2021/12/16 更新

写真a

ササキ タカノリ
佐々木 崇了
SASAKI Takanori
所属
医歯薬学域 助教
職名
助教
外部リンク

学位

  • 医学博士 ( 岡山大学 )

研究分野

  • ライフサイエンス / 獣医学

  • ライフサイエンス / 放射線科学

学歴

  • 岡山大学大学院   医歯薬学総合研究科  

    2008年4月 - 2012年3月

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  • 岩手大学   Faculty of Agriculture   Department of Veterinary medicine

    2001年4月 - 2007年3月

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経歴

  • 岡山大学大学院   医歯薬学総合研究科   助教

    2011年4月 - 現在

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  • 倉敷芸術科学大学   生命動物科学科   助教

    2007年4月 - 2011年3月

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論文

  • The number of glutamines in the N-terminal of the canine androgen receptor affects signalling intensities. 国際誌

    Kazuhiko Ochiai, Samak Sutijarit, Mitsuki Uemura, Masami Morimatsu, Masaki Michishita, Eri Onozawa, Marika Maeda, Takanori Sasaki, Masami Watanabe, Yoshikazu Tanaka, Toshinori Omi

    Veterinary and comparative oncology   19 ( 2 )   399 - 403   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Most male dogs are castrated at young ages, making them easy to rear following androgen deprivation. Although the incidence of canine prostate cancer is low, several patients have resistance to androgen therapy and poor clinical prognosis. These outcomes are similar to those of end-stage human androgen-independent prostate cancer. The androgen receptor (AR) of canines has two polyglutamine (polyQ) sequences (Q × 10 and Q × 23) at its N-terminal. The length of polyQ may be a risk factor for the development of prostate cancer in dogs; however, there is no evidence to support this. Hence, we artificially created polyQ deletion mutants of canine AR and evaluated their effects on AR signalling. The deletions of Q × 10 and Q × 23 were associated with significant reductions in AR signalling intensities. The Q × 10 mutants, which increase or decrease Q sequentially, also altered AR signalling. Furthermore, the Q × 10 deletion mutant, compared with the Q × 10 control, altered the intensities of the binding of polyQ to the C-terminal of AR, which contains a ligand-binding domain; this was not observed with the Q × 9, 11, and 12 variants. The number of glutamines in the N-terminals of canine ARs may influence AR signalling intensities and contribute to the risk of prostate cancer in dogs.

    DOI: 10.1111/vco.12663

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  • A Novel 89Zr-labeled DDS Device Utilizing Human IgG Variant (scFv): “Lactosome” Nanoparticle-Based Theranostics for PET Imaging and Targeted Therapy

    Melissa Siaw Han Lim, Takashi Ohtsuki, Fumiaki Takenaka, Kazuko Kobayashi, Masaru Akehi, Hirotaka Uji, Hirotsugu Kobuchi, Takanori Sasaki, Eiichi Ozeki, Eiji Matsuura

    Life   11 ( 2 )   158 - 158   2021年2月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    “Theranostics,” a new concept of medical advances featuring a fusion of therapeutic and diagnostic systems, provides promising prospects in personalized medicine, especially cancer. The theranostics system comprises a novel 89Zr-labeled drug delivery system (DDS), derived from the novel biodegradable polymeric micelle, “Lactosome” nanoparticles conjugated with specific shortened IgG variant, and aims to successfully deliver therapeutically effective molecules, such as the apoptosis-inducing small interfering RNA (siRNA) intracellularly while offering simultaneous tumor visualization via PET imaging. A 27 kDa-human single chain variable fragment (scFv) of IgG to establish clinically applicable PET imaging and theranostics in cancer medicine was fabricated to target mesothelin (MSLN), a 40 kDa-differentiation-related cell surface glycoprotein antigen, which is frequently and highly expressed by malignant tumors. This system coupled with the cell penetrating peptide (CPP)-modified and photosensitizer (e.g., 5, 10, 15, 20-tetrakis (4-aminophenyl) porphyrin (TPP))-loaded Lactosome particles for photochemical internalized (PCI) driven intracellular siRNA delivery and the combination of 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) offers a promising nano-theranostic-based cancer therapy via its targeted apoptosis-inducing feature. This review focuses on the combined advances in nanotechnology and material sciences utilizing the “89Zr-labeled CPP and TPP-loaded Lactosome particles” and future directions based on important milestones and recent developments in this platform.

    DOI: 10.3390/life11020158

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  • Tumor suppressor REIC/Dkk-3 and its interacting protein SGTA inhibit glucocorticoid receptor to nuclear transport. 国際誌

    Takehiro Iwata, Takuya Sadahira, Kazuhiko Ochiai, Hideo Ueki, Takanori Sasaki, Peng Haung, Motoo Araki, Toyohiko Watanabe, Yasutomo Nasu, Masami Watanabe

    Experimental and therapeutic medicine   20 ( 2 )   1739 - 1745   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    REIC/Dkk-3 is a tumor suppressor, and its expression is significantly downregulated in a variety of human cancer types. A previous study performed yeast two-hybrid screening and identified the small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA), known as a negative modulator of cytoplasmic androgen receptor (AR) signaling, which is a novel interacting partner of REIC/Dkk-3. The previous study also indicated that the REIC/Dkk-3 protein interferes with the dimerization of SGTA and then upregulates the AR transport and signaling in human prostate cancer PC3 cells. Since the transport of some steroid receptors to nucleus is conducted similarly by dynein motor-dependent way, the current study aimed to investigate the role of SGTA and REIC/Dkk-3 in the transport of other glucocorticoid receptors (GR). In vitro reporter assays for the cytoplasmic GR transport were performed in human prostate cancer PC3 cells and 293T cells. As for the SGTA protein, a suppressive effect on the GR transport to the nucleus was observed in the cells. As for the REIC/Dkk-3 protein, an inhibitory effect was observed for the GR transport in PC3 cells. Under the depleted condition of SGTA by short-hairpin (sh)RNA, the downregulation of GR transport by REIC/Dkk-3 was significantly enhanced compared with the non-depleted condition in PC3 cells, suggesting a compensatory role of REIC/Dkk-3 in the SGTA mediated inhibition of GR transport. The current study therefore demonstrated that SGTA inhibited the cytoplasmic transport of GR in 293T and PC3 cells, and REIC/Dkk-3 also inhibited the cytoplasmic transport of GR in PC3 cells. These results may be used to gain novel insight into the GR transport and signaling in normal and cancer cells.

    DOI: 10.3892/etm.2020.8819

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  • Robotic CT-guided out-of-plane needle insertion: comparison of angle accuracy with manual insertion in phantom and measurement of distance accuracy in animals. 査読 国際誌

    Toshiyuki Komaki, Takao Hiraki, Tetsushi Kamegawa, Takayuki Matsuno, Jun Sakurai, Ryutaro Matsuura, Takuya Yamaguchi, Takanori Sasaki, Toshiharu Mitsuhashi, Soichiro Okamoto, Mayu Uka, Yusuke Matsui, Toshihiro Iguchi, Hideo Gobara, Susumu Kanazawa

    European radiology   30 ( 3 )   1342 - 1349   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: To evaluate the accuracy of robotic CT-guided out-of-plane needle insertion in phantom and animal experiments. METHODS: A robotic system (Zerobot), developed at our institution, was used for needle insertion. In the phantom experiment, 12 robotic needle insertions into a phantom at various angles in the XY and YZ planes were performed, and the same insertions were manually performed freehand, as well as guided by a smartphone application (SmartPuncture). Angle errors were compared between the robotic and smartphone-guided manual insertions using Student's t test. In the animal experiment, 6 robotic out-of-plane needle insertions toward targets of 1.0 mm in diameter placed in the kidneys and hip muscles of swine were performed, each with and without adjustment of needle orientation based on reconstructed CT images during insertion. Distance accuracy was calculated as the distance between the needle tip and the target center. RESULTS: In the phantom experiment, the mean angle errors of the robotic, freehand manual, and smartphone-guided manual insertions were 0.4°, 7.0°, and 3.7° in the XY plane and 0.6°, 6.3°, and 0.6° in the YZ plane, respectively. Robotic insertions in the XY plane were significantly (p < 0.001) more accurate than smartphone-guided insertions. In the animal experiment, the overall mean distance accuracy of robotic insertions with and without adjustment of needle orientation was 2.5 mm and 5.0 mm, respectively. CONCLUSION: Robotic CT-guided out-of-plane needle insertions were more accurate than smartphone-guided manual insertions in the phantom and were also accurate in the in vivo procedure, particularly with adjustment during insertion. KEY POINTS: • Out-of-plane needle insertions performed using our robot were more accurate than smartphone-guided manual insertions in the phantom experiment and were also accurate in the in vivo procedure. • In the phantom experiment, the mean angle errors of the robotic and smartphone-guided manual out-of-plane needle insertions were 0.4° and 3.7° in the XY plane (p < 0.001) and 0.6° and 0.6° in the YZ plane (p = 0.65), respectively. • In the animal experiment, the overall mean distance accuracies of the robotic out-of-plane needle insertions with and without adjustments of needle orientation during insertion were 2.5 mm and 5.0 mm, respectively.

    DOI: 10.1007/s00330-019-06477-1

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  • CT透視ガイド下針穿刺ロボットの自動化のための医師の手技中における針の軌道修正の調査 査読

    亀川 哲志, 高山 和真, 松野 隆幸, 平木 隆夫, 櫻井 淳, 小牧 稔幸, 松浦 龍太郎, 佐々木 崇了, 五福 明夫

    日本コンピュータ外科学会誌   22 ( 1 )   14 - 20   2020年1月

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    記述言語:日本語   出版者・発行元:(一社)日本コンピュータ外科学会  

    著者らは、術者の被ばく量低減を目的として、遠隔操作型のCT透視ガイド下針穿刺ロボット(Zerobot)の研究開発を開始している。今回、動物実験のCT画像をもとに術者である医師がロボットを遠隔操作してブタの体内にある標的に対して穿刺を行う場合に、針と標的との位置関係によってどのように針の軌道修正の作業を行うのか調査した。Zerobotを用いて、X軸、Y軸、Z軸の三つの直動軸で三次元方向の並進運動を行い、針の位置を決定した。A軸、B軸の二つの回転軸で回転運動を行い、針の姿勢を決定した。調査に使用したデータはブタを用いた穿刺精度試験で得られたものであった。ロボットを医師が遠隔操作することによる穿刺において、針が標的に近づくにつれ修正回数は指数的に増加していることが分かった。なお、残りの穿刺深さが約10mmとなるのをピークに、それ以降はA軸とB軸の修正回数は減少し、一方で刺し直し回数が増加している様子が観察された。合計60回の穿刺のうち、A軸の修正は110回、B軸の修正は66回、刺し直しは37回であった。自動穿刺シミュレーションの結果、穿刺経路と針との距離と角度がゼロに収束しており、針先を三次元的な穿刺経路に追従させることができることを確認した。針が標的に近づくにしたがって穿刺速度が減速していることが示された。

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  • Measurement of Needle Trajectory Correction in Doctor’s Procedure for Automation of CT-guided Needle Insertion Robot

    Tetsushi Kamegawa, Kazuma Takayama, Takayuki Matsuno, Takao Hiraki, Jun Sakurai, Toshiyuki Komaki, Ryutaro Matsuura, Takanori Sasaki, Akio Gofuku

    Journal of Japan Society of Computer Aided Surgery   22 ( 1 )   14 - 20   2020年

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:The Japan Society of Computer Aided Surgery  

    DOI: 10.5759/jscas.22.14

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  • The canine RAD51 mutation leads to the attenuation of interaction with PALB2. 査読 国際誌

    Mitsuki Uemura, Kazuhiko Ochiai, Masami Morimatsu, Masaki Michishita, Eri Onozawa, Daigo Azakami, Yumiko Uno, Yasunaga Yoshikawa, Takanori Sasaki, Masami Watanabe, Toshinori Omi

    Veterinary and comparative oncology   18 ( 2 )   247 - 255   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    RAD51 forms a complex with BRCA2 and plays a central role in the DNA damage response pathway that is associated with homologous recombination. The structures of RAD51 and its homologues are highly conserved from prokaryotes to higher eukaryotes. Although a large number of BRCA2 mutations have been reported, there are only a few reports on the mutations of RAD51, which have been shown in humans and dogs. However, several mutations of canine RAD51 were identified from mammary gland tumour tissues in a recent study. Some of these mutations seem to have an influence on the homo-oligomerization or interaction with "Partner and localizer of BRCA2" (PALB2). In this study, we cloned the canine PALB2 homologue and investigated the effect on its interaction with the RAD51 mutants to evaluate the alteration in the function of RAD51 mutants. The A209S and T225S mutants of RAD51 show an attenuation of the interaction between RAD51 and PALB2. These results indicate that the canine RAD51 mutations can potentially alter the homologous recombination pathways in response to DNA damage in dogs.

    DOI: 10.1111/vco.12542

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  • Novel single‐chain variant of antibody against mesothelin established by phage library 査読

    Hiromasa Yakushiji, Kazuko Kobayashi, Fumiaki Takenaka, Yoshiro Kishi, Midori Shinohara, Masaru Akehi, Takanori Sasaki, Eiji Ohno, Eiji Matsuura

    Cancer Science   110 ( 9 )   2722 - 2733   2019年9月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1111/cas.14150

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14150

  • Fluorine-18 (18F)-labeled retinoid x receptor (RXR) partial agonist whose tissue transferability is affected by other RXR ligands. 査読 国際誌

    Takamura Y, Shibahara O, Watanabe M, Fujihara M, Yamada S, Akehi M, Sasaki T, Hirano H, Kakuta H

    Bioorganic & medicinal chemistry   27 ( 14 )   3128 - 3134   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bmc.2019.05.045

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  • Correction to Synthesis of 11C-Labeled RXR Partial Agonist 1-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic Acid (CBt-PMN) by Direct [11C]Carbon Dioxide Fixation via Organolithiation of Tri 査読

    Shibahara O, Watanabe M, Takamura Y, Yamada S, Akehi M, Sasaki T, Akahoshi A, Hanada T, Hirano H, Nakatani S, Nishioka H, Takeuchi Y, Kakuta H

    Journal of medicinal chemistry   62 ( 9 )   4780 - 4781   2019年5月

  • Robotic Insertion of Various Ablation Needles Under Computed Tomography Guidance: Accuracy in Animal Experiments 査読

    Takao Hiraki, Takayuki Matsuno, Tetsushi Kamegawa, Toshiyuki Komaki, Jun Sakurai, Ryutaro Matsuura, Takuya Yamaguchi, Takanori Sasaki, Toshihiro Iguchi, Yusuke Matsui, Hideo Gobara, Susumu Kanazawa

    European Journal of Radiology   105   162 - 167   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier Ireland Ltd  

    Objective: To evaluate the accuracy of robotic insertion of various ablation needles at various locations under computed tomography (CT) guidance in swine. Materials and methods: The robot was used for CT-guided insertion of four ablation needles, namely a single internally cooled radiofrequency ablation (RFA) needle (Cool-tip), a multi-tined expandable RFA needle (LeVeen), a cryoablation needle (IceRod), and an internally cooled microwave ablation needle (Emprint). One author remotely operated the robot with the operation interface in order to orient and insert the needles under CT guidance. Five insertions of each type of ablation needle towards 1.0-mm targets in the liver, kidney, lung, and hip muscle were attempted on the plane of an axial CT image in six swine. Accuracy of needle insertion was evaluated as the three-dimensional length between the target centre and needle tip. The accuracy of needle insertion was compared according to the type of needle used and the location using one-way analysis of variance. Results: The overall mean accuracy of all four needles in all four locations was 2.8 mm. The mean accuracy of insertion of the Cool-tip needle, LeVeen needle, IceRod needle, and Emprint needle was 2.8 mm, 3.1 mm, 2.5 mm, and 2.7 mm, respectively. The mean accuracy of insertion into the liver, kidney, lung, and hip muscle was 2.7 mm, 2.9 mm, 2.9 mm, and 2.5 mm, respectively. There was no significant difference in insertion accuracy among the needles (P =.38) or the locations (P =.53). Conclusion: Robotic insertion of various ablation needles under CT guidance was accurate regardless of type of needle or location in swine.

    DOI: 10.1016/j.ejrad.2018.06.006

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  • Mutants of β2-glycoprotein I: Their features and potent applications. 査読

    Shen L, Azmi NU, Tan XW, Yasuda S, Wahyuningsih AT, Inagaki J, Kobayashi K, Ando E, Sasaki T, Matsuura E

    Best practice & research. Clinical rheumatology   32 ( 4 )   572 - 590   2018年8月

  • Endogenous Leu332Gln mutation in p53 disrupts the tetramerization ability in a canine mammary gland tumor cell line. 査読 国際誌

    Kazuhiko Ochiai, Daigo Azakami, Masami Morimatsu, Hinako Hirama, Shota Kawakami, Takayuki Nakagawa, Masaki Michishita, Ai S Egusa, Takanori Sasaki, Masami Watanabe, Toshinori Omi

    Oncology reports   40 ( 1 )   488 - 494   2018年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mutations in the p53 gene are associated with more than half of all human cancers. These mutations often cause a disruption of the tumor-suppressor function of p53 and induce genomic instabilities. Wild‑type p53 requires tetramerization to function as an initiator of cell cycle arrest and apoptosis. Although alterations in p53 tetramerization caused by mutation have been well studied, there are few cell lines containing an endogenous mutation in the tetramerization domain of p53. Here, we report the discovery of a canine mammary gland tumor cell line CTB‑m2, which contains the Leu332Gln (L332Q) mutation corresponding to Leu344 in the tetramerization domain of human p53. Although CTB‑m2 cells are genetically heterozygous for the Leu332Gln mutation, the mutant mRNA was almost exclusively expressed. CTB‑m2 cells showed enhanced cell proliferation compared to wild‑type p53-expressing CTB‑m cells of the same lineage. A p53 tetramerization reporter assay showed that the ability of the p53 mutant to form tetramers was significantly lower than that of wild‑type p53. An immunoblot analysis of cross-linked p53 oligomerized forms demonstrated that the L332Q mutant lacked the ability to form tetramers but retained the ability to form dimers. These data suggest that the p53 mutant cell line CTB‑m2 could be a useful tool for analyzing the precise tetramerization mechanisms of p53 and verifying the effects of therapeutic agents against tumors expressing p53 mutants that lack the ability to tetramerize.

    DOI: 10.3892/or.2018.6409

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  • Robotically Driven CT-guided Needle Insertion: Preliminary Results in Phantom and Animal Experiments 査読

    Takao Hiraki, Tetsushi Kamegawa, Takayuki Matsuno, Jun Sakurai, Yasuzo Kirita, Ryutaro Matsuura, Takuya Yamaguchi, Takanori Sasaki, Toshiharu Mitsuhashi, Toshiyuki Komaki, Yoshihisa Masaoka, Yusuke Matsui, Hiroyasu Fujiwara, Toshihiro Iguchi, Hideo Gobara, Susumu Kanazawa

    RADIOLOGY   285 ( 2 )   454 - 461   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:RADIOLOGICAL SOC NORTH AMERICA  

    Purpose: To evaluate the accuracy of the remote-controlled robotic computed tomography (CT)-guided needle insertion in phantom and animal experiments.
    Materials and Methods: In a phantom experiment, 18 robotic and manual insertions each were performed with 19-gauge needles by using CT fluoroscopic guidance for the evaluation of the equivalence of accuracy of insertion between the two groups with a 1.0-mm margin. Needle insertion time, CT fluoroscopy time, and radiation exposure were compared by using the Student t test. The animal experiments were approved by the institutional animal care and use committee. In the animal experiment, five robotic insertions each were attempted toward targets in the liver, kidneys, lungs, and hip muscle of three swine by using 19-gauge or 17-gauge needles and by using conventional CT guidance. The feasibility, safety, and accuracy of robotic insertion were evaluated.
    Results: The mean accuracies of robotic and manual insertion in phantoms were 1.6 and 1.4 mm, respectively. The 95% confidence interval of the mean difference was 20.3 to 0.6 mm. There were no significant differences in needle insertion time, CT fluoroscopy time, or radiation exposure to the phantom between the two methods. Effective dose to the physician during robotic insertion was always 0 mSv, while that during manual insertion was 5.7 mSv on average (P&lt;.001). Robotic insertion was feasible in the animals, with an overall mean accuracy of 3.2 mm and three minor procedure-related complications.
    Conclusion: Robotic insertion exhibited equivalent accuracy as manual insertion in phantoms, without radiation exposure to the physician. It was also found to be accurate in an in vivo procedure in animals. (C) RSNA, 2017

    DOI: 10.1148/radiol.2017162856

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  • Anti-high Mobility Group Box 1 Antibody Ameliorates Albuminuria in MRL/lpr Lupus-Prone Mice 査読

    Haruki Watanabe, Katsue S. Watanabe, Keyue Liu, Sumie Hiramatsu, Sonia Zeggar, Eri Katsuyama, Noriko Tatebe, Akiya Akahoshi, Fumiaki Takenaka, Takahisa Hanada, Masaru Akehi, Takanori Sasaki, Ken-ei Sada, Eiji Matsuura, Masahiro Nishibori, Jun Wada

    MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT   6   31 - 39   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    We evaluated the efficacy of a neutralizing anti-high mobility group box 1 (HMGB1) monoclonal antibody in MRL/lpr lupus-prone mice. The anti-HMGB1 monoclonal antibody (5 mg/kg weight) or class-matched control immunoglobulin G2a (IgG2a) was administered intravenously twice a week for 4-15 weeks. Urine albumin was monitored, and histological evaluation of the kidneys was conducted at 16 weeks. Lymphadenopathies were evaluated by 1-(2'-deoxy-2'-[F-18]fluoro-beta-D-arabinofuranosyl) cytosine ([F-18] FAC) positron emission tomography/computed tomography (PET/CT) at 12 weeks. Following 4-week treatment, [F-18]FAC-PET/CT showed similar accumulation in cervical and axillary lymph nodes at 12 weeks of age. However, anti-HMGB1 monoclonal antibody sufficiently inhibited the increase in albuminuria compared to an isotype control following 15-week treatment. Complement deposition was also improved; however, there were no significant differences in IgG deposition and renal pathological scores between the two groups. Anti-double-stranded DNA (dsDNA) antibody titers and cytokine and chemokine levels were also unaltered. Although there were no significant differences in glomerular macrophage infiltration, neutrophil infiltration was significantly decreased by the anti-HMGB1 monoclonal antibody. Antagonizing HMGB1 treatment suppressed HMGB1 translocation from nuclei in the kidney and suppressed neutrophil extracellular traps. The anti-HMGB1 monoclonal antibody demonstrated therapeutic potential against albuminuria in lupus nephritis by inhibiting neutrophil recruitment and neutrophil extracellular traps.

    DOI: 10.1016/j.omtm.2017.05.006

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  • Synthesis of C-11-Labeled RXR Partial Agonist 14(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)aminoThenzotriazole-5-carboxylic Acid (CBt-PMN) by Direct [C-11]Carbon Dioxide Fixation via Organolithiation of Trialkyltin Precursor and PET Imaging Thereof 査読

    Osamu Shibahara, Masaki Watanabe, Shoya Yamada, Masaru Akehi, Takanori Sasaki, Akiya Akahoshi, Takahisa Hanada, Hiroyuki Hirano, Shunsuke Nakatani, Hiromi Nishioka, Yasuo Takeuchi, Hiroki Kakuta

    JOURNAL OF MEDICINAL CHEMISTRY   60 ( 16 )   7139 - 7145   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    The retinoid X receptor (RXR) partial agonist 1-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic acid (1; CBt-PMN, E-max = 75%, EC50 = 143 nM) is a candidate for treatment of central nervous system (CNS) diseases such as Alzheimers and Parkinsons diseases based on reports that RXR-full agonist 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) shows therapeutic effects on these disease in rodent models. Here, we synthesized carbon-11-labeled ([C-11]1) as a tracer for positron emission tomography (PET) and used it in a PET imaging study to examine the brain uptake and biodistribution of 1. We found that (CO2)-C-11 fixation after tinlithium exchange at -20 degrees C afforded [C-11]1. This methodology may also be useful for synthesizing (CO2H)-C-11-PET tracer derivatives of other compounds bearing pi-rich heterocyclic rings. A PET/CT imaging study of [C-11]1 in mice indicated 1 is distributed to the brain and is thus a candidate for treatment of CNS diseases.

    DOI: 10.1021/acs.jmedchem.7b00817

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  • In vivo distribution of single chain variable fragment (scFv) against atherothrombotic oxidized LDL/β2-glycoprotein I complexes into atherosclerotic plaques of WHHL rabbits: Implication for clinical PET imaging. 査読

    Sasaki T, Kobayashi K, Kita S, Kojima K, Hirano H, Shen L, Takenaka F, Kumon H, Matsuura E

    Autoimmunity reviews   16 ( 2 )   159 - 167   2017年2月

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  • The Function of β2-glycoprotein I in Angiogenesis and Its in Vivo Distribution in Tumor Xenografts. 査読

    Wahyuningsih AT, Shen L, Kobayashi K, Sasaki T, Takenaka F, Hanada T, Akehi M, Akahoshi A, Ozeki E, Ando E, Matsuura E

    Acta medica Okayama   70 ( 1 )   13 - 24   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.18926/AMO/53999

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  • Positron Emission Tomography to Elucidate Pharmacokinetic Differences of Regioisomeric Retinoid X Receptor Agonists 査読

    Toshiki Kobayashi, Yuki Furusawa, Shoya Yamada, Masaru Akehi, Fumiaki Takenaka, Takanori Sasaki, Akiya Akahoshi, Takahisa Hanada, Eiji Matsuura, Hiroyuki Hirano, Akihiro Tai, Hiroki Kakuta

    ACS MEDICINAL CHEMISTRY LETTERS   6 ( 3 )   334 - 338   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    RXR partial agonist NEt-41B (2a, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: EC50 = 169 nM, E-max = 55%) showed a blood concentration higher than its Emax after single oral administration at 30 mg/kg to mice, and repeated oral administration at 10 mg/kg/day to KK-A(y) mice afforded antitype 2 diabetes activity without the side effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (la), in which the isobutoxy and isopropyl groups of 2a are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with tracers [C-11] la, [C-11]2a and fluorinated derivatives [F-18] lb, [F-18]2b, which have longer half-lives, to examine the reason why la and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with la.

    DOI: 10.1021/ml500511m

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  • A novel PET imaging using ⁶⁴Cu-labeled monoclonal antibody against mesothelin commonly expressed on cancer cells. 査読

    Kobayashi K, Sasaki T, Takenaka F, Yakushiji H, Fujii Y, Kishi Y, Kita S, Shen L, Kumon H, Matsuura E

    Journal of immunology research   2015   268172   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1155/2015/268172

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  • A purification system for 64Cu produced by a biomedical cyclotron for antibody PET imaging 査読

    Teruaki Toyota, Tadashi Hanafusa, Takashi Oda, Iwane Koumura, Takanori Sasaki, Eiji Matsuura, Hiromi Kumon, Tsuneo Yano, Toshiro Ono

    Journal of Radioanalytical and Nuclear Chemistry   298 ( 1 )   295 - 300   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ion exchange is a simple and efficient method for separating no-carrier-added 64Cu from an irradiated Ni target. We developed a semi-automated two-round 64Cu separation system equipped with a strong-base anion exchange resin column. We first verified the efficiency of the system using a non-radioactive substitute consisting of 25 mg of Ni and 127 ng of Cu, and confirmed that Cu was completely eluted at the second round of the separation step. After the bombardment, separation of 64Cu from the Ni target was achieved with high radiochemical purity. 64Cu produced and separated in this study had an extremely low level of Ni impurity. It could be used for labeling monoclonal antibodies for antibody positron emission tomography imaging and synthesizing radiopharmaceuticals. © 2012 The Author(s).

    DOI: 10.1007/s10967-012-2340-7

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  • In vitro assessment of factors afecting the apparent difusion coefcient of jurkat cells using bio-phantoms 査読

    Kazunori Katashima, Masahiro Kuroda, Masakazu Ashida, Takanori Sasaki, Takehito Taguchi, Hidenobu Matsuzaki, Jun Murakami, Yoshinobu Yanagi Hisatomi, Marina Hara, Hirokazu Kato, Yuichi Ohmura, Tomoki Kobayashi, Susumu Kanazawa, Sosuke Harada, Mitsuhiro Takemoto, Seiichiro Ohno, Seiichi Mimura, Junichi Asaumi

    Acta Medica Okayama   67 ( 6 )   359 - 367   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    It is well known that many tumor tissues show lower apparent diffusion coefficient (ADC) values, and that several factors are involved in the reduction of ADC values. The aim of this study was to clarify how much each factor contributes to decreases in ADC values. We investigate the roles of cell density, extracellular space, intracellular factors, apoptosis and necrosis in ADC values using bio-phantoms. The ADC values of bio-phantoms, in which Jurkat cells were encapsulated by gellan gum, were measured by a 1.5-Tesla magnetic resonance imaging device with constant diffusion time of 30 sec. Heating at 42° C was used to induce apoptosis while heating at 48°C was used to induce necrosis. Cell death after heating was evaluated by flow cytometric analysis and electron microscopy. The ADC values of bio-phantoms including non-heated cells decreased linearly with increases in cell density, and showed a steep decline when the distance between cells became less than 3/um. The analysis of ADC values of cells after destruction of cellular structures by sonication suggested that approximately two-thirds of the ADC values of cells originate from their cellular structures. The ADC values of bio-phantoms including necrotic cells increased while those including apoptotic cells decreased. This study quantitatively clarified the role of the cellular factors and the extracellular space in determining the ADC values produced by tumor cells. The intermediate diffusion time of 30 msec might be optimal to distinguish between apoptosis and necrosis.

    DOI: 10.18926/AMO/52009

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  • 岡山大学におけるPET研究施設の治験薬GMP(Good Manufacturing Practice)体制 招待

    佐々木崇了, 松浦栄次, 公文裕巳, 矢野恒夫

    Pharm Tech Japan   29   123 - 128   2013年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • In Vitro Assessment of Factors Affecting the Apparent Diffusion Coefficient of Ramos Cells Using Bio-phantoms 査読

    Takanori Sasaki, Masahiro Kuroda, Kazunori Katashima, Masakazu Ashida, Hidenobu Matsuzaki, Junichi Asaumi, Jun Murakami, Seiichiro Ohno, Hirokazu Kato, Susumu Kanazawa

    ACTA MEDICA OKAYAMA   66 ( 3 )   263 - 270   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    The roles of cell density, extracellular space, intracellular factors, and apoptosis induced by the molecularly targeted drug rituximab on the apparent diffusion coefficient (ADC) values were investigated using bio-phantoms. In these bio-phantoms, Ramos cells (a human Burkitt's lymphoma cell line) were encapsulated in gellan gum. The ADC values decreased linearly with the increase in cell density, and declined steeply when the extracellular space became less than 4 gm. The analysis of ADC values after destruction of the cellular membrane by sonication indicated that approximately 65% of the ADC values of normal cells originate from the cell structures made of membranes and that the remaining 35% originate from intracellular components. Microparticles, defined as particles smaller than the normal cells, increased in number after rituximab treatments, migrated to the extracellular space and significantly decreased the ADC values of bio-phantoms during apoptosis. An in vitro study using bio-phantoms was conducted to quantitatively clarify the roles of cellular factors and of extracellular space in determining the ADC values yielded by tumor cells and the mechanism by which apoptosis changes those values.

    DOI: 10.18926/AMO/48566

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  • Administration of warmed intravenous fluids for medetomidine-induced hypothermia in normal dogs 査読

    Kanda T, Ikeda M, Ouchi M, Nagasaki A, Yamamoto R, Morishita T, Maeta N, Sasaki T, Furumoto K, Kake S, Murao N, Furukawa

    Japanese Journal of Veterinary Anesthesia and Surgery   42 ( 1 )   7 - 12   2011年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.2327/jvas.42.7

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  • 小動物臨床における3Dプリンターの応用 査読

    神田鉄平, 佐々木崇了, 前田憲孝, 藤岡透, 長井新, 古本佳代, 古川敏紀

    日本獣医師会雑誌   64 ( 8 )   640 - 643   2011年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.12935/jvma.64.640

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  • 耳鏡を用いたラットの性周期判定 査読

    古本佳代, 神田鉄平, 前田憲孝, 佐々木崇了, 村尾信義, 古川敏紀

    実験動物技術   46 ( 2 )   2011年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • 外側鼓室胞骨切り術に超音波手術器を使用した慢性化膿性中耳炎のアメリカン・コッカー・スパニエルの1例 査読

    前田 憲孝, 佐々木 崇了, 神田 鉄平, 藤岡 透, 古川 敏紀

    獣医麻酔外科学雑誌   42 ( 2 )   21 - 24   2011年

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    記述言語:日本語   出版者・発行元:獣医麻酔外科学会  

    DOI: 10.2327/jvas.42.21

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  • Spinal epidural empyema in a cat 査読

    Noritaka Maeta, Teppei Kanda, Takanori Sasaki, Takehito Morita, Toshinori Furukawa

    JOURNAL OF FELINE MEDICINE AND SURGERY   12 ( 6 )   494 - 497   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI LTD  

    The diagnosis and surgical treatment of spinal epidural empyema (SEE) in a 2-year-old neutered male domestic shorthaired cat is described. SEE was diagnosed by computed tomographic myelography (CT myelography) and surgical exploration. The lesion was missed on both non-enhanced CT and conventional myelography. SEE should be considered in the differential diagnosis of progressive myelopathy in cats, and CT myelography should be undertaken when magnetic resonance imaging (MRI) cannot be performed. (C) 2010 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jfms.2010.01.015

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  • A new phantom using polyethylene glycol as an apparent diffusion coefficient standard for MR imaging 査読

    Ryohei Matsuya, Masahiro Kuroda, Yoshitsugu Matsumoto, Hirokazu Kato, Hidenobu Matsuzaki, Junichi Asaumi, Jun Murakami, Kazunori Katashima, Masakazu Ashida, Takanori Sasaki, Tetsuro Sei, Kengo Himei, Kuniaki Katsui, Norihisa Katayama, Mitsuhiro Takemoto, Susumu Kanazawa, Seiichi Mimura, Seiichiro Oono, Takuichi Kitayama, Seiji Tahara, Keiji Inamura

    INTERNATIONAL JOURNAL OF ONCOLOGY   35 ( 4 )   893 - 900   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPANDIDOS PUBL LTD  

    In recent years, magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) has seen wide clinical use, such as for early detection of cerebrovascular diseases and whole body screening for tumors. The apparent diffusion coefficient (ADC) standard phantom, which mimics the ADC values of several lesions in the body, is indispensable for the development of new pulse sequences for DWI, such as diffusion-weighted whole-body imaging with background body-signal suppression (DWIBS). However, information on the ADC values of the previously reported ADC standard phantoms is limited, because these phantoms were made using only a few different materials at a limited range of concentrations, and the ADC values were measured only at certain temperatures. It has been considered difficult, if not impossible, to create a phantom that provides arbitrary ADC values, because it is difficult to calculate the concentrations of the materials and the temperature at ADC measurement. In this study, we used polyethylene glycol (PEG) as a phantom material, and developed an empirical formula to calculate the PEG concentration at any measurement temperature to obtain arbitrary ADC values of the phantom. DWI images of phantoms made using seven different PEG concentrations were taken under heating from 17 to 46 degrees C at 1 degrees C intervals. Using ADC values calculated from these DWI images, we developed two empirical formulas: i) an empirical formula to calculate the ADC values of phantoms made using any PEG concentration at any measurement temperature; and ii) an empirical formula to calculate PEG concentrations to obtain arbitrary ADC values at any measurement temperature. We inspected the accuracy of these empirical formulas by newly made PEG phantoms. A comparison between the ADC values calculated with the empirical formulas and the measured ADC values confirmed the high accuracy of these formulas. PEG phantoms are safe, inexpensive and easy to make, compared with the previously reported ADC standard phantoms. Our empirical formulas enable us to calculate PEG concentrations that provide arbitrary ADC values at any measurement temperature. The empirical formulas could be used within a range of ADC values from 0.37x10(-3) to 3.67x10(-3) mm(2)/s, PEG concentrations from 0 to 120 mM, and measurement temperatures from IS to 45 degrees C. Using these formulas, it would be possible to make standard phantoms that mimic the ADC values of any clinical lesions. The PEG phantom might thus be an excellent new ADC standard phantom for MRI with DWI.

    DOI: 10.3892/ijo_00000404

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  • In vitro experimental study of the relationship between the apparent diffusion coefficient and changes in cellularity and cell morphology 査読

    Yoshitsugu Matsumoto, Masahiro Kuroda, Ryohei Matsuya, Hirokazu Kato, Koichi Shibuya, Masataka Oita, Atsushi Kawabe, Hidenobu Matsuzaki, Junichi Asaumi, Jun Murakami, Kazunori Katashima, Masakazu Ashida, Takanor Sasaki, Tetsuro Sei, Susumu Kanazawa, Seiichi Mimura, Seiichiro Oono, Takuichi Kitayama, Seiji Tahara, Keiji Inamura

    ONCOLOGY REPORTS   22 ( 3 )   641 - 648   2009年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPANDIDOS PUBL LTD  

    Diffusion-weighted magnetic resonance imaging (MRI) is frequently used clinically, and is available for the whole-body screening for tumors. The exact mechanism by which the apparent diffusion coefficient (ADC) value decreases in tumorous tissue remains unclear, although various theories have been proposed, including intracellular and extracellular factor theories. It is impossible to distinguish each factor in the intracellular and extracellular spaces as the source of MR signal generation by means of conventional comparison between MR images and pathological specimens. Other factors which have been reported to affect ADC include cellularity and cellular edema of human tissues, and temperature of phantoms at the time of measurement. We employed a new technique that enables cellular MR imaging using a newly developed bio-phantom containing a living culture tumor cell line, Jurkat-N1. We investigated possible reasons for observed decreases in ADC values for tumors, and we considered the contribution of both the intracellular and extracellular space to such a decrease. The ADC values of the bio-phantom increased with increasing heat exposure from 27 to 45 degrees C. ADC values also increased after the destruction by sonication of tumor cell membranes. ADC values decreased as cellularity increased in the bio-phantorn. ADC values decreased due to cellular edema caused by a low salt concentration in the bio-phantom. Changes in pressure in the bio-phantom had no effect on the observed ADC values. We calculated both the intracellular ADC and extracellular ADC values using the ADC values, cellularity, and cellular volume of Jurkat-N1 cells in the bio-phantom. The extracellular ADC values in the bio-phantom were estimated to be lower than the ADC value of distilled water. These results indicate that not only intracellular ADC values, but also extracellular ADC values contribute to the determination of the ADC values of bio-phantoms. This is the first report to have examined the contribution of intracellular and extracellular space on the ADC values of bio-phantoms containing cultured tumor cells.

    DOI: 10.3892/or_00000484

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MISC

  • F-containing retinoid X receptor (RXR) partial agonist F-CBt-PMN whose tissue transferability is affected by coadministration of another RXR ligand

    Yuta Takamura, Osamu Shibahara, Masaki Watanabe, Michiko Fujihara, Masaru Akehi, Takanori Sasaki, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   258   2019年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER CHEMICAL SOC  

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  • Synthesis of 11C labeled RXR partial agonist CBt-PMN by [11C] carbon dioxide fixation via organolithiation of trialkyltin precursor and PET imaging thereof

    Osamu Shibahara, Masaki Watanabe, Masaru Akehi, Takanori Sasaki, Takahisa Hanada, Akiya Akahoshi, Hiroyuki Hirano, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   254   2017年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER CHEMICAL SOC  

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  • PETイメージングを用いたRXRパーシャルアゴニストCBt-PMNの脳移行性の評価

    芝原 理, 小林 俊貴, 渡邊 将貴, 西井 緑, 明日 卓, 佐々木 崇了, 赤星 彰也, 花田 貴寿, 平野 裕之, 加来田 博貴

    日本薬学会年会要旨集   137年会 ( 2 )   118 - 118   2017年3月

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    記述言語:日本語   出版者・発行元:(公社)日本薬学会  

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  • Evaluation of brain migration and therapeutic effects of novel RXR partial agonist CBt-PMN on cognitive impairment in mice

    Toshiki Kobayashi, Osamu Shibahara, Masaki Watanabe, Shoya Yamada, Masaru Akehi, Takanori Sasaki, Takahisa Hanada, Akiya Akahoshi, Hiroyuki Hirano, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   252   2016年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER CHEMICAL SOC  

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  • SIGNIFICANT ACCUMULATION OF OXLDL/BETA2-GLYCOPROTEIN I COMPLEXES IN ARTERIAL LESIONS OF WHHL RABBITS: PET/CT IMAGING USING AN AUTO ANTIBODY'S SCFV VARIANT

    T. Sasaki, Y. Matsunami, F. Takenaka, S. Kita, H. Hirano, L. Shen, K. Kobayashi, E. Matsuura

    ATHEROSCLEROSIS   235 ( 2 )   E68 - E68   2014年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER IRELAND LTD  

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  • Elucidation of the pharmacokinetic difference of regioisomeric retinoid X receptor agonists having an alkoxy group by PET imaging

    Toshiki Kobayashi, Kohei Kawata, Mariko Nakayama, Yuki Furusawa, Shoya Yamada, Hiroyuki Hirano, Fumiaki Takenaka, Masaru Akehi, Takanori Sasaki, Eiji Matsuura, Akihiro Tai, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   248   2014年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER CHEMICAL SOC  

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  • PETイメージングを用いたアルコキシ基を有するレチノイドX受容体アゴニストの体内動態解析

    加来田 博貴, 小林 俊貴, 古沢 優貴, 山田 翔也, 竹中 文章, 明日 卓, 佐々木 崇了, 松浦 栄次, 田井 章博

    ビタミン   88 ( 4 )   213 - 213   2014年4月

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    記述言語:日本語   出版者・発行元:(公社)日本ビタミン学会  

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  • アルコキシ基を有するレチノイドX受容体アゴニストの位置異性体間における体内動態差の解明とその応用

    小林 俊貴, 古沢 優貴, 山田 翔也, 平野 裕之, 竹中 文章, 明日 卓, 佐々木 崇了, 松浦 栄次, 田井 章博, 加来田 博貴

    日本薬学会年会要旨集   134年会 ( 4 )   81 - 81   2014年3月

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    記述言語:日本語   出版者・発行元:(公社)日本薬学会  

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共同研究・競争的資金等の研究

  • 脳梗塞後リハビリテーションによる大脳基底核経路ネットワーク改変メカニズムの解明

    研究課題/領域番号:20H04058  2020年04月 - 2024年03月

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

    岡部 直彦, 宮本 修, 佐々木 崇了, 矢作 綾野, 西松 伸一郎, 丸山 恵美, 氷見 直之, 氏原 嘉洋

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    配分額:17810000円 ( 直接経費:13700000円 、 間接経費:4110000円 )

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  • 脳酸素代謝画像を用いた代謝性脳障害のメカニズム解明に向けて

    研究課題/領域番号:20K08136  2020年04月 - 2023年03月

    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)

    佐々木 智章, 浅沼 幹人, 佐々木 崇了

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

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  • がん免疫治療における免疫細胞追跡のためのイメージング技術基盤の確立

    研究課題/領域番号:20K08109  2020年04月 - 2023年03月

    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)

    佐々木 崇了

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

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  • Zr-89標識イメージング技術に基づく次世代抗体医薬の創生プラットフォームの形成

    研究課題/領域番号:19KK0215  2019年10月 - 2023年03月

    日本学術振興会  科学研究費助成事業 国際共同研究加速基金(国際共同研究強化(B))  国際共同研究加速基金(国際共同研究強化(B))

    佐々木 崇了, 樋口 隆弘, 渡部 昌実

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    配分額:18070000円 ( 直接経費:13900000円 、 間接経費:4170000円 )

    本研究はドイツーヴュルツブルグ大学におけるニ重特異性を有する次世代の人工抗体作成技術を導入し、本国研究組織におけるイメージング技術と融合することで、複数のがん抗原を同時に標的とした革新的な放射標識低分子抗体プローブを作成し、2種のがん抗原の重複を可視化することで、がん特異性を飛躍的に向上させたイメージング基盤技術の創出を目的とする。2019年度はニ重特異性抗体による高特異性・強調イメージング技術の検討として、高特異性・強調メージングプローブの開発のために、モデルとして多発性骨髄腫における表面抗原CD19およびCD20に対する人工抗体のPETプローブ化の準備及び検討を行った。トレーサー化のための分子設計をドイツにて行い、分子量の設定、重合体形成のためのリンカー構造の変更、低分子抗体の等電点などの最適化の検討を始めた。また日本ではプローブ化の検討として人工抗体の安定性と親和性の検討を開始した。

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  • 細胞膜・血液脳関門通過型Aβオリゴマーマイクロ抗体による新規PET画像診断の創出

    研究課題/領域番号:19H03566  2019年04月 - 2023年03月

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

    松原 悦朗, 佐々木 崇了, 藪内 健一, 松浦 栄次

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    配分額:17030000円 ( 直接経費:13100000円 、 間接経費:3930000円 )

    Aβオリゴマーはシナプス毒性を持ち、アルツハイマー病の発症分子基盤と考えられている。申請者の発明抗体をヒト化した抗体を使用したAβオリゴマーを標的とした純国産疾患修飾薬を用いて、欧州5か国と本邦において前駆期から中等度のアルツハイマー型認知症を対象とした第I相臨床試験が施行され無事終了した。申請者らの先行研究で世界に先駆けてこうした標的分子治療抗体をプローブ化することで脳内Aβオリゴマーをリアルタイムで可視化する新規画像バイオマーカーの創出を試みてきたが、その最大の障壁はフルボディー抗体低い血液脳関門透過性であった。
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    本研究ではこの弱点を克服するために開発した細胞膜透過型・血液脳関門通過型のマイクロ抗体をプローブ化して細胞内外に局在する脳内AβオリゴマーのPET画像での可視化を目指している。本年度はこのマイクロ抗体の脳移行性における対照群として、同一の特異性を有するフルボディー抗体6H4をPETプローブ化し、アルツハイマー病モデルマウス(App(NL-F/NL-F)およびApp(NL-G-F/NL-G-F)マウス)における脳への集積を再評価した。12か月齢以上のマウスにおける脳への抗体集積は、抗Aβオリゴマー抗体6H4を投与した対照マウスおよびコントロール抗体を投与した同一月齢のアルツハイマー病モデルマウスと比べ有意に高く、Aβオリゴマーへの特異性をインビボで示すことができた。フルボディー抗体の脳移行性は投与した放射標識プローブ全体の0.05~0.1%とこれまでの報告と同等であった。

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  • 腫瘍部位におけるホウ素濃度の計測を可能とするBNCT用薬剤の創出

    研究課題/領域番号:19K05735  2019年04月 - 2022年03月

    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)

    加来田 博貴, 濱野 毅, 小川原 亮, 佐々木 崇了, 井川 和代

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

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  • 脳機能イメージングによる能動的低代謝の原理解明

    研究課題/領域番号:18K06347  2018年04月 - 2021年03月

    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)

    砂川 玄志郎, 佐々木 崇了

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    本研究では絶食によって生じるマウスの休眠をMRI内で誘導し、マウス休眠における脳の局所的活動ダイナミクスを観察することが目的である。マウスの頭部を固定したまま、体を保定した状態で24時間拘束し、この間に休眠を誘導する必要がある。2019年度は昨年度に引き続き予定していた3つの目標のうち、目標1「休眠を誘導しながら機能的MRIを測定する」と目標2「MRI装置内で全身の代謝を測定する」を中心に実験を進めた。目標3「低代謝に至る脳活動ダイナミクスを明らかにする」は目標1と目標2が達成され次第、すすめていく予定である。目標1に関してはMRIのマウス用コイルに入りうる頭部固定装置をデザインしようとしたが、マウスを24時間固定し続けるためには大きさが足りなかったため、ラット用のMRIコイルに装着できるマウス頭部工程装置を開発し、マウスを固定した状態で24時間生存できることを確認した。同固定装置にマウスを保定した状態で休眠誘導を試みているが現在は成功していない。また、MRIを測定しながら代謝を評価するために非侵襲に検出された呼吸波形を機械学習を用いて代謝を推定するアルゴリズムを開発するための呼吸波形を取得する予定であったが、リソースの問題で2019年度内に成し遂げられなかった。計画2はラット用のMRIコイルでマウスの頭部の機能的MRIを撮影している。休眠が誘導されたマウスの基礎代謝は著しく低下するため、代謝が低下した状態を鋭敏に検出する必要があるが、麻酔をかけたマウスと死後マウスの差を描出できることを確認した。

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  • 標的医療用Aβオリゴマー抗体をPETプローブ化した新規画像バイオマーカーの創出

    研究課題/領域番号:16H05228  2016年04月 - 2019年03月

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

    松原 悦朗, 松浦 栄次, 佐々木 崇了, 藪内 健一, 三浦 由真子

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    配分額:17940000円 ( 直接経費:13800000円 、 間接経費:4140000円 )

    89Zr標識Aβオリゴマー(AβO)特異的抗体によるPET診断に向けて、キレート剤(DFO)標識による抗原性低下のない非標識抗体と同様の特異性を担保した放射標識抗体プローブ作成に成功した。残念ながらこの抗体プローブをもちいたインビボPETイメージングにより非侵襲的に検出することはできなかったが、摘出脳における放射能量定量とオートラジオグラフィーによる分布評価で、アルツハイマー病モデルマウスにおいて脳への移行性を確認した。以上の結果から、Aβオリゴマーに対する放射標識抗体をもちいることで、脳内移行性やS/N比の改善などによる非侵襲的な生体イメージングによる検出の可能性を示すことができた。

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  • 動脈硬化性疾患の早期診断を可能にする分子イメージング・リピドーム解析技術の構築

    研究課題/領域番号:26253036  2014年04月 - 2017年03月

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

    松浦 栄次, 保田 晋助, 佐々木 崇了, 小林 和子, 竹中 文章, 小関 英一, 藤分 秀司, 小渕 浩嗣

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    配分額:41860000円 ( 直接経費:32200000円 、 間接経費:9660000円 )

    B2-glycoprotein Iは、止血・血栓、血管新生を制御する多機能血漿タンパク質である。本タンパク質は、plasminによる限定分解を受けることで、特定のリン脂質、酸化脂質、タンパク質との結合能を制御し自らの生理活性を調節する。本研究では、plasminによる限定分解部位を新規に特定すると共に、plasmin抵抗性のドメインI、Vの組換えタンパク質を作製した。また、本タンパク質のPETによる血管新生部位への局在や生理機能を解析すると共に、アフィニティーカラムとLC-MS/MSの組み合わせにより動脈硬化関連の酸化脂質を網羅的に解析できるメタボロミックス技術の構築を試みた。

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  • 新規核種(89Zr)標識ヒト化低分子抗体によるがんのPET画像診断法の開発

    研究課題/領域番号:25670273  2013年04月 - 2015年03月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    松浦 栄次, 竹中 文章, 佐々木 崇了, 小林 和子, 喜多 祥一

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    配分額:3900000円 ( 直接経費:3000000円 、 間接経費:900000円 )

    種々のがんの高感度検出が可能で、かつ低被爆の「抗体PETプローブ」の開発を目的として、がん抗原mesothelin(MSLN)に対する低分子化抗体scFvを作製した。scFv抗体のMSLNに対する解離定数は約10-50nMで、これをキレート剤DFOにより修飾し、ジルコニウム(Zr)-89で標識した。89Zr標識抗MSLN-scFv抗体をNCI-H226中皮腫細胞移植担がんマウスに尾静脈より投与し、その生体内分布をPETイメージングおよび解剖後の臓器放射能測定により調べた。その結果、PETでは投与48時間後に最もコントラストが高く腫瘍が描出され、本PETプローブのがん検出への有用性が示された。

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