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Background Recently, presepsin has been reported to be a useful biomarker for early diagnosis of sepsis and evaluation of prognosis in septic patients. However, few reports have evaluated its usefulness in patients with urinary tract infections (UTI). This study aimed to evaluate whether presepsin could be a valuable marker for detecting severe sepsis, and whether it could predict the therapeutic course in patients with UTI compared with markers already used: procalcitonin (PCT) and C-reactive protein (CRP). Methods From April 2014 to December 2016, a total of 50 patients with urinary tract infections admitted to Gunma university hospital were enrolled in this study. Vital signs, presepsin, PCT, CRP, white blood cell (WBC) count, causative agents of urinary-tract infections, and other data were evaluated on the enrollment, third, and fifth days. The patients were divided into two groups: with (n = 11) or without (n = 39) septic shock on the enrollment day, and with (n = 7) or without (n = 43) sepsis on the fifth day, respectively. Presepsin was evaluated as a biomarker for systemic inflammatory response syndrome (SIRS) or septic shock. Results Regarding the enrollment day, there was no significant difference of presepsin between the SIRS and non-SIRS groups (p = 0.276). The median value of presepsin (pg/mL) was significantly higher in the septic shock group (p p = 0.007). ROC curve for diagnosing septic shock indicated an area under the curve (AUC) of 0.881 for presepsin (vs. 0.690, 0.583, and 0.527 for PCT, CRP and WBC, respectively). Regarding the 5th day after admission, the median presepsin value on the enrollment day was significantly higher in the SIRS groups than in the non-SIRS groups (p = 0.006). On the other hand, PCT (≥ 2 ng/ml) on the enrollment day was an independent risk factor for SIRS. ROC curve for diagnosing sepsis on the fifth day indicated an AUC of 0.837 for PCT (vs. 0.817, 0.811, and 0.802 for presepsin, CRP, and WBC, respectively). Conclusions This study showed that presepsin may be a good marker for diagnosing septic shock based on admission data in patients with UTI.

Background Enzalutamide (ENZ) is used to treat patients with castration-resistant prostate cancer (CRPC). However, the kinetics of serum androgens before and after ENZ treatment are unknown. Objective To elucidate the kinetics of serum androgens and explore the possibility of identifying a useful marker for predicting the effects of ENZ. Design, setting, and participants We conducted a prospective study from 2014 to 2018 at Gunma University Hospital and related facilities. Data were analyzed for 104 patients with CRPC treated with ENZ. Outcome measurements and statistical analysis We measured serum androgen levels using liquid chromatography-tandem mass spectrometry. Relationships with outcomes were assessed using multivariable Cox regression and log-rank analyses. Results and limitations The median age of the patients was 73 yr. Median serum testosterone, dihydrotestosterone (DHT), androstenedione, and dehydroepiandrosterone sulfate levels were 49.0, 5.8, 222.2, and 326.3 pg/ml, respectively. We performed multivariate analysis using Cox regression to predict prostate-specific antigen progression–free survival (PSA-PFS) and overall survival (OS). Hemoglobin level (≥12.5 vs, Take Home Message The effect of enzalutamide was significantly better for cases with high blood androgen levels before treatment. In addition, the incidence of adverse events of anorexia, malaise, and fatigue tended to be low. These results suggest that serum androgen levels before enzalutamide treatment may be useful for predicting efficacy, prognosis, and the incidence of adverse events.

Background Recently, presepsin is reported to be a biomarker for early diagnosis of sepsis and evaluation of prognosis in septic patients, but there are few reports about urinary-tract infections. The objective of this study is to evaluate whether presepsin is a recent marker for detecting severe sepsis, and whether it can predict the therapeutic course in UTI when compared with procalcitonin (PCT) and C-reactive protein (CRP), already used markers.Methods From April 2014 to December 2016, a total of 50 patients, who were admitted into Gunma university hospital with urinary-tract infections, were enrolled in this study. Vital signs, presepsin, PCT, CRP, white blood cell (WBC), causative diseases of urinary-tract infections and other data were evaluated at the enrollment, third and fifth days. The patients were divided into two groups; with (n=11) or without (n=39) septic shock at the enrollment day, and with (n=7) or without (n=43) sepsis at the fifth day, respectively. Presepsin was evaluated for systemic inflammatory response syndrome (SIRS) or septic shock. Results Concerning the enrollment day, there was no significant difference of presepsin between SIRS and non-SIRS groups (p=0.276). The median presepsin (pg/mL) was significantly higher in the septic shock group (pConclusions This study shows that presepsin may be a good marker for diagnosis of severe patients who need vasopressor therapy at the data of admission, and PCT may be a good marker for predicting hard-to-treat cases in UTI.

Background/Aim: There are several treatment options for metastatic hormone-sensitive prostate cancer (mHSPC) in the world. In recent years, the use of docetaxel, abiraterone, enzalutamide, and apalutamide has been used for mHSPC, but combined androgen blockade (CAB) therapy using first-generation antiandrogens has been widely used in Japan. There is a background. We performed a consecutive study of patients who received combined androgen blockade (CAB) at a single institute to determine the prognostic factors for mHSPC. Patients and Methods: We conducted a consecutive study of 237 mHSPC patients treated with CAB from 2003 to 2017 at the Gunma University Hospital. Prostate-specific antigen progression-free survival (PSA-PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. The associations between pre-treatment risk factors and the PSA response 3 months after starting CAB, PSA-PFS, and OS were evaluated by the Cox proportional hazards model. Results: Among the 237 cases, the median PSA-PFS and OS times were 63.0 and 91.4 months, respectively. The median PSA-PFS and OS times of M1 cases (174 cases, 73.4% of all 237 cases) were 36.1 and 75.9 months, respectively. The Eastern Cooperative Oncology Group performance status (ECOG PS) score, hemoglobin (Hb), lactate dehydrogenase, extent of disease, visceral metastasis (no vs. yes), and PSA response after 3 months were significant predictors of OS according to Cox regression analysis of prognostic factors in M1 patients. The ECOG PS, Hb, visceral metastasis (no vs. yes), and PSA response after 3 months predicted OS high-risk patients in LATITUDE criteria. The OS was 92.1 months in the low-risk group (0-1 risk factors), 48.2 months in the intermediate-risk group (2 risk factors), and 16.9 months in the high-risk group (3-4 risk factors). Conclusion: CAB should be considered as a treatment option for strictly selected patients with mHSPC, even though novel treatments are available.

Objectives To investigate the predictive value of various molecular forms of prostate-specific antigen in men with baseline prostate-specific antigen

BACKGROUND The effects of a steroidal antiandrogen (AA) and 5-alpha-reductase inhibitor (5ARI) on prostate tissue hormone content and metabolism are not fully elucidated. The objective of this study is to investigate the hormone content and metabolism of the prostate tissues of patients treated with AA or 5ARI using the ultra-sensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) method. METHODS Thirty-nine patients with benign prostatic hyperplasia (BPH) undergoing transurethral surgery were included. Serum and prostate tissue hormone and prostate tissue hormone metabolism analyses were performed using LC-MS/MS after 1 month of treatment with chlormadinone acetate (CMA; steroidal AA, 50 mg/day) or dutasteride (DUTA; dual 5ARI, 0.5 mg/day). RESULTS Serum testosterone (T), dihydrotestosterone (DHT), and adrenal androgen levels were lower in the CMA group than the control group. Prostate tissue T and DHT levels were also lower in the CMA group than the control group. In the DUTA group, only serum and prostate DHT concentrations were reduced compared to the control group; in contrast, those of other hormones, especially T and 4-androstene-3,17-dione in the prostate tissue, showed marked elevations up to 70.4- and 11.4-fold normal levels, respectively. Moreover, the hormone metabolism assay confirmed that the conversion of T to DHT was significantly suppressed while that of T to 4-androstene-3,17-dione was significantly accelerated in the prostate tissue of DUTA-treated patients. CONCLUSIONS Although treatment with AA and 5ARI show similar clinical outcomes, their effect on tissue hormone content and metabolism varied greatly. Prostate 9999: XX–XX, 2017. © 2017 Wiley Periodicals, Inc.

Differences in the incidence and mortality rate of prostate cancer between the USA and Japan have been decreasing over time, and were only twofold in 2017. Therefore, countermeasures against prostate cancer could be very important not only in Western countries, but also in developed Asian countries. Screening for prostate cancer in the general population using transrectal ultrasonography, digital rectal examination and/or prostate acid phosphatase began in Japan in the early 1980s, and screening with prostate-specific antigen and digital rectal examination has been widespread in the USA since the late 1980s. Large- and mid-scale randomized controlled trials on screening for prostate cancer began around 1990 in the USA, Canada and Europe. However, most of these studies failed as randomized controlled trials because of high contamination in the control arm, low compliance in the screening arm or insufficient screening setting about screening frequency and/or biopsy indication. The best available level 1 evidence is data from the European Randomized Study of Screening for Prostate Cancer and the Goteborg screening study. However, several non-urological organizations and lay media around the world have mischaracterized the efficacy of prostate-specific antigen screening. To avoid long-term confusion about screening for prostate cancer, leading professional urological organizations, including the Japanese Urological Association, are moving toward the establishment of an optimal screening system that minimizes the drawbacks of overdetection, overtreatment and loss of quality of life due to treatment, and maximizes reductions in the risk of death as a result of prostate cancer and the development of metastatic prostate cancer.

Background: There are some reports about the antitumor effects of statins in these days. Statins decrease the level of cholesterol in the blood by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Inhibition of this enzyme decreases intracellular cholesterol synthesis. Thus, the expression of low-density lipoprotein receptor (LDLr) is increased to import more cholesterol from the bloodstream. In this study, we assessed the effects of statins on the proliferation of prostate cancer cells, and studied the relationship between the expression of LDLr and the effects of statins. Methods: Simvastatin was used in the experiments. We studied the effect of simvastatin on PC-3 and LNCaP cell proliferation using the MTS assay, and evaluated the expression of LDLr after administration of simvastatin by quantitative polymerase chain reaction and Western blotting. Intracellular cholesterol levels in the prostate cancer cells were measured after administration of simvastatin. Furthermore, small interfering RNA (siRNA) was used to knockdown the gene expression of LDLr. Results: In PC-3 cells, simvastatin inhibited cell proliferation. In LNCaP cells, only a high concentration of simvastatin (100μM) inhibited cell proliferation. In LNCaP cells, the protein level of LDLr was increased by simvastatin. In PC-3 cells, the protein levels of LDLr were unregulated. In PC-3 cells, but not in LNCaP cells, intracellular cholesterol levels were significantly decreased by simvastatin. After knocking down LDLr expression by siRNA, intracellular cholesterol levels were decreased, and cell proliferation was inhibited by simvastatin in LNCaP cells. Conclusion: Simvastatin inhibited prostate cancer cell growth by decreasing cellular cholesterol and could be more effective in androgen-independent prostate cancer, where there is loss of regulation of LDLr expression. LDLr was shown to play an important role in the statin-induced inhibition of prostate cancer cell proliferation. These results suggest that future studies evaluating the cholesterol-lowering effects of statin may lead to new approaches to the prevention and treatment of prostate cancer.

146 Background: Enzalutamide (ENZ) is commonly used to treat patients with castration resistant prostate cancer (CRPC). However, the kinetics of serum androgen levels before and after ENZ treatment are unknown. We elucidated the kinetics of serum androgens and explored the possibility of identifying a useful marker for predicting the effects of ENZ. Methods: We conducted a prospective study from 2014 to 2018 at Gunma University Hospital and related facilities. 104 CRPC patients treated with ENZ were analyzed. We investigated the PSA reduction rate (50%, 90%), PSA-progression-free survival (PFS), and overall survival (OS) after administration. To measure levels of androgens accurately we measured serum androgen levels using LC-MS/MS. OS and PSA-PFS were assessed according to the PCWG 2 criteria. This study was approved by the Institutional Review Board of Gunma University Hospital (No. 1177). Results: The 50% and 90% PSA decline rates were 62.5% and 25.0%, respectively. Median serum testosterone (T), dihydrotestosterone (DHT), androstenedione (A-dione), and dehydroepiandrosterone-sulfate levels were 49.0, 5.8, 222.2, and 326.3 pg/ml, respectively. Mean serum levels of T, DHT, and A-dione increased significantly 12 and 24 weeks after compared to before treatment (p < 0.05). We performed a multivariate analysis using a Cox regression to predict OS and PSA-PFS. ECOG PS (0 vs. 1–2), hemoglobin (Hb ≥ 12.5 vs. < 12.5 g/dL), albumin (≥ 3.9 vs. < 3.9 g/dL), visceral metastasis (no vs. yes), EOD (0–2 vs. 3–4), docetaxel treatment (no vs. yes), and DHT level (≥11.25 vs. < 11.25 pg/mL, 11.25 was third quartile) were significant predictors of OS (p < 0.05). Hb (≥12.5 vs. < 12.5 g/dL), docetaxel treatment (no vs. yes), and level of DHT (≥ 5.9 vs. < 5.9 pg/mL) were significant predictors of PSA-PFS (p < 0.05). As a result of the binomial logistic analysis of the predictors of fatigue and decreased appetite, the presence of visceral metastasis (yes) and low DHT (

Japan has experienced a drastic increase in the incidence of prostate cancer (PC). To assess changes in the risk for PC, we investigated baseline prostate specific antigen (PSA) levels in first-time screened men, across a 25-year period. In total, 72,654 men, aged 50-79, underwent first-time PSA screening in Gunma prefecture between 1992 and 2016. Changes in the distribution of PSA levels were investigated, including the percentage of men with a PSA above cut-off values and linear regression analyses comparing log10 PSA with age. The 'ultimate incidence' of PC and clinically significant PC (CSPC) were estimated using the PC risk calculator. Changes in the age-standardized incidence rate (AIR) during this period were analyzed. The calculated coefficients of linear regression for age versus log10 PSA fluctuated during the 25-year period, but no trend was observed. In addition, the percentage of men with a PSA above cut-off values varied in each 5-year period, with no specific trend. The 'risk calculator (RC)-based AIR' of PC and CSPC were stable between 1992 and 2016. Therefore, the baseline risk for developing PC has remained unchanged in the past 25 years, in Japan. The drastic increase in the incidence of PC, beginning around 2000, may be primarily due to increased PSA screening in the country.

Androgens deprivation therapy for prostate cancer (PCa) has been widely established for the treatment of metastatic PCa cases and some localized PCa cases. With the discovery of LHRH agonists, it became possible to perform medical castration, and the range of options further expanded, but flare-up in progressive cases has been considered as a problem. As GnRH antagonists became available, we were able to begin the treatment without flare-up in advanced cases. In this chapter, we discuss the topics on LHRH agonists and antagonists and the relationships with adrenal androgens examined in our laboratory.

Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment.

Background Adrenal androgens play an important role in the development of castration-resistant prostate cancer therapeutics. The effect of gonadotropin-releasing hormone (GnRH) antagonists on adrenal androgens has not been studied sufficiently. We measured testicular and adrenal androgen levels in patients treated with a GnRH antagonist. Methods This study included 47 patients with histologically proven prostate cancer. All of the patients were treated with the GnRH antagonist degarelix. The mean patient age was 73.6 years. Pre-treatment blood samples were collected from all of the patients, and post-treatment samples were taken at 1, 3, 6, and 12 months after starting treatment. Testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), 17β-estradiol (E2), and androstenedione (A-dione) were measured by liquid chromatography-mass spectrometry. Dehydroepiandrosterone-sulfate (DHEA-S), luteinizing hormone, and follicle-stimulating hormone levels were measured by electro-chemiluminescence immunoassays. Results A significant reduction in T level (97.3% reduction) was observed in the patients 1 month after initiating treatment. In addition, levels of DHT, E2, DHEA-S, and A-dione decreased 1 month after initiating treatment (93.3, 84.9, 16.8, and 35.9% reduction, respectively). T, DHT, E2, DHEA-S, and A-dione levels remained significantly suppressed (97.1, 94.6, 85.3, 23.9, and 40.5% reduction, respectively) 12 months after initiating treatment. A significant decrease in DHEA level (15.4% reduction) was observed 12 months after initiating treatment. Conclusions Serum adrenal androgen levels decreased significantly in patients treated with a GnRH antagonist. Thus, long-term GnRH antagonist treatment may reduce serum adrenal androgen levels.

292 Background: Recent studies have shown that an early PSA response to AR-targeting agents in mCRPC is associated with a better prognosis. We analyzed the early PSA response to enzalutamide (ENZ) by measuring the PSA doubling time (PSADT) and PSA Velocity while monitoring oncologic outcomes and survival in Japanese patients. Methods: A total of 241 patients with mCRPC treated with ENZ were analyzed. Patients’ median age is 75±7.9 (range 53-93). The patients pre-docetaxel settings were 171 cases (71 %), post-docetaxel settings were 70 cases (29 %). The PSA-PFS and OS were assessed according to PCWG2 criteria. This study was approved by the institutional review board of Gunma University Hospital (No.1595). Results: A case where PSA did not decline at all was defined as Primary Resistance (PR). A case in which PSA once declined after treatment but then progressed was defined as Acquired Resistance (AR). Those in which PSA remained low after treatment were defined as Good Response (GR). We observed 77 PR cases (31.9 %), 125 AR cases (51.9 %) and 39 GR cases (16.2 %).PSA-PFS and OS pre-docetaxel were significantly increased as compared to patients’ post-docetaxcel (PSA-PFS; 47.0 wks vs. 13.4 wks p < 0.001, OS; Not Yet Reached vs. 80.7 wks p < 0.001). Multivariate analysis of prognostic factors, including the PSA response at 4 weeks, was performed using a Cox regression analysis. The PS (0 or 1-2), Hb (≧11.4 or < 11.4), time to CRPC(≧12 m or < 12 m), docetaxel treatment history (none or done) and a PSA decrease of 50% at 4 weeks were all significant factors for the prediction of OS (all variables, p < 0.05). In cases of acquired resistance (n = 125), a multivariate analysis using PSA kinetics factors such as PSADT and PSA Velocity (ng/mL/month) at PSA progression, Hb, time to CRPC(≧12 m or < 12 m), PSADT (≧2 months or < 2 months) and PSA Velocity ( < 20 ng/mL/month or≧20 ng/mL/month), were all factors predicting OS following PSA progression (p < 0.05). Conclusions: Our study has demonstrated that PSA dynamics after ENZ administration may be a useful prognostication factor for mCRPC patients.

Purpose: The β form of p120 is reported to be a strong coactivator of the androgen receptor. We investigated the gene expression profiles of the α and β forms of p120 in prostate cancer cell lines, benign prostatic hyperplasia (BPH), nontreated prostate cancer (NTPC), and prostate cancer after androgen deprivation therapy (PCA-ADT). Methods: We obtained 154 prostate needle biopsy specimens (81 in BPH, 51 in NTPC, and 22 in PCA-ADT). Levels of p120α and β expression were determined by multiplex real-time polymerase chain reaction. Results: Prostate cancer cell lines, LNCaP, PC-3, DU-145, and LNCaP-LA, which is a derivative of LNCaP under androgen deprivation, expressed both p120α and p120β. p120α expression levels were significantly higher than those of p120 β in all cell lines examined. In human prostate tissues, p120α expression was significantly higher than that of p120 β in BPH and NTPC. p120α expression in BPH was significantly higher than in other groups. In contrast, p120 β expression was significantly higher in NTPC and PCA-ADT than in BPH. Expression of the two forms of p120 was not correlated with age, prostate-specific antigen, or Gleason score. Conclusions: The expression profiles of p120 α and p120β significantly differ in cancerous and benign prostatic tissues.

Prostate cancer is a common disease in modern, developed societies and has a high incidence and mortality. High-density lipoprotein cholesterol (HDL-C) has recently received much attention as a possible risk marker of prostate cancer development and prognosis. In the present article, we summarized findings from epidemiologic studies of the association between HDL-C and prostate cancer. Low HDL-C level was found to be a risk and prognostic factor of prostate cancer in several epidemiologic studies, although the overall linkage between HDL and prostate cancer has not been definitively established. The mechanisms for this association remain uncertain; however, limited data from experimental studies imply a possible role of HDL in the pathophysiology of prostate cancer. More epidemiologic research, in combination with experimental studies, is needed in this field.

Aim: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reverses statin resistance in statin-resistant renal cell cancer (RCC). Materials and Methods: We induced simvastatin resistance in a renal clear cell carcinoma cell line (Caki-1-staR). In vitro and in vivo models were used to test the efficacy of YM155 and simvastatin. Results: Survivin gene expression was significantly stronger in Caki-1-staR cells than in its parent cells (Caki-1). In Caki-1-staR cells, YM155 significantly reduced expression of survivin gene and cell proliferation in a dose-dependent manner. Treatment with YM155 significantly reversed simvastatin resistance in Caki-1-staR cells. YM155 significantly inhibited the growth of Caki-1-staR tumors in a nude mouse tumor xenograft model. Furthermore, YM155 significantly enhanced the antitumor effects of simvastatin on Caki-1-staR tumors. Conclusion: Our results indicate that inhibition of survivin by YM155 overcomes statin resistance in RCC cells.

Background/Aim: Recent studies have shown that an early prostate-specific antigen (PSA) response to androgen receptor (AR)-targeting agents in metastatic castration-resistant prostate cancer (mCRPC) is associated with a better prognosis. We analyzed early PSA response to enzalutamide and oncological outcomes to study their prognostic significance in the Japanese population. Patients and Methods: Fifty-one patients with mCRPC (26 of pre-docetaxel and 25 of post-docetaxel status) were treated with enzalutamide. The PSA progression-free survival (PFS), radiographic PFS (rPFS) and overall survival (OS) were assessed. The association of rPFS and OS in patients with an early PSA response at 4 weeks after commencement of enzalutamide was studied. Results: Early PSA responses were significantly associated with a longer rPFS (median of 47.9 vs. 20.1 weeks, p

Recently, adrenal androgens have been targeted as key hormones for the development of castration-resistant prostate cancer therapeutics. Although circulating adrenal androgens originate mainly from the adrenal glands, the testes also supply about 10%. Although widely used in androgen deprivation medical castration therapy, the effect of luteinizing hormone-releasing hormone (LH-RH) agonist on adrenal androgens has not been fully studied. In this study, changes in testicular and adrenal androgen levels were measured and compared to adrenocorticotropic hormone levels. To assess the possible role of LH in the adrenal glands, immunohistochemical studies of the LH receptor in normal adrenal glands were performed. Forty-seven patients with localized or locally progressive prostate cancer were treated with LH-RH agonist with radiotherapy. Six months after initiation of treatment, testosterone, dihydrotestosterone, and estradiol levels were decreased by 90%-95%, and dehydroepiandrosterone-sulfate, dehydroepiandrosterone, and androstenedione levels were significantly decreased by 26%-40%. The suppressive effect of LH-RH agonist at 12 months was maintained. Adrenocorticotropic hormone levels showed an increasing trend at 6 months and a significant increase at 12 months. LH receptors were positively stained in the cortex cells of the reticular layer of the adrenal glands. The long-term LH-RH agonist treatment reduced adrenal-originated adrenal androgens. LH receptors in the adrenal cortex cells of the reticular layer might account for the underlying mechanism of reduced adrenal androgens.

BACKGROUND High fat diets are known to be a risk factor for prostate cancer. In this study, we investigated the effect of high fat diet on mouse prostate gene expression. METHODS C57BL/6J mice were fed either a control or high fat diet for 12 weeks. Microarray analyses were performed on mouse ventral prostate (VP) and dorsolateral prostate (DLP), followed by canonical pathway analysis and regulatory network identification. mRNA changes were confirmed by real time PCR. RESULTS Approximately 2,125, and 1,194 genes responded significantly to the high fat diet in VP, DLP, respectively. Pathways and networks related to oxidative stress, glutathione metabolism, NRF-mediated oxidative stress response and NF-kappaB were all differentially regulated by high fat diet. Glutathione peroxidase 3 (GPx3) mRNA levels were decreased by approximately twofold by high fat diet in all three prostate lobes. In human non-transformed prostate cells (PrSC, PrEC, and BPH-1), cholesterol loading decreased GPx3 expression, and increased H2O2 levels of culture medium. Troglitazone increased GPx3 expression in three normal prostate cells, and decreased H2O2 levels. In addition, troglitazone attenuated cholesterol-induced H2O2 increase. Tissue from prostate cancer biopsies had decreased GPx3 mRNA and its level was inversely related to the Gleason score. CONCLUSIONS High fat diet alters pathways related to many genes concerned with oxidative stress. GPx3, a gene identified by this analysis, was found to be down-regulated by high fat diet and appears be decreased in human prostate cancers, suggesting that GPx3 may have a possible role in modulating carcinogenesis. Prostate 71:1499–1509, 2011. © 2011 Wiley-Liss, Inc.

BACKGROUND Androgen deprivation therapy in men with prostate cancer leads to a significant increase of high density lipoprotein (HDL), but the effect of HDL on prostate cancer is unknown. Recently, HDL, which transports sphingosine-1-phosphate (S1P), was reported to activate signal transducer and activator of transcription 3 (Stat3) in cardiomyocytes. In this study, we examined the effect of HDL and S1P on Stat3 activation in prostate cancer cells and the involvement of S1P receptors in this process in three prostate cancer cell lines (PC-3, LNCaP, and DU145). METHODS Discordial reconstituted(r) HDL containing POPC, apoA-1, and S1P were prepared by the cholate dialysis method. The phosphorylations of Stat3, ERK1/2, and Akt were detected by Western blotting. Cell migration and invasion were determined by wound-healing assay and matrigel invasion chamber assay. RESULTS HDL increased serine 727 phosphorylation of Stat3, but not tyrosine 705 only in DU145 cells. S1P and rHDL-S1P also induced the phosphorylation, but not rHDL without S1P. They also induced DU145 cells migration and invasion. PD98059, a MEK inhibitor, and pertussis toxin, a Gi inhibitor, attenuated HDL-, S1P-, and rHDL-S1P-induced Stat3 phosphorylation, whereas LY294002, a PI3K inhibitor, had no effect. Concerning S1P receptors, S1P1 expression was much lower than S1P2 and S1P3 in DU145 cells. Both JTE013, a S1P2 antagonist, and VPC23019, a S1P1/S1P3 antagonist, attenuated HDL-, S1P-, and rHDL-S1P-induced Stat3 phosphorylations and cell migrations. CONCLUSIONS These results suggest that the change in HDL plasma levels by androgen deprivation therapy may alter prostate cancer growth and metastasis. Prostate 71:690–699, 2011. © 2010 Wiley-Liss, Inc.

Androgen deprivation therapy for prostate cancer leads to a significant increase of high-density lipoprotein (HDL), which is generally viewed as beneficial, particularly for cardiovascular disease, but the effect of HDL on prostate cancer is unknown. In this study, we investigated the effect of HDL on prostate cancer cell proliferation, migration, intracellular cholesterol levels, and the role of cholesterol transporters, namely ABCA1, ABCG1, and SR-BI in these processes. HDL induced cell proliferation and migration of the androgen-independent PC-3 and DU145 cells by a mechanism involving extracellular signal-regulated kinase (ERK) 1/2 and Akt, but had no effect on the androgen-dependent LNCaP cell, which did not express ABCA1 unlike the other cell lines. Treatment with HDL did not significantly alter the cholesterol content of the cell lines. Knockdown of ABCA1 but not ABCG1 or SR-BI by small interfering RNA (siRNA) inhibited HDL-induced cell proliferation, migration, and ERK1/2 and Akt signal transduction in PC-3 cells. Moreover, after treatment of LNCaP cells with charcoal-stripped fetal bovine serum, ABCA1 was induced ∼10-fold, enabling HDL to induce ERK1/2 activation, whereas small interfering RNA knockdown of ABCA1 inhibited HDL-induced ERK1/2 activation. Simvastatin, which inhibited ABCA1 expression in PC-3 and DU145 cells, attenuated HDL-induced PC-3 and DU145 cell proliferation, migration, and ERK1/2 and Akt phosphorylation. In human prostate biopsy samples, ABCA1 mRNA expression was ∼2-fold higher in the androgen deprivation therapy group than in subjects with benign prostatic hyperplasia or pretreatment prostate cancer groups. In summary, these results suggest that HDL by an ABCA1-dependent mechanism can mediate signal transduction, leading to increased proliferation and migration of prostate cancer cells. Mol Cancer Res; 8(9); 1284–94. ©2010 AACR.

To assess the effect of survivin gene expression on the proliferation of prostate cancer (PCa) cells and study the association of suvivin and its spliced isoforms gene expression levels with the pathologic grade of PCa.Gene expression of survivin and its spliced isoforms in the LNCaP and PC-3 PCa cell lines was determined using reverse transcriptase-polymerase chain reaction. We knocked down the gene expression of survivin using small interfering RNA and assessed the cell proliferation using the MTS assay. Next, we quantified the gene expression levels of survivin and its isoforms in prostate biopsy samples (PCa, n = 37; benign prostatic hyperplasia, n = 13; PCa after androgen deprivation therapy, n = 12) using the quantitative real-time polymerase chain reaction method.In PCa cells, survivin and survivin-2alpha and survivin-2B were expressed more than survivin-DeltaEx3. The decrease in survivin gene expression by transfection of siRNA was accompanied by the inhibition of cell proliferation of PCa cells (31% and 25% decreased in LNCaP and PC-3 cells, P0.01). In the prostate biopsy samples, the survivin expression in PCa was significantly greater than that in BPH or PCa after androgen deprivation therapy (PCa, 1; BPH, 0.16; PCa after androgen deprivation therapy, 0.27; P0.01). In the PCa samples, the survivin expression level was associated significantly with high-grade cancer (Gleason score 8 or 9; Gleason score 7 versus 8 or 9, 1 versus 2.00, respectively; P0.05). The survivin-2B/survivin ratio in high-grade cancer was lower than that in low-grade (Gleason score 7) cancer (Gleason score 7 versus 8 or 9, 1 versus 0.69; P0.10).These findings suggest that survivin and its spliced isoforms have associations with PCa cell proliferation and aggressive phenotypes.

Bartter症候群では一般的に腎不全に進行することは少ない. 今回われわれは腎不全を呈した小児Bartter症候群type IV症例に対して生体腎移植を施行した1例を経験したので報告する. 患者は15歳男児で, 新生児期より哺乳不良, 体重増加不良であり, 10か月時多飲多尿が出現した. 1歳9か月時の精査にて血漿レニン活性の高値, 低カリウム血症, 難聴などを認めたことからBartter症候群type IVと診断されインドメタシン, スピロノラクトン, 塩化カリウムの投与が開始された. 腎機能に関しては, 乳児期より低下していたが思春期になりさらに低下し, 生体腎移植目的に2004年4月に当科紹介受診となった. 2004年11月中旬に移植予定であったが, 10月中旬にBUN 156mg/dL, Cr 17.2mg/dLと腎機能の悪化を認めたため, 腎移植前のコンディショニングとして血液透析を開始し, 11月中旬に40歳の母親をドナーとして生体腎移植を施行した. Bartter症候群の腎移植症例として, 術前にRAA系の亢進は認めていなかったがマレイン酸エナラプリルとロサルタンカリウムを移植前より投与した. 腎移植後, 腎機能は改善しRAA系の亢進も認めていない. Bartter症候群では一般的に腎不全に進行することはまれであり, 腎不全の因子としてはBartter症候群の病態だけでなく, Bartter症候群の治療に用いられるNSAIDsもその因子のうちの一つである. またこれまでの報告を含め, 腎不全を呈したBartter症候群に対しては, 腎移植後に腎不全だけでなくBartter症候群による内分泌学的異常も改善し, 腎移植が有用な治療であると考えられた.

Background: It has been postulated that insulin-like growth factor-binding protein-3 (IGFBP-3) is a mediator of growth suppression signals. Recently, a correlation between the promoter hypermethylation of IGFBP-3 and cancer risk was reported in hepatocellular cancer and in non-small-cell lung cancer (NSCLC). We investigated whether the methylation status of IGFBP-3 promoter in prostate tissues influences the progression and prognosis of prostate cancer. Methods: We conducted a case-control study consisting of 38 prostate cancer patients and 57 control subjects, and assessed the relationship of promoter hypermethylation at IGFBP-3 with the clinical and pathological tumor characteristics of these patients. The methylation status was analyzed by two methylation-specific PCR techniques. Results: Hypermethylation of the IGFBP-3 promoter was found in 13 (34.2%) of the 38 cases, and 11 (19.3%) of the 57 controls with one method using a hepatocellular primer as described by Hanafusa et al. With other methods using a NSCLC-primer, as described by Chang et al., hypermethylation was found in four (10.5%) of the cases and two (3.5%) of the controls. No significant differences were observed in the methylation frequencies between the controls and the cases. When the cases were stratified based on their clinical stage (localized or metastatic) and pathological grade (Gleason score of

Background: The Ile to Val polymorphism at codon 655 of HER-2 was reported to be associated with a risk of sporadic prostate cancer and breast cancer. In this study, we examined the association of the HER-2 polymorphism with familial prostate cancer in a Japanese population. Materials and methods: We performed a case-control study consisting of 144 familial prostate cancer cases and 119 normal control subjects. The genetic polymorphism was analyzed by the restriction fragment length polymorphism method. Results: There was no significant difference between the case group and the control group for the allele or genotype distribution. Conclusion: In the present study, we could not confirm any significant association between the HER-2 polymorphism with familial prostate cancer risk in a Japanese population. Further large-scale studies are warranted to confirm the association of the HER-2 polymorphism with the risk of development of prostate cancer.

Summary Intratumoural steroidogenesis may play a significant role in the progression of prostate cancer (PC) in the context of long-term ablation of circulating testosterone (T). To clarify the mechanism accounting for the progression of PC in a 74-year-old man who had undergone bilateral orchiectomy when he was 5 years old, we performed immunohistochemical studies of androgen receptor (AR) and steroidogenic enzymes in the prostate. We also measured steroid hormone levels in the serum and prostate, as well as mRNA levels of genes mediating androgen metabolism in the prostate. Positive nuclear staining of AR was detected in malignant epithelial cells. The levels of androstenedione (Adione), T, and 5-alpha dihydrotestosterone (DHT) in the serum of the patient were similar to those in PC patients receiving neoadjuvant androgen deprivation therapy (ADT), but were higher in the patient's prostate than in PC patients not receiving ADT. The gene expression of CYP17A1 and HSD3B1 was not detected, whereas that of STS, HSD3B2, AKR1C3, SRD5A1, and SRD5A2 was detected. Moreover, cytoplasmic staining of HSD3B2, AKR1C3, SRD5A1, and SRD5A2 was detected in malignant epithelial cells. Hence, in the present case (a man with primary hypogonadism), steroidogenesis in PC tissues from adrenal androgens, especially dehydroepiandrosterone sulphate, was the mechanism accounting for progression of PC. This mechanism might help elucidate the development of castration-resistant PC.

We previously conducted a genome-wide linkage analysis of Japanese nuclear families affected with prostate cancer and showed that the susceptibility to prostate cancer was closely linked to D8S550 at 8p23. The role of farnesyl diphosphate farnesyltransferase (FDFT1), which is located under the peak marker D8S550 at 8p23, and squalene synthase, the enzyme encoded by FDFT1, in prostate cancer was studied.The association among common variants of FDFT1 with prostate cancer risk, the promoter activities of FDFT1 with different genotypes and the effects of inhibition of squalene synthase were studied, and the FDFT1 transcript levels of human prostate samples were quantified.The A allele of rs2645429 was significantly associated with prostate cancer risk in a Japanese familial prostate cancer population. Rs2645429 was located in the promoter region of FDFT1, and the AA genotype showed significantly increased promoter activity. The knockdown of FDFT1 mRNA expression or squalene synthase inhibition led to a significant decrease in prostate cancer cell proliferation. Additionally, human prostate cancer specimens expressed significantly higher levels of FDFT1 mRNA compared with noncancerous specimens. Finally, aggressive cancers showed higher transcript levels.FDFT1 and its encoded enzyme, squalene synthase, may play an important role in prostate cancer development and its aggressive phenotypes.

Several prior studies show a relationship between genetic markers at chromosome 8q24 and an increased prostate cancer risk. We confirmed the association of 8q24 markers with prostate cancer in the Japanese population and the association of these genetic variants with clinical characteristics.Included in this study were 134 patients with familial prostate cancer, 158 with sporadic prostate cancer and 119 controls. All were Japanese. We genotyped the 2, 8q24 markers SNP rs1447295 and microsatellite marker DG8S737 using real-time polymerase chain reaction and polymerase chain reaction based assay with fluorescence labeled primers.There was a significant positive association between the DG8S737 -12 allele and familial prostate cancer risk (OR 1.86, 95% CI 1.11-3.00, p = 0.02) and a significant association of risk with the rs1447295 A allele (OR 2.36, 95% CI 1.41-3.94, p = 0.002). Significant associations were noted for each marker in men with a high Gleason score.Two alleles at 8q24 are genetic risk factors for familial prostate cancer and high grade disease.

Background: Hypertriglyceridemia has been shown to be one of the risk factors for prostate cancer. In this study, we investigated the effect of remnant lipoproteins on cell growth in prostate cancer cell lines. Methods: Remnant lipoproteins were isolated as remnant like particles (RLP) from human plasma. We used RLP for TG-rich lipoproteins and low density lipoproteins (LDL) for cholesterol-rich lipoproteins respectively and examined the effect of lipoproteins on proliferation of PC-3 and LNCaP cells using MTS assays. Moreover, we studied the effect of RLP and LDL treatment on the regulation of lipoprotein receptors in prostate cancer cells to investigate the relationship between lipoprotein-induced cell proliferation and lipoprotein receptor expression using real-time PCR, Western blotting assays and siRNA. Results: RLP effectively induced PC-3 cell proliferation more than LDL, whereas both RLP and LDL could not induce LNCaP cell proliferation except at a higher concentration of RLP. LDL receptor (LDLr) was expressed in both prostate cancer cells but there was a sharp difference of sterol regulation between two cells. In PC-3 cells, LDL decreased the LDLr expression in some degree, but RLP did not. Meanwhile LDLr expression in LNCaP was easily downregulated by RLP and LDL. Blocking LDLr function significantly inhibited both RLP- and LDL-induced PC-3 cell proliferation. Conclusions: This study demonstrated that RLP-induced PC-3 cell proliferation more than LDL; however, both RLP and LDL hardly induced LNCaP cell proliferation. The differences of proliferation by lipoproteins might be involved in the regulation of LDLr expression.

Objectives To investigate the levels of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prostate-specific antigen (PSA) in prostate cancer patients before and after the switch from degarelix to leuprolide treatments. Methods We enrolled 40 treatment-naïve prostate cancer patients who were treated initially with degarelix and were later switched to leuprolide. The subjects were divided into three groups depending on when they were switched to leuprolide: the 3-month group (3m; switched after 84 days, n=10), the 2-month group (2m; 56 days, n=10), and the 1-month group (1m; 28 days, n=20). Patient symptoms and hormone levels were measured after switching therapy. The castration level was defined as a serum testosterone level ≤50 ng/dl. Results Thirty-nine subjects (97.5%) achieved castration levels of testosterone (11±5.8 ng/dl) 2 weeks after degarelix was first administered, and the characteristics of these patients were investigated. Testosterone levels increased and exceeded the castration level in one subject each of the 3m (142 ng/dl), 2m (72 ng/dl), and 1m groups (63 ng/dl). All subjects achieved the castration level by day 5. In contrast to testosterone levels, the LH and FSH surge on day 2 was significantly higher in the 1m group than in the other groups. The clinical symptoms were not exacerbated before or after switching in any patients. Conclusions A testosterone surge was observed in 8.3 % of the study patients; however, it was very short-lived and mild. LH and FSH levels were significantly higher 1 month after administration compared with 2 or 3 months after degarelix administration.

Background: Many studies have shown the relationship between pretreatment serum testosterone levels and the clinical stage or histological grade, but the clinical significance of pretreatment testosterone levels is controversial. We studied the association of pretreatment total testosterone levels with the clinical stage and histological grade of prostate cancer. Methods: We evaluated 2914 patients whose pretreatment testosterone levels were recorded from 1982 to 2002. Serum testosterone levels were measured by radioimmunoassay. Results: There was a trend toward decreasing testosterone values with worsening clinical staging. There was a trend toward decreasing testosterone values with worsening histological grading, too. Patients with poorly differentiated adenocarcinoma had significantly lower testosterone levels than those with the others (versus well; p p Conclusions: Newly diagnosed patients with poorly differentiated adenocarcinoma of prostate have lower testosterone levels than the others.

Genistein is a major component of soybean isoflavone and has multiple functions resulting in antitumor effects. Prostate cancer is 1 of the targets for the preventive role of genistein. We examined the effect of genistein on human prostate cancer (LNCaP and PC-3) cells. Proliferation of both cell lines was inhibited by genistein treatment in a dose-dependent manner. To obtain the gene expression profile of genistein in LNCaP cells, we performed cDNA microarray analysis. The expression of many genes, including apoptosis inhibitor (survivin), DNA topoisomerase II, cell division cycle 6 (CDC6) and mitogen-activated protein kinase 6 (MAPK 6), was downregulated. Expression levels were increased more than 2-fold in only 4 genes. The glutathione peroxidase (GPx)-1 gene expression level was the most upregulated. Quantitative real-time polymerase chain reaction revealed significant elevation of transcript levels of GPx-1 in both LNCaP and PC-3 cells. Upregulation of gene expression levels accompanied elevation of GPx enzyme activities. In contrast, no significant changes were observed in the gene expression levels and enzyme activities of the other antioxidant enzymes, superoxide dismutase and catalase. GPx activation might be one of the important characteristics of the effects of genistein on prostate cancer cells.

(a) Introduction and Objective: Signal transducer and activator of transcription 3 (Stat3) has been implicated in the promotion of migration, invasion and growth of prostate cancer cells. Recently, HDL, which transports the bioactive lipid sphingosine-1-phosphate (S1P), was reported to activate Stat3 in cardiomyocytes and is a known mitogen for several cell types. S1P acts by binding to several G protein-coupled receptors, namely S1P1, S1P2 and S1P3, which are expressed in prostate cancer cell lines. Androgen deprivation therapy in men with prostate cancer leads to a significant increase of HDL-C, but the effect of HDL on prostate cancer is unknown. In this study, we examined the effect of HDL and S1P on Stat3 activation in prostate cancer cells and the involvement of ERK1/2, Akt, and S1P receptors in this process in 3 prostate cancer cell lines (PC-3, LNCaP and DU145). (b) Methods: We used HDL isolated from health volunteer men. Discordial reconstituted(r) HDL containing POPC and apoA-1, (POPC/A-1)rHDL or POPC, S1P and A-1, (POPC/S1P/A-1)rHDL were prepared by the cholate dialysis method. The phosphorylations of Stat3, ERK1/2 and Akt were detected by Western blot analysis. mRNA expressions of PC cells were evaluated by quantitative real-time PCR. Cell viability, migration and invasion were determined by MTS assay, would healing assay and matrigel invasion chamber assay, respectively. (c) Results: HDL increased a dose and a time dependent Ser727 phosphorylation of Stat3, but not Tyr705 in DU145 cells but not in the other two cell lines. S1P and (POPC/S1P/A-1)rHDL also induced the phosphorylation, but not rHDL made without S1P (POPC/A-1). They also induced DU145 cells proliferation, migration, invasion and phosphorylations of ERK1/2 and Akt. PD98059, a MEK inhibitor, and pertussis toxin, a Gi inhibitor, attenuated HDL-, S1P- and (POPC/S1P/A-1)rHDL-induced Stat3 phosphorylation, whereas LY294002, a PI3K inhibitor, had no effect. Concerning S1P receptors, S1P1 expression was much lower than S1P2 and S1P3 in DU145 cells. Both JTE013, a S1P2 antagonist, and VPC23019, a S1P1/S1P3 antagonist, attenuated HDL-, S1P- and (POPC/S1P/A-1)rHDL-induced Stat3 phosphorylations and cell migrations. (d) Conclusions: HDL was shown to induce Ser727 phosphorylation of Stat3 via its S1P constituent and involved both S1P2 and S1P3 receptors in DU145 cells. Moreover, ERK1/2 activation is involved in cell activation by HDL. These results suggest that the change in HDL plasma levels by androgen deprivation therapy HDL may alter prostate cancer growth and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5107.