CANE, a Component of the NLRP3 Inflammasome, Promotes Inflammasome Activation.

The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3, also called cryopyrin) inflammasome is an intracellular innate immune complex, which consists of the pattern-recognition receptor NLRP3, the adaptor apoptosis-assciated speck-like protein containing a caspase recruitment domain, and procaspase-1. Aberrant activation of the NLRP3 inflammasome causes an autoinflammatory disease called cryopyrin-associated periodic syndrome (CAPS). CAPS is caused by gain-of-function mutations in the NLRP3-encoding gene CIAS1; however, the mechanism of CAPS pathogenesis has not been fully understood. Thus, unknown regulators of the NLRP3 inflammasome, which are associated with CAPS development, are being investigated. To identify novel components of the NLRP3 inflammasome, we performed a high-throughput screen using a human protein array, with NLRP3 as the bait. We identified a NLRP3-binding protein, which we called the cryopyrin-associated nano enhancer (CANE). We demonstrated that CANE increased IL-1ß secretion after NLRP3 inflammasome reconstitution in human embryonic kidney 293T cells and formed a "speck" in the cytosol, a hallmark of NLRP3 inflammasome activity. Reduced expression of endogenous CANE decreased IL-1ß secretion upon stimulation with the NLRP3 agonist nigericin. To investigate the role of CANE in vivo, we developed CANE-transgenic mice. The PBMCs and bone marrow-derived macrophages of CANE-transgenic mice exhibited increased IL-1ß secretion. Moreover, increased autoinflammatory neutrophil infiltration was observed in the s.c. tissue of CANE-transgenic versus wild-type mice; these phenotypes were consistent with those of CAPS model mice. These findings suggest that CANE, a component of the NLRP3 inflammasome, is a potential modulator of the inflammasome and a contributor to CAPS pathogenesis.

Impact of timing of urinary drainage on clinical outcomes in patients with obstructive pyelonephritis associated with upper urinary tract stones: a propensity score-matched analysis.

OBJECTIVE: We aimed to assess the impact of the timing of urinary drainage on clinical outcomes in patients with obstructive pyelonephritis (OPN) associated with upper urinary tract (UUT) stones. METHODS: We retrospectively evaluated the multicenter dataset of 240 patients with OPN associated with UUT stones who underwent urinary drainage. We divided the patients into two groups depending on the timing of urinary drainage; emergency drainage, defined as within 12 h from admission, and delayed drainage, defined as between 12 and 48 h from admission. The outcomes were the length of hospital stay, time to leukocyte normalization, and time to body temperature normalization. One-to-two propensity score matching (PSM) was applied to minimize the effect of confounders between the two groups. Subsequently, predictive patient factors for emergency drainage were analyzed using the logistic regression model. RESULTS: Only the time from admission to normal body temperature was significantly shorter in the emergency drainage group when compared with the delayed drainage group (median: 2 vs. 3 days; p = 0.02), while there was no difference in time from drainage to body temperature normalization between the two groups. On multivariable analysis, high pretreatment C-reactive protein (CRP) was associated with implementing emergency drainage within 12 h. CONCLUSIONS: The timing of urinary drainage was only associated with the duration of high fever, but it did not affect the postdrainage course. Emergency urinary drainage is more likely to be performed in severe patients, such as high pretreatment CRP.

River-estuary continuum highlighted by variabilities in carbon and nitrogen stable isotope ratios of the catadromous eel Anguilla japonica.

Estuaries exhibit high physicochemical variability and the properties of estuaries and the constituent segments are not yet systematically understood. This study aims to reveal the spatial heterogeneity of predominant organic sources using carbon and nitrogen stable isotope ratios (δ13C and δ15N, respectively) of Japanese eels (Anguilla japonica), one of the ideal natural samplers. In the Miyakoda River, Japan, our study site, the effectiveness of eel δ13C and δ15N values as standard indices of predominant organic sources was tested by employing the River Continuum Concept. This study then extended the application of these indices to the estuary, i.e., the Hamana Lake system, into which the Miyakoda River flows. Once in the upper estuary, eel δ13C and δ15N values became high, with the latter peaking in this river-estuary continuum, indicating that artificial labile subsidies (nutrients and organic matter) with high δ15N values were rapidly assimilated into the food web. Eel δ15N values decreased again in the middle estuary. Nevertheless, the influence of terrestrial organic subsidies extended into this segment, as evidenced by the low δ13C values of eels. These results suggest that refractory organic matter with low δ15N values, such as plant-derived ones, is slowly assimilated into the food web in the downstream estuarine segments. The higher δ13C values in the lower estuary suggested that the contribution of eelgrass or macroalgae occurred in addition to benthic microalgae. Thus, our results emphasize the need to consider the multiple energy flows to understand the estuary as a continuum.

Associations between early changes in the neutrophil-to-lymphocyte ratio after radical nephroureterectomy and treatment outcomes.

OBJECTIVES: This study explored the impacts of peri-operative changes in the neutrophil-to-lymphocyte ratio (NLR) on the survival rate after radical nephroureterectomy. METHODS: This retrospective analysis included a multicentric cohort of patients diagnosed with upper tract urothelial carcinoma (UTUC) who had undergone radical nephroureterectomy from 2012 to 2021. We assessed the preoperative NLR, postoperative NLR, delta-NLR (difference between postoperative and preoperative NLRs), and NLR change (ratio of postoperative to preoperative NLR). Additionally, patients were categorized according to increases in their preoperative and/or postoperative NLRs. Associations of survival with peri-operative changes in the NLR were investigated using Cox multivariate regression models. RESULTS: A total of 488 patients were included in the study, with a median age of 73 years. Among the patients, 105 (21.5%) exhibited elevated preoperative and postoperative NLRs, 88 (18.0%) exhibited elevated preoperative NLR only, 53 (10.9%) exhibited elevated postoperative NLR only, and 242 (49.6%) exhibited normal NLRs. Multivariate analysis indicated significant negative correlations between both preoperative and postoperative increased NLRs and oncological outcomes, including nonurothelial tract recurrence-free survival and cancer-specific survival (hazard ratio [HR]: 1.65, P = 0.017; HR: 2.12, P = 0.014, respectively). CONCLUSION: This is the first study to evaluate the association between peri-operative changes in the NLR and the outcomes of patients with UTUC who underwent radical nephroureterectomy. Patients with elevated NLRs at both time points experienced considerably worse outcomes. Further research should explore whether increases in the NLR during long-term follow-up could indicate impending disease recurrence.

Trimodal therapy with high-dose-rate brachytherapy and hypofractionated external beam radiation combined with long-term androgen deprivation for unfavorable-risk prostate cancer.

PURPOSE: To assess the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiation therapy (EBRT) combined with long-term androgen deprivation therapy (ADT) in very-high-risk (VHR) versus high-risk (HR) prostate cancer (PCa), as defined in the National Comprehensive Cancer Network (NCCN) criteria. METHODS: Data from 338 consecutive HR or VHR PCa patients who had undergone this tri-modal therapy between 2005 and 2018 were retrospectively analyzed. Biochemical recurrence (BCR)-free, progression-free, overall, and cancer-specific survival (BCRFS/PFS/OS/CSS) rates were analyzed using the Kaplan-Meier method and Wilcoxon test. Cox regression models were used to evaluate candidate prognostic factors for survival. C­indexes were used to assess model discrimination. RESULTS: Within a median follow-up of 84 months, 68 patients experienced BCR, 58 had disease progression including only 3 with local progression, 27 died of any cause, and 2 died from PCa. The 5­year BCRFS, PFS, OS, and CSS rates were 82.2% (HR 86.5%; VHR 70.0%), 90.0% (HR 94.3%; VHR 77.6%), 95.7% (HR, 97.1%; VHR, 91.8%), and 99.6% (HR, 100%; VHR, 98.0%), respectively. In multivariable analyses that adjusted for standard clinicopathologic features, the risk subclassification was associated both PFS and OS (p = 0.0003 and 0.001, respectively). Adding the risk subclassification improved the accuracy of models in predicting BCRFS, PFS, and OS. CONCLUSION: While the outcome of this trimodal approach appears favorable, VHR PCa patients had significantly worse oncological outcomes than those with HR PCa. The NCCN risk subclassification should be integrated into prognostic tools to guide risk stratification, treatment, and follow-up for unfavorable PCa patients receiving this trimodal therapy.

Tumor Location and Pathological Features of Latent and Incidental Prostate Cancer in Contemporary Japanese Men.

PURPOSE: The incidence of prostate cancer is increasing in Asian countries. Studies using prostatectomy specimens have reported a racial difference in tumor location within the prostate, with a greater incidence of transition zone cancer in Asian men compared with Caucasian men. However, there may be potential biases in studies based on surgical specimens. We describe the pathological features of subclinical prostate cancer, such as latent cancer and incidental cancer, to elucidate tumor location of contemporary Japanese patients. We also compare the prevalence of latent and incidental prostate cancer to determine whether the incidence of prostate cancer is higher in patients with bladder cancer. MATERIALS AND METHODS: Overall 182 men autopsied and 148 who underwent cystoprostatectomy for bladder cancer were included in the study. Each prostate gland was fixed and sliced in step sections. Histological evaluation was performed by a single genitourinary pathologist. The index tumor location was categorized into transition zone or peripheral zone. RESULTS: Prostate cancer was found in 39.0% of the autopsy specimens and 31.6% of the cystoprostatectomy specimens. The prevalence and pathological characteristics were not significantly different between latent and incidental cancer. The prevalence of transition zone cancer was 39.0% (46 of 118). In elderly men peripheral zone cancer was more frequently diagnosed than transition zone cancer (p=0.049). The pathological characteristics of transition and peripheral zone cancers were similar except for the pT stage. CONCLUSIONS: Transition zone cancer was prevalent in contemporary Japanese men. The incidence of prostate cancer in men with bladder cancer might not be higher than that in healthy men.

Post-Anesthesia Evaluation Shows No Relationship Between Body Conditions and Salinity-Choice Propensities in Anguilla japonica Glass Eels.

Anguillid eels generally exhibit catadromous migration between oceanic spawning grounds and freshwater growth habitats, but some individuals remain in coastal or estuarine saline waters for growth. This migratory plasticity had been considered to be a conditional strategy based on individual energetic status during the glass eel stage. Several studies have examined whether salinity-based habitat selection is linked to individual body conditions, but while frozen specimens of European eels showed this relationship, anesthetized samples of American eels did not. Here, we report that freezing preservation under different salinity levels influences body-condition evaluation in Japanese eels. Behavioral tests of Japanese eels did not reveal significant differences in anesthetized body conditions between those choosing saltwater and those choosing freshwater. In conclusion, the body conditions of glass-eel-stage Japanese eels are unlikely to be associated with their salinity-choice propensity.

Lactate dehydrogenase predicts combined progression-free survival after sequential therapy with abiraterone and enzalutamide for patients with castration-resistant prostate cancer.

BACKGROUND: An array of clinical issues remains to be resolved for castration-resistant prostate cancer (CRPC), including the sequence of drug use and drug cross-resistance. At present, no clear guidelines are available for the optimal sequence of use of novel agents like androgen-receptor axis-targeted (ARAT) agents, particularly enzalutamide, and abiraterone. METHODS: This study retrospectively analyzed a total of 69 patients with CRPC treated with sequential therapy using enzalutamide followed by abiraterone or vice versa. The primary outcome measure was the comparative combined progression-free survival (PFS) comprising symptomatic and/or radiographic PFS. Patients were also compared for total prostate-specific antigen (PSA)-PFS, overall survival (OS), and PSA response. The predictors of combined PFS and OS were analyzed with a backward-stepwise multivariate Cox model. RESULTS: Of the 69 patients, 46 received enzalutamide first, followed by abiraterone (E-A group), and 23 received abiraterone, followed by enzalutamide (A-E group). The two groups were not significantly different with regard to basic data, except for hemoglobin values. In a comparison with the E-A group, the A-E group was shown to be associated with better combined PFS in Kaplan-Meier analysis (P = 0.043). Similar results were obtained for total PSA-PFS (P = 0.049), while OS did not differ between groups (P = 0.62). Multivariate analysis demonstrated that pretreatment lactate dehydrogenase (LDH) values and age were significant predictors of longer combined PFS (P < 0.05). Likewise, multivariate analysis demonstrated that pretreatment hemoglobin values and performance status were significant predictors of longer OS (P < 0.05). CONCLUSIONS: The results of this study suggested the A-E sequence had longer combined PSA and total PSA-PFS compared to the E-A sequence in patients with CRPC. LDH values in sequential therapy may serve as a predictor of longer combined PFS.

Metastatic Prostate Cancer in Men Initially Treated with Active Surveillance.

PURPOSE: Active surveillance is an approach to low and low intermediate risk prostate cancer that is designed to decrease overtreatment. Despite close monitoring a small subset of patients progress to metastatic disease. We analyzed the clinical and pathological correlates of surveillance in patients who eventually experienced metastasis. MATERIALS AND METHODS: This was a single center, prospective cohort study. Eligible patients were treated with an expectant approach. The main outcome measure was metastasis-free survival. Predictive factors for metastasis were identified. RESULTS: Metastasis developed in 30 of 980 patients, of whom 211 were classified at intermediate risk, including 14 who progressed to metastatic disease. Median followup was 6.3 years, median age was 70 years, median prostate specific antigen was 6.2 ng/ml and median time to metastasis was 8.9 years. Metastases developed in bone in 18 patients (60%) and in lymph nodes in 13 (43%). Prostate specific antigen doubling time less than 3 years (HR 3.7, 95% CI 1.4-9.4, p = 0.0006), Gleason score 7 (HR 3.0, 95% CI 1.2-7.3, p = 0.0018) and a total of 3 or more positive cores (HR 2.7, 95% CI 1.1-6.8, p = 0.0028) were independent predictors of metastasis. Although the intermediate risk group was at higher risk for metastasis, those with Gleason score 6 and prostate specific antigen greater than 10 ng/ml were not at increased risk for metastasis. Metastasis developed in only 2 patients with Gleason score 6 and neither had surgical pathology grading. CONCLUSION: Active surveillance appears safe in patients at low risk and in select patients at intermediate risk, particularly those with Gleason score 6 and prostate specific antigen greater than 10 ng/ml. Patients with elements of Gleason pattern 4 on diagnostic biopsy are at increased risk for eventual metastasis when treated with an initial conservative approach.

Time Trends in Histological Features of Latent Prostate Cancer in Japan.

PURPOSE: The incidence of prostate cancer is reported to be increasing in Asia, including Japan. Although this trend has been attributed partly to a more Western diet, this assumption may involve variable confounders. Thus, we examined the histological features of contemporary vs historical latent prostate cancer. MATERIALS AND METHODS: Prostate specimens from a consecutive autopsy series (127, present study, 2008 to 2013) were examined. Each prostate gland was fixed and sliced in step sections. The findings were compared to those from another autopsy series (501 subjects, 1983 to 1987) at our institution. RESULTS: The mean age of subjects in the present study was 68.9 years while the mean age was not available from the earlier study. However, the mean age of the 566 entrants in the expanded database (1983 to 1989) was 63.5 years (p=0.0001). Prostate weight was significantly greater in the present study (p <0.0001). Latent prostate cancer was found more frequently in the present study than in the previous study (43.3% and 20.8%, respectively, p <0.0001). No distinct difference was seen in the proportion of tumor grade between the groups. An increasing trend of moderately to poorly differentiated tumors with advancing age was more evident in the present study. Index cancer volume was greater in the present study with 25.5% measuring 500 mm(3) or greater vs only 9.6% of cancers in the previous study (p=0.008). CONCLUSIONS: Chronological changes in the histological characteristics of Japanese latent prostate cancer were noted as it is more prevalent in the contemporary series. Our data may reflect a worldwide trend in increasingly aging societies.

Active Surveillance for Intermediate Risk Prostate Cancer: Survival Outcomes in the Sunnybrook Experience.

PURPOSE: To assess the applicability of active surveillance in patients with intermediate risk prostate cancer, we compared the survival outcomes of patients with low risk and intermediate risk disease. MATERIALS AND METHODS: Active surveillance was offered to all patients with low risk (cT1-T2b and Gleason score 6 and prostate specific antigen 10 ng/ml or less) and select intermediate risk disease (age greater than 70 years with cT2c or prostate specific antigen 15 ng/ml or less, or Gleason score 3+4 or less). Data from November 1995 to May 2013 were extracted from a prospectively collected database. The primary outcome was metastasis-free survival, and secondary outcomes were overall survival, cause specific survival and treatment-free survival. RESULTS: A total of 213 intermediate risk and 732 low risk cases were identified. Median age was 72 years (IQR 67.3, 76.8) in the intermediate risk cohort and 67 years (IQR 60.6, 71.9) in the low risk group. Median followup was comparable (6.7 years for intermediate risk vs 6.5 years for low risk). Gleason 7 disease comprised 60% of the intermediate risk cohort. The 15-year metastasis-free, overall, cause specific and treatment-free survival rates were inferior in the intermediate risk group (metastasis-free survival HR 3.14, 95% CI 1.51-6.53, p=0.001, 82% for intermediate risk vs 95% for low risk). On further evaluation the estimated 15-year metastasis-free survival for cases of Gleason 6 or less with prostate specific antigen less than 10 ng/ml was 94%, Gleason 6 or less with prostate specific antigen 10 to 20 ng/ml was 94%, Gleason 3+4 with prostate specific antigen 20 ng/ml or less was 84% and Gleason 4+3 with prostate specific antigen 20 ng/ml or less was 63%. CONCLUSIONS: These data support the use of active surveillance in low risk and intermediate risk cases of Gleason 6 but not Gleason 7 prostate cancer. Multiparametric magnetic resonance imaging and novel biomarkers might be vital in detecting favorable Gleason 7 disease.

The antibacterial activity of levofloxacin eye drops against staphylococci using an in vitro pharmacokinetic model in the bulbar conjunctiva.

The incidence of fluoroquinolone-resistant staphylococcal isolates from the conjunctival sac is increasing. We compared pharmacological effects of levofloxacin (LVFX) against Staphylococcus epidermidis using an in vitro pharmacokinetic (PK) model simulating the concentration in the bulbar conjunctiva after applying eye drops of 0.5% and 1.5% LVFX. We used S. epidermidis conjunctival sac isolates [minimum inhibitory concentrations (MICs) of LVFX, 0.125 µg/mL]. LVFX-resistant strains were obtained from parental strains after culture with LVFX. The in vitro PK model simulated the concentration in the bulbar conjunctiva following three topical applications of 0.5% or 1.5% LVFX ophthalmic solution (0, 4, and 8 h) to rabbit eyes. Parental and LVFX-resistant strains were exposed to LVFX in the in vitro PK model, and changes in viable bacterial counts were evaluated for 12 h. The MICs of LVFX for the resistant isolates were 2-32 times higher than the parental strain, and those with MICs ≥2 ug/mL had mutations in the quinolone resistance-determining region. The PK model simulation predicts that 1.5% LVFX exerts bactericidal and bacteriostatic effects against strains with MICs of 0.125-2 and 4 µg/mL, respectively, whereas 0.5% LVFX would only be effective against strains with MICs of 0.125-1 µg/mL. The PK model predicts that the 1.5% LVFX ophthalmic solution exhibits a stronger bactericidal effect against resistant staphylococci in the bulbar conjunctiva than the 0.5% LVFX ophthalmic solution.

Safety of fondaparinux for prevention of postoperative venous thromboembolism in urological malignancy: A prospective randomized clinical trial.

OBJECTIVES: To prospectively evaluate the safety of postoperative fondaparinux in comparison with low molecular weight heparin in patients undergoing uro-oncological surgery. METHODS: The present study was a prospective, single-blind, non-inferiority randomized trial. A total of 359 patients undergoing surgery for urological malignancy were enrolled from January 2011 to December 2012. A total of 298 of these patients (fondaparinux group, 152; low molecular weight heparin group, 146) were evaluable for the intention-to-treat-analysis. Patients were randomly assigned to low-dose unfractionated heparin, 5000 units twice daily until postoperative day 1 plus either fondaparinux 2.5 mg once daily or low molecular weight heparin 2000 units twice daily until postoperative day 5. The primary end-point was postoperative bleeding as by independent review, and the study was powered to show the non-inferiority of fondaparinux versus low molecular weight heparin. The other adverse events were evaluated. D-dimer and soluble fibrin monomer complex levels were measured perioperatively. RESULTS: Bleeding occurred in 21 patients (12 in the fondaparinux group and 9 in low molecular weight heparin group, respectively). No significant differences were detected in the incidence of postoperative bleeding and the other adverse events between the two groups. The D-dimer was elevated on postoperative day 1 in one patient (16.6 µg/mL). In another patient, the soluble fibrin monomer complex was elevated (109 µg/mL). CONCLUSIONS: Fondaparinux is non-inferior to low molecular weight heparin with respect to risk of bleeding. The favorable safety profile of fondparinux supports its prophylactic use as an alternative to low molecular weight heparin after surgery for urological malignancy.

Interaction of poly(ethylene glycol)-conjugated phospholipids with supported lipid membranes and their influence on protein adsorption.

We studied real-time interaction between poly(ethylene glycol)-conjugated phospholipids (PEG-lipids) and a supported lipid membrane by surface plasmon resonance (SPR) spectroscopy to understand dynamic behaviors of PEG-lipids on living cell membranes. Supported lipid membranes formed on a hydrophobic surface were employed as a model of living cell membrane. We prepared three kinds of PEG-lipids that carried alkyl chains of different lengths for SPR measurements and also performed fluorescence recovery after photobleaching (FRAP) to study the influence of acyl chain length on dynamics on the supported membrane. PEG-lipids were uniformly anchored to lipid membranes with high fluidity without clustering. Incorporation and dissociation rates of PEG-lipids into supported membranes strongly depended on the length of acyl chains; longer acyl chains reduced the incorporation rate and the dissociation rate of PEG-lipid. Furthermore, protein adsorption experiment with bovine serum albumin indicated that PEG modification prevented the adsorption of bovine serum albumin on such supported membrane.

Capsaicin reduces the metastatic burden in the transgenic adenocarcinoma of the mouse prostate model.

BACKGROUND: Capsaicin, the active compound in chili peppers, has demonstrated anti- carcinogenic properties in vitro in a number of malignancies, including the prostate. In the present study, we investigate the chemopreventive potential of capsaicin on prostate cancer using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The TRAMP is a murine model that resembles the progression of human disease. METHODS: Thirty-five 6-week-old TRAMP x C57BL/6 mice were randomized between treatment with capsaicin (5 mg/kg body weight) or control (saline) three times a week by oral gavage until 30 weeks of age. Body weight of animals was recorded thrice weekly. At termination, all tumors were extracted, recorded, and analyzed for histopathological analysis. To understand the effect of capsaicin on migration and invasion, in vitro experiments were carried out using PC3 cells. RESULTS: Mice in the control group expressed an overall trend of higher-grade disease with 37.5% poorly differentiated (PD), 18.75% moderately differentiated (MD), and 44% of well-differentiated (WD) adenocarcinoma, compared to the capsaicin-treated group with only 27.7% PD, 61.0% of WD, and 11.1% of intraepithelial neoplasia (PIN). The treatment group demonstrated a higher incidence of noncancerous PIN lesions compared to the control group. The capsaicin group also demonstrated a significant reduction (P < 0.05) in the metastatic burden compared to the controls, which correlated to a reduction in p27(Kip) (1) expression and neuroendocrine differentiation in prostate tumors. Furthermore, there were no differences in body weight between groups overtime, and no pathological toxicities in the liver and gastrointestinal tract with capsaicin consumption. In vitro studies revealed a dose-dependent reduction in the invasion and migration capacity of PC3 cells. CONCLUSION: The following study provides evidence supporting the safety and chemopreventive effects of capsaicin in the TRAMP model.

Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis.

One of the central goals of human genetics is to discover the genes and pathways driving human traits. To date, most of the common risk alleles discovered through genome-wide association studies (GWAS) map to nonprotein-coding regions. Because of our relatively poorer understanding of this part of the genome, the functional consequences of trait-associated variants pose a considerable challenge. To identify the genes through which risk loci act, we hypothesized that the risk variants are regulatory elements. For each of 12 known risk polymorphisms, we evaluated the correlation between risk allele status and transcript abundance for all annotated protein-coding transcripts within a 1-Mb interval. A total of 103 transcripts were evaluated in 662 prostate tissue samples [normal (n = 407) and tumor (n = 255)] from 483 individuals [European Americans (n = 233), Japanese (n = 127), and African Americans (n = 123)]. In a pooled analysis, 4 of the 12 risk variants were strongly associated with five transcripts (NUDT11, MSMB, NCOA4, SLC22A3, and HNF1B) in histologically normal tissue (P ≤ 0.001). Although associations were also observed in tumor tissue, they tended to be more attenuated. Previously, we showed that MSMB and NCOA4 participate in prostate cancer pathogenesis. Suppressing the expression of NUDT11, SLC22A3, and HNF1B influences cellular phenotypes associated with tumor-related properties in prostate cancer cells. Taken together, the data suggest that these transcripts contribute to prostate cancer pathogenesis.

Differences in prostate cancer grade, stage, and location in radical prostatectomy specimens from United States and Japan.

BACKGROUND: To compared prostate cancer at radical prostatectomy between men in the United States (US) and Japan in the modern era. METHODS: Three hundred seventy consecutive totally embedded RP cases (159 US; 211 Japan) from 2010 to 2012 were reviewed. RESULTS: US men were significantly younger (mean age 58.8 years) than Japanese men (mean age 64.6 years; P < 0.00001). Japanese patients presented with higher PSA levels (mean = 10.9 ng/ml) compared to US patients (mean = 5.8 ng/ml, P < 0.00001) and higher clinical stage (P = 0.003). Japanese tumors were: higher grade; larger; more advanced stage; with increased lymphovascular invasion; and more commonly TZ in location (P < 0.00001). In multivariate analysis, independent predictors of high tumor volume were PSA level, clinical stage, TZ location, Gleason grade, and country of origin (Japan). Independent predictors of TZ location were clinical stage, tumor volume, and country of origin (Japan). CONCLUSION: A major factor for larger, higher grade and stage tumors in Japanese patients is the lower prevalence of screening for prostate cancer in Japan. Another contributing factor may be their TZ location, where they are not palpable until advanced and where they are difficult to sample on needle biopsy possibly leading to a delay in diagnosis. The finding of a difference in zonality of prostate cancer between US and Japanese cases is novel and may reflect differences in biology rather than different health care practice between the groups. If this data is confirmed, consideration should be given to TZ sampling as part of routine needle biopsies in Japanese men.

Mid-term outcome of permanent prostate iodine-125 brachytherapy in Japanese patients.

OBJECTIVES: To analyze mid-term oncological outcomes of low-dose rate brachytherapy in Japanese patients. METHODS: Between 2003 and 2010, 604 consecutive patients with clinically localized prostate cancer were treated with low-dose rate brachytherapy at Jikei University Hospital in Tokyo, Japan. Median follow up was 48 months. Of these patients, 260 (43%) were treated with neoadjuvant therapy, 45 (7.5%) with adjuvant hormonal therapy and 75 (12.4%) with supplemental external beam radiation therapy. Biochemical recurrence was defined as the prostate-specific antigen nadir plus 2 ng/mL. RESULTS: Of the 604 patients, 219 (36.2%) were low risk, 361 (59.8%) were intermediate risk and 24 (4.0%) had high-risk disease. The median biologically effective dose was 174.4 Gy2. At 8 years, biochemical recurrence-free survival, cancer-specific survival, and overall survival were 82.2%, 100% and 95.6%, respectively. Biochemical recurrence-free survival at 8 years was 89.9%, 79.4% and 52.5%, for the low-, intermediate-, and high-risk groups, respectively. Biochemical recurrence-free survival for the high-risk group was significantly lower than the low- and intermediate-risk groups (P < 0.001). Biochemical recurrence-free survival did not differ significantly by biologically effective dose stratification. In multivariate analysis, younger age (P = 0.045), higher prostate-specific antigen (P = 0.004), higher Gleason score (P = 0.006) and higher clinical T stage (P = 0.008) were significant covariates associated with biochemical recurrence. The addition of hormonal therapy or external beam radiation therapy was associated with significantly better outcomes than low-dose rate brachytherapy monotherapy (P = 0.0021 and 0.010). Just four patients experienced G3 genitourinary or gastrointestinal toxicity. CONCLUSIONS: Low-dose rate brachytherapy results in excellent mid-term oncological outcomes and acceptable toxicity in Japanese patients. In our experience, biologically effective dose does not represent a significant predictor for biochemical recurrence.

Synthesis of Dicarboxylic Acids Comprising an Ether Linkage and Cyclic Skeleton and Its Further Application for High-Performance Aluminum Electrolyte Capacitors.

Aluminum electrolytic capacitors are essential components in all electronic devices, and it is known that their longevity depends on the performance of their electrolytes. We synthesized dicarboxylic acids having ether bonds showing the good solubility in ethylene glycol as a solvent and simultaneously developed a complete halogen removal method, which is strictly prohibited in capacitors. Moreover, the incorporation of bulky α-substituents and cyclic structures dramatically improved their heat resistance and can withstand high voltage, i.e., 764 V.