Reactivation of androgen receptor (AR) appears to be the major mechanism driving the resistance of castration-resistant prostate cancer (CRPC) to second-generation antiandrogens and involves AR overexpression, AR mutation, and/or expression of AR splice variants lacking ligand-binding domain. There is a need for novel small molecules targeting AR, particularly those also targeting AR splice variants such as ARv7. A high-throughput/high-content screen was previously reported that led to the discovery of a novel lead compound, 2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)-1-(4-(2,3-dimethylphenyl)piperazin-1-yl)ethan-1-one (IMTPPE), capable of inhibiting nuclear AR level and activity in CRPC cells, including those resistant to enzalutamide. A novel analogue of IMTPPE, JJ-450, has been investigated with evidence for its direct and specific inhibition of AR transcriptional activity via a pulldown assay and RNA-sequencing analysis, PSA-based luciferase, qPCR, and chromatin immunoprecipitation assays, and xenograft tumor model 22Rv1. JJ-450 blocks AR recruitment to androgen-responsive elements and suppresses AR target gene expression. JJ-450 also inhibits ARv7 transcriptional activity and its target gene expression. Importantly, JJ-450 suppresses the growth of CRPC tumor xenografts, including ARv7-expressing 22Rv1. Collectively, these findings suggest JJ-450 represents a new class of AR antagonists with therapeutic potential for CRPC, including those resistant to enzalutamide.

Bisphosphonates for Osteoporosis in Nonmetastatic Prostate Cancer Patients Receiving Androgen-deprivation Therapy: A Systematic Review and Meta-analysis Bisphosphonates;osteoporosis;prostate cancer;androgen-deprivation therapy;meta-analysis; This systematic review was conducted to assess the efficacy and safety of bisphosphonates for prevention and treatment of osteopenia or osteoporosis in men with non-metastatic prostate cancer receiving androgendeprivation therapy. We searched for randomised controlled trials (RCTs) of bisphosphonates compared with placebo from Pubmed, Embase, the Cochrane Library, and ISI - Science Citation Index. Meta-analyses of prespecified outcomes (bone mineral density, fractures, and adverse events) were performed using Review Manager. Ten RCTs with a total patient population of 1,017 were identified. There was generally more improvement in bone mineral density of the lumbar spine for patients who received bisphosphonate treatment than placebo or other medical treatment at 12 months (WMD 6.02,95%CI 5.39 to 6.65). Similar effects were also observed for total hip, trochanter or femoral neck bone mineral density. However, there was no significant reduction in fractures. Fever and gastrointestinal symptoms were the most common adverse events (10.4% vs. 1.2%; 0.10% vs. 0.03%). Currently, our meta-analysis suggested that oral and intravenous bisphosphonates caused a rapid increase in spine and hip or femoral BMD in non-metastatic prostate cancer patients receiving androgen-deprivation therapy. Fever and gastrointestinal symptoms were common with the use of bisphosphonates. These short-term trials (maximum of 12 months) did not show fracture reduction. In future, more efficient performance of higher quality, more rigorous, large sample, long-term randomised controlled trials (>12 months) are needed where outcomes are detailed.

To evaluate the efficacy of Silodosin as a medical expulsive therapy of ureteral stones, we searched PubMed, EMBASE, the Cochrane Library, and CBM up to June 2015. All randomized controlled trials (RCTs) were identified in which patients were randomized to receive Silodosin versus placebo or other therapies for ureteral stones. Outcome measures assessed were overall stone expulsion rate (primary) and expulsion time, analgesics times, and the incidence of additional treatment and regarding treatment complications (secondary). Two authors independently assessed study quality and extracted data. All data were analyzed using RevMan 5.3. Seven RCTs with a total of 1035 patients met the inclusion criteria. The pooled meta-analysis showed a significant improvement in stone clearance with Silodosin (Silodosin versus placebo, OR =1.69, 95% CI [1.19–2.40], p = 0.003; Silodosin versus tamsulosin, OR =2.82, 95% CI [1.79–4.44], p < 0.00001). According to the size and location of ureteral stone, the pooling effects of Silodosin were analyzed, with a meaningful expulsion rate in distal ureteral stone when the size was 5–10 mm. In addition, a shorter expulsion time, fewer analgesics times, and additional treatments were observed. The common side effect was retrograde ejaculation. In summary, Silodosin appears to be more effective than either placebo or tamsulosin. Within the limits of available data, high-quality multicenter RCTs are needed to thoroughly evaluate the outcome in the future.

Introduction: We conducted a systematic review and meta-analysis to assess the available literature regarding the postoperative effects of anti-reflux anastomosis and direct anastomosis in orthotopic ileal neobladder (ONB). Methods: We searched PubMed, Embase, and the Cochrane Library in October 2021. We included 11 studies of patients with bladder cancer who underwent radical cystectomy and ONB as urinary diversion. Outcomes evaluated in this review were ureteroenteric anastomotic stricture (UEAS), vesicoureteral reflux, renal function (RFn) impairment, and pyelonephritis. All data were analyzed using Review Manager 5.4.4 and subgroup analyses were applied. Results: A total of 11 studies were eligible for meta-analysis. The synthetic data suggested that anti-reflux anastomosis and direct anastomosis were comparable in terms of RFn impairment (odds ratio (OR) = 1.69; 95% confidence interval (CI): 0.18–15.6; p = 0.65, I² = 69%) and pyelonephritis (OR = 1.13; 95% CI: 0.65–1.99; p = 0.66, I² = 1%) without significant difference in each group statistically. The pooled study data showed a significantly higher incidence of UEAS (OR = 2.84; 95% CI: 1.75–4.61, p < 0.0001, I² = 50%) and a lower incidence of vesicoureteral reflux (OR = 0.24; 95% CI: 0.10–0.59; p = 0.002, I² = 75%) in anti-reflux anastomosis compared to direct anastomosis. In subgroup analysis, anti-reflux anastomosis was more likely to result in UEAS than direct anastomosis, especially when ureteral stent was removed within 14 days. Conclusion: Although meta-analysis showed that overall incidence of vesicoureteral reflux was higher with direct anastomosis than anti-reflux anastomosis, the rate of vesicoureteral reflux was not directly related to impairment of RFn. The anti-reflux mechanism of ONB was positively associated with a higher incidence of significant UEAS compared to the direct approach, which can lead to kidney damage and an increased risk of secondary surgical procedures.