Updated on 2024/02/02

写真a

 
SASAKI Takanori
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Assistant Professor
Position
Assistant Professor
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Research Areas

  • Life Science / Veterinary medical science

  • Life Science / Radiological sciences

Education

  • kayama University Graduate School   of Medicine, Dentistry, and Pharmaceutical Sciences  

    2008.4 - 2012.3

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  • Iwate University   農学部   獣医学科

    2001.4 - 2007.3

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Research History

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

    2011.4

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  • Kurashiki University of Science and the Arts   Department of Comparative Animal ScienceA   Assistant Professor

    2007.4 - 2011.3

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Papers

  • Teratogenicity and Fetal-Transfer Assessment of the Retinoid X Receptor Agonist Bexarotene. International journal

    Yuta Takamura, Izumi Kato, Manami Fujita-Takahashi, Midori Azuma-Nishii, Masaki Watanabe, Rui Nozaki, Masaru Akehi, Takanori Sasaki, Hiroyuki Hirano, Hiroki Kakuta

    ACS pharmacology & translational science   5 ( 9 )   811 - 818   2022.9

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    Language:English   Publishing type:Research paper (scientific journal)  

    Bexarotene, a retinoid X receptor (RXR) agonist, is used to treat cutaneous T-cell lymphoma, and drug repositioning research has also been reported, despite warnings of teratogenicity. However, fetal transfer of bexarotene and its effect on rat fetal bone formation have not been examined. In this study, we conducted a detailed teratogenicity and fetal transferability assessment of bexarotene in rats. Repeated administration of bexarotene during pregnancy caused marked fetal atrophy and bone dysplasia. Although fetal transfer was not detectable by dynamic imaging of [11C]bexarotene by means of positron emission tomography, transfer to the fetus was confirmed by using a gamma counter. Similar levels were found in mother and fetus. In addition, we found that bexarotene was accumulated in the placenta. These findings will be useful for the toxicity assessment of bexarotene as well as for drug discovery research targeting RXR agonists, which are expected to have therapeutic effects in various diseases.

    DOI: 10.1021/acsptsci.2c00126

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

    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   2021.6

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    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   2021.2

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    Publishing type:Research paper (scientific journal)   Publisher: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. International journal

    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   2020.8

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    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. Reviewed International journal

    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   2020.3

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    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 Reviewed

    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   2020.1

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    Language:Japanese   Publisher:(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

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    DOI: 10.5759/jscas.22.14

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  • The canine RAD51 mutation leads to the attenuation of interaction with PALB2. Reviewed International journal

    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   2019.9

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    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 Reviewed

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

    Cancer Science   110 ( 9 )   2722 - 2733   2019.9

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    Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1111/cas.14150

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    Other Link: 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. Reviewed International journal

    Yuta Takamura, Osamu Shibahara, Masaki Watanabe, Michiko Fujihara, Shoya Yamada, Masaru Akehi, Takanori Sasaki, Hiroyuki Hirano, Hiroki Kakuta

    Bioorganic & medicinal chemistry   27 ( 14 )   3128 - 3134   2019.7

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    Bexarotene (1), a retinoid X receptor (RXR) agonist approved for the treatment of cutaneous T cell lymphoma (CTCL), was reported to migrate into baboon brain based on findings obtained by positron emission tomography (PET) with a 11C-labeled tracer. However, co-administration of non-radioactive 1 had no effect on the distribution of [11C]1, probably due to non-specific binding of 1 as a result of its high lipophilicity. Here, we report a fluorine-18 (18F)-labeled PET tracer [18F]6 derived from RXR partial agonist CBt-PMN (2), which has lower lipophilicity and weaker RXR-binding ability than [11C]1. The concomitant administration of 1 or 2 with [18F]6 with resulted in decreased accumulation of [18F]6 in liver, together with increased brain uptake and increased accumulation in kidney and muscle, as visualized by PET. A plausible explanation of these findings is the inhibition of [18F]6 uptake into the liver by concomitantly administered 1 or 2, leading to an increase in blood concentration of [18F]6 followed by increased accumulation in other tissues.

    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 Reviewed

    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   2019.5

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    DOI: 10.1021/acs.jmedchem.9b00617

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

    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   2018.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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. Reviewed

    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   2018.8

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    Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.berh.2019.01.007

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  • Endogenous Leu332Gln mutation in p53 disrupts the tetramerization ability in a canine mammary gland tumor cell line. Reviewed International journal

    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   2018.7

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    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 Reviewed

    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   2017.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Reviewed

    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   2017.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Reviewed

    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   2017.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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/beta(2)-glycoprotein I complexes into atherosclerotic plaques of WHHL rabbits: Implication for clinical PET imaging Reviewed

    Takanori Sasaki, Kazuko Kobayashi, Shoichi Kita, Kazuo Kojima, Hiroyuki Hirano, Lianhua Shen, Fumiaki Takenaka, Hiromi Kumon, Eiji Matsuura

    AUTOIMMUNITY REVIEWS   16 ( 2 )   159 - 167   2017.2

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    Background: Oxidized LDL (oxLDL) can exist as a complex with beta(2)-glycoprotein I (beta(2)GPI) in plasma/serum of patients with non-autoimmune atherosclerotic disease or antiphospholipid syndrome (APS). Nonetheless, direct in vivo evidence supporting the pathophysiological involvement of oxLDL/beta(2)GPI complexes and specific autoantibody against the complexes in developing atherothrombosis has yet been established. In the present study, we demonstrated in vivo distribution of single chain variable fragment of IgG anti-oxLDL/beta(2)GPI complexes (3H3-scFv) in Watanabe heritable hyperlipidemic (WHHL) rabbits by PET/CT imaging.
    Methods: An antibody-based PET probe, Cu-64-3H3-scFv, was established, and WHHL rabbits were applied for a non-autoimmune atherosclerotic model to demonstrate in vivo distribution of the probe.
    Results: 3H3-scFv has exhibits specificity towards beta(2)GPI complexed with oxLDL but neither a free form of beta(2)GPI nor oxLDL alone. Post-intravenous administration of Cu-64-3H3-scFv into WHHL rabbits has demonstrated a noninvasive approach for in vivo visualization of atherosderotic lesion. The imaging probe achieved ideal blood clearance and distribution for optimal imaging capacity in 24 h, significantly shorter than that of an intact IgG-based imaging probe. Cu-64-3H3-scFv targeted on atherosclerotic plaques in aortas of WHHL rabbits where extensive accumulation of lipid deposits was observed by lipid staining and autoradiography. The accumulation of Cu-64-3H3scFv in aortic segments of WHHL rabbits was 2.8-folds higher than that of controls (p = 0.0045).
    Conclusions: The present in vivo evidence supports the pathophysiological involvement of oxLDL/beta(2)GPI complexes in atherosclerotic complications of WHHL rabbits. Cu-64-3H3-scFv represents a novel PET imaging probe for non-invasive pathophysiological assessment of oxLDL/beta(2)GPI complexes accumulated in atherosclerotic plaques. (C) 2016 Elsevier B.V. All rights reserved.

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  • The Function of beta 2-glycoprotein I in Angiogenesis and Its in Vivo Distribution in Tumor Xenografts Reviewed

    Arum Tri Wahyuningsih, Lianhua Shen, Kazuko Kobayashi, Takanori Sasaki, Fumiaki Takenaka, Takahisa Hanada, Masaru Akehi, Akiya Akahoshi, Eiichi Ozeki, Eiji Ando, Eiji Matsuura

    ACTA MEDICA OKAYAMA   70 ( 1 )   13 - 24   2016.2

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    Intact beta 2-glycoprotein I (i beta 2GPI) is a glycoprotein that regulates coagulation and fibrinolysis. Nicked beta 2GPI (n beta 2GPI) possesses an angiogenic property at a relatively low concentration, and an anti-angiogenic property at a high concentration. Here we investigated the functions of i beta 2GPI and n beta 2GPI in vascular endothelial growth factor (VEGF)-A-induced endothelial cell proliferation and tube formation. We used noninvasive PET imaging to analyze the in vivo distribution of intravenously injected beta 2GPI variants in tumor lesions in mice. i beta 2GPI was incubated with plasmin to obtain n beta 2GPI, and its N-terminal sequence was analyzed. n beta 2GPI had at least one other cleavage site upstream of the beta 2GPFs domain V, whereas the former plasmin-cleavage site locates between K-317 and T-318. Both of intact and nicked beta 2GPI significantly inhibited the VEGF-A-induced cell proliferation and the tube formation of human umbilical vein endothelial cells (HUVECs). PET imaging visualized considerably distributed intensities of all tested beta 2GPI variants in tumor lesions of pancreatic tumor cell-xenografts. These results indicate that beta 2GPI may be physiologically and pathophysiologically important in the regulation of not only coagulation and fibrinolysis, but also angiogenesis.

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

    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   2015.3

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    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.

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  • A Novel PET Imaging Using Cu-64-Labeled Monoclonal Antibody against Mesothelin Commonly Expressed on Cancer Cells Reviewed

    Kazuko Kobayashi, Takanori Sasaki, Fumiaki Takenaka, Hiromasa Yakushiji, Yoshihiro Fujii, Yoshiro Kishi, Shoichi Kita, Lianhua Shen, Hiromi Kumon, Eiji Matsuura

    JOURNAL OF IMMUNOLOGY RESEARCH   2015   268172   2015

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    Mesothelin (MSLN) is a 40-kDa cell differentiation-associated glycoprotein appearing with carcinogenesis and is highly expressed in many human cancers, including the majority of pancreatic adenocarcinomas, ovarian cancers, and mesotheliomas, while its expression in normal tissue is limited to mesothelial cells lining the pleura, pericardium, and peritoneum. Clone 11-25 is a murine hybridoma secretingmonoclonal antibody (mAb) against human MSLN. In this study, we applied the 11-25 mAb to in vivo imaging to detect MSLN-expressing tumors. In in vitro and ex vivo immunochemical studies, we demonstrated specificity of 11-25 mAb to membranous MSLN expressed on several pancreatic cancer cells. We showed the accumulation of Alexa Fluor 750-labeled 11-25 mAb in MSLN-expressing tumor xenografts in athymic nude mice. Then, 11-25 mAb was labeled with Cu-64 via a chelating agent DOTA and was used in both in vitro cell binding assay and in vivo positron emission tomography (PET) imaging in the tumorbearing mice. We confirmed that Cu-64-labeled 11-25 mAb highly accumulated in MSLN-expressing tumors as compared to MSLN negative ones. The Cu-64-labeled 11-25 mAb is potentially useful as a PET probe capable of being used for wide range of tumors, rather than F-18-FDG that occasionally provides nonspecific accumulation into the inflammatory lesions.

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

    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

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    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 Reviewed

    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

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    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.

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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 Invited

    佐々木崇了, 松浦栄次, 公文裕巳, 矢野恒夫

    Pharm Tech Japan   29   123 - 128   2013

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

    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   2012.6

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    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.

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

    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   2011.10

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    DOI: 10.2327/jvas.42.7

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  • Application of 3D printer for Small Animal Practice Reviewed

    Kanda T, Sasaki T, Maeta N, Fujioka T, Nagai A, Furumoto K, Furukawa T

    Journal of the Japan Veterinary Medical Association   64 ( 8 )   640 - 643   2011.8

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    DOI: 10.12935/jvma.64.640

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    Other Link: http://search.jamas.or.jp/link/ui/2011302179

  • Determination of the estrous cycle stage in rat by using an otoscope Reviewed

    Furumoto K, Kanda T, Maeta N, Sasaki T, Murao N, Furukawa T

    The journal of experimental animal technology   46 ( 2 )   2011

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  • A Case of the American Cocker Spaniel of the Chronic Suppurative Otitis Media Surgically Treated Using an Ultrasonic Osteotome for Osteotomy Reviewed

    MAETA Noritaka, SASAKI Takanori, KANDA Teppei, FUJIOKA Tooru, FURUKAWA Toshinori

    Japanese Journal of Veterinary Anesthesia & Surgery   42 ( 2 )   21 - 24   2011

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    DOI: 10.2327/jvas.42.21

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  • Spinal epidural empyema in a cat Reviewed

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

    JOURNAL OF FELINE MEDICINE AND SURGERY   12 ( 6 )   494 - 497   2010.6

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    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.

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

    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   2009.10

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    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.

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

    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   2009.9

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    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.

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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   2019.8

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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   2017.8

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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   2017.3

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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   2016.8

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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   2014.8

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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   2014.8

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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   2014.4

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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   2014.3

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  • 腫瘍のADC値の成因と治療後変化のメカニズムに関するバイオファントムを用いた検討

    黒田 昌宏, 田口 勇仁, 加藤 博和, 佐々木 崇了, 片嶋 和典, 芦田 昌和, 金澤 右, 浅海 淳一, 松崎 秀信

    Japanese Journal of Radiology   30 ( Suppl.I )   68 - 68   2012.2

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  • 後躯麻痺の猫にみられた脊髄硬膜外膿瘍

    前田憲孝, 神田鉄平, 佐々木崇了, 森田剛仁, 古川敏紀

    日本産業動物獣医学会(中国)・日本小動物獣医学会(中国)・日本獣医公衆衛生学会(中国)   2010   2010

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Research Projects

  • 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

    Grant number:20H04058  2020.04 - 2024.03

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

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  • Evaluation for metabolic brain diseases using cerebral oxygen metabolism imaging

    Grant number:20K08136  2020.04 - 2023.03

    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)

    佐々木 智章, 浅沼 幹人, 佐々木 崇了

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

    コロナ渦のためPETのキャリブレーションおよび動物実験などがなかなか始められなかったが、ファントムを用いた実験はすぐに始められた。
    代謝性脳疾患の一つであるWernicke脳症において脈絡叢のエネルギー産生供給不足から脳脊髄液の組成の違いが起こるということを想定して、MRIにおいて髄液の組成(Na、glucoseあるいはアルブミン濃度)や体温が変化した場合、その違いが見かけの拡散係数(ADC値)の変化からdetectできるかの基礎研究から行った。
    常温(20℃)にてNa(基準濃度は1%)は基準濃度から半分希釈や2倍濃度でもほとんどADC値に変化がなかった(0.99-1.03倍)が、40℃でADC値は0.91-0.94倍と変動幅が増大した。常温アルブミン(基準5%)では0.93-1.06倍に変化したが、40℃(変性あり参考程度)では0.81-1.06倍に変化した。常温glucose(基準濃度5%)は2倍濃度でADC値は0.91倍に変化し、40℃で0.93倍に変化した。いずれもそれぞれの基準濃度で、各試料を20℃から40℃に変化させた時のADC値は2.0-2.5倍程上昇し、特にglucoseとアルブミンで変動幅が大きくなる傾向が見られた。分子径の大きい物質の濃度変化による変動がADC値に影響を及ぼしやすい可能性が示唆された。Wernicke脳症が脈絡叢障害による髄液のglucoseやアルブミン濃度異常が病態の一因であるとすれば髄液のADC値変化から診断補助に活用できる可能性がある。
    また、MRIにおいて脳酸素代謝画像はT2減衰を反映したシークエンスを使用するが、その検証のため金属釘による基礎研究も別に行った。さらにいくつかの先天性代謝性疾患の詳細な画像解析も行い、エネルギー代謝に関係する代謝経路の理解をより深めた。

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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

    Grant number:20K08109  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)

    佐々木 崇了

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

    本研究では、がん免疫治療において、その治療効果に主要な役割を担う免疫細胞を直接放射標識することで、免疫細胞そのものを治療効果判定のイメージングプローブ
    として開発を行い、がん免疫および細胞治療の細胞追跡評価のプラットフォーム技術の確立を目指す。
    本年度は免疫細胞プローブとして放射標識したCD8Tcellを作成し、PETイメージングを行った。
    昨年度確立した免疫治療効果判定のための動物モデルである腫瘍移植マウスを用いたPD-1、PD-L1、CTLA-4抗体による治療モデルに、放射標識したCD8Tcellを投与し腫瘍浸潤リンパ球(TIL)の程度をPETイメージングおよび病理組織学的検査をもとに評価した。
    治療効果と相関したPETシグナルを得ることができ、免疫治療の効果をTILの浸潤の可視化として定量することに成功した。

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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

    Grant number:19KK0215  2019.10 - 2023.03

    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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    Grant amount:\18070000 ( Direct expense: \13900000 、 Indirect expense:\4170000 )

    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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  • Novel PET imaging of Abeta oligomer using cell- and BBB-penetrating microantibody

    Grant number:19H03566  2019.04 - 2023.03

    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)

    松原 悦朗, 佐々木 崇了, 藪内 健一, 松浦 栄次

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

    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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  • Creation of new agents for BNCT that enable to measure boron concentration at tumor site

    Grant number:19K05735  2019.04 - 2022.03

    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)

    Kakuta Hiroki

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

    Boron neutron capture therapy (BNCT) depends on the collision of 10B and neutrons, so the concentration of boron in the cancer tissue is an important factor. However, there is no boron compounds whose boron concentration in cancer tissue can be measured. In this study, we aimed to create new compounds for BNCT to solve this problem. Focusing on the quantification of iodine concentration in X-ray CT, we designed compounds having diiodobenzene and BSH, which is a boron cluster. Among them, BS-DIP-OEF (3c), which has a fluoroethyl group, showed quantifiability in X-ray CT at iodine concentrations above 800 ppm. When neutron beam irradiation is performed on the cells treated with 3c, the boron neutron capture reaction (BNCR) were highly correlated with intracellular boron concentration.

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  • Functional MRI Brain imaging in Torpid Mice

    Grant number:18K06347  2018.04 - 2021.03

    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)

    Genshiro Sunagawa

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

    This project aims to observe the local dynamics of the brain during torpor. Torpor is induced by 24-hour fasting of mice. The brain of any torpid animals, including hibernators, have not been reported to be evaluated under functional MRI. Active hypometabolism of torpor is promising for harmful high-metabolism conditions in medicine. We experienced difficulty inducing torpor in the MRI; however, we have nearly overcome the issue by developing QIH, an inducible hibernation-like condition in mice.

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  • Development of a novel imaging biomarker of Abeta oligomers in the brain

    Grant number:16H05228  2016.04 - 2019.03

    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)

    Matsubara Etsuro

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    Grant amount:\17940000 ( Direct expense: \13800000 、 Indirect expense:\4140000 )

    The aim of this study was to develop in vivo imaging biomarker for Aβ oligomers (AβOs) in the brain. Chelation of anti-AβO gave 89Zr-labelling efficiencies of more than 80%, resulted in ideal probe with preserved specificity almost identical to unlabeled antibody. Unfortunately, we did not make Aβ oligomers accumulation in the brain visible in vivo, whereas both ex vivo autoradiography and biodistribution study unequivocally revealed that brain uptake of 89Zr-labelled anti-AβO was significantly higher in APP-KI mice than in wild-type mice, indicating that the antibody can cross the blood-brain barrier. These findings indicated that further improvement of several factors (ex. BBB-penetrating activity, S/N ratio, and so on) is still necessary. However, 89Zr-labelled anti-ABO might be a potential candidate for in vivo imaging of AβO accumulation in the brain.

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  • Establishment of Molecular Imaging and Lipidomics Technologies for Early Diagnosis of Atherosclerotic Disease

    Grant number:26253036  2014.04 - 2017.03

    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)

    MATSUURA Eiji, SASAKI Takanori, KOBAYASHI Kazuko, TAKENAKA Fumiaki, OZEKI Eiichi, FUJIWAKE Hideshi, KOBUCHI Hirotsugu

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    Grant amount:\41860000 ( Direct expense: \32200000 、 Indirect expense:\9660000 )

    B2-Glycoprotein I (B2GPI) is a multifunctional plasma protein consisting of five homologous domains that control thrombosis/hemostasis and angiogenesis. Its physiological activity and binding affinity to particular phospholipids, oxidized lipids and/or proteins are regulated by the enzymatic activity of plasmin. In the present study, we identified a novel cleavage site by plasmin and produced plasmin-resistant recombinant proteins of domain V and domain I. With these, we have confirmed their localization at angiogenic legions in mouse xenograft models via PET imaging, and their respective physiological functions in vitro and in vivo. In addition, a metabolomic-based approach involving the combination of B2GPI-affinity column and LC-MS/MS has also been constructed to comprehensively analyse oxidized lipids involved in the development of atherosclerotic diseases.

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  • Development of a PET imaging system for cancer diagnosis using Zr-89 lableled anti-mesothelin scFv

    Grant number:25670273  2013.04 - 2015.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    MATSUURA Eiji, TAKENAKA Fumiaki, SASAKI Takanori, KOBAYASHI Kazuko, KITA Shoichi

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    Grant amount:\3900000 ( Direct expense: \3000000 、 Indirect expense:\900000 )

    For the purpose of developing an antibody-based PET imaging agent of cancer, we produced scFv against mesothelin (MSLN). MSLN is a 40-kDa cell differentiation-associated glycoprotein appeared with carcinogenesis and a potential target for a wide range of cancer diagnosis and therapy. Anti-MSLN scFv was conjugated with a chelator deferoxamine (DFO) and radiolabeled with zirconium-89. 89Zr-labeled anti-MSLN scFv was administered intravenously to NCI-H226 tumor bearing mice and imaged with PET/CT up to 48 h post administration followed by terminal biodistribution studies. 89Zr-labeled anti-MSLN scFv was highly accumulated in tumor and a PET image with the highest contrast of tumor to background was obtained at 48 h post injection. These results indicate the high potential of 89Zr-labeled anti-MSLN scFv as a PET probe for the detection of cancer.

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