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| 1.
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Konaka, Hiroyuki ; Egawa, Shin ; Saito, Shiro ; Yorozu, Atsunori ; Takahashi, Hiroyuki ; Miyakoda, Keiko ; Fukushima, Masanori ; Dokiya, Takushi ; Yamanaka, Hidetoshi ; Stone, Nelson N. ; Namiki, Mikio ; 小中, 弘之 ; 並木, 幹夫
概要:
金沢大学医薬保健研究域医学系<br />Background: Patients with high Gleason score, elevated prostate specific antigen (PSA) level, and ad
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vanced clinical stage are at increased risk for both local and systemic relapse. Recent data suggests higher radiation doses decrease local recurrence and may ultimately benefit biochemical, metastasis-free and disease-specific survival. No randomized data is available on the benefits of long-term hormonal therapy (HT) in these patients. A prospective study on the efficacy and safety of trimodality treatment consisting of HT, external beam radiation therapy (EBRT), and brachytherapy (BT) for high-risk prostate cancer (PCa) is strongly required.Methods/Design: This is a phase III, multicenter, randomized controlled trial (RCT) of trimodality with BT, EBRT, and HT for high-risk PCa (TRIP) that will investigate the impact of adjuvant HT following BT using iodine-125 ( 125I-BT) and supplemental EBRT with neoadjuvant and concurrent HT. Prior to the end of September 2012, a total of 340 patients with high-risk PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from more than 41 institutions, all of which have broad experience with 125I-BT. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will commonly undergo 6-month HT with combined androgen blockade (CAB) before and during 125I-BT and supplemental EBRT. Those randomly assigned to the long-term HT group will subsequently undergo 2 years of adjuvant HT with luteinizing hormone-releasing hormone agonist. All participants will be assessed at baseline and every 3 months for the first 30 months, then every 6 months until 84 months from the beginning of CAB.The primary endpoint is biochemical progression-free survival. Secondary endpoints are overall survival, clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, and adverse events.Discussion: To our knowledge, there have been no prospective studies documenting the efficacy and safety of trimodality therapy for high-risk PCa. The present RCT is expected to provide additional insight regarding the potency and limitations of the addition of 2 years of adjuvant HT to this trimodality approach, and to establish an appropriate treatment strategy for high-risk PCa.Trial registration: UMIN000003992. © 2012 Konaka et al; licensee BioMed Central Ltd.
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| 2.
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Kitagawa, Yasuhide ; Machioka, Kazuaki ; Yaegashi, Hiroshi ; Nakashima, Kazufumi ; Ofude, Mitsuo ; Izumi, Kouji ; Ueno, Satoru ; Kadono, Yoshifum ; Konaka, Hiroyuki ; Mizokami, Atsushi ; Namiki, Mikio ; 北川, 育秀 ; 泉, 浩二 ; 上野, 悟 ; 小中, 弘之 ; 溝上, 敦 ; 並木, 幹夫
概要:
金沢大学医薬保健研究域医学系<br />To clarify the recent trends in prostate-specific antigen (PSA) distribution in men in Japan, we ana
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lyzed the PSA distributions of men undergoing PSA-based population screening. We summarized the annual individual data of PSA-based population screening in Kanazawa, Japan, from 2000 to 2011, and analyzed baseline serum PSA values of the participants at the first population screening. Serum PSA distributions were estimated in all participants and those excluding prostate cancer patients according to age. From 2000 to 2011, 19 620 men participated aged 54-69 years old in this screening program. Mean baseline serum PSA level of all participants at the first screening was 2.64 ng ml⁻¹ in 2000, and gradually decreased to approximately 1.30 ng ml⁻¹ in 2006. That of participants excluding prostate cancer patients was 1.46 ng ml⁻¹ in 2000, and there was no remarkable change during the study period. The 95 th percentiles in the participants excluding prostate cancer patients detected at the first population screening of men aged 54-59, 60-64, and 65-69 years old were 2.90, 3.60, and 4.50 ng ml⁻¹, respectively. After the commencement of population screening, the proportion of prostate cancer patients with high serum PSA levels decreased. However, there were no changes in serum PSA levels in men without prostate cancer. Age-specific PSA reference level of men without prostate cancer in Japan was similar to that in China and Korea.
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| 3.
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Miyamoto, Toshinobu ; Tsujimura, Akira ; Miyagawa, Yasushi ; Koh, Eitetsu ; Sakugawa, Naoko ; Miyakawa, Hiroe ; Sato, Hisashi ; Namiki, Mikio ; Okuyama, Akihiko ; Sengoku, Kazuo ; 高, 栄哲 ; 並木, 幹夫
概要:
金沢大学医薬保健研究域医学系<br />Genetic mechanisms have been implicated as a cause of some cases of male infertility. Recently, 10 n
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ovel genes involved in human spermatogenesis were identified by microarray analysis of human testicular tissue. One of these is spermatogenesis-associated 17 (SPATA17). To investigate whether defects in the SPATA17 gene are associated with azoospermia due to meiotic arrest, a mutational analysis was conducted, in which the SPATA17 coding regions of 18 Japanese patients with this condition were sequenced. A statistical analysis was carried out that included 18 patients with meiotic arrest, 20 patients with Sertoli-cell-only syndrome (SCOS) and 96 healthy control men. No mutations were found in SPATA17. However, three coding single nucleotide polymorphisms (cSNPs: SNP1-SNP3) were detected in the patients with meiotic arrest. No significant differences in the genotype or allele frequencies of SNP1 and SNP2 were found between patients with meiotic arrest and the others. However, the frequency of the SNP3 allele was significantly elevated in the meiotic arrest group (P < 0.05). This study suggests that SPATA17 may play a critical role in human spermatogenesis, especially in meiosis.
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Miyamoto, Toshinobu ; Tsujimura, Akira ; Miyagawa, Yasushi ; Koh, Eitetsu ; Namiki, Mikio ; Horikawa, Michiharu ; Saijo, Yasuaki ; Sengoku, Kazuo ; 高, 栄哲 ; 並木, 幹夫
概要:
金沢大学医薬保健研究域医学系<br />Genetic mechanisms are implicated as a cause of some male infertility, yet are poorly understood. Me
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iosis is unique to germ cells and essential for reproduction. The synaptonemal complex is a critical component for chromosome pairing, segregation and recombination. Hormad1 is essential for mammalian gametogenesis as knockout male mice are infertile. Hormad1-deficient testes exhibit meiotic arrest in the early pachytene stage and synaptonemal complexes cannot be visualized. To analyze the hypothesis that the human HORMAD1 gene defects are associated with human azoospermia caused by meiotic arrest, mutational analysis was performed in all coding regions by direct sequence analysis of 30 Japanese men diagnosed with azoospermia resulting from meiotic arrest. By the sequence analysis, three polymorphism sites, Single Nucleotide Polymorphism 1 (c. 163A>G), SNP2 (c. 501T>G) and SNP3 (c. 918C>T), were found in exons 3, 8 and 10. The 30 patients with azoospermia and 80 normal pregnancy-proven, fertile men were analyzed for HORMAD1 polymorphisms. Both SNP1 and SNP2 were associated with human azoospermia caused by complete early meiotic arrest (P<0.05). We suggest that the HORMAD1 has an essential meiotic function in human spermatogenesis. © 2012 AJA, SIMM & SJTU. All rights reserved.
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Kawaguchi, Shohei ; Shigehara, Kazuyoshi ; Sasagawa, Toshiyuki ; Shimamura, Masayoshi ; Nakashima, Takao ; Sugimoto, Kazuhiro ; Nakashima, Kazufumi ; Furubayashi, Keiichi ; Namiki, Mikio ; 川口, 昌平 ; 重原, 一慶 ; 笹川, 寿之 ; 島村, 正喜 ; 中嶋, 孝夫 ; 杉本, 和宏 ; 中嶋, 一史 ; 古林, 敬一 ; 並木, 幹夫
概要:
金沢大学医薬保健研究域医学系<br />Liquid-based urine cytology (LB-URC) was evaluated for cytological diagnosis and detection of human
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papillomavirus (HPV), Mycoplasma, and Ureaplasma. Midstream urine samples were collected from 141 male patients with urethritis and 154 controls without urethritis, and sediment cells were preserved in liquid-based cytology solution. Urethral swabs from urethritis patients were tested for the presence of Neisseria gonorrhoeae and Chlamydia trachomatis. Papanicolaou tests were performed for cytological evaluation. HPV, Mycoplasma, and Ureaplasma genomes were determined by PCR-based methods, and localization of HPV DNA in urothelial cells was examined by in situ hybridization (ISH). The β-globin gene was positive in 97.9% of LB-URC samples from urethritis patients and in 97.4% of control samples, suggesting that high-quality cellular DNA was obtained from the LB-URC samples. HPV DNA was detected in 29 (21.0%) urethritis cases and in five (3.3%) controls (P<0.05). HPV type 16 (HPV 16) was most commonly found in urethritis patients. Cytological evaluations could be performed for 92.1% of urethritis patients and 64.3% of controls. Morphological changes suggestive of HPV infection were seen in 20.7% of the HPV-positive samples, and ISH demonstrated the presence of HPV DNA in both squamous and urothelial cells in HPV-positive samples. Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma parvum, and Ureaplasma urealyticum were detected in 14.5%, 10.9%, 6.5%, and 12.3% of urethritis patients, respectively. The prevalence rates of these microorganisms (except Ureaplasma parvum) were significantly higher in urethritis cases than controls (P<0.05). LB-URC is applicable for detection of HPV, Mycoplasma, and Ureaplasma. HP infection occurs in urothelial cells, especially in gonococcal urethritis. Copyright © 2012, American Society for Microbiology. All Rights Reserved.
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| 6.
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並木, 幹夫 ; 奥山, 明彦 ; Namiki, Mikio ; Okuyama, Akihiko
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金沢大学医薬保健研究域医学系<br />出版者照会後に全文公開
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| 7.
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並木, 幹夫 ; Namiki, Mikio
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金沢大学医薬保健研究域医学系<br />出版者照会後に全文公開
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| 8.
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Kadono, Yoshifumi ; Miwa, Sotaro ; Shima, Takashi ; Konaka, Hiroyuki ; Mizokami, Atsushi ; Yotsuyanagi, Satoshi ; Hirata, Akio ; Takase, Yasukazu ; Sugata, Toshiaki ; Shimamura, Masayoshi ; Namiki, Mikio ; 角野, 佳史 ; 三輪, 聰太郎 ; 小中, 弘之 ; 溝上, 敦 ; 並木, 幹夫
概要:
金沢大学医薬保健研究域医学系<br />Interferon-alpha (IFN-α) has been used in systemic treatment for metastatic renal cell carcinoma (mR
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CC). IFN-α has at least 14 subtypes, each of which has different biological activity. There have been reports that mRCC resistant to an IFN-α treatment responded to another IFN-α subtype. This study was performed to evaluate the effectiveness of alternation of different IFN-α subtypes for mRCC that did not respond to initial IFN-α treatment. In our department and associated institutions, alternating therapy of IFN-α was provided for 15 initial IFN-α refractory mRCC cases from June 2005 to September 2008. Among the 15 patients, the effects of alternating IFN-α therapy were as follows: complete response (CR), 0 cases; partial response (PR), 1 case; stable disease (SD), 3 cases; progressive disease (PD), 11 cases. The response rate (CR+PR) was 7% and disease control rate (CR+PR+SD) was 27%. No severe side effects were observed in any of these cases. The PR case is still in PR 21 months after alternating IFN-α therapy. Among the three SD cases, one has continued SD for 14 months and the other for 12 months. Alternating IFN-α therapy for mRCC can be attempted even if other cytokines are not effective. © 2012 Biomedical Research Press.
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| 9.
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Takami, Akiyoshi ; Asakura, Hidesaku ; Koshida, Kiyoshi ; Namiki, Mikio ; Nakao, Shinji ; 高見, 昭良 ; 朝倉, 英策 ; 越田, 潔 ; 並木, 幹夫 ; 中尾, 眞二
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金沢大学医薬保健研究域医学系<br />We report the cases of 3 patients with advanced renal cell carcinoma who underwent reduced-intensity
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allogeneic stem cell transplantation. In 2 partial responders, histologic analyses of metastases revealed prominent accumulation of CD8+ T cells and degenerative changes of clear cell carcinoma, suggestive of induction of tumor-specific cytotoxic T lymphocytes.
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| 10.
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Iwamoto, Hiroaki ; Shigehara, Kazuyoshi ; Miyagi, Tohru ; Nakashima, Takao ; Shimamura, Masayoshi ; Namiki, Mikio ; 岩本, 大旭 ; 重原, 一慶 ; 並木, 幹夫
概要:
金沢大学大学院医学系研究科泌尿器集学的治療学 / Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Me
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dical Sciences<br />Background Prevalence of fluoroquinolone (FQ)-resistant Escherichia coli has been recently increasing worldwide. We analyzed the incidence and characteristics of acute bacterial prostatitis after transrectal ultrasound-guided needle prostate biopsy (TRUSP-Bx) with prophylactic tazobactam/piperacillin (TAZ/PIPC) treatment as an alternative regimen. Methods A total of 391 patients who underwent TRUSP-Bx were included in the study. All patients received intravenous TAZ/PIPC (4.5 g) 30 minutes before and 6 hours after TRUSP-Bx. Results Acute bacterial prostatitis developed in six patients (1.5%); the frequency of its occurrence was significantly higher in patients in whom rectal disinfection was not performed (P < 0.05). These six patients developed clinical symptoms of acute bacterial prostatitis a median of 24 hours after the biopsy. Escherichia coli was isolated in urine or blood bacterial cultures in four cases, and Klebsiella pneumoniae in two cases. All of the isolated organisms showed excellent sensitivity to TAZ/PIPC. Conclusions The incidence rate of acute prostatitis with prophylactic TAZ/PIPC was consistent with those reported previously with FQ-based regimens, despite the favorable sensitivity of isolated organisms. Two-time regimen of TAZ/PIPC may not always prevent the post-TRUSP-Bx infection, possibly due to the pharmacokinetic characteristics of TAZ/PIPC. However, if each case was considered individually to select the best setting and frequency of dosage of TAZ/PIPC, this can be an optimal prophylaxis in the era of widespread FQ-resistant microorganisms. Copyright © 2015 Asian Pacific Prostate Society, Published by Elsevier. All rights reserved.
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Izumi, Kouji ; Mizokami, Atsushi ; Namiki, Mikio ; Inoue, Shogo ; Tanaka, Nobumichi ; Yoshio, Yuko ; Ishibashi, Kei ; Kamiyama, Manabu ; Kawai, Noriyasu ; Enokida, Hideki ; Shima, Takashi ; Takahara, Shizuko ; 泉, 浩二 ; 溝上, 敦 ; 並木, 幹夫
概要:
金沢大学附属病院泌尿器科<br />Background: Both enzalutamide and abiraterone have demonstrated improved radiographic progression-free
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and overall survival for castration-resistant prostate cancer (CRPC) compared with placebo controls before docetaxel treatment in phase III studies. These oral agents target androgen and androgen receptor signaling and are thought to be less toxic than chemotherapy. Cross-resistance to these agents was recently reported because of their similar mechanism of action, and it is important to assess which agent is more effective to use initially for CRPC. Methods/design: The present study is a phase III, investigator-initiated, multicenter, head-to-head, randomized controlled trial investigating enzalutamide vs. abiraterone as a first-line treatment for CRPC patients. Patients will be randomly assigned to an enzalutamide or an abiraterone treatment group. The primary endpoint is the time to prostate-specific antigen progression. The target sample size is set at 100 patients per group (total, 200 patients). The study duration is 5 years, and the duration for recruitment is 2 years and 6 months. Discussion: Thus far, there have been no prospective head-to-head studies comparing enzalutamide and abiraterone. This ENABLE study will clarify which agent should be prioritized for CRPC patients and enable clinicians to decide the appropriate treatment before chemotherapy. Trial registration: University hospital Medical Information Network (UMIN) Center identifier UMIN000015529. Registrated 11/1/2014. © 2017 The Author(s).
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| 12.
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Namiki, Mikio ; Kitagawa, Yasuhide ; Mizokami, Atsushi ; Koh, Eitetsu
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金沢大学医薬保健研究域医学系<br />Background: The basic mechanisms and clinical efficacy of primary androgen deprivation therapy (PADT
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), especially combined androgen blockade (CAB) for localized or locally advanced prostate cancer (PCa) have been outlined. An important point relates to which patients are suitable candidates for PADT. Methods: A retrospective review of the efficacy of PADT in 628 patients with localized or locally advanced PCa treated with PADT at seven institutions in Japan was carried out. Results: It was found that more than 30% of low- or intermediate-risk localized PCa patients could have their disease controlled over the long-term by PADT alone. Short-term or intermittent PADT could not be recommended because of the possibility of character change in the cancer cells as a result of incomplete androgen ablation. Conclusion: Algorithms are proposed for the treatment of localized PCa not only in low- and intermediate-risk groups, but also in the high-risk group. Future research directions are indicated. © 2008 WPMH GmbH.
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| 13.
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Sugimoto, Kazuhiro ; Koh, Eitetsu ; Sin, Ho-Su ; Maeda, Yuji ; Narimoto, Kazutaka ; Izumi, Koji ; Kobori, Yoshitomo ; Kitamura, Eiko ; Nagase, Hiroki ; Yoshida, Atsumi ; Namiki, Mikio
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Numerous CpG islands containing tissue-specific differentially methylated regions (TDMRs) are potential methylation site
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s in normal cells and tissues. The VASA (also known as DDX4) gene is believed to be under the control of TDMRs. A total of 131 male patients with idiopathic azoospermia or severe oligospermia were evaluated histologically, and the methylation status of CpG islands in the VASA gene was screened. Genome DNAs were obtained from testicular biopsy and modified with sodium bisulfite, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was applied. This system is capable of analyzing both the methylated and unmethylated CpG island in the genome. The methylation analysis is conducted by an epigram as graphic data. On histological assessment, 17 of 131 patients revealed maturation arrest (MA).In all, 6 of the 17 patients showed particularly high VASA TDMR methylation rates, whereas the remaining 11 patients and controls had low methylation rates. This study may imply that the VASA TDMR methylation is significantly higher among patients with MA, in whom the VASA gene expression was silenced. This finding represents an important contribution to the molecular basis of meiotic arrest as one possible cause of idiopathic infertility. © 2009 The Japan Society of Human Genetics All rights reserved.
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| 14.
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Sin, Ho-Su ; Koh, Eitetsu ; Kim, Dae-Soo ; Murayama, Miho ; Sugimoto, Kazuhiro ; Maeda, Yuji ; Yoshida, Atsumi ; Namiki, Mikio
概要:
金沢大学医薬保健研究域医学系<br />The male-specific region of Y chromosome (MSY) has accumulated a higher density of human endogenous
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retroviruses (HERVs) and related sequences when compared with other regions of the human genome. Here, we focused on one HERV family, HERV-K14C that seemed to integrate preferentially into the Y chromosome in humans. To identify every copies of HERV-K14C in the human genome, we applied computational screening to map precisely the locus of individual HERV-K14C copies. Interestingly, 29 of all 146 copies were located in Y chromosome, and these 29 copies were mostly dispersed in the palindromic region. Three distinct HERV-K14C-related transcripts were found and were exclusively expressed in human testis tissue. Based on our phylogenetic analysis of the solitary LTRs derived from HERV-K14C on the Y chromosome we suggested that these sequences were generated as pairs of identical sequences. Specifically, analysis of HERV-K14C-related sequences in the palindromic region demonstrated that the Y chromosomal amplicons existed in our common ancestors and the duplicated pairs arose after divergence of great apes approximately 8-10 million years ago. Taken together, our observation suggested that HERV-K14C-related sequences contributed to genomic diversification of Y chromosome during speciation of great ape lineage. © 2010 The Japan Society of Human Genetics All rights reserved.<br />出版社許諾要件により、2012年6月より全文公開.
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| 15.
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Shin, Ho-Su ; Koh, Eitetsu ; Kim, Dae-Soo ; Murayama, Miho ; Sugimoto, Kazuhiro ; Maeda, Yuji ; Yoshida, Atsumi ; Namiki, Mikio
概要:
金沢大学医薬保健研究域医学系<br />The male-specific region of Y chromosome (MSY) has accumulated a higher density of human endogenous
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retroviruses (HERVs) and related sequences when compared with other regions of the human genome. Here, we focused on one HERV family, HERV-K14C that seemed to integrate preferentially into the Y chromosome in humans. To identify every copies of HERV-K14C in the human genome, we applied computational screening to map precisely the locus of individual HERV-K14C copies. Interestingly, 29 of all 146 copies were located in Y chromosome, and these 29 copies were mostly dispersed in the palindromic region. Three distinct HERV-K14C-related transcripts were found and were exclusively expressed in human testis tissue. Based on our phylogenetic analysis of the solitary LTRs derived from HERV-K14C on the Y chromosome we suggested that these sequences were generated as pairs of identical sequences. Specifically, analysis of HERV-K14C-related sequences in the palindromic region demonstrated that the Y chromosomal amplicons existed in our common ancestors and the duplicated pairs arose after divergence of great apes approximately 8-10 million years ago. Taken together, our observation suggested that HERV-K14C-related sequences contributed to genomic diversification of Y chromosome during speciation of great ape lineage. © 2010 The Japan Society of Human Genetics All rights reserved.
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| 16.
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Namiki, Mikio ; Kitagawa, Yasuhide ; Mizokami, Atsushi ; Koh, Eitetsu
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金沢大学医薬保健研究域医学系<br />In spite of clinical practice guidelines such as NCI-PDQ - in which primary androgen deprivation the
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rapy (PADT) is not recommended as the primary treatment for localized prostate cancer - many patients have been treated with PADT. One of the reasons is that urologists themselves permit patients' desire because they know the effectiveness of PADT for some patients in their experiences. In this review we demonstrate basic mechanisms and the clinical efficacy of primary combined androgen blockade (PCAB) for localized or locally advanced prostate cancer. Then we discuss which patients are candidates for PCAB, and show that more than 30% of low- or intermediate-risk localized prostate cancers could be controlled in the long term with only PCAB. Short-term or intermittent PADT could not be recommended because of the possibilities of changing the character of the cancer cells by incomplete androgen ablation. We propose algorithms for the treatment of localized prostate cancer not only in low- and intermediate-risk groups but also in the high-risk group. © 2008.
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Kawaguchi, Shohei ; Izumi, Kouji ; Nohara, Takahiro ; Miyagi, Tohru ; Konaka, Hiroyuki ; Mizokami, Atsushi ; Koh, Eitetsu ; Namiki, Mikio
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金沢大学医薬保健研究域医学系<br />Antiphospholipid syndrome is a systemic autoimmune disease with thrombotic tendency. Consensus guide
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lines for pregnancy with antiphospholipid syndrome recommend low-dose aspirin combined with unfractionated or low-molecular-weight heparin because antiphospholipid syndrome causes habitual abortion. We report a 36-year-old pregnant woman diagnosed with antiphospholipid syndrome receiving anticoagulation treatment. The patient developed left abdominal pain and gross hematuria at week 20 of pregnancy. An initial diagnosis of left ureteral calculus was made. Subsequently abdominal-pelvic computed tomography was required for diagnosis because of the appearance of severe contralateral pain. Computed tomography revealed serious renal hemorrhage, and ureteral stent placement and pain control by patient-controlled analgesia were required. After treatment, continuance of pregnancy was possible and vaginal delivery was performed safely. This is the first case report of serious renal hemorrhage in a pregnant woman with antiphospholipid syndrome receiving anticoagulation treatment and is an instructive case for urological and obstetrical practitioners. Copyright © 2011 Shohei Kawaguchi et al.
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| 18.
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Namiki, Mikio ; Mizokami, Atsushi ; Akaza, Hideyuki
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金沢大学医薬保健研究域医学系<br />This Practice Point commentary discusses the study by Lu-Yao et al. in which primary androgen depriv
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ation therapy (PADT) was compared with conservative treatment in elderly men with localized prostate cancer. Overall, PADT was associated with worse cancer-specific survival than conservative management; however, in the subgroup of patients with poorly differentiated cancer, PADT was associated with improved cancer-specific survival. Although the authors defined conservative treatment as no definitive treatment during the 180 days after diagnosis, many patients in the conservative treatment group would have subsequently received definite treatments, including surgery or radiation therapy. The results of this study, therefore, do not necessarily demonstrate inferiority of PADT to conservative treatment. Accurate evaluation of the efficacy of PADT is confounded by a number of factors, such as the type of androgen deprivation therapy used. Efforts should be made to reduce the adverse effects of androgen deprivation therapy because a high proportion of patients actively choose this treatment modality as primary therapy.全文公開200905
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| 19.
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Koh, Eitetsu ; Sin, Ho-Su ; Fukushima, Masato ; Namiki, Mikio
概要:
金沢大学医薬保健研究域医学系<br />Recently, work has shown that azoospermia factor (AZF) microdeletions result from homologous recombi
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nation between almost identical blocks in this gene region. These microdeletions in the Y chromosome are a common molecular genetic cause of spermatogenetic failure leading to male infertility. After completion of the sequencing of the Y chromosome, the classical definition of AZFa, AZFb, and AZFc was modified to five regions, namely AZFa, P5/proximal-P1, P5/distal-P1, P4/distal-P1, and AZFc, as a result of the determination of Y chromosomal structure. Moreover, partial AZFc deletions have also been reported, resulting from recombination in their sub-ampliconic identical pair sequences. These deletions are also implicated in a possible association with Y chromosome haplogroups. In this review, we address Y chromosomal complexity and the modified categories of the AZF deletions. Recognition of the association of Y deletions with male infertility has implications for the diagnosis, treatment, and genetic counseling of infertile men, in particular candidates for intracytoplasmic sperm injection. © 2010 Japan Society for Reproductive Medicine.
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| 20.
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Demura, Masashi ; Wang, Fen ; Yoneda, Takashi ; Karashima, Shigehiro ; Mori, Shunsuke ; Oe, Masashi ; Kometani, Mitsuhiro ; Sawamura, Toshitaka ; Cheng, Yuan ; Maeda, Yuji ; Namiki, Mikio ; Ino, Hidekazu ; Fujino, Noboru ; Uchiyama, Katsuharu ; Tsubokawa, Toshinari ; Yamagishi, Masakazu ; Nakamura, Yasuhiro ; Ono, Katsuhiko ; Sasano, Hironobu ; Demura, Yoshiki ; Takeda, Yoshiyu
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金沢大学医薬保健研究域医学系<br />Objective: Nuclear receptors are involved in a wide variety of functions, including aldosteronogenes
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is. Nuclear receptor families NR4A [nerve growth factor-induced clone B (NGFIB), Nur-related factor 1 (NURR1) and neuron-derived orphan receptor 1 (NOR1)] and NR2F [chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TFI), COUP-TFII and NR2F6) activate, whereas NR5A1 [steroidogenic factor 1 (SF1)] represses CYP11B2 (aldosterone synthase) gene transcription. The present study was undertaken to elucidate the mechanism of differential regulation of nuclear receptors between cardiovascular and adrenal tissues. Methods: We collected tissues of artery (n = 9), cardiomyopathy muscle (n = 9), heart muscle (noncardiomyopathy) (n = 6), adrenal gland (n = 9) and aldosterone-producing adenoma (APA) (n = 9). 5′-rapid amplification of cDNA ends (RACE) identified transcription start sites. Multiplex reverse-transcription PCR (RT-PCR) determined use of alternative noncoding exons 1 (ANEs). Results: In adrenocortical H295R cells, angiotensin II, KCl or cAMP, all stimulated CYP11B2 transcription and NR4A was upregulated, whereas NR2F and NR5A1 were downregulated. 5′-RACE and RT-PCR revealed four ANEs of NGFIB (NR4A1), three of NURR1 (NR4A2), two of NOR1 (NR4A3) and two of SF1 (NR5A1) in cardiovascular and adrenal tissues. Quantitative multiplex RT-PCR showed NR4A and NR5A1 differentially employed multiple ANEs in a tissue-specific manner. The use of ANEs of NGFIB and NURR1 was significantly different between APA and artery. Changes in use of ANEs of NGFIB and NOR1 were observed between cardiomyopathy and noncardiomyopathy. The NR4A mRNA levels in artery were high compared with cardiac and adrenal tissues, whereas the NR5A1 mRNA level in adrenal tissues was extremely high compared with cardiovascular tissues. Conclusion: NR4A and NR5A1 genes are complex in terms of alternative promoter use. The use of ANEs may be associated with the pathophysiology of the heart and adrenal gland. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
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| 21.
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Sugimoto, Kazuhiro ; Koh, Eitetsu ; Iijima, Masashi ; Taya, Masaki ; Maeda, Yuji ; Namiki, Mikio
概要:
Increasing evidence shows a relationship between epigenetic regulation and male infertility. The GTF2A1L gene promoter c
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ontains the DNA methylation site of a tissue-specific differentially methylated region (TDMR). Eighty-six patients with non-obstructive azoospermia were assessed for the DNA methylation state of CpG islands in the GTF2A1L promoter using testicular genomic DNA. Based on histological criteria, 26 of the 86 patients had normal spermatogenesis (controls), 17 had hypospermatogenesis and 26 had a Sertoli cell-only phenotype or tubular sclerosis. GTF2A1L TDMR methylation was significantly lower in testes DNA from control samples than from hypospermatogenic samples (P=0.029). Patients with hypospermatogenesis were divided into two subgroups: high DNA methylation (HM, n=5) and low DNA methylation (LM, n=12). The GTF2A1L TDMR methylation rate differed significantly between the HM and LM groups (P=0.0019), and GTF2A1L expression was significantly higher among the LM than in the HM patients (P=0.023). High TDMR methylation was correlated with low GTF2A1L gene expression levels. Both groups demonstrated relatively good outcomes with respect to sperm retrieval, fertilisation, pregnancy and childbirth rates. We observed that aberrant GTF2A1L gene expression was not correlated with fertilisation rates. The testicular sperm extraction (TESE) technique may be used to overcome male infertility due to aberrant TDMR methylation. © 2013 AJA, SIMM & SJTU. All rights reserved.
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| 22.
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Namiki, Mikio ; Konaka, Hiroyuki
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| 23.
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Sin, Ho-Su ; Koh, Eitetsu ; Taya, Masaki ; IIjima, Masashi ; Sugimoto, Kazuhiro ; Maeda, Yuji ; Yoshida, Atsumi ; Iwamoto, Teruaki ; Namiki, Mikio
概要:
Purpose: We identified the endogenous retroviruses associated with TTYs (testis specific transcripts linked to the Y) in
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the AZFb region. We evaluated the relationship between endogenous retroviruses, and TTY expression patterns and function in spermatogenesis. Materials and Methods: We identified family members of TTYs in the AZFb region using computational screening. After investigating the relationship between the endogenous retrovirus genome and TTY expression patterns we screened genomic polymerase chain reaction products from TTY13 amplified from 790 Japanese men, including 275 with azoospermia, 285 with oligozoospermia and 230 who were fertile. Results: Computational screening revealed that 3 members of the TTY family, TTY9, 10 and 13, were regulated by endogenous retroviruses in the AZFb region. Homologous recombination between long terminal repeat of the TTY13 associated human endogenous retrovirus-K14C resulted in TTY13 deletion events. These deletions were more common in patients with azoospermia and oligozoospermia than in fertile males. Specifically 15.63% of the azoospermia group, 10.88% of the oligozoospermia group and 0% of fertile controls had only the deletion variant, indicating an association between the homologous recombination rate and the severity of spermatogenesis failure that was statistically significant (p <0.05). Conclusions: Because of the finding of what are to our knowledge novel microdeletions due to endogenous retrovirus in the AZFb region, our study raises the possibility that specific variations in genomic structure may contribute to some forms of human idiopathic male infertility. © 2011 American Urological Association Education and Research, Inc.
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| 24.
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Izumi, Kouji ; Mizokami, Atsushi ; Sugimoto, Kazuhiro ; Narimoto, Kazutaka ; Kitagawa, Yasuhide ; Koh, Eitetsu ; Namiki, Mikio
概要:
Androgen deprivation therapy (ADT) for prostate cancer (PCa) causes bone loss. Although we reported previously that rise
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dronate significantly recovers bone mineral density (BMD) for up to 12 months, there have been no reports with longer follow-up periods to date. This study extended our earlier series extending the follow-up period to 24 months. Eligible patients had histologically confirmed PCa without lumbar spine metastasis and underwent ADT. Lumbar spine BMD, urinary deoxypyridinoline (uDPD) and serum bone alkaline phosphatase were measured at 6, 12 and 24 months. Among the total of 96 patients, we analyzed 26 and 18 patients in risedronate administration and control groups, respectively. BMD relative to the young adult mean ratio, uDPD and serum bone alkaline phosphatase of the risedronate administration group recovered significantly after 24 months compared with the control group (P0.0001, P0.0001, and P0.0001, respectively). Transient blurred vision, malaise and vertigo were observed in 1 patient each among the 46 patients treated with risedronate within 28 days after first administration. Oral administration of risedronate is safe and effective for the recovery of ADT-induced bone loss in PCa patients even at 24 months after commencement of treatment. © 2011 Macmillan Publishers Limited All rights reserved.
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| 25.
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Yaegashi, Hiroshi ; Izumi, Kouji ; Kitagawa, Yasuhide ; Kadono, Yoshifumi ; Konaka, Hiroyuki ; Mizokami, Atsushi ; Namiki, Mikio
概要:
It is difficult to determine the cause of high fever in patients with advanced cancer, because they tend to have both ne
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oplastic fever and concomitant bacterial infections with elevated white blood cells and C-reactive protein levels. Procalcitonin has been reported to be a valuable marker for bacterial infections in a wide range of clinical scenarios. However, there have been no studies regarding the usefulness of procalcitonin to differentiate between febrile episodes caused by bacterial infections and neoplastic fever in patients with advanced urological cancer. In the present study, 37 febrile episodes were retrospectively analyzed. Although there were no differences in white blood cell number, C-reactive protein level or body temperature between bacterial infections and non-bacterial infections, procalcitonin levels were significantly higher in the former than the latter. Our findings suggest that measurement of procalcitonin might be valuable to determine the cause of febrile episodes in patients with advanced urological cancer, and can help clinicians to make appropriate decisions for treatment. © 2013 The Japanese Urological Association.
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| 26.
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Namiki, Mikio ; Ueno, Satoru ; Kitagawa, Yasuhide ; Fukagai, Takashi ; Akaza, Hideyuki
概要:
Recently, novel anti-androgens and inhibitors of androgen biosynthesis have been developed through the elucidation of me
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chanisms of castration resistance of prostate cancer. We believe that these new developments will improve hormonal therapy. On the other hand, there has been an increase in criticism of hormonal therapy, because hormonal therapy is supposed to induce adverse effects such as cardiovascular disease. In this review, we have introduced the Japanese experience of hormonal therapy, because we believe that there may be ethnic differences between Caucasians and Asian people in the efficacy and adverse effects of hormonal therapy. First, we showed that primary hormonal therapy can achieve long-term control of localized prostate cancer in some cases and that quality of life of patients receiving hormonal therapy is rather better than previously thought. Neoadjuvant and adjuvant hormonal therapy in cases undergoing radical prostatectomy or radiotherapy are very useful for high-risk or locally advanced prostate cancer. Further clinical trials are required to confirm the efficacy of neoadjuvant or adjuvant hormonal therapy. We showed that the death from cardiovascular diseases in Japanese patients receiving hormonal therapy was not higher than that in the general population. However, efforts should be made to decrease the adverse effects of hormonal therapy, because life-style change may increase the susceptibility to adverse effects by hormonal therapy even in Japan. Managements of endocrine and metabolic dysfunction, such as diabetes mellitus, are essential. New hormonal compounds such as selective androgen receptor modulators capable of specifically targeting prostate cancer are expected to be developed. © 2012 AJA, SIMM & SJTU. All rights reserved.
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| 27.
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Kadono, Yoshifumi ; Ueno, Satoru ; Kadomoto, Suguru ; Iwamoto, Hiroaki ; Takezawa, Yuta ; Nakashima, Kazufumi ; Nohara, Takahiro ; Izumi, Kouji ; Mizokami, Atsushi ; Gabata, Toshifumi ; Namiki, Mikio
概要:
Aims: To examine which preoperative factors, including urodynamic evaluations, and operative procedures could predict co
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ntinence status after robot-assisted radical prostatectomy (RARP) in this study. Materials and Methods: Univariate and multivariate logistic regression analyses of preoperative factors such as age, body mass index, prostate-specific antigen level before biopsy, prostate size before surgery, membranous urethral length measured using magnetic resonance imaging (MRI), bladder compliance and maximum urethral closure pressure (MUCP) measured by urodynamic study (UDS), and nerve-sparing (NS) status predicting 24-hr pad test >2 g/day at 1 year after RARP were examined in 111 patients enrolled in this study. Results: The number of patients with incontinence at 1 year after RARP was 39 (35.1%). The only predictive factor for urinary continence was NS grades. To investigate the contribution of NS to urinary continence, 84 patients underwent UDS three times; before, immediately after, and 1 year after RARP. Chronological UDS revealed that recovery patterns of storage and voiding functions were the same among non-NS, unilateral-NS, and bilateral-NS groups, and that higher degrees of NS contributed to lesser decreases in MUCP and longer functional urethral length (FUL) after RARP. Conclusion: Preoperative factors, including the results of UDS, could not predict continence 1 year after RARP. The NS procedure contributed to continence status. NS favorably affected MUCP and FUL; however, it did not affect bladder function after RARP. Neurourol. Urodynam. 35:1034–1039, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.<br />Embarogo Period 12 months
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| 28.
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山本, 肇 ; 打林, 忠雄 ; 並木, 幹夫 ; Yamamoto, Hajime ; Uchibayashi, Tadao ; Namiki, Mikio
概要:
(Background) We report basic animal experimental study which we evaluated the thermocoagulation effects of two different
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type of Nd: YAG laser (pulse and continuous wave (CW) laser). (Methods) The Rotalase internally reflecting fiber delivery system coupled to the pulse and CW Nd: YAG laser was used to create lesions in Seminoma tissue implanted Scid mice with the fiber tip 2mm away from the target tissue under the water. Laser power output used was 20, 40 and 60-watt for varying times (30-180sec) of irradiation. Stationary lesions, where a single spot of target was irradiated, were created. On the other hand, we measured tissue temperatures at 7, 10 and 14mm from tissue surface. The seminoma tissues removed from Scid mice were photographed after bisection, the fixed in 10% formalin and examined histologically. (Results) For the purpose of these experiments, ablated tissue is defined as the volume of tissue that has been destroyed by both coagulation and vaporization. Estimates of the volume of ablated tissue were made by macroscopic examintion of the bisected lesion, measuring the depth and width of the lesion as seen from the edges of the coagulated area around vaporized zone. The mean depth and width penetration, volume ablation and rising of the tissue temperature at pulsed 60-watt, 60 seconds was greater than that observed at other groups. Irradiated spot lesions were characterized by an initial 10-20 second period of tissue blanching followed by an audible “popcorn phenomenon” which meant more than 100°C in tissue temperature, then formation of small surface bubbles as tissue began to evaporate and char. (Conclusion) This study suggests the potential usefulness of the pulse Nd: YAG laser for Visual Laser Ablation of the Prostate (VLAP). (背景と目的) ヒト精巣セミノーマ移植腫瘍に対し, 共通の90度側射ファイバーを使用し, パルス波と連続波発振Nd: YAGレーザー光による温熱効果と組織内温度上昇について両レーザー間で比較検討した. (対象と方法) 担癌マウスを仰臥位で固定し, 水没した腫瘍に対し側射ファイバー反射面より2mmの距離で固定照射を行った. 各群は5匹ずつとし, 照射出力, 時間は, 20W, 180秒照射群, 40W, 90秒および120秒照射群, 60W, 30秒, 60秒および90秒照射群とした. 照射終了後, 移植腫瘍の腫瘍割面像で, 凝固層の深さと幅を測定した. 照射時の組織内温度上昇は腫瘍表面より7, 10, 14mmの距離で両レーザー出力20W, 40Wおよび60Wにて90秒照射し, 経時的に温度測定を行った. (結果と結論) 同エネルギー量3600J, 6群 (パルス波, 連続波: 20W, 180秒照射群, 40W, 90秒照射群, 60W, 60秒照射群) における比較検討でパルス波60W, 60秒照射群 (深さ, 幅, 仮想体積: 平均10.6mm, 12.7mm, 736mm3) がその他のいずれの群より凝固層の拡大を認めた. さらに組織内温度からも明らかにパルス波の良好な熱伝達性が証明された (パルス波60W: 腫瘍表面から7, 10, 14mmの位置でそれぞれ平均96, 77, 40℃).
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| 29.
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Iijima, Masashi ; Koh, Eitetsu ; Izumi, Kouji ; Taya, Masaki ; Maeda, Yuji ; Kyono, Kouichi ; Yoshida, Atsumi ; Namiki, Mikio
概要:
Objectives: Deletions in the azoospermia factor regions are the most common known molecular genetic cause of human male
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infertility involving spermatogenetic failure. Testing for these deletions in Japanese DNA samples using conventional sequence-tagged site probes occasionally lead to considerable non-specific or faint products in the Japanese population. The aim of the present study was to evaluate the sensitivity and specificity of a newly developed kit for the detection of azoospermia factor microdeletions in the Japanese population. Methods: Sequence-tagged site probes were reselected and the Luminex suspension array assay was carried out. Validation was retrospectively carried out with 2014 DNA sequences with known microdeletions, which were divided into four categories. Results: Category1 deletions that corresponded to the conventional classification of azoospermia factor deletion were present in 83 men (4.2%), which can result in intrachromosomal homologous recombination. Kit data confirmed the presence of deletions of this type in DNA sequences known to harbor the azoospermia factor deletions. Category2 deletions involved cytogenetic abnormalities in 28 men (1.4%), whereas category3 deletions in 759 men (37.7%) were atypical classifications including the gr/gr deletion. As these deletions are thought to be a result of palindromic units and non-homologous recombination, these microdeletions might impact in the interpretation of some clinical findings. The rest of the 1145 cases (56.8%) were assigned to category4 as normal variants (polymorphism/no deletion). Conclusions: The present findings show that this new kit offers good sensitivity and specificity with the advantage of saving in terms of cost and time. © 2014 The Japanese Urological Association.
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| 30.
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Mizokami, Atsushi ; Namiki, Mikio
概要:
Androgen blockade-naïve prostate cancer (PCa) develops into CRPC during androgen deprivation therapy (ADT) by various ge
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netic actions. The androgen-AR signaling axis plays a key role in this development. PCa cells mainly adapt themselves to the environment of lower androgen concentrations and change into androgen-hypersensitive cells or androgen-independent cells. Androgens of adrenal origin and their metabolites synthesized in the microenvironment in an intracrine/paracrine fashion act on surviving PCa cells and secrete prostate specific antigen (PSA). Total androgen deprivation (TAD) (castration, antiandrogen, and CYP17A1 inhibitor) can become an effective therapeutic strategy concerning the androgen signaling axis-related pathway. However, it is important to ascertain whether elevation of serum PSA results from AR activation or from an androgen-independent tumor volume effect. Then, clinicians can judge it adequately using the imaging studies such as CT or bone scan as well as PSA and bone metabolic markers, an approach which is necessary to judge which treatment is most suitable for the CRPC patients. This article is part of a Special Issue entitled 'Essential role of DHEA'.
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| 31.
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Taya, Masaki ; Koh, Eitetsu ; Izumi, Kouji ; Iijima, Masashi ; Maeda, Yuji ; Matsushita, Tomohiko ; Iwamoto, Teruaki ; Namiki, Mikio
概要:
Objectives: To determine testosterone fractions in Japanese men and to compare these values with those of Framingham Hea
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rt Study participants. Methods: We enrolled 498 healthy Japanese men. Total testosterone was assayed by liquid chromatography tandem mass spectrometry, sex hormone-binding globulin was assayed by immunoassay and free testosterone was calculated by a laboratory at the Boston Medical Center. Analog-based free testosterone and immunoassay-based total testosterone were determined by immunoassay. We compared mass spectrometry assay-based total testosterone and calculated free testosterone values in the Japanese participants with values in the American Framingham Heart Study third generation cohort. Results: The mean serum mass spectrometry assay-based total testosterone, sex hormone-binding globulin, and calculated free testosterone values were 439.4±167ng/dL, 65.34±30.61nmol/L, and 58.75±20.0pg/mL, respectively. The correlation coefficients with age for mass spectrometry assay-based total testosterone, sex hormone-binding globulin, and calculated free testosterone were 0.0010, 0.5041, and -0.496, respectively. There were no age-related changes in mass spectrometry assay-based total testosterone values in healthy men (P=0.981), whereas sex hormone-binding globulin and calculated free testosterone levels showed similar age-related changes (P<0.0001). Serum analog-based free testosterone levels (8.24±2.9pg/mL) showed age-related changes (P<0.0001) regardless of immunoassay-based total testosterone levels (P=0.828). Serum immunoassay-based total testosterone values (486.1±162.5ng/dL) correlated with serum mass spectrometry assay-based total testosterone values (r=0.740, 95% confidence interval 0.6965-0.7781, P<0.0001). Similarly, analog-based free testosterone and calculated free testosterone values showed a highly significant correlation (r=0.706, 95% confidence interval 0.6587-0.7473, P<0.0001). The analog-based free testosterone values were approximately 10% of the calculated free testosterone values. Conclusions: In contrast to the Framingham Heart Study cohort, total testosterone values in Japanese men are not associated with advancing age; thus, they cannot be used to diagnose late-onset hypogonadism in Japan. The analog-based free testosterone value can be considered instead as a suitable biochemical determinant for diagnosing late-onset hypogonadism syndrome. © 2014 The Japanese Urological Association.
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| 32.
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Izumi, Kouji ; Namiki, Mikio
概要:
azuizu2003@yahoo.co.jp
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| 33.
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Kadono, Yoshifumi ; Ueno, Satoru ; Yaegashi, Hiroshi ; Ofude, Mitsuo ; Izumi, Kouji ; Maeda, Yuji ; Mizokami, Atsushi ; Miwa, Sotaro ; Miyagi, Tohru ; Namiki, Mikio
概要:
Objective To evaluate continence status and mechanism of urinary incontinence immediately after robot-assisted radical p
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rostatectomy (RARP) by performing urodynamic evaluation. Methods A total of 87 patients with localized prostate cancer who underwent RARP were included. Filling cystometry, urethral pressure profilometry, and abdominal leak point pressure (ALPP) tests were performed before and immediately after RARP. Results The mean urine loss ratio (ULR), calculated by dividing the total urine volume by the weight of urine loss after RARP, was 17.8%. Nerve-sparing (NS) surgery significantly affected ULR compared with non-NS surgery. In the comparison between preoperative and postoperative results, the mean maximal cystometric capacity (MCC) and maximal closure urethral pressure (MUCP) decreased from 341 mL and 84.6 cm H 2O to 250 mL and 35.6 cm H2O, respectively. No urine leakage was observed in ALPP test preoperatively; however, urine leakage was observed postoperatively in 75 patients (86%), with a mean ALPP of 47.7 cm H2O. Multivariate analysis revealed that MCC, MUCP, and ALPP after RARP were predictive factors for ULR. Linear correlations were found between ULR and MUCP and between ULR and ALPP after RARP. NS status and MUCP after RARP (r = 0.247; P =.021) and the ALPP (r = 0.254; P =.018) were significantly correlated. Conclusion In urodynamic evaluation immediately after RARP, MCC, MUCP, and ALPP were found to predictive factors for urinary incontinence. The NS procedure contributed to continence status after RARP. © 2014 Elsevier Inc.
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| 34.
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Izumi, Kouji ; Lin, Wen-Jye ; Miyamoto, Hiroshi ; Huang, Chiung-Kuei ; Maolake, Aerken ; Kitagawa, Yasuhide ; Kadono, Yoshifumi ; Konaka, Hiroyuki ; Mizokami, Atsushi ; Namiki, Mikio
概要:
Purpose Prostate-specific antigen (PSA) is a useful biomarker of prostate cancer (PCa). High-risk localized PCa is defin
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ed using T stage, Gleason score (GS), and PSA. However, PSA level defining high-risk PCa is at most 20 ng/mL. In PCa patients with high PSA, it is unclear whether PSA itself can be a prognostic factor. Methods Of 642 patients who were diagnosed as PCa, 90 patients with PSA > 100 ng/mL were retrospectively analyzed. Patients were divided into three groups according to PSA level: very high (>1,000 ng/mL), moderately high (200-1,000 ng/mL), and slightly high (100-200 ng/mL). Results There were no significant differences in overall survival or PCa-specific survival (PCaSS) among the three groups. Regardless of PSA level, high M stage and GS significantly reduced PCaSS. When the risk classification was made using M stage and GS (high risk = M1 and GS ≥ 9, low risk = M0 and GS < 9, and intermediate risk = others), PCaSS was significantly different among high-, intermediate-, and low-risk groups with 5-year survival rates of 58.2, 80.6, and 100 %, respectively. Although there were no differences in treatment performed during the castration-resistant stage, patients undergoing alternative anti-androgen and zoledronic acid treatment had better PCaSS after being castration-resistant. Conclusions As PSA could not be a prognostic factor in PCa patients with high PSA > 100 ng/mL, the novel risk classification using M stage and GS may help clinicians to predict PCaSS and to plan follow-up schedules after diagnosis. © 2014 Springer-Verlag Berlin Heidelberg.
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| 35.
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Izumi, Kouji ; Itai, Shingo ; Takahashi, Yoshiko ; Maolake, Aerken ; Namiki, Mikio
概要:
Hypertension (HT) is the common adverse event associated with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKI). The present study was performed to identify the predictive factors of TKI-induced HT
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and to determine the classes of antihypertensive agents (AHTA) that demonstrate optimal efficacy against this type of HT. The charts of 50 cases of patients that had received VEGFR-TKI treatment were retrospectively examined. The association between patient background and TKI-induced HT, and the effect of administering AHTA were analyzed. High systolic blood pressure at baseline was identified to be a predictive factor for HT. In addition, there was no difference observed between calcium channel blockers (CCBs) and angiotensin receptor II blockers (ARBs) as first-line AHTA for the control of HT. The findings of the present study may aid with predicting the onset of TKI-induced HT, as well as for its management via the primary use of either CCBs or ARBs.
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| 36.
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Nakamura, Ritsuko ; Oyama, Takeru ; Tajiri, Ryosuke ; Mizokami, Atsushi ; Namiki, Mikio ; Nakamoto, Masaru ; Ooi, Akishi
概要:
Neural epidermal growth factor-like like (NELL) 1 and 2 constitute a family of multimeric and multimodular extracellular
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glycoproteins. Although the osteogenic effects of NELL1 and functions of NELL2 in neural development have been reported, their expression and functions in cancer are largely unknown. In this study, we examined expression of NELL1 and NELL2 in renal cell carcinoma (RCC) using clinical specimens and cell lines. We show that, whereas NELL1 and NELL2 proteins are strongly expressed in renal tubules in non-cancerous areas of RCC specimens, their expression is significantly downregulated in cancerous areas. Silencing of NELL1 and NELL2 mRNA expression was also detected in RCC cell lines. Analysis of NELL1/2 promoter methylation status indicated that the CpG islands in the NELL1 and NELL2 genes are hypermethylated in RCC cell lines. NELL1 and NELL2 bind to RCC cells, suggesting that these cells express a receptor for NELL1 and NELL2 that can transduce signals. Furthermore, we found that both NELL1 and NELL2 inhibit RCC cell migration, and NELL1 further inhibits RCC cell adhesion. These results suggest that silencing of NELL gene expression by promoter hypermethylation plays roles in RCC progression by affecting cancer cell behavior. We found that the down-regulation of NELL1 and NELL2 in renal cell carcinoma (RCC) is in part due to the hypermethylation of CpG islands in their putative promoter regions. Furthermore, we found that NELL1 suppresses and NELL2 partially suppresses RCC cell migration, and NELL1 further inhibits RCC cell adhesion. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
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| 37.
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Izumi, Kouji ; Mizokami, Atsushi ; Lin, Hsiu-Ping ; Ho, Hui-Min ; Iwamoto, Hiroaki ; Maolake, Aerken ; Natsagdorj, Ariunbold ; Kitagawa, Yasuhide ; Kadono, Yoshifumi ; Miyamoto, Hiroshi ; Huang, Chiung-Kuei ; Namiki, Mikio ; Lin, Wen-Jye
概要:
Prostate-specific antigen (PSA) is regarded as the most sensitive biomarker for prostate cancer. Although androgen/andro
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gen receptor (AR) signaling promotes prostate cancer progression, suppression of AR signaling induces chemokine (CC motif) ligand 2 (CCL2), which enables prostate cancer cells to gain metastatic potential. AR-controlled PSA alone may be an unreliable biomarker for patients receiving androgen deprivation therapy. Therefore, we investigated the validity of CCL2 as a complementary biomarker to PSA for prostate cancer. Our in vitro approach of enriching for prostate cancer cells with higher migration potential showed that CCL2 activated cellular migration. Importantly, we found that CCL2 levels were significantly different between men (n = 379) with and without prostate cancer. Patients with CCL2 ≥ 320 pg/mL had worse overall survival and prostate cancer -specific survival than those with CCL2 < 320 pg/mL. A novel risk classification was developed according to the risk factors CCL2 ≥ 320 pg/mL and PSA ≥ 100 ng/mL, and scores of 2, 1, and 0 were defined as poor, intermediate, and good risk, respectively, and clearly distinguished patient outcomes. CCL2 may serve as a novel biomarker for prostate cancer. The novel risk classification based on combining CCL2 and PSA is more reliable than using either alone.
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| 38.
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Sato, Youichi ; Tajima, Atsushi ; Tsunematsu, Kouki ; Nozawa, Shiari ; Yoshiike, Miki ; Koh, Eitetsu ; Kanaya, Jiro ; Namiki, Mikio ; Matsumiya, Kiyomi ; Tsujimura, Akira ; Komatsu, Kiyoshi ; Itoh, Naoki ; Eguchi, Jiro ; Imoto, Issei ; Yamauchi, Aiko ; Iwamoto, Teruaki
概要:
STUDY QUESTION Are the four candidate loci (rs7867029, rs7174015, rs12870438 and rs724078) for human male fertility trai
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ts, identified in a genome-wide association study (GWAS) of a Hutterite population in the USA, associated with male infertility in a Japanese population? SUMMARY ANSWER rs7867029, rs7174015 and rs12870438 are significantly associated with the risk of male infertility in a Japanese population. WHAT IS KNOWN ALREADY Recently, a GWAS of a Hutterite population in the USA revealed that 41 single-nucleotide polymorphisms (SNPs) were significantly correlated with family size or birth rate. Of these, four SNPs (rs7867029, rs7174015, rs12870438 and rs724078) were found to be associated with semen parameters in ethnically diverse men from Chicago. STUDY DESIGN, SIZE, DURATION This is a case-control association study in a total of 917 Japanese subjects, including 791 fertile men, 76 patients with azoospermia and 50 patients with oligozoospermia. PARTICIPANTS/MATERIALS, SETTING, METHODS Azoospermia was diagnosed on the basis of semen analysis (the absence of sperm in ejaculate), serum hormone levels and physical examinations. Oligozoospermia was defined as a sperm concentration of <20 × 106/ml. We excluded patients with any known cause of infertility (i.e. obstructive azoospermia, varicocele, cryptorchidism, hypogonadotropic hypogonadism, karyotype abnormalities or complete deletion of AZF a, b or c). The SNPs rs7867029, rs7174015, rs12870438 and rs724078 were genotyped using DNA from peripheral blood samples and either restriction fragment length polymorphism PCR or TaqMan probes. Genetic associations between the four SNPs and male infertility were assessed using a logistic regression analysis under three different comparative models (additive, recessive or dominant). MAIN RESULTS AND THE ROLE OF CHANCE The genotypes of all four SNPs were in Hardy-Weinberg equilibrium in the fertile controls. The SNPs rs7867029 and rs7174015 are associated with oligozoospermia [rs7867029: odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.07-2.68, P = 0.024 (log-additive); rs7174015: OR = 6.52, 95% CI = 1.57-27.10, P = 0.0099 (dominant)] and rs12870438 is associated with azoospermia (OR = 10.90, 95% CI = 2.67-44.60, P = 0.00087 (recessive)] and oligozoospermia [OR = 8.54, 95% CI = 1.52-47.90, P = 0.015 (recessive)]. The association between rs7174015 and oligozoospermia under a dominant model and between rs12870438 and azoospermia under additive and recessive models remained after correction for multiple testing. There were no associations between rs724078 and azoospermia or oligozoospermia. LIMITATIONS, REASONS FOR CAUTION Even though the sample size of case subjects was not very large, we found that three SNPs were associated with the risk of male infertility in a Japanese population. WIDER IMPLICATIONS OF THE FINDINGS The three infertility-associated SNPs may be contributing to a quantitative reduction in spermatogenesis. STUDY FUNDING/COMPETING INTEREST(S) This study was supported in part by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T. I.) and the Takeda Science Foundation (to A.Ta.). None of the authors has any competing interests to declare. © 2015 The Author. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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| 39.
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Sato, Youichi ; Tajima, Atsushi ; Tsunematsu, Kouki ; Nozawa, Shiari ; Yoshiike, Miki ; Koh, Eitetsu ; Kanaya, Jiro ; Namiki, Mikio ; Matsumiya, Kiyomi ; Tsujimura, Akira ; Komatsu, Kiyoshi ; Itoh, Naoki ; Eguchi, Jiro ; Imoto, Issei ; Yamauchi, Aiko ; Iwamoto, Teruaki
概要:
STUDY QUESTION Are the four candidate loci (rs7867029, rs12870438, rs7174015 and rs724078) for human male fertility trai
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ts, identified in a genome-wide association study (GWAS) of a Hutterite population in the USA, associated with semen quality traits in a Japanese population? SUMMARY ANSWER The four single nucleotide polymorphisms (SNPs) rs7867029, rs12870438, rs7174015 and rs724078 have no association with semen parameters in a meta-analysis of two Japanese male cohorts. WHAT IS KNOWN ALREADY Four (rs7867029, rs12870438, rs7174015 and rs724078) of the SNPs associated with family size or birth rate in the GWAS of a Hutterite population in the USA were associated with semen parameters in ethnically diverse men from Chicago, USA. STUDY DESIGN, SIZE, DURATION This is a replication study in a total of 2015 Japanese subjects, including 791 fertile men and 1224 young men from the general population. PARTICIPANTS/MATERIALS, SETTING, METHODS We performed a replication study in two cohorts to assess whether the SNPs rs7867029, rs12870438, rs7174015 and rs724078 are associated with sperm concentration, semen volume, total sperm numbers, total motile sperm numbers or sperm motility. The rs12870438 SNP was detected by restriction fragment length polymorphism PCR while rs7174015, rs724078 and rs7867029 SNPs were genotyped using TaqMan probes. MAIN RESULTS AND THE ROLE OF CHANCE This study indicated that none of the four SNPs rs7867029, rs12870438, rs7174015 and rs724078 displayed a significant association with semen parameters in the meta-analysis of two Japanese male cohorts. LIMITATIONS, REASONS FOR CAUTION Only four SNPs identified in the Hutterite GWAS were examined for associations with semen quality traits in a Japanese population. In addition, the linkage disequilibrium structures around the testing markers were different between ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS Locus mapping studies using a set of tagging SNPs across the loci will be necessary in populations with larger sample sizes in order to understand the contribution of specific genes to semen quality. STUDY FUNDING/COMPETING INTEREST (S) This study was supported in part by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T.I.), and the Takeda Science Foundation (to A.Ta.). None of the authors has any competing interests to declare. © 2015 The Author. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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| 40.
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山本, 肇 ; 打林, 忠雄 ; 並木, 幹夫 ; Yamamoto, Hajime ; Uchibayashi, Tadao ; Namiki, Mikio
概要:
(背景と目的) ヒト精巣セミノーマ移植腫瘍に対し, 共通の90度側射ファイバーを使用し, パルス波と連続波発振Nd: YAGレーザー光による温熱効果と組織内温度上昇について両レーザー間で比較検討した. (対象と方法) 担癌マウスを仰臥位で固
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定し, 水没した腫瘍に対し側射ファイバー反射面より2mmの距離で固定照射を行った. 各群は5匹ずつとし, 照射出力, 時間は, 20W, 180秒照射群, 40W, 90秒および120秒照射群, 60W, 30秒, 60秒および90秒照射群とした. 照射終了後, 移植腫瘍の腫瘍割面像で, 凝固層の深さと幅を測定した. 照射時の組織内温度上昇は腫瘍表面より7, 10, 14mmの距離で両レーザー出力20W, 40Wおよび60Wにて90秒照射し, 経時的に温度測定を行った. (結果と結論) 同エネルギー量3600J, 6群 (パルス波, 連続波: 20W, 180秒照射群, 40W, 90秒照射群, 60W, 60秒照射群) における比較検討でパルス波60W, 60秒照射群 (深さ, 幅, 仮想体積: 平均10.6mm, 12.7mm, 736mm3) がその他のいずれの群より凝固層の拡大を認めた. さらに組織内温度からも明らかにパルス波の良好な熱伝達性が証明された (パルス波60W: 腫瘍表面から7, 10, 14mmの位置でそれぞれ平均96, 77, 40℃). (Background) We report basic animal experimental study which we evaluated the thermocoagulation effects of two different type of Nd: YAG laser (pulse and continuous wave (CW) laser). (Methods) The Rotalase internally reflecting fiber delivery system coupled to the pulse and CW Nd: YAG laser was used to create lesions in Seminoma tissue implanted Scid mice with the fiber tip 2mm away from the target tissue under the water. Laser power output used was 20, 40 and 60-watt for varying times (30-180sec) of irradiation. Stationary lesions, where a single spot of target was irradiated, were created. On the other hand, we measured tissue temperatures at 7, 10 and 14mm from tissue surface. The seminoma tissues removed from Scid mice were photographed after bisection, the fixed in 10% formalin and examined histologically. (Results) For the purpose of these experiments, ablated tissue is defined as the volume of tissue that has been destroyed by both coagulation and vaporization. Estimates of the volume of ablated tissue were made by macroscopic examintion of the bisected lesion, measuring the depth and width of the lesion as seen from the edges of the coagulated area around vaporized zone. The mean depth and width penetration, volume ablation and rising of the tissue temperature at pulsed 60-watt, 60 seconds was greater than that observed at other groups. Irradiated spot lesions were characterized by an initial 10-20 second period of tissue blanching followed by an audible “popcorn phenomenon” which meant more than 100°C in tissue temperature, then formation of small surface bubbles as tissue began to evaporate and char. (Conclusion) This study suggests the potential usefulness of the pulse Nd: YAG laser for Visual Laser Ablation of the Prostate (VLAP).<br />出版者照会後に全文公開 / 許可を得て公開
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| 41.
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Maolake, Aerken ; Izumi, Kouji ; Shigehara, Kazuyoshi ; Natsagdorj, Ariunbold ; Iwamoto, Hiroaki ; Kadomoto, Suguru ; Takezawa, Yuta ; Machioka, Kazuaki ; Narimoto, Kazutaka ; Namiki, Mikio ; Lin, Wen-Jye ; Wufuer, Guzailinuer ; Mizokami, Atsushi
概要:
Previous studies have found that tumor-associated macrophages (TAMs) promote cancer progression. We previously reported that TAMs promote prostate cancer metastasis via activation of the CCL2-CCR2 axis. The CCR4 (receptor of CCL17 and
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CCL22) expression level in breast cancer was reported to be associated with lung metastasis. The aim of this study was to elucidate the role of CCR2 and CCR4 in prostate cancer progression. CCR2 and CCR4 were expressed in human prostate cancer cell lines and prostate cancer tissues. In vitro co-culture of prostate cancer cells and macrophages resulted in increased CCL2 and CCR2 levels in prostate cancer cells. The addition of CCL2 induced CCL22 and CCR4 production in prostate cancer cells. The migration and invasion of prostate cancer cells via enhanced phosphorylation of Akt were promoted by CCL17 and CCL22. CCR4 may be a potential candidate for molecular-targeted therapy.
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| 42.
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Izumi, Kouji ; Mizokami, Atsushi ; Sugimoto, Kazuhiro ; Narimoto, Kazutaka ; Miyagi, Tohru ; Maeda, Yuji ; Kitagawa, Yasuhide ; Kadono, Yoshifumi ; Konaka, Hiroyuki ; Namiki, Mikio
概要:
金沢大学附属病院泌尿器科<br />The effect of chelating ligands on iron (Fe) uptake and growth of radish (Raphanus sativus L.) was inv
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estigated. The ethylenediaminetetraacetic acid (EDTA) increased 55Fe uptake in roots of radish though its subsequent translocation from roots to shoots and leaves did not increase. About 70%-80% of the total 55Fe was distributed in the roots while about 5%-15% and 11%-17% were in shoots and leaves, respectively. The EDTA increased iron uptake into the roots of radish, but not in the above ground parts of the plant. The growth of radish (Raphanus sativus L.) decreased drastically in alkaline condition (pH > 9), even though the concentration of iron was sufficient in the growth medium. The growth of radish was enhanced successfully by the addition of hydroxyiminodisuccinic acid (HIDS) and EDTA. This might be because HIDS and EDTA solubilize iron from its precipitation with hydroxides at higher pH, and increase iron bioavailability. The influence of EDTA and HIDS on radish growth was comparable. Increase of radish growth by ethylenediaminedisuccinic acid (EDDS) and methylglicinediacetic acid (MGDA) was less than those by EDTA and HIDS. Considering the reproducibility of the radish growth (biomass production) at pH 10, HIDS is supposed to be more effective compared to EDTA. © Taylor & Francis Group, LLC.
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Namiki, Mikio ; Konaka, Hiroyuki
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Shigehara, Kazuyoshi ; Mizokami, Atsushi ; Komatsu, Kazuto ; Koshida, Kiyoshi ; Namiki, Mikio
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金沢大学医学部附属病院泌尿器科<br />Background: We evaluated the efficacy and complications of high dose rate (HDR) brachytherapy using
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iridium-192 (192Ir) combined with external beam radiotherapy (EBRT) in patients with prostate cancer. Methods: Ninety-seven patients underwent 192Ir HDR brachytherapy combined with EBRT at our institution between February 1999 and December 2003. Of these, 84 patients were analysed in the present study. 192Ir was delivered three times over a period of 2 days, 6 Gy per time, for a total dose of 18 Gy. Interstitial application was followed by EBRT at a dose of 44 Gy. Progression was defined as three consecutive prostate-specific antigen (PSA) rises after a nadir according to the American Society for Therapeutic Radiology and Oncology criteria. The results were classified into those for all patients and for patients who did not undergo adjuvant hormone therapy. Results: The 4-year overall survival of all patients, the nonadjuvant hormone therapy group (NAHT) and the adjuvant hormone therapy group (AHT) was 87.2%, 100%, and 70.1%, respectively. The PSA progression-free survival rate of all patients, NAHT, and AHT was 82.6%, 92.0%, and 66.6%, respectively. Of all patients, the 4-year PSA progression-free survival rates of PSA < 20 and PSA ≥ 20 groups were 100%, and 46.8%, respectively. According to the T stage classification, PSA progression-free survival rates of T1c, T2, T3, and T4 were 100%, 82.8%, 100%, and 12.1%, respectively. Prostate-specific antigen progression-free survival rates of groups with Gleason scores (GS) < 7 and GS ≥ 7 were 92.8% and 60.1%, respectively. Of NAHT, PSA progression-free survival of PSA < 20 was 100% vs 46.8% for PSA ≥ 20, that of T1c was 100% vs 75% for T2, and that of GS < 7 was 100% vs 75% for GS ≥ 7. No significant intraoperative or postoperative complications requiring urgent treatment occurred except cerebellum infarction. Conclusions: 192Ir HDR brachytherapy combined with EBRT was as effective as radical prostatectomy and had few associated complications。
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| 45.
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Takeda, Masashi ; Mizokami, Atsushi ; Mamiya, Kiminori ; You, Qiang Li ; Jian, Zhang ; Keller, Evan T. ; Namiki, Mikio
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金沢大学医学部附属病院泌尿器科<br />BACKGROUND. Although paclitaxel is used for hormone-resistant prostate cancer, relapse definitely o
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ccurs later. Details of the molecular mechanism responsible for paclitaxel- resistance remain unclear. METHODS. We established paclitaxel-resistant cells, DU145-TxR and PC-3-TxR from parent DU145 and PC-3. To characterize these cells, we examined cross-resistance to other anticancer drugs. Expression of several potential genes that had been related to drug-resistance was compared with parent cells by RT-PCR and Western blotting. Methylation analysis of multiple drug resistance (MDR1) promoter was carried out using bisulfite-modified DNA from cell lines. Knockdown experiments using small interfering RNA (siRNA) were also performed to confirm responsibility of drug-resistance. Finally, cDNA microarray was performed to quantify gene expression in PC-3 and PC-3-TxR cells. RESULTS. The IC50 for paclitaxel in DU145-TxR and PC-3-TxR was 34.0- and 43.4-fold higher than that in both parent cells, respectively. Both cells showed cross-resistance to some drugs, but not to VP-16 and cisplatin. Methylation analysis revealed that methylated CpG sites of MDR1 promoter in DU145 and PC-3 cells were demethylated in DU145-TxR cells, but not in PC-3-TxR cells. Knockdown of P-glycoprotein (P-gp), which was up-regulated in resistant cells, by MDR-1 siRNA restored paclitaxel sensitivity in DU145-TxR but not in PC-3-TxR, indicating that upregulation of P-gp was not always main cause of paclitaxel-resistance. Microarray analysis identified 201 (1.34%) up-regulated genes and 218 (1.45%) out of screened genes in PC-3-TxR. CONCLUSIONS. Our data will provide molecular mechanisms of paclitaxel-resistance and be useful for screening target genes to diagnose paclitaxel sensitivity. © 2007 Wiley-Liss, Inc.
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Takeda, Masashi ; Mizokami, Atsushi ; Mamiya, Kiminori ; Li, You Qiang ; Zhang, Jian ; Keller, Evan T. ; Namiki, Mikio
概要:
金沢大学医学部附属病院泌尿器科<br />BACKGROUND. Although paclitaxel is used for hormone-resistant prostate cancer, relapse definitely o
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ccurs later. Details of the molecular mechanism responsible for paclitaxel- resistance remain unclear. METHODS. We established paclitaxel-resistant cells, DU145-TxR and PC-3-TxR from parent DU145 and PC-3. To characterize these cells, we examined cross-resistance to other anticancer drugs. Expression of several potential genes that had been related to drug-resistance was compared with parent cells by RT-PCR and Western blotting. Methylation analysis of multiple drug resistance (MDR1) promoter was carried out using bisulfite-modified DNA from cell lines. Knockdown experiments using small interfering RNA (siRNA) were also performed to confirm responsibility of drug-resistance. Finally, cDNA microarray was performed to quantify gene expression in PC-3 and PC-3-TxR cells. RESULTS. The IC50 for paclitaxel in DU145-TxR and PC-3-TxR was 34.0- and 43.4-fold higher than that in both parent cells, respectively. Both cells showed cross-resistance to some drugs, but not to VP-16 and cisplatin. Methylation analysis revealed that methylated CpG sites of MDR1 promoter in DU145 and PC-3 cells were demethylated in DU145-TxR cells, but not in PC-3-TxR cells. Knockdown of P-glycoprotein (P-gp), which was up-regulated in resistant cells, by MDR-1 siRNA restored paclitaxel sensitivity in DU145-TxR but not in PC-3-TxR, indicating that upregulation of P-gp was not always main cause of paclitaxel-resistance. Microarray analysis identified 201 (1.34%) up-regulated genes and 218 (1.45%) out of screened genes in PC-3-TxR. CONCLUSIONS. Our data will provide molecular mechanisms of paclitaxel-resistance and be useful for screening target genes to diagnose paclitaxel sensitivity. © 2007 Wiley-Liss, Inc.
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Nagasawa, Joji ; Mizokami, Atsushi ; Koshida, Kiyoshi ; Yoshida, Sei ; Naito, Kenjiro ; Namiki, Mikio
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金沢大学医学部附属病院泌尿器科<br />Purpose: TAK-165 is a new potent inhibitor of human epidermal growth factor receptor 2 (HER2) tyros
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ine kinase. Several reports suggest HER2 expression in bladder cancer, renal cell carcinoma (RCC) and androgen-independent prostate cancer. We therefore investigated the antitumor effect of TAK-165 on these urological cancer cells. Materials and methods: Western blot analysis was performed to confirm HER2 expression in cell lines. To study in vitro efficacy, cells were treated with TAK-165 at various concentrations for 72 h and then counted using a hemocytometer. Then the IC50 value was calculated. In the xenograft model, after the tumor reached 200-300 mm3 in volume, mice were orally administered TAK-165 10 mg/kg per day or 20 mg/kg per day or saline for 14 consecutive days (n = 6-8). Results: HER2 expression was observed in HT1376, UMUC3, T24 (bladder), ACHN (kidney), DU145, LNCaP, LN-REC4 (prostate), although the expression level in these cells was weak compared with BT474 (a breast cancer cell line which expresses HER2 strongly). IC50 was varied from 0.09 to greater than 25 μmol/L in the bladder cancer cell line. ACHN cells were less sensitive in vitro. The prostate cancer cell lines studied were all sensitive (IC50 0.053-4.62 μmol/L). In the xenograft model, treatment with TAK-165 significantly inhibited growth of UMUC-3, ACHN, and LN-REC4. The antitumor effect (T/C [%] = growth of TAK-165 treated tumor/average growth of control tumor × 100) after 14 days treatment were 22.9%, 26.0%, and 26.5% in UMUC3, ACHN and LN-REC4, respectively. Conclusions: TAK-165 may be a hopeful new agent for bladder, kidney and androgen-independent prostate cancer.
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Asahi, Hideki ; Mizokami, Atsushi ; Miwa, Sotaro ; Keller, Evan T. ; Koshida, Kiyoshi ; Namiki, Mikio
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金沢大学医学部附属病院泌尿器科<br />Aim: Bisphosphonates are well established for the management of cancer-induced skeletal complicatio
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ns. Recent studies suggest that bisphosphonates promote apoptosis of cancer cells as well as osteoclasts in bone metastatic sites. To determine the direct effects of bisphosphonate on prostate cancer, we examined the effects of minodronate on prostatic cancer cell growth and the expression of apoptosis-related proteins and osteoclastogenic factors. Methods: PC-3, DU145 and LNCaP cells were treated with amino-bisphosphonate minodronate. Then proliferation, apoptosis and expression of bcl-2, bax, poly (ADP)-ribose polymerase (PARP), caspase-3, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinases-2 (MMP-2), and parathyroid hormone related protein (PTHrP) were assessed. Results: The proliferation of prostatic cancer cells was inhibited by minodronate. DNA fragmentation and TUNEL-positive nuclei were observed in minodronate-treated PC-3 cells. Minodronate decreased bcl-2 expression and induced bax expression, caspase-3 activity and degradation of PARP in DU145 and PC-3 cells. Minodronate decreased expression of RANKL, PTHrP and MMP-2 in PC-3 cells. Conclusions: Our results suggest that bisphosphonate not only promotes apoptosis directly but also decreases pro-osteoclastic gene expression in prostate cancer cells.
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Izumi, Kouji ; Mizokami, Atsushi ; Itai, Shingo ; Shima, Takashi ; Shigehara, Kazuyoshi ; Miwa, Sotaro ; Maeda, Yuji ; Konaka, Hiroyuki ; Koh, Eitetsu ; Namiki, Mikio
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金沢大学附属病院泌尿器科<br />Study Type - Prognosis (case series) Level of Evidence4 What's known on the subject? and What does the
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study add? Bone turnover markers such as BAP and 1CTP in patients with SRE or metastatic bone progression were significantly higher at later phase after starting treatment with zoledronic acid compared with those without SRE or progression. However, there are no evident biomarkers predicting SRE or survival at an early phase after starting zoledronic acid treatment. The increase in serum 1CTP and BAP levels at an early phase after starting zoledronic acid treatment predicts short SRE-free survival and overall survival. The measurement of bone turnover markers may be useful for physicians to inform patients of their prognosis and to determine the subsequent treatment plan. OBJECTIVE: To examine whether bone turnover markers could be predictive markers of the probability of newly arising skeletal-related events (SRE) after the start of zoledronic acid treatment in patients with prostate cancer with bone metastasis. PATIENTS AND METHODS: In all, 30 patients with prostate cancer with bone metastasis were treated with zoledronic acid infusion every 4 weeks. Serum C-terminal crosslinking telopeptide of type 1 collagen (1CTP), bone alkaline phosphatase (BAP), and prostate-specific antigen (PSA) levels were measured at the start of zoledronic acid treatment to establish baseline values, and every 4 weeks thereafter. To judge in the early phase whether zoledronic acid is effective in these patients, we retrospectively compared 1CTP, BAP, and PSA levels at 1, 3, and 6 months after starting zoledronic acid treatment with those at baseline. RESULTS: SRE-free survival of patients with increases of 1CTP levels at 1 and 3 months and BAP levels at 3 months were significantly poorer than those of patients with decreases in 1CTP or BAP levels (P = 0.001, P = 0.042, and P = 0.004, respectively). Overall survival of patients with increases of 1CTP levels at 1 and 3 months and of BAP levels at 6 months were significantly poorer than those of patients with decreases of 1CTP or BAP levels (P = 0.013, P = 0.027, and P = 0.035, respectively). CONCLUSION: The measurement of 1CTP and BAP levels at an early phase after starting zoledronic acid treatment may be useful for physicians to inform patients of their prognosis and to determine the subsequent treatment plan. © 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.<br />発行後1年より最終稿.
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Kadono, Yoshifumi ; Yaegashi, Hiroshi ; Machioka, Kazuaki ; Ueno, Satoru ; Miwa, Sotaro ; Maeda, Yuji ; Miyagi, Tohru ; Mizokami, Atsushi ; Fujii, Yuka ; Tsubokawa, Tsunehisa ; Yamamoto, Ken ; Namiki, Mikio
概要:
Background: Robot-assisted laparoscopic radical prostatectomy (RALP) requires a steep Trendelenburg position and CO2 pne
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umoperitoneum for several hours to secure the surgical visual field. The present study was performed to investigate the influence of each angle of Trendelenburg position during RALP on cardiovascular and respiratory homeostasis. Methods: Forty-seven ASA physical status 1 and 2 patients underwent open retropubic radical prostatectomy (RRP) or RALP. Patients receiving RALP were randomized to undergo the operation in the 20°, 25° or 30° Trendelenburg position. Heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR), end-tidal CO2 pressure (PetCO2), tidal volume (Vt), peak inspiratory pressure (PIP) and dynamic compliance (Cdyn) were recorded during the operation. Results: Angle of head-down tilt was significantly correlated with MAP, PIP and Cdyn, but not with HR, RR or PetCO2. MAP decreased gradually over time in each group in the Trendelenburg position with pneumoperitoneum. As the angle of head-down tilt became stronger, MAP, RR, PetCO2 and PIP tended to increase and Cdyn tended to decrease. Conclusions: This study demonstrated that the degree of the head-down angle at RALP affected the cardiovascular and respiratory parameters. Pneumoperitoneum with head-down position in RALP influenced the cardiovascular and respiratory system to a greater extent than RRP, and these effects were stronger with deeper head-down angle. © 2013 John Wiley & Sons, Ltd.
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Kadono, Yoshifumi ; Miwa, Sotaro ; Shima, Takashi ; Konaka, Hiroyuki ; Mizokami, Atsushi ; Yotsuyanagi, Satoshi ; Hirata, Akio ; Takase, Yasukazu ; Sugata, Toshiaki ; Shimamura, Masayoshi ; Namiki, Mikio
概要:
Interferon-alpha (IFN-α) has been used in systemic treatment for metastatic renal cell carcinoma (mRCC). IFN-α has at le
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ast 14 subtypes, each of which has different biological activity. There have been reports that mRCC resistant to an IFN-α treatment responded to another IFN-α subtype. This study was performed to evaluate the effectiveness of alternation of different IFN-α subtypes for mRCC that did not respond to initial IFN-α treatment. In our department and associated institutions, alternating therapy of IFN-α was provided for 15 initial IFN-α refractory mRCC cases from June 2005 to September 2008. Among the 15 patients, the effects of alternating IFN-α therapy were as follows: complete response (CR), 0 cases; partial response (PR), 1 case; stable disease (SD), 3 cases; progressive disease (PD), 11 cases. The response rate (CR+PR) was 7% and disease control rate (CR+PR+SD) was 27%. No severe side effects were observed in any of these cases. The PR case is still in PR 21 months after alternating IFN-α therapy. Among the three SD cases, one has continued SD for 14 months and the other for 12 months. Alternating IFN-α therapy for mRCC can be attempted even if other cytokines are not effective.
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Kadono, Yoshifumi ; Ueno, Satoru ; Iwamoto, Daiki ; Takezawa, Yuta ; Nohara, Takahiro ; Izumi, Kouji ; Mizokami, Atsushi ; Namiki, Mikio
概要:
Objective To examine chronological changes in urethral and bladder functions before, immediately after, and 1 year after
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robot-assisted radical prostatectomy (RARP), urodynamic studies were prospectively performed. Methods Sixty-three consecutive patients underwent pressure-flow studies, urethral pressure profiles, and abdominal leak point pressure (ALPP) tests 1-2 days before, immediately after, and 1 year after RARP. Results The mean bladder compliance was 28.3 mL/cm H<inf>2</inf>O before RARP; it worsened to 16.3 mL/cm H<inf>2</inf>O immediately after RARP and recovered to 27.1 mL/cm H<inf>2</inf>O at 1 year. The mean detrusor pressure at maximum flow rate was 61.9 cm H<inf>2</inf>O before RARP; it decreased to 34.3 cm H<inf>2</inf>O immediately after RARP and remained at 35.6 cm H<inf>2</inf>O at 1 year. The mean maximum urethral closure pressure was 84.2 cm H<inf>2</inf>O before RARP; it decreased to 33.4 cm H<inf>2</inf>O immediately after RARP and recovered to 63.0 cm H<inf>2</inf>O at 1 year. Intrinsic sphincter deficiency (ISD) evaluated by the ALPP test was observed in 53 patients immediately after RARP, although no patient showed ISD before RARP. ISD remained in 7 patients at 1 year. Both ALPP and maximum urethral closure pressure at 1 year were significant factors for continence in multivariate analysis. Conclusion Urethral sphincter and bladder function worsen immediately after RARP and recover over time. The bladder storage function after RARP returns to almost the same level before RARP, and the voiding function improves compared with the condition before RARP; however, the urethral sphincter function does not return to its preoperative level. Urethral sphincter dysfunction is considered the main factor for urinary incontinence after RARP. © 2015 Elsevier Inc.<br />Embargo Period 12 months
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Kadono, Yoshifumi ; Nohara, Takahiro ; Ueno, Satoru ; Izumi, Kouji ; Kitagawa, Yasuhide ; Konaka, Hiroyuki ; Mizokami, Atsushi ; Onozawa, Mizuki ; Hinotsu, Shiro ; Akaza, Hideyuki ; Namiki, Mikio
概要:
Purpose: The current tumor–node–metastasis (TNM) classification system has been used for many years. The prognosis of pa
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tients with metastatic prostate cancer (mPC) treated using primary androgen deprivation therapy (PADT) was analyzed according to the TNM classification. Methods: A total of 5618 cases with lymph node metastases only (N1M0), non-regional lymph node metastasis (M1a), bone metastasis (M1b), and distant metastasis (M1c) were selected from the Japanese Study Group of Prostate Cancer database. Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) rates were calculated using Kaplan–Meier analysis. The influence of clinical variables on patient prognosis was evaluated using the Cox proportional hazard regression model. Results: The 5-year OS, CSS, and PFS were 76.0, 83.2, and 38.8 % in N1M0, 57.5, 69.0, and 23.0 % in M1a, 54.0, 63.1, and 23.0 % in M1b, and 40.0, 51.5, and 16.6 % in M1c, respectively. OS, CSS, and PFS worsened as the stages progressed. OS, CSS, and PFS were all significantly worse in N1M1b compared with N0M1b. Multivariate analysis revealed that OS and CSS were worse in patients with a Gleason score ≥8 and that combined androgen blockade (CAB) treatment provided better OS than non-CAB treatments at any tumor stage. However, OS and CSS were worse in individuals with a prostate-specific antigen >100 ng/ml only in M1b. Conclusions: Patient prognosis worsened with stage progression; therefore, current TNM classification system of mPC for PADT was shown to be trustworthy. Each PC cell that develops bone or lymphoid metastasis may exhibit different characteristics. © 2015, Springer-Verlag Berlin Heidelberg.
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Li, You Qiang ; Mizokami, Atsushi ; Izumi, Kouji ; Narimoto, Kazutaka ; Shima, Takashi ; Zhang, Jian ; Dai, Jinlu ; Keller, Evan T. ; Namiki, Mikio
概要:
金沢大学附属病院泌尿器科<br />BACKGROUND. Recently, we established paclitaxel-resistant prostate cancer cell lines (PC-3-TxR and DU1
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45-TxR). To determine the mechanisms of paclitaxel resistance in PC-3-TxR cells, we compared the gene expression profiles between PC-3 and PC-3-TxR cells. Our results indicated that expression of the C-terminal tensin like protein (CTEN, tensin 4) gene was down-regulated by 10-fold in PC-3-TxR cells. We investigated the possibility that CTEN overexpression restores paclitaxel sensitivity. METHODS. We investigated how knockdown and overexpression of CTEN in androgen-independent cell lines affect paclitaxel sensitivity by colony formation assay and growth inhibition assay. To determine the mechanisms by which CTEN affects paclitaxel sensitivity, we investigated the relationships between CTEN and F-actin or epidermal growth factor receptor (EGFR) in PC-3 cells. We also examined the association between expression of CTEN and grade of prostate cancer by immunohistochemistry using tissue microarray analysis. RESULTS. Down-regulation of CTEN, which is located in the cytoskeleton, played an important role in paclitaxel resistance in PC-3-TxR cells. Knockdown of CTEN expression in PC-3 cells induced paclitaxel resistance. Overexpression of CTEN in PC-3-TxR and DU145-TxR cells restored paclitaxel sensitivity. CTEN expression was inversely correlated with F-actin and EGFR expression. Then knockdown of actin and EGFR in PC-3-TxR cells recovered paclitaxel sensitivity, indicating that CTEN down-regulation mediates paclitaxel resistance through elevation of EGFR and actin expression. Moreover, CTEN expression was inversely correlated with Gleason score. CONCLUSIONS. These results strongly suggested that CTEN plays an important role in paclitaxel sensitivity and that CTEN expression level may be a prognostic predictive factor for PCa patients. © 2009 Wiley-Liss, Inc.
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Shigehara, Kazuyoshi ; Sasagawa, Toshiyuki ; Doorbar, John ; Kawaguchi, Shohei ; Kobori, Yoshitomo ; Nakashima, Takao ; Shimamura, Masayoshi ; Maeda, Yuji ; Miyagi, Tohru ; Kitagawa, Yasuhide ; Kadono, Yoshifumi ; Konaka, Hiroyuki ; Mizokami, Atsushi ; Koh, Eitetsu ; Namiki, Mikio
概要:
金沢大学附属病院泌尿器科<br />Purpose. We performed a randomised controlled study regarding the effects of androgen replacement ther
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apy (ART) on lower urinary tract symptoms (LUTS) in hypogonadal men with benign prostate hypertrophy (BPH). Methods. Fifty-two patients with hypogonadism and BPH were randomly assigned to receive testosterone (ART group) as 250 mg of testosterone enanthate every 4 weeks or to the untreated control group. We compared International Prostate Symptom Score (IPSS), uroflowmetry data, post-voiding residual volume (PVR) and systemic muscle volume at baseline and 12 months after treatment. Results. Forty-six patients (ART group, n=23; control, n=23) were included in the analysis. At the 12-month visit, IPSS showed a significant decrease compared with baseline in the ART group (15.7±8.7 vs. 12.5 ± 9.5; p < 0.05). No significant changes were observed in the control group. The ART group also showed improvement in maximum flow rate and voided volume (p < 0.05), whereas no significant improvements were observed in the controls. PVR showed no significant changes in either group. In addition, the ART group showed significant enhancement of mean muscle volume (p < 0.05), whereas no significant changes were seen in the controls. Conclusion. ART improved LUTS in hypogonadal men with mild BPH. © 2010 Informa UK, Ltd.
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| 56.
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Izumi, Kouji ; Mizokami, Atsushi ; Narimoto, Kazutaka ; Sugimoto, Kazuhiro ; Koh, Eitetsu ; Kumano, Tomoyasu ; Namiki, Mikio
概要:
金沢大学附属病院泌尿器科<br />We report 3 Japanese patients with cranial nerve deficit caused by skull metastasis of prostate cancer
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(PCa). Case 1 was a 75-year-old patient with a chief complaint of diplopia. The cause of diplopia was right oculomotor nerve palsy from the skull metastasis. External beam radiation therapy (EBRT) to the whole brain, 40 Gy in 20 fractions, was performed and the diplopia improved. Case 2 was a 72-year-old patient with a chief complaint of facioplegia. Bone scintigraphy and computed tomography (CT) of the head revealed right occipital bone metastasis of PCa resulting in right facial nerve palsy. EBRT to the right occipital bone, 50 Gy in 25 fractions, with daily oral dexamethasone (DEX) was performed and facioplegia showed complete recovery. At 12 months after onset, the patient was followed-up with no symptoms. Case 3 was a 74-year-old patient with a chief complaint of diplopia. Diffusion-weighted magnetic resonance imaging (MRI) and positron emission tomography (PET) showed right petrous bone metastasis resulting in right abducent nerve palsy. EBRT to the right petrous bone, 44 Gy in 22 fractions, with oral DEX was performed and diplopia showed complete recovery. At 13 months after onset, the patient was followed-up with no symptoms. MRI and PET may detect PCa metastasis in the skull base more clearly than other imaging modalities. EBRT with 40-50 Gy in 20-25 fractions in association with corticosteroid administration may be reasonable treatment of patients with metastatic PCa who develop cranial nerve dysfunction. © 2010 Japan Society of Clinical Oncology.
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| 57.
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Mizokami, Atsushi ; Koh, Eitetsu ; Izumi, Kouji ; Narimoto, Kazutaka ; Takeda, Masashi ; Honma, Seijiro ; Dai, Jinlu ; Keller, Evan T. ; Namiki, Mikio
概要:
金沢大学附属病院泌尿器科<br />One of the mechanisms through which advanced prostate cancer (PCa) usually relapses after androgen dep
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rivation therapy (ADT) is the adaptation to residual androgens in PCa tissue. It has been observed that androgen biosynthesis in PCa tissue plays an important role in this adaptation. In the present study, we investigated how stromal cells affect adrenal androgen dehydroepiandrosterone (DHEA) metabolism in androgen-sensitive PCa LNCaP cells. DHEA alone had little effect on prostate-specific antigen (PSA) promoter activity and the proliferation of LNCaP cells. However, the addition of prostate stromal cells or PCa-derived stromal cells (PCaSC) increased DHEA-induced PSA promoter activity via androgen receptor activation in the LNCaP cells. Moreover, PCaSC stimulated the proliferation of LNCaP cells under physiological concentrations of DHEA. Biosynthesis of testosterone or dihydrotestosterone from DHEA in stromal cells and LNCaP cells was involved in this stimulation of LNCaP cell proliferation. Androgen biosynthesis from DHEA depended upon the activity of various steroidogenic enzymes present in stromal cells. Finally, the dual 5a-reductase inhibitor dutasteride appears to function not only as a 5a-reductase inhibitor but also as a 3b-hydroxysteroid dehydrogenase inhibitor in LNCaP cells. Taken together, this coculture assay system provides new insights of coordinate androgen biosynthesis under the microenvironment of PCa cells before and after ADT, and offers a model system for the identification of important steroidogenic enzymes involved in PCa progression and for the development of the corresponding inhibitors of androgen biosynthesis. © 2009 Society for Endocrinology.
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| 58.
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Narimoto, Kazutaka ; Mizokami, Atsushi ; Izumi, Kouji ; Mihara, Shinya ; Sawada, Kiyoshi ; Sugata, Toshiaki ; Shimamura, Masayoshi ; Miyazaki, Kimiomi ; Nishino, Akio ; Namiki, Mikio
概要:
金沢大学附属病院泌尿器科<br />Objectives: To analyze the clinical effects of flutamide as a second-line anti-androgen for combined a
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ndrogen blockade in patients with castration-resistant prostate cancer (CRPC) initially treated with bicalutamide as a first-line anti-androgen. Methods: Our study population consisted of 16 patients with CRPC who were treated with flutamide (375 mg daily) as second-line hormonal therapy. Dehydroepiandrosterone (DHEA), androstenedione, androstenediol, testosterone and dihydrotestosterone were measured to investigate the relationship between plasma androgens and outcome following treatment. Furthermore, adrenal androgen levels in a medium of adrenal cancer cell line were also measured. Results: Second-line hormonal therapy using flutamide resulted in a reduction of the prostate-specific antigen (PSA) level in 14 (87.5%) of 16 patients. A PSA decline greater than 50% was observed in 8 (50%) of the 16 patients. The duration of median responsiveness was 6.25 months. PSA elevation of baseline androstenediol level was a predictive factor of PSA responsiveness. The lower DHEA group improved the duration of responsiveness to flutamide. In vitro, 3 μmol/L flutamide suppressed DHEA, androstenedione and androstenediol synthesis compared with bicalutamide in a medium of adrenal cancer cell line. Conclusions: Our data show that flutamide suppresses the adrenal androgens in comparison with bicalutamide. The responsiveness and response duration of flutamide can be predicted in patients with a higher baseline androstenediol level and a lower DHEA level. Metabolites from adrenal androgens contribute to the progression of prostate cancer. © 2010 The Japanese Urological Association.
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| 59.
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並木, 幹夫 ; Namiki, Mikio
概要:
金沢大学医薬保健研究域医学系<br />癌スクリーニングシステムには高い正確性(診断精度),簡便性,迅速性,および非侵襲性等,が要求される.我々はこれらの条件に合致したバイオ診断チップの開発をすすめ,2年間で以下の成果を得ることができた.1
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.従来のイムノクロマトセンサーに既存抗体を配置したチップを作成し,金ナノ粒子,クロマト担体材料などの選別,最適化した.さらに,マイクロビース配置型やクロマト機能材料配置型に基づいた複数の抗体マーカーが配置可能なマルチ型イムノセンサーを構築した.2.マイクロ流体チップ技術と分離素材技術を連携させ,サンプルに混在するセンサー阻害物質除去能と微量サンプル濃縮能を有する試料前処理チップを作製した.3.発色,蛍光,電極法等のデバイスを用いてマイクロリットルレベルでの微量採血でも診断が可能な高感度測定デバイスを設計し,デバイスを小型化した.4.設計試作した各種センサーの特性を,1)センサー応答の評価,2)前処置条件の検討及びチップ作成,3)サンプリング及び導入装置,4)測定デバイスと小型化の検討,等の観点から再検討し,低侵襲型診断システムを最適化した.5.固相として塗布している抗体溶液中に金コロイド修飾抗体を混ぜることによって,抗原測定時に僅かな抗原捕捉金コロイド修飾2次抗体しかない場合(抗原濃度が薄い)でも固相側の金コロイドによって発色を増強する方法(金コロイド修飾抗体入り固相化抗体塗布法)を開発し,テストストリップの高感度化を達成した.6.金コロイド修飾抗体入り固相化抗体塗布法を用いて,血清total-PSA値2ng/mlを検出目標としたテストストリップを作製した.臨床応用を図るべく,既に当院泌尿器科外来において臨床検体約50例を文橡に同キットを使用したPSAの検出を試み,簡便性,迅速性,正確性,再現性,実用性等を評価した.7.pro-PSAがtotal PSAを凌駕しうる前立腺癌の新規マーカーとなりうるかを検討すべく,ペプチド合成を行いpro-PSAのモノクローナル抗体を作製する予定であったが,適切な抗体が作製できず,今後の検討課題となった.<br />研究課題/領域番号:17659498, 研究期間(年度):2005 – 2006<br />出典：「泌尿器悪性腫瘍に対するバイオ診断チップを用いたセルフスクリーニングシステム」研究成果報告書 課題番号17659498（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-17659498/)を加工して作成
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並木, 幹夫 ; Namiki, Mikio
概要:
金沢大学医薬保健研究域医学系<br />癌組織においてORP150をはじめとする分子シャペロンは多量に発現されており、慢性的な低酸素等のストレスから自らを守っている。逆に、宿主側は癌細胞の分子シャペロンを癌特異抗原の認識のために利用している
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と考えられている。すなわち、分子シャペロンに結合した腫瘍ペプチドは非常に効率よく宿主に認識されることが知られており、腫瘍由来の分子シャペロンは宿主の癌特異免疫を活性化するためのアジュバントとして使われていると考えられている。今回、ORP150のその強力な抗原提示誘導能を利用して、マウス由来膀胱癌に対して癌免疫治療が可能かどうか検討した。まず実験Aでは、樹状細胞をC3Hマウスより採取し、IL-4,GM-CSFを添加して培養した。一方、MBT2由来のORP150をFPLCを用いて精製した。続いて、前述した処理を施した樹状細胞と精製したMBT2由来のORP150をco-cultureし、これをMBT2を接種して腫瘍が形成されたC3Hマウスの皮下に接種したところ、著明な腫瘍の退縮が確認された。実験Bでは、まずMBT2由来のORP150を発現するアデノウイルスベクターを作製し、さらにC3Hマウスより採取した樹状細胞にこのアデノウイルスベクターを感染させた。続いて、前述した処理をした樹状細胞をMBT2を接種して腫瘍が形成されたC3Hマウスの皮下に接種したところ、著明な腫瘍の退縮が確認された。以上の結果から、ORP150は免疫治療、ワクチン療法を、より強力に行うための重要な役割を有していることが明らかになった。今後、ORP150の作用機序の解明を含め、課題が残ったが、将来の臨床応用が期待できる成果をあげることが出来た。<br />研究課題/領域番号:14657405, 研究期間(年度):2002 – 2003<br />出典：「小胞体分子シャペロンORP150を用いた膀胱癌に対する癌免疫治療の実験的検討」研究成果報告書 課題番号14657405（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-14657405/)を加工して作成
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並木, 幹夫 ; Namiki, Mikio
概要:
金沢大学医薬保健研究域医学系<br />前立腺癌組織において発現が減少し、活性酸素の代謝に関わる遺伝子Superoxide disumutase 3 (SOD3)のを同定し、SOD3が腫瘍抑制因子として働いていることを突き止めた。前立腺癌細
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胞と前立腺癌由来間質細胞を共培養し、大量のテストステロンを添加すると、間質細胞において活性型エストロゲンの産生され、それが癌細胞の増殖を抑制することを明らかにした。さらに、アンドロゲン感受性前立腺癌細胞を非感受性前立腺癌細胞を培養すると、cross-talkにより、それぞれの増殖が促進されたり、浸潤能が変化することが明らかとなった。フラボノイド誘導体を合成し、前立腺癌細胞での抗腫瘍効果を確認した。<br />We identified identified superoxide disumutase 3 (SOD3) which expression was decreased in prostate caner tissue compared with normal tissue. SOD3 was related with metabolism of the active oxygen and worked as a tumor inhibiting factor.When prostate cancer cells were cocultured with derived derived from and prostate cancer and added a large quantity of testosterone into coculture, the proliferation of the prostate cancer cells was inhibited. This mechanism was involved in estrogen synthesis in stroll cells.Furthermore, when androgen-sensitive prostate cancer cells were cocultured with andorgen-insensitive prostate cancer cells, the proliferation of androgen-sensitive prostate cancer cells in the presence of androgen was accelerated by androgen-insensitive cells. Moreover, invasion of androgen-insensitive cells was induced by androgen-sensitive cells. We synthesized flavored derivatives and confirmed anti-caner effect.<br />研究課題/領域番号:26293350, 研究期間(年度):2014-04-01 - 2017-03-31
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並木, 幹夫 ; Namiki, Mikio
概要:
金沢大学医薬保健研究域医学系<br />Y染色体遠位側にあるBPY２遺伝子とAlu配列間にRepeatMaskerの分析および患者精巣組織の遺伝子発現実験において関連はなかった。一方、公開されているアレイデータベースを利用して、バイオインフ
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ォマチックスの手法を用いてリボゾーム経路が精子形成に関与している事を明らかにした。リボゾームの塩基配列はSINE由来と考えられているので、Y染色体遠位部領域にあるnon-coding RNA配列と各リボゾーム配列の関連ついて分析が必要である事を示唆した。<br />Both BPY2 genes and Alu sequences located in distal of Y chromosome were not correlated with each other using RepeetMasker database or gene expression study in patients' testicular samples. According to technique of the bioinformatics, we demonstrated that ribosomal pathway was involved in spermatogenesis in this study. Because the ribosomal sequences were thoght to be SINE origin, we propose to suggest evaluation between non-coding RNA sequences in the distal region of Y chromosome and each ribosomal sequences.<br />研究課題/領域番号:25670679, 研究期間(年度):2013-04-01 – 2015-03-31
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| 63.
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並木, 幹夫 ; Namiki, Mikio
概要:
前立腺組織と前立腺癌組織でのcDNA microarrayを行い、癌組織で発現の減弱している遺伝子としてSOD3を同定した。SOD3の発現減弱が癌の増殖や浸潤に関わっていることを明らかにした。また、細胞外マトリックスSPARCに注目した。S
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PARCは正常間質細胞より癌細胞由来間質細胞で発現が減弱し、AKTリン酸化を阻害することにより癌細胞の増殖や遊走能を抑制した。さらにインテグリンβ1を受容体として癌細胞に作用していた。また、植物フラボノイドの2’-hydroxyflavanoneが前立腺癌に対して抗腫瘍効果を示し、アンドロゲン受容体の活性を阻害することを明らかにした。<br />We performed cDNA microarray analysis with normal prostate tissue and the prostate cancer tissue, and identified SOD3 as the gene which the expression attenuated with prostate cancer tissue.We revealed that expression diminishment of SOD3 was associated with proliferation of prostate cancer, migration, and invasion. Also, we paid attention to extracellular matrix SPARC. Expression of SPARC attenuated with prostate cancer-derived stromal cells than normal stromal cells, and inhibited a proliferation and the migration of the cancer cells by inhibiting AKT phosphorylation. SPARC acted on cancer cells via integrin beta 1 as a receptor. Also, 2'-hydroxyflavanone which is the plant flavonoid showed antitumor effect for prostate cancer via apoptosis, and revealed that 2'-hydroxyflavanone inhibited androgen receptor activity, but did not inhibit androgen synthesis.<br />研究課題/領域番号:23390379, 研究期間(年度):2011-11-18 – 2014-03-31<br />研究機関: 金沢大学医学系
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並木, 幹夫 ; Namiki, Mikio
概要:
1.前立腺癌の再燃に関与する因子として重要なものに副腎性アンドロゲンDHEAがあるが、これは、前立腺がん組織において癌細胞と間質細胞の協調的働きによりDHTに変換され、前立腺癌の再増殖に寄与することを証明した。2.前立腺癌の骨転移に関しては
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骨由来TGF-βの作用が重要で、抗アレルギー薬であるトラニラストが、その作用を抑制し、抗腫瘍効果をもたらす可能性があることを示した。3.再燃前立腺癌に対してはタキサン系抗癌剤を使用することが多いが、その薬剤に対する耐性メカニズムのひとつにCTENの発現低下が関与していることを証明した。<br />1. Adrenal androgen, DHEA, is important for recurrence of prostate cancer. Prostate cancer stromal cells and prostate cancer cells coordinately activate the androgen receptor through synthesis of T and DHT from DHEA. 2. Tranilast inhibits hormone refractory prostate cancer cell proliferation and suppresses TGF-β-associated osteoblastic changes. 3. We identified CTEN, one of important genes that is associated with paclitaxel resistance. Expression of CTEN recovered paclitacel-resistance.<br />研究課題/領域番号:2039042, 研究期間(年度):2008-2010<br />研究機関: 金沢大学医学系
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並木, 幹夫 ; Namiki, Mikio
概要:
進行性前立腺癌がどのような機序で再燃するかは、まだはっきりしないことが多いため、我々は前立腺が感受性細胞株LNCaPからアンドロゲン非存在下でも増殖しうる細胞株LNCaP-SFとLN-REC4を樹立し、そのcharacterizationを
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行った。その結果、LN-REC4は血管新生が亢進していることが判明した。LNCaP-SFはアンドロゲンで逆に増殖が抑制される特徴を有していた。現在、LNCaPとLNCaP-SFを用いてアンドロゲンでの反応性の異なる遺伝子を同定中である。また、これまで、よいモデルがほとんどなかった造骨性骨転移のモデルをLNCaP-SFを用いて樹立することに成功した。造骨性転移においても破骨細胞が重要な役割を示しており、第3世代のビスフォスフォネート製剤は破骨細胞の抑制を介して、前立腺癒の溶骨性骨転移だけでなく、造骨性骨転移も抑制しうることを証明した。さらに、ビスフォスフォネート製剤は破骨細胞を介した間接的な作用だけでなく、癌細胞に対してアポトーシスの誘導や、骨でのケモカイン受容体CXCR-4の発現抑制を介した浸潤能の抑制という直接的な効果も引き起こす可能性が示唆され、第3世代のビスフォスフォネート製剤による新たな前立腺癌の骨転移予防薬という可能性が見いだされた。さらに、再燃前立腺癌において発現が亢進しているとされる癌遺伝子Her-2に対する分子標的治療薬の開発のために、分子標的治療薬を用いてのin vitro、in vivoでの抗腫瘍効果を確認した。<br />Since it is not clear why advanced prostate cancer relapses during hormone therapy, we established androgen-independent prostate cancer, LNCaP-SF and LN-REC4 cells from androgen-sensitive cell line, LNCaP. We characterized these cell lines in order to investigate what kinds of mechanisms are involved in progression. LNCaP-SF cells proliferation was stimulated in the absence of androgen and repressed in the presence of androgen. It was suggested that LN-REC4 induced angiogenesis. Now we are investigating the genes which are differentially regulated by androgen.We also succeeded in establishment of osteoblastic metastatic model of prostate cancer using LNCaP-SF cells. Osteoclast showed important role in osteoblastic metastasis of prostate cancer cells, and we certified that the 3rd generation of bisphosphonates could inhibit osteoblastic bone metastasis as well as osteolytic bone metastasis of prostatic cancer. through inhibition of osteoclast. Furthermore, bisphosphonates not only showed indirect action through osteoclast but also directly induced apoptosis of cancer cells and inhibited invasion through repression of chemokine receptor, CXCR-4 expression. These results indicate that the 3rd generation of bisphosphonates has potency of bone metastasis preventive medicine for prostate cancer.For development of molecular target drug for oncogene Her-2 assumed that the expression is enhanced in recrudescence prostatic cancer, we also used Her-2 specific-tyrosine kinase inhibitor and confirmed the antitumor effect in vitro and in vivo.<br />研究課題/領域番号:15390488, 研究期間(年度):2003-2005<br />研究機関: 金沢大学医学系研究科<br />出典：「再燃前立腺癌に対する遺伝子治療・分子標的治療に関する基礎的研究」研究成果報告書 課題番号15390488 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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| 66.
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並木, 幹夫 ; Namiki, Mikio
概要:
本研究では,申請者らがクローニングしたhTERTのプロモーター領域(1375bP)を利用して,遺伝子治療の基礎的検討を行った.平成12年度においては,プロモーターのマッピングや活性調節因子の解析などを行った.10種類のdeletion mu
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tantを用いて,各種細胞株におけるプロモーター活性をLuciferase assay法を用いて解析した.その結果,転写開始点から378bp上流までの領域は,コントロールとして用いたSV40プロモーターの約80%の活性を示した.次にこの活性領域の脱メチル化を行い,抑制されていたp16やE-cadherinの発現がメチレーションの関与を受けていることを確認した.さらにPCR-based methylation assayにて,脱メチル化による発現であることを証明した.自殺遺伝子治療に用いられるCD遺伝子を378bpプロモーター下流につなぎ,各種ヒト癌細胞株を用いてin vitro実験を行った結果,コントロールとして用いた正常上皮細胞や線維芽細胞では殺細胞効果は認められなかったが、癌細胞株では泌尿器癌だけでなく婦人科癌においても高い殺細胞効果が認められた.さらなる活性増強を目的に、現在この378bpプロモーターをタンデムリピートし,同様の手法で検討中である.平成13年度においては,in vivoでの治療実験を行うため378bPプロモーター+CDをアデノウィルスベクタに組み入れた.予備実験として,ex vivoでアデノウィルスによりCD遺伝子を導入した前立腺癌細胞を、SCIDマウスに同所移植後5FCを腹腔内投与した.その結果明かな腫瘍縮少効果が認められた.今後このアデノウィルスベクターをマウス尾静脈から投与し,in vivoでの治療実験を行う予定であるが,上記実験から明かなように,hTERTプロモーターは幅広い癌腫で活性を示すと考えられ,高い抗腫瘍効果が各種癌種で得られるものと期待している.<br />Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, which is highly active in immortalized cells. We herein carried out basic experiments on cancer gene therapy utilizing the hTERT promoter. The core promoter region was identified by deletion analysis, and demethylation of this region accelerated the expression of p16 and E-cadherin. Cytosine deaminase gene was ligated in downstream of hTERT promoter. In vitro experiments demonstrated that cell- kill effect was only seen in cancer cells not in normal cells. Tandem repeat promoter is now under construction for creating more active and specific tool in gene therapy. Adenovirus vector containing hTERT promoter and CD was constructed, and used in vivo experiments. The data was promising and could be widely utilized in the field of cancer gene therapy because of its specificity.<br />研究課題/領域番号:12470330, 研究期間(年度):2000-2001<br />研究機関: 金沢大学医学系研究科
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| 67.
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並木, 幹夫 ; Namiki, Mikio
概要:
1.研究目的申請当時の計画に従い、小型で新型の光力学的診断治療の青紫色半導体レーザー装置(ILS-LD400型,石川島播磨重工業株式会社製)を用いて本レーザーの特性を癌培養細胞と実験腫瘍モデルで、蛍光診断とがん治療の開発に適用することを目的
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とした。2.研究方法および成果(1)がん由来培養細胞の光力学的レーザー治療と超音波力学的治療との併用治療:ヒト悪性黒色腫由来培養細胞(HMF)に新光感受性物質5-ALA(5-Aminolevulinic Acid)を4時間取り込ませて洗浄後、本レーザ光照射(405nm,2mW/10min)及び超音波照射(47kHz,50W)を行い、生体蛍光染色キットにて染色してアポトーシスとネクローシス細胞死の割合をフローサイトメーターで計測した。その結果併用治療の場合は単独治療に比してネクローシス細胞死の割合が有意に増大した。照射順序による差を検討した結果、レーザー光照射を超音波照射より先に試行した方が、その増大率が大であった。今後、この種の併用治療には、レーザ光照射を先行させるべき治療指針を得た。(2)実験腫瘍モデルでの新光増感剤の取り込み蛍光診断:実験腫瘍モデル(扁平上皮癌:SCC)移植C3H/Heマウスを用いて光増感剤5-Aminolevulinic Acid(=5-ALA)の経皮的投与における腫瘍細胞の光増感剤取込みに対する超音波照射(1MHz)の効果を検討した。5-ALAが腫瘍内で代謝生成したProtoporphyrin-IX(Pp-IX:実質的光増感剤)生成量を本レーザ励起により蛍光観察した。その結果、超音波非照射群に比してPp-IX蛍光が約2倍に増大し、取り込み部位の腫瘍実質への移行が蛍光分光分析、蛍光顕微鏡観測および本レーザー光励起により肉眼的にも観測できた。3.結論および今後の展開本研究成果より、膀胱への5-ALA生理食塩水の直接注入後の超音波照射法はPp-IX光増感剤の腫瘍集積性を増大させる可能性が期待できる。今後、上記5-ALA膀胱直接注入法と合わせて本レーザー光励起による膀胱がん診断に応用し、具体的臨床治験の申請を行う予定である。<br />We investigated the photodynamic macrotic diagnosis (PDMD) of a cancer by a new semiconductor laser (iLS-LD400 model, 405 nm, 5 mW) using the photosensitizer protoporphyrin-IX (Pp-IX) generated in vivo from 5-aminolevulittic acid=5-ALA which has an affinity for the squamous cell carcinoma (SCC) tumor transplanted on the back of C3H/He mouse. In the result, it was found the specific affinity of the Pp-IX in the SCC tumor from the spectroscopic data that the Pp-IX fluorescent intensity in the tissue was enhanced 2 times by the ultrasound irradiation (47 kHz, 50 W, 10 min).Furthermore, it was also investigated the combination therapy of photodynamic (PDT) and sonodynamic (SDT)(47 kHz, 50 W, 10 sec) treatments of a melanoma cultivated cell (HMF) using a sonosensitizer ATX-70, gallium porphyrin derivative, and the new laser iLS-LD400 (405 nm, 5 mW, 10 min). In the results, its was found that the necrotic cell death was enhanced by the combination therapy, especially in the case of the first treatment of the photoirradiation before the sonolysis, the enhancing effect was better than the other case.In conclusion, it will be established to do the macrotic diagnosis the bladder tumor incorporated 5-ALA in the bladder model using a new semiconductor laser (iLS-LD400 model, IHI) and to treat the epithelium transitional cell carcinoma by the laser light.<br />研究課題/領域番号:11557116, 研究期間(年度):1999-2000<br />研究機関: 金沢大学医学部<br />出典：「YAG-OPOレーザーによる膀胱癌の光力学的治療」研究成果報告書 課題番号11557116 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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| 68.
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並木, 幹夫 ; Namiki, Mikio
概要:
精子形成に関わる遺伝子(無精子症原因遺伝子)AZFの同定を目指し、以下の実験結果を得た。特発性無精子症151例のゲノムDNAに対して行なったSTS分析の結果、Y染色体長腕遠位側に微小欠失を持つ18例の患者を認めた。これら患者の欠失領域はST
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SブライマーDYS7Cを中心に共通しており、AZFの候補領域と考えられた。一方、妊孕性のある父親と無精子症患者間に、STS上共通した領域を欠失する稀な1家系を見い出し、その父子におけるDNA配列の差を同定することを目指した。短腕から長腕に至る18の座および既知のAZF候補遺伝子のRBMとDAZの有無について検証した。その結果、この父子の欠失はDYS7CからDYS239まで共通しており、父親の欠失は共通領域内において患者のそれより小さいと考えられた。この配列の差こそ新規AZF領域と考えられ、RBMやDAZを含んでいないことも確認した。この欠失領域を含むYACライブラリーからyOX21を選択確定した。これを制限酵素で消化した100kbp DNA断片をブローブとしたゲノムサザンプロット法で両者間のDNA鎖長に差を認めたため、新規AZFがこの100kbp断片内に存在することが判明した。次にこの領域のDNAを用いてエクソントラップ法を行ない、約20のエクソンを得た。遺伝子バンクの検索で多くの未知の遺伝子が採取されていたため、ヒト精巣cDNAライブラリーを用いてスクリーニング中であり、新規AZFの同定まであとわずかである。<br />1) Cloning of Azoospermy factor gene (AZF)We found YAC in which AZF should be included and subcloned the cosmid contig mede from the YAC to a plasmid vector. AZF was included within 30 Kb DNA.Then, using Exon trapping we picked up severalfunctional exons from each cosmid. After all of sequences were analyzed using the DNA data base in the Gene Bank, not a few exons revealed unknown sequences. Screening using the testis cDNA libraryis is now on in progree.2) Cloning of genes which induce differentiation of human testis germ cellsFor molecular cloning of genes which induce differentiation of human testis germ cells we screened human testis cDNA library using mouse cDNAs as probes. We isolated human SCP-1 which appears in the phase before the miosis and determined sequences of the DNA and the protein.3) Establishment of in vitro culture of human germ cellsWe established in vitro culture system of human germ cells which has been very difficult. Using this system we will be able to do experiments in vitro differentiation human germ cells.<br />研究課題/領域番号:09470343, 研究期間(年度):1997-1998<br />研究機関: 金沢大学医学部<br />出典：「ヒトY染色体上の無精子症原因遺伝子の同定とその機能解明に関する研究」研究成果報告書 課題番号09470343 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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| 69.
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並木, 幹夫 ; Namiki, Mikio
概要:
1)Azoospermy factor gene (AZF) のcloning男性不妊症患者のDNA分析により発見したY染色体長腕上に存在する精子形成関連遺伝子AZFのcliningを行うため、無精子症患者または乏精子症患者のY染色体欠失地
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図を作成し、AZFが存在する座位の欠失区間を同定した。さらに、AZFが含まれるYACを特定し、YACから作成したcosmid libraryを用いて、cosmid contigを作成した。さらにこれをrestriction cutし、plasmidにsubcloningた。現在、無精子症患者父子の微妙な欠失の違いからAZFを、約30kbの範囲内にしぼりこんだ。また、Exon tapping法によっても、AZFのcloningを同時進行で行っている。2)ヒト精細胞分化誘導遺伝子のcloningマウス精細胞を特異的に認識する種々の抗体を作成し、この抗体をプローブとしてマウス精巣cDNA libraryより19 cloneを単離した。このうち、mouse SCP-1をプローブとしてヒト精巣cDNA libraryよりhuman SCP-1 をcloningした。human SCP-1は精細胞の減数分裂前期に出現し、正常な分裂に必要な構造体であるsynaptonemal complexの一部を構成する蛋白をコードし、精細胞の分化に重要な役割を有していると考えられた。3)精細胞培養系の確立上記遺伝子のcloningをふまえ、上記遺伝子導入実験の予備実験として、ラット精細胞をin vitroで一定期間培養することに成功した。<br />1) Cloning of Azoospermy factor gene (AZF)For molecular cloning of AZF which is the candidate gene related human spermatogenesis located on the long arm of Y chromosome we made a deletion map of the long arm of Y chromosome from the results of the DNA analysis of male infertile patients with azoospermia or severe oligozoospermia and identified a specific location in which AZF should be included. Then, we found YAC in which AZF should be included and subcloned the cosmid contig mede from the YAC to a plasmid vector. AZF is now included within 30 Kb DNA.Another method using Exon trapping for the cloning of AZF is also on going.2) Cloning of genes which induce differentiation of human testis germ cellsFor molecular cloning of genes which induce differentiation of human testis germ cells we screened human testis cDNA library using mouse cDNAs as probes. We isolated human SCP-1 which appears in the phase before the miosis and determined sequences of the DNA and the protein.3) Establishment of in vitro culture of human germ cellsWe established in vitro culture system of human germ cells which has been very difficult. Using this system we will be able to do experiments in vitro differentiation human germ cells.<br />研究課題/領域番号:07457372, 研究期間(年度):1995-1996<br />研究機関: 金沢大学医学部<br />出典：「ヒト精子形成機構およびヒト精子形成障害の病態解明のための分子生物学的研究」研究成果報告書 課題番号07457372 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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| 70.
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並木, 幹夫 ; Namiki, Mikio
概要:
金沢大学医学系研究科<br />無精子症叉は高度乏精子症患者の5-15%にY染色体微小欠失が認められ、この様な微小欠失領域にはAZFと称される精子形成候補遺伝子が存在することが明らかになった。これらのAZF欠失を伴う無精子症叉は高度乏精子症
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患者よりTESEで得られた精子を用いて挙児が得られると、AZF欠失が男児に伝播されることが実際に報告されてきた。この様な背景から、ヨーロッパ諸国では、Y染色体微小欠失診断を標準化し、検査の正確さのみならず、遺伝カウンセリングにも配慮したDNA診断が行われている。日本では日本産婦人科学会では平成16年度から産婦人科生殖遺伝カウンセリング指導医制度をスタートさせ、日本泌尿器科学でも独自の制度を早急に立ち上げる必要性が生じている。本企画調査では、以下の調査を行い、日本の実状にあった制度作りの参考とした。1.Y染色体微小欠失の国際標準化の確立(1)国内の泌尿器科、産婦人科施設に協力を得てY染色体微小欠失データの集積した。(2)韓国釜山大学泌尿器科Park教授の協力で韓国でのY染色体微小欠失データの集積した。(3)ドイツのSimoni教授の協力でヨーロッパでのY染色体微小欠失データの集積した。2.泌尿器科生殖遺伝カウンセリング専門医制度の作成(1)上記Y染色体微小欠失以外に検査が必要な遺伝学的な異常につき討議した。(2)海外での同様な制度につき調査した(3)日本産婦人科学会、日本不妊学会、日本アンドロロジー学会と、それぞれの立場から生殖遺伝カウンセリング専門医制度について討議した。(4)専門外の学識経験者、一般市民および不妊患者から広く意見を聴取した。<br />研究課題/領域番号:17639017, 研究期間(年度):2005<br />出典：「泌尿器科生殖遺伝カウンセリング専門医制度作成に向けての国際調査」研究成果報告書 課題番号17639017（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-17639017/)を加工して作成
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並木, 幹夫 ; Namiki, Mikio
概要:
金沢大学医薬保健研究域医学系<br />男性不妊の半分をしめる特発性男性不妊の多くは遺伝子疾患である可能性が高い。Y染色体長腕上には精子形成関連遺伝子領域が存在し、AZF領域とされている。ここ10年、PCRを基礎としたSTSプローブを用いた
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方法により、各領域に微小欠失が報告されている。しかし、研究者により用いるSTSプローブが異なることや人種差により多型性により、遅れていた世界標準のDNA診断をめざし以下の調査を行った。I.本邦での取り組み(1)申請者らの施設が中心となり、各施設で行っているY染色体微小欠失検出のPCR条件やプローブを取りまとめてデータベース化し分析を行った。また、無精子症・乏精子症・無力精子症について、それぞれの各微小欠失をまとめた。(2)Y染色体微小欠失に対して、匿名化された患者データから、ホルモン値、精巣生検組織を一括したデータベースを構築し、その類型性の検討により、AZFa,b,cの概念の有用性を検討した。II.アジアでの検討本邦と同様な取り組みを韓国釜山大学およびオーストラリアのMonash大学に依頼し、アジア・オセアニア地域のデータベースを確立してもらい、本邦のデータも加え総合評価を行った。さらに、オーストラリアのMonash大学において、Y染色体微小欠失と組織学的な精巣組織障害の相関について、一人の専任病理医に評価を依頼した。上記のデータベースをヨーロッパ連合アンドロロジー学会のY染色体微小欠失の取りまとめ役であるドイツのM.Simoni博士とデータの突き合わせ、今後のY染色体微小欠失検出の世界標準化を行う。<br />研究課題/領域番号:16639016, 研究期間(年度):2004<br />出典：「アジア・オセアニア地域の男性不妊患者のY染色体微小欠失診断標準化に向けての調査」研究成果報告書 課題番号16639016（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-16639016/)を加工して作成
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