Demographic, clinical and lifestyle predictors for severity of erectile dysfunction and biomarkers level in Malaysian patients

The incidence of erectile dysfunction (ED) is rising worldwide and its prevalence is one of the main health concerns that affect overall men well-being in Malaysia. The cluster of demographic, clinical and lifestyle factors may have contributed to the severity of ED and changes in biomarkers level; nevertheless these have not been studied extensively. This cross sectional study involved a total of 276 patients with 138 was diagnosed with ED. The demographic, clinical, lifestyle factors and severity of ED were assessed using a set of questionnaire and the International Index of Erectile Function (IIEF-5). Meanwhile, Total Testosterone (TT) and Asymmetric dimethylarginine (ADMA) levels were determined using the enzyme-linked immunosorbant assay (ELISA). Binary logistic regression test was used to demonstrate the predictors of severity of ED, TT and ADMA levels. Significant predictors for worsening of severity of ED are self-employed [10.55 (0.43 – 257.06), p=0.004], pensioner [8.07 (0.19 – 352.45), p=0.026], nongovernment employee [1.16 (0.05 – 26.26), p=0.04] and TT [0.41 (0.25 – 0.69), p=0.001]. Nevertheless, pensioner [0.08 (0.01 – 0.87), p=0.038] and unemployed [0.04 (0.01 – 0.42), p=0.007], were the predictors that may influence the changes of TT levels. On the other hand, academic qualification (secondary) [4.51 (0.48 – 42.83), p=0.014] and intensity of physical activities (< 1 hour/day) [2.61 (0.65 – 10.48), p=0.008] were the predictors which were more likely to influence the changes of ADMA levels in ED patients. TT and ADMA levels were influenced by demographic and lifestyle factors whilst severity of ED was predicted by demographic and clinical factors in Malaysian ED population. These predictors may provide new knowledge on risk factors of severity of ED and help in management of ED. Thus, the predictive models could serve as a primary guidance to physicians to ensure ED being managed and treated more effectively

Linkage between prostate cancer occurrence and Y-chromosomal DYS loci in Malaysian subjects..

Purpose: Prostate cancer differs markedly in incidence across ethnic groups. Since this disease is influenced by complex genetics, it is many genetic factors may affect the level of susceptibility to development of the disease. In this study, four Y-linked short tandem repeats (STRs), DYS388, DYS435, DYS437, and DYS439, were genotyped to compare Malaysian prostate cancer patients and normal control males. Materials and methods: A total of 175 subjects comprising 84 patients and 91 healthy individuals were recruited. Multiplex PCR was optimized to co-amplify DYS388, DYS435, DYS437, and DYS439 loci. All samples were genotyped for alleles of four DYS loci using a Genetic Analysis System. Results: Of all DYS loci, allele 10 (A) of DYS388 had a significantly lower incidence of disease in compare with other alleles of this locus, while a higher incidence of disease was found among males who had either allele 12 (C) of DYS388 or allele 14 (E) of DYS439. Moreover, a total of 47 different haplotypes comprising different alleles of four DYS loci were found among the whole study samples, of which haplotypes AABC and CAAA showed a lower and higher frequency among cases than controls, respectively. Conclusions: It is likely that Malaysian males who belong to Y-lineages with either allele 12 of DYS388, allele 14 of DYS439, or haplotype CAAA are more susceptible to develop prostate cancer, while those belonging to lineages with allele 10 of DYS388 or haplotype AABC are more resistant to the disease

Doctors' approaches to decision support in counseling patients with localized prostate cancer: an Asian perspective

There are many treatment options for localized prostate cancer, and there is clinical equipoise in relation to the treatment outcomes. This study aimed to explore doctors’ approaches to decision support in counselling patients with localized prostate cancer in a country with a less established system of support and care delivery for cancer treatment. Four in-depth interviews and three focus group discussions were conducted with seven government policy makers/consultant urologists, three oncologists, four private urologists and six urology trainees in Malaysia between 2012 and 2013. Doctors facilitated the treatment decision by explaining about the disease and the treatment options, which included monitoring, side effects and complications of each treatment option. Paper-based (charts and diagram drawings) or electronic (ipad apps and websites) illustrations and physical models were used as patient education aids. Further reading materials and websites links were often provided to patients. Patients were given time till subsequent follow up to decide on the treatment and family involvement was encouraged. Referral to other healthcare professionals (oncologist, radiotherapist or other urologist) for second opinion was offered to the patients. The doctors would recommend patients to speak to prostate cancer survivors for peer support but official support groups were not easily accessible. This study highlighted a multi-faceted approach to support patients with localized prostate cancer in making a treatment decision. It not only involved the doctors (urologist or oncologist) themselves, but also empowered the patients and their social network to support the decision making process

Who makes the decision? Malaysian healthcare professionals' views on prostate cancer treatment

Purpose: This study aimed to explore the views of Malaysian healthcare professionals (HCPs) on the roles of various stakeholders who were involved in making decisions about prostate cancer treatment. Method: Four in-depth interviews and three focus group discussions were conducted with HCPs from government and private hospitals in Malaysia between December 2012 and March 2013. HCPs consisted of private urologists (n=4), government urologists (n=6), urology trainees (n=5), government policy maker (n=1) and oncologists (n=3). There were 16 male and three female participants. Trained researchers used a topic guide to guide the interviews which were audio-recorded, transcribed verbatim, checked and managed with Nvivo 10 software. Thematic approach was used to analyse the data. Result: Three parties were involved in the decision making process: HCPs, patients and family. Patients who did not understand prostate cancer and its treatment had difficulty in making decisions. These patients tended to leave the decision to the HCPs. Some patients made their own treatment decision. Some patients avoid asking too many questions to avoid the possibility of being influenced towards one option by their HCP. HCPs would leave the final say to the patient because of three reasons: to avoid patients’ regret (“patient will not be happy at the end of the day”); wanting the patient to “balance what they wanted and what was the reality of each option”; and knowing there was no single best treatment option. The family members, especially children, made the decision for some patients. This may be due to Malaysia’s close-knit family culture where patients were concerned about their children’s emotions. While some patients were able to make their own decisions for non-invasive treatment (e.g. hormonal treatment), they would like to involve their family if they were considering surgery. HCPs observed that patients rarely involved their wives in decision making. Conclusion: Decision making during prostate cancer treatment involves three parties; HCP, patient and family. The decisional roles depend on the patients personal preferences, understanding of the illness, and the family dynamics

miR-137-mediated loss of KDM5B expression leads to suppression of the malignant phenotype of bladder cancer cells

The oncogenic role of KDM5B is implicated in the pathogenesis of many cancers including bladder cancer (BC). KDM5B is a histone demethylase enzyme that modifies the chromatin structure to specify cellular transcriptional states. Overexpression of KDM5B in cancer cells is correlated with an increased proliferative capacity. Intriguingly, KDM5B is a cancer/testis antigen; while its expression in tumours is ectopically amplified, KDM5B expression in normal conditions is limited to embryonic stem cells (ESCs) and the testis in adults. These unique characteristics make KDM5B a potential pan-cancer therapeutic target. Thus, this study was aimed at identifying potential regulators of KDM5B. Since KDM5B expression in ESCs is orchestrated by microRNAs (miRNAs) and the expression of many miRNAs are altered in BC, we hypothesized that miRNAs may be the switch that can abate KDM5B expression to mitigate the BC malignant phenotype. Based on IHC- and RT-QPCR analysis, we found that KDM5B protein and transcript levels were differentially expressed in cancer tissues and cell lines, respectively. Amongst several in silico-predicted putative KDM5B-targeting miRNAs, the in vitro basal expression of miR-137 was inversely correlated with KDM5B expression. We demonstrated that the overexpression of miR-137 significantly attenuated KDM5B expression, induced G1 cell-cycle arrest, suppressed cell growth and blocked invasion and migration of BC cells. In contrast, downregulation of miR-137 expression led to the reverse effect. By integrating in silico screens of miR-137 putative target genes and microarray data using the Ingenuity Pathway Analysis (IPA), we revealed that miR-137 possibly exerts control over the cell-cycle through Rb and adenylyl cyclic signalling pathways by targeting key regulators of cyclin A. We also showed that miR-137 gain-of-function increased the expression of tumor suppressor, JDP2. While our results suggest that miR-137 can mitigate the KDM5B-associated BC phenotype, further studies on understanding the effect on aberrant histone methylation patterns are warranted

Overexpression of CTAG1B is a potential biomarker in bladder cancer

Urothelial cell carcinoma (UCC) is the most common form of bladder cancer and is associated with the need for life-long surveillance once a patient is diagnosed with a non-invasive disease. Due to the long-term risk of recurrence and the need for life-long routine monitoring and therapy, the cost per UCC patient from diagnosis to death is the highest of all cancers. The development of non-invasive biomarkers of recurrence and progression can increase survival, decrease treatment costs and improve patient quality of life. However, to date, no biomarker(s) have been endorsed for the use in the clinical management of UCC, especially in predicting risk of progression and recurrence. CTAG1B was previously found to be highly expressed in high-stage and grade bladder cancer, albeit in Caucasian cohorts. However, despite its potential as a target for cancer immunotherapy, the effect of expression modulation on cellular phenotypes has never been reported. In this study, we overexpressed CTAG1B in an invasive bladder cancer cell line, EJ28 after we confirmed that this cell line minimally expressed CTAG1B. The cells were transfected with CTAG1B-pcDNA3.1(-) and the level of expression was confirmed by qRT-PCR. Once the expression was confirmed to persist up to 72h post-transfection, the transfected cells were subjected to various phenotypic assays. In addition, the pattern of CTAG1B expression in a cohort of Malaysian bladder cancer paraffin-embedded tissues was also determined using immunohistochemistry. The effect of CTAG1B overexpression on the cell cycle, migratory and proliferative potential was observed. The changes in phenotype were compared with that of untransfected and mock controls. CTAG1B was overexpressed 20 times as compared to the untransfected and mock controls in the transfected cells. CTAG1B overexpression resulted in cells to migrate slower at 24h post-transfection but proliferate significantly faster after 72-96h post-transfection. In addition, CTAG1B was more frequently expressed in advanced bladder cancer stages and grades. The findings from this study contribute to the current knowledge of CTAG1B‟s role in tumourigenesis. Further functional studies will contribute towards realising the potential of CTAG1B as a biomarker for predicting the risk of progression and recurrence of bladder cancer

The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families

An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

Abstract: It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes