Publications by authors named "Yasuhiro Shibata"

80 Publications

Combination therapy with novel androgen receptor antagonists and statin for castration-resistant prostate cancer.

Prostate 2021 Nov 29. Epub 2021 Nov 29.

Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Background: One of the growth mechanisms of castration-resistant prostate cancer (CRPC) is de novo androgen synthesis from intracellular cholesterol, and statins may be able to inhibit this mechanism. In addition, statins have been reported to suppress the expression of androgen receptors (ARs) in prostate cancer cell lines. In this study, we investigated a combination therapy of novel AR antagonists and statin, simvastatin, for CRPC.

Methods: LNCaP, 22Rv1, and PC-3 human prostate cancer cell lines were used. We developed androgen-independent LNCaP cells (LNCaP-LA). Microarray analysis was performed, followed by pathway analysis, and mRNA and protein expression was evaluated by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. Cell viability was determined by MTS assay and cell counts. All evaluations were performed on cells treated with simvastatin and with or without AR antagonists (enzalutamide, apalutamide, and darolutamide).

Results: The combination of darolutamide and simvastatin most significantly suppressed proliferation in LNCaP-LA and 22Rv1 cells. In a 22Rv1-derived mouse xenograft model, the combination of darolutamide and simvastatin enhanced the inhibition of cell proliferation. In LNCaP-LA cells, the combination of darolutamide and simvastatin led to reduction in the mRNA expression of the androgen-stimulated genes, KLK2 and PSA; however, this reduction in expression did not occur in 22Rv1 cells. The microarray data and pathway analyses showed that the number of differentially expressed genes in the darolutamide and simvastatin-treated 22Rv1 cells was the highest in the pathway termed "role of cell cycle." Consequently, we focused our efforts on the cell cycle regulator polo-like kinase 1 (PLK1), cyclin-dependent kinase 2 (CDK2), and cell cycle division 25C (CDC25C). In 22Rv1 cells, the combination of darolutamide and simvastatin suppressed the mRNA and protein expression of these three genes. In addition, in PC-3 cells (which lack AR expression), the combination of simvastatin and darolutamide enhanced the suppression of cell proliferation and expression of these genes.

Conclusions: Simvastatin alters the expression of many genes involved in the cell cycle in CRPC cells. Thus, the combination of novel AR antagonists (darolutamide) and simvastatin can potentially affect CRPC growth through both androgen-dependent and androgen-independent mechanisms.
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http://dx.doi.org/10.1002/pros.24274DOI Listing
November 2021

Ratio of the expression levels of androgen receptor splice variant 7 to androgen receptor in castration refractory prostate cancer.

Oncol Lett 2021 Dec 13;22(6):831. Epub 2021 Oct 13.

Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.

In clinical samples, the expression of androgen receptor (AR) and of AR splice variant 7 (AR-V7) is higher in castration-resistant prostate cancer (CRPC) compared with that in hormone-sensitive prostate cancer (PCa). However, there are only a few reports on the ratio of the expression levels of AR-V7 to AR (AR-V7/AR) in prostate tissue. The present study evaluated AR-V7/AR expression in various types of human prostate tissues and CRPC cells. Pretreatment prostate tissue samples from patients with benign prostatic hyperplasia (BPH; n=18), Gleason score 7 (n=17), and Gleason score 8-10 (n=26) were collected at the time of prostate biopsy, and tissue samples from CRPC patients (n=10) were collected at the time of transurethral resection of the prostate. Furthermore, androgen-independent LNCaP cells were established. The mRNA expression levels of AR and AR-V7, cell proliferation and prostate-specific antigen (PSA) production were evaluated by reverse transcription quantitative PCR, MTS assay and chemiluminescent enzyme immunoassay, respectively. There was a significant difference in AR-V7/AR expression ratios between the CRPC group and the BPH and pre-treatment PCa groups (CRPC, 7%; BPH and pre-treatment PCa, 1%). Subsequently, we compared the AR and AR-V7 expression levels in CRPC samples with those in the pretreatment prostate tissues from the same patients. The results demonstrated that the AR-V7/AR ratio increased from 3 to 9% after CRPC onset. Furthermore, experiment demonstrated that AR-V7 expression in LNCaP cells was increased after transforming into CRPC cells. The AR-V7/AR ratio also increased from 0.05 to 0.3%. In addition, small interfering (si)-RNA-mediated knockdown of AR inhibited the proliferation of and PSA production from androgen-independent LNCaP cells; however, AR-V7 knockdown had no effect. Conversely, siRNA-mediated knockdown of both AR and AR-V7 inhibited the proliferation of VCAP cells. In summary, the findings from the present study demonstrated that AR-V7 expression and AR-V7/AR ratio were increased after the onset of CRPC, which had a limited role in CRPC cell proliferation. Further investigation is required to clarify the roles of AR other splice variants and AR-V7 in CRPC.
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http://dx.doi.org/10.3892/ol.2021.13092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527558PMC
December 2021

Presepsin as a predictor of septic shock in patients with urinary tract infection.

BMC Urol 2021 Oct 12;21(1):144. Epub 2021 Oct 12.

Department of Urology, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi, 371-8511, Japan.

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 < 0.001). Multivariate logistic regression analysis showed that presepsin (≥ 500 pg/ml) was an independent risk factor for septic shock (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.
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http://dx.doi.org/10.1186/s12894-021-00906-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513358PMC
October 2021

Mediterranean fever gene-associated enterocolitis in an elderly Japanese woman.

Clin J Gastroenterol 2021 Dec 24;14(6):1661-1666. Epub 2021 Aug 24.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S1, W16, Chuo-ku, Sapporo, 060-8543, Japan.

An 86-year-old woman was admitted to our hospital with anemia. She had never experienced symptoms of serositis. Colonoscopy revealed colitis with erosions and a friable mucosa. First, she was diagnosed with unclassified inflammatory bowel disease (IBD-U). We suspected familial Mediterranean fever as a differential diagnosis of IBD-U, and MEFV gene analysis showed heterozygosity for Exon2 R202Q. The patient was treated with colchicine 0.5 mg. After 4 months, a follow-up colonoscopy showed remarkable improvement of the mucosal inflammation throughout the entire colon. MEFV gene-associated enterocolitis responding to colchicine may be observed in patients with IBD-U and elucidating the role of MEFV gene mutations in intestinal inflammation is a future challenge.
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http://dx.doi.org/10.1007/s12328-021-01497-1DOI Listing
December 2021

Prognostic Factors in Hormone-sensitive Prostate Cancer Patients Treated With Combined Androgen Blockade: A Consecutive 15-year Study at a Single Japanese Institute.

In Vivo 2021 Jan-Feb;35(1):373-384

Department of Urology, Gunma University Graduate School of Medicine, Gunma, Japan.

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.
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http://dx.doi.org/10.21873/invivo.12268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880762PMC
June 2021

Polo-like kinase 4 and Stromal antigen 3 are not associated with recurrent pregnancy loss caused by embryonic aneuploidy.

Hum Genome Var 2020 29;7:18. Epub 2020 May 29.

Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

No genetic association with recurrent pregnancy loss (RPL) caused by embryonic aneuploidy has been found. Recent studies have indicated that the common genetic variant rs2305957, surrounding the gene, contributes to mitotic-origin aneuploidy risk during human early embryo development. The decrease in meiosis-specific cohesin causes predivision of sister chromatids in the centromere and chromosome segregation errors. is a component of cohesin and is a meiosis-specific gene. Our case-control study included 184 patients with RPL whose previous products of conception (POC) exhibited aneuploidy and 190 fertile control women without a history of miscarriage. We performed a genetic association study to examine the genotype distribution at (rs2305957) and in patients with RPL caused by aneuploidy compared with controls. Regarding , SNPs with a minor allele frequency (MAF) threshold > 0.05 that were predicted to be binding sites of transcription factors and that showed significant associations in expression quantitative trait locus (e-QTL) analysis were selected. No significant differences in the MAF or distribution in any model of (rs2305957) and 5 selected tag SNPs in were found between the patients and controls. A further genome-wide association study is needed since a combination of genetic risk alleles might be useful in predicting future age-dependent RPL caused by aneuploidy.
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http://dx.doi.org/10.1038/s41439-020-0106-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260232PMC
May 2020

An exploratory retrospective multicenter study of prognostic factors in mCRPC patients undergoing enzalutamide treatment: Focus on early PSA decline and kinetics at time of progression.

Prostate 2019 09 23;79(12):1462-1470. Epub 2019 Jul 23.

Department of Urology, Gunma University Hospital, Japan.

Background: Recent studies have shown that an early prostate-specific antigen (PSA) response to androgen receptor-targeting agents in metastatic castration-resistant prostate cancer (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 (PSAV) while monitoring oncologic outcomes and survival in Japanese patients.

Methods: We analyzed a total of 241 patients with mCRPC who were treated with ENZ. The patients' median age was 75 ± 7.9 years (range, 53-93 years). There were 171 (71%) predocetaxel cases, and 70 (29%) post docetaxel cases. PSA-progression-free survival (PFS) and overall survival (OS) were assessed according to Prostate Cancer Working Group 2 criteria. This study was approved by the Institutional Review Board of Gunma University Hospital (No. 1595).

Results: We observed 77 good response (GR; case in which PSA remained low after treatment) cases (31.9%), 125 acquired resistance (AR; decline in PSA after treatment followed by progression) cases (51.9%), and 39 primary resistance (PR; lack of decline in PSA) cases (16.2%). Predocetaxel, PSA-PFS, and OS were significantly higher compared with post docetaxel (PSA-PFS: 47.0 vs 13.4 weeks, P < .001; OS: not yet reached vs 80.7 weeks, P < .001). Multivariate analysis of prognostic factors, including PSA response at 4 weeks, was performed using Cox regression analysis. ECOG PS (0 vs 1-2), hemoglobin (Hb; ≥ 12.2 vs < 12.2 g/dL), time to CRPC ( ≥ 12 vs < 12 m), docetaxel treatment history (no vs yes), and a PSA reduction of 50% at 4 weeks were significant predictors of OS (all, P < .05). In cases of AR (n = 125), multivariate analysis showed that PSA kinetic factors, such as PSADT and PSAV (ng/mL/m), Hb, time to CRPC, PSADT ( ≥ 2 vs < 2 m), and PSAV ( < 20 vs ≥ 20 ng/mL/m), were all predictive of OS following PSA-progression (P < .05).

Conclusions: Our study has demonstrated that PSA dynamics after ENZ administration may be a useful prognostic factor for mCRPC patients.
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http://dx.doi.org/10.1002/pros.23865DOI Listing
September 2019

Screening for prostate cancer: History, evidence, controversies and future perspectives toward individualized screening.

Int J Urol 2019 10 10;26(10):956-970. Epub 2019 Jun 10.

Institute for Preventive Medicine, Kurosawa Hospital, Takasaki, Gunma, Japan.

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 Göteborg 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.
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http://dx.doi.org/10.1111/iju.14039DOI Listing
October 2019

Improved Arterial Preservation Achieved by Combined Use of Indocyanine Green Angiography and Doppler Detector During Microsurgical Subinguinal Varicocelectomy.

J Invest Surg 2020 Dec 9;33(10):941-947. Epub 2019 May 9.

Department of Clinical Investigation and Research Unit, Gunma University Graduate School of Medicine, Maebashi, Japan.

The microsurgical approach is considered the most reliable procedure in varicocelectomy. However, as there are difficulties in identifying the spermatic artery at the peripheral level, we had introduced intraoperative indocyanine green angiography (ICGA) for identification of arteries. In this study, we further investigated the usefulness of intraoperative ICGA in combination with an ordinary Doppler detector in microsurgical subinguinal varicocelectomy. : A total of 140 men who underwent microsurgical subinguinal varicocelectomy at Gunma University Hospital were included. An operating microscope equipped with a near-infrared charge-coupled device was used for intraoperative ICGA. After exposing the vessels, arteries were identified using endoscopic vision only or with assistance of Doppler detector or ICGA, or of both. The number of preserved arteries was compared among the groups. : ICGA clearly visualized the internal spermatic arteries in all cases, allowing the surgeon to perform real-time identification and isolation of the spermatic artery intraoperatively. The use of ICGA or Doppler detector significantly increased the number of preserved arteries compared to the microscope-only operation from 1.11 to 1.75 ( < 0.05) and 1.57 ( < 0.05), respectively. The additional use of ICGA with Doppler detector further increased the number of preserved arteries to 2.41 ( < 0.05). : Intraoperative ICGA facilitated safe and quick microsurgical subinguinal varicocelectomy by enabling visualization of thin spermatic cord blood vessels. Improved preservation of thin arteries, which is essential for patients with infertility, can be achieved with the combined use of ICGA and ordinary Doppler detector.
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http://dx.doi.org/10.1080/08941939.2019.1577516DOI Listing
December 2020

Long-term longitudinal changes in baseline PSA distribution and estimated prevalence of prostate cancer in male Japanese participants of population-based PSA screening.

Int J Cancer 2018 10 14;143(7):1611-1619. Epub 2018 May 14.

Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Japan.

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 log 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 log 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.
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http://dx.doi.org/10.1002/ijc.31560DOI Listing
October 2018

Assessment of antimicrobiral prophylaxis in transperineal prostate biopsy: A single-center retrospective study of 485 cases.

J Infect Chemother 2018 Aug;24(8):637-640

Department of Urology, Gunma University Hospital, Japan.

To verify the validity of our antimicrobial prophylaxis regimen for transperineal prostate biopsies, we investigated the rate of infectious complications in this procedure. We retrospectively investigated the infectious complications in 485 patients who underwent a transperineal prostate biopsy between 2014 and 2016 at our hospital. In the clinic, we use cefazolin (CEZ) for antimicrobial prophylaxis. Infectious complications were assessed up to postoperative day (POD) 30. Patients with infectious complications were further investigated to determine the site of infection, outbreak day, and type of pathogenic bacteria. The rate of infectious complications was 0.82% (4 out of 485 patients). Three patients developed prostatitis, 1 progressed into septic shock, and 1 patient developed epididymitis. The pathogenic bacteria identified were Pseudomonas aeruginosa (1 of 4), Enterococcus faecalis (1 of 4) and Escherichia coli that harbour extended-spectrum beta lactamase (ESBL-productive E. coli) (2 of 4). The earliest outbreak was POD 2 and the latest was POD 14. Infectious complications tended to increase in patients in whom an indwelling urethral catheter was inserted (p = 0.0567). However, there were no statistically significant relationships between any risk factor and the occurrence of infectious complications. We concluded that CEZ is adequate for the prevention of perioperative infectious complications in transperineal prostate biopsies. Furthermore, we reaffirmed the importance of correct perioperative management, including preoperative assessment.
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http://dx.doi.org/10.1016/j.jiac.2018.03.014DOI Listing
August 2018

Effect of Androgen-deprivation Therapy on Bone Mineral Density in Japanese Patients with Prostate Cancer.

In Vivo 2018 Mar-Apr;32(2):409-412

Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Japan.

Background/aim: To evaluate bone mineral density (BMD) in Japanese patients with prostate cancer (PCa) after administering androgen deprivation therapy (ADT) for 2 years.

Patients And Methods: A total of 84 Japanese patients with PCa were enrolled in this study during the period 2008-2011. BMD was measured by dual energy X-ray absorptiometry, every 6 months. The fracture risk assessment tool (FRAX) score was calculated before starting ADT. We evaluated the change in BMD over a 2-year period and the relationship between this change, the FRAX score, and the estimated glomerular filtration rate (eGFR).

Results: Compared to baseline, BMD decreased by 2.50% at 6 months after ADT, by 4.28% after 12 months, by 5.34% after 18 months, and by 6.16% after 2 years (all p<0.05). Multivariate analysis revealed that the eGFR, according to a threshold rate of 73.5 ml/min, was a significant factor in BMD.

Conclusion: Lumbar BMD in Japanese patients with PCa decreased by 4.28% at 1 year after ADT and by 6.16% after 2 years. We found a correlation between the decrease in BMD and the eGFR before initiating ADT, suggesting a small BMD reduction in patients with PCa who have good renal function.
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http://dx.doi.org/10.21873/invivo.11254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905214PMC
August 2018

Simvastatin in combination with meclofenamic acid inhibits the proliferation and migration of human prostate cancer PC-3 cells via an AKR1C3 mechanism.

Oncol Lett 2018 Mar 29;15(3):3167-3172. Epub 2017 Dec 29.

Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.

Statins have become of interest in research due to their anticancer effects. However, the exact mechanism of their anticancer properties remains unclear. The authors previously reported that statins decrease intracellular cholesterol levels in androgen-independent prostate cancer cells. In androgen synthesis, cholesterol is the primary material and certain enzymes have important roles. The present study aimed to determine whether simvastatin alters the expression of androgen synthesis-associated enzymes in androgen-independent prostate cancer cells. A novel combination therapy of statins and other drugs that inhibit the overexpression of enzymes involved in androgen synthesis was explored. The cytotoxicity of simvastatin and meclofenamic acid was assessed in prostate cancer cells using MTS and migration assays. Testosterone and dihydrotestosterone concentrations in the culture medium were measured using liquid chromatography-tandem mass spectrometry. RAC-α-serine/threonine-protein kinase (Akt) phosphorylation was detected by western blot analysis. Following treatment with simvastatin, aldo-keto reductase family 1 member C3 (AKR1C3) expression increased in PC-3 (>60-fold) and LNCaP-LA cells, however not in 22Rv1 cells. Small interfering (si)RNA was used to clarify the effects of AKR1C3 expression. The reduction in AKR1C3 expression in PC-3 cells following siRNA transfection was not associated with basal cell proliferation and migration; however, treatment with simvastatin decreased cell proliferation and migration. The combination of simvastatin and meclofenamic acid, an AKR1C3 inhibitor, further enhanced the inhibition of cell proliferation and migration compared with treatment with either drug alone. Furthermore, treatment with simvastatin attenuated insulin-like growth factor 1-induced Akt activation; however, the combination of simvastatin and meclofenamic acid further inhibited Akt activation. These results suggest that the combination of simvastatin and meclofenamic acid may be an effective strategy for the treatment of castration-resistant prostate cancer.
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http://dx.doi.org/10.3892/ol.2017.7721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778917PMC
March 2018

High salt loading induces urinary storage dysfunction via upregulation of epithelial sodium channel alpha in the bladder epithelium in Dahl salt-sensitive rats.

J Pharmacol Sci 2017 Nov 10;135(3):121-125. Epub 2017 Oct 10.

Department of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe do-ri, Mizuho-ku, Nagoya 467-8603, Japan; Department of Clinical Pharmaceutics, Graduate School of Medical Sciences, Nagoya City University, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Electronic address:

We aimed to investigate whether high salt intake affects bladder function via epithelial sodium channel (ENaC) by using Dahl salt-resistant (DR) and salt-sensitive (DS) rats. Bladder weight of DR + high-salt diet (HS, 8% NaCl) and DS + HS groups were significantly higher than those of DR + normal-salt diet (NS, 0.3% NaCl) and DS + NS groups after one week treatment. We thereafter used only DR + HS and DS + HS group. Systolic and diastolic blood pressures were significantly higher in DS + HS group than in DR + HS group after the treatment period. Cystometrogram showed the intercontraction intervals (ICI) were significantly shorter in DS + HS group than in DR + HS group during infusion of saline. Subsequent infusion of amiloride significantly prolonged ICI in DS + HS group, while no intra-group difference in ICI was observed in DR + HS group. No intra- or inter-group differences in maximum intravesical pressure were observed. Protein expression levels of ENaCα in the bladder were significantly higher in DS + HS group than in DR + HS group. ENaCα protein was localized at bladder epithelium in both groups. In conclusion, high salt intake is considered to cause urinary storage dysfunction via upregulation of ENaC in the bladder epithelium with salt-sensitive hypertension, suggesting that ENaC might be a candidate for therapeutic target for urinary storage dysfunction.
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http://dx.doi.org/10.1016/j.jphs.2017.10.001DOI Listing
November 2017

A gonadotropin-releasing hormone antagonist reduces serum adrenal androgen levels in prostate cancer patients.

BMC Urol 2017 Aug 29;17(1):70. Epub 2017 Aug 29.

Department of Urology, Gunma University Graduate School of Medicine, 3-9-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.

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.
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http://dx.doi.org/10.1186/s12894-017-0261-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575925PMC
August 2017

Evaluation of Bone Turnover / Quality Markers and Bone Mineral Density in Prostate Cancer Patients Receiving Androgen Deprivation Therapy with or without Denosumab.

Anticancer Res 2017 07;37(7):3667-3671

Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Japan.

Background/aim: Androgen deprivation therapy (ADT) is a mainstay therapy for prostate cancer (PCa). ADT induces bone loss and increases the risk of osteoporosis and fractures. Recently, loss of bone quality has received attention as a factor that causes loss of bone strength independent of bone mineral density (BMD). Pentosidine has been identified as a surrogate marker of bone quality. Therefore, bone quality markers were evaluated retrospectively in PCa patients receiving ADT with or without denosumab.

Patients And Methods: This study included 46 PCa patients. Twenty patients received denosumab. We measured pentosidine as bone quality marker and TRACP-5b as bone turnover marker. Pre- and 12-month BMD was measured in the lumbar spine and femoral neck.

Results: In the denosumab group (D+), BMD at the lumbar spine was increased by 6.7% compared with the group that did not receive denosumab (D-) at 12 months (p=0.0015). BMD at the femoral neck was increased by 3.1% at 12 months (p=0.0076). The mean value of TRAP-5b was lower in the D+ group than the D- group at 12 months (p<0.001). The mean serum levels of pentosidine in the D+ group were decreased by -39.6% compared with the D- group at 12 months (p=0.0036).

Conclusion: Denosumab increased BMD during ADT for PCa and inhibited the increasing levels of serum pentosidine in PCa patients undergoing ADT.
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http://dx.doi.org/10.21873/anticanres.11737DOI Listing
July 2017

Predictive value of different prostate-specific antigen-based markers in men with baseline total prostate-specific antigen <2.0 ng/mL.

Int J Urol 2017 08 31;24(8):602-609. Epub 2017 May 31.

Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Objectives: To investigate the predictive value of various molecular forms of prostate-specific antigen in men with baseline prostate-specific antigen <2.0 ng/mL.

Methods: The case cohort comprised 150 men with a baseline prostate-specific antigen level <2.0 ng/mL, and who developed prostate cancer within 10 years. The control cohort was 300 baseline prostate-specific antigen- and age-adjusted men who did not develop prostate cancer. Serum prostate-specific antigen, free prostate-specific antigen, and [-2] proenzyme prostate-specific antigen were measured at baseline and last screening visit. The predictive impact of baseline prostate-specific antigen- and [-2] proenzyme prostate-specific antigen-related indices on developing prostate cancer was investigated. The predictive impact of those indices at last screening visit and velocities from baseline to final screening on tumor aggressiveness were also investigated.

Results: The baseline free to total prostate-specific antigen ratio was a significant predictor of prostate cancer development. The odds ratio was 6.08 in the lowest quintile baseline free to total prostate-specific antigen ratio subgroup. No serum indices at diagnosis were associated with tumor aggressiveness. The Prostate Health Index velocity and [-2] proenzyme prostate-specific antigen/free prostate-specific antigen velocity significantly increased in patients with higher risk D'Amico risk groups and higher Gleason scores.

Conclusions: Free to total prostate-specific antigen ratio in men with low baseline prostate-specific antigen levels seems to predict the risk of developing prostate cancer, and it could be useful for a more effective individualized screening system. Longitudinal changes in [-2] proenzyme prostate-specific antigen-related indices seem to correlate with tumor aggressiveness, and they could be used as prognostic tool before treatment and during active surveillance.
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http://dx.doi.org/10.1111/iju.13381DOI Listing
August 2017

Effects of Steroidal Antiandrogen or 5-alpha-reductase Inhibitor on Prostate Tissue Hormone Content.

Prostate 2017 May 1;77(6):672-680. Epub 2017 Feb 1.

Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Japan.

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 77: 672-680, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/pros.23315DOI Listing
May 2017

Consequences of an Early PSA Response to Enzalutamide Treatment for Japanese Patients with Metastatic Castration-resistant Prostate Cancer.

Anticancer Res 2016 11;36(11):6141-6149

Department of Urology, Gunma University Graduate School of Medicine, Gunma, Japan

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<0.001, in patients exhibiting a 50% PSA response; median of 40.9 vs. 20.1 weeks, p=0.016, in patients exhibiting a 30% PSA response). OS was also significantly associated with an early PSA response (p=0.002 for patients exhibiting a 50% PSA response, p=0.003 for patients exhibiting a 30% PSA response). Multivariate analysis showed that the predictors of a 50% PSA response were an interval to mCRPC and a docetaxel treatment history, while the predictor of a 30% PSA response was a docetaxel treatment history. Furthermore, a 50% PSA response was independently prognostic of rPFS.

Conclusion: An early PSA response to enzalutamide was significantly associated with a longer rPFS and OS. This information will aid in the management of patients treated with enzalutamide.
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http://dx.doi.org/10.21873/anticanres.11205DOI Listing
November 2016

Efficacy of Indocyanine Green Angiography on Microsurgical Subinguinal Varicocelectomy.

J Invest Surg 2017 Aug 13;30(4):247-251. Epub 2016 Oct 13.

a Department of Urology , Gunma University Graduate School of Medicine , Maebashi , Japan.

Objectives: Microsurgical subinguinal varicocelectomy is one of the best treatment modalities for varicoceles related to male infertility and scrotal pain. However, the difficulty in identifying testicular arteries, which should be spared, is a limitation of this technique. To visualize and identify the testicular arteries in spermatic cord during the operation, we examined the efficacy of intraoperative indocyanine green angiography (ICGA), which is regularly used in microsurgical neurosurgery.

Methods: After the exposure of the spermatic cord blood vessels, ICG was injected intravenously under a surgical microscope for observing infrared fluorescence in patients to identify and isolate the testicular artery.

Results: The testicular artery was clearly identified by ICGA and was able to separate under ICGA view. Thereafter, the varicose veins were repeatedly ligated, while preserving a few lymphatic vessels and the spermatic duct. The preserved arteries were confirmed by repeated ICGA at the end of microsurgical operation. The number of arteries identified by ICGA was greater than the number detected by preoperative computed tomography angiogram.

Conclusions: Microsurgical subinguinal varicocelectomy using intraoperative ICGA facilitated safe and quick surgery by enabling the visualization of the spermatic cord blood vessels. This is the first report to indicate the usefulness of vessel visualization by ICGA during microsurgical subinguinal varicocelectomy.
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http://dx.doi.org/10.1080/08941939.2016.1236855DOI Listing
August 2017

[EFFICACY OF MICROSURGICAL SUBINGUINAL VARICOCELECTOMY USING INDOCYANINE GREEN FLUORESCENCE ANGIOGRAPHY: A PILOT STUDY].

Nihon Hinyokika Gakkai Zasshi 2015 Oct;106(4):293-8

Microsurgical subinguinal varicocelectomy is one of the best treatment modalities for varicoceles. However, the difficulty in identifying testicular arteries that should be spared is a limitation of this technique. We assessed the efficacy of intraoperative indocyanine green angiography (ICGA) during microsurgical subinguinal varicocelectomy in three pilot cases. We performed microsurgical subinguinal varicocelectomy using a surgical microscope for observing infrared fluorescence in patients with infertility or chronic pain associated with varicoceles. After the exposure of the spermatic cord blood vessels, ICG was injected intravenously to identify and isolate the testicular artery. Thereafter, the varicose veins were repeatedly ligated, while preserving a few lymphatic vessels and the spermatic duct. The testicular artery could be clearly identified by ICGA and were able to separate under ICGA. The preserved arteries were confirmed by ICGA at the end of microsurgical operation. Though, all the internal spermatic veins could be safely ligated, while sparing the testicular arteries and lymphatic vessels. Microsurgical subinguinal varicocelectomy using intraoperative ICGA facilitated safe and quick surgery by enabling the visualization of the spermatic cord blood vessels. This is the first report to indicate the usefulness of vessel visualization by ICGA during microsurgical subinguinal varicocelectomy.
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http://dx.doi.org/10.5980/jpnjurol.106.293DOI Listing
October 2015

[SQUAMOUS CELL CARCINOMA WITH CLOACAL EXSTROPHY: A CASE REPORT].

Nihon Hinyokika Gakkai Zasshi 2015 Oct;106(4):274-9

A 41-year-old man with a history of cloacal exstrophy presented to a local clinic with abdominal pain and bowel sounds. He was noted to have pain at the site of scarring due to cloacal exstrophy and a laceration at its center, which was stained with feces. He was referred to our department because of an enterocutaneous fistula. Skin biopsy of the neoplastic lesion at this site led to a diagnosis of squamous cell carcinoma. Computed tomography showed tumor invasion of the ileum and right inguinal lymph node enlargement. We performed tumor resection, partial enterectomy, intestinal anastomosis, abdominal wall reconstruction with a left pedicled anterolateral thigh flap, split-thickness skin grafting, and right inguinal lymph node biopsy. Histopathological examination revealed cancer growth, invasion, and pearl formation in the lymph nodes, leading to a diagnosis of abdominal squamous cell carcinoma with metastasis to the inguinal lymph nodes. The skin graft took well, and the patient was discharged. He is scheduled for right inguinal lymph node dissection at a later date.
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http://dx.doi.org/10.5980/jpnjurol.106.274DOI Listing
October 2015

A CASE OF GROWING TERATOMA SYNDROME.

Nihon Hinyokika Gakkai Zasshi 2016 ;107(2):115-120

Department of Pathology, Gunma University Hospital.

A 25-year-old man with a left testicular tumor underwent a high inguinal orchiectomy. Histopathological examination of the resected specimen revealed tumors of more than one histological type, mixed forms (seminoma, immature teratoma). Further evaluation revealed no metastasis (pT1N0M0S1 Stage IS).Four months after orchiectomy, alpha-fetoprotein (AFP) was elevated.CT scan revealed retroperitoneal masses of recurrent tumor. Although the AFP returned to normal level after four courses of BEP (bleomycin, etoposide and cisplatin), the retroperitoneal lymph nodes continued to grow. He underwent excision of the retroperitoneal lymph node dissection. Histopathological examination of the resected specimen revealed mature teratoma.Few reports examined about the development mechanism of growing teratoma syndrome (GTS). We considered that the development mechanism of GTS in this case is induction of differentiation. In this case report, we discuss the development mechanism of GTS based on bibliographical consideration.
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http://dx.doi.org/10.5980/jpnjurol.107.115DOI Listing
August 2018

Mechanical prophylaxis is a heparin-independent risk for anti-platelet factor 4/heparin antibody formation after orthopedic surgery.

Blood 2016 Feb 9;127(8):1036-43. Epub 2015 Dec 9.

Japanese National Hospital Organization (NHO)-Evidence-Based Medicine Study Group for the Clinical Study of Prevention and Actual Situation of Venous Thromboembolism After Total Arthroplasty, Tokyo, Japan; Department of Orthopedic Surgery, NHO Nagasaki Medical Center, Nagasaki, Japan.

Platelet-activating antibodies, which recognize platelet factor 4 (PF4)/heparin complexes, induce spontaneous heparin-induced thrombocytopenia (HIT) syndrome or fondaparinux-associated HIT without exposure to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). This condition mostly occurs after major orthopedic surgery, implying that surgery itself could trigger this immune response, although the mechanism is unclear. To investigate how surgery may do so, we performed a multicenter, prospective study of 2069 patients who underwent total knee arthroplasty (TKA) or hip arthroplasty. Approximately half of the patients received postoperative thromboprophylaxis with UFH, LMWH, or fondaparinux. The other half received only mechanical thromboprophylaxis, including dynamic (intermittent plantar or pneumatic compression device), static (graduated compression stockings [GCSs]), or both. We measured anti-PF4/heparin immunoglobulins G, A, and M before and 10 days after surgery using an immunoassay. Multivariate analysis revealed that dynamic mechanical thromboprophylaxis (DMT) was an independent risk factor for seroconversion (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.34-3.02; P = .001), which was confirmed with propensity-score matching (OR, 1.99; 95% CI, 1.17-3.37; P = .018). For TKA, the seroconversion rates in patients treated with DMT but no anticoagulation and in patients treated with UFH or LMWH without DMT were similar, but significantly higher than in patients treated with only GCSs. The proportion of patients with ≥1.4 optical density units appeared to be higher among those treated with any anticoagulant plus DMT than among those not treated with DMT. Our study suggests that DMT increases risk of an anti-PF4/heparin immune response, even without heparin exposure. This trial was registered to www.umin.ac.jp/ctr as #UMIN000001366.
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http://dx.doi.org/10.1182/blood-2015-06-651620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768427PMC
February 2016

Low serum dehydroepiandrosterone examined by liquid chromatography-tandem mass spectrometry correlates with poor prognosis in hormone-naïve prostate cancer.

Prostate 2016 Mar 30;76(4):376-82. Epub 2015 Nov 30.

Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Background: There is no consensus on blood adrenal androgen concentrations in men with different stages and pathological grades of prostate cancer. In this study, dehydroepiandrosterone (DHEA) concentrations in blood were examined by ultrasensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS). We analyzed the correlation between DHEA concentrations in blood and clinicopathological findings of prostate cancer.

Methods: We analyzed 196 men (mean age 70 years) with prostate cancer. The patients underwent systematic needle biopsy, and peripheral blood sampling was conducted for measurement of DHEA. DHEA concentrations in blood were determined using LC-MS/MS method. Patient age, serum prostate-specific antigen, prostate volume measured by ultrasound, and DHEA levels in blood were compared with Gleason score and clinical stage by multivariate analyses.

Results: Median value of PSA and prostate volume were 11.5 ng/ml and 27.7 ml, respectively. Median concentration of DHEA in blood was 1,506.4 pg/ml. There was no correlation between serum DHEA and clinical variables such as age, serum PSA, and prostate volume. In multivariate analysis, low serum DHEA levels in prostate cancer patients were significantly related to high Gleason score and advanced clinical stage. Serum PSA levels in prostate cancer patients were also significantly associated with high Gleason score and advanced clinical stage. High serum PSA and low serum DHEA levels were significantly associated with poor prognosis factors in men with hormone-naïve prostate cancer.

Conclusions: DHEA concentrations in blood were examined by newly developed ultrasensitive LC-MS/MS. We confirmed that low serum DHEA levels in prostate cancer patients were related to high Gleason score and advanced clinical stage. These results suggest that serum DHEA level may be a useful prognostic factor in prostate cancer patients.
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http://dx.doi.org/10.1002/pros.23129DOI Listing
March 2016

Basal cells express functional TRPV4 channels in the mouse nasal epithelium.

Biochem Biophys Rep 2015 Dec 16;4:169-174. Epub 2015 Sep 16.

Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

Basal cells in the nasal epithelium (olfactory and airway epithelia) are stem/progenitor cells that are capable of dividing, renewing and differentiating into specialized cells. These stem cells can sense their biophysical microenvironment, but the underlying mechanism of this process remains unknown. Here, we demonstrate the prominent expression of the transient receptor potential vanilloid type 4 (TRPV4) channel, a Ca-permeable channel that is known to act as a sensor for hypo-osmotic and mechanical stresses, in the basal cells of the mouse nasal epithelium. TRPV4 mRNA was expressed in the basal portions of the prenatal mouse nasal epithelium, and this expression continued into adult mice. The TRPV4 protein was also detected in the basal layers of the nasal epithelium in wild-type but not in TRPV4-knockout (TRPV4-KO) mice. The TRPV4-positive immunoreactions largely overlapped with those of keratin 14 (K14), a marker of basal cells, in the airway epithelium, and they partially overlapped with those of K14 in the olfactory epithelium. Ca imaging analysis revealed that hypo-osmotic stimulation and 4α-phorbol 12,13 didecanoate (4α-PDD), both of which are TRPV4 agonists, caused an increase in the cytosolic Ca concentration in a subset of primary epithelial cells cultured from the upper parts of the nasal epithelium of the wild-type mice. This response was barely noticeable in cells from similar parts of the epithelium in TRPV4-KO mice. Finally, there was no significant difference in BrdU-labeled proliferation between the olfactory epithelia of wild-type and TRPV4-KO mice under normal conditions. Thus, TRPV4 channels are functionally expressed in basal cells throughout the nasal epithelium and may act as sensors for the development and injury-induced regeneration of basal stem cells.
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http://dx.doi.org/10.1016/j.bbrep.2015.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668914PMC
December 2015

Clinical endocrinological evaluation of the gonadal axis (testosterone, LH and FSH) in prostate cancer patients switched from a GnRH antagonist to a LHRH agonist.

Basic Clin Androl 2015 3;25. Epub 2015 Jul 3.

Department of Urology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511 Gunma, Japan.

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.
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http://dx.doi.org/10.1186/s12610-015-0023-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490683PMC
July 2015

Expression and Regulation of Cav3.2 T-Type Calcium Channels during Inflammatory Hyperalgesia in Mouse Dorsal Root Ganglion Neurons.

PLoS One 2015 14;10(5):e0127572. Epub 2015 May 14.

Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

The Cav3.2 isoform of the T-type calcium channel is expressed in primary sensory neurons of the dorsal root ganglion (DRG), and these channels contribute to nociceptive and neuropathic pain in rats. However, there are conflicting reports on the roles of these channels in pain processing in rats and mice. In addition, the function of T-type channels in persistent inflammatory hyperalgesia is poorly understood. We performed behavioral and comprehensive histochemical analyses to characterize Cav3.2-expressing DRG neurons and examined the regulation of T-type channels in DRGs from C57BL/6 mice with carrageenan-induced inflammatory hyperalgesia. We show that approximately 20% of mouse DRG neurons express Cav3.2 mRNA and protein. The size of the majority of Cav3.2-positive DRG neurons (69 ± 8%) ranged from 300 to 700 μm2 in cross-sectional area and 20 to 30 μm in estimated diameter. These channels co-localized with either neurofilament-H (NF-H) or peripherin. The peripherin-positive cells also overlapped with neurons that were positive for isolectin B4 (IB4) and calcitonin gene-related peptide (CGRP) but were distinct from transient receptor potential vanilloid 1 (TRPV1)-positive neurons during normal mouse states. In mice with carrageenan-induced inflammatory hyperalgesia, Cav3.2 channels, but not Cav3.1 or Cav3.3 channels, were upregulated in ipsilateral DRG neurons during the sub-acute phase. The increased Cav3.2 expression partially resulted from an increased number of Cav3.2-immunoreactive neurons; this increase in number was particularly significant for TRPV1-positive neurons. Finally, preceding and periodic intraplantar treatment with the T-type calcium channel blockers mibefradil and NNC 55-0396 markedly reduced and reversed mechanical hyperalgesia during the acute and sub-acute phases, respectively, in mice. These data suggest that Cav3.2 T-type channels participate in the development of inflammatory hyperalgesia, and this channel might play an even greater role in the sub-acute phase of inflammatory pain due to increased co-localization with TRPV1 receptors compared with that in the normal state.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127572PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431781PMC
February 2016

Effects of a luteinizing hormone-releasing hormone agonist on cognitive, sexual, and hormonal functions in patients with prostate cancer: relationship with testicular and adrenal androgen levels.

Basic Clin Androl 2015 6;25. Epub 2015 Apr 6.

Department of Urology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, 371-8511 Gunma Japan.

Purpose: To assess the cognitive and sexual/hormonal functioning of prostate cancer patients treated with a luteinizing hormone-releasing hormone (LH-RH) agonist, and the relationships thereof with adrenal and residual testicular androgen levels.

Materials And Methods: Previously, we reported the effect of a luteinizing hormone-releasing hormone (LH-RH) agonist on testicular and adrenal androgen production in patients with prostate cancer. A 6-month treatment with an LH-RH agonist significantly reduced testicular androgens by 90-95% and adrenal androgens by 26-40%. This study evaluated the changes in cognitive and sexual/hormonal functions in the same cohort using the Mini-Mental State Evaluation (MMSE) and Expanded Prostate Cancer Index Composite (EPIC) questionnaire, respectively. In addition, the associations of each function with the serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), dehydroepiandrosterone-sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione (A-dione), and cortisol levels were studied.

Results: Cognitive functions did not change significantly during the treatment. Sexual functions were relatively low before treatment and worsened significantly after 6 and 12 months of treatment. Interestingly, sexual bothers were improved with the treatment. The treatment significantly worsened hormonal functions and bothers. Regarding specific items in the hormonal domains, hot flashes and body weight changes were the main effects of worsened hormonal function. Low levels of T and E2 and high levels of A-dione were associated with low MMSE scores at 6 months. Regarding sexual and hormonal functions, A-dione, E2, T, cortisol, and DHEA-S were associated with poorer functioning and bother. Especially, low T levels and high E2 levels were the most significant factors associated with worse sexual and hormonal bothers.

Conclusion: The LH-RH agonist monotherapy worsened sexual and hormonal functions and hormonal bothers, but not sexual bothers or cognitive functions. The changes in these functions were related to the testicular and adrenal androgens levels.
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http://dx.doi.org/10.1186/s12610-015-0019-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395772PMC
April 2015

The role of TRPV1 channels in carrageenan-induced mechanical hyperalgesia in mice.

Neuroreport 2015 Feb;26(3):173-8

Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

Peripheral inflammation leads to ipsilateral and contralateral mechanical hyperalgesia. The transient receptor potential channel vanilloid type 1 (TRPV1), a nonselective cation channel expressed in mammalian primary sensory neurons and the spinal cord, may be involved in peripheral inflammation, but there is no consensus on the role of this channel in inflammation-induced mechanical hyperalgesia. Here, we examined the role of TRPV1 channels in carrageenan-induced mechanical hyperalgesia using wild-type and TRPV1-knockout (KO) mice and compared the results with those obtained in mice peripherally administered capsazepine, a TRPV1 antagonist, or capsaicin, a TRPV1 agonist. In the TRPV1-KO mice, ipsilateral mechanical hyperalgesia was significantly reduced during the acute phase (10-60 min), and the contralateral mechanical hyperalgesia nearly disappeared during both the acute and subacute phases. Blocking peripheral TRPV1 using capsazepine before carrageenan administration resulted in similar effects as those observed in the TRPV1-KO mice, except that it was less effective against contralateral mechanical hyperalgesia during the subacute phase. In contrast, capsaicin remarkably decreased ipsilateral and contralateral mechanical hyperalgesia throughout both phases, but this analgesic effect was not observed in the TRPV1-KO mice. Thus, TRPV1 channels could be involved in the development of both ipsilateral and contralateral mechanical hyperalgesia after inflammation. Peripheral TRPV1 could participate in acute hyperalgesia, whereas central TRPV1 may participate in subacute secondary hyperalgesia. Capsaicin potentially acts on both primary and secondary hyperalgesia in a TRPV1-dependent manner.
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http://dx.doi.org/10.1097/WNR.0000000000000322DOI Listing
February 2015
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