Faculty Bibliography

Although ras is a potent mitogenic oncogene, its tumorigenicity depends on cellular context and cooperative events. Here we show that low-level expression of a constitutively active Ha-ras in mouse urothelium induces simple urothelial hyperplasia that is resistant to progression to full-fledged bladder tumors even in the absence of Ink4a/Arf. In stark contrast, doubling of the gene dosage of the activated Ha-ras triggered early-onset, rapidly growing, and 100% penetrant tumors throughout the urinary tract. Tumor initiation required superseding a rate-limiting step between simple and nodular hyperplasia, the latter of which is marked by the emergence of mesenchymal components and the coactivation of AKT and STAT pathways as well as PTEN inactivation. These results indicate that overactivation of Ha-ras is both necessary and sufficient to induce bladder tumors along a low-grade, noninvasive papillary pathway, and they shed light on the recent findings that ras activation, via point mutation, overexpression, or intensified signaling from FGF receptor 3, occurs in 70%-90% of these tumors in humans. Our results highlight the critical importance of the dosage/strength of Ha-ras activation in dictating its tumorigenicity - a mechanism of oncogene activation not fully appreciated to date. Finally, our results have clinical implications, as inhibiting ras and/or its downstream effectors, such as AKT and STAT3/5, could provide alternative means to treat low-grade, superficial papillary bladder tumors, the most common tumor in the urinary system

The evolution of alpha blocker therapy for benign prostatic hyperplasia (BPH) has focused on improving convenience and tolerability. Indications for treating BPH include reversing signs and symptoms or preventing progression of the disease. The indication that most commonly drives the need for intervention is relief of lower urinary tract symptoms (LUTS) with the intent of improving quality of life. Alpha blockers are the most effective, least costly, and best tolerated of the drugs for relieving LUTS. Four long-acting alpha 1 blockers are approved by the Food and Drug Administration for treatment of symptomatic LUTS/BPH: terazosin, doxazosin, tamsulosin, and alfuzosin. All are well tolerated and have comparable dose-dependent effectiveness. Tamsulosin and alfuzosin SR do not require dose titration. Alfuzosin, terazosin, and doxazosin have all been shown to be effective in relieving LUTS/BPH independent of prostate size

Spontaneous renal artery dissection (SRAD) is a rare event, and thus may be a challenge for physicians to diagnose and treat. We report a case of SRAD in a healthy 56-year-old male who presented with flank pain, fever, and elevated white blood cell count. The patient was initially diagnosed with nephrolithiasis versus pyelonephritis and was admitted for observation. Multiple imaging modalities, including non-contrast computed tomography (CT), magnetic resonance imaging (MRI) with gadolinium, CT angiogram, and intraoperative angiogram, were used to make the final diagnosis of SRAD. The patient was treated with endovascular stent placement and is currently free of pain with normal laboratory values and blood pressure

This article reviews the issues and controversies relevant to the treatment of advanced prostate cancer with androgen deprivation therapy. Initially, diethylstilbestrol was used for achieving androgen deprivation, but was replaced by luteinizing hormone-releasing hormone (LHRH). Adverse events associated with LHRH agonists include the flare phenomenon, hot flashes, loss of libido, erectile dysfunction, depression, muscle wasting, anemia, and osteoporosis. Intermittent therapy has been advocated to reduce morbidity of treatment. The addition of an antiandrogen provides maximum androgen blockade. There remains controversy regarding the timing of the addition of an antiandrogen. Secondary hormonal therapies include antiandrogens, adrenal androgen inhibitors, and estrogens

PURPOSE: We identified factors that predict return to part-time and full-time work and resumption of unlimited physical activity following open radical retropubic prostatectomy. MATERIALS AND METHODS: Between July 1, 2002 and February 28, 2005, 537 men with clinically localized prostate cancer underwent open radical retropubic prostatectomy, as performed by a single surgeon. Intraoperative, perioperative and postoperative parameters were recorded in real time and entered into a database. An assessment was made 1 and 3 months postoperatively regarding time to return to work and unrestricted physical activity. RESULTS: Of the men 50% returned to part-time and full-time work, and unrestricted activity within 14, 21 and 30 days after discharge home, respectively. Patient age and hematocrit at hospital discharge significantly predicted return to part-time and full-time work, and unlimited physical activity. The number of days that the urinary catheter was indwelling was also associated with return to part-time work. Occupation (blue vs white collar) and marital status were also associated with return to full-time work. In the multivariate model a unit increase in hematocrit decreased the time to return to part-time and full-time work, and unrestricted physical activity by 0.50, 0.60 and 0.59 days, respectively. Men with discharge hematocrit greater than 32% were 1.57 (p = 0.059), 1.65 (p = 0.041) and 2.03 (p = 0.002) times more likely to return to part-time and full-time work, and unlimited activity before 14, 21 and 30 days, respectively. Overall models were developed that accounted for 9.4%, 14.0% and 4.0% of the time to return to part-time work, full-time work and unrestricted physical activity, respectively. CONCLUSIONS: Efforts to increase discharge hematocrit by minimizing intraoperative blood loss or using preoperative blood management strategies and earlier removal of the urinary catheter have a favorable impact on the return to work and physical activity

Prostate carcinoma and benign prostatic hypertrophy may both originate in stem cells, highlighting the importance of the characterization of these cells. The prostate gland contains a network of ducts each of which consists of a proximal (adjacent to the urethra), an intermediate, and a distal region. Here, we report that two populations of cells capable of regenerating prostatic tissue in an in vivo prostate reconstitution assay are present in different regions of prostatic ducts. The first population (with considerable growth potential) resides in the proximal region of ducts and in the urethra, and the survival of these cells does not require the presence of androgens. The second population (with more limited growth potential) is found in the remaining ductal regions and requires androgen for survival. In addition, we find that primitive proximal prostate cells that are able to regenerate functional prostatic tissue in vivo are also programmed to re-establish a proximal-distal ductal axis. Similar to their localization in the intact prostate, cells with the highest regenerative capacity are found in the proximal region of prostatic ducts formed in an in vivo prostate reconstitution assay. The primitive proximal cells can be passaged through four generations of subrenal capsule grafts. Together, these novel findings illustrate features of primitive prostate cells that may have implications for the development of therapies for treating proliferative prostatic diseases