Faculty Bibliography

Cofactors modulate nuclear receptor activity and impact human health and disease, yet surprisingly little is known about their transcriptional regulation. Androgen receptor trapped clone-27 (ART-27) is a cofactor that binds to androgen receptor (AR) amino terminus and modulates AR-dependent transcription. Interestingly, ART-27 displays both a cell type- and developmental stage-specific expression pattern. However, the cis-acting elements and trans-acting factors affecting ART-27 gene expression have not been elucidated. We found that ART-27 gene expression is repressed and its promoter is histone H3-K27 tri-methylated in human embryonic kidney cells, but not prostate cells, and the histone deacetylase inhibitor, trichostatin A, relieves this inhibition. The DNA response elements that control the induction of ART-27 gene expression were also characterized. The major cis-acting element corresponds to a consensus cAMP-responsive element (CRE) and binds the CRE-binding protein (CREB) as shown by EMSA and chromatin immunoprecipitation assays. Furthermore, ART-27 promoter activity is induced upon CREB overexpression. Epidermal growth factor, which activates CREB via phosphorylation, also induces ART-27 expression, whereas a reduction in CREB phosphorylation or expression blocks this induction in prostate cells. In human prostate development, both epithelial and stromal cells express CREB; however, active phosphorylated CREB is restricted to epithelial cells where ART-27 is expressed. Based on these findings, we propose a transcriptional regulatory circuit for the developmental expression of ART-27 that includes repression by chromatin modification through a trichostatin A-sensitive factor and activation upon growth factor stimulation via CREB

PURPOSE: Men with prostate cancer may live as long as men their age without prostate cancer. Those with low-risk disease may benefit from expectant management, which actively monitors disease progression. Dutasteride, a dual 5alpha-reductase inhibitor (5ARI), may delay prostate cancer progression or extend the time to initiation of more aggressive therapy. MATERIALS AND METHODS: The Reduction by Dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial will evaluate whether dutasteride decreases time to prostate cancer progression. Three hundred candidates for expectant management with biopsy-proven, low-risk, localized prostate cancer will receive dutasteride 0.5 mg/day or placebo for 3 years. Eligible men are between 50 and 80 years of age, have clinical stage T1c-T2a prostate cancer, a Gleason score of less than or equal to 6, and serum prostate-specific antigen (PSA) less than or equal to 10 ng/mL. Entry biopsy of at least 10 cores had to be performed within 6 months of screening and will be repeated at 1.5 and 3 years. Men will complete questionnaires to measure symptoms, quality of life (QOL), and anxiety. Because PSA is an important monitoring tool in expectant management that may impact patients' comfort levels, actual PSA values will be provided to physicians and subjects. Time-to-disease progression (primary therapy for prostate cancer or pathologic progression), positive cores, change in Gleason score, and QOL assessments will be compared between groups. RESULTS: The trial completed recruitment of 302 subjects in March 2007. The study will be completed in 2010. CONCLUSIONS: The REDEEM study will evaluate the potential for dutasteride to delay disease progression in men with low-risk, localized prostate cancer. This study will better define which patients with prostate cancer can be managed with less invasive and potentially less debilitating therapy

OBJECTIVE: To compare the surgical outcomes of elderly patients with renal masses treated with laparoscopic partial nephrectomy (LPN) or laparoscopic cryoablation (LCA). PATIENTS AND METHODS: All 15 patients who had LCA at the authors' institution between May 2003 and July 2005 were included, and compared with a matched cohort of 15 patients selected by patient age and tumour size, from a pre-existing database of 104 patients who had LPN from July 2002 to July 2005. The two groups were compared for gender, number of comorbidities, American Society of Anesthesiologists status (ASA), body mass index (BMI), baseline renal function and haematocrit, location and size of lesion, length of stay, operative time, estimated blood loss (EBL), transfusion rate, number and type of complications, conversion rate, and postoperative renal function and haematocrit. RESULTS: The two groups were similar in age, sex, BMI, ASA, baseline renal function, haematocrit, size and side of tumour, the percentage of exophytic tumours, and the likelihood of more than one comorbidity. Surgical outcomes between the groups were also relatively similar. The length of stay, creatinine and haematocrit levels after surgery did not differ between the groups. The LPN group had a significantly longer operation (248 vs 152 min, P < 0.001) and higher EBL (222 vs 59 mL, P = 0.007) than the LCA group, but only one patient required a transfusion and there was no discernible difference in discharge haematocrit values. No recurrences were detected in either group, with a similar mean follow-up of 9.8 and 11.9 months, respectively. CONCLUSION: Although this matched-cohort comparison showed that LPN had a higher mean EBL, a longer operation and higher relative risk of open conversion, the overall clinical outcome was similar in terms of complication rates, length of stay and changes in creatinine and haematocrit after surgery. In this small retrospective evaluation, there was similar morbidity, treatment outcome and short-term efficacy with LCA and LPN. At present, although still experimental, LCA is a good choice for elderly patients with comorbidities precluding blood loss or renal ischaemia. However, in experienced hands, LPN is a preferred option for most elderly patients and should be considered when contemplating definitive treatment of renal masses