Concurrent EAF2 and ELL2 loss phenocopies individual EAF2 or ELL2 loss in prostate cancer cells and murine prostate.

Elongation factor for RNA polymerase II 2 (ELL2) and ELL-associated factor 2 (EAF2) are two functionally related androgen responsive gene-encoded proteins with prostate tumor suppressor characteristics. EAF2 and ELL2 have both been shown to be down-regulated in advanced prostate cancer, and mice with either Eaf2 or Ell2 deficiency developed murine prostatic intraepithelial neoplasia (mPIN), increased cellular proliferation and increased vascularity. Functional studies have revealed that EAF2 and ELL2 can bind to each other and have similar roles in regulating cell proliferation, angiogenesis and prostate homeostasis. Here, cell line experiments showed that knockdown of EAF2 or ELL2 induced an increase in proliferation and migration in C4-2 and 22Rv1 prostate cancer cells. Concurrent knockdown of EAF2 and ELL2 increased proliferation and migration similarly to the loss of EAF2 or ELL2 alone. Mice with homozygous deletion of Ell2 or heterozygous deletion of Eaf2 developed mPIN lesions characterized by increased epithelial proliferation, intraductal microvessel density, and infiltrating intraductal CD3-positive T-cells compared to wild-type controls. Mice with combined heterozygous deletion of Eaf2 and Ell2 developed mPIN lesions that were similar to those observed in mice with deficiency in Eaf2 or Ell2 alone. These results suggest that EAF2 and ELL2 have similar functions and are likely to require each other in their regulation of prostate epithelial cell proliferation and migration in prostate cancer cells as well as their tumor suppressive properties in the murine prostate.

Salvage Surgery After Renal Mass Ablation.

Thermal ablative techniques represent treatment options for patients with small renal masses who are not candidates for surgery. The oncologic efficacy of ablation has not been compared in a randomized fashion with nephron-sparing surgery, and the urologist must be knowledgeable regarding the workup and treatment of patients with suspected residual or recurrent tumor following these therapies. Surveillance of patients with tumor recurrence after ablation may be indicated in select circumstances. When patients are deemed appropriate for salvage therapy, most undergo a repeat course of the same ablative modality. Salvage surgery is possible but often complicated by the prior ablative techniques.

Minimally Invasive Versus Open Approach for Cystectomy: Trends in the Utilization and Demographic or Clinical Predictors Using the National Cancer Database.

OBJECTIVE: To examine temporal national trends of operative approach for cystectomy and identify demographic or clinical predictive factors that influence choice of approach. METHODS: We performed a retrospective cohort study of patients who underwent cystectomy for bladder cancer between 2010 and 2013 using the National Cancer Database. Approach was stratified by open vs minimally invasive (robotic or laparoscopic). Univariate Pearson chi-square and multivariate logistic regression analysis were used to assess the relationships between demographic and hospital factors and the receipt of minimally invasive or open surgical approach. RESULTS: A total of 9439 patients met our inclusion criteria, of which 34.1% received a minimally invasive approach (MIA). Frequency of MIA increased from 26.3% in 2010 to 39.4% in 2013 (P < .0001). Univariate analysis identified statistically significant associations between year of diagnosis, sex, age, race, clinical T stage, insurance status, income, education, distance from hospital, facility type, geographic location, and facility cystectomy volume, and the choice of approach (all P < .01). On multivariate analysis, independent predictors of MIA included increasing year of diagnosis, male gender, lower clinical T stage, private insurance vs Medicaid, nonacademic vs academic program, northeastern geographic region, receipt of neoadjuvant chemotherapy, and lower cystectomy volume. CONCLUSION: Utilization of MIA for cystectomy has increased nationally over the last several years likely due to increased surgeon familiarity with robotic laparoscopic pelvic surgery. Factors associated with MIA included male sex, locally confined disease, receipt of neoadjuvant chemotherapy, lower cystectomy volume centers, and nonacademic centers.

Preoperative Erythrocyte Sedimentation Rate Independently Predicts Overall Survival in Localized Renal Cell Carcinoma following Radical Nephrectomy.

Objectives. To determine the relationship between preoperative erythrocyte sedimentation rate (ESR) and overall survival in localized renal cell carcinoma (RCC) following nephrectomy. Methods. 167 patients undergoing nephrectomy for localized RCC had ESR levels measured preoperatively. Receiver Operating Characteristics curves were used to determine Area Under the Curve and relative sensitivity and specificity of preoperative ESR in predicting overall survival. Cut-offs for low (0.0-20.0 mm/hr), intermediate (20.1-50.0 mm/hr), and high risk (>50.0 mm/hr) groups were created. Kaplan-Meier analysis was conducted to assess the univariate impact of these ESR-based groups on overall survival. Univariate and multivariate Cox regression analysis was conducted to assess the potential of these groups to predict overall survival, adjusting for other patient and tumor characteristics. Results. Overall, 55.2% were low risk, while 27.0% and 17.8% were intermediate and high risk, respectively. Median (95% CI) survival was 44.1 (42.6-45.5) months, 35.5 (32.3-38.8) months, and 32.1 (25.5-38.6) months, respectively. After controlling for other patient and tumor characteristics, intermediate and high risk groups experienced a 4.5-fold (HR: 4.509, 95% CI: 0.735-27.649) and 18.5-fold (HR: 18.531, 95% CI: 2.117-162.228) increased risk of overall mortality, respectively. Conclusion. Preoperative ESR values represent a robust predictor of overall survival following nephrectomy in localized RCC.

S-adenosyl-L-methionine inhibits collagen secretion in hepatic stellate cells via increased ubiquitination.

BACKGROUND: Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) components that disrupt normal liver microcirculation and lead to organ injury. Hepatic stellate cells (HSCs), following transdifferentiation, are the central mediators of hepatic fibrosis through increased secretion of ECM components, including type I collagen. AIMS: The mechanism(s) by which the antioxidant S-adenosyl-L-methionine (SAMe) acts to modulate type I collagen secretion in activated HSCs was examined. METHODS: Hepatic stellate cells were culture-activated for 13-15 days and treated with SAMe. Type I collagen, proteasomal activity and resident endoplasmic reticulum (ER) protein [78-kDa glucose-regulated protein (Grp78) and protein disulphide isomerase (PDI)] expression were measured. Nuclear factor-κB (NF-κB) activity, and its role in SAMe-mediated collagen inhibition, was determined. Type I collagen polyubiquitination was examined. RESULTS: S-adenosyl-L-methionine significantly inhibited type I collagen secretion without significant changes in type I collagen mRNA expression. SAMe also increased NF-κB activity, and blocking NF-κB activity using a dominant-negative IκBα abolished the SAMe-mediated type I collagen secretion. Examination of the post-transcriptional fate of procollagen demonstrated that SAMe treatment led to intracellular type I collagen polyubiquitination accompanied by diminution of proteasomal activity. Expression of Grp78 and PDI (resident ER proteins) were significantly decreased by SAMe treatment. CONCLUSIONS: S-adenosyl-L-methionine inhibits collagen processing leading to increased ubiquitination and decreased secretion. These findings represent a novel mechanism for modulating type I collagen expression in activated HSCs.