Association between plasma fluorescent oxidation products and erectile dysfunction: A prospective study.

BACKGROUND: Existing epidemiological studies of the association between oxidative stress and erectile dysfunction (ED) are sparse and inconclusive, which is likely due to cross-sectional design and small sample size. Therefore, we investigated the association between biomarkers of oxidative stress and ED in prospective setting among a relatively large sample size of men. METHODS: We conducted the prospective study among 917 men ages between 47 and 80 years at the time of blood draw, which is a part of nested prospective case-control study of prostate cancer in the Health Professionals Follow-up Study. Plasma fluorescent oxidation products (FlOPs), a global biomarker for oxidative stress, were measured at three excitation/emission wavelengths (360/420 nm named as FlOP_360; 320/420 nm named as FlOP_320 and 400/475 nm named as FlOP_400). RESULTS: Approximately 35% of men developed ED during follow-up. We did not find an independent association between FlOP_360, FlOP_320, FlOP_400 and risk of ED in the multivariable adjusted model (Tertile 3 vs. tertile 1: odds ratio [OR] = 0.90, 95% confidence interval [CI] = 0.61-1.34, P(trend) = 0.54 for FlOP_360; OR = 0.73, 95% CI = 0.49-1.07, P(trend) = 0.27 for FlOP_320; and OR = 0.98, 95% CI = 0.66-1.45, P(trend) = 0.72 for FlOP_400). Further analysis of the association between FlOPs and ED in the fasting samples or controls only (free of prostate cancer incidence) did not change the results appreciably. CONCLUSIONS: Plasma FlOPs were not associated with the risk of ED, suggesting oxidative stress may not be an independent risk factor for ED.

Identification of Differential Patterns of Oxidative Biomarkers in Prostate Cancer Progression.

INTRODUCTION: Oxidative stress has been found to be associated with the progression of prostate cancer (PCa); however, human studies which identify differential roles of each oxidation pathway in PCa progression are lacking. We aimed to identify which oxidative stress markers, specifically lipid and global oxidation and glycation, are associated with PCa progression. PATIENTS AND METHODS: We recruited 3 groups of patients from a urologic clinic at the University of Cincinnati Medical Center: men with PCa who had undergone prostatectomy, men with PCa under watchful waiting, and men with benign prostatic hyperplasia (BPH). We used the most commonly used lipid oxidation marker, F2-isoprostanes; global oxidation markers, fluorescent oxidation products (FlOPs); and the commonly used marker for advanced glycation end products, carboxymethyllysine. These biomarkers were measured in plasma samples at baseline entry. Plasma prostate-specific antigen (PSA) was measured at enrollment and follow-up visits. RESULTS: Compared with men with BPH, men with PCa who had undergone prostatectomy had 26% (P = .01) higher levels of F2-isoprostanes and 20% (P = .08) higher levels of carboxymethyllysine. All the oxidation markers were similar when comparing men under watchful waiting with men with BPH. When examining the associations between baseline oxidation markers and follow-up PSAs, we found that different oxidation markers had differential patterns associated with PSA elevation. F2-isoprostanes were positively associated with PSA elevation among men with PCa; FlOP_320 was positively associated with PSA elevation among both men with PCa and men with BPH, whereas among men with PCa under watchful waiting, FlOP_360 and FlOP_400 had opposite trends of associations with PSA elevation. CONCLUSIONS: Our study suggested that high levels of lipid oxidation were associated with PCa progression, whereas different global oxidation markers had different patterns associated with PCa progression. Large-scale clinical studies are needed to confirm our associations. Our study provides a comprehensive view of the relationship between biomarkers and PCa progression.

A duplex quantitative polymerase chain reaction assay based on quantification of alpha-methylacyl-CoA racemase transcripts and prostate cancer antigen 3 in urine sediments improved diagnostic accuracy for prostate cancer.

PURPOSE: Most men with increased serum prostate specific antigen and negative biopsy require repeat biopsy because of the lack of a sensitive and specific prostate cancer detection test. In this study we evaluated the diagnostic potential of a duplex assay for prostate cancer by quantifying transcript levels of alpha-methylacyl-CoA racemase and prostate cancer antigen 3 in urine sediments following prostatic massage. MATERIALS AND METHODS: Urine sediments from 92 patients, 43 with and 49 without prostate cancer, were collected after digital rectal examination. Transcript levels of AMACR, PCA3 and PSA in total RNA isolated from these samples were determined by absolute quantitative real-time polymerase chain reaction. AMACR and PCA3 scores were obtained by normalizing the transcript level to that of prostate specific antigen for each sample and multiplying by 100. RESULTS: AMACR (p = 0.006) and PCA3 (p = 0.014) scores, but not serum prostate specific antigen (p = 0.306), distinguished specimens from patients with prostate cancer from specimens from patients without prostate cancer, and ROC analysis established the diagnostic cutoff scores for the AMACR and PCA3 tests at 10.7 and 19.9, respectively. As determined from these cutoff scores the AMACR test had 70% (95% CI 56-83) sensitivity and 71% (95% CI 59-84) specificity, whereas the PCA3 test had 72% (95% CI 59-85) sensitivity and 59% (95% CI 45-73) specificity for prostate cancer detection. The combined use of AMACR and PCA3 scores in a dual marker test increased sensitivity to 81% (95% CI 70-93) and specificity to 84% (95% CI 73-94). CONCLUSIONS: Urinary AMACR and PCA3 tests were superior to a serum prostate specific antigen test for detecting prostate cancer. Their combined use in a dual marker test further improved sensitivity and accuracy, and could serve as a surveillance test after repeat negative prostate biopsies.

Impact of Oxidative Stress Biomarkers and Carboxymethyllysine (an Advanced Glycation End Product) on Prostate Cancer: A Prospective Study.

OBJECTIVE: Biomarkers of oxidative stress and advanced glycation end products (AGE) have been linked to the development of prostate cancer, but evidence from human studies is scarce or controversial. METHODS: We conducted a prospective nested case-control study among 48 men (24 prostate cancer cases and 24 controls) aged 48 to 76 years at baseline. The participants of our study were a part of the Fernald Community Cohort. Prostate cancer cases and controls were matched individually on age (± 3 years) with a 1:1 ratio. Biomarkers included urine F2-isoprostanes (markers of lipid oxidation), plasma fluorescent oxidation products (markers of global oxidation), and carboxymethyllysine (CML) (a major end-stage AGE). RESULTS: At baseline, cases had similar age, body mass index, proportion of family history of prostate cancer, history of benign prostatic hyperplasia, history of hypertension, history of diabetes, number of smokers, and plasma glucose levels compared with controls. Levels of plasma CML were significantly higher in cases than in controls (182 vs. 152 µg/mL, P < .05). In the conditional logistic regression model, an increase in CML equivalent to 1 standard deviation was associated with an increased risk of incident prostate cancer (relative risk, 1.79; 95% confidence interval, 1.00-3.21) and accounted for approximately 8% variance of prostate cancer liability. Urine F2-isoprostanes and plasma fluorescent oxidation products were not associated with prostate cancer incidence. CONCLUSIONS: Higher levels of plasma CML were associated with increased risk of prostate cancer. This suggests a potential new pathway for prostate cancer prediction and treatment.

Exposure to bisphenol A correlates with early-onset prostate cancer and promotes centrosome amplification and anchorage-independent growth in vitro.

Human exposure to bisphenol A (BPA) is ubiquitous. Animal studies found that BPA contributes to development of prostate cancer, but human data are scarce. Our study examined the association between urinary BPA levels and Prostate cancer and assessed the effects of BPA on induction of centrosome abnormalities as an underlying mechanism promoting prostate carcinogenesis. The study, involving 60 urology patients, found higher levels of urinary BPA (creatinine-adjusted) in Prostate cancer patients (5.74 µg/g [95% CI; 2.63, 12.51]) than in non-Prostate cancer patients (1.43 µg/g [95% CI; 0.70, 2.88]) (p = 0.012). The difference was even more significant in patients <65 years old. A trend toward a negative association between urinary BPA and serum PSA was observed in Prostate cancer patients but not in non-Prostate cancer patients. In vitro studies examined centrosomal abnormalities, microtubule nucleation, and anchorage-independent growth in four Prostate cancer cell lines (LNCaP, C4-2, 22Rv1, PC-3) and two immortalized normal prostate epithelial cell lines (NPrEC and RWPE-1). Exposure to low doses (0.01-100 nM) of BPA increased the percentage of cells with centrosome amplification two- to eight-fold. Dose responses either peaked or reached the plateaus with 0.1 nM BPA exposure. This low dose also promoted microtubule nucleation and regrowth at centrosomes in RWPE-1 and enhanced anchorage-independent growth in C4-2. These findings suggest that urinary BPA level is an independent prognostic marker in Prostate cancer and that BPA exposure may lower serum PSA levels in Prostate cancer patients. Moreover, disruption of the centrosome duplication cycle by low-dose BPA may contribute to neoplastic transformation of the prostate.

α-Methylacyl-CoA racemase spliced variants and their expression in normal and malignant prostate tissues.

OBJECTIVES: To evaluate the possibility of using α-methylacyl-CoA racemase (AMACR) variants to improve the specificity of prostate cancer (CaP) detection. AMACR has been used as a diagnostic biomarker for CaP and is now a standard biomarker for needle biopsy specimens with ambiguous lesions. METHODS: We used in silico analysis and molecular cloning to discover new AMACR variants and quantitative reverse transcription-polymerase chain reaction (RT-PCR) to measure the transcript levels of AMACR and its variants in 4 prostate cell lines and in 23 pairs of CaP and adjacent normal tissue. RESULTS: We found 4 novel variants, IAs, IBL, IBLd, and IBLi. Transcript levels of most AMACR variants were significantly upregulated in CaP compared with its adjacent normal counterparts. A variants, the functional variants based on bioinformatic analysis, showed levels of transcript expression in CaP in this order: IA≫IAd=IIA≫IIAs>IAs. In contrast, the expression of the B variants, which appear to be nonfunctional due to the absence of exon 3, was lower than that of the A variants. IB was the most abundant form of B variant; and expression of IIB was negligible. More important, the difference between levels of variant IA, IAd, IIA, IIAs, IB, and IBLi in CaP and normal tissue was significantly higher than the difference in levels of total AMACR. CONCLUSIONS: Our data suggest that AMACR variants have better power than total AMACR in discriminating between CaP and adjacent normal tissue. These findings may be useful for the development of future diagnostic assays.