Updated on 2022/09/05

写真a

 
MICHIUE Hiroyuki
 
Organization
Neutron Medical Research Center Associate Professor
Position
Associate Professor
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Degree

  • 医学博士 ( 2005.6   岡山大学 )

Research Interests

  • malignant brain tumor

  • BNCT Boron Neutron Capture Therapy

  • cell penetrating peptide

  • peptide discovery

  • drug repositioning

  • glioblastoma

  • cell invasion

  • actin polymerization

  • cancer stem cell

  • brain tumor stem cell

  • drug delivery system

  • blood brain barrier

  • Immune combination therapy

  • Boron drug

  • Malignant melanoma

Research Areas

  • Life Science / Neurosurgery  / malignant brain tumor

  • Life Science / Tumor biology  / Drug Repositioning

  • Nanotechnology/Materials / Nanobioscience  / Peptide drug discovery

  • Life Science / Pharmaceutical chemistry and drug development sciences  / Boron drug discovery

  • Life Science / Dermatology  / Boron neutron capture therapy for malignant melanoma

  • Life Science / Tumor diagnostics and therapeutics  / Boron Neutron Capture Therapy

  • Life Science / Digestive surgery  / Pancreatic cancer targeted treatment /CA19-9

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Education

  • Okayama University   大学院医歯薬学総合研究科   博士課程

    1999.4 - 2005.6

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    Country: Japan

    Notes: 医学博士

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  • Okayama University   医学部   医学科

    1993.4 - 1999.3

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    Country: Japan

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Research History

  • Okayama University   Neutron Therapy Research Center   Associate Professor

    2017.4

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    Country:Japan

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  • Okayama University   Graduate School of Medicine , Dentistry and Pharmaceutical Sciences   Assistant Professor

    2010.4 - 2017.3

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    Country:Japan

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  • Okayama University   Graduate School of Medicine , Dentistry and Pharmaceutical Sciences   Assistant Professor

    2007.11 - 2010.3

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    Country:Japan

    Notes:内閣府連携政策群「遺伝子細胞治療に携わる若手医師育成プログラム」

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  • University of California, San Diego   School of medicine   Researcher

    2005.6 - 2007.10

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    Country:Japan

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  • Okayama University   University Hospital   Medical Doctor

    2001.11 - 2002.10

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    Country:Japan

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  • Matsuyama Shimin Hospital   Department of Neurosurgery   Medical Doctor

    1999.11 - 2001.10

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    Country:Japan

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  • Okayama University   University Hospitals   Medical Doctor

    1999.6 - 1999.10

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    Country:Japan

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Professional Memberships

  • The Japan Cancer Association

    2018.7

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  • Japanese Society of Neutron Capture Therapy

    2009.4

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  • Physiological Society of Japan

    2006.10

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  • The Japan Society for Neuro-Oncology

    2003.11

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  • The Japan Stroke Society

    2003.4

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  • The Japan Neurosurgical Society

    2000.4

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Committee Memberships

  • ナノ・バイオ融合によるエネルギー集積・高度利用研究拠点形成   シンポジウムオーガナイザー  

    2021.3   

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    Committee type:Other

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  • Japanese Society of Neutron Capture Therapy   member of committee  

    2020.6   

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    Committee type:Academic society

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  • 日本生理学会中国四国支部   中国四国支部幹事  

    2014.4   

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Papers

  • Regulatory T cells induce a suppressive immune milieu and promote lymph node metastasis in intrahepatic cholangiocarcinoma. International journal

    Daisuke Konishi, Yuzo Umeda, Kazuhiro Yoshida, Kunitoshi Shigeyasu, Shuya Yano, Tomohiro Toji, Sho Takeda, Ryuichi Yoshida, Kazuya Yasui, Tomokazu Fuji, Kazuyuki Matsumoto, Hiroyuki Kishimoto, Hiroyuki Michiue, Fuminori Teraishi, Hironari Kato, Hiroshi Tazawa, Hiroyuki Yanai, Takahito Yagi, Ajay Goel, Toshiyoshi Fujiwara

    British journal of cancer   2022.5

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    BACKGROUND: Emerging evidence indicates that immunogenicity plays an important role in intrahepatic cholangiocarcinoma (ICC). Herein, we systematically evaluated the clinical relevance of immunogenicity in ICC. METHODS: Highly immunogenic ICCs identified in the public dataset and the Cancer Immunome Atlas (TCIA) were assessed to determine the prognostic impact of immunogenicity in ICC and key components after curative resection. We also investigated the clinical relevance of the immune milieu in ICC. RESULTS: Using the Gene Expression Omnibus dataset 89749 and TCIA, we identified CD8+/forkhead box P3 (FoxP3)+ tumour-infiltrating lymphocytes (TILs), T-cell immunoglobulin and mucin domain 3 (TIM-3) and human leukocyte antigen-A (HLA-A) in highly immunogenic ICCs. Immunohistochemical analysis of the in-house cohort showed that intratumoral FoxP3+ TILs correlated with CD8+ TILs (P = 0.045, Fisher's exact test) and that high FoxP3+/CD8+ ratio (FCR) was an important marker for poor survival (P < 0.001, log-rank test). Furthermore, the FCR was higher in tumour-free lymph nodes in ICCs with lymph node metastases than in those without lymph node metastases (P = 0.003, Mann-Whitney U test). CONCLUSIONS: FCR should be considered an important biomarker that represents the immune environment of ICC based on its potentially important role in tumour progression, especially lymph node metastasis.

    DOI: 10.1038/s41416-022-01838-y

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  • Combination of Ad-SGE-REIC and bevacizumab modulates glioma progression by suppressing tumor invasion and angiogenesis. International journal

    Yasuhiko Hattori, Kazuhiko Kurozumi, Yoshihiro Otani, Atsuhito Uneda, Nobushige Tsuboi, Keigo Makino, Shuichiro Hirano, Kentaro Fujii, Yusuke Tomita, Tetsuo Oka, Yuji Matsumoto, Yosuke Shimazu, Hiroyuki Michiue, Hiromi Kumon, Isao Date

    PloS one   17 ( 8 )   e0273242   2022

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    Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor and its overexpression has been shown to exert anti-tumor effects as a therapeutic target gene in many human cancers. Recently, we demonstrated the anti-glioma effects of an adenoviral vector carrying REIC/Dkk-3 with the super gene expression system (Ad-SGE-REIC). Anti-vascular endothelial growth factor treatments such as bevacizumab have demonstrated convincing therapeutic advantage in patients with glioblastoma. However, bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. In this study, we examined the effects of Ad-SGE-REIC on glioma treated with bevacizumab. Ad-SGE-REIC treatment resulted in a significant reduction in the number of invasion cells treated with bevacizumab. Western blot analyses revealed the increased expression of several endoplasmic reticulum stress markers in cells treated with both bevacizumab and Ad-SGE-REIC, as well as decreased β-catenin protein levels. In malignant glioma mouse models, overall survival was extended in the combination therapy group. These results suggest that the combination therapy of Ad-SGE-REIC and bevacizumab exerts anti-glioma effects by suppressing the angiogenesis and invasion of tumors. Combined Ad-SGE-REIC and bevacizumab might be a promising strategy for the treatment of malignant glioma.

    DOI: 10.1371/journal.pone.0273242

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  • Complementary leucine zippering system for effective intracellular delivery of proteins by cell-penetrating peptides. International journal

    Mizuki Kitamatsu, Hiroki Yuasa, Takashi Ohtsuki, Hiroyuki Michiue

    Bioorganic & medicinal chemistry   33   116036 - 116036   2021.3

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    A heterodimeric leucine zipper composed of a pair of leucine zipper peptides containing acidic or basic amino acid residues at appropriate positions in each peptide was used as a molecular glue to connect protein cargos to a cell-penetrating peptide (CPP) carrier. To investigate the hybridization properties by fluorescence experiments, we prepared an enhanced green fluorescent protein (EGFP) fused with an acidic leucine zipper (LzK), EGFP-LzK, and a basic leucine zipper (LzE) modified with a CPP, LzE-CPP. The LzK and LzE formed a 1:1 hybrid when EGFP-LzK and LzE-CPP were mixed in phosphate buffer saline, thereby conjugating the EGFP with the CPP. The formation of the 1:1 hybrid was confirmed by fluorescence spectra and fluorescence titration curves. Results from fluorescence microscopy experiments showed that EGFP was successfully delivered into cells by conjugating with the CPP via formation of the LzK/LzE hybrid. We also fused the apoptotic protein p53 with LzK (p53-LzK) and investigated the inhibition of cell proliferation of various cell lines by incubation with the p53-LzK/LzE-CPP hybrid. This hybrid was found to localize in nuclei and successfully inhibited cell-specific proliferation. The LzE/LzK zipper system inhibited cell proliferation more efficiently than the directly fused conjugate, p53-CPP. Our method will be a useful drug delivery system for delivering bioactive proteins to treat various diseases.

    DOI: 10.1016/j.bmc.2021.116036

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  • Self-assembling A6K peptide nanotubes as a mercaptoundecahydrododecaborate (BSH) delivery system for boron neutron capture therapy (BNCT). International journal

    Hiroyuki Michiue, Mizuki Kitamatsu, Asami Fukunaga, Nobushige Tsuboi, Atsushi Fujimura, Hiroaki Matsushita, Kazuyo Igawa, Tomonari Kasai, Natsuko Kondo, Hideki Matsui, Shuichi Furuya

    Journal of controlled release : official journal of the Controlled Release Society   330   788 - 796   2021.2

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    Boron neutron capture therapy (BNCT) is a tumor selective therapy, the effectiveness of which depends on sufficient 10B delivery to and accumulation in tumors. In this study, we used self-assembling A6K peptide nanotubes as boron carriers and prepared new boron agents by simple mixing of A6K and BSH. BSH has been used to treat malignant glioma patients in clinical trials and its drug safety and availability have been confirmed; however, its contribution to BNCT efficacy is low. A6K nanotube delivery improved two major limitations of BSH, including absence of intracellular transduction and non-specific drug delivery to tumor tissue. Varying the A6K peptide and BSH mixture ratio produced materials with different morphologies-determined by electron microscopy-and intracellular transduction efficiencies. We investigated the A6K/BSH 1:10 mixture ratio and found high intracellular boron uptake with no toxicity. Microscopy observation showed intracellular localization of A6K/BSH in the perinuclear region and endosome in human glioma cells. The intracellular boron concentration using A6K/BSH was almost 10 times higher than that of BSH. The systematic administration of A6K/BSH via mouse tail vein showed tumor specific accumulation in a mouse brain tumor model with immunohistochemistry and pharmacokinetic study. Neutron irradiation of glioma cells treated with A6K/BSH showed the inhibition of cell proliferation in a colony formation assay. Boron delivery using A6K peptide provides a unique and simple strategy for next generation BNCT drugs.

    DOI: 10.1016/j.jconrel.2020.11.001

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  • Improvement of water solubility of mercaptoundecahydrododecaborate (Bsh)-peptides by conjugating with ethylene glycol linker and interaction with cyclodextrin

    Mizuki Kitamatsu, Ayaka Nakamura-Tachibana, Yoshimichi Ishikawa, Hiroyuki Michiue

    Processes   9 ( 1 )   1 - 11   2021.1

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    We previously developed a conjugate consisting of B cluster BSH and tri-arginine peptide (BSH-3R). This could potentially be used as a boron agent for boron neutron capture therapy; however, it possesses poor water solubility and thus needs to be improved for use as medicine. In this study, we devised several means of improving the water solubility of BSH-3R. As one of them, we used cyclodextrin (CD), which was expected to improve the water solubility resulting from interaction of the BSH-3R with CD. We evaluated the solubility of BSH-3R in aqueous CD solution by using reverse-phase high-performance liquid chromatography. As we expected, the solubility of BSH-3R was increased in a manner dependent on the addition of β-CD and γ-CD in aqueous solution. Furthermore, we synthesized BSH conjugated to oligoarginine having various chain lengths (BSH-nR) and BSH-3R with ethylene glycol linkers introduced between BSH and 3R (BSH-nEg-3R). The water solubility of these BSH peptides was also evaluated and the results showed that the introduction of nEg to BSH-3R markedly improved the water solubility. Furthermore, we found that the water solubility of these peptides can be further improved by also applying CD. 10

    DOI: 10.3390/pr9010167

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  • 細胞内局在を標的とした新規ホウ素製剤が切り拓く次世代BNCT

    藤村 篤史, 井川 和代, 植田 愛, 渡辺 香里, 道上 宏之, 市川 康明, 古矢 修一

    Medical Science Digest   46 ( 8 )   535 - 537   2020.7

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    Language:Japanese   Publisher:(株)ニュー・サイエンス社  

    病院設置型のBPA-BNCT治療システムがいよいよ社会実装されるに至った。今後BNCTががん治療法の一端を担うことになると広く期待されているが、一方で、現行のホウ素薬剤BPAによるホウ素送達が適していないがん種や症例に対しては、異なるメカニズムを有した新たなホウ素製剤の開発が必要である。BPA-BNCTは、F-BPAを用いたPET検査により適応可否が判断できる治療システムであるが、後続するホウ素製剤においても同様に患者層別化が可能であることが求められる。本稿では、我々が最近開発に取り組んでいるBSH製剤を例に、これからのホウ素製剤を用いたBNCTが患者層別化可能な治療法であるためには、どのような観点から開発に取り組むべきかを考察したい。(著者抄録)

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  • A leucine zipper-based peptide hybrid delivers functional Nanog protein inside the cell nucleus. Reviewed International journal

    Yoshiyuki Hakata, Hiroyuki Michiue, Takashi Ohtsuki, Masaaki Miyazawa, Mizuki Kitamatsu

    Bioorganic & medicinal chemistry letters   29 ( 7 )   878 - 881   2019.4

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    We synthesized a pair of compounds containing leucine zipper peptides to deliver protein cargo into cells. One is a cell-penetrating peptide (CPP) with Lz(E), a leucine zipper peptide containing negatively charged amino acids, and the other is a Nanog protein with Lz(K), a leucine zipper peptide containing positively charged amino acids. When cells were treated with these equimolar mixtures, Nanog-Lz(K) hybridized with Lz(E)-CPP was successfully delivered into the cells. Furthermore, Nanog-Lz(K) exerted its proper function after nuclear transport.

    DOI: 10.1016/j.bmcl.2019.02.004

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  • Physical modification of carbon nanotubes with a dendrimer bearing terminal mercaptoundecahydrododecaborates (Na2B12H11S) Reviewed

    Masahiro Yamagami, Tomoyuki Tajima, Kango Ishimoto, Hideaki Miyake, Hiroyuki Michiue, Yutaka Takaguchi

    HETEROATOM CHEMISTRY   29 ( 5-6 )   2018.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY-HINDAWI  

    The thiol-substituted B-12-cluster mercaptoundecahydro-closo-dodecaborate Na-2[B12H11SH] (BSH) was successfully attached to a poly(amido)amine (PAMAM) dendrimer, which contains a bis(decyloxy)decane core. The physical modification of single-walled carbon nanotubes (SWCNTs) with dendrimer(SB12)(4) afforded a SWCNT/dendrimer(SB12)(4) nanohybrid that exhibited NIR-I-to-NIR-II fluorescence. Herein, we describe a promising strategy for in vivo imaging of boron clusters that may be widely applicable to boron neutron capture therapy.

    DOI: 10.1002/hc.21467

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  • Boron Neutron Capture Therapy Combined with Early Successive Bevacizumab Treatments for Recurrent Malignant Gliomas - A Pilot Study Reviewed

    Hiroyuki Shiba, Koji Takeuchi, Ryo Hiramatsu, Motomasa Furuse, Naosuke Nonoguchi, Shinji Kawabata, Toshihiko Kuroiwa, Natsuko Kondo, Yoshinori Sakurai, Minoru Suzuki, Koji Ono, Shiro Oue, Eiichi Ishikawa, Hiroyuki Michiue, Shin-Ichi Miyatake

    NEUROLOGIA MEDICO-CHIRURGICA   58 ( 12 )   487 - 494   2018.12

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    Recurrent malignant gliomas (RMGs) are difficult to control, and no standard protocol has been established for their treatment. At our institute, we have often treated RMGs by tumor-selective particle radiation called boron neutron capture therapy (BNCT). However, despite the cell-selectivity of BNCT, brain radiation necrosis (BRN) may develop and cause severe neurological complications and sometimes death. This is partly due to the full-dose X-ray treatments usually given earlier in the treatment course. To overcome BRN following BNCT, recent studies have used bevacizumab (BV). We herein used extended BV treatment beginning just after BNCT to confer protection against or ameliorate BRN, and evaluated; the feasibility, efficacy, and BRN control of this combination treatment. Seven patients with RMGs (grade 3 and 4 cases) were treated with BNCT between June 2013 and May 2014, followed by successive BV treatments. They were followed-up to December 2017. Median overall survival (OS) and progression-free survival (PFS) after combination treatment were 15.1 and 5.4 months, respectively. In one case, uncontrollable brain edema occurred and ultimately led to death after BV was interrupted due to meningitis. In two other cases, symptomatic aggravation of BRN occurred after interruption of BV treatment. No BRN was observed during the observation period in the other cases. Common terminology criteria for adverse events grade 2 and 3 proteinuria occurred in two cases and necessitated the interruption of BV treatments. Boron neutron capture therapy followed by BV treatments well-prevented or well-controlled BRN with prolonged OS and acceptable incidence of adverse events in our patients with RMG.

    DOI: 10.2176/nmc.oa.2018-0111

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  • Oxytocin Inhibits Corticosterone-induced Apoptosis in Primary Hippocampal Neurons. Reviewed International journal

    Hein Min Latt, Hiroaki Matsushita, Miku Morino, Yuuri Koga, Hiroyuki Michiue, Teiichi Nishiki, Kazuhito Tomizawa, Hideki Matsui

    Neuroscience   379   383 - 389   2018.5

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    Stress is an adaptive and coordinated response to endogenous or exogenous stressors that pose an unpleasant and aversive threat to an individual's homeostasis and wellbeing. Glucocorticoids, corticosterone (CORT) in rodents and cortisol in humans, are adrenal steroids which are released in response to stressful stimuli. Although they help individuals to cope with stress, their overexposure in animals has been implicated in hippocampal dysfunction and neuronal loss. Oxytocin (OT) plays an active role in adaptive stress-related responses and protects hippocampal synaptic plasticity and memory during stress. In this study, we showed that OT protects primary mouse hippocampal neurons from CORT-induced apoptosis. OT receptors (OTR) were expressed in primary mouse hippocampal neurons and glial cells. CORT induced apoptosis in hippocampal neurons, but had no effect on apoptosis in glial cells. OT inhibited CORT-induced apoptosis in primary hippocampal neurons. OT was unable to protect primary hippocampal neurons prepared from OTR KO mice from CORT-induced apoptosis. These results indicate that OT has inhibitory effects on CORT-induced neuronal death in primary hippocampal neurons via acting on OTR. The findings suggest a therapeutic potential of OT in the treatment of stress-related disorders.

    DOI: 10.1016/j.neuroscience.2018.03.025

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  • Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion. Reviewed International journal

    Y Otani, T Ichikawa, K Kurozumi, S Inoue, J Ishida, T Oka, T Shimizu, Y Tomita, Y Hattori, A Uneda, Y Matsumoto, H Michiue, I Date

    Oncogene   37 ( 6 )   777 - 786   2018.2

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    Glioblastoma has the poorest prognosis, and is characterized by excessive invasion and angiogenesis. To determine the invasive mechanisms, we previously used two glioma cell lines (J3T-1 and J3T-2) with different invasive phenotypes. The J3T-1 showed abundant angiogenesis and tumor cell invasion around neovasculature, while J3T-2 showed diffuse cell infiltration into surrounding healthy parenchyma. Microarray analyses were used to identify invasion-related genes in J3T-2 cells, and the expressed genes and their intracellular and intratumoral distribution patterns were evaluated in J3T-2 cell lines, human glioma cell lines, human glioblastoma stem cells and human glioblastoma specimens. To determine the role of the invasion-related genes, invasive activities were evaluated in vitro and in vivo. Fibroblast growth factor 13 (FGF13) was overexpressed in J3T-2 cells compared to J3T-1 cells, and in human glioma cell lines, human glioblastoma stem cells and human glioblastoma specimens, when compared to that of normal human astrocytes. Immunohistochemical staining and the RNA-seq (sequencing) data from the IVY Glioblastoma Atlas Project showed FGF13 expression in glioma cells in the invasive edges of tumor specimens. Also, the intracellular distribution was mainly in the cytoplasm of tumor cells and colocalized with tubulin. Overexpression of FGF13 stabilized tubulin dynamics in vitro and knockdown of FGF13 decreased glioma invasion both in vitro and in vivo and prolonged overall survival of several xenograft models. FGF13 was negatively regulated by hypoxic condition. Silencing of FGF13 also decreased in vivo bevacizumab-induced glioma invasion. In conclusion, FGF13 regulated glioma cell invasion and bevacizumab-induced glioma invasion, and could be a novel target for glioma treatment.

    DOI: 10.1038/onc.2017.373

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  • FIBROBLAST GROWTH FACTOR 13 REGULATES GLIOMA CELL INVASION Reviewed

    Yoshihiro Otani, Tomotsugu Ichikawa, Kazuhiko Kurozumi, Satoshi Inoue, Joji Ishida, Tetsuo Oka, Toshihiko Shimizu, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Yuji Matsumoto, Hiroyuki Michiue, Isao Date

    NEURO-ONCOLOGY   19   21 - 21   2017.11

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  • PIK3R1Met326Ile germline mutation correlates with cysteine-rich protein 61 expression and poor prognosis in glioblastoma Reviewed International journal

    Yoshihiro Otani, Joji Ishida, Kazuhiko Kurozumi, Tetsuo Oka, Toshihiko Shimizu, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Yuji Matsumoto, Hiroyuki Michiue, Shuta Tomida, Takehiro Matsubara, Tomotsugu Ichikawa, Isao Date

    SCIENTIFIC REPORTS   7 ( 1 )   7391 - 7391   2017.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:NATURE PUBLISHING GROUP  

    Despite therapeutic advances, glioblastoma represents a lethal brain tumor. Recently, research to identify prognostic markers for glioblastoma has intensified. Our previous study demonstrated that median progression-free survival (PFS) and overall survival (OS) of patients with high cysteine-rich protein 61 (CCN1) expression was significantly shorter than that of patients with low CCN1 expression. To understand the molecular mechanisms that regulate CCN1 expression, we examined 147 tumour samples from 80 patients with glioblastoma and 67 patients with lower grade glioma. Next-generation and Sanger sequencing showed that PIK3R1Met326Ile was more frequent in the CCN1 high expression group (10/37 cases, 27.0%) than the CCN1 low expression group (3/38 cases, 7.9%) in glioblastoma. This mutation was also detected in corresponding blood samples. In multivariate analysis, high CCN1 expression and PIK3R1Met326Ile in glioblastoma patients were prognostic factors for OS [HR = 2.488 (1.298-4.769), p = 0.006] and [HR = 2.089 (1.020-4.277), p = 0.0439], respectively. Thus, the PIK3R1Met326Ile germline appears to be correlated with CCN1 expression and poor prognosis in glioblastoma.

    DOI: 10.1038/s41598-017-07745-0

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  • Actin bundling by dynamin 2 and cortactin is implicated in cell migration by stabilizing filopodia in human non-small cell lung carcinoma cells Reviewed International journal

    Hiroshi Yamada, Tetsuya Takeda, Hiroyuki Michiue, Tadashi Abe, Kohji Takei

    INTERNATIONAL JOURNAL OF ONCOLOGY   49 ( 3 )   877 - 886   2016.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:SPANDIDOS PUBL LTD  

    The endocytic protein dynamin participates in the formation of actin-based membrane protrusions such as podosomes, pseudopodia, and invadopodia, which facilitate cancer cell migration, invasion, and metastasis. However, the role of dynamin in the formation of actin-based membrane protrusions at the leading edge of cancer cells is unclear. In this study, we demonstrate that the ubiquitously expressed dynamin 2 isoform facilitates cell migration by stabilizing F-actin bundles in filopodia of the lung cancer cell line H1299. Pharmacological inhibition of dynamin 2 decreased cell migration and filopodial formation. Furthermore, dynamin 2 and cortactin mostly colocalized along F-actin bundles in filopodia of serum-stimulated H1299 cells by immunofluorescent and immunoelectron microscopy. Knockdown of dynamin 2 or cortactin inhibited the formation of filopodia in serum-stimulated H1299 cells, concomitant with a loss of F-actin bundles. Expression of wild-type cortactin rescued the punctate-like localization of dynamin 2 and filopodial formation. The incubation of dynamin 2 and cortactin with F-actin induced the formation of long and thick actin bundles, with these proteins colocalizing at F-actin bundles. A depolymerization assay revealed that dynamin 2 and cortactin increased the stability of F-actin bundles. These results indicate that dynamin 2 and cortactin participate in cell migration by stabilizing F-actin bundles in filopodia. Taken together, these findings suggest that dynamin might be a possible molecular target for anticancer therapy.

    DOI: 10.3892/ijo.2016.3592

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  • Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization. Reviewed International journal

    Keiichiro Hayashi, Hiroyuki Michiue, Hiroshi Yamada, Katsuyoshi Takata, Hiroki Nakayama, Fan-Yan Wei, Atsushi Fujimura, Hiroshi Tazawa, Akira Asai, Naohisa Ogo, Hiroyuki Miyachi, Tei-ichi Nishiki, Kazuhito Tomizawa, Kohji Takei, Hideki Matsui

    Scientific reports   6   23372 - 23372   2016.3

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    Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a median survival time about one year. Invasion of GBM cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM. Therefore, we hypothesized that inhibitors of actin polymerization can suppress GBM migration and invasion. First, we adopted a drug repositioning system for screening with a pyrene-actin-based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood-brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity. Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing both FAK and Akt/mammalian target of rapamycin signaling. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same dose of anti-depressant effect. In conclusion, fluvoxamine is a promising anti-invasive treatment against GBM with reliable approach.

    DOI: 10.1038/srep23372

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  • Detection of γH2AX foci in mouse normal brain and brain tumor after boron neutron capture therapy Reviewed

    Natsuko Kondo, Hiroyuki Michiue, Yoshinori Sakurai, Hiroki Tanaka, Yosuke Nakagawa, Tsubasa Watanabe, Masaru Narabayashi, Yuko Kinashi, Minoru Suzuki, Shin-Ichiro Masunaga, Koji Ono

    Reports of Practical Oncology and Radiotherapy   21 ( 2 )   108 - 112   2016.3

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    Aim: In this study, we investigated γH2AX foci as markers of DSBs in normal brain and brain tumor tissue in mouse after BNCT. Background: Boron neutron capture therapy (BNCT) is a particle radiation therapy in combination of thermal neutron irradiation and boron compound that specifically accumulates in the tumor. 10B captures neutrons and produces an alpha (4He) particle and a recoiled lithium nucleus (7Li). These particles have the characteristics of extremely high linear energy transfer (LET) radiation and therefore have marked biological effects. High LET radiation causes severe DNA damage, DNA DSBs. As the high LET radiation induces complex DNA double strand breaks (DSBs), large proportions of DSBs are considered to remain unrepaired in comparison with exposure to sparsely ionizing radiation. Materials and methods: We analyzed the number of γH2AX foci by immunohistochemistry 30 min or 24 h after neutron irradiation. Results: In both normal brain and brain tumor, γH2AX foci induced by 10B(n,α)7Li reaction remained 24 h after neutron beam irradiation. In contrast, γH2AX foci produced by γ-ray irradiation at contaminated dose in BNCT disappeared 24 h after irradiation in these tissues. Conclusion: DSBs produced by 10B(n,α)7Li reaction are supposed to be too complex to repair for cells in normal brain and brain tumor tissue within 24 h. These DSBs would be more difficult to repair than those by γ-ray. Excellent anti-tumor effect of BNCT may result from these unrepaired DSBs induced by 10B(n,α)7Li reaction.

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  • Tumor-specific delivery of BSH-3R for boron neutron capture therapy and positron emission tomography imaging in a mouse brain tumor model. Reviewed International journal

    Yoshiya Iguchi, Hiroyuki Michiue, Mizuki Kitamatsu, Yuri Hayashi, Fumiaki Takenaka, Tei-Ichi Nishiki, Hideki Matsui

    Biomaterials   56   10 - 7   2015.7

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    Glioblastoma, a malignant brain tumor with poor disease outcomes, is managed in modern medicine by multimodality therapy. Boron neutron capture therapy (BNCT) is an encouraging treatment under clinical investigation. In malignant cells, BNCT consists of two major factors: neutron radiation and boron uptake. To increase boron uptake in cells, we created a mercapto-closo-undecahydrododecaborate ([B12HnSH](2-)2Na(+), BSH) fused with a short arginine peptide (1R, 2R, 3R) and checked cellular uptake in vitro and in vivo. In a mouse brain tumor model, only BSH with at least three arginine domains could penetrate cell membranes of glioma cells in vitro and in vivo. Furthermore, to monitor the pharmacokinetic properties of these agents in vivo, we fused BSH and BSH-3R with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); DOTA is a metal chelating agent for labeling positron emission tomography (PET) probe with (64)Cu. We administered BSH-DOTA-(64)Cu and BSH-3R-DOTA-(64)Cu to the tumor model through a mouse tail vein and determined the drugs' pharmacokinetics by PET imaging. BSH-3R showed a high uptake in the tumor area on PET imaging. We concluded that BSH-3R is the ideal boron compound for clinical use during BNCT and that in developing this compound for clinical use, the BSH-3R PET probe is essential for pharmacokinetic imaging.

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  • Annexin A2 regulates angiogenesis and invasion phenotypes of malignant glioma Reviewed

    Manabu Onishi, Tomotsugu Ichikawa, Kazuhiko Kurozumi, Satoshi Inoue, Tomoko Maruo, Yoshihiro Otani, Kentaro Fujii, Joji Ishida, Yosuke Shimazu, Koichi Yoshida, Hiroyuki Michiue, E. Antonio Chiocca, Isao Date

    BRAIN TUMOR PATHOLOGY   32 ( 3 )   184 - 194   2015.7

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    We have established a pair of animal models (J3T-1 and J3T-2) with different invasive and angiogenic phenotypes, and demonstrated that annexin A2 is expressed at higher levels in J3T-1 than J3T-2 cells. The function of annexin A2 in relation to angiogenesis and invasion was investigated using these models. Stable silencing or overexpression of annexin A2 in J3T-1 and J3T-2 cells (J3T-1shA and J3T-2A cells) was established and used. Thirty human glioblastoma samples were evaluated for expression of annexin A2, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). Immunohistochemical and quantitative reverse-transcription polymerase chain reaction analyses revealed higher expression of annexin A2, VEGF and PDGF in J3T-1 and J3T-2A cells. Cultured J3T-1 and J3T-2A cells exhibited higher adhesive ability to endothelial cells. Histopathological analysis of animal brain tumors revealed that J3T-1 and J3T-2A tumors displayed marked angiogenesis and invasion along the neovasculature, whereas J3T-2 and J3T-1shA tumors exhibited diffuse, infiltrative invasion without angiogenesis. Positive expression of annexin A2 was observed in tumor cells surrounding dilated vessels in 25/30 human glioblastoma specimens. Our results reveal that the phenotype of glioma invasion is closely related to angiogenesis. We identify annexin A2 as a factor regulating angiogenesis and invasion of malignant gliomas.

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  • Cdk5rap1-Mediated 2-Methylthio Modification of Mitochondrial tRNAs Governs Protein Translation and Contributes to Myopathy in Mice and Humans Reviewed International journal

    Fan-Yan Wei, Bo Zhou, Takeo Suzuki, Keishi Miyata, Yoshihiro Ujihara, Haruki Horiguchi, Nozomu Takahashi, Peiyu Xie, Hiroyuki Michiue, Atsushi Fujimura, Taku Kaitsuka, Hideki Matsui, Yasutoshi Koga, Satoshi Mohri, Tsutomu Suzuki, Yuichi Oike, Kazuhito Tomizawa

    CELL METABOLISM   21 ( 3 )   428 - 442   2015.3

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    Transfer RNAs (tRNAs) contain a wide variety of post-transcriptional modifications that are important for accurate decoding. Mammalian mitochondrial tRNAs (mt-tRNAs) are modified by nuclear-encoded tRNA-modifying enzymes; however, the physiological roles of these modifications remain largely unknown. In this study, we report that Cdk5 regulatory subunit-associated protein 1 (Cdk5rap1) is responsible for 2-methyl-thio (ms(2)) modifications of mammalian mt-tRNAs for Ser(UCN), Phe, Tyr, and Trp codons. Deficiency in ms(2) modification markedly impaired mitochondrial protein synthesis, which resulted in respiratory defects in Cdk5rap1 knockout (KO) mice. The KO mice were highly susceptive to stress-induced mitochondrial remodeling and exhibited accelerated myopathy and cardiac dysfunction under stressed conditions. Furthermore, we demonstrate that the ms(2) modifications of mt-tRNAs were sensitive to oxidative stress and were reduced in patients with mitochondrial disease. These findings highlight the fundamental role of ms(2) modifications of mt-tRNAs in mitochondrial protein synthesis and their pathological consequences in mitochondrial disease.

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  • A novel leucine zipper motif-based hybrid peptide delivers a functional peptide cargo inside cells. Reviewed International journal

    Y Hakata, S Tsuchiya, H Michiue, T Ohtsuki, H Matsui, M Miyazawa, M Kitamatsu

    Chemical communications (Cambridge, England)   51 ( 2 )   413 - 6   2015

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    A hybrid comprising an autophagy-inducing peptide (AIP) and a cell-penetrating peptide (CPP) connected via heterodimeric leucine zippers was generated and delivered into cells. The hybrid successfully induced autophagy without significant cell death, while the same AIP directly connected to a CPP caused both autophagy and significant cell death.

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  • Reduced neurotoxicity with combined treatment of high-dose methotrexate, cyclophosphamide, doxorubicin, vincristine and prednisolone (M-CHOP) and deferred radiotherapy for primary central nervous system lymphoma. Reviewed International journal

    Tomotsugu Ichikawa, Kazuhiko Kurozumi, Hiroyuki Michiue, Joji Ishida, Yoshinobu Maeda, Eisei Kondo, Akihiro Kawasaki, Isao Date

    Clinical neurology and neurosurgery   127   106 - 11   2014.12

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    OBJECTIVE: Although high-dose methotrexate and whole-brain radiation therapy (WBRT) is the current standard for primary central nervous system lymphoma (PCNSL), it has a limited response rate and produces radiation-induced neurotoxicity. We report the effect of a combined treatment of high-dose methotrexate, cyclophosphamide, doxorubicin, vincristine and prednisolone (M-CHOP) for immunocompetent patients with PCNSL. METHODS: We analyzed 24 patients who had received M-CHOP administered in 28-day cycles with or without WBRT. The response rate to M-CHOP, overall survival (OS), and recurrence-free survival (RFS) were analyzed. RESULTS: Nine patients were treated with M-CHOP plus WBRT and 15 patients were treated with M-CHOP alone. Twenty-one patients achieved a complete response and three patients achieved a partial response to M-CHOP, for a 100% response rate. With a median follow-up of 70 months, the median OS and RFS were 33 and 13 months, respectively. The median OS for patients treated with M-CHOP plus WBRT and M-CHOP alone was 33 and 32 months, respectively. Of the 13 patients whose age was above 65 years, the median OS for the M-CHOP plus WBRT group (two patients) and the M-CHOP alone group (11 patients) was 14 and 32 months, respectively. Toxicities related to M-CHOP were mostly hematologic and generally mild to moderate. Two patients whose age was above 65 years in the M-CHOP plus WBRT group developed neurotoxicity. CONCLUSION: Combined treatment with M-CHOP was well tolerated and produced a high response rate. Deferring WBRT was associated with reduced neurotoxicity without worsening the prognosis, especially in elderly patients.

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  • [The use of the ubiquitin-proteasome system in neurosurgery and the clinical applications of protein therapy]. Reviewed

    Hiroyuki Michiue, Isao Date

    No shinkei geka. Neurological surgery   42 ( 10 )   899 - 906   2014.10

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  • Methylphenidate improves learning impairments and hyperthermia-induced seizures caused by an Scn1a mutation Reviewed International journal

    Iori Ohmori, Nozomi Kawakami, Sumei Liu, Haijiao Wang, Ikuko Miyazaki, Masato Asanuma, Hiroyuki Michiue, Hideki Matsui, Tomoji Mashimo, Mamoru Ouchida

    EPILEPSIA   55 ( 10 )   1558 - 1567   2014.10

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    ObjectiveDevelopmental disorders including cognitive deficit, hyperkinetic disorder, and autistic behaviors are frequently comorbid in epileptic patients with SCN1A mutations. However, the mechanisms underlying these developmental disorders are poorly understood and treatments are currently unavailable. Using a rodent model with an Scn1a mutation, we aimed to elucidate the pathophysiologic basis and potential therapeutic treatments for developmental disorders stemming from Scn1a mutations.MethodsWe conducted behavioral analyses on rats with the N1417H-Scn1a mutation. With high-performance liquid chromatography, we measured dopamine and its metabolites in the frontal cortex, striatum, nucleus accumbens, and midbrain. Methylphenidate was administered intraperitoneally to examine its effects on developmental disorder-like behaviors and hyperthermia-induced seizures.ResultsBehavioral studies revealed that Scn1a-mutant rats had repetitive behavior, hyperactivity, anxiety-like behavior, spatial learning impairments, and motor imbalance. Dopamine levels in the striatum and nucleus accumbens in Scn1a-mutant rats were significantly lower than those in wild-type rats. In Scn1a-mutant rats, methylphenidate, by increasing dopamine levels in the synaptic cleft, improved hyperactivity, anxiety-like behavior, and spatial learning impairments. Surprisingly, methylphenidate also strongly suppressed hyperthermia-induced seizures.SignificanceDysfunction of the mesolimbic dopamine reward pathway may contribute to the hyperactivity and learning impairments in Scn1a-mutant rats. Methylphenidate was effective for treating hyperactivity, learning impairments, and hyperthermia-induced seizures. We propose that methylphenidate treatment may ameliorate not only developmental disorders but also epileptic seizures in patients with SCN1A mutations.

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  • The transdermal inhibition of melanogenesis by a cell-membrane-permeable peptide delivery system based on poly-arginine Reviewed International journal

    Nanako Ookubo, Hiroyuki Michiue, Mizuki Kitamatsu, Maho Kamamura, Tei-ichi Nishiki, Iori Ohmori, Hideki Matsui

    BIOMATERIALS   35 ( 15 )   4508 - 4516   2014.5

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    Topical therapy is the most favored form of treatment for whitening against hyper-pigmentation and sunburn because it lends itself to self-administration, patient compliance and an absence of systemic adverse effects. However, high-molecular-weight, hydrophilic chemicals are difficult to use as transdermal delivery drugs and the use of topical drugs has been highly limited. There are now many potent tyrosinase inhibitors, for example, sulfite or kojic acid, but the efficacy of their skin transduction remains a big problem. Furthermore, melanogenesis inhibitors from natural sources have great potential, as they are considered to be safe and largely free from adverse side effects. We applied 11-arginine (11R), a cell-membrane-permeable peptide, as a transdermal delivery system with a skin delivery enhancer, pyrenbutyrate. We performed intracellular screening for melanogenesis inhibitors with 11R fused with several kinds of tyrosinase inhibitory peptides from natural sources. Of 28 tyrosinase peptides, 13 melanin synthesis inhibitory peptides were selected. Peptide No. 10 found in gliadin protein, a wheat component, most strongly inhibited melanin production. This No. 10 peptide, of only 8 amino acids, fused to 11R showed no cytotoxicity and inhibited melanin synthesis as determined through melanin content measured using an absorption spectrometer and observation with a transmission electron microscope. Next, we transduced this 11R-No. 10 into skin with an 11R transdermal delivery system after previous treatment with pyrenbutyrate and performed daily repetitive topical application for two weeks against a UV-induced sun-tanning guinea pig model. We observed a whitening effect in a model skin sample by Masson-Fontana staining and the 11R-No. 10 peptide-applied area showed significant melanogenesis inhibition. These results show that 11R using a transdermal drug delivery system with melanogenesis inhibitory peptide is a very safe and promising method for applications from cosmetics to the pharmaceutical industry. (C) 2014 Elsevier Ltd. All rights reserved.

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  • The acceleration of boron neutron capture therapy using multi-linked mercaptoundecahydrododecaborate (BSH) fused cell-penetrating peptide. Reviewed International journal

    Hiroyuki Michiue, Yoshinori Sakurai, Natsuko Kondo, Mizuki Kitamatsu, Feng Bin, Kiichiro Nakajima, Yuki Hirota, Shinji Kawabata, Tei-ichi Nishiki, Iori Ohmori, Kazuhito Tomizawa, Shin-ichi Miyatake, Koji Ono, Hideki Matsui

    Biomaterials   35 ( 10 )   3396 - 405   2014.3

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    New anti-cancer therapy with boron neutron capture therapy (BNCT) is based on the nuclear reaction of boron-10 with neutron irradiation. The median survival of BNCT patients with glioblastoma was almost twice as long as those receiving standard therapy in a Japanese BNCT clinical trial. In this clinical trial, two boron compounds, BPA (boronophenylalanine) and BSH (sodium borocaptate), were used for BNCT. BPA is taken up into cells through amino acid transporters that are expressed highly in almost all malignant cells, but BSH cannot pass through the cell membrane and remains outside the cell. We simulated the energy transfer against the nucleus at different locations of boron from outside the cell to the nuclear region with neutron irradiation and concluded that there was a marked difference between inside and outside the cell in boron localization. To overcome this disadvantage of BSH in BNCT, we used a cell-penetrating peptide system for transduction of BSH. CPP (cell-membrane penetrating peptide) is very common peptide domains that transduce many physiologically active substances into cells in vitro and in vivo. BSH-fused CPPs can penetrate the cell membrane and localize inside a cell. To increase the boron ratio in one BSH-peptide molecule, 8BSH fused to 11R with a dendritic lysine structure was synthesized and administrated to malignant glioma cells and a brain tumor mouse model. 8BSH-11R localized at the cell nucleus and showed a very high boron value in ICP results. With neutron irradiation, the 8BSH-11R administrated group showed a significant cancer killing effect compared to the 100 times higher concentration of BSH-administrated group. We concluded that BSH-fused CPPs were one of the most improved and potential boron compounds in the next-stage BNCT trial and 8BSH-11R may be applied in the clinical setting.

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  • Cyclin G2 promotes hypoxia-driven local invasion of glioblastoma by orchestrating cytoskeletal dynamics. Reviewed International journal

    Atsushi Fujimura, Hiroyuki Michiue, Yan Cheng, Atsuhito Uneda, Yasunari Tani, Tei-ichi Nishiki, Tomotsugu Ichikawa, Fan-Yan Wei, Kazuhito Tomizawa, Hideki Matsui

    Neoplasia (New York, N.Y.)   15 ( 11 )   1272 - 81   2013.11

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    Microenvironmental conditions such as hypoxia potentiate the local invasion of malignant tumors including glioblastomas by modulating signal transduction and protein modification, yet the mechanism by which hypoxia controls cytoskeletal dynamics to promote the local invasion is not well defined. Here, we show that cyclin G2 plays pivotal roles in the cytoskeletal dynamics in hypoxia-driven invasion by glioblastoma cells. Cyclin G2 is a hypoxia-induced and cytoskeleton-associated protein and is required for glioblastoma expansion. Mechanistically, cyclin G2 recruits cortactin to the juxtamembrane through its SH3 domain-binding motif and consequently promotes the restricted tyrosine phosphorylation of cortactin in concert with src. Moreover, cyclin G2 interacts with filamentous actin to facilitate the formation of membrane ruffles. In primary glioblastoma, cyclin G2 is abundantly expressed in severely hypoxic regions such as pseudopalisades, which consist of actively migrating glioma cells. Furthermore, we show the effectiveness of dasatinib against hypoxia-driven, cyclin G2-involved invasion in vitro and in vivo. Our findings elucidate the mechanism of cytoskeletal regulation by which severe hypoxia promotes the local invasion and may provide a therapeutic target in glioblastoma.

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  • Inhalation of 10% carbon dioxide rapidly terminates Scn1a mutation-related hyperthermia-induced seizures. Reviewed International journal

    Iori Ohmori, Keiichiro Hayashi, Haijiao Wang, Mamoru Ouchida, Naohiro Fujita, Takushi Inoue, Hiroyuki Michiue, Teiichi Nishiki, Hideki Matsui

    Epilepsy research   105 ( 1-2 )   220 - 4   2013.7

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    The aim of this study was to assess the anticonvulsant effect of carbon dioxide (CO2) on Scn1a mutation-related febrile seizures. We examined physiological changes in the blood gas levels after the induction of hyperthermia-induced seizures (HISs), which were associated with the Scn1a missense mutation. We determined the efficacy of inhalation of 5% or 10% CO2 to treat HISs. HISs were evoked in Scn1a mutant and wild-type (WT) rats by hot water baths. To determine the anticonvulsant effect of CO2 inhalation, rats were placed in a chamber filled with air or mixed gas containing 5% CO2 or 10% CO2 for 3 min, immediately after the induction of HISs. We also analyzed the blood gas levels at the end of inhalation of CO2. Hot water bathing induced a significant reduction in the partial pressure of CO2 (pCO2) and respiratory alkalosis in the WT and Scn1a mutant rats. HISs were evoked in 100% of the Scn1a mutant rats within 5 min, but in none of the WT rats. The Scn1a mutant rats demonstrated a higher HISs susceptibility associated with respiratory alkalosis than the WT rats. Inhalation of 10% CO2 shortened the seizure duration from 62.6±12.1 s to 15.5±1.0 s. Blood gas analysis after the inhalation of 10% CO2 demonstrated an elevated pCO2 level and respiratory acidosis. Inhalation of 10% CO2 demonstrated a potent and fast-acting anticonvulsant effect against HISs.

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  • Bimodal anti-glioma mechanisms of cilengitide demonstrated by novel invasive glioma models Reviewed International journal

    Manabu Onishi, Tomotsugu Ichikawa, Kazuhiko Kurozumi, Kentaro Fujii, Koichi Yoshida, Satoshi Inoue, Hiroyuki Michiue, E. Antonio Chiocca, Balveen Kaur, Isao Date

    NEUROPATHOLOGY   33 ( 2 )   162 - 174   2013.4

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    Integrins are expressed in tumor cells and tumor endothelial cells, and likely play important roles in glioma angiogenesis and invasion. We investigated the anti-glioma mechanisms of cilengitide (EMD121974), an v3 integrin inhibitor, utilizing the novel invasive glioma models, J3T-1 and J3T-2. Immunohistochemical staining of cells in culture and brain tumors in rats revealed positive v3 integrin expression in J3T-2 cells and tumor endothelial cells, but not in J3T-1 cells. Established J3T-1 and J3T-2 orthotopic gliomas in athymic rats were treated with cilengitide or solvent. J3T-1 gliomas showed perivascular tumor cluster formation and angiogenesis, while J3T-2 gliomas showed diffuse single-cell infiltration without obvious angiogenesis. Cilengitide treatment resulted in a significantly decreased diameter of the J3T-1 tumor vessel clusters and its core vessels when compared with controls, while an anti-invasive effect was shown in the J3T-2 glioma with a significant reduction of diffuse cell infiltration around the tumor center. The survival of cilengitide-treated mice harboring J3T-1 tumors was significantly longer than that of control animals (median survival: 57.5 days and 31.8 days, respectively, P<0.005), while cilengitide had no effect on the survival of mice with J3T-2 tumors (median survival: 48.9 days and 48.5, P=0.69). Our results indicate that cilengitide exerts a phenotypic anti-tumor effect by inhibiting angiogenesis and glioma cell invasion. These two mechanisms are clearly shown by the experimental treatment of two different animal invasive glioma models.

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  • CACNA1A variants may modify the epileptic phenotype of Dravet syndrome. Reviewed International journal

    Iori Ohmori, Mamoru Ouchida, Katsuhiro Kobayashi, Yoshimi Jitsumori, Akiko Mori, Hiroyuki Michiue, Teiichi Nishiki, Yoko Ohtsuka, Hideki Matsui

    Neurobiology of disease   50   209 - 17   2013.2

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    Dravet syndrome is an intractable epileptic syndrome beginning in the first year of life. De novo mutations of SCN1A, which encode the Na(v)1.1 neuronal voltage-gated sodium channel, are considered the major cause of Dravet syndrome. In this study, we investigated genetic modifiers of this syndrome. We performed a mutational analysis of all coding exons of CACNA1A in 48 subjects with Dravet syndrome. To assess the effects of CACNA1A variants on the epileptic phenotypes of Dravet syndrome, we compared clinical features in two genotype groups: 1) subjects harboring SCN1A mutations but no CACNA1A variants (n=20) and 2) subjects with SCN1A mutations plus CACNA1A variants (n=20). CACNA1A variants detected in patients were studied using heterologous expression of recombinant human Ca(v)2.1 in HEK 293 cells and whole-cell patch-clamp recording. Nine CACNA1A variants, including six novel ones, were detected in 21 of the 48 subjects (43.8%). Based on the incidence of variants in healthy controls, most of the variants seemed to be common polymorphisms. However, the subjects harboring SCN1A mutations and CACNA1A variants had absence seizures more frequently than the patients with only SCN1A mutations (8/20 vs. 0/20, p=0.002). Moreover, the former group of subjects exhibited earlier onset of seizures and more frequent prolonged seizures before one year of age, compared to the latter group of subjects. The electrophysiological properties of four of the five novel Ca(v)2.1 variants exhibited biophysical changes consistent with gain-of-function. We conclude that CACNA1A variants in some persons with Dravet syndrome may modify the epileptic phenotypes.

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  • 細胞膜透過ドメイン11Rを用いたHO-1蛋白の脳血管攣縮に対する効果

    小川 智之, 小野 成紀, Haenggi Daniel, 武 玉梅, 道上 宏之, 富澤 一仁, 松井 秀樹, Steiger Hans-Jakob, 伊達 勲

    脳血管攣縮   28   29 - 32   2013.2

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    優れたタンパク質透過ドメインとして開発された「11R」を用い、脳血管拡張作用が報告されているHeme-oxygenase(HO)-1タンパクを融合させ、その有用性について検討した。まず11R-HO-1タンパク質の導入効率について、ラット大槽内より髄液を吸入した後に11R-HO-1タンパク質を注入し、免疫蛍光染色により脳底動脈の蛍光強度を測定した。その結果、注入2時間後には著明なHO-1タンパク質の発現を認め、発現は48時間以上持続し、高い導入効率が明らかとなった。次にラットクモ膜下出血モデルを用い、11R-HO-1タンパク質を注入して6時間後に血管径を測定したところ、HO-1注入群、11R注入群、11R-EGFP注入群に比較して脳底動脈径は有意に拡張しており、血管攣縮に対する効果が示された。

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  • [Surgical and endovascular treatment for superior cerebellar artery aneurysms: report of two cases]. Reviewed

    Jun Haruma, Kenji Sugiu, Yosuke Shimazu, Hiroyuki Michiue, Koji Tokunaga, Isao Date

    No shinkei geka. Neurological surgery   41 ( 1 )   45 - 51   2013.1

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    Aneurysms located on the superior cerebellar artery (SCA) are uncommon and their presentation, natural history, and clinical management are poorly understood. Reports related to the endovascular or surgical management of SCA aneurysms are rare. Herein, we report two cases of SCA aneurysm. The first is that of a 70-year-old woman who presented with subarachnoid hemorrhage (SAH). Surgical treatment (neck clipping) of the ruptured SCA aneurysm was performed, and the flow of the parent artery disappeared. The second is that of a 69-year-old woman with an unruptured SCA aneurysm who underwent endovascular surgery to occlude the parent artery. Neither patients exhibited any additional neurological deficits. SCA aneurysms often have either relatively wide or undefinable necks, so it is difficult to preserve the parent artery. According to several surgical reports, occlusion of the SCA appears well tolerated for a variety of reasons.

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  • Theranostic protein targeting ErbB2 for bioluminescence imaging and therapy for cancer. Reviewed International journal

    Xiao-Jian Han, Ling-Fei Sun, Yuki Nishiyama, Bin Feng, Hiroyuki Michiue, Masaharu Seno, Hideki Matsui, Kazuhito Tomizawa

    PloS one   8 ( 9 )   e75288   2013

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    A combination of molecular-targeted cancer imaging and therapy is an emerging strategy to improve cancer diagnosis and minimize the side effects of conventional treatments. Here, we generated a recombinant protein, EC1-GLuc-p53C, by fusing EC1 peptide, an artificial ligand of ErbB2, with Gaussia luciferase (GLuc) and a p53-activating peptide, p53C. EC1-GLuc-p53C was expressed and purified from E. coli BL21. In vitro experiments showed that EC1-GLuc-p53c was stable in luminescent activity and selectively targeted ErbB2-overexpressing BT474 cells for bioluminescence imaging. Moreover, the internalized EC1-GLuc-p53C in BT474 cells exerted its function to reactivate p53 and significantly inhibited cellular proliferation. In tumor-bearing mice, the ErbB2-targeted bioluminescence imaging and therapeutic effect of EC1-GLuc-p53C were also observed specifically in BT474 tumors but not in MCF7 tumors, which does not overexpress ErbB2. Thus, the present study demonstrates EC1-GLuc-p53C to be an effective theranostic reagent targeting ErbB2 for bioluminescence imaging and cancer therapy.

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  • Gene expression profiling of the anti-glioma effect of Cilengitide Reviewed International journal

    Manabu Onishi, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Hiroyuki Michiue, Kentaro Fujii, Joji Ishida, Yosuke Shimazu, E. Antonio Chiocca, Balveen Kaur, Isao Date

    SPRINGERPLUS   2 ( 1 )   160 - 160   2013

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    Cilengitide (EMD121974), an inhibitor of the adhesive function of integrins, demonstrated preclinical efficacy against malignant glioma. It is speculated that cilengitide can inhibit tumor growth, invasion, and angiogenesis. However, the effects of cilengitide on these processes have not been sufficiently examined. In this study, we investigated the anti-glioma effect of cilengitide using DNA microarray analysis. U87 Delta EGFR cells (human malignant glioma cell line) were used for this experiment. The cells were harvested after 16 h of cilengitide treatment, and mRNA was extracted. Gene expression and pathway analyses were performed using a DNA microarray (CodeLink (TM) Human Whole Genome Bioarray). The expression of 265 genes was changed with cilengitide treatment. The expression of 214 genes was up-regulated by more than 4-fold and the expression of 51 genes was down-regulated by more than 4-fold compared to the controls. In pathway analysis, "apoptotic cleavage of cellular proteins" and "TNF receptor signaling pathway" were over-represented. Apoptotic-associated genes such as caspase 8 were up-regulated. Gene expression profiling revealed more detailed mechanism of the anti-glioma effect of cilengitide. Genes associated with apoptosis were over-represented following cilengitide treatment.

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  • Induction of autophagic cell death of glioma-initiating cells by cell-penetrating D-isomer peptides consisting of Pas and the p53 C-terminus Reviewed International journal

    Yutaka Ueda, Fan-Yan Wei, Taku-ichiro Hide, Hiroyuki Michiue, Kentaro Takayama, Taku Kaitsuka, Hideo Nakamura, Keishi Makino, Jun-ichi Kuratsu, Shiroh Futaki, Kazuhito Tomizawa

    BIOMATERIALS   33 ( 35 )   9061 - 9069   2012.12

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    Glioblastoma multiforme (GBM) is the most aggressive and fatal brain tumor. GBM is resistant to chemotherapy and radiation. Recent studies have shown that glioma-initiating cells (GICs), which have characteristics of cancer stem cells, are responsible for the resistance to chemotherapy and radiation and regrowth. No effective therapy for GICs has been developed. Here we showed that D-isomer peptides (dPasFHV-p53C') consisting of a cell-penetrating peptide (FHV), penetration accelerating sequence (Pas) and C-terminus of p53 (p53C') induced the cell death of GICs. dPasFHV-p53C' was effectively transduced into human GICs. The peptides dose-dependently inhibited cell growth and at 3 mu M completely blocked the growth of GICs but not embryonic stem cells. Autophagic cell death was observed in the GICs treated with dPasFHV-p53C' but apoptosis was not. dPasFHV without p53C' showed the same effect as dPasFHV-p53C', suggesting Pas to play a critical role in the cell death of GICs. Finally, dPasFHV-p53C' reduced tumor mass in mice transplanted with GICs. Peptide transduction therapy using dPasFHV-p53C' could be a new method for the treatment of GBM. (C) 2012 Elsevier Ltd. All rights reserved.

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  • Combining poly-arginine with the hydrophobic counter-anion 4-(1-pyrenyl)-butyric acid for protein transduction in transdermal delivery. Reviewed International journal

    Gerile Candan, Hiroyuki Michiue, Sanae Ishikawa, Atsushi Fujimura, Keiichiro Hayashi, Atsuhito Uneda, Akiko Mori, Iori Ohmori, Tei-ichi Nishiki, Hideki Matsui, Kazuhito Tomizawa

    Biomaterials   33 ( 27 )   6468 - 75   2012.9

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    Topical therapy is the most favored form of treatment for whitening against hyperpigmentation and sunburn because it lends itself to self-administration, patient compliance, and absence of systemic adverse effects. However, transdermal delivery of hydrophilic chemicals is difficult. The main purpose of this study is to develop a delivering system of hydrophilic drugs and proteins across the skin. Hydroquinone (HQ), a well-known tyrosinase inhibitor and antimelanogenesis compound, and enhanced green fluorescent protein (EGFP) were fused with eleven poly-arginine (11R). Both HQ-11R and EGFP-11R were efficiently delivered in B16 cells, a mouse melanoma cell line. HQ-11R was as effective as HQ alone at inhibiting melanin synthesis in B16 cells. EGFP-11R was efficiently delivered into cells of the epidermis with 4-(1-pyrenyl)-butyric acid (PB), a counteranion bearing an aromatic hydrophobic moiety, in vivo, but EGFP alone or EGFP-11R without PB was not. Finally, topical application of HQ-11R with PB significantly inhibited UV irradiation-induced pigmentation in guinea pigs compared with HQ alone. These results suggest that topical therapy using poly-arginine in combination with PB is useful for the delivery of hydrophilic drugs and proteins by the transdermal route.

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  • A protein transduction method using oligo-arginine (3R) for the delivery of transcription factors into cell nuclei. Reviewed International journal

    Takashi Hitsuda, Hiroyuki Michiue, Mizuki Kitamatsu, Atsushi Fujimura, Feifei Wang, Takahiro Yamamoto, Xiao-Jian Han, Hiroshi Tazawa, Atsuhito Uneda, Iori Ohmori, Tei-ichi Nishiki, Kazuhito Tomizawa, Hideki Matsui

    Biomaterials   33 ( 18 )   4665 - 72   2012.6

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    Protein transduction with cell-penetrating peptides such as poly-arginine and HIV TAT peptides is widely used to deliver proteins, peptides, siRNA and biologically active compounds. It has been thought that poly-arginine peptides transduce proteins in a manner dependent on the number of arginine residues and oligo-peptides such as three arginines (3R) are ineffective. Here we showed that 3R-fused proteins were effectively delivered and functioned in cells co-treated with pyrenebutyrate, a counteranion bearing an aromatic hydrophobic moiety. Little 3R was transduced in glioma cells without pyrenebutyrate whereas the oligo-arginine was effectively delivered with pyrenebutyrate. Enhanced green fluorescence protein (eGFP) fused with 3R was effectively delivered into various kinds of cells including primary cultured cells and suspended cells in the presence of pyrenebutyrate. p53 fused with 3R (3R-p53) was delivered into glioma cells without pyrenebutyrate but could not be translocated into the nucleus. In contrast, 3R-p53 was observed in nuclei of glioma cells when co-applied with pyrenebutyrate. Although 3R-p53 was delivered less effectively than 11R-p53 with pyrenebutyrate, its transcriptional activity was higher than that of 11R-p53. Moreover, a single administration of 3R-p53 with pyrenebutyrate significantly inhibited the growth of cancer cells. These results suggest protein transduction using an oligo-arginine (3R) with pyrenebutyrate to be a good tool for the delivery of functional transcription factors and a promising method of treating cancer.

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  • オキシトシンの抗うつ作用に関わるマウス海馬神経細胞内シグナル伝達経路

    松崎 光博, 松下 博昭, 韓 小建, 沖本 直輝, 道上 宏之, 西木 禎一, 大守 伊織, 富澤 一仁, 松井 秀樹

    日本生理学雑誌   74 ( 2 )   46 - 46   2012.3

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  • Antidepressant-like effect of sildenafil through oxytocin-dependent cyclic AMP response element-binding protein phosphorylation. Reviewed International journal

    H Matsushita, M Matsuzaki, X-J Han, T-I Nishiki, I Ohmori, H Michiue, H Matsui, K Tomizawa

    Neuroscience   200   13 - 8   2012.1

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    Oxytocin (OT) levels in plasma increase during sexual response and are significantly lower in patients with depression. A drug for the treatment of sexual dysfunction, sildenafil, enhances the electrically evoked release of OT from the posterior pituitary. In this study, we showed that sildenafil had an antidepressant-like effect through activation of an OT signaling pathway. Application of sildenafil reduced depression-related behavior in male mice. The antidepressant-like effect was blocked by an OT receptor (OTR) antagonist and was absent in OTR knockout (KO) mice. Sildenafil increased the phosphorylation of cAMP response element-binding protein (CREB) in the hippocampus. The OTR antagonist inhibited sildenafil-induced CREB phosphorylation and sildenafil had no effect on CREB phosphorylation in OTR KO mice. These results suggest sildenafil to have an antidepressant-like effect through the activation of OT signaling and to be a promising drug for the treatment of depression.

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  • Ca(2+)-independent syntaxin binding to the C(2)B effector region of synaptotagmin. Reviewed International journal

    Toshio Masumoto, Koichiro Suzuki, Iori Ohmori, Hiroyuki Michiue, Kazuhito Tomizawa, Atsushi Fujimura, Tei-ichi Nishiki, Hideki Matsui

    Molecular and cellular neurosciences   49 ( 1 )   1 - 8   2012.1

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    Although synaptotagmin I, which is a calcium (Ca(2+))-binding synaptic vesicle protein, may trigger soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated synaptic vesicle exocytosis, the mechanisms underlying the interaction between these proteins remain controversial, especially with respect to the identity of the protein(s) in the SNARE complex that bind(s) to synaptotagmin and whether Ca(2+) is required for their highly effective binding. To address these questions, native proteins were solubilized, immunoprecipitated from rat brain extracts, and analyzed by immunoblotting. SNARE complexes comprising syntaxin 1, 25-kDa synaptosomal-associated protein (SNAP-25), and synaptobrevin 2 were coprecipitated with synaptotagmin I in the presence of ethylene glycol tetraacetic acid. The amount of coprecipitated proteins was significantly unaltered by the addition of Ca(2+) to the brain extract. To identify the component of the SNARE complex that bound to synaptotagmin, SNARE was coexpressed with synaptotagmin in HEK293 cells and immunoprecipitated. Syntaxin, but not SNAP-25 and synaptobrevin, bound to synaptotagmin in a Ca(2+)-independent manner, and the binding was abolished in the presence of 1M NaCl. Synaptotagmin contains 2 Ca(2+)-binding domains (C(2)A, C(2)B). Mutating the positively charged lysine residues in the putative effector-binding region of the C(2)B domain, which are critical for transmitter release, markedly inhibited synaptotagmin-syntaxin binding, while similar mutations in the C(2)A domain had no effect on binding. Synaptotagmin-syntaxin binding was reduced by mutating multiple negatively charged glutamate residues in the amino-terminal half of the syntaxin SNARE motif. These results indicate that synaptotagmin I binds to syntaxin 1 electrostatically through its C(2)B domain effector region in a Ca(2+)-independent fashion, providing biochemical evidence that synaptotagmin I binds SNARE complexes before Ca(2+) influx into presynaptic nerve terminals.

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  • Protein therapy using heme-oxygenase-1 fused to a polyarginine transduction domain attenuates cerebral vasospasm after experimental subarachnoid hemorrhage. Reviewed International journal

    Tomoyuki Ogawa, Daniel Hänggi, Yumei Wu, Hiroyuki Michiue, Kazuhito Tomizawa, Shigeki Ono, Hideki Matsui, Isao Date, Hans-Jakob Steiger

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism   31 ( 11 )   2231 - 42   2011.11

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    A sequence of 11 consecutive arginine residues (11R) is one of the best protein transduction domains for introducing proteins into cell membranes. Heme-oxygenase-1 (HO-1) is involved in heme catabolism and reduces the contractile effect of hemoglobin after subarachnoid hemorrhage (SAH). Therefore, we constructed 11R-fused HO-1 protein to achieve successful transduction of the protein into the cerebral arteries and examined the therapeutic effect of the 11R-HO-1 protein for cerebral vasospasm (CV) after SAH. We injected the 11R-HO-1 protein into the cisterna magna of male rats and, several hours after the injection, performed immunofluorescence staining and western blotting analysis of the rat basilar arteries (BAs) to determine transduction efficacy. We also assessed intraarterial HO-1 activity as cGMP (cyclic guanosine 3', 5'-cyclic monophosphate) accumulation in SAH and determined whether protein transduction of 11R-HO-1 quantified the therapeutic effect in a rat double-hemorrhage model of SAH. The BAs expressed significantly more HO-1 in the group injected with 11R-HO-1 (3.56±0.54 (11R-HO-1) versus control (saline)), and transduction of 11R-HO-1 resulted in higher activity (>3.25-fold) in rat BAs with SAH. Moreover, the results of the rat double-hemorrhage model showed that the 11R-HO-1 protein significantly attenuated CV after SAH (317.59±23.48 μm (11R-HO-1) versus 270.08±14.66 μm (11R-fused enhanced green fluorescent protein), 252.05±13.95 μm (saline), P<0.01).

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  • Deficit of tRNA(Lys) modification by Cdkal1 causes the development of type 2 diabetes in mice Reviewed International journal

    Fan-Yan Wei, Takeo Suzuki, Sayaka Watanabe, Satoshi Kimura, Taku Kaitsuka, Atsushi Fujimura, Hideki Matsui, Mohamed Atta, Hiroyuki Michiue, Marc Fontecave, Kazuya Yamagata, Tsutomu Suzuki, Kazuhito Tomizawa

    JOURNAL OF CLINICAL INVESTIGATION   121 ( 9 )   3598 - 3608   2011.9

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    The worldwide prevalence of type 2 diabetes (T2D), which is caused by a combination of environmental and genetic factors, is increasing. With regard to genetic factors, variations in the gene encoding Cdk5 regulatory associated protein 1-like 1 (Cdkal1) have been associated with an impaired insulin response and increased risk of T2D across different ethnic populations, but the molecular function of this protein has not been characterized. Here, we show that Cdkal1 is a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N-6-threonylcarbamoyladenosine (ms(2)t(6)A) in tRNA(Lys)(UUU) and that it is required for the accurate translation of AAA and AAG codons. Mice with pancreatic beta cell-specific KO of Cdkal1 (referred to herein as beta cell KO mice) showed pancreatic islet hypertrophy, a decrease in insulin secretion, and impaired blood glucose control. In Cdkal1-deficient beta cells, misreading of Lys codon in proinsulin Occurred, resulting in a reduction of glucose-stimulated proinsulin synthesis. Moreover, expression of ER stress-related genes was upregulated in these cells, and abnormally structured ER was observed. Further, the beta cell KO mice were hypersensitive to high fat diet-induced ER stress. These findings suggest that glucose-stimulated translation of proinsulin may require fully modified tRNA(Lys)(UUU), which could potentially explain the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.

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  • Expression of a constitutively active calcineurin encoded by an intron-retaining mRNA in follicular keratinocytes. Reviewed International journal

    Atsushi Fujimura, Hiroyuki Michiue, Tei-ichi Nishiki, Iori Ohmori, Fan-Yan Wei, Hideki Matsui, Kazuhito Tomizawa

    PloS one   6 ( 3 )   e17685   2011.3

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    Hair growth is a highly regulated cyclical process. Immunosuppressive immunophilin ligands such as cyclosporin A (CsA) and FK506 are known as potent hair growth modulatory agents in rodents and humans that induce active hair growth and inhibit hair follicle regression. The immunosuppressive effectiveness of these drugs has been generally attributed to inhibition of T cell activation through well-characterized pathways. Specifically, CsA and FK506 bind to intracellular proteins, principally cyclophilin A and FKBP12, respectively, and thereby inhibit the phosphatase calcineurin (Cn). The calcineurin (Cn)/NFAT pathway has an important, but poorly understood, role in the regulation of hair follicle development. Here we show that a novel-splicing variant of calcineurin Aß CnAß-FK, which is encoded by an intron-retaining mRNA and is deficient in the autoinhibitory domain, is predominantly expressed in mature follicular keratinocytes but not in the proliferating keratinocytes of rodents. CnAß-FK was weakly sensitive to Ca(2+) and dephosphorylated NFATc2 under low Ca(2+) levels in keratinocytes. Inhibition of Cn/NFAT induced hair growth in nude mice. Cyclin G2 was identified as a novel target of the Cn/NFATc2 pathway and its expression in follicular keratinocytes was reduced by inhibition of Cn/NFAT. Overexpression of cyclin G2 arrested the cell cycle in follicular keratinocytes in vitro and the Cn inhibitor, cyclosporin A, inhibited nuclear localization of NFATc2, resulting in decreased cyclin G2 expression in follicular keratinocytes of rats in vivo. We therefore suggest that the calcineurin/NFAT pathway has a unique regulatory role in hair follicle development.

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  • Transdifferentiation of glioblastoma cells into vascular endothelial cells Reviewed International journal

    Yasushi Soda, Tomotoshi Marumoto, Dinorah Friedmann-Morvinski, Mie Soda, Fei Liu, Hiroyuki Michiue, Sandra Pastorino, Meng Yang, Robert M. Hoffman, Santosh Kesari, Inder M. Verma

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   108 ( 11 )   4274 - 4280   2011.3

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    Glioblastoma (GBM) is the most malignant brain tumor and is highly resistant to intensive combination therapies and anti-VEGF therapies. To assess the resistance mechanism to anti-VEGF therapy, we examined the vessels of GBMs in tumors that were induced by the transduction of p53(+/-) heterozygous mice with lentiviral vectors containing oncogenes and the marker GFP in the hippocampus of GFAP-Cre recombinase (Cre) mice. We were surprised to observe GFP(+) vascular endothelial cells (ECs). Transplantation of mouse GBM cells revealed that the tumor-derived endothelial cells (TDECs) originated from tumor-initiating cells and did not result from cell fusion of ECs and tumor cells. An in vitro differentiation assay suggested that hypoxia is an important factor in the differentiation of tumor cells to ECs and is independent of VEGF. TDEC formation was not only resistant to an anti-VEGF receptor inhibitor in mouse GBMs but it led to an increase in their frequency. A xenograft model of human GBM spheres from clinical specimens and direct clinical samples from patients with GBM also showed the presence of TDECs. We suggest that the TDEC is an important player in the resistance to anti-VEGF therapy, and hence a potential target for GBM therapy.

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  • Poly-arginine domainによる細胞内導入効率と細胞制御について

    櫃田 隆, 道上 宏之, 山口 晃正, 藤村 篤史, 富澤 一仁, 松井 秀樹

    日本生理学雑誌   73 ( 2 )   36 - 36   2011.2

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  • Ca2+-dependent dissociation of synaptotagmin I from SNARE complexes Reviewed

    Koichiro Suzuki, Toshio Masumoto, Iori Ohmori, Hiroyuki Michiue, Tei-ichi Nishiki, Hideki Matsui

    NEUROSCIENCE RESEARCH   71   E314 - E314   2011

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  • The neuroprotective effects of GDNF-pretreatment for neural stem cell transplantation in the 6-OHDA-lesioned rats Reviewed

    Feifei Wang, Hiroyuki Michiue, Masahiro Kameda, Teiichi Nishiki, Iori Ohmori, Isao Date, Hideki Matsui

    NEUROSCIENCE RESEARCH   71   E137 - E138   2011

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  • Electrophysiological properties of variant voltage-gated calcium channels in patients with epilepsy

    Iori Ohmori, Mamoru Ouchida, Haijiao Wang, Yuichiro Kitagawa, Hiroyuki Michiue, Teiichi Nishiki, Hideki Matsui

    NEUROSCIENCE RESEARCH   71   E294 - E294   2011

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  • 脳腫瘍治療の新潮流(転移性脳腫瘍を含む) 膠芽腫に対するホウ素中性子捕捉療法、X線外照射、化学療法 第II相臨床試験の近況

    川端 信司, 宮武 伸一, 平松 亮, 宮田 至朗, 嶽北 葉子, 黒岩 敏彦, 道上 宏之, 小野 公二

    日本癌治療学会誌   45 ( 2 )   384 - 384   2010.9

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  • Development of a bifunctional immunoliposome system for combined drug delivery and imaging in vivo. Reviewed International journal

    Bin Feng, Kazuhito Tomizawa, Hiroyuki Michiue, Xiao-Jian Han, Shin-ichi Miyatake, Hideki Matsui

    Biomaterials   31 ( 14 )   4139 - 45   2010.5

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    The diverse characteristics of immunoliposomes provide advantages for utilization in drug delivery systems. In this study, we fused the antibody affinity motif of protein A (ZZ) with Gaussia luciferase (GLase). The fused protein conjugated with an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (GLase-ZZ-His-mAb) was effectively delivered into glioma cells expressing an activated EGFR mutant (EGFRvIII) and the bioluminescence was visualized in the cells. Immunoliposomes were further constructed with DSPE-PEG-MAL for covalent GLase-ZZ-His-mAb conjugation. A fluorescence dye (HPTS) encapsulated in immunoliposomes conjugated with GLase-ZZ-His-mAb was effectively delivered into EGFRvIII-expressing glioma cells. In a murine xenograft model of glioma, moreover, specific targeting of the immunoliposomes was visualized in the tumor. This new bifunctional immunoliposome system has the potential for drug delivery and imaging in vivo.

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  • Development of a new theranostics for ErbB 2-overexpressing cancer Reviewed

    Lingfei Sun, Xiao-Jian Han, Yuki Nishiyama, Hiroyuki Michiue, Kazuhito Tomizawa, Hideki Matsui

    JOURNAL OF PHYSIOLOGICAL SCIENCES   60   S108 - S108   2010

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  • Induction of in vivo synthetic lethal RNAi responses to treat glioblastoma. Reviewed International journal

    Hiroyuki Michiue, Akiko Eguchi, Miriam Scadeng, Steven F Dowdy

    Cancer biology & therapy   8 ( 23 )   2306 - 13   2009.12

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    Glioblastoma multiforme remains one of the most intractable human malignancies. Glioblastomas arise due to activation of multiple oncogenic pathways leading to increased cellular growth, proliferation and tumor cell survival. siRNA induced RNA Interference (RNAi) responses result in the degradation of specific mRNA species. In theory, RNAi responses can selectively target intersecting oncogenic pathways to induce a tumor cell specific RNAi synthetic lethal response. However, the concept of inducing in vivo synthetic lethal RNAi responses has not yet been addressed. Here we tested the in vivo ability of synthetic lethal RNAi responses to treat glioblastoma. To deliver siRNAs into cells, we fused a peptide transduction delivery domain to a dsRNA-binding domain (PTD-DRBD). DRBDs avidly bind to siRNAs, masking the siRNA anionic negative charge and allowing for efficient PTD-mediated siRNA delivery into the entire cell population. Combinatorial targeting of EGF-Receptor (EGFR) and Akt2, but not Ak1 or Akt3, by PTD-DRBD delivered siRNAs synergized to induce tumor cell specific apoptosis. In vivo PTD-DRBD delivery of EGFR and Akt2 siRNAs induced tumor specific apoptosis and significantly increased survival in intracerebral glioblastoma mouse models (p < 0.0005), whereas delivery of irrelevant control siRNAs did not alter longevity. Thus, siRNA induced synthetic lethal RNAi responses have great potential for personalized medicine treatment of cancer.

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  • Enhanced intracellular delivery using arginine-rich peptides by the addition of penetration accelerating sequences (Pas) Reviewed International journal

    Kentaro Takayama, Ikuhiko Nakase, Hiroyuki Michiue, Toshihide Takeuchi, Kazuhito Tomizawa, Hideki Matsui, Shiroh Futaki

    JOURNAL OF CONTROLLED RELEASE   138 ( 2 )   128 - 133   2009.9

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    Cell penetrating peptides (CPPs), including arginine-rich peptides, are attractive tools for the intracellular delivery of various bioactive molecules with a low membrane permeability. We showed that the accelerated intracellular delivery of arginine-rich peptides was achieved by the addition of a short peptide segment (penetration accelerating sequence, Pas) to arginine-rich CPPs. The cytosolic release of the Pas-attached arginine-rich CPPs was observed within 5 min after the treatment of the cells with the peptides even in the presence of serum. Effectiveness of the Pas segment in the intracellular delivery of bioactive peptides using arginine-rich CPPs was exemplified through the enhanced growth inhibition activity of the malignant glioma cells by a retro-inverso peptide derived from the p53 C-terminal 22-amino-acid segment (positions 361-382). All rights reserved. (C) 2009 Elsevier B.V. All rights reserved.

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  • Survival benefit from boron neutron capture therapy for the newly diagnosed glioblastoma patients. Reviewed International journal

    Shinji Kawabata, Shin-Ichi Miyatake, Naosuke Nonoguchi, Ry Hiramatsu, Kyoko Iida, Shiro Miyata, Kunio Yokoyama, Atsushi Doi, Yuzo Kuroda, Toshihiko Kuroiwa, Hiroyuki Michiue, Hiroaki Kumada, Mitsunori Kirihata, Yoshio Imahori, Akira Maruhashi, Yoshinori Sakurai, Minoru Suzuki, Shin-Ichiro Masunaga, Koji Ono

    Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine   67 ( 7-8 Suppl )   S15-8   2009.7

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    OBJECTIVE: Since 2002-2007, we applied boron neutron capture therapy (BNCT) to >50 cases of malignant gliomas (MGs) with epithermal neutron irradiations. Recently, we showed the early radiographical improvement of malignant glioma patients by our modified BNCT, with simultaneous use of BPA (borono-phenylalanine) and BSH (sodium borocaptate). In this time, we focused on the survival benefit from BNCT for the newly diagnosed glioblastoma patients. METHODS: BNCT group including 21 newly histological confirmed glioblastoma patients treated with surgical removal followed by BNCT in Osaka Medical College during 2002-2006 period. Ten patients were treated with BNCT only, and in the other 11 patients, 20-30 Gy fractionated external beam X-ray irradiation therapy (XRT) was performed after BNCT. No chemotherapy was administered until tumor progression was observed. RESULTS: Treatments were well tolerated. Any kind of acute systemic or local severe toxicity were not demonstrated. Mean over all survival of the patients treated by BNCT was 20.7 and the median was 15.6 months with 2-years survival of 25%. Stratification by RPA criteria showed 6, 6, 8 and 1 patients, respectively, in classes III-VI. Three patients out of six in class III and one out of eight in class V are alive at the end point of this study. All the patients in classes IV and VI died. Median survival time for the BNCT group compared to the RTOG database was as follows: 20.6 months vs. 17.9 months for class III; 16.9 months vs. 11.1 months for class IV; 13.2 months vs. 8.9 months for class V. CONCLUSION: The RTOG RPA prognostic criteria were helpful in establishing which class of glioma patients could potentially benefit from BNCT. BNCT showed a survival benefit in all of the RPA classes of the RTOG database not only for the good prognosis group.

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  • Survival benefit of boron neutron capture therapy for recurrent malignant gliomas. Reviewed International journal

    Shin-Ichi Miyatake, Shinji Kawabata, Kunio Yokoyama, Toshihiko Kuroiwa, Hiroyuki Michiue, Yoshinori Sakurai, Hiroaki Kumada, Minoru Suzuki, Akira Maruhashi, Mitsunori Kirihata, Koji Onoc

    Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine   67 ( 7-8 Suppl )   S22-4   2009.7

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    We have applied boron neutron capture therapy (BNCT) to malignant brain tumors. Here we evaluated the survival benefit of BNCT for recurrent malignant glioma (MG). Since 2002, we have treated 22 cases of recurrent MG with BNCT. Survival time was analyzed with special reference to recursive partitioning analysis (RPA) classification, by Carson et al. Median survival times (MSTs) after BNCT for all patients and for glioblastoma as on-study histology at recurrence was 10.8 months (n=22; 95% CI, 7.3-12.8 months) and 9.6 months (n=19; 95% CI, 6.9-11.4 months), respectively. In our study, MST for the high-risk RPA classes was 9.1 months (n=11; 95% CI, 4.4-11.0 months). By contrast, the original journal data showed that the MST of the same RPA classes was 4.4 months (n=129; 95% CI, 3.6-5.4 months). BNCT showed a survival benefit for recurrent MG, especially in the high-risk group.

    DOI: 10.1016/j.apradiso.2009.03.032

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  • Delivery of sodium borocaptate to glioma cells using immunoliposome conjugated with anti-EGFR antibodies by ZZ-His. Reviewed International journal

    Bin Feng, Kazuhito Tomizawa, Hiroyuki Michiue, Shin-ichi Miyatake, Xiao-Jian Han, Atsushi Fujimura, Masaharu Seno, Mitsunori Kirihata, Hideki Matsui

    Biomaterials   30 ( 9 )   1746 - 55   2009.3

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    Nanoparticles are effective of delivering cargo into cells. Here, sodium borocaptate (BSH) was encapsulated in liposomes composed of nickel lipid, and anti-epidermal growth factor receptor (EGFR) antibodies were conjugated to the liposomes using the antibody affinity motif of protein A (ZZ) as an adaptor (immunoliposomes). The immunoliposomes were used to deliver BSH into EGFR-overexpressing glioma cells. Immunohistochemical analysis using an anti-BSH monoclonal antibody revealed that BSH was delivered effectively into the cells but not into EGFR-deficient glioma or primary astrocytes. In an animal model of brain tumors, both the liposomes and the BSH were only observed in the tumor. Moreover, the efficiency of (10)B's delivery into glioma cells was confirmed by inductively coupled plasma-atomic emission spectrometry (ICP-AES) both in vitro and in vivo. The results suggest that this system utilizing immunoliposomes provides an effective means of delivering (10)B into glioma cells in boron neutron capture therapy (BNCT).

    DOI: 10.1016/j.biomaterials.2008.12.010

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  • Protein Transduction therapyを用いた新規siRNA導入システムの開発

    道上 宏之, 黒住 和彦, 市川 智継, Dowdy S., 伊達 勲, 松井 秀樹, 富澤 一仁

    日本生理学雑誌   71 ( 3 )   151 - 151   2009.3

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  • Survival benefit of Boron neutron capture therapy for recurrent malignant gliomas. Reviewed International journal

    Shin-Ichi Miyatake, Shinji Kawabata, Kunio Yokoyama, Toshihiko Kuroiwa, Hiroyuki Michiue, Yoshinori Sakurai, Hiroaki Kumada, Minoru Suzuki, Akira Maruhashi, Mitsunori Kirihata, Koji Ono

    Journal of neuro-oncology   91 ( 2 )   199 - 206   2009.1

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    We have applied boron neutron capture therapy (BNCT) to malignant brain tumors. Here we evaluated the survival benefit of BNCT for recurrent malignant glioma (MG). Since 2002, we have treated 22 cases of recurrent MG with BNCT. Survival time was analyzed with special reference to recursive partitioning analysis (RPA) classification, by Carson et al. (J Clin Oncol 25:2601-2606, 2007). Median survival times (MSTs) after BNCT for all patients and for glioblastoma as on-study histology at recurrence was 10.8 months (n = 22; 95% CI, 7.3-12.8 months) and 9.6 months (n = 19; 95% CI, 6.9-11.4 months), respectively. In our study, MST for the high-risk RPA classes was 9.1 months (n = 11; 95% CI, 4.4-11.0 months). By contrast, the original journal data showed that the MST of the same RPA classes was 4.4 months (n = 129; 95% CI, 3.6-5.4 months). BNCT showed a survival benefit for recurrent MG, especially in the high-risk group.

    DOI: 10.1007/s11060-008-9699-x

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  • Boron neutron capture therapy for newly diagnosed glioblastoma. Reviewed International journal

    Shinji Kawabata, Shin-Ichi Miyatake, Toshihiko Kuroiwa, Kunio Yokoyama, Atsushi Doi, Kyoko Iida, Shiro Miyata, Naosuke Nonoguchi, Hiroyuki Michiue, Masatsugu Takahashi, Taisuke Inomata, Yoshio Imahori, Mitsunori Kirihata, Yoshinori Sakurai, Akira Maruhashi, Hiroaki Kumada, Koji Ono

    Journal of radiation research   50 ( 1 )   51 - 60   2009.1

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    We evaluate the clinical results of a form of tumor selective particle radiation known as boron neutron capture therapy (BNCT) for newly-diagnosed glioblastoma (NDGB) patients, especially in combination with X-ray treatment (XRT). Between 2002 and 2006, we treated 21 patients of NDGB with BNCT utilizing sodium borocaptate and boronophenylalanine simultaneously. The first 10 were treated with only BNCT (protocol 1), and the last 11 were treated with BNCT followed by XRT of 20 to 30 Gy (protocol 2) to reduce the possibility of local tumor recurrence. No chemotherapy was applied until tumor progression was observed. The patients treated with BNCT (protocol 1 plus 2) showed a significant survival prolongation compared with the institutional historical controls. BNCT also showed favorable results in correspondence with the RTOG- and EORTC-RPA subclasses. The median survival time (MST) was 15.6 months for protocols 1 and 2 together. For protocol 2, the MST was 23.5 months. The main causes of death were cerebrospinal fluid dissemination as well as local recurrence. Our modified BNCT protocol showed favorable results of patients with NDGB not only for those with good prognoses but also for those with poor prognoses.

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  • MICE OVEREXPRESSING DOMINANT NEGATIVE Cdk5 IN THE PANCREATIC BETA CELLS SHOW THE DIABETES MELLITUS Reviewed

    Yoshihiro Ohtani, Kazuhito Tomizawa, Toshio Ohshima, Hiroyuki Michiue, Teiichi Nishiki, Iori Ohmori, Hideki Matsui

    JOURNAL OF PHYSIOLOGICAL SCIENCES   59   532 - 532   2009

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  • 悪性神経膠腫新規診断例におけるホウ素中性子捕捉療法の治療成績

    川端 信司, 宮武 伸一, 横山 邦生, 野々口 直助, 宮田 至朗, 黒岩 敏彦, 道上 宏之, 今堀 良夫, 切畑 光統, 小野 公二

    日本脳神経外科学会総会CD-ROM抄録集   67回   3G - 03   2008.10

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  • がんに対する放射線治療の現状と展望 再発悪性神経膠腫に対する硼素中性子捕捉療法 自験22例の検討

    川端 信司, 宮武 伸一, 横山 邦生, 野々口 直助, 宮田 至朗, 黒岩 敏彦, 道上 宏之, 小野 公二

    日本癌治療学会誌   43 ( 2 )   267 - 267   2008.10

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  • 硼素中性子捕捉療法は再発悪性グリオーマの生命予後改善に貢献しているか?

    宮武 伸一, 川端 信司, 横山 邦生, 黒岩 敏彦, 道上 宏之, 桜井 良憲, 鈴木 実, 丸橋 晃, 切畑 光統, 小野 公二

    日本脳神経外科学会総会CD-ROM抄録集   67回   3G - 04   2008.10

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  • Development of bionanocapsules targeting brain tumors Reviewed International journal

    Yumi Tsutsui, Kazuhito Tomizawa, Mana Nagita, Hiroyuki Michiue, Tei-ichi Nishiki, Iori Ohmori, Masaharu Seno, Hideki Matsui

    JOURNAL OF CONTROLLED RELEASE   122 ( 2 )   159 - 164   2007.9

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    Bionanocapsules (BNCs) are hollow nanoparticles that are composed of L protein (the hepatitis B virus surface antigen) and show specific affinity for human hepatocytes. The pre-S1 peptide displayed on the surface of BNCs is the specific ligand for binding to the receptor on human hepatocytes. Therefore, BNCs are not delivered to other tissues, such as the brain. The aim of the present study was to develop a novel drug delivery system (DIDS) targeting brain tumors using BNCs that selectively targeted brain tumors. Epidermal growth factor receptor (EGFR), especially a constitutively active genomic sequence deletion variant of EGFR (EGFRvIII), is overexpressed in human glioblastoma. In the present study, we replaced the pre-S1 peptide with the antibody affinity motif of protein A and made hybrid BNCs conjugated with anti-human EGFR antibody recognizing EGFRvIII. The hybrid BNCs were efficiently delivered to glioma cells but not normal glial cells. Moreover, we confirmed the specific delivery of the hybrid BNCs to brain tumors in an in vivo brain tumor model. These results suggest that this new approach using BNCs is a promising system for brain tumor-targeted drug delivery. (C) 2007 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.jconrel.2007.06.019

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  • 蛋白導入システム"Protein Transduction System"を利用したプロテインセラピーの発展と現状について 悪性脳腫瘍に対する蛋白導入法の利用を中心に

    道上 宏之, 富澤 一仁, 魏 范研, 松下 正之, 陸 雲飛, 市川 智継, 田宮 隆, 松井 秀樹, 伊達 勲

    岡山医学会雑誌   118 ( 3 )   205 - 208   2007.1

  • Ubiquitination-resistant p53 protein transduction therapy facilitates anti-cancer effect on the growth of human malignant glioma cells. Reviewed International journal

    Hiroyuki Michiue, Kazuhito Tomizawa, Masayuki Matsushita, Takashi Tamiya, Yun-Fei Lu, Tomotsugu Ichikawa, Isao Date, Hideki Matsui

    FEBS letters   579 ( 18 )   3965 - 9   2005.7

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    Protein transduction therapy using poly-arginine can deliver the bioactive p53 protein into cancer cells and inhibits the proliferation of the cells. However, one disadvantage of such therapy is the short intracellular half-life of the delivered protein. Here, we generated mutant proteins in which multiple lysine residues in the C-terminal were substituted by arginines. The mutant proteins were effectively delivered in glioma cells and were resistant to Mdm2-mediated ubiquitination. Moreover, the mutant proteins displayed higher transcription regulatory activity and powerful inhibition of the proliferation of glioma cells. These results suggest that ubiquitination-resistant p53 protein therapy may become a new effective cancer therapy.

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  • The NH2 terminus of influenza virus hemagglutinin-2 subunit peptides enhances the antitumor potency of polyarginine-mediated p53 protein transduction. Reviewed International journal

    Hiroyuki Michiue, Kazuhito Tomizawa, Fan-Yan Wei, Masayuki Matsushita, Yun-Fei Lu, Tomotsugu Ichikawa, Takashi Tamiya, Isao Date, Hideki Matsui

    The Journal of biological chemistry   280 ( 9 )   8285 - 9   2005.3

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    Protein transduction therapy is a newly developing method that allows proteins, peptides, and biologically active compounds to penetrate across the plasma membrane by being fused with cell-penetrating peptides such as polyarginine. Polyarginine-fused p53 protein penetrates across the plasma membrane of cancer cells and inhibits the growth of the cells. However, the protein is often entrapped inside macropinosomes in the cytoplasm. Therefore, high dose concentrations of the protein are needed for it to function effectively. To overcome this problem, in the present study, polyarginine-fused p53 was linked with the NH(2)-terminal domain of influenza virus hemagglutinin-2 subunit (HA2), which is a pH-dependent fusogenic peptide that induces the lysis of membranes at low pH levels. The protein was capable of efficiently translocating into the nucleus of glioma cells and induced p21(WAF1) transcriptional activity more effectively than did polyarginine-fused p53 protein. Moreover, low concentrations of the protein significantly inhibited the growth of cancer cells. These results suggest that protein transduction therapy using polyarginine and HA2 may be useful as a method for cancer therapy.

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  • The relationship between peritumoral brain edema and the expression of vascular endothelial growth factor and its receptors in intracranial meningiomas. Reviewed International journal

    Shinji Otsuka, Takashi Tamiya, Yasuhiro Ono, Hiroyuki Michiue, Kazuhiko Kurozumi, Shigeru Daido, Hirokazu Kambara, Isao Date, Takashi Ohmoto

    Journal of neuro-oncology   70 ( 3 )   349 - 57   2004.12

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    We examined the radiological and histological features of, and the influences of the expression of VEGF and its two major receptors, Flt-1 and Flk-1, on the development of peritumoral brain edema (PTBE) in patients with intracranial meningiomas. The expressions of VEGF and VEGF receptors in the immunohistochemical study were analyzed in relation to several factors, including tumor size, location, vascularity, and blood supply, as seen on digital subtraction angiographic studies. The edema volume (P = 0.0003) and edema index (P < 0.0001) had a significantly positive relation to VEGF expression. The positivity of Flt-1 and Flk-1 was mainly observed in tumor vessels; 44 cases (37.2%) were positive for the Flt-1 antibody and 37 cases (31.4%) for the Flk-1 antibody. The mean value of the edema index of the positive-Flt-1 group (5.220 +/- 11.586) was significantly higher than that of the negative-Flt-1 group (1.782 +/- 2.559) (P < 0.0001). The mean value of the edema index of the positive-Flk-1 group (3.925 +/- 5.870) was slightly higher than that of the negative-Flk-1 group (2.671 +/- 8.136) (P < 0.0001). Our data suggest that the expressions of VEGF and VEGF receptors positively relate to each other and to the formation of PTBE in patients with meningiomas.

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  • エンドソームリリーシングペプチドを利用したp53蛋白質導入法による悪性腫瘍抑制効果

    道上 宏之, 富澤 一仁, 魏 范研, 松下 正之, 陸 雲飛, 市川 智継, 田宮 隆, 伊達 勲, 松井 秀樹

    日本癌学会総会記事   63回   511 - 511   2004.9

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  • Photo-acceleration of protein release from endosome in the protein transduction system. Reviewed International journal

    Masayuki Matsushita, Hirofumi Noguchi, Yun-Fei Lu, Kazuhito Tomizawa, Hiroyuki Michiue, Sheng-Tian Li, Kenzo Hirose, Susan Bonner-Weir, Hideki Matsui

    FEBS letters   572 ( 1-3 )   221 - 6   2004.8

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    The protein transduction system has been employed for delivery of bioactive proteins into cells via an endocytotic mechanism. However, trapping of endocytosed proteins in the endosome may significantly attenuate biological actions in cells. The present investigation demonstrated that endosomal release of transduced protein could be artificially accelerated by exposure to fluorescent light. Exposure to light at 480 nm stimulated endosomal release of transduced FITC-11 arginine-protein transduction domain (11R-PTD), TAT-PTD and Antennapedia-PTD. Moreover, FITC-11R-p53 protein was released from endosomes following stimulation with light. These data suggest that photo-acceleration is a more efficient strategy in terms of the protein transduction system.

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  • [Rupture of previously documented asymptomatic unruptured aneurysms--aneurysm size: risk factor for aneurysm rupture]. Reviewed

    Masakazu Suga, Yuji Yamamoto, Norio Sunami, Tomoyasu Abe, Hiroyuki Michiue

    No shinkei geka. Neurological surgery   30 ( 6 )   609 - 15   2002.6

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    The natural history of asymptomatic unruptured aneurysms is not clear. We conducted a follow up study of 100 patients (since 1993) with 122 asymptomatic unruptured aneurysms that had not been operated on. We report five patients with previously documented asymptomatic unruptured aneurysms smaller than 10 mm in diameter that subsequently ruptured. Among the 100 patients, five had suffered subarachnoid hemorrhage (SAH) due to rupturing of an aneurysm. Of the 5 cases, 1 was male and 4 were female, with ages ranging from 59-73 years (mean age, 68 years). The aneurysms were on the MCA in 3, on the BA-SCA in 1, on the IC-PC in 1. The maximal diameter of the aneurysms at diagnosis ranged from 4.5 to 8 mm. The period from discovery to SAH was from 4 to 69 months and the cumulative rate of rupture of the aneurysms was 1.5 percent per year. Four of the 5 cases increased in size after the rupture. In our series, 2 of the 5 cases showed enlargement and the development of an aneurysmal bleb in the follow up MRA and 3D-CTA. The present study demonstrates that five asymptomatic unruptured aneurysms less than 10 mm in diameter subsequently ruptured. We ought to seriously consider the assertion published in the New England Journal of Medicine (Dec. 10, 1998), that unruptured aneurysms less than 10 mm in diameter have a very low probability of subsequent rupture.

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  • [A case of hypertrophic cranial pachymeningitis developed skull lesion]. Reviewed

    S Mizumatsu, H Michiue, M Suga, N Sunami, Y Yamamoto

    No to shinkei = Brain and nerve   52 ( 12 )   1103 - 8   2000.12

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    We report a case of hypertrophic cranial pachymeningitis (HCP) developed skull lesion. A 70-year-old male presented with the symptom of left hemiconvulsion. MRI revealed that the enhanced intraosseous mass infiltrated into the the dura and brain parenchyma under the parasagittal region of the right parietal bone. Histological examination revealed chronic inflammation with lymphoplasmacytic infiltrate and fibrosis of both intraosseous mass and dural invasive lesion. Steroid therapy resulted in improvement of clinical symptoms and enhanced lesion of MRI. Three years later, the patient presented with generalized convulsion and weakness of right upper and lower limbs. MRI revealed dural thickening with gadolinium enhancement in the bilateral parasagittal region and falx. Angiography showed occlusion of the superior sagittal sinus. The cause of relapsing symptoms in this patient may have been related to the occlusion of the superior sagittal sinus, due to HCP. We considered that the incipient intraosseous mass resulted from a response of the marrow by destructive progression of chronic inflammation passed through the fracture crack or the cavity of arachnoid granulation.

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MISC

  • Evaluation of reaction between boron cluster BSH and chloroacetyl-modified tripeptides

    藤本翔夢, 井上健, 北松瑞生, 道上宏之

    日本化学会春季年会講演予稿集(Web)   102nd   2022

  • BNCT応用へ向けた即発γ線分析による非観血的生体内ホウ素薬物動態測定技術の開発

    道上宏之, 櫻井良憲, 北松瑞生

    中谷医工計測技術振興財団年報   ( 34 )   2021

  • Developing a tumor-selective boron agent for next generation BNCT

    藤村篤史, 藤村篤史, 井川和代, 植田愛, 渡辺香里, 道上宏之, 市川康明, 古矢修一

    月刊メディカル・サイエンス・ダイジェスト   46 ( 8 )   2020

  • NEW A6K BORON DRUG DELIVERY SYSTEM FOR CLINICAL APPLICATION OF BORON NEUTRON CAPTURE THERAPY (BNCT)

    Hiroyuki Michiue, Asami Fukunaga, Atsushi Fujimura, Kazuyo Igawa, Hideki Matsui, Shuichi Furuya

    NEURO-ONCOLOGY   20   73 - 73   2018.11

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  • 初発膠芽腫に対するホウ素中性子捕捉療法の第II相臨床試験

    川端 信司, 平松 亮, 松下 葉子, 池田 直廉, 古瀬 元雅, 黒岩 敏彦, 小野 公二, 宮武 伸一

    日本癌治療学会学術集会抄録集   56回   P62 - 5   2018.10

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  • CORRELATION BETWEEN PIK3R1MET326ILE MUTATION, CYSTEINE-RICH PROTEIN 61 EXPRESSION AND POOR PROGNOSIS IN GLIOBLASTOMA

    Kentaro Fujii, Yoshihiro Otani, Joji Ishida, Kazuhiko Kurozumi, Tetsuo Oka, Toshihiko Shimizu, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Yuji Matsumoto, Hiroyuki Michiue, Tomotsugu Ichikawa, Isao Date

    NEURO-ONCOLOGY   19   97 - 97   2017.11

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  • Microtubule dynamicsを介したグリオーマの浸潤に関与する遺伝子FGF13の機能解析

    松本悠司, 大谷理浩, 市川智継, 黒住和彦, 藤井謙太郎, 清水俊彦, 冨田祐介, 服部靖彦, 畝田篤仁, 道上宏之, 伊達勲

    日本分子脳神経外科学会プログラム・抄録集   18th   2017

  • PIK3R1 germline mutationはglioblastomaにおけるCCN1発現および予後と相関する

    畝田篤仁, 大谷理浩, 黒住和彦, 藤井謙太郎, 清水俊彦, 冨田祐介, 服部靖彦, 松本悠司, 道上宏之, 市川智継, 伊達勲

    日本脳腫瘍学会プログラム・抄録集   35th   2017

  • グリオーマ浸潤規定遺伝子FGF13の同定と動物モデルを用いた機能解析

    市川智継, 大谷理浩, 黒住和彦, 藤田謙太郎, 清水俊彦, 冨田祐介, 服部靖彦, 畝田篤仁, 松本悠司, 道上宏之, 伊達勲

    日本脳腫瘍学会プログラム・抄録集   35th   2017

  • PIK3R1germline mutationはglioblastoma multiformeにおけるCCN1発現および予後と相関する

    畝田篤仁, 大谷理浩, 黒住和彦, 藤井謙太郎, 清水俊彦, 冨田祐介, 服部靖彦, 松本悠司, 道上宏之, 市川智継, 伊達勲

    日本分子脳神経外科学会プログラム・抄録集   18th   2017

  • Peptide Zipperingを介した新規タンパク質細胞内導入法の検討

    湯浅啓生, 道上宏之, 北松瑞生, 松下博昭, 西木禎一, 松井秀樹

    日本生理学雑誌(Web)   78 ( 1 )   2016

  • 抗うつ薬フルボキサミンを用いた悪性グリオーマ治療法の開発

    道上宏之, 道上宏之, 林佳一郎, 山田浩司, 黒住和彦, 市川智継, 松下博昭, 西木禎一, 松井秀樹

    日本脳腫瘍学会プログラム・抄録集   34th   2016

  • 低酸素安定化ドメインを用いた脳腫瘍治療ペプチドの開発

    山口貴博, 道上宏之, 北松瑞生, 松下博昭, 西木禎一, 松井秀樹

    日本生理学雑誌(Web)   78 ( 1 )   2016

  • 神経伝達物質放出のCa2+センサーDoc2の神経系における局在解析

    岩藤亮太, 藤野加奈子, 西木禎一, 松下博昭, 道上宏之, 高橋正身, 松井秀樹

    日本生理学雑誌(Web)   78 ( 1 )   2016

  • Development of the new boron agent, BSH-peptide, towards clinical application (第53回 日本癌治療学会学術集会Educational Book) -- (教育シンポジウム 医工連携と癌治療)

    松井 秀樹, 道上 宏之

    日本癌治療学会誌 = The journal of Japan Society of Clinical Oncology   50 ( 2 )   437 - 442   2015.9

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    Other Link: http://search.jamas.or.jp/link/ui/2015406906

  • 悪性黒色腫に対する抗腫瘍p53 Fragment Peptideスクリーニングと経皮的導入による治療効果の検討

    澄田憲祐, 道上宏之, 北松瑞生, 松下博昭, 西木禎一, 松井秀樹

    日本生理学雑誌   77 ( 1 (Web) )   2015

  • 抗血管新生療法に対する脳腫瘍幹細胞由来腫瘍血管の反応

    道上宏之, 中山大輝, 松下博昭, 西木禎一, 松井秀樹

    日本脳腫瘍学会プログラム・抄録集   33rd   2015

  • ANNEXIN A2 REGULATES ANGIOGENESIS AND INVASION PHENOTYPES OF MALIGNANT GLIOMA

    Tomotsugu Ichikawa, Manabu Onishi, Kazuhiko Kurozumi, Tomoko Maruo, Satoshi Inoue, Hiroyuki Michiue, Koichi Yoshida, Kentaro Fuji, Joji Ishida, Yosuke Shimazu, Tetsuo Oka, E. A. Chiocca, Isao Date

    NEURO-ONCOLOGY   16   2014.7

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    DOI: 10.1093/neuonc/nou206.35

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  • THE INTEGRIN ANTAGONIST CILENGITIDE AUGUMENTS ANTITUMOR EFFICACY OF VASCULOSTATIN-EXPRESSING ONCOLYTIC VIRAL THERAPY

    Kentaro Fujii, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Koichi Yoshida, Manabu Onishi, Hiroyuki Michiue, E. Antonio Chiocca, Balveen Kaur, Isao Date

    JOURNAL OF GENE MEDICINE   16 ( 7-8 )   264 - 264   2014.7

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  • 脳血液関門通過可能なアクチン重合抑制薬による膠芽腫に対する抗浸潤効果の検討

    道上宏之, 林桂一郎, 山田浩司, 中山大輝, 黒住和彦, 市川智継, 松下博昭, 西木禎一, 竹居孝二, 富澤一仁, 松井秀樹

    日本脳腫瘍学会プログラム・抄録集   32nd   2014

  • ホウ素中性子捕捉療法に用いるPETイメージング可能なBSH-ペプチドの合成

    井口佳哉, 道上宏之, 北松瑞生, 大守伊織, 西木禎一, 松井秀樹

    日本化学会講演予稿集   94th ( 3 )   2014

  • Establishment of hair-growth promoting peptides : an example of Trans-Dermal Approach

    Fragrance journal   41 ( 11 )   23 - 27   2013.11

  • ヘテロ二量体化ロイシンジッパーによる緑色蛍光タンパク質の細胞内輸送

    出口宝, 北松瑞生, 中島真実, 大槻高史, 道上宏之

    日本化学会講演予稿集   93rd ( 3 )   2013

  • 神経伝達物質放出を司るSNARE複合体からのCa2+センサーシナプトタグミンの解離

    鈴木孝一朗, 増本年男, 大守伊織, 道上宏之, 西木禎一, 松井秀樹

    日本生理学雑誌   74 ( 2 )   2012

  • INHIBITION OF GLIOMA PROLIFERATION BY MODIFIED P53 PROTEIN FUSED WITH PROTEIN TRANSDUCTION DOMAINS

    Hiroyuki Michiue, Tomotsugu Ichikawa, Kazuhito Tomizawa, Kazuhiko Kurozumi, Hideki Matsui, Isao Date

    NEURO-ONCOLOGY   11 ( 6 )   957 - 957   2009.12

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  • A CONSTITUTIVELY ACTIVE CALCINEURIN ENCODED BY AN INTRON-RETAINING MESSENGER RNA IS REQUIRED FOR HAIR FOLLICLE DEVELOPMENT

    Atsushi Fujimura, Kazuhito Tomizawa, Hiroyuki Michiue, Tei-ichi Nishiki, Iori Ohmori, Hideki Matsui

    JOURNAL OF PHYSIOLOGICAL SCIENCES   59   244 - 244   2009

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  • DELIVERY OF SODIUM BOROCAPTATE TO GLIOMA CELLS USING IMMUNOLIPOSOME CONJUGATED WITH ANTI-EGFR ANTIBODIES BY ZZ-HIS

    Bin Feng, Kazuhito Tomizawa, Hiroyuki Michiue, Xiao-Jian Han, Atsushi Fujimura, Iori Ohmori, Tei-ichi Nishiki, Hideki Matsui

    JOURNAL OF PHYSIOLOGICAL SCIENCES   59   441 - 441   2009

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  • CAN BORON NEUTRON CAPTURE THERAPY PROLONG THE SURVIVAL OF RECURRENT MALIGNANT GLIOMA PATIENTS?

    S. Miyatake, S. Kawabata, N. Nonoguchi, K. Iida, S. Miyata, K. Yokoyama, T. Kuroiwa, H. Michiue, M. Kirihata, K. Ono

    NEURO-ONCOLOGY   10 ( 6 )   1098 - 1098   2008.12

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  • Direct protein transduction method to cerebral arteries by using 11R: new strategy for the treatment of cerebral vasospasm after subarachnoid haemorrhage

    T. Ogawa, S. Ono, T. Ichikawa, H. Michiue, S. Arimitsu, K. Onoda, K. Tokunaga, K. Sugiu, K. Tomizawa, H. Matsui, I. Date

    CEREBRAL VASOSPASM: NEW STRATEGIES IN RESEARCH AND TREATMENT   104   161 - +   2008

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    Background. Gene transfer with some vectors may be useful for treatmcnt of cerebral vasospasm after subarachnoid haemorrhage (SAH) [2, 3, 6, 10, 12, 13, 19]. However, this method has some safety problems [18]. Previous studies have shown that direct delivery of therapeutic proteins by using protein transduction domain (PTD) may reduce these problems [14, 15]. Here, we examined the transduction efficiency of eleven consecutive arginines (11R), which is one of the most effective PTD 18, 91, into the rat cerebral arteries by using 11R-enhanced-green fluorescent protein (11R-EGFP).
    Method. 11R-EGFP or EGFP was injected into the cisterna magna of the rats with SAH. SAH model was made by autologous blood injection. The proteins were injected just after the autologous blood injection in SAH rats. The expression of 11R-EGFP or EGFP was observed by fluorescence microscope.
    Findings. The signal of 11R-EGFP was much stronger than that of EGFP in all the layers of the rat basilar artery (BA). The 11R-EGFP was especially transduced into the tunica media of the basilar artery 2 It after the injection.
    Conclusions. Our results demonstrate that 11R-fused fluorescent protein effectively penetrates into the all layers of the rat BA, and especially into the tunica media.

    DOI: 10.1007/978-3-211-75718-5-31

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  • 新しい脳特異的C dk5アクチベータ(P39^<nck5ai>)のラット脳の発育に伴う局在の変化について

    富澤 一仁, 三宅 孝佳, 道上 宏之, 大沼 英晴, 徳田 雅明, 畠瀬 修, 松井 秀樹

    日本分子生物学会年会プログラム・講演要旨集   19   201 - 201   1996.8

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Presentations

  • Future BNCT strategy based on boron drug development Invited

    Hiroyuki Michiue, M.D. Ph.D

    Okayama University Neutron Therapy Research Center 5th Symposium "Development of New Cancer Treatment Developed by BNCT"  2021.12.10 

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    Event date: 2021.12.10

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

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  • New boron agent with the complex of BSH & peptide DDS

    Hiroyuki Michiue, M.D. Ph.D

    17th Congress on Neutron Capture Therapy  2021.7.10 

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    Event date: 2021.7.10 - 2021.7.11

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  • Boron peptide drug discovery using amphipathic peptides Invited

    Hiroyuki Michiue, M.D. Ph.D

    SYMPOSIUM "Towards a new future for peptides "  2021.3.2 

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    Event date: 2021.3.2

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

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  • Kill cancer with "boron" and "peptides"! Developed a high-performance new boron drug that can be used for cancer treatment and BNCT Invited

    Hiroyuki Michiue, M.D. Ph.D

    Okayama University Press Release  2020.12.17 

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    Event date: 2020.12.17

    Language:Japanese   Presentation type:Media coverage  

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  • "Current status of boron drug development-From basic research to clinical research- Invited

    Hiroyuki Michiue

    2020.8.22 

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    Event date: 2020.8.22

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  • Translational research in hair generation from lab to life Invited

    Hiroyuki Michiue

    National Symposium and Workshop in Anti-Aging Medicine committee  2020.2.8 

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    Event date: 2020.2.7 - 2020.2.9

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  • The role of calcineurin in controlling cell function in hair generation Invited

    Hiroyuki Michiue

    National Symposium and Workshop in Anti-Aging Medicine  2020.2.8 

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  • Efforts to formulate new boron drug formulations using peptide DDS

    Hiroyuki Michiue

    The 3rd Neutron Therapy Research Center Symposium  2019.12.10 

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  • New boron(10B) drugs against GBM Invited

    Hiroyuki Michiue

    SickKids Hospital Reserch meeting organized by the Labatt Brain Tumor Research Centre  2019.11.27 

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    Event date: 2019.11.27

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  • New drug discovery with drug re-positioning system toward GBM treatment

    Hiroyuki Michiue

    the 24th Annual Meeting of the Society for Neuro-Oncology  2019.11.22 

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    Event date: 2019.11.21 - 2019.11.24

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  • New peptide Drug Delivery System with BSH toward future BNCT clinical application

    H. Michiue, A. Fukunaga, M. Kitamatsu, N. Kondo, Y. Sakurai, A. Fujimura, K. Igawa, H. Matsui, S. Furuya

    10th Young Researchers BNCT meeting  2019.9.26 

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    Event date: 2019.9.26 - 2019.9.29

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  • The cell biological evaluation with Nagoya University BNCT system

    H. Michiue, K. Igawa, S. Furuya, Y. Ichikawa, Y. Yoshihasi, A. Uritani, K. Watanabe, Y. Kiyanagi, K. Tsuchida

    The 16th Congress on Neutron Capture Therapy  2019.9.7 

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    Event date: 2019.9.7 - 2019.9.8

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  • New melanoma multidisciplinary therapy with BNCT in Okayama University Invited

    H. Michiue

    2nd synposium of Neutron Therapy Research Center in Okayama University  2018.12.12 

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    Event date: 2018.12.12

    Language:Japanese   Presentation type:Symposium, workshop panel (nominated)  

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  • The novel anti-angiogenic treatment against tumor vasculature derived from glioma stem cells

    H. Michiue, H. Nakayama, K. Tatekabe, K. Kurozumi, K. Fujii, H. Matsui

    The 36th Annual Meeting of the Japanese Society of Neuro Oncology  2018.12.2 

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    Event date: 2018.12.2 - 2018.12.4

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  • New A6k boron drug delivery system for clinical application

    H. Michiue, A. Fukunaga, A. Fujimura, K. Igawa, H. Matsui, S. Furuya

    2018 Annual Meeting and Education Day of the Society for Neuro-Oncology.  2018.11.17 

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    Event date: 2018.11.15 - 2018.11.18

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  • New self-assembling peptide Drug Delivery System with BSH toward clinical application

    Hiroyuki Michiue, Asami Fukunaga, Atsushi Fujimura, Kazuyo Igawa, Shuichi Furuya, Hideki Matsui

    18th International Congress on Neutron Capture Therapy  2018.10.28 

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    Event date: 2018.10.27 - 2018.11.1

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  • New multidisciplinary treatment with Boron Neutron Capture Therapy (BNCT) against melanoma Invited

    H Michiue

    The 77th Annual Meeting of the Japanese Cancer Association  2018.9.28 

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    Event date: 2018.9.27 - 2018.9.29

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  • The BNCT challenge of Neutron Therapy Research Center in Okayama University Invited

    H. Michiue

    BNCT synposium in Nakamozu  2018.9.6 

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    Event date: 2018.9.6

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  • New boron development with peptide Drug Delivery System

    H. Michiue, A. Fukunaga, M. Kitamastu, N. Kondo, Y. Sakurai, A. Fujimura, K. Igawa, H. Mastui, S. Furuya

    The;th Congress on;Neutron Capture Therapy  2018.9.1 

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    Event date: 2018.9.1 - 2018.9.2

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  • 再発メラノーマに対するBNCTを含めた新規集学的治療の取り組み

    道上 宏之

    第22回日本がん免疫学会総会  2018.8.2 

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    Event date: 2018.8.1 - 2018.8.3

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  • メラノーマ治療におけるホウ素中性子捕捉療法(BNCT) ~BNCTの基礎より最新の研究まで~ Invited

    道上 宏之

    第6回岡山メラノーマ治療研究会  2018.5.22 

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    Event date: 2018.5.22

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  • The function of brain tumor stem cell Invited

    H. Michiue

    The 95th Annual Meeting of the Physiological Society of Japan  2018.3.28 

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    Event date: 2018.3.28 - 2018.3.30

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  • 現状の標準治療と課題、BNCTに対する期待 Invited

    道上 宏之

    第1回中性子医療研究センターシンポジウム  2017.12.5 

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  • Anti-depressant, SSRI found by drug repositioning system, blocked glioblastoma invasion with targeting to inhibit actin polymerization

    Hiroyuki Michiue, Keiichiro Hayashi, Atsushi Fujimura, Hiroaki Matsushita, Tei-ichi Nishiki, Hideki Matsui

    22ND ANNUAL SCIENTIFIC MEETING AND EDUCATION DAY OF THE SOCIETY FOR NEURO-ONCOLOGY  2017.11.18 

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    Event date: 2017.11.16 - 2017.11.19

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  • The next generation Boron agents with BSH fused Cell Penetrating Peptide toward clinical application

    Hiroyuki Michiue, Mizuki Kitamatsu, Natsuko Kondo, Yoshinori Sakurai, Hideki Matsui

    9th Young Researchers' BNCT Meeting  2017.11.14 

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    Event date: 2017.11.13 - 2017.11.15

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  • New boron drug development and new cancer therapy with BNCT Invited

    H. Michiuew

    Symposium of metal bioscience 2017  2017.10.14 

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    Event date: 2017.10.13 - 2017.10.14

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  • :細胞膜通過ペプチド(CPP)を用いた新規ホウ素薬剤開発の展望

    道上宏之, 北松瑞生, 櫻井良憲, 近藤夏子, 藤村篤史, 松下博昭, 西木禎一, 市川康明, 松井秀樹

    第14回日本中性子捕捉療法学会学術大会  2017.9.29 

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    Event date: 2017.9.29 - 2017.9.30

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  • What is BNCT and What is Neutron Therapy Research Center in Okayama University

    H. Michiue

    2017.8.28 

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  • The peptide transdermal therapy against melanoma with a novel p53 peptide screened from p53-overlapping fragment peptide library

    Hiroyuki Michiue, Mizuki Kitamatsu, Kensuke Sumita Hiroaki, Matsusita Tei-ichi Nishiki Hideki Matsui

    The 25th America Peptide Symposium  2017.6.19 

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    Event date: 2017.6.17 - 2017.6.22

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Industrial property rights

  • グルコース結合ホウ素薬剤

    道上 宏之, 高口 豊

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    Applicant:国立大学法人 岡山大学

    Application no:特願2021-046789  Date applied:2021.3.22

    Announcement no:特開2021-152000  Date announced:2021.9.30

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  • ホウ素含有化合物およびそれを含む薬剤

    北松 瑞生, 副島 哲朗, 山形 尚紀, 道上 宏之, 大槻 高史

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    Applicant:学校法人近畿大学

    Application no:特願2019-196902  Date applied:2019.10.30

    Announcement no:特開2020-117479  Date announced:2020.8.6

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  • ホウ素中性子捕捉療法のための新規BSH複合体

    松井 秀樹, 古矢 修一, 道上 宏之, 加来田 博貴, 竹内 康明

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    Applicant:国立大学法人 岡山大学

    Application no:特願2018-553029  Date applied:2017.11.24

    Patent/Registration no:特許第6548060号  Date registered:2019.7.5 

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  • 血管新生阻害薬

    道上 宏之, 松井 秀樹, 立壁 賢

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    Applicant:国立大学法人 岡山大学

    Application no:特願2017-065166  Date applied:2017.3.29

    Announcement no:特開2017-178943  Date announced:2017.10.5

    Patent/Registration no:特許第6952980号  Date registered:2021.10.1 

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  • 細胞内導入機能を有するホウ素を含むデンドリマー

    道上 宏之, 福永 麻美, 松井 秀樹, 高口 豊, 田嶋 智之, 石本 寛伍, 大津 裕貴

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    Applicant:国立大学法人 岡山大学

    Application no:特願2017-038462  Date applied:2017.3.1

    Announcement no:特開2018-145107  Date announced:2018.9.20

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  • 細胞膜透過型ホウ素ペプチド

    道上 宏之, 松井 秀樹, 北松 瑞生, 王 飛霏, 富澤 一仁

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    Applicant:国立大学法人 岡山大学

    Application no:特願2016-140473  Date applied:2016.7.15

    Announcement no:特開2016-204378  Date announced:2016.12.8

    Patent/Registration no:特許第6320469号  Date registered:2018.4.13 

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  • 電子書籍表示装置、電子書籍表示方法、及び、電子書籍表示システム

    道上 徹

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    Applicant:京セラドキュメントソリューションズ株式会社

    Application no:特願2015-193130  Date applied:2015.9.30

    Announcement no:特開2017-068012  Date announced:2017.4.6

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  • PET用ホウ素化合物

    道上 宏之, 井口 佳哉, 松井 秀樹, 富澤 一仁, 北松 瑞生

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    Applicant:国立大学法人 岡山大学

    Application no:特願2014-144412  Date applied:2014.7.14

    Announcement no:特開2016-020316  Date announced:2016.2.4

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  • 抗がん剤

    道上 宏之, 松井 秀樹, 林 桂一郎, 竹居 孝二, 山田 浩司, 宮地 弘幸, 浅井 章良

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    Applicant:国立大学法人 岡山大学

    Application no:特願2012-263317  Date applied:2012.11.30

    Announcement no:特開2014-108930  Date announced:2014.6.12

    Patent/Registration no:特許第5922563号  Date registered:2016.4.22 

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  • 新規ペプチド複合体、そのハイブリッド複合体およびその用途

    北松 瑞生, 道上 宏之, 王 飛霏, 中島 真実, 大槻 高史

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    Applicant:国立大学法人 岡山大学

    Application no:JP2012076654  Date applied:2012.10.16

    Publication no:WO2013-061818  Date published:201352

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  • 細胞導入ペプチドと皮膚導入促進剤とを組み合わせた皮膚導入システムおよび美白剤

    松井 秀樹, 道上 宏之, 石川 早苗

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    Applicant:国立大学法人 岡山大学

    Application no:特願2013-531360  Date applied:2012.8.29

    Patent/Registration no:特許第5940542号  Date registered:2016.5.27 

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  • 抗浸潤薬の新規スクリーニング法

    山田 浩司, 道上 宏之, 竹居 孝二, 松井 秀樹, 浅井 章良

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    Applicant:国立大学法人 岡山大学

    Application no:特願2012-137489  Date applied:2012.6.19

    Announcement no:特開2014-002043  Date announced:2014.1.9

    Patent/Registration no:特許第5806168号  Date registered:2015.9.11 

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Awards

  • 15th International Congress of Radiation Research Excellent Poster Award

    2015.5   15th International Congress of Radiation Research   The Development of BSH Fused Cell-penetrating Peptide towards Clinical Application

    Hiroyuki Michiue, Yoshiya Iguchi, Mizuki Kitamatsu, Hiroaki Matsushita, Tei-ichi Nishiki, Hideki Matsui

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  • Yuuki Award in Okayama Medical Association

    2014.6   Okayama Medical Association   The acceleration of boron neutron capture therapy using multi-linked mercaptoundecahydrododecaborate (BSH) fused cell-penetrating peptide.

    Hiroyuki Michiue

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  • Research Award in The Physiological Society of Japan in CHUGOKU

    2010.11   The Physiological Society of Japan   Novel siRNA delivery system with protein transduction method

    Hiroyuki Michiue

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  • Yamada Prize in Okayama Medical Association

    2006.6   Okayama Medical Association  

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  • President's Award of the Economic Federation of CHUGOKU

    2005.1   The 3rd Campus Venture Grand Prix in CHUGOKU  

    Hiroyuki Michiue, Fan-Yan Wei, Rika Fujita

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Research Projects

  • BNCT併用メラノーマ複合免疫療法へ向けた前臨床探索研究と新規ホウ素薬剤開発

    Grant number:20K08652  2020.04 - 2023.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    山崎 修, 道上 宏之

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

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  • 難治性消化器がんを標的としたホウ素中性子捕捉療法の開発と効果予測マーカーの探索

    Grant number:19K09122  2019.04 - 2022.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    寺石 文則, 藤原 俊義, 道上 宏之, 重安 邦俊

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    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

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  • 細胞内局在を標的とした新規ホウ素薬剤の開発とBNCT

    Grant number:18K07324  2018.04 - 2021.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    市川 康明, 道上 宏之

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

    次世代のがん治療であるホウ素中性子捕捉療法(Boron Neutron Capture Therapy, BNCT)は、ホウ素を取込ませたがん細胞に中性子線を照射し、ホウ素と中性子の核反応により細胞を破壊する。BNCTの中性子源としては1950年代から利用されてきた原子炉に代わり、中性子発生装置の一部が企業治験段階に進み、今後のBNCTの成功の可否はホウ素薬剤に大きく依存する。BNCTにより発生した数マイクロメートル飛程の2次粒子は、腫瘍細胞へ細胞障害を誘導する際に、ホウ素薬剤が細胞のどの位置(細胞外膜、細胞質、核膜、ミトコンドリア、核内など)に局在するかによりその効果が異なると、これまで報告してきた。現在治験中薬剤BPA(ホウ素フェニルアラニン)はアミノ酸フェニルアラニンに1個のホウ素が結合したホウ素アミノ酸誘導体である。腫瘍細胞は、正常細胞と比較して一般的にアミノ酸代謝が亢進しており、様々なアミノ酸取り込みが高いとされている。同様にフェニルアラニンの誘導体であるBPAも腫瘍に特異的に取り込まれ、さらに正常細胞と比較して腫瘍細胞にフェニルアラニンの取り込みを行うアミノ酸トランスポーターLAT1が強発現していることより、BPAは腫瘍特異的なホウ素分子標的薬とも言える。アミノ酸を標的としたホウ素薬剤は非常に素晴らしい取り込み能を示している一方で、腫瘍細胞の中には、一部取り込み能の低いものも存在し、BNCT後の再発の原因となっている。我々は、これまで細胞内導入困難とされてきたホウ素12個からなる正20面体構造を有するホウ素立体分子BSH(Na2B12H11SH)をアミノ酸・ペプチド修飾することにより細胞内導入することに成功した。本薬剤を用いて、中性子照射により生じる殺細胞効果を細胞内のホウ素薬剤の細胞内小器官の局在の見地より評価し、今後のホウ素薬剤開発への発展へ繋げる。

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  • ドラッグリポジショニングを用いた非VEGF経路に対する新規抗血管新生薬開発

    Grant number:18K08944  2018.04 - 2021.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    道上 宏之

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    現在の悪性脳腫瘍治療では外科手術、放射線療法、化学療法を用いた集学的治療である。最も悪性度の高い膠芽腫では治療技術の発達向上にもかかわらず、平均生存期間約1年数か月、5年生存率数%と極めて予後不良である。また、悪性腫瘍への抗血管新生療法の概念は古く1970年代より提唱されており、抗ヒトVEGFモノクローナル抗体のベバシズマブ(アバスチン; 中外製薬)が、国内外において切除不能進行・再発大腸癌に対する標準治療と認可された後、卵巣癌、非小細胞肺癌、子宮頸癌等に対しても承認されている。悪性脳腫瘍(膠芽腫)に対する抗血管新生薬を用いた代表的な北米臨床試験AVAglio studyにて、標準治療に抗血管新生薬アバスチン(ベバシズマブ)追加群に生存期間延長は認めなかった。そこで我々は、膠芽腫の抗血管新生療法抵抗性の原因の一つが、がん血管新生阻害薬の多くの作用点がVEGFR/VEGF-R経路にあることに着目した。言うまでも無く、VEGF経路は腫瘍血管新生において最も中心的役割果たす代表的な経路である。そこで我々は、「悪性脳腫瘍において、VEGFは腫瘍血管形成において重要な経路であるが、VEGF経路が阻害されても非VEGF経路により腫瘍血管形成が代償される機構が存在し、腫瘍血管は維持され、そのためアバスチン単独では抗血管新生治療による予後延長が得られない」との、仮説を立て実験を行った。抗血管新生薬を用いた抗血管新生療法は、理論として問題なく、抑制する経路が腫瘍により異なるのではないかと考えられた。本プロジェクトにより、VEGF非依存的な血管新生の経路を同定し、ドラッグリポジショニングに基づく阻害薬発見を行う予定である。

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  • Clinical trial of boron neutron capture therapy with the combination of successive bevacizumab treatments for recurrent malignant gliomas

    Grant number:17K10877  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    宮武 伸一, 近藤 夏子, 川端 信司, 道上 宏之, 古瀬 元雅

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    Grant amount:\4680000 ( Direct expense: \3600000 、 Indirect expense:\1080000 )

    再発悪性グリオーマの予後は不良であり、標準治療は存在しない。ことに予後不良再発群(J Clin Oncol 25:2601-2606, 2007,以下JCO RPA 3+7群)は、再発後に何らかの補助治療を施行してもその治療以降の生存期間中央値が4.4ヶ月と極めて不良である。この予後不良再発悪性グリオーマに対象を絞って、その予後を改善するために、二つの治療、すなわちホウ素中性子捕捉療法およびベバシズマブ投与のコンビネーションによる臨床試験を行い、その治療効果を明らかにし、ひいては将来の加速器中性子源を用いた再発悪性グリオーマに対する標準治療への布石にすることが本研究の目的である。
    平成29,30年度とも以下のプロトコールに従い、再発悪性グリオーマ(MG)予後不良群(JCO,RPA 3+7群+Bev使用後再発群)に対して、原子炉BNCTを施行し、その2-4週後より、Bev10mg/kg, biweekly の投与をRANOの診断基準での悪化まで継続し、全生存(OS)を主要評価項目として、single arm, 第二相臨床試験を行う。以上の研究計画を実施予定としており、プロトコールの確立を医療イノベーション推進センター(旧称臨床研究情報センター)とともに行い、CRFも作成し、電子入力システムを構築した。平成29年8月に京都大学原子炉(KUR)が再開後、UMIN上にも本臨床試験を公開し、患者entry を開始したが、その直後からKURが施設上の不具合が発生し臨床試験を2ヶ月間休止せざるを得なかった。現在までに4例の症例のentry を行い、follow-up中である。

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  • Neurogenesis and depression in the central nervous system disorders

    Grant number:17H04303  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    伊達 勲, 黒住 和彦, 道上 宏之, 藤井 謙太郎, 安原 隆雄, 亀田 雅博, 菱川 朋人, 田尻 直輝, 市川 智継

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    Grant amount:\17030000 ( Direct expense: \13100000 、 Indirect expense:\3930000 )

    平成30年度も順調に研究が進んだと言える。特筆すべきは、カプセル化細胞移植による、うつ病モデルラットに対する治療効果を示すことができたことである。(Kin K, et al. Mol Pshychiatry 2018) カプセル化骨髄幹細胞移植により、うつ病モデルラット脳内の神経新生が増幅され、うつ病様行動も改善を示した。そのメカニズムの一つとして、カプセル化細胞移植によって、脳内の神経栄養因子や成長因子濃度が上昇し、シグナルが活性化されたことも明らかにすることができた。また、リチウムとセロトニン再取り込み阻害剤の併用療法による治療効果メカニズムについても検討を進めた。(投稿中)パーキンソン病モデルラットに対する電気刺激研究においても、脊髄硬膜外刺激、迷走神経刺激両社によって明らかな治療効果が行動学的、組織学的に示されており、現在論文執筆中であり、次年度には掲載が見込まれる。特に、小型・持続電気刺激が可能であり、刺激調整も可能な電気刺激システムを用いており、極めて臨床での電気刺激に近似した実験系を確立したことは意義深い。一方で、脳梗塞モデルラットにおけるうつ様行動の解析は、厳しい状況にあると言える。うつ病モデルとして用いているWistar Kyoto ratは虚血耐性があり、均一な脳梗塞を作製することが難しく、そのために、うつ病様行動にも相当なばらつきが出てしまうことが明確になった。Wistar Kyoto ratにおける両側頚動脈閉塞による低灌流モデルでは明確なうつ様行動に与える影響が得られなかった。現在、Wistar ratを用いた脳梗塞モデルを用いて、うつ病様行動の解析を現在行っており、神経新生との関与を検討している。

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  • Effective functional improvement of proteins and peptides delivered into cell by peptide zipper method

    Grant number:16K05856  2016.04 - 2019.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    KITAMATSU Mizuki, HAKATA Yoshiyuki

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    Grant amount:\4940000 ( Direct expense: \3800000 、 Indirect expense:\1140000 )

    We aim to treat diseases by safely and efficiently delivering proteins and functional peptides into cells. Here, we conjugated the Nanog protein to a heterodimeric leucine zipper peptide (LzK). In addition, an cell-penetrating peptide was conjugated to LzE peptide that forms a hybrid with LzK. When these peptides were mixed, the Nanog protein was successfully delivered into the cytoplasm and further into the nucleus, and the function possessed by Nanog protein was successfully expressed.

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  • Depression and Neurogenesis

    Grant number:16K10722  2016.04 - 2019.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Yasuhara Takao

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    Grant amount:\4550000 ( Direct expense: \3500000 、 Indirect expense:\1050000 )

    Recently, we are living in a stressful world. Depression is a big problem. The solution and new therapies for depression is awaited. In this study, we revealed following by the research using depression model rats.1. Neurogenesis in the hippocampus of Wistar Kyoto rats with depression-like behavior is declined.2. Intraventricular transplantation of encapsulated mesenchymal stem cells against Wistar Kyoto rats exerts therapeutic potentials with enhanced neurogenesis.3. The mechanisms underlying the therapeutic potentials contains secretions several trophic factors from the transplanted cells,

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  • Development of the anti-invasive drug for treatment of malignant glioma by drug-repositioning of anti-depressant.

    Grant number:16K10756  2016.04 - 2019.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    ABE TADASHI

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    Grant amount:\4810000 ( Direct expense: \3700000 、 Indirect expense:\1110000 )

    For treatment of malignant glioma, highly invasive glioma cells become obstacle to surgical removal of primary tumor. To suppress the high invasive activity of glioma cells, we identified the novel anti-invasive drug, a fluvoxamine, by drug repositioning of anti-depressant. Screening for more potent anti-invasive drugs using fluvoxamine as a lead compound are currently in progress. Furthermore, we found that actin-bundling by dynamin-cortactin complex is required for glioma cell invation. Cortactin is phosphorylated by cyclin dependent kinase 5 (CDK5), and its phosphorylation negatively regulates glioma cell invasion.

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  • New BNCT against brain tumor stem cell with BSH-peptide

    Grant number:15K10333  2015.04 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Michiue Hiroyuki, KITAMATSU Mizuki

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    Grant amount:\4810000 ( Direct expense: \3700000 、 Indirect expense:\1110000 )

    We already succeeded to create new boron compound with cell penetrating peptide (CPP) for boron neutron capture therapy (BNCT). The CPP fused multi-BSH was synthesized in previous project, but it was very difficult to apply to high-volume synthesis for clinical use. In this time, we made up new BSH-CPP with possibility of clinical application and showed new boron drug imaging system for pharmacokinetic evaluation.
    A) We made up BSH-3R with fused minimum number of CPP, 3R for clinical use. B) We observed intra-cellular localization of BSH-3R in human glioma cells and finally this boron compound localized at the nucleus of glioma cells. C) We created new positron emission tomography (PET) probe, BSH-3R-DOTA-64Cu. This BSH-3R-DOTA-64Cu was consisted of boron compound part (BSH), CPP part (3R), metal chelate part (DOTA, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and radioactive substance part (64Cu).

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  • Development of new boron drugs and molecular imaging targeting for cancer stem cell

    Grant number:15H04906  2015.04 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    Matsui Hideki, MIYATAKE Shin-ichi, MATSUSHITA Hiroaki, KITAMATSU Mizuki

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    Grant amount:\17680000 ( Direct expense: \13600000 、 Indirect expense:\4080000 )

    We developed a new drug delivery method which deliver boron into cancer cells. The method showed an efficient delivery of 10B into cultured Glioblastoma and Mammary cancer cell lines. The efficiency and the specificity were higher for cancer stem cells than ordinary cancer cells. We further developed molecular agent for PET imaging of boron compound.

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  • Cell therapy and electrical stimulation for diseases in the central nervous system

    Grant number:26293323  2014.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    Date Isao

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    Grant amount:\15860000 ( Direct expense: \12200000 、 Indirect expense:\3660000 )

    We revealed the following.
    1. Neuroprotective effects of spinal cord stimulation for Parkinson’s disease model of rats 2. Strong therapeutic effects of transplantation of mesenchymal stem cells at 24 hours after onset for stroke model of rats 3. Enhanced migratory effects of transplanted mesenchymal stem cells by electrical stimulation for stroke model of rats

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  • Development of intracellular delivery method of proteins by hetero-dimerized leucine zippers

    Grant number:25410181  2013.04 - 2016.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    KITAMATSU Mizuki, MICHIUE Hiroyuki

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    Grant amount:\5330000 ( Direct expense: \4100000 、 Indirect expense:\1230000 )

    For purpose of treatment of disease, we develop a method for delivering a functional proteins or functional peptides into cells. In this work, we synthesized an autophagy-inducing peptide (Beclin 1) modified with a hetero-dimerization leucine zipper peptide (LzK). We also synthesized a cell-penetrating peptide modified with a pair of LzK (LzE). When these peptides were mixed, Beclin 1 was successfully delivered into the cell, and the peptide induced autophagy.

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  • New BNCT with boron-peptide against malingnat brain tumor

    Grant number:24791502  2012.04 - 2015.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    MICHIUE Hiroyuki

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

    Boron neutron capture therapy (BNCT) is an encouraging treatment under clinical investigation. In malignant cells, BNCT consists of two major factors: neutron radiation and boron uptake. To increase boron uptake in cells, we established new boron compound with peptide. New BSH-peptide will be very important drug for next generation BNCT.

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  • tumor specific new boron agent for BNCT

    Grant number:24390293  2012.04 - 2015.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    MATSUI Hideki, MICHIUE Hiroyuki, ONO Koji, MIYATAKE Shin-ichi

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    Grant amount:\17810000 ( Direct expense: \13700000 、 Indirect expense:\4110000 )

    New anti-cancer therapy with boron neutron capture therapy (BNCT) is based on the nuclear reaction of boron-10 with neutron irradiation. In BNCT clinical trial, two boron compounds, BPA (boronophenylalanine) and BSH (sodium borocaptate), were used for BNCT. BPA is taken up into cells through amino acid transporters that are expressed highly in almost all malignant cells, but BSH cannot pass through the cell membrane and remains outside the cell. To overcome this disadvantage of BSH in BNCT, we used a cell-penetrating peptide system for transduction of BSH. CPP (cell-membrane penetrating peptide) is very common peptide domains that transduce many physiologically active substances into cells in vitro and in vivo. BSH-fused CPPs can penetrate the cell membrane and localize inside a cell. BSH-CPP is one of the most promising boron agent in next generation BNCT.

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  • Tumor-selective high LET and high RBE particles can overcome the radiation-resistant glioma stem cells

    Grant number:23390355  2011.04 - 2014.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    MIYATAKE Shin-Ichi, KAWABATA Shinji, MICHIUE Hiroyuki, KUROIWA Toshihiko, KAJIMOTO Yoshinaga, KIRIHATA Mitsunori, MASUNAGA Shin-ichirou, ONO Koji

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    Grant amount:\18720000 ( Direct expense: \14400000 、 Indirect expense:\4320000 )

    GSLC were induced from GBM cell line A172. The phenotypes of GSLCs were confirmed by stem cell markers. These cells were irradiated with 60Co gamma rays or reactor neutron beams. Under neutron beam irradiation, high-LET proton particles can be produced. Radiosensitivity was assessed by a CFA, and the DNA double-strand breaks (DSBs) were assessed by gamma-H2AX focus assay. In stem cell culture medium, GSLCs could form neurosphere-like cells and express neural stem cell markers, Sox2 and Musashi, abundantly in comparison with their parental cells. GSLCs were significantly more radioresistant to gamma rays than their parental cells, but neutron beams overcame this resistance. Twenty-four hours after irradiation with gamma rays, there were significantly fewer gamma-H2AX foci in A172 GSLCs than in their parental cultured cells, while there was no apparent difference following neutron beam irradiation. High-LET radiation can overcome the radioresistance of GSLCs.

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  • Development of new therapeutic agents for brain tumor using protein therapy

    Grant number:20249009  2008 - 2010

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)  Grant-in-Aid for Scientific Research (A)

    MATSUI Hideki, MICHIUE Hiroyuki

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    Grant amount:\50050000 ( Direct expense: \38500000 、 Indirect expense:\11550000 )

    Boron neutron capture therapy (BNCT) is a novel cancer treatment modality that can selectively target the tumor without causing excessive radiation damage to the normal tissues. In this project, we developed 2 types of new therapeutic agents for BNCT : cell-penetrating peptides using the protein therapy or nanoparticles, which are effective of delivering cargo into cells, to deliver ^<10>B into the tumor cells as BNCT agents. In both in-vitro studies using the cultured tumor cells and in-vivo studies using tumor-bearing mice, these agents were only observed in the tumor. The results suggest that our systems utilizing peptides or nanoparticles provide an effective means of delivering ^<10>B into tumor cells selectively in BNCT.

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