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1.  Anti-inflammatory drugs, antioxidants, and prostate cancer prevention 
Current opinion in pharmacology  2009;9(4):419-426.
Prostate cancer may be the most common preventable cancer among men in the United States (US) and the rest of the developed world. Emerging insights into the molecular pathogenesis of prostate cancer suggest that damage to the prostate epithelium, potentially inflicted by a variety of exposures, triggers procarcinogenic inflammatory processes to promote disease development. In this milieu, the damaged epithelium may generate proliferative inflammatory atrophy (PIA) lesions, which may progress to prostatic intraepithelial neoplasia (PIN) or to prostate cancer. To attenuate prostatic carcinogenesis driven by chronic or recurrent prostate inflammation, rational chemoprevention has thus far featured anti-inflammatory drugs and antioxidants. Results from clinical trials of these approaches have been mixed, emphasizing the need for mechanistic studies of the contribution of inflammation to prostatic carcinogenesis, more extensive analyses of the pharmacology, including distribution of drugs into target tissue, and, rational development of biomarkers to identify patients that are most likely to respond to anti-inflammatory drugs and antioxidants (targeted chemoprevention), alone, or in combination (combination chemoprevention).
doi:10.1016/j.coph.2009.06.002
PMCID: PMC4479123  PMID: 19574101
2.  USP2a Activation of MYC in Prostate Cancer 
Cancer discovery  2012;2(3):206-207.
Summary
Ubiquitin-specific protease 2a, a deubiquitinating enzyme, elevates MYC levels in prostate cancer cells via its stabilization of MDM2, undermining p53 regulation of microRNAs that target MYC mRNA.
doi:10.1158/2159-8290.CD-12-0027
PMCID: PMC4479124  PMID: 22585990
3.  Circulating Total Testosterone and PSA Concentrations in a Nationally Representative Sample of Men Without a Diagnosis of Prostate Cancer 
The Prostate  2015;75(11):1167-1176.
Background
The association between serum sex steroid hormones and PSA in a general population has not been described.
Methods
Included were 378 men aged 40-85 years who participated in the National Health and Nutrition Examination Survey in 2001-2004, who did not have a prostate cancer diagnosis, and had not had a recent biopsy, rectal examination, cystoscopy, or prostate infection or inflammation. Serum total PSA, total testosterone, androstanediol glucuronide (3α-diol-G), estradiol, and sex hormone binding globulin (SHBG) concentrations were previously measured. Free testosterone was estimated by mass action. We applied sampling weights and calculated geometric mean PSA concentration by hormone quintiles adjusting for age and race/ethnicity, and also for body mass index, waist circumference, smoking, diabetes, and mutually for hormones. We estimated the OR of PSA ≥2.5 ng/mL per hormone quintile using logistic regression.
Results
Geometric mean PSA increased across testosterone quintiles after age and race/ethnicity (Q1: 0.80, Q5: 1.14 ng/mL; P-trend=0.002) and multivariable (Q1: 0.79, Q5: 1.16 ng/mL; P-trend=0.02) adjustment; patterns were similar for free testosterone and 3α-diol-G. SHBG was inversely associated with PSA only after multivariable adjustment (Q1: 1.32, Q5: 0.82 nmol/L; P-trend=0.01). Estradiol and PSA were not associated. The OR of PSA ≥2.5 ng/mL was 1.54 (95% CI 1.18-2.01) per testosterone quintile after age and race/ethnicity adjustment, and 1.78 (95% CI 1.16-2.73) after multivariable adjustment.
Conclusions
In this nationally representative sample, men with higher testosterone had higher PSA even after taking into account other hormones and modifiable factors. Men with higher SHBG had lower PSA, but only after multivariable adjustment.
doi:10.1002/pros.22998
PMCID: PMC4475411  PMID: 25919471
testosterone; prostate specific antigen; men
4.  Resistance Emerges to Second Generation Anti-Androgens in Prostate Cancer 
Cancer discovery  2013;3(9):971-974.
Summary
The appearance of a mutant androgen receptor, F876L-AR, in prostate cancer cells chronically exposed to enzalutamide or ARN-509 promotes a switch from antagonist to agonist receptor function, undermining the potential long term effectiveness of these second generation anti-androgen drugs.
doi:10.1158/2159-8290.CD-13-0405
PMCID: PMC3800038  PMID: 24019330
5.  The Diet as a Cause of Human Prostate Cancer 
Asymptomatic prostate inflammation and prostate cancer have reached epidemic proportions among men in the developed world. Animal model studies implicate dietary carcinogens, such as the heterocyclic amines from over-cooked meats and sex steroid hormones, particularly estrogens, as candidate etiologies for prostate cancer. Each acts by causing epithelial cell damage, triggering an inflammatory response that can evolve into a chronic or recurrent condition. This milieu appears to spawn proliferative inflammatory atrophy (PIA) lesions, a type of focal atrophy that represents the earliest of prostate cancer precursor lesions. Rare PIA lesions contain cells which exhibit high c-Myc expression, shortened telomere segments, and epigenetic silencing of genes such as GSTP1, encoding the π-class glutathione S-transferase, all characteristic of prostatic intraepithelial neoplasia (PIN) and prostate cancer. Subsequent genetic changes, such as the gene translocations/deletions that generate fusion transcripts between androgen-regulated genes (such as TMPRSS2) and genes encoding ETS family transcription factors (such as ERG1), arise in PIN lesions and may promote invasiveness characteristic of prostatic adenocarcinoma cells. Lethal prostate cancers contain markedly corrupted genomes and epigenomes. Epigenetic silencing, which seems to arise in response to the inflamed microenvironment generated by dietary carcinogens and/or estrogens as part of an epigenetic “catastrophe” affecting hundreds of genes, persists to drive clonal evolution through metastatic dissemination. The cause of the initial epigenetic “catastrophe” has not been determined but likely involves defective chromatin structure maintenance by over-exuberant DNA methylation or histone modification. With dietary carcinogens and estrogens driving pro-carcinogenic inflammation in the developed world, it is tempting to speculate that dietary components associated with decreased prostate cancer risk, such as intake of fruits and vegetables, especially tomatoes and crucifers, might act to attenuate the ravages of the chronic or recurrent inflammatory processes. Specifically, nutritional agents might prevent PIA lesions or reduce the propensity of PIA lesions to suffer “catastrophic” epigenome corruption.
doi:10.1007/978-3-642-38007-5_4
PMCID: PMC4486067  PMID: 24114474
Prostate; Proliferative inflammatory atrophy; Heterocyclic amines; Epigenetics; DNA methylation
6.  New answers prompt new questions regarding cell of origin 
Nature reviews. Urology  2010;7(12):650-652.
Controversies remain regarding the precise cell type from which prostate cancers originate. In the last 2 years, two separate studies have arrived at apparently conflicting models for the cell type involved in prostate cancer initiation. However, these results are not mutually exclusive: there are potential solutions, and alternative views on the initiating cell derivation of prostate tumors also exist.
doi:10.1038/nrurol.2010.188
PMCID: PMC4486068  PMID: 21139640
7.  Beefing up Prostate Cancer Therapy with Performance-Enhancing (Anti-) Steroids 
Cancer cell  2011;20(1):7-9.
In the May 26th issue of the New England Journal of Medicine, de Bono et al. report that the inhibition of androgen synthesis by abiraterone acetate prolonged the survival of men with prostate cancer previously treated by androgen suppression.
doi:10.1016/j.ccr.2011.06.019
PMCID: PMC4479125  PMID: 21741594
8.  The Translational Research Working Group Developmental Pathway for Anticancer Agents (Drugs or Biologics) 
The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of the National Cancer Institute’s investment in translational research and envision its future. The TRWG conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of agents—both small molecules and biologics—for the treatment and prevention of cancer. The Agents Developmental Pathway was conceived not as a comprehensive description of the corresponding real-world processes, but rather as a tool designed to facilitate movement of an agent through the translational process to the point where it can begin definitive clinical testing. This article presents the Agents Developmental Pathway and discusses key challenges associated with the processes described.
doi:10.1158/1078-0432.CCR-08-1265
PMCID: PMC3978169  PMID: 18794076
9.  Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial* 
Background
Chronic inflammation is hypothesized to influence prostate cancer development, although a definitive link has not been established.
Methods
Prostate cancer cases (N=191) detected on a for-cause (clinically indicated) or end-of-study (protocol directed) biopsy, and frequency-matched controls (N=209), defined as negative for cancer on an end-of-study biopsy, were sampled from the placebo arm of the Prostate Cancer Prevention Trial. Inflammation prevalence and extent in benign areas of biopsy cores were visually assessed using digital images of H&E stained sections. Logistic regression was used to estimate associations.
Results
86.2% of cases and 78.2% of controls had at least one biopsy core (of 3 assessed) with inflammation in benign areas, most of which was chronic. Men who had at least one biopsy core with inflammation had 1.78 (95% CI 1.04–3.06) times the odds of prostate cancer compared with men who had zero cores with inflammation. The association was stronger for high-grade disease (Gleason sum 7–10, N=94; odds ratio [OR]=2.24, 95% CI 1.06–4.71). These patterns were present when restricting to cases and controls in whom intraprostatic inflammation was the least likely to have influenced biopsy recommendation because their PSA was low (<2 ng/mL at biopsy).
Conclusion
Inflammation, most of which was chronic, was common in benign prostate tissue, and was positively associated with prostate cancer, especially high-grade. The association did not appear to be due to detection bias.
Impact
This study supports an etiologic link between inflammation and prostate carcinogenesis, and suggests an avenue for prevention by mitigating intraprostatic inflammation.
doi:10.1158/1055-9965.EPI-13-1126
PMCID: PMC4012292  PMID: 24748218
10.  The association between circulating high-sensitivity C-reactive protein concentration and pathologic measures of colonic inflammation 
Cancer causes & control : CCC  2014;25(4):409-418.
Purpose
C-reactive protein (CRP), an inflammation marker, is associated with colorectal cancer (CRC) risk in some prospective studies. Whether increased CRP is indicative of colonic inflammation, a possible CRC cause, or of other sources of inflammation (e.g., adiposity), is unknown. Thus, we evaluated the association between CRP and colonic mucosal measures of inflammation.
Methods
151 adults undergoing colonoscopy provided a blood sample and random left and right side colonic mucosal biopsies. Height and weight were measured and lifestyle information was collected. hsCRP was measured by immunoturbidometric assay. A gastrointestinal pathologist evaluated biopsies for 7 colonic inflammation measures. Of 119 participants with complete information, 24 had an inflammatory bowel disease (IBD) history and were analyzed separately. We calculated number of colonic inflammation measures present in both biopsies, and separately for right and left biopsies. Adjusted geometric mean hsCRP was calculated using linear regression, overall, by demographic and lifestyle factors, and inflammation measures.
Results
Most participants had ≥1 colonic inflammation measure (0: 21%, 1: 39%, ≥2: 40%). Adjusted mean hsCRP did not increase with increasing number of inflammation measures (0: 1.67; 1: 1.33; ≥2: 1.01 mg/L; p-trend=0.21). Obese (2.03 mg/L) and overweight (1.61 mg/L) participants had higher adjusted mean hsCRP than normal weight participants (0.62 mg/L; p-trend<0.0001). Patterns were similar for IBD history.
Conclusions
hsCRP concentration was not associated with colonic inflammation, although hsCRP increased with adiposity. The hsCRP-CRC association may be explained by residual confounding by other risk factors, such as adiposity, rather than by CRP marking colonic inflammation.
doi:10.1007/s10552-014-0343-0
PMCID: PMC3951758  PMID: 24435936
C-reactive protein; inflammation; colorectal cancer; obesity
11.  Association between endogenous sex steroid hormones and insulin-like growth factor proteins in US men 
Cancer causes & control : CCC  2014;25(3):353-363.
Purpose
Sex steroid hormone concentrations and insulin-like growth factor (IGF) proteins have been independently associated with risk of cancer, chronic diseases, and mortality. However, studies that evaluated the inter-relation between the sex hormones and IGF pathways have provided mixed results. We examined the association between endogenous sex hormones and sex hormone-binding globulin (SHBG) with IGF-1 and IGF-binding protein 3 (IGFBP-3) in a population-based sample of US men.
Methods
Data from 1,135 men aged 20 years or older participating in the third National Health and Nutrition Examination Survey (NHANES III) were analyzed. Weighted linear regression was used to estimate geometric means and 95 % confidence intervals for IGF-1 and IGFBP-3 concentrations by sex steroid hormones and SHBG after adjusting for age, race/ethnicity, body mass index, waist circumference, alcohol consumption, cigarette smoking, physical activity, diabetes, and mutually adjusting for other sex hormones and SHBG.
Results
No significant association was observed between sex steroid hormones, SHBG, and IGF-1 concentrations. Total estradiol (% difference in Q5 − Q1 geometric means −9.7 %; P-trend 0.05) and SHBG (% difference −7.3 %; P-trend 0.02) were modestly inversely associated with IGFBP-3. Total testosterone was modestly inversely associated with IGFBP-3 (% difference −6.2 %; P-trend 0.01), but this association disappeared after adjustment for total estradiol and SHBG (% difference 2.6 %; P-trend 0.23). Androstanediol glucuronide was not associated with IG-FBP-3.
Conclusions
These findings suggest that there may be inter-relationships between circulating total estradiol, SHBG, and IGFBP-3 concentrations. Future research may consider these inter-relationships when evaluating potential joint effects of the sex hormones and IGF pathways.
doi:10.1007/s10552-013-0336-4
PMCID: PMC4332790  PMID: 24395140
Testosterone; Estradiol; Sex hormone-binding globulin (SHBG); Insulin growth factor-1 (IGF-1); Insulin growth factor-binding protein 3 (IGFBP-3)
12.  A panel of DNA methylation markers reveals extensive methylation in histologically benign prostate biopsy cores from cancer patients 
Biomarker Research  2014;2:25.
Background
Men with a negative first prostate biopsy will undergo one or more additional biopsies if they remain at high suspicion of prostate cancer. To date, there are no diagnostic tests capable of identifying patients at risk for a positive diagnosis with the predictive power needed to eliminate unnecessary repeat biopsies. Efforts to develop clinical tests using the epigenetic signature of cores recovered from first biopsies have been limited to a few markers and lack the sensitivity and specificity needed for widespread clinical adoption.
Methods
We developed methylation-specific quantitative polymerase chain reaction assays for a panel of 24 markers that are preferentially methylated in prostate cancer. We modified the bisulfite conversion conditions to allow the integration of the methylation information from multiple markers. We determined the methylation status of the 24 markers in 213 prostate biopsy cores from 104 patients, 37 prostate cancer patients and 67 controls. We performed logistic regression on combinations of markers as well as the entire panel of 24 markers to identify the best candidates for a diagnostic test.
Results
The marker panel differentiated between cancer cores and benign cores from non-cancer patients with 100% sensitivity and 97% specificity. Furthermore, the panel detected significant methylation in benign cores from prostate cancer patients that was not present in controls. Using methylation of 5 out of 24 to define a cancer case, the analysis of a single benign biopsy core identified 62% of prostate cancer patients undergoing repeat biopsies. ROC curve analysis showed that markers commonly methylated in benign cores from cancer patients are the best candidates for a diagnostic test. The results suggest that 5 to 10 markers will be needed to achieve optimal predictive power.
Conclusions
This study shows that epigenetic field effects differ significantly between cancer patients and controls. Their detection in benign biopsy cores can form the basis of diagnostic tests to identify patients in need of repeat biopsies, reducing the cost of continued PCA screening by up to 40%. They could also be used to identify prostate cancer patients with low grade disease who are likely candidates for active surveillance or focal therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s40364-014-0025-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s40364-014-0025-9
PMCID: PMC4278343  PMID: 25548652
DNA methylation; Prostate cancer; Repeat biopsies; High grade prostatic intraepithelial lesions; Atypical small acinar proliferation; Early cancer diagnostics
13.  Association between endogenous sex steroid hormones and inflammatory biomarkers in US men 
Andrology  2013;1(6):10.1111/j.2047-2927.2013.00129.x.
Sex steroid hormones and inflammatory biomarkers are both associated with the development and progression of chronic diseases, but their interrelationship is relatively uncharacterized. We examined the association of sex hormones and sex hormone binding globulin (SHBG) with biomarkers of inflammation, C-reactive protein (CRP) and white blood cell (WBC) count. The study included data from 809 adult men in the National Health and Nutrition Examination Survey 1999–2004. Geometric means and 95% confidence intervals were estimated separately for CRP and WBC concentrations by sex steroid hormones and SHBG using weighted linear regression models. Higher concentrations of total (slope per 1 quintile in concentration, −0.18; P-trend, 0.001) and calculated free (slope, −0.13; P-trend, 0.03) testosterone were statistically significantly associated with lower concentrations of CRP, but not with WBC count. Men in the bottom quintile of total testosterone (≤3.3 ng/mL), who might be considered to have clinically low testosterone, were more likely to have elevated CRP (≥ 3 mg/L) compared to men in the top four quintiles (OR, 1.61; 95% CI, 1.00 – 2.61). Total and calculated free estradiol (E2) were positively associated with both CRP (Total E2: slope, 0.14; P-trend, <0.001; Free E2: slope, 0.15; P-trend, <0.001) and WBC (Total E2: slope, 0.02; P-trend, 0.08; Free E2: slope, 0.02; P-trend, 0.02) concentrations. SHBG concentrations were inversely associated with WBC count (slope, −0.03; P-trend, 0.04), but not with CRP. These cross-sectional findings are consistent with the hypothesis that higher androgen and lower estrogen concentrations may have an anti-inflammatory effect in men.
doi:10.1111/j.2047-2927.2013.00129.x
PMCID: PMC3812341  PMID: 24124163
testosterone; estradiol; C-reactive protein; white blood cell; cross-sectional study
14.  Global DNA hypomethylation in intratubular germ cell neoplasia and seminoma, but not in nonseminomatous male germ cell tumors 
Alterations in methylation of CpG dinucleotides at the 5 position of deoxycytidine residues (5mC) are a hallmark of cancer cells, including testicular germ cell tumors. Virtually all testicular germ cell tumors are believed to be derived from intratubular germ cell neoplasia unclassified (IGCNU), which is thought to arise from primordial germ cells. Prior studies revealed that seminomas contain reduced levels of global DNA methylation as compared with nonseminomatous germ cell tumors. Smiraglia et al have proposed a model whereby seminomas arise from IGCNU cells derived from primordial germ cells that have undergone 5mC erasure, and nonseminomas arise from IGCNU cells derived from primordial germ cells that have already undergone de novo methylation after the original erasure of methylation and contain normal 5mC levels. Yet the methylation status of IGCNU has not been determined previously. We used immunohistochemical staining against 5mC to evaluate global methylation in IGCNU and associated invasive testicular germ cell tumors. Strikingly, staining for 5mC was undetectable (or markedly reduced) in the majority of IGCNU and seminomas, yet there was robust staining in nonseminomatous germ cell tumors. The lack of staining for 5mC in IGCNU and seminomas was also found in mixed germ cell tumors containing both seminomatous and nonseminomatous components. Lack of 5mC staining was not related to a lack of the maintenance methyltransferase (DNA methyltransferase 1) protein. We conclude that testicular germ cell tumors are derived in most cases from IGCNU cells that have undergone developmentally programmed 5mC erasure and that the degree of subsequent de novo methylation is most closely related to the differentiation state of the neoplastic cells. That is, IGCNU cells and seminoma cells remain unmethylated, whereas all other histological types appear to arise after de novo methylation.
doi:10.1038/modpathol.2008.127
PMCID: PMC4086525  PMID: 18622385
seminoma; nonseminomatous germ cell tumors; IGCNU; global methylation
15.  Bioactivity of Autologous Irradiated Renal Cell Carcinoma Vaccines Generated by ex Vivo Granulocyte-Macrophage Colony-stimulating Factor Gene Transfer1 
Cancer research  1997;57(8):1537-1546.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication-defective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.
PMCID: PMC4084516  PMID: 9108457
16.  Tight correlation of 5-hydroxymethylcytosine and Polycomb marks in health and disease 
Cell Cycle  2013;12(12):1835-1841.
Modifications to DNA and histone tails represent key epigenetic marks involved in establishing and maintaining cell identity and can be dysregulated in human diseases, including cancer. Two such modifications, tri-methylation of lysine-27 on histone H3 (H3K27me3) mediated by the Polycomb complex and hydroxymethylation of cytosines on DNA, have recently been shown to be dynamically regulated during differentiation. Here, we show that global levels of 5-hydroxymethylcytosine (5hmC) and H3K27me3 are highly correlated across a variety of somatic tissues. In multiple hierarchically organized tissues, both marks showed almost identical cell-by-cell distribution patterns that exhibited a tight association with differentiation. In particular, tissue stem cell compartments were characterized by low levels of both marks, whereas differentiated cell compartments exhibited high levels of 5hmC and H3K27me3. This pattern of correlation between the two marks could be recapitulated in an in vitro model system of induced differentiation in prostate epithelial cells. While the correlation between 5hmC and H3K27me3 levels is also maintained in human cancers, the degree of correlation is reduced. These findings suggest a previously unappreciated link between 5hmC and H3K27me3 regulation that should be explored in future mechanistic studies.
doi:10.4161/cc.25010
PMCID: PMC3735697  PMID: 23676216
5-hydroxymethylcytosine; DNA methylation; differentiation; cancer; H3K27me3; polycomb; epigenetics
17.  Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer 
The Journal of pathology  2013;230(2):174-183.
TMPRSS2-ERG rearrangements occur in approximately 50% of prostate cancers and therefore represent one of the most frequently observed structural rearrangements in all cancers. However, little is known about the genomic architecture of such rearrangements. We therefore designed and optimized a pipeline involving target-capture of TMPRSS2 and ERG genomic sequences coupled with paired-end next generation sequencing to resolve genomic rearrangement breakpoints in TMPRSS2 and ERG at nucleotide resolution in a large series of primary prostate cancer specimens (n = 83). This strategy showed >90% sensitivity and specificity in identifying TMPRSS2-ERG rearrangements, and allowed identification of intra- and inter-chromosomal rearrangements involving TMPRSS2 and ERG with known and novel fusion partners. Our results indicate that rearrangement breakpoints show strong clustering in specific intronic regions of TMPRSS2 and ERG. The observed TMPRSS2-ERG rearrangements often exhibited complex chromosomal architecture associated with several intra- and inter-chromosomal rearrangements. Nucleotide resolution analysis of breakpoint junctions revealed that the majority of TMPRSS2 and ERG rearrangements (~88%) occurred at or near regions of microhomology or involved insertions of one or more base pairs. This architecture implicates nonhomologous end joining (NHEJ) and microhomology mediated end joining (MMEJ) pathways in the generation of such rearrangements. These analyses have provided important insights into the molecular mechanisms involved in generating prostate cancer-specific recurrent rearrangements.
doi:10.1002/path.4186
PMCID: PMC3668093  PMID: 23447416
TMPRSS2; ERG; rearrangement; hybrid capture; targeted next generation sequencing; prostate cancer; genomic breakpoint detection
18.  Association of serum calcium with serum sex steroid hormones in men in NHANES III 
Background
Bone is a positive regulator of male fertility, which indicates a link between regulation of bone remodeling and reproduction or more specifically a link between calcium and androgens. This possibly suggests how calcium is linked to prostate cancer development through its link with the reproductive system. We studied serum calcium and sex steroid hormones in the Third National Health and Nutrition Examination Survey (NHANES III).
Methods
Serum calcium and sex steroid hormones were measured for 1,262 men in NHANES III. We calculated multivariable-adjusted geometric means of serum concentrations of total and estimated free testosterone and estradiol, androstanediol glucuronide (AAG), and sex hormone binding globulin (SHBG) by categories of calcium (lowest 5% [<1.16 mmol/L], mid 90%, top 5% [≥1.30 mmol/L]).
Results
Levels of total and free testosterone, total estradiol, or AAG did not differ across categories of serum calcium. Adjusted SHBG concentrations were 36.4 for the bottom 5%, 34.2 for the mid 90%, and 38.9 nmol/L for the top 5% of serum calcium (Ptrend=0.006), free estradiol levels were 0.88, 0.92, and 0.80 pg/ml (Ptrend=0.048).
Conclusions
This link between calcium and sex steroid hormones, in particular the U-shaped pattern with SHBG, may, in part, explain why observational studies have found a link between serum calcium and risk of prostate cancer.
doi:10.3109/13685538.2013.772133
PMCID: PMC4005327  PMID: 23672276
cross-sectional studies; gonadal steroid hormones; serum calcium
19.  A Mouse Model of Chronic Prostatic Inflammation Using a Human Prostate Cancer-Derived Isolate of Propionibacterium acnes 
The Prostate  2013;73(9):1007-1015.
BACKGROUND
Prostatic inflammation has been linked to a number of prostatic diseases such as benign prostatic hyperplasia (BPH), prostatitis syndromes, and prostate cancer. Major unanswered questions include what pathogenic mechanisms, such as bacterial infections, may drive the accumulation of inflammatory infiltrates in the human prostate, and how inflammation might contribute to disease. To study this potential link in an in vivo system, we developed a mouse model of long-term bacteria-induced chronic inflammation of the prostate using a human prostatectomy-derived strain of Propionibacterium acnes.
METHODS
C57BL/6J mice were inoculated, via urethral catheterization, with vehicle control or a prostatectomy-derived strain of P. acnes (PA2). Animals were assessed at 2 days, 1, 2, or 8 weeks post-inoculation via histology and immunohistochemistry (IHC).
RESULTS
PA2 inoculation resulted in severe acute and chronic inflammation confined to the dorsal lobe of the prostate. Chronic inflammation persisted for at least 8 weeks post-inoculation. Inflammatory lesions were associated with an increase in the Ki-67 proliferative index, and diminished Nkx3.1 and androgen receptor (AR) production. Interestingly, the observed response required live bacteria and both IHC and in situ hybridization assays for P. acnes indicated a potential intracellular presence of P. acnes in prostate epithelial cells.
CONCLUSIONS
To our knowledge, this is the first mouse model of long-term prostatic inflammation induced by P. acnes, and more generally, any prostatectomy-derived bacterial isolate. This model may serve as a valuable preclinical model of chronic prostatic inflammation that can be used to mechanistically study the link between inflammation and prostatic disease.
doi:10.1002/pros.22648
PMCID: PMC3991131  PMID: 23389852
prostate; Propionibacterium acnes; inflammation; mouse model
20.  Correction: Dietary Chemoprevention of PhIP Induced Carcinogenesis in Male Fischer 344 Rats with Tomato and Broccoli 
PLoS ONE  2014;9(1):10.1371/annotation/1ac6412e-619f-4575-8b63-f5e16bd3252b.
doi:10.1371/annotation/1ac6412e-619f-4575-8b63-f5e16bd3252b
PMCID: PMC3883743
21.  Correction: Dietary Chemoprevention of PhIP Induced Carcinogenesis in Male Fischer 344 Rats with Tomato and Broccoli 
PLoS ONE  2014;9(1):10.1371/annotation/3fd9703c-a6d9-4715-9c93-cf5279ea4fa6.
doi:10.1371/annotation/3fd9703c-a6d9-4715-9c93-cf5279ea4fa6
PMCID: PMC3883746
23.  Racial/ethnic differences in serum sex steroid hormone concentrations in US adolescent males 
Cancer causes & control : CCC  2013;24(4):10.1007/s10552-013-0154-8.
Objective
Contrary to the hypothesis that the racial/ethnic disparity in prostate cancer has a hormonal basis, we did not observe a difference in serum testosterone concentration between non-Hispanic black and white men in the Third National Health and Nutrition Examination Survey (NHANES III), although non-Hispanic black men had a higher estradiol level. Unexpectedly, Mexican-American men had the highest testosterone level. Next, we evaluated whether the same patterns are observed during adolescence, the time of prostate maturation.
Methods
We measured serum testosterone, estradiol, and sex hormone binding globulin (SHBG) by immunoassay in 134 males aged 12–19 in NHANES III. Mean concentrations were compared by race/ethnicity adjusting for age, Tanner stage, percent body fat, waist, physical activity, tobacco smoke, and the other hormones.
Results
After multivariable adjustment, in the 12–15 year-old males, testosterone concentration was lower in non-Hispanic blacks than whites (P=0.043), SHBG concentration did not significantly differ between the two groups. Mexican-Americans had the highest testosterone (versus non-Hispanic black: P=0.002) and lowest SHBG (versus non-Hispanic white: P=0.010; versus non-Hispanic black: P=0.047) concentrations. Estradiol concentration was lower in non-Hispanic blacks (P=0.11) and Mexican-Americans (P=0.033) compared with non-Hispanic whites. After multivariable adjustment, in the 16–19 year-old males, testosterone, estradiol, and SHBG concentrations did not differ between non-Hispanic blacks and whites. Mexican-Americans had the highest testosterone concentration (versus non-Hispanic white: P=0.08), but did not differ from the other groups on estradiol and SHBG concentrations. In both age groups, these patterns were generally present, but less pronounced after adjusting for age and Tanner stage only.
Conclusion
In adolescent males, non-Hispanic blacks did not have a higher testosterone concentration than non-Hispanic whites, and Mexican-Americans had the highest testosterone concentration, patterns similar to adult males.
doi:10.1007/s10552-013-0154-8
PMCID: PMC3850289  PMID: 23354421
testosterone; adolescence; race and ethnicity
24.  Dietary Chemoprevention of PhIP Induced Carcinogenesis in Male Fischer 344 Rats with Tomato and Broccoli 
PLoS ONE  2013;8(11):e79842.
The heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-B]pyridine (PhIP), found in meats cooked at high temperatures, has been implicated in epidemiological and rodent studies for causing breast, prostate, and colorectal cancers. A previous animal study using a xenograft model has shown that whole tomato and broccoli, when eaten in combination, exhibit a marked effect on tumor reduction compared to when eaten alone. Our aim was to determine if PhIP-induced carcinogenesis can be prevented by dietary consumption of whole tomato + broccoli powders. Male Fischer 344 rats (n = 45) were randomized into the following treatment groups: control (AIN93G diet), PhIP (200 ppm in AIN93G diet for the first 20 weeks of the study), or tomato + broccoli + PhIP (mixed in AIN93G diet at 10% each and fed with PhIP for 20 weeks, and then without PhIP for 32 weeks). Study animals were monitored for 52 weeks and were euthanized as necessary based on a set of criteria for health status and tumor burden. Although there appeared to be some hepatic and intestinal toxicity due to the combination of PhIP and tomato + broccoli, these rodents had improved survival and reduced incidence and/or severity of PhIP-induced neoplastic lesions compared to the PhIP-alone treated group. Rats eating tomato + broccoli exhibited a marked decrease in the number and size of cribiform prostatic intraepitheilial neoplasia/carcinoma in situ (cribiform PIN/CIS) lesions and in the incidence of invasive intestinal adenocarcinomas and skin carcinomas. Although the apparent toxic effects of combined PhIP and tomato + broccoli need additional study, the results of this study support the hypothesis that a diet rich in tomato and broccoli can reduce or prevent dietary carcinogen-induced cancers.
doi:10.1371/journal.pone.0079842
PMCID: PMC3842290  PMID: 24312188
25.  Body fatness and sex steroid hormone concentrations in US men – Results from NHANES III 
Cancer causes & control : CCC  2011;22(8):10.1007/s10552-011-9790-z.
Objective
Obesity is associated with a variety of chronic diseases, including cancer, which may partly be explained by its influence on sex steroid hormone concentrations. Whether different measures of obesity, i.e., body mass index (BMI), waist circumference, and percent body fat were differentially associated with circulating levels of sex steroid hormones was examined in 1,265 men, aged 20 to 90+ years, attending the morning examination session of the Third National Health and Nutrition Examination Survey (NHANES III).
Methods and Methods
Serum hormones were measured by immunoassay. Weight, height, and waist circumference were measured by trained staff. Percent body fat was estimated from bioelectrical impedance. Multivariate linear regression was used to estimate associations between body fatness measures and hormone levels.
Results
Total and free testosterone and sex hormone binding globulin concentrations decreased, whereas total and free estradiol increased with increasing BMI, waist circumference, and percent body fat (all P-trend <0.05). The magnitude of change in these hormones was similar for a one quartile increase in each body fatness measure.
Conclusion
Measured BMI, waist circumference, and percent body fat led to similar inferences about their association with hormone levels in men.
doi:10.1007/s10552-011-9790-z
PMCID: PMC3818569  PMID: 21678033
NHANES III; testosterone; estradiol; obesity

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