Stichoposide C and Rhizochalin as Potential Aquaglyceroporin Modulators.

Aquaporins (AQPs) are a family of integral membrane proteins that selectively transport water and glycerol across the cell membrane. Because AQPs are involved in a wide range of physiological functions and pathophysiological conditions, AQP-based therapeutics may have the broad potential for clinical utility, including for disorders of water and energy balance. However, AQP modulators have not yet been developed as suitable candidates for clinical applications. In this study, to identify potential modulators of AQPs, we screened 31 natural products by measuring the water and glycerol permeability of mouse erythrocyte membranes using a stopped-flow light scattering method. None of the tested natural compounds substantially affected the osmotic water permeability. However, several compounds considerably affected the glycerol permeability. Stichoposide C increased the glycerol permeability of mouse erythrocyte membranes, whereas rhizochalin decreased it at nanomolar concentrations. Immunohistochemistry revealed that AQP7 was the main aquaglyceroporin in mouse erythrocyte membranes. We further verified the effects of stichoposide C and rhizochalin on aquaglyceroporins using human AQP3-expressing keratinocyte cells. Stichoposide C, but not stichoposide D, increased AQP3-mediated transepithelial glycerol transport, whereas the peracetyl aglycon of rhizochalin was the most potent inhibitor of glycerol transport among the tested rhizochalin derivatives. Collectively, stichoposide C and the peracetyl aglycon of rhizochalin might function as modulators of AQP3 and AQP7, and suggests the possibility of these natural products as potential drug candidates for aquaglyceroporin modulators.

Adjuvant Low-dose Statin Use after Radical Prostatectomy: The PRO-STAT Randomized Clinical Trial.

PURPOSE: Statin use is reportedly associated with the risk of prostate cancer, outcomes after treatment, and prostate cancer-specific mortality. We sought to determine the efficacy of adjuvant atorvastatin in prostate cancer after radical prostatectomy. PATIENTS AND METHODS: In this randomized, double-blind trial, we assigned patients with pathologic high-risk prostate cancer to receive either low-dose atorvastatin (20 mg/day, n = 183) or placebo (n = 181) for 1 year after radical prostatectomy. The primary endpoint was the 1-year biochemical recurrence rate. The secondary endpoints included the 5-year biochemical recurrence-free survival and changes in lipid, testosterone, and sex hormone binding globulin levels. RESULTS: From October 2012 through January 2019, a total of 364 patients underwent randomization. Among 59 total primary end points, 30 (16.4%) and 29 (16.0%) occurred in the atorvastatin and placebo groups, respectively. Atorvastatin did not significantly reduce the primary endpoint of 1-year biochemical recurrence [HR, 0.96; 95% confidence interval (CI), 0.58-1.60]. During a median follow-up of 24 months, 131 patients experienced biochemical recurrence (68 in the atorvastatin group and 63 in the placebo group), representing Kaplan-Meier estimated event rates of 24.0% and 25.4% in the atorvastatin and placebo groups, respectively, at 24 months (HR, 1.00; 95% CI, 0.71-1.41). We observed no significant between-group differences in the testosterone and sex hormone binding globulin levels. CONCLUSIONS: Among patients with high-risk pathologic features after radical prostatectomy for prostate cancer, 1-year adjuvant use of atorvastatin was not associated with a lower risk of disease recurrence compared with that for placebo. (ClinicalTrials.gov number, NCT01759836).See related commentary by Murtola and Siltari, p. 4947.

A randomized controlled comparison between periprostatic nerve block and pelvic plexus block at the base and apex of 14-core prostate biopsies.

PURPOSE: To compare the pain control efficacies of the pelvic plexus block (PPB), periprostatic nerve block (PNB), and controls during a 14-core basal and apical core prostate biopsy. METHODS: This randomized controlled study, performed between January 2015 and January 2016, included patients with an abnormal serum prostate-specific antigen (PSA > 3 ng/mL) level or a palpable nodule on digital rectal examination. The enrolled patients were randomized into three groups: Group 1, intrarectal local anesthesia (IRLA, 10 mL of 2% lidocaine jelly) and PPB with 3.0 mL of 2% lidocaine injected at the bilateral pelvic plexus; Group 2, IRLA and PNB with 3.0 mL of 2% lidocaine injected at both periprostatic nerves; and Group 3, only IRLA. Patients answered the visual analog scale (VAS) questionnaire at 6 time points. RESULTS: This study consisted of 163 patients (Group 1 = 55, Group 2 = 55, and Group 3 = 53). Pain at the apical biopsy location was less in Groups 1 and 2 than in Group 3 (p < 0.001, p < 0.001) and between the two local anesthetic groups (PNB + IRLA vs PPB + IRLA). Group 2 patients reported less pain than Group 1 patients (p = 0.022). Pain during the basal core biopsy was significantly less in Groups 1 and 2 than in Group 3 (p = 0.002, p < 0.001), but there were no significant differences in pain control between the two methods (PNB + IRLA vs PPB + IRLA, p = 0.054) during basal core biopsy. CONCLUSIONS: PNB + IRLA is an effective local anesthetic method for reducing pain when performing apical biopsies compared with PPB + IRLA or IRLA alone.

Loss of Aquaporin-3 in Placenta and Fetal Membranes Induces Growth Restriction in Mice.

Aquaporin (AQP) 3, a facilitated transporter of water and glycerol, expresses in placenta and fetal membranes, but the detailed localization and function of AQP3 in placenta remain unclear. To elucidate a role of AQP3 in placenta, we defined the expression and cellular localization of AQP3 in placenta and fetal membranes, and investigated the structural and functional differences between wild-type and AQP3 null mice. Gestational sacs were removed during mid-gestational period and amniotic fluid was aspirated for measurements of volume and composition. Fetuses with attached placenta and fetal membranes were weighed and processed for histological assessment. AQP3 strongly expressed in basolateral membrane of visceral yolk sac cells of fetal membrane, the syncytiotrophoblasts of the labyrinthine placenta and fetal nucleated red blood cell membrane. Mice lacking AQP3 did not exhibit a significant defect in differentiation of trophoblast stem cells and normal placentation. However, AQP3 null fetuses were smaller than their control litter mates in spite of a decrease in litter size. The total amniotic fluid volume per gestational sac was reduced, but the amniotic fluid-to-fetal weight ratio was increased in AQP3 null mice compared with wild-type mice. Glycerol, free fatty acid and triglyceride levels in amniotic fluid of AQP3 null mice were significantly reduced, whereas lactate level increased when compared to those of wild-type mice. These results suggest a role for AQP3 in supplying nutrients from yolk sac and maternal blood to developing fetus by facilitating transport of glycerol in addition to water, and its implication for the fetal growth in utero.

The effect of AQP3 deficiency on fuel selection during a single bout of exhausting exercise.

Aquaporin-3 (AQP3) is an integral membrane protein that facilitates the transport of water and glycerol across cell membranes. However, the precise localization and function of AQP3 in skeletal muscles is currently unknown. In this study, we investigated the capacity of AQP3 knockout mice to perform a single bout of exhausting exercise and analyzed the parameters related to skeletal muscle energy metabolism during exhausting exercise. Mice were exposed to a single bout of treadmill running at a speed of 12 m/min with 10° inclination until exhaustion, and sacrificed immediately, 24 h and 48 h after exercise. Both immunohistochemistry and double immunofluorescence staining revealed that AQP3 is expressed at the cell surface with no evidence of colocalization with either AQP1 or AQP4 in hamstring skeletal muscles. When exposed to a single bout of exhaustive exercise, AQP3 knockout mice fatigued more easily with the average time to exhaustion shorter than the wild-type mice. After exhausting exercise, plasma glucose, muscle glycogen, muscle triglyceride, and muscle free fatty acid levels decreased compared with the values before exercise in both AQP3 knockout and wild-type mice. However, muscle glycerol concentration after exercise decreased in the wild-type mice, but rather increased in AQP3 knockout mice. These findings suggest that decreased glycerol efflux from the skeletal muscles in AQP3 knockout mice may result in low exercise capacity, presumably due to the limitations in the constant energy supply through hepatic gluconeogenesis from glycerol during the prolonged endurance exercise.

Prognostic impact of preoperative statin use after radical nephroureterectomy for upper urinary tract urothelial carcinoma.

PURPOSE: The objective was to investigate the impact of statin use on prognosis after radical nephroureterectomy for upper urinary tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: A retrospective review of medical records identified 277 patients who underwent radical nephroureterectomy for primary UTUC at Asan Medical Center between January 2006 and December 2011. Information on preoperative statin use was obtained from patient charts in an electronic database. We assessed the impact of statin use on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: Of these 277 patients, 62 (22.4%) were taking statin medications. Compared to the statin nonusers, the statin users were older, had a higher body mass index, and had higher rates of cardiovascular disease and diabetes. The 5-year RFS rates of statin users and nonusers were 78.5% and 72.5%, respectively (p=0.528); the 5-year CSS rates were 85.6% and 77.7%, respectively (p=0.516); and the 5-year OS rates were 74.5% and 71.4%, respectively (p=0.945). In the multivariate analysis, statin use was not an independent prognostic factor for RFS (hazard ratio, 0.47; p=0.056), CSS (hazard ratio, 0.46; p=0.093), or OS (hazard ratio, 0.59; p=0.144) in patients who underwent radical nephroureterectomy for UTUC. CONCLUSIONS: Statin use was not associated with improved RFS, CSS, or OS in the sample population of patients with UTUC.

Comparison of perioperative outcomes between running versus interrupted vesicourethral anastomosis in open radical prostatectomy: A single-surgeon experience.

PURPOSE: To compare perioperative outcomes between running and interrupted vesicourethral anastomosis in open radical prostatectomy (RP). MATERIALS AND METHODS: The medical records of 112 patients who underwent open RP for prostate cancer at our institution from 2006 to 2008 by a single surgeon were retrospectively reviewed. Preoperative, intraoperative, and postoperative parameters were measured. RESULTS: Of 112 consecutive patients, 62 patients underwent vesicourethral anastomosis by use of the running technique, whereas 50 patients underwent anastomosis with the interrupted technique. The groups did not differ significantly in age, body mass index, prostate-specific antigen, prostate volume, or pathologic findings. The intraoperative extravasation rate was significantly lower in the running group (8.1% vs. 24.0%, p=0.01). The mean anastomosis time was 15.1±5.3 and 19.3±4.6 minutes in the running and interrupted groups, respectively (p=0.04). The rates of postoperative extravasation were similar for both groups (6.4% vs. 10.0%, p=0.12). The duration of catheterization was significantly shorter in the running group (9.0±3.0 days vs. 12.9±6.4 days, p<0.01). The rate of urinary retention after catheter removal and the rate of bladder neck contracture were not significantly different between the two groups. The rate of urinary continence at 3, 6, 9, and 12 months after RP was also similar in both groups. CONCLUSIONS: Both anastomosis techniques provided similar functional results and a similar rate of postoperative urine extravasation. However, running vesicourethral anastomosis decreased the rate of intraoperative extravasation and time for anastomosis, without increasing the risk of urinary retention or bladder neck contracture.

A novel simple one-step air jet spinning approach for deposition of poly(vinyl acetate)/hydroxyapatite composite nanofibers on Ti implants.

A biocompatible coating consists of a poly(vinyl acetate)/hydroxyapatite (PVAc/HA) composite nanofiber mat was applied to NaOH-treated titanium metal by means of a novel, facile and efficient air jet spinning (AJS) approach. Results showed that HA nanoparticles (NPs) strongly embedded onto the AJS single fiber surface resulting in a strong chemical interfacial bonding between the two phases due to the difference in kinetic energies. It was proven that AJS membrane coatings can provide significant improvement in the corrosion resistance of titanium substrate. Interestingly, the biocompatibility using MC3T3-E1 osteoblast to the PVAc/HA fiber composite layer coated on Ti was significantly higher than pure titanium-substrates.

Effect of Gleason scores of lymph node metastases on prognosis of patients with prostate cancer.

The long-term mortality risk from prostate cancer increases in lymph node (LN) positive patients. This study was done to assess the effect of lymph node Gleason score (LNGS) on prognosis in patients with LN-positive prostate cancer. Among the 1,415 patients who received pelvic lymph node dissection (PLND), 117 (8.4%) patients had a positive LN. The PGS of the prostate specimens and the LNGS of the positive LNs were assessed by uropathologists. The median age of patients at surgery was 67 years (interquartile range [IQR], 62-71 years) and the median follow-up duration was 44.3 months (IQR, 27.0-78.5 months). Pathologic Gleason scores (PGS) of 6-9 included one (0.9%), 53 (49.5%), 22 (20.6%), and 31 (29.0%) patients. The median total number of retrieved LNs was 9.0 (IQR, 5.3-12.8). The median number of positive LNs was one (IQR, 1-2). Cancer architecture with a Gleason pattern and score were observed in LNs as in ordinary prostate specimens. LNGS 6-9 included nine (8.1%), 57 (51.4%), 31 (27.9%), and 14 (12.6%) patients. The speaman's analysis showed the meaningful correlation between PGS and LNGS (P = 0.249, P = 0.011). The univariate analysis showed that the number of positive LNs and LNGS were significantly associated with prostate cancer-specific survival (P = 0.028; P = 0.005). The same architecture that is seen in the prostate was seen in positive LNs, and LNGS may be a significant prognostic factor in patients with LN-positive prostate cancer.

Prognosis of prostate cancer with other primary malignancies.

PURPOSE: The objective was to investigate the clinicopathological characteristics and the prognosis of prostate cancer patients affected by other primary malignancies. MATERIALS AND METHODS: From 1990 to 2008, we retrospectively reviewed the medical records of 1,317 patients who underwent radical prostatectomy (RP) for prostate cancer. We assessed the effect of other primary malignancies on clinicopathological features, biochemical recurrence (BCR)-free survival, cancer-specific survival (CSS), and overall survival (OS). RESULTS: Of 1,317 patients, at least one additional other primary malignancy was detected in 187 patients (14.2%). A comparison of patient groups according to the presence or absence of other primary malignancies showed no significant differences in preoperative serum prostate-specific antigen concentrations, pathological Gleason scores, or pathological staging. Prostate cancer patients with other primary malignancies were older than patients without other primary malignancies (p<0.001). No significant differences in 5-year BCR-free survival (80.2% compared with 77.7%; p=0.656) or CSS (98.9% compared with 98.5%; p=0.733) were found between these groups, respectively. Five-year OS was significantly lower in prostate cancer patients with than in those without other primary malignancies (89.3% compared with 95.4%; p<0.001). Multivariate analysis showed that other primary malignancies diagnosed after RP for prostate cancer were independent predictors of OS (hazard ratio, 4.10; p<0.001) but not of BCR-free survival or CSS. Conversely, other primary malignancies diagnosed before RP for prostate cancer did not independently predict BCR-free survival, OS, or CSS. CONCLUSIONS: Prostate cancer prognosis after RP is not dependent on the presence or absence of other primary malignancies. However, other primary malignancies diagnosed after RP for prostate cancer negatively affect OS.