals, Inc.)