V R Marshall

University of Adelaide, Tarndarnya, South Australia, Australia

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Publications (116)354.18 Total impact

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    ABSTRACT: Extract: Prostate cancer (PCa) is the most commonly diagnosed malignancy among men living in Western countries and a major cause of cancer-related deaths. Biopsy-based diagnosis of PCa is usually undertaken following an elevated serum prostate specific antigen (PSA) measurement and/or abnormal digital rectal examination (DRE). The deficiencies of serum PSA as a biomarker have been well documented (Roobol and Carlsson 2013). While it is highly specific for tissue of prostatic origin, PSA is not cancer-specific, resulting in many unnecessary biopsies of benign disease. Moreover, PSA screening has resulted in substantial over-diagnosis and over-treatment of indolent tumours without having a significant effect on prostate cancer mortality (Schroder, et al. 2009). Biomarkers that could identify patients with clinically significant PCa would be ideal but are currently lacking ...
    Endocrine Related Cancer 05/2014; 21(4). DOI:10.1530/ERC-14-0234 · 4.91 Impact Factor
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    ABSTRACT: Circulating microRNAs (miRNAs) are emerging as useful non-invasive markers of disease. The objective of this study was to use a mouse model of prostate cancer as a tool to discover serum miRNAs that could be assessed in a clinical setting. Global miRNA profiling identified 46 miRNAs at significantly altered levels (p ≤ 0.05) in the serum of TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice with advanced prostate cancer compared to healthy controls. A subset of these miRNAs with known human homologues were validated in an independent cohort of mice and then measured in serum from men with metastatic castration-resistant prostate cancer (mCRPC; n = 25) or healthy men (n = 25). Four miRNAs altered in mice, mmu-miR-141, mmu-miR-298, mmu-miR-346 and mmu-miR-375, were also found to be at differential levels in the serum of men with mCRPC. Three of these (hsa-miR-141, hsa-miR-298 and hsa-miR-375) were upregulated in prostate tumors compared with normal prostate tissue, suggesting that they are released into the blood as disease progresses. Moreover, the intra-tumoral expression of hsa-miR-141 and hsa-miR-375 were predictors of biochemical relapse after surgery. This study is the first to demonstrate that specific serum miRNAs are common between human prostate cancer and a mouse model of the disease, highlighting the potential of such models for the discovery of novel biomarkers.
    International Journal of Cancer 08/2012; 131(3):652-61. DOI:10.1002/ijc.26405 · 5.01 Impact Factor
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    ABSTRACT: The response of prostate cells to androgens reflects a combination of androgen receptor (AR) transactivation and transrepression, but how these two processes differ mechanistically and influence prostate cancer risk and disease outcome remain elusive. Given recent interest in targeting AR transrepressive processes, a better understanding of AR/corepressor interaction and responses is warranted. Here, we used transactivation and interaction assays with wild-type and mutant ARs, and deletion AR fragments, to dissect the relationship between AR and the corepressor, silencing mediator for retinoic acid and thyroid hormone receptors (SMRT). We additionally tested how these processes are influenced by AR agonist and antagonist ligands, as well as by variation in the polyglutamine tract in the AR amino terminal domain (NTD), which is encoded by a polymorphic CAG repeat in the gene. SMRT was recruited to the AR ligand binding domain by agonist ligand, and as determined by the effect of strategic mutations in activation function 2 (AF-2), requires a precise conformation of that domain. A distinct region of SMRT also mediated interaction with the AR-NTD via the transactivation unit 5 (TAU5; residues 315-538) region. The degree to which SMRT was able to repress AR increased from 17% to 56% as the AR polyglutamine repeat length was increased from 9 to 42 residues, but critically this effect could be abolished by increasing the SMRT:AR molar ratio. These data suggest that the extent to which the CAG encoded polyglutamine repeat influences AR activity represents a balance between corepressor and coactivator occupancy of the same ligand-dependent and independent AR interaction surfaces. Changes in the homeostatic relationship of AR to these molecules, including SMRT, may explain the variable penetrance of the CAG repeat and the loss of AR signaling flexibility in prostate cancer progression.
    Molecular and Cellular Endocrinology 06/2011; 342(1-2):20-31. DOI:10.1016/j.mce.2011.05.023 · 4.24 Impact Factor
  • The Journal of Urology 04/2011; 185(4). DOI:10.1016/j.juro.2011.02.1465 · 3.75 Impact Factor
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    ABSTRACT: The role of endogenous testosterone in the pathogenesis of type 2 diabetes mellitus remains vague. We investigated whether associations between endogenous testosterone and diabetes prevalence in men could be partially explained by modifiable risk factors. A random population-based cross-sectional study of 1195 men aged 35-80 years living in the north-west regions of Adelaide, Australia. Data collections occurred between 2002 and 2005, and response rate was 45.1%. Diabetes (non-specific) was classified by either: (1) self-report for doctor diagnosis of diabetes; (2) prescription medication for diabetes; (3) fasting plasma glucose ≥ 7 mmol/L; or (4) glycosylated haemoglobin ≥ 6.2%. Logistic regressions were used to estimate odds ratios (OR [with 95% confidence intervals]) for diabetes, with stepwise adjustments for demographic, lifestyle, and clinical factors. Diabetes prevalence was positively associated with age groups 45-54 years (2.8 [1.4, 5.8]), 55-64 years (3.9 [1.9, 8.3]) and ≥ 65 years (4.0 [1.8, 8.9]), lowest income group (1.8 [1.0, 3.4]), ex-smoker (1.8 [1.2, 2.9]), lowest (3.2 [1.9, 5.5]) and middle (1.9 [1.1, 3.4]) alcohol tertiles, cardiovascular disease (1.9 [1.2, 2.8]), metabolic syndrome (4.0 [2.6, 6.1]), and lowest plasma total testosterone tertile (1.8 [1.1, 3.0]), but negatively associated with middle (0.5 [0.3, 0.8]) and highest (0.4 [0.3, 0.7]) sugar intake tertiles, arthritis (0.6 [0.3, 1.0]), and elevated LDL cholesterol (0.5 [0.3, 0.8]); ORs showed an inverted 'U' shape for middle and highest voiding lower urinary tract symptoms tertiles. Body composition, muscle strength, and cardio-metabolic factors partially explained the association between low plasma total testosterone and diabetes. Plasma total testosterone was inversely and independently associated with diabetes prevalence, that might have been partially explained by several modifiable risk factors.
    Maturitas 03/2011; 68(3):279-85. DOI:10.1016/j.maturitas.2010.12.007 · 2.86 Impact Factor
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    ABSTRACT: To define specific medical conditions associated with clinically significant depressive symptoms in men. A cross-sectional study was conducted in a community-based sample of Australian men (N = 1,195, aged 35-80 years; for 2002-2005). Depression was defined by: (1) symptomatic depression (current symptoms) or (2) current prescription for antidepressant(s) or (3) previously diagnosed depression. Logistic regression was used to determine prevalence odds ratios (OR) for depression independently associated with an extensive range of demographic, lifestyle, and clinical factors. Adjusted population attributable risk (PAR%) estimates were also computed. Depression was significantly (ORs at P < 0.05) associated with previously diagnosed anxiety (12.0) and insomnia (4.4), not married (1.7), current smoker (1.7), low muscle strength tertile (1.7, P = 0.059), high triglycerides (1.6), high storage lower urinary tract symptoms (LUTS) tertile (1.8), past year general practitioner visits 5-9 (1.9), middle energy density tertile (0.4), and high systolic blood pressure (0.5). Significant PAR% estimates (at P < 0.05) were for previous anxiety (27.0%) and insomnia (16.1%), middle energy density tertile (-17.2%), high SBP (-23.5%), high triglycerides (15.2%), and high storage LUTS tertile (12.6%). Results strengthened when depression-related factors (previous anxiety and insomnia, psycholeptics, and cognition) were omitted, and became significant for CVD (OR 1.6; PAR 13.9%). Medical conditions associated with depression in men include high triglycerides, low muscle strength, CVD, and LUTS. Depressed men are likely to use health services frequently, be current smokers, not be married, eat unhealthily, and report previous diagnosis of anxiety and insomnia; which has important implications for clinicians managing male patients.
    Social Psychiatry 10/2010; 46(12):1303-12. DOI:10.1007/s00127-010-0302-3 · 2.58 Impact Factor
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    ABSTRACT: To determine the prevalence of, and associated risk factors for, voiding and storage lower urinary tract symptoms (LUTS) in a population-based sample of Australian men. Data were collected from 1,103 men randomly selected, community-dwelling men, as part of the Florey Adelaide Male Ageing Study, after exclusion of men with prostate or bladder cancer or prior surgery to either organ. The presence of LUTS was assessed using the International Prostate Symptom Score. Urine flow was measured via flow meter. Demographic, clinical, and bio-psychosocial data were collected by questionnaire. The prevalence of total, storage, and voiding LUTS was 18.1, 28.0 and 12.6%, respectively. The most common storage symptoms were frequency (12.3%), nocturia (9.9%) and urgency (8.1%), and voiding symptoms were weak stream (8.5%), intermittency (5.4%), incomplete emptying (5.1%) and straining (2.4%). There were linear associations between storage LUTS and increased abdominal fat mass, plasma glucose and low HDL cholesterol (components of the metabolic syndrome), obstructive sleep apnoea (OSA) risk, and retirement. Voiding symptoms were associated with a previous diagnosis of benign prostatic enlargement (BPH), mean peak urine flow, total energy intake, elevated risk of OSA, erectile dysfunction, physician-diagnosed thyroid dysfunction and higher household income. The close association of storage LUTS with the metabolic syndrome, and of both storage and voiding LUTS with OSA, suggest that these conditions should be considered in men presenting with LUTS.
    World Journal of Urology 10/2010; 29(2):179-84. DOI:10.1007/s00345-010-0605-8 · 3.42 Impact Factor
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    ABSTRACT: Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis. Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions. H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P < 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3-fold increased risk of relapse (P < 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort. This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis. Impact: Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover, testing for aberrant expression of epigenetic genes such as those identified in this study may be beneficial in predicting individual patient response to epigenetic therapies.
    Cancer Epidemiology Biomarkers & Prevention 10/2010; 19(10):2611-22. DOI:10.1158/1055-9965.EPI-10-0555 · 4.32 Impact Factor
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    ABSTRACT: Book reviews in this article:Between 1978 and 1988, 108 patients underwent bladder neck incision (BNI) for bladder outflow obstruction. These patients were compared to a similar group who underwent transurethral resection of the prostate (TURP), during the same time period. Only patients with minimal prostatic enlargement (< 10 g) with prominent bladder necks and small lateral lobes were included in the study. In addition, all patients in the resection group had a resection weight of less than 10 g on the histopathology report. Patients were followed up by means of a posted questionnaire to which 59 patients in the BNI group and 86 in the TURP group responded. Pre-operative and peri-operative data were also collected from these respondents by a retrospective case record review. This found both operations to be safe with low morbidity and mortality. BNI was better than TURP in terms of shorter operation length (P < 0.017) and shorter duration of catheterization (P < 0.004). No other peri-operative differences were found. Follow-up results from the questionnaire showed no significant differences in symptoms between the two groups. Similarly, there was no difference in the number of re-operations performed over the 10 year period studied. Patient assessment of their operation was initially favourable in both groups (> 80% patient approval) however, both treatment groups experienced a gradual drop in patient approval over the 10 year period. There were no differences in the level of approval between the BNI and TURP groups.
    ANZ Journal of Surgery 09/2010; 62(2):116 - 122. DOI:10.1111/j.1445-2197.1992.tb00008.x · 1.12 Impact Factor
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    ABSTRACT: Knowledge of preanalytic conditions that biospecimens are subjected to is critically important because novel surgical procedures, tissue sampling, handling, and storage might affect biomarker expression or invalidate tissue samples as analytes for some technologies. We investigated differences in RNA quality, gene expression by quantitative real-time PCR, and immunoreactive protein expression of selected prostate cancer biomarkers between tissues from retropubic radical prostatectomy (RRP) and robot-assisted laparoscopic prostatectomy (RALP). Sections of tissue microarray of 23 RALP and 22 RRP samples were stained with antibodies to androgen receptor (AR) and prostate-specific antigen (PSA) as intersite controls, and 14 other candidate biomarkers of research interest to three laboratories within the Australian Prostate Cancer BioResource tissue banking network. Quantitative real-time PCR was done for AR, PSA (KLK3), KLK2, KLK4, and HIF1A on RNA extracted from five RALP and five RRP frozen tissue cores. No histologic differences were observed between RALP and RRP tissue. Biomarker staining grouped these samples into those with increased (PSA, CK8/18, CKHMW, KLK4), decreased (KLK2, KLK14), or no change in expression (AR, ghrelin, Ki67, PCNA, VEGF-C, PAR2, YB1, p63, versican, and chondroitin 0-sulfate) in RALP compared with RRP tissue. No difference in RNA quality or gene expression was detected between RALP and RRP tissue. Changes in biomarker expression between RALP and RRP tissue exist at the immunoreactive protein level, but the etiology is unclear. Future studies should account for changes in biomarker expression when using RALP tissues, and mixed cohorts of RALP and RRP tissue should be avoided.
    Cancer Epidemiology Biomarkers & Prevention 07/2010; 19(7):1755-65. DOI:10.1158/1055-9965.EPI-10-0059 · 4.32 Impact Factor
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    ABSTRACT: Previous studies from our laboratory demonstrated a strong association between an elevated level of chondroitin sulfate (CS) in peritumoral stroma and PSA-relapse in patients with early stage disease. In this study we determined whether CS levels could predict overall survival in men diagnosed with advanced prostate cancer subsequently treated by orchiectomy alone. CS was localized in archived prostatic tissues by immunohistochemistry, and the level of CS expression as measured by video image analysis was compared in cohorts of 157 and 60 men with early stage or advanced disease, respectively. The CS levels in the peritumoral stroma of patients without relapse after treatment for early stage disease was significantly reduced compared to levels in prostate tissue from patients who either relapsed (P = 0.003) or were diagnosed with advanced prostate cancer (P < 0.00001). There was no difference between the median CS level in the peritumoral prostatic stroma of early stage patients that relapsed after treatment and patients diagnosed with advanced prostate cancer. Increased CS levels (P < 0.0001) and high Gleason score (P < 0.0001) were associated with an increased rate of PSA-relapse in the cohort of patients with early stage disease. However, neither CS level nor Gleason score alone or in combination could predict survival outcome in patients with advanced prostate cancer following androgen deprivation therapy. Although peritumoral CS levels and Gleason score are strong predictors of relapse-free survival in early stage prostate cancer patients, neither peritumoral CS levels nor Gleason score can predict survival outcome in patients with advanced disease.
    The Prostate 05/2009; 69(7):761-9. DOI:10.1002/pros.20926 · 3.57 Impact Factor
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    ABSTRACT: The androgen receptor (AR) is an important signaling molecule in multiple tissues, yet its mode of action and cell-specific activities remain enigmatic. AR function has been best studied in the prostate, in which it is essential for growth and homeostasis of the normal organ as well as each stage of cancer development. Investigation of mechanisms responsible for continued AR action that evolve during prostate cancer progression or after hormonal management of the disease have been instructive in defining AR signaling pathways. In the current paper, we use sequence similarity and the collocation of somatic mutations in prostate cancer to define residues 501-535 of the AR amino-terminal domain as an important mediator of receptor function. Specifically, the 501-535 region is required for optimal interaction of the amino-terminal domain with both the p160 coactivator, nuclear receptor coactivator-2, and the AR-ligand binding domain in the amino/carboxyl (N/C) interaction. The N/C interaction is decreased by deletion of the 501-535 region but is distinct from deletion of the (23)FQNLF(27) peptide in that it does not affect the capacity of the AR to activate transcription from a chromatin integrated reporter or recruitment of the receptor to androgen-responsive loci in vivo. Collectively, we have been able to outline two classes of N/C-deficient AR variant that are divergent in their capacity to act in a chromatin context, thereby further defining the interplay between N/C interaction and coregulator recruitment via multiple receptor domains. These mechanisms are likely to be key determinants of the cell and promoter specific activities of the AR.
    Endocrinology 04/2009; 150(6):2674-82. DOI:10.1210/en.2008-1181 · 4.64 Impact Factor
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    ABSTRACT: The glycosaminoglycan chondroitin sulfate is significantly increased in the peritumoral stroma of prostate tumors compared with normal stroma and is an independent predictor of prostate-specific antigen (PSA) relapse following radical prostatectomy. In this study, we determined whether specific alterations in the sulfation pattern of glycosaminoglycan chains in clinically organ-confined prostate cancer are associated with PSA relapse. Immunoreactivity to distinct glycosaminoglycan disaccharide epitopes was assessed by manually scoring the staining intensity in prostate tissues from patients with benign prostatic hyperplasia (n = 19), early-stage cancer (cohort 1, n = 55 and cohort 2, n = 275), and advanced-stage cancer (n = 20). Alterations to glycosaminoglycans in benign and malignant prostate tissues were determined by cellulose acetate chromatography and high-pressure liquid chromatography. Glycosaminoglycan disaccharide epitopes were localized to the peritumoral stroma of clinically localized prostate cancer. The level of immunostaining for unsulfated disaccharides (C0S) in the peritumoral stroma, but not for 4-sulfated (C4S) or 6-sulfated disaccharides (C6S), was significantly associated with the rate of PSA relapse following radical prostatectomy. High levels of C0S immunostaining were determined to be an independent predictor of PSA relapse (1.6-fold, P = 0.020). Advanced-stage prostate cancer tissues exhibited reduced electrophoretic mobility for chondroitin sulfate and increased unsulfated disaccharides when compared with benign prostatic hyperplasia tissues, whereas the sulfated disaccharide levels were unaffected. The level of C0S immunostaining in the peritumoral stroma is an independent determinant of PSA failure in clinically localized prostate cancer. Specific alterations to chondroitin sulfate side chains occurring during tumor development may be a crucial step for disease progression in prostate cancer.
    Cancer Epidemiology Biomarkers & Prevention 10/2008; 17(9):2488-97. DOI:10.1158/1055-9965.EPI-08-0204 · 4.32 Impact Factor
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    ABSTRACT: In this study, we investigated the expression of HER-2/neu and AR in clinically organ-confined prostate cancer to determine whether alterations in these signaling pathways contribute to the development of metastatic disease. HER-2/neu and AR immunoreactivity were evaluated in archived prostatic tissues obtained from 53 men with clinically organ-confined disease who underwent radical prostatectomy. Associations between AR and HER-2/neu immunostaining and disease outcome were determined. Seventy percent (37/53) of tumors exhibited high levels of HER-2/neu immunostaining and 68% (36/53) of tumors had elevated AR levels. Patients with high levels of both HER-2/neu and AR had the highest rate of PSA failure (56%, 15/27) compared with no PSA failures amongst seven patients with low levels of both HER-2/neu and AR (log rank statistic 7.69, P = 0.021). Concurrent high levels of HER-2/neu and AR expression were significantly associated with high pathological stage (P = 0.027) and development of metastatic disease (P = 0.022). These findings support the notion that both the HER-2/neu and AR signaling pathways may contribute to development of metastatic disease. The subset of prostate tumors with increased HER-2/neu and AR levels may benefit from treatment strategies that target both signaling pathways.
    The Prostate 06/2008; 68(8):830-8. DOI:10.1002/pros.20747 · 3.57 Impact Factor
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    ABSTRACT: A prospective study of steroid hormone and epidermal growth factor receptor expression in 57 meningiomas is presented. Scatchard analysis of radioligand binding identified 20% of meningiomas as expressing classical oestrogen receptors (ER) at levels below that normally accepted for positivity, the remainder being negative. ER could not be visualized in any meningioma using immunocytochemistry. Alternatively, 74% of meningiomas demonstrated the presence of progesterone receptors (PR) by Scatchard analysis, the specificity of which could not be attributed to glucocorticoid or androgen receptors. Confirmation of classical PR presence was determined by immunocytochemical staining. The presence of epidermal growth factor receptor (EGFR) was demonstrated in 100% of meningiomas using immunocytochemical staining. These data are reviewed in the context of previously reported results and are discussed in relation to the potential for medical therapy as an adjunct to surgery.
    ANZ Journal of Surgery 01/2008; 59(11):881 - 888. DOI:10.1111/j.1445-2197.1989.tb07033.x · 1.12 Impact Factor
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    ABSTRACT: Although the androgen receptor (AR) is accepted as the major determinant of prostate cancer cell survival throughout disease progression, it is currently unclear how the receptor sustains genomic signaling under conditions of systemic androgen ablation. Here, we show that the evolutionarily conserved Hsp70/Hsp90 cochaperone, small glutamine-rich tetratricopeptide repeat containing protein alpha (alphaSGT), interacts with the hinge region of the human AR in yeast and mammalian cells. Overexpression and RNA interference revealed that alphaSGT acts to (a) promote cytoplasmic compartmentalization of the AR, thereby silencing the receptors basal/ligand-independent transcriptional activity, (b) regulate the sensitivity of receptor signaling by androgens, and (c) limit the capacity of noncanonical ligands to induce AR agonist activity. Immunofluorescence, coactivator, and chromatin immunoprecipitation analyses strongly suggest that these effects of alphaSGT on AR function are mediated by interaction in the cytoplasm and are distinct from the receptors response to classic coregulators. Quantitative immunohistochemical analysis of alphaSGT and AR levels in a cohort of 32 primary and 64 metastatic human prostate cancers revealed dysregulation in the level of both proteins during disease progression. The significantly higher AR/alphaSGT ratio in metastatic samples is consistent with the sensitization of prostate tumor cells to androgen signaling with disease progression, particularly in a low-hormone environment. These findings implicate alphaSGT as a molecular rheostat of in vivo signaling competence by the AR, and provide new insight into the determinants of androgen sensitivity during prostate cancer progression.
    Cancer Research 11/2007; 67(20):10087-96. DOI:10.1158/0008-5472.CAN-07-1646 · 9.28 Impact Factor
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    ABSTRACT: Background The prevalence of lower urinary tract symptoms was determined by survey as an initial step in estimating the significance of benign prostatic hyperplasia (BPH) in Asia and Australia.Methods The symptom index (0 to 35) and quality-of-life (QOL) index (0 to 6) of the international prostate symptom score were measured in 7588 men in 9 Asian countries and 146 men in Australia.Results The percentages of Asian men considered to be symptomatic (symptom index ≧ 8) were 18%, 29%, 40%, and 56% in the age groups of 40 to 49, 50 to 59, 60 to 69, and 70 to 79 years, respectively. For Australian men, these figures were 36%, 33%, and 37% in the 50 to 59, 60 to 69, and 70 to 79 year age groups, respectively.Conclusions Our estimates indicate that the prevalences of symptomatic men in Asia and Australia are similar to or greater than those in Europe and America, and suggest BPH is similarly common in these areas.
    International Journal of Urology 06/2007; 4(1):40 - 46. DOI:10.1111/j.1442-2042.1997.tb00138.x · 1.80 Impact Factor
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    ABSTRACT: Previous studies have demonstrated that high levels of hyaluronan (HA) and the chondroitin sulfate proteoglycan, versican in the peritumoral stroma are associated with metastatic spread of clinical prostate cancer. In vitro integration of HA and versican into a pericellular sheath is a prerequisite for proliferation and migration of vascular smooth muscle cells. In this study, a particle exclusion assay was used to determine whether human prostate cancer cell lines are capable of assembling a pericellular sheath following treatment with versican-containing medium and whether formation of a pericellular sheath modulated cell motility. PC3 and DU145, but not LNCaP cells formed prominent polarized pericellular sheaths following treatment with prostate fibroblast-conditioned medium. The capacity to assemble a pericellular sheath correlated with the ability to express membranous HA receptor, CD44. HA and versican histochemical staining were observed surrounding PC3 and DU145 cells following treatment with prostatic fibroblast-conditioned medium. The dependence on HA for integrity of the pericellular sheath was demonstrated by its removal following treatment with hyaluronidase. Purified versican or conditioned medium from Chinese hamster ovary K1 cells overexpressing versican V1, but not conditioned medium from parental cells, promoted pericellular sheath formation and motility of PC3 cells. Using time lapse microscopy, motile PC3 cells treated with versican but not non-motile cells exhibited a polar pericellular sheath. Polar pericellular sheath was particularly evident at the trailing edge but was excluded from the leading edge of PC3 cells. These studies indicate that prostate cancer cells recruit stromal components to remodel their pericellular environment and promote their motility.
    Journal of Biological Chemistry 05/2007; 282(14):10814-25. DOI:10.1074/jbc.M606991200 · 4.60 Impact Factor
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    ABSTRACT: Proteoglycans are structural and informational molecules important during embryogenesis and organ maturation. Maturation of the prostate is influenced by androgens and estrogens, but changes in the relative spatiotemporal expression of steroid receptors and proteoglycans during hormonal change are unexplored. Guinea pig prostate was used to define hormone-induced changes in the expression of androgen (AR) and estrogen (ER(alpha)) receptors, chondroitin sulfate (CS) glycosaminoglycan and core proteins of versican and syndecan-1. Tissue locations of AR, ER(alpha), CS and the proteoglycans versican and syndecan-1 were determined by immunohistochemistry. Cellular content of ER(alpha) and syndecan-1 was assessed visually. Versican, CS56 epitope, and AR were quantified by image analysis. AR expression within prostate epithelial and stromal cell nuclei decreased following castration and increased following treatment of castrate animals with dihydrotestosterone (DHT). ER(alpha) expression was restricted to prostate stromal cell nuclei and decreased during puberty, and following treatment of castrate animals with DHT. Versican was present in periacinar stroma immediately peripheral to basal epithelial cells, fibromuscular stromal tissue bands surrounding acinar units, and loose fibrovascular connective tissue interspersed between individual acini. Versican and native CS expression decreased (>10-fold) in periacinar stroma during puberty and following administration of DHT to castrated animals. Expression of syndecan-1 was restricted to fibromuscular cells of prostate stroma, and remained constant during puberty and hormone manipulation. ER(alpha), versican core protein and CS side chain epitopes are negatively regulated in prostate stromal tissue by DHT, whilst AR levels are positively regulated.
    The Prostate 02/2007; 67(3):288-300. DOI:10.1002/pros.20524 · 3.57 Impact Factor
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    ABSTRACT: Although up to 30% of men who undergo radical prostatectomy for clinically organ-confined prostate cancer will relapse with disseminated disease, currently it is not possible to predict these patients. Androgen receptor (AR) immunoreactivity in stromal and epithelial compartments of tumor foci was evaluated by video image analysis in 53 radical prostatectomy specimens. Kaplan-Meier and Cox Regression analyses were used to determine whether AR immunostaining was related to rate and risk of relapse, respectively. Ninety-eight percent (52/53) of the tumors contained AR positive malignant epithelial cells. Kaplan-Meier analysis indicated that patients with high AR levels (>64% AR positive nuclear area) in the malignant epithelial cells or low AR levels (<or=45% AR positive nuclear area) in the peritumoral stroma cells, were more likely to relapse earlier following radical prostatectomy. The shortest time to relapse and the highest relapse rate was for patients with both high AR in the malignant epithelial cells and low AR in the peritumoral stromal cells. These findings suggest that AR is an important determinant of disease relapse in early stage prostate cancer, and that altered AR levels in the malignant epithelial cells or in the peritumoral stroma is indicative of non-organ confined prostate cancer.
    The Prostate 05/2005; 63(1):19-28. DOI:10.1002/pros.20154 · 3.57 Impact Factor

Publication Stats

3k Citations
354.18 Total Impact Points

Institutions

  • 2009–2014
    • University of Adelaide
      • School of Medicine
      Tarndarnya, South Australia, Australia
  • 2012
    • Hanson Institute
      Tarndarnya, South Australia, Australia
  • 2005–2011
    • Royal Adelaide Hospital
      Tarndarnya, South Australia, Australia
  • 1992–2010
    • Repatriation General Hospital
      Tarndarnya, South Australia, Australia
  • 1986–2008
    • Flinders Medical Centre
      Tarndarnya, South Australia, Australia
  • 2001
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1992–2001
    • Flinders University
      • Flinders Medical Centre
      Tarndarnya, South Australia, Australia
  • 1998
    • Methodist Hospitals
      Gary, Indiana, United States
  • 1994
    • University of South Australia
      Tarndarnya, South Australia, Australia