Antiproliferative B cell translocation gene 2 protein is down-regulated post-transcriptionally as an early event in prostate carcinogenesis.

B cell translocation gene 2 (BTG2) is a p53 target that negatively regulates cell cycle progression in response to DNA damage and other stress. The objective of this study was to examine the expression, regulation and tumor suppressor properties of BTG2 in prostate cells. By immunohistochemistry BTG2 protein was detected in approximately 50% of basal cells in benign glands from the peripheral zone of the human prostate. BTG2 was expressed in all hyperproliferative atrophic peripheral zone lesions examined (simple atrophy, post-atrophic hyperplasia and proliferative inflammatory atrophy), but was undetectable or detectable at very low levels in the hyperproliferative epithelial cells of HGPIN and prostate cancer. BTG2 mRNA was detected in non-malignant prostate epithelial (PE) cells and in LNCaP cells, but not in PC-3 cells, consistent with p53-dependent regulation. In PE cells BTG2 protein was detected in areas of cell confluence by immunohistochemistry. BTG2 protein in LNCaP cells was undetectable by immunohistochemistry but was detected by immunoblotting at 8- to 9-fold lower levels than in PE cells. BTG2 protein levels were shown to be regulated by the ubiquitin-proteosome system. Forced expression of BTG2 in PC-3 cells was accompanied by a decreased rate of cell proliferation and decreased tumorigenicity of these cells in vivo. Taken together, these findings suggest that BTG2 functions as a tumor suppressor in prostate cells that is activated by cell quiescence, cell growth stimuli as part of a positive feedback mechanism and in response to DNA damage or other cell stress. The low steady-state levels of BTG2 protein in HGPIN and prostate cancer, a potential consequence of increased proteosomal degradation, may have important implications in the initiation and progression of malignant prostate lesions. Furthermore, these findings suggest that a significant component of the p53 G(1) arrest pathway might be inactivated in prostate cancer even in the absence of genetic mutations in p53.

Prospects for gene therapy in human prostate cancer.

Prostate cancer is the most common neoplasm in men and a significant cause of mortality in affected patients. Despite significant advances, current methods of treatment are effective only in the absence of metastatic disease. Gene therapy offers a renewed hope of using the differential characteristics of normal and malignant tissue in constructing treatment strategies. Several clinical trials in prostate cancer gene therapy are currently under way, using immunomodulatory genes, anti-oncogenes, tumor suppressor genes and suicide genes. A continued understanding of the etiological mechanisms involved in the establishment and progression of prostate cancer, along with advances in gene therapy technology, should make gene therapy for prostate cancer therapeutically valuable in the future.

The etiology of post-radical prostatectomy incontinence and correlation of symptoms with urodynamic findings.

PURPOSE: We evaluated men with post-radical prostatectomy incontinence to determine the incidence of intrinsic sphincter deficiency and bladder dysfunction, and the contribution of each to incontinence. In addition, we determined if subjective symptoms of stress urinary incontinence and urge incontinence correlated with urodynamic findings of intrinsic sphincter deficiency and bladder dysfunction, respectively. MATERIALS AND METHODS: A total of 60 consecutive patients (mean age 64.8 years) were prospectively evaluated with multichannel video urodynamics. All patients were evaluated at least 6 months postoperatively and had achieved a stable level of continence. Patients characterized incontinence as stress or urge related, and stress urinary incontinence was graded from 0 to 3. Intrinsic sphincter deficiency was defined as incontinence associated with increased intraabdominal pressure and was further assessed by Valsalva's leak point pressure. Bladder dysfunction included urodynamic findings of detrusor instability or decreased compliance. RESULTS: Intrinsic sphincter deficiency was demonstrated in 54 patients (90%). Some component of bladder dysfunction was seen in 27 patients (45%), including detrusor instability in 24 and decreased compliance in 3, but incontinence was actually a result of bladder dysfunction in only 16 (27%). Incontinence was due to intrinsic sphincter deficiency alone in 40 patients (67%), intrinsic sphincter deficiency and bladder dysfunction in 14 (23%), and bladder dysfunction alone in only 2 (3%). Incontinence was not demonstrated on video urodynamics in 4 patients (7%). Of the 57 men who complained of stress urinary incontinence 54 demonstrated intrinsic sphincter deficiency for a positive predictive value of 95%. The 3 patients without stress urinary incontinence did not demonstrate intrinsic sphincter deficiency for a negative predictive value of 100%. Positive and negative predictive values for urge incontinence were 44 and 81%, respectively. CONCLUSIONS: Incontinence after radical prostatectomy is associated with intrinsic sphincter deficiency in the overwhelming majority of patients. Bladder dysfunction rarely is an isolated cause. When present on urodynamic tests bladder dysfunction may not always be a significant contributor to incontinence. The symptom of stress urinary incontinence (or its absence) accurately predicts the finding (or absence) of intrinsic sphincter deficiency on urodynamics. Urge incontinence is not as reliable in predicting incontinence due to bladder dysfunction.

Borrelia burgdorferi upregulates expression of adhesion molecules on endothelial cells and promotes transendothelial migration of neutrophils in vitro.

The accumulation of leukocytic infiltrates in perivascular tissues is a key step in the pathogenesis of Lyme disease, a chronic inflammatory disorder caused by Borrelia burgdorferi. During an inflammatory response, endothelial cell adhesion molecules mediate the attachment of circulating leukocytes to the blood vessel wall and their subsequent extravasation into perivascular tissues. Using cultured human umbilical vein endothelial cells (HUVEC) in a whole-cell enzyme-linked immunosorbent assay, we demonstrated that B. burgdorferi activated endothelium in a dose- and time-dependent fashion as measured by upregulation of the adhesion molecules E-selectin, vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1). As few as one spirochete per endothelial cell stimulated increased expression of these molecules. Expression of E-selectin peaked after spirochetes and HUVEC were coincubated for 4 h and returned to near-basal levels by 24 h. In contrast, expression of VCAM-1 and ICAM-1 peaked at 12 h and remained elevated at 24 h. HUVEC monolayers cultured on acellular amniotic tissue were used to investigate the consequences of endothelial cell activation by spirochetes. After incubation of HUVEC-amnion cultures with B. burgdorferi, subsequently added neutrophils migrated across the endothelial monolayers. This process was mediated by E-selectin and by CD11/CD18 leukocytic integrins. The extent of migration depended on both the number of spirochetes used to stimulate the HUVEC and the length of the coincubation period. These results raise the possibility that B. burgdorferi induces a host inflammatory response and accompanying perivascular damage through activation of vascular endothelium.