Ethnicity Is an Independent Determinant of Age-Specific PSA Level: Findings from a Multiethnic Asian Setting

Objectives

To study the baseline PSA profile and determine the factors influencing the PSA levels within a multiethnic Asian setting.

Materials and Methods

We conducted a cross-sectional study of 1054 men with no clinical evidence of prostate cancer, prostate surgery or 5α-reductase inhibitor treatment of known prostate conditions. The serum PSA concentration of each subject was assayed. Potential factors associated with PSA level including age, ethnicity, height, weight, family history of prostate cancer, lower urinary tract voiding symptoms (LUTS), prostate volume and digital rectal examination (DRE) were evaluated using univariable and multivariable analysis.

Results

There were 38 men (3.6%) found to have a PSA level above 4 ng/ml and 1016 (96.4%) with a healthy PSA (≤4 ng/ml). The median PSA level of Malay, Chinese and Indian men was 1.00 ng/ml, 1.16 ng/ml and 0.83 ng/ml, respectively. Indians had a relatively lower median PSA level and prostate volume than Malays and Chinese, who shared a comparable median PSA value across all 10-years age groups. The PSA density was fairly similar amongst all ethnicities. Further analysis showed that ethnicity, weight and prostate volume were independent factors associated with age specific PSA level in the multivariable analysis (p<0.05).

Conclusion

These findings support the concept that the baseline PSA level varies between different ethnicities across all age groups. In addition to age and prostate volume, ethnicity may also need to be taken into account when investigating serum PSA concentrations in the multiethnic Asian population.     

Proteomic analysis of plasma membrane and tonoplast from the leaves of mangrove plant Avicennia officinalis

In order to understand the salt tolerance and secretion in mangrove plant species, gel electrophoresis coupled with LC‐MS‐based proteomics was used to identify key transport proteins in the plasma membrane (PM) and tonoplast fractions of Avicennia officinalis leaves. PM and tonoplast proteins were purified using two‐aqueous‐phase partitioning and density gradient centrifugation, respectively. Forty of the 254 PM proteins and 31 of the 165 tonoplast proteins identified were predicted to have transmembrane domains. About 95% of the identified proteins could be classified based on their functions. The major classes of proteins were predicted to be involved in transport, metabolic processes, defense/stress response, and signal transduction, while a few of the proteins were predicted to be involved in other functions such as membrane trafficking. The main classes of transporter proteins identified included H⁺‐ATPases, ATP‐binding cassette transporters, and aquaporins, all of which could play a role in salt secretion. These data will serve as the baseline membrane proteomic dataset for Avicennia species. Further, this information can contribute to future studies on understanding the mechanism of salt tolerance in halophytes in addition to salt secretion in mangroves. All MS data have been deposited in the ProteomeXchange with identifier PXD000837 ( http://proteomecentral.proteomexchange.org/dataset/PXD000837 ).     

Cardiovascular Risk Factors and Ethnicity Are Independent Factors Associated with Lower Urinary Tract Symptoms

Objectives

To determine the lower urinary tract symptoms (LUTS) profile and factors affecting its degree of severity including cardiovascular risk profile, age, ethnicity, education level and prostate volume in a multiethnic Asian setting.

Materials and Methods

We conducted a cross-sectional study of 1021 men aged 40–79 years with no clinical evidence of prostate cancer, prostate surgery or 5α-reductase inhibitor treatment of known prostate conditions. The severity of LUTS was assessed using the International Prostate Symptom Score (IPSS). Potential factors associated with LUTS including age, ethnicity, education, history of hypertension, diabetes and hypercholesterolemia, height, weight, and prostate volume were evaluated using univariable and multivariable analyses.

Results

There were 506 (50%) men found to have moderate-to-severe LUTS attaining an IPSS above 7. Overall, nocturia (45.5%) was the most frequently reported symptom. Multivariable analysis showed that age, ethnicity, prostate volume and history of hypertension and hypercholesterolemia were independent factors associated with severity of LUTS (p < 0.05). Considering individual lower urinary tract symptoms, we found a strong association of storage symptom with history of hypertension and hypercholesterolemia. Malay men were significantly bothered by post micturition symptom compared to their Chinese and Indian counterparts. Stratified analyses of LUTS demonstrated a mutually exclusive cardiovascular risk factors profile defined by ethnicity.

Conclusion

Severity of LUTS varies between different ethnicities across all age groups. In addition to age and prostate volume, ethnicity and cardiovascular risk factors including hypertension and hypercholesterolemia may also need to be taken into account in managing men with LUTS.     

Cytotoxic mechanisms of panduratin A on A375 melanoma cells: A quantitative and temporal proteomics analysis

Melanoma is a lethal form of skin cancer with rising global incidence. However, limited treatment options are available for advanced melanoma and this is further compounded by the development of resistance toward existing drugs. Panduratin A (PA), a cyclohexanyl chalcone found in Boesenbergia rotunda, was investigated for its cytotoxic potentials against human malignant melanoma A375 cells. Our initial findings revealed that mitochondrion is the primary acting site of PA on A375 cancer cells and the cytotoxic mechanisms of PA were further investigated using a temporal quantitative proteomics approach by iTRAQ 2D‐LC‐MS/MS. Comprehensive proteomics analysis identified 296 proteins that were significantly deregulated in PA‐treated A375 cells and revealed the involvement of mitochondrial oxidative phosphorylation, secretory and ER stress pathway, and apoptosis. We further confirmed that the PA‐induced apoptosis was mediated by prolonged ER stress at least in part via the PERK/eIF2α/ATF4/CHOP pathway. Pretreatment with cycloheximide, an ER stress inhibitor rescued PA‐induced cell death, which was accompanied by the suppression of ER‐stress‐related HSPA5 and CHOP proteins. The present study provides comprehensive mechanistic insights into the cytotoxic mechanisms of PA.     

Unravelling the proteome of degenerative human mitral valves

Degenerative mitral valve disease (DMVD), which includes the syndromes of mitral valve prolapse (MVP) and flail leaflet, is a common valvular condition which can be complicated by mitral regurgitation and adverse cardiovascular outcomes. Although several genetic and other studies of MVP in dog models have provided some information regarding the underlying disease mechanisms, the proteins and molecular events mediating human MVP pathogenesis have not been unraveled. In this study, we report the first large‐scale proteome profiling of mitral valve tissue resected from patients with MVP. A total of 1134 proteins were identified, some of which were validated using SWATH‐MS and western blotting. GO annotation of these proteins confirmed the validity of this proteome database in various cardiovascular processes. Among the list of proteins, we found several structural and extracellular matrix proteins, such as asporin, biglycan, decorin, lumican, mimecan, prolargin, versican, and vinculin, that have putative roles in the pathophysiology of MVP. These proteins could also be involved in the cardiac remodeling associated with mitral regurgitation. All MS data have been deposited in the ProteomeXchange with identifier PXD000774 ( http://proteomecentral.proteomexchange.org/dataset/PXD000774 ).     

Concentric Gel System to Study the Biophysical Role of Matrix Microenvironment on 3D Cell Migration

The ability of cells to migrate is crucial in a wide variety of cell functions throughout life from embryonic development and wound healing to tumor and cancer metastasis. Despite intense research efforts, the basic biochemical and biophysical principles of cell migration are still not fully understood, especially in the physiologically relevant three-dimensional (3D) microenvironments. Here, we describe an in vitro assay designed to allow quantitative examination of 3D cell migration behaviors. The method exploits the cell’s mechanosensing ability and propensity to migrate into previously unoccupied extracellular matrix (ECM). We use the invasion of highly invasive breast cancer cells, MDA-MB-231, in collagen gels as a model system. The spread of cell population and the migration dynamics of individual cells over weeks of culture can be monitored using live-cell imaging and analyzed to extract spatiotemporally-resolved data. Furthermore, the method is easily adaptable for diverse extracellular matrices, thus offering a simple yet powerful way to investigate the role of biophysical factors in the microenvironment on cell migration.     

To Share or Not to Share: Malaysian Healthcare Professionals' Views on Localized Prostate Cancer Treatment Decision Making Roles

Aim

To explore the views of Malaysian healthcare professionals (HCPs) on stakeholders’ decision making roles in localized prostate cancer (PCa) treatment.

Methods

Qualitative interviews and focus groups were conducted with HCPs treating PCa. Data was analysed using a thematic approach. Four in-depth interviews and three focus group discussions were conducted between December 2012 and March 2013 using a topic guide. Interviews were audio-recorded, transcribed verbatim, and analysed thematically.

Findings

The participants comprised private urologists (n = 4), government urologists (n = 6), urology trainees (n = 6), government policy maker (n = 1) and oncologists (n = 3). HCP perceptions of the roles of the three parties involved (HCPs, patients, family) included: HCP as the main decision maker, HCP as a guide to patients’ decision making, HCP as a facilitator to family involvement, patients as main decision maker and patient prefers HCP to decide. HCPs preferred to share the decision with patients due to equipoise between prostate treatment options. Family culture was important as family members often decided on the patient’s treatment due to Malaysia’s close-knit family culture.

Conclusions

A range of decision making roles were reported by HCPs. It is thus important that stakeholder roles are clarified during PCa treatment decisions. HCPs need to cultivate an awareness of sociocultural norms and family dynamics when supporting non-Western patients in making decisions about PCa.     

Proteomics Analysis of Candida albicans dnm1 Haploid Mutant Unraveled the Association between Mitochondrial Fission and Antifungal Susceptibility

Candida albicans is a major fungal pathogen, accounting for approximately 15% of healthcare infections with associated mortality as high as 40% in the case of systemic candidiasis. Antifungal agents for C. albicans infections are limited, and rising resistance is an inevitable problem. Therefore, understanding the mechanism behind antifungal responses is among the top research focuses in combating Candida infections. Herein, the recently developed C. albicans haploid model is employed to examine the association between mitochondrial fission, regulated by Dnm1, and the pathogen's response to antifungals. Proteomic analysis of dnm1Δ and its wild‐type haploid parent, GZY803, reveal changes in proteins associated with mitochondrial structures and functions, cell wall, and plasma membrane. Antifungal susceptibility testing revealed that dnm1Δ is more susceptible to SM21, a novel antifungal, than GZY803. Analyses of reactive oxygen species release, antioxidant response, lipid peroxidation, and membrane damages uncover an association between dnm1Δ and the susceptibility to SM21. Dynasore‐induced mitochondrial inhibition in SC5314 diploids corroborate the findings. Interestingly, Dynasore‐primed SC5314 cultures exhibit increased susceptibility to all antifungals tested. These data suggest an important contribution of mitochondrial fission in antifungal susceptibility of C. albicans. Hence, mitochondrial fission can be a potential target for combined therapy in anti‐C. albicans treatment.     

Curcumin inhibits telomerase and induces telomere shortening and apoptosis in brain tumour cells

Curcumin, a polyphenolic compound isolated from Curcuma longa (Turmeric) is widely used in traditional Ayurvedic medicine. Its potential therapeutic effects on a variety of diseases have long been known. Though anti‐tumour effects of curcumin have been reported earlier, its mode of action and telomerase inhibitory effects are not clearly determined in brain tumour cells. In the present study, we demonstrate that curcumin binds to cell surface membrane and infiltrates into cytoplasm to initiate apoptotic events. Curcumin treatment has resulted in higher cytotoxicity in the cells that express telomerase enzyme, highlighting its potential as an anticancer agent. Curcumin induced growth inhibition and cell cycle arrest at G2/M phase in the glioblastoma and medulloblastoma cells used in the study. Gene and protein expression analyses revealed that curcumin down‐regulated CCNE1, E2F1 and CDK2 and up‐regulated the expression of PTEN genes resulting in growth arrest at G2/M phase. Curcumin‐induced apoptosis is found to be associated with increased caspase‐3/7 activity and overexpression of Bax. In addition, down‐regulation of Bcl2 and survivin was observed in curcumin‐treated cells. Besides these effects, we found curcumin to be inhibiting telomerase activity and down‐regulating hTERT mRNA expression leading to telomere shortening. We conclude that telomerase inhibitory effects of curcumin underscore its use in adjuvant cancer therapy. J. Cell. Biochem. 114: 1257–1270, 2013. © 2012 Wiley Periodicals, Inc.