Expression of Pigment Epithelium-derived Factor in Bladder Tumour Is Correlated with Interleukin-8 yet Not with Interleukin-1α

Pigment epithelium-derived factor （PEDF） is an antiangiogenic factor which is effective in tumour inhibition in a variety of tumours and has not yet been studied in bladder tumour before. In this study the expression of PEDF, interleukin-1α （IL-1α） and -8 （IL-8） in bladder tumours was investigated. Immunohistochemistry was performed on 64 bladder tumour and 23 normal uroepithelium samples. Expression change of the factors was compared with clinicopathological parameters. Correlations between PEDF, IL-1α and IL-8 were analyzed. None of the factors was in relation to gender, tumour occurrence, and size or onset pattern. PEDF （P=0.014） and IL-1α （P=0.049） expression was down-regulated with grade progression. PEDF expression was lower in normal uroepithelium than in papillary urothelial neoplasm of low malignant potential （PUNLMP） （P=0.000） and carcinoma （P=0.009） whilst IL-1α （P=0.000 and P=0.000 respectively） and IL-8 （P=0.000 and P=0.023 respectively） expression was higher in the same grouping. PEDF expression had a negative correlation with IL-8 in PUNLMP （P=0.049, r=-0.578） as well as in tumour grouping （P=0.033, r=-0.276）. Deranged expressional change of PEDF, IL-1α and IL-8 could be in relation to loss of differentiation from normal uroepithelium to papillary lesion and eventually to carcinoma.

The Xu＇s chart for prostate biopsy： a visual presentation of the added value of biomarkers to prostate-specific antigen for estimating detection rates of prostate cancer

Elevated serum prostate-specific antigen （PSA） level is the primaryindication for prostate biopsy for detection of prostate cancer （PCa） in the modern era. The detection rate of PCa from biopsy is typically below 30%, especially among patients with PSA levels at 4-10 ng ml-1. In the past several years, additional biomarkers, such as Prostate Health Index, PCA3 and genetic risk score （GRS） derived from multiple PCa risk-associated single nucleotide polymorphisms （SNPs） have been shown to provide added value to PSA in discriminating prostate biopsy outcomes. However,

Prostate cancer risk-associated genetic markers and their potential clinical utility

Prostate cancer （PCa） is one of the most common cancers among men in Western developed countries and its incidence has increased considerably in many other parts of the world, including China. The etiology of PCa is largely unknown but is thought to be multifactorial, where inherited genetics plays an important role. In this article, we first briefly review results from studies of familial aggregation and genetic susceptibility to PCa. We then recap key findings of rare and high-penetrance PCa susceptibility genes from linkage studies in PCa families. We devote a significant portion of this article to summarizing discoveries of common and Iow-penetrance PCa risk-associated single-nucleotide polymorphisms （SNPs） from genetic association studies in PCa cases and controls, especially those from genome-wide association studies （GWASs）. A strong focus of this article is to review the literature on the potential clinical utility of these implicated genetic markers. Most of these published studies described PCa risk estimation using a genetic score derived from multiple risk-associated SNPs and its utility in determining the need for prostate biopsy. Finally, we comment on the newly proposed concept of genetic score; the notion is to treat it as a marker for genetic predisposition, similar to family history, rather than a diagnostic marker to discriminate PCa patients from non-cancer patients. Available evidence to date suggests that genetic score is an objective and better measurement of inherited risk of PCa than family history. Another unique feature of this article is the inclusion of genetic association studies of PCa in Chinese and Japanese populations.

Somatic DNA copy number alterations and their potential clinical utility for predicting lethal prostate cancer

Current clinicopathologic indicators are insufficient to distinguish the small percentage of aggressive prostate cancer （PCa） from the vast majority of indolent disease at diagnosis, leading to overtreatment of PCa. A recent study reported and confirmed a strong association of PCa-specific mortality with somatic DNA copy number alterations （CNAs） in primary pro- state tumors.

Performance of the Prostate Health Index in predicting prostate biopsy outcomes among men with a negative digital rectal examination and transrectal ultrasonography

The [-2]proPSA （p2PSA） and its derivatives, the p2PSA-to-free PSA ratio （%p2PSA）, and the Prostate Health Index （PHI） have greatly improved discrimination between men with and without prostate cancer （PCa） in prostate biopsies. However, little is known about their performance in cases where a digital rectal examination （DRE） and transrectal ultrasonography （TRUS） are negative. A prospective cohort of 261 consecutive patients in China with negative DRE and TRUS were recruited and underwent prostate biopsies. A serum sample had collected before the biopsy was used to measure various PSA derivatives, including total prostate-specific antigen （tPSA）, free PSA, and p2PSA. For each patient, the free-to-total PSA ratio （%fPSA）, PSA density （PSAD）, p2PSA-to-free PSA ratio （%p2PSA）, and PHI were calculated. Discriminative performance was assessed using the area under the receiver operating characteristic curve （AUC） and the biopsy rate at 91% sensitivity. The AUC scores within the entire cohort with respect to age, tPSA, %fPSA, PSAD, p2PSA, %p2PSA, and PHI were 0.598, 0.751, 0.646, 0.789, 0.814, 0.808, and 0.853, respectively. PHI was the best predictor of prostate biopsy results, especially in patients with a tPSA of 10.1-20 ng ml-1. Compared with other markers, at a sensitivity of 91%, PHI was the most useful for determining which men did not need to undergo biopsy, thereby avoiding unnecessary procedures. The use of PHI could improve the accuracy of PCa detection by predicting prostate biopsy outcomes among men with a negative DRE and TRUS in China.

Population-standardized genetic risk score： the SNP-based method of choice for inherited risk assessment of prostate cancer

Several different approaches are available to clinicians for determining prostate cancer （PCa） risk. The clinical validity of various PCa risk assessment methods utilizing single nucleotide polymorphisms （SNPs） has been established; however, these SNP-based methods have not been compared. The objective of this study was to compare the three most commonly used SNP-based methods for PCa risk assessment. Participants were men （n = 1654） enrolled in a prospective study of PCa development. Genotypes of 59 PCa risk-associated SNPs were available in this cohort. Three methods of calculating SNP-based genetic risk scores （GRSs） were used for the evaluation of individual disease risk such as risk allele count （GRS-RAC）, weighted risk allele count （GRS-wRAC）, and population-standardized genetic risk score （GRS-PS）. Mean GRSs were calculated, and performances were compared using area under the receiver operating characteristic curve （AUC） and positive predictive value （PPV）. All SNP-based methods were found to be independently associated with PCa （all P 〈 0.05; hence their clinical validity）. The mean GRSs in men with or without PCa using GRS-RAC were 55.15 and 53.46, respectively, using GRS-wRAC were 7.42 and 6.97, respectively, and using GRS-PS were 1.12 and 0.84, respectively （all P 〈 0.05 for differences between patients with or without PCa）. All three SNP-based methods performed similarly in discriminating PCa from non-PCa based on AUC and in predicting PCa risk based on PPV （all P 〉 0.05 for comparisons between the three methods）, and all three SNP-based methods had a significantly higher AUC than family history （all P 〈 0.05）. Results from this study suggest that while the three most commonly used SNP-based methods performed similarly in discriminating PCa from non-PCa at the population level, GRS-PS is the method of choice for risk assessment at the individual level because its value （where 1.0 represents average population risk） can be easily interpreted regardless of the number of risk-associated SNPs used in the calculation.

Clinically available RNA profiling tests of prostate tumors： utility and comparison

In the postscreening era, physicians are in need of methods to discriminate aggressive from nonaggressive prostate cancer （PCa） to reduce overdiagnosis and overtreatment. However, studies have shown that prognoses （e.g., progression and mortality） differ even among individuals with similar clinical and pathological characteristics. Existing risk classifiers （TMN grading system, Gleason score, etc.） are not accurately enough to represent the biological features of PCa. Using new genomic technologies, novel biomarkers and classifiers have been developed and shown to add value to clinical or pathological risk factors for predicting aggressive disease. Among them, RNA testing （gene expression analysis） is useful because it can not only reflect genetic variations but also reflect epigenetic regulations. Commercially available RNA profiling tests （Oncotype Dx, Prolaris, and Decipher） have demonstrated strong abilities to discriminate PCa with poor prognosis from less aggressive diseases. For instance, these RNA profiling tests can predict disease progression in active surveillance patients or early recurrence after radical treatments. These tests may offer more dependable methods for PCa prognosis prediction to make more accurate and personal medical decisions.

Prostate cancer antigen 3 and genetic risk score as markers for the detection of prostate cancer in the Chinese population

Dear Editor We report here the performance of prostate cancer antigen 3 （PCA3） and genetic risk score （GRS） in predicting prostate cancer （PCa） from the prostate biopsy. To the best of our knowledge, this is the first report of simultaneously evaluating these two biomarkers in the same study.

Aldosterone induces inflammatory cytokines in penile corpus cavernosum by activating the NF-κB pathway

Emerging evidence indicates that aldosterone and mineralocorticoid receptors （MRs） are associated with the pathogenesis of erectile dysfunction. However, the molecular mechanisms remain largely unknown. In this study, freshly isolated penile corpus cavernosum tissue from rats was treated with aldosterone, with or without MRs inhibitors. Nuclear factor （NF）-kappa B （NF-κB） activity was evaluated by real-time quantitative PCR, luciferase assay, and immunoblot. The results demonstrated that mRNA levels of the NF-κB target genes, including inhibitor of NF-κB alpha （IκB-α, NF-κB1, tumor necrosis factor-alpha （TNF-α, and interleukin 6 （IL-6）, were higher after aldosterone treatment. Accordingly, phosphorylation of p65/RelA, IκB-α, and inhibitor of NF-κB kinase-β was markedly increased by aldosterone. Furthermore, knockdown of MRs prevented activation of the NF-κB canonical pathway by aldosterone. Consistent with this finding, ectopic overexpression of MRs enhanced the transcriptional activation of NF-κB by aldosterone. More importantly, the MRs antagonist, spironolactone blocked aldosterone-mediated activation of the canonical NF-κB pathway. In conclusion, aldosterone has an inflammatory effect in the corpus cavernosum penis, inducing NF-κB activation via an MRs-dependent pathway, which may be prevented by selective MRs antagonists. These data reveal the possible role of aldosterone in erectile dysfunction as well as its potential as a novel pharmacologic target for treatment.

Association between diacylglycerol kinase kappa variants and hypospadias susceptibility in a Han Chinese population

Previous genome-wide association studies have identified variants in the diacylglycerol kinase kappa （DGKtO gene associated with hypospadias in populations of European descent. However, no variants of DGKKwere confirmed to be associated with hypospadias in a recent Han Chinese study population, likely due to the limited number of single-nucleotide polymorphisms （SNPs） included in the analysis. In this study, we aimed to address the inconsistent results and evaluate the association between DGKK and hypospadias in the Han Chinese population through a more comprehensive analysis of DGKK variants. We conducted association analyses for 17 SNPs in or downstream of DGKKwith hypospadias among 322 cases （58 mild, 113 moderate, 128 severe, and 23 unknown） and 1008 controls. Five SNPs （rs2211122, rs4554617, rs7058226, rs7063116, and rs5915254） in DGKK were significantly associated with hypospadias （P 〈 0.05）, with odds ratios （ORs） of 1.64-1.76. When only mild and moderate cases were compared to controls, 10 SNPs in DGKKwere significant （P〈 0.05）, with ORs of 1.56-2.13. No significant SNP was observed when only severe cases were compared to controls. This study successfully implicated DGKK variants in hypospadias risk among a Han Chinese population, especially for mild/moderate cases. Severe forms of hyposDadias are likely due to other genetic factors.

Prostate volume does not provide additional predictive value to prostate health index for prostate cancer or clinically significant prostate cancer:results from a multicenter study in China

To evaluate whether prostate volume(PV)would provide additional predictive utility to the prostate health index(phi)for predicting prostate cancer(PCa)or clinically significant prostate cancer,we designed a prospective,observational multicenter study in two prostate biopsy cohorts.Cohort 1 included 595 patients from three medical centers from 2012 to 2013,and Cohort 2 included 1025 patients from four medical centers from 2013 to 2014.Area under the receiver operating characteristic curves(AUC)and logistic regression models were used to evaluate the predictive performance of PV-based derivatives and models.Linear regression analysis showed that both total prostate-specific antigen(tPSA)and free PSA(fPSA)were significantly correlated with PV(all P<0.05).[-2]proPSA(p2PSA)was significantly correlated with PV in Cohort 2(P<0.001)but not in Cohort 1(P=0.309),while no significant association was observed between phi and PV.When combining phi with PV,phi density(PHID)and another phi derivative(PHIV,calculated as phi/PV°5)did not outperform phi for predicting PCa or clinically significant PCa in either Cohort 1 or Cohort 2.Logistic regression analysis also showed that phi and PV were independent predictors for both PCa and clinically significant PCa(all P<0.05);however,PV did not provide additional predictive value to phi when combining these derivatives in a regression model(all models vs phi were not statistically significant,all P>0.05).In conclusion,PV-based derivatives(both PHIV and PHID)and models incorporating PV did not improve the predictive abilities of phi for either PCa or clinically significant PCa.

Race-specific genetic risk score is more accurate than nonrace-specific genetic risk score for predicting prostate cancer and high-grade diseases

Genetic risk score （GRS） based on disease risk-associated single nucleotide polymorphisms （SNPs） is an informative tool that can be used to provide inherited information for specific diseases in addition to family history, However, it is still unknown whether only SNPs that are implicated in a specific racial group should be used when calculating GRSs. The objective of this study is to compare the performance of race-specific GRS and nonrace-specitic GRS for predicting prostate cancer （PCa） among 1338 patients underwent prostate biopsy in Shanghai, China. A race-specific GRS was calculated with seven PCa risk-associated SNPs implicated in East Asians （GRS7）, and a nonrace-specific GRS was calculated based on 76 PCa risk-associated SNPs implicated in at least one racial group （GRS76）. The means of GRS7 and GRS76 were 1.19 and 1.85, respectively, in the study population. Higher GRS7 and GRS76 were independent predictors for PCa and high-grade PCa in univariate and multivariate analyses. GRS7 had a better area under the receiver-operating curve （AUC） than GRS76 for discriminating PCa （0.602 vs 0.573） and high-grade PCa （0.603 vs 0.575） but did not reach statistical significance. GRS7 had a better （up to 13% at different cutoffs） positive predictive value （PPV） than GRS76. In conclusion, a race-specific GRS is more robust and has a better performance when predicting PCa in East Asian men than a GRS calculated using SNPs that are not shown to be associated with East Asians.