tom@pelhamcourt.clara.co.uk Introduction Epigenetic silencing mechanisms are increasingly thought to play a major role in the development of human cancers, including prostate cancer. The two major epigenetic regulatory mechanisms involve alterations in DNA methylation and histone acetylation status. Promoter CpG island hypermethylation and histone hypoacetylation, catalysed by DNA methyltransferase (DNMT) and histone deacetylase (HDAC) respectively, are associated with transcriptional repression. Evidence in other cancers suggests the two mechanisms are dynamically linked, yet few studies have examined the potential interaction of the two pathways in prostate cancer. Here we report a synergistic, apoptotic effect of treatment with a demethylating agent and a histone deacetylase inhibitor on cultured prostate cancer cells, with associated re-expression of the putative antiproliferative agent oestrogen receptor beta.Methods LNCaP, DU-145 and PC-3 cells were pre-treated with the DNMT inhibitor 5'-aza-2'-deoxycytidine (5-AZAC) for 72 hours followed by 24 hours combined treatment with 5-AZAC and the HDAC inhibitor trichostatin A (TSA). Following treatment, cells were either processed for cell proliferation, cell toxicity, cell viability and apoptosis assays, or harvested for quantitative real-time RT-PCR gene expression analyses. Assessed target genes were oestrogen receptor beta (ERβ), androgen receptor (AR), progesterone receptor (PGR) and prostate specific antigen (PSA). ResultsIn all cell-lines co-treatment with 5-AZAC and TSA was associated with significantly reduced cell proliferation when compared with control groups (p<0.05); associated reduced cell viability and increased cell death was seen in all cases. Caspase activation was significantly increased in the co-treatment group, indicating that apoptosis was a major mechanism of cell death. Most marked effects were seen in the androgen-dependent, AR-positive LNCaP cell-line. In all cell-lines a marked synergistic re-expression of ERβ was identified in the co-treatment group, a finding which was not seen for either AR or PSA. A similar re-expression of PGR was also identified. ConclusionsAt concentrations associated with gene re-expression, the DNA demethylating agent 5-AZAC and the HDAC inhibitor TSA co-operate in an additive and synergistic way to induce apoptosis in prostate cancer cell-lines. Increased apoptosis in the co-treatment group was associated with marked re-expression of ERβ, which is an intriguing finding, raising the possibility of further targeting of prostate cancer cells with ERβ-selective agents such as phytooestrogens and selective oestrogen receptor modulators (SERMs).

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Nineteen patients with Peyronie's disease were treated by a modification of Nesbit's operation. The deformity was completely corrected in 18 patients. Potency was restored to 4 of the 6 impotent patients and satisfactory coitus became possible for 15 patients, whereas it had been possible for only 3 before operation.

Fifty-five patients with chronic urinary retention and incipient or actual renal failure were studied. In the majority of patients renal function improved after bladder decompression, irrespective of whether or not a diuresis occurred. Excessive loss of salt and water was rarely a matter of concern and most patients did not require intravenous fluid replacement. Several lost weight and experienced a fall in blood pressure during the period of diuresis without adverse effect upon renal functional recovery. A profound fall in blood pressure occurred in only three patients, all of whom required long-term sodium supplementation. It is concluded that the problem of salt and water loss after bladder decompression in patients with renal failure is exaggerated and difficult to predict. Over-enthusiastic replacement of fluid in strict accordance with output could readily lead to fluid overload and prolongation of the diuretic period. Therefore fluid replacement should be determined by the clinical condition of the patient and measurement of improving renal function with less emphasis on urine output and its electrolyte content.

Plasma testosterone, oestradiol, luteinising hormone (LH) growth hormone and prolactin were measured serially in 140 patients with advanced prostatic carcinoma (T3, T4, MI and MO) randomised in a trial of diethylstilboestrol 3 mg/day against estramustine 560 mg/day. Both drugs suppressed plasma testosterone and LH and increased plasma growth hormone and prolactin, though estramustine induced a greater rise in prolactin. Oestradiol levels fell on stilboestrol but were considerably elevated on estramustine. Initial hormone levels reflected neither the extent of disease nor the response to treatment. The data also showed that close attention should be given to plasma LH in identifying patients who are unreliable, since intermittent hormone dosage caused an exaggerated rise even when plasma testosterone remained at castrate levels.

The morphological response of the bladder surface to acute and chronic urinary tract infection (UTI) was investigated using both scanning and transmission electron microscopy of bladder biopsies taken during routine cystoscopy. Acute bacterial infection only minimally altered bladder epithelium, whereas in chronic infections the surface layers showed gross changes which included loss of the outer layers of epithelial cells and alteration of the bladder contour. In addition, more erythrocytes and polymorphonucleocytes were present in chronic infection. In both acute and chronic urinary infection, bacteria were confined to a limited number of sites on the bladder surface and appeared to be arranged in microcolonies, but more bacteria were attached to bladder surfaces in chronic than in acute UTI. These findings were confirmed by studying epithelial cells shed from patients with proven urinary infections. A few patients who had been treated with antibiotics before cystoscopy and biopsy were also studied. These antibiotics included cephalosporins which had been previously shown to produce bacterial morphological variations in vitro. Some of these changes were subsequently observed in the biopsies and the results suggest mechanisms whereby bacteria involved in urinary tract infection can survive exposure to antibiotics.

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The influence of human leucocyte antigen (HLA) matching on the incidence of acute rejection and graft survival was examined in 181 consecutive patients receiving cadaveric renal transplants. Allografts with better HLA-DR and HLA-B matching showed significantly lower rejection rates than less well matched grafts on both univariate (rejection rates 25, 62 and 82 per cent for zero, one and two DR mismatches; P < 0.001) and multivariate analysis. Rejection episodes occurred earlier in mismatched grafts (P < 0.001). Superior matching was associated with improved graft function at 1 year after transplantation (mean serum creatinine level 137, 180 and 225 mumol l-1 for zero, one and two DR mismatches; P < 0.05). No association was, however, demonstrated between the degree of matching and overall graft survival. Good HLA matching reduces the number of acute rejection episodes, producing significant savings in drug costs and hospital stay. Long-term graft function is improved and minimizing early graft damage helps to avoid later development of chronic rejection.