The activation of the Ras-related GTPase R-Ras, which has been implicated in the regulation of various cellular functions, by G protein-coupled receptors (GPCRs) was studied in HEK-293 cells stably expressing the M3 muscarinic acetylcholine receptor (mAChR), which can couple to several types of heterotrimeric G proteins. Activation of the receptor induced a very rapid and transient activation of R-Ras. Studies with inhibitors and activators of various signaling pathways indicated that R-Ras activation by the M3 mAChR is dependent on cyclic AMP formation but is independent of protein kinase A. Similar to the rather promiscuous M3 mAChR, two typical G(s)-coupled receptors also induced R-Ras activation. The receptor actions were mimicked by an Epac-specific cyclic AMP analog and suppressed by depletion of endogenous Epac1 by small interfering RNAs, as well as expression of a cyclic AMP binding-deficient Epac1 mutant, but not by expression of dominant negative Rap GTPases. In vitro studies demonstrated that Epac1 directly interacts with R-Ras and catalyzes GDP/GTP exchange at this GTPase. Finally, it is shown that the cyclic AMP- and Epac-activated R-Ras plays a major role in the M3 mAChR-mediated stimulation of phospholipase D but not phospholipase C. Collectively, our data indicate that GPCRs rapidly activate R-Ras, that R-Ras activation by the GPCRs is apparently directly induced by cyclic AMP-regulated Epac proteins, and that activated R-Ras specifically controls GPCR-mediated phospholipase D stimulation.

The combination of docetaxel and ifosfamide is active in previously treated patients with urothelial cancer, although it appears to be a reasonable treatment option only in those with lymph node dominant recurrence. The mild toxicity underlines the usefulness of the regimen in this setting. Further investigation of the combination in previously untreated patients seems warranted.

Prostate cancer is the most frequent cancer in males. Because of the high cure rates, early detection of prostate cancer should identify organ-confined prostate cancers. An early detection examination should be performed annually starting at the age of 50 years and ending when life expectancy is less than 10 years. Digital rectal examination is supplemented by determination of prostate-specific antigen (PSA). Before the first PSA test, the patient must be informed of possible consequences such as biopsy recommendation and treatment options. A threshold of 4 ng/ml is defined as the indication for prostate biopsy. Imaging methods do not play a major role in early detection of prostate cancer today. Early detection identifies many latent prostate cancers, and patients may receive overtreatment. A possible solution is to change the early detection paradigm from detection of all prostate cancers to identification of aggressive ones. In this article, early detection is discussed based on the recent literature.

Introduction: Cystoscopy and cytology are standard procedures for diagnosis and follow-up of patients with bladder cancer. Urinary cytodiagnosis is a descriptive method for tumor characterization. We correlated histopathologic diagnosis of noninvasive urothelial carcinomas with cytological evaluation and, furthermore, we validated cytology by cytometric analysis. Patients and Methods: 94 patients with a history of bladder cancer were included in the study. 25 patients were negative for tumors, 22 showed pTa G1 carcinomas, 25 had pTaG2 and 22 patients had G3 carcinomas. All patients underwent cytological and cytometric evaluation. Nuclear diameter and circumference were measured for 15 representative nuclei per specimen. Statistical evaluation was performed using Graph Pad Software. Results: Cytology showed excellent tumor detection for G2 and G3 carcinomas, with a sensitivity of 100% combined with a specificity of 100%. Using cytometry, we can significantly distinguish between unsuspicious patients and G1 carcinomas on the one hand and high-grade carcinomas on the other. Furthermore, in 6 of 25 patients (24%) with noninvasive G2 carcinomas, but G3 cytological evaluation, tumor progression occurred. Conclusions: Urinary cytology is an excellent instrument for detection of clinically relevant high-grade bladder cancer. Descriptive alterations of the cytopathology can be validated by objective data using cytometric analysis.

Background: It is common to start with PSA (prostate-specific antigen)-testing at the age of 50. If patients with a PSA value greater than 4 ng/mL should be considered for prostate biopsy, approximately 20% of all men undergoing test are considered for biopsy at the time of first early-detection examination.Methods: We have screened 2,592 asymptomatic men younger than 45 years. With a short questionnaire, we assessed age, body mass index (BMI), concomitant diseases, last sexual intercourse, and last bicycle riding. We compared this cohort with a group of 11,656 men aged 45-75 years from a nationwide prostate cancer screening trial.Results: In this cohort, only 4 men with a PSA value greater than 4 ng/mL and 10 with a PSA greater than 3 ng/mL were identified. More than 99% of all men younger than 45 years had a PSA lesser than 4 ng/mL. Sexual intercourse, bicycle riding, or BMI had a significant but minimal influence on the PSA value.Conclusions: It is reasonable to start with PSA testing at the age of 40 years. The advantage of screening younger patients is that almost no one should be considered for biopsy at the time of first early-detection examination. We identified a baseline value at which only a minimal influence was exerted by benign prostatic hypertrophy. In comparison with many current guidelines, we gained a lead time of 10 years for observation of PSA dynamics.Impact: The importance of PSA velocity for stratification of patients at risk for development of significant prostate cancer will grow. Cancer Epidemiol Biomarkers Prev; 20(6); 1190-5. Ó2011 AACR.