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Development of a novel targeted single cell drug/gene delivery system

Research Project

Project/Area Number 18200036
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical systems
Research InstitutionFukuoka University

Principal Investigator

TACHIBANA Katsuro  Fukuoka University, 医学部, 教授 (40271605)

Co-Investigator(Kenkyū-buntansha) AI Hiroyuki  福岡大学, 理学部, 助教 (20330897)
Project Period (FY) 2006 – 2008
Project Status Completed (Fiscal Year 2008)
Budget Amount *help
¥41,730,000 (Direct Cost: ¥32,100,000、Indirect Cost: ¥9,630,000)
Fiscal Year 2008: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
Fiscal Year 2007: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2006: ¥19,890,000 (Direct Cost: ¥15,300,000、Indirect Cost: ¥4,590,000)
Keywords超音波エネルギー / 神経細胞 / 周波数 / 超小型超音波プローブ / 遺伝子導入
Research Abstract

本課題の目標であった超音波照射時における浮遊単細胞のリアルタイム顕微鏡観察システムを構築することができた。また、高速ビデオカメラにてマイクロバブルの挙動を観察すると同時に薬物が細胞内に流入する現象を初めてデジタル映像でとらえることができた。この顕微鏡システムを用いることで超音波の最適条件と各種のマイクロバブルの比較が可能となった。得られたデータ解析より、多種の細胞にこの技術が応用可能と考えられる。

Report

(4 results)
  • 2008 Annual Research Report   Final Research Report ( PDF )
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • Research Products

    (62 results)

All 2009 2008 2007 2006 Other

All Journal Article (32 results) (of which Peer Reviewed: 26 results) Presentation (26 results) Book (2 results) Remarks (2 results)

  • [Journal Article] Evaluation and comparison of three novel microbubbles : enhancement of ultrasound-induced cell death and free radicals production2009

    • Author(s)
      Hassan MA, Feril LB Jr, Suzuki K, Kudo N, Tachibana K, Kondo T
    • Journal Title

      Ultrason Sonochem 16(3)

      Pages: 372-8

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Response characteristics of vibration-sensitive interneurons related to Johnston's organ in the honeybee, Apis nielllfera2009

    • Author(s)
      Hiroyuki Ai, Jurgen Rybak, Randolf Menzel, Tsunao Itoh
    • Journal Title

      J. Comp. Neurol. 515

      Pages: 145-160

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] A novel strategy utilizing ultrasound for antigen delivery in dendritic cell-based cancer immunotherapy2009

    • Author(s)
      Suzuki R
    • Journal Title

      J Control Release. 133

      Pages: 198-205

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evaluation and comparison of three novel microbubbles : Enhancement of ultrasound-induced cell death and free radicals production2009

    • Author(s)
      Hassan MA
    • Journal Title

      Ultrason Sonochem. 16/3

      Pages: 372-378

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gene Transfection through microbubble-aided sonication in cancer cells2009

    • Author(s)
      Dickerson C. Moreno
    • Journal Title

      Philippine Physics Journal 31

      Pages: 1-6

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 超音波感受性マイクロバブルを利用した血管壁へのドラッグデリバリー2008

    • Author(s)
      立花克郎
    • Journal Title

      血管医学 9(3)

      Pages: 287-291

    • Related Report
      2008 Annual Research Report 2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Sonodynamic therapy2008

    • Author(s)
      Tachibana K, Feril LB Jr, Ikeda-Dantsuji Y
    • Journal Title

      Ultrasonics 48(4)

      Pages: 253-259

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Therapeutic potential of low-intensity ultrasound (part 2) : biomolecular effects, sonotransfection, and sonoporation2008

    • Author(s)
      Feril LB Jr, Tachibana K, Ikeda-Dantsuji Y, Endo H, Harada Y, Kondo T, Ogawa R
    • Journal Title

      Journal of Medical Ultrasonics 35

      Pages: 161-167

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Three-dimensional reconstruction of neural tracts and commissures in the bee brain2008

    • Author(s)
      H Ai, Y Kusakabe, T Itoh
    • Journal Title

      Comparative Biochemistry and Physiology, Part B, Biochemistry & molecular biology 151(4)

      Pages: 457-457

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Therapeutic Potential of Low-Intensity Ultrasound(Part1) : Thermal and Sonomechanical Effects2008

    • Author(s)
      Feril Loreto, Tachibana K, Ogawa K, Irie Y
    • Journal Title

      J. Med Ultrasonics 35

      Pages: 153-160

    • NAID

      10025327393

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Therapeutic Potential of Low-Intensity Ultrasound(Part1) : Thermal and Sonomechanical Effects2008

    • Author(s)
      FERIL Loreto
    • Journal Title

      J. Med Ultrasonics 35

      Pages: 153-160

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Therapeutic potentials of low-intensity ultrasound (part II) : Biomolecular effects, sonotransfection and sonopermeabilization2008

    • Author(s)
      FERIL Loreto
    • Journal Title

      J. Med Ultrasonics 35

      Pages: 161-167

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Genetic networks responsive to low-intensity pulsed ultrasound in human lymphoma U937 cells2008

    • Author(s)
      Tabuchi Y
    • Journal Title

      Cancer Letters 270/2

      Pages: 286-294

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sonodynamic Therapy2008

    • Author(s)
      Tachibana Katsuro
    • Journal Title

      Ultrasonic 48

      Pages: 253-259

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Growth inhibition of neurofibroma by ultrasound-mediated interferon γ transfection2008

    • Author(s)
      Yamaguchi K
    • Journal Title

      Journal of Medical Ultrasonics 36

      Pages: 3-8

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 超音波を利用した部位特異的遺伝子デリバリーシステムの開発2008

    • Author(s)
      鈴木 亮、小田 雄介、生井 栄祐、滝澤 知子、根岸 洋一、宇都宮 直樹、立花 克郎、丸山 一雄
    • Journal Title

      薬学雑誌 128(2)

      Pages: 187-1192

    • NAID

      110006572172

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gene Transfer/delivery and Expression of DNA and RNA Gene Transfer/delivery and Expression of DNA and RNA Sonoporation : An Efficient Technique for the Introduction of Genes into Chick Embryos(Edited by Theodore Friedmann, John Rossi)2007

    • Author(s)
      Ohta S, Ogino Y, Suzuki K, Kamimura M, Tachibana K, and Yamada G
    • Journal Title

      Cold Spring Harbor Laboratory Press

      Pages: 711-716

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Journal of Comparative Neurology, Topographic organization of sensory afferents of Johnston's organ in the honeybee brain2007

    • Journal Title

      Wiley-Liss, Inc

      Pages: 1030-1046

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] A novel bubble liposome and ultrasound-mediated gene transfer to ocular surface : RC-1 cells in vitro and conjunctiva in vivo2007

    • Author(s)
      Yamashita T, Sonoda S, Suzuki R, Arimura N, Tachibana K, Maruyama K, and Sakamoto T
    • Journal Title

      Experimental Eye Reserch 85(6)

      Pages: 741-748

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Biomolecular Effects of Low Intensity Ultrasound : Apoptosis, Sonotransfection, and Gene Expression2007

    • Author(s)
      Feril LB Jr, Kondo T, Tabuchi Y, Ogawa R, Zhao Q-L, Nozaki T, Yoshida T, Kudo N, and Tachibana K
    • Journal Title

      Japanese Journal of Applied Physics 46(7B)

      Pages: 4435-4440

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Cessation of gastrulation is mediated by supPression of epithelial-mesenchymal transition at the ventral ectodermal ridge2007

    • Author(s)
      Ohta S, Suzuki K, Tachibana K, Tanaka H, Yamada G
    • Journal Title

      Development 134

      Pages: 4315-4324

    • NAID

      120002468517

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel bubble liposome and ultrasound-mediated gene transfer toocular surface: RC-1 cells in vitro and conjunctiva in vivo2007

    • Author(s)
      Yamashita T, Sonoda S, Suzuki R, Arimura N, Tachibana K, Maruyama K, and Sakamoto T
    • Journal Title

      Exp Eye Res 85(6)

      Pages: 741-748

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biomolecular Effects of Low Intensity Ultrasound: Apoptosis, Sonotransfection, and Gene Expression2007

    • Author(s)
      Feril LB Jr, Kondo T, Tabuchi Y, Ogawa R, Zhao Q-L, Nozaki T, Yoshida T, Kudo N, and Tachibana K
    • Journal Title

      Japanese Journal of Applied Physics 46

      Pages: 4435-4440

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Antitumor Effect of TNP-470, an Angiogenesis Inhibitor, Combined with Ultrasound Irradiation for Human Uterine Sarcoma Xenografts Evaluated by Contrast Color Doppler Ultrasound2007

    • Author(s)
      Emoto M, Tachibana K, Iwasaki H and Kawarabayashi T
    • Journal Title

      Cancer Science 98

      Pages: 929-935

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of melanoma by ultrasound-microbubble-aided drug delivery suggests membrane permeabilization2007

    • Author(s)
      Sonoda S, Tachibana K, Uchino E, Yamashita T, Sakoda K, Sonoda KH, Hisatomi T, Izumi Y, Sakamoto T.
    • Journal Title

      Cancer Biol Ther 6(8)

      Pages: 1276-1283

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biomolecular effects of low intensity ultrasound : apoptosis, sonotransfection, and gene expression.2007

    • Author(s)
      Feril LB Jr, Kondo T, Tabuchi, Ogawa R, Zhao Q-L, Nozaki T, Toru Y, Kudo N, Tachibana K
    • Journal Title

      Japanese Journal of Applied Physics (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Bioeffects of Ultrasound for Therapy2007

    • Author(s)
      Feril LB Jr, Tachibana K, Yamaguchi K, Ogawa K, Dantsuji Y, Irie Y, Endo H
    • Journal Title

      Philippine Physics Journal (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Biological Effects of Ultrasound : Sonomechanical Mechanism, and Its Implications on Therapy and Biosafety2007

    • Author(s)
      Feril LB Jr, Kondo T, Tachibana K, Ogawa R, Ogawa K
    • Journal Title

      Therapeutic Ultrasound : 5th International Symposium on Therapeutic Ultrasound (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Emerging Technologies Using Ultrasound for Drug Delivery : Emerging Therapeutic Ultrasound2006

    • Author(s)
      Katsuro Tachibana
    • Journal Title

      World Scientific

      Pages: 131-166

    • Related Report
      2008 Final Research Report
    • Peer Reviewed
  • [Journal Article] Ultrasound in Medicine : To Search and diseased Tissues.2006

    • Author(s)
      Feril LB Jr, Tachibana K.
    • Journal Title

      Philippine Physics journal 28

      Pages: 67-72

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Optimized ultrasound-mediated gene transfection in cancer cells.2006

    • Author(s)
      Feril LB Jr, Ogawa R, Tachibana K, Kondo T.
    • Journal Title

      Cancer Sci. 97(10)

      Pages: 1111-1114

    • NAID

      10019378415

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 超音波の治療への応用2006

    • Author(s)
      立花克郎, 入江 豊, 小川皓一
    • Journal Title

      J Med Ultrasound 33(6)

      Pages: 631-639

    • NAID

      10020611604

    • Related Report
      2006 Annual Research Report
  • [Presentation] マイクロバブルと超音波治療2009

    • Author(s)
      立花克郎
    • Organizer
      第4回超音波分子診断治療研究会
    • Place of Presentation
      名古屋
    • Year and Date
      2009-01-09
    • Related Report
      2008 Final Research Report
  • [Presentation] マイクロバブルの治療への応用2008

    • Author(s)
      立花克郎
    • Organizer
      第10回国際造影超音波シンポジウム
    • Place of Presentation
      東京医科大学病院
    • Year and Date
      2008-12-13
    • Related Report
      2008 Annual Research Report 2008 Final Research Report
  • [Presentation] 神経超音波の基礎2008

    • Author(s)
      立花克郎
    • Organizer
      第11回日本栓子検出と治療学会(エンボラス学会)
    • Place of Presentation
      倉敷
    • Year and Date
      2008-11-01
    • Related Report
      2008 Annual Research Report 2008 Final Research Report
  • [Presentation] Low-intensity ultrasound inhibits cancer growth by modifying cell cycle2008

    • Author(s)
      FERIL Loreto
    • Organizer
      8th International Symposium on Therapeutic Ultrasound
    • Place of Presentation
      Minneapolis, USA
    • Year and Date
      2008-09-12
    • Related Report
      2008 Annual Research Report
  • [Presentation] U937細胞におけるドキシルと超音波併用による殺細胞効果について2008

    • Author(s)
      原田慶美、遠藤日富美、山口和記、立花克郎
    • Organizer
      第2回超音波分子診断治療研究会(第2回基礎技術研究会共催)
    • Place of Presentation
      北海道大学
    • Year and Date
      2008-08-08
    • Related Report
      2008 Final Research Report
  • [Presentation] Anti-tumor Effects of Dendritic Cell-Based Cancer Immunotherapy Utilizing Novel Liposomal Bubbles and Ultrasound as Antigen Delivery System2008

    • Author(s)
      Yusuke Oda
    • Organizer
      第11回国際リボソーム研究会議
    • Place of Presentation
      横浜
    • Year and Date
      2008-07-21
    • Related Report
      2008 Annual Research Report
  • [Presentation] The Effect of Cell Killing by Ultrasound and Encapsulating Doxorubicin Bubble Liposomes(EDBL)2008

    • Author(s)
      原田慶美
    • Organizer
      第11回国際リポソーム研究会議
    • Place of Presentation
      横浜
    • Year and Date
      2008-07-20
    • Related Report
      2008 Annual Research Report
  • [Presentation] Cancer Immunotherapy Based on Liposomal Bubbles-Mediated Antigen Delivery to Dendritic Cells2008

    • Author(s)
      Ryo Suzuki
    • Organizer
      第11回国際リボソーム研究会議
    • Place of Presentation
      横浜
    • Year and Date
      2008-07-20
    • Related Report
      2008 Annual Research Report
  • [Presentation] Catheter-based ultrasound thrombolysis2008

    • Author(s)
      Tachibana K
    • Organizer
      International Sonothrombolysis Conference
    • Place of Presentation
      Heidelberg, Germany
    • Year and Date
      2008-07-05
    • Related Report
      2008 Annual Research Report
  • [Presentation] Sonoporation法による皮膚への遺伝子導入2008

    • Author(s)
      入江豊
    • Organizer
      日本超音波学会第81回学術集会
    • Place of Presentation
      神戸
    • Year and Date
      2008-05-24
    • Related Report
      2008 Annual Research Report
  • [Presentation] バブルリポソームと超音波の併用による肝臓特異的遺伝子導入法の開発2008

    • Author(s)
      立花克郎
    • Organizer
      日本超音波医学会第81回学術集会
    • Place of Presentation
      神戸
    • Year and Date
      2008-05-24
    • Related Report
      2008 Annual Research Report
  • [Presentation] 超音波血栓溶解療法の臨床応用について2008

    • Author(s)
      立花克郎
    • Organizer
      日本超音波医学会第81回学術集会
    • Place of Presentation
      神戸
    • Year and Date
      2008-05-24
    • Related Report
      2008 Annual Research Report
  • [Presentation] 超音波による眼科領域疾患に対する治療の可能性2008

    • Author(s)
      坂本泰二
    • Organizer
      日本超音波医学会第81回学術集会
    • Place of Presentation
      神戸
    • Year and Date
      2008-05-24
    • Related Report
      2008 Annual Research Report
  • [Presentation] 超音波・マイクロバブル・抗がん剤の併用による癌細胞株U937への殺細胞効果について2008

    • Author(s)
      原田慶美, 立花克郎, 遠藤日富美, フェリル ロリト, 山口和記
    • Organizer
      日本超音波医学会第81回学術集会
    • Place of Presentation
      神戸
    • Year and Date
      2008-05-23
    • Related Report
      2008 Annual Research Report 2008 Final Research Report
  • [Presentation] Low-intensity ultrasound inhibits melanoma growth in vitro and in vivo2008

    • Author(s)
      FERIL Loreto
    • Organizer
      Conjoint Meeting of XXth International Pigment Cell Conference (IPCC) & Vth International Melanoma Research Congress (IMRC)
    • Place of Presentation
      Sapporo, Hokkaido
    • Year and Date
      2008-05-11
    • Related Report
      2008 Annual Research Report
  • [Presentation] Development of a novel antigen delivery method to dendritic cells with liposomal bubbles and ultrasound2007

    • Author(s)
      Ryo Suzuki, Yusuke Oda, Naoki Utoguchi, Naoki Okada, Norimitsu Kadowaki, Katsuro Tchibana, Kazuo Maruyama
    • Organizer
      The 9th International Symposium on Ultrasound Contrast Imaging
    • Place of Presentation
      大阪
    • Year and Date
      2007-12-15
    • Related Report
      2007 Annual Research Report
  • [Presentation] The effect of cell killing by Ultrasound-Microbubble-Anticancer drug2007

    • Author(s)
      Yoshimi Harada, Katsuro Tachibana
    • Organizer
      The 9th International Symposium on Ultrasound Contrast Imaging
    • Place of Presentation
      大阪
    • Year and Date
      2007-12-15
    • Related Report
      2007 Annual Research Report
  • [Presentation] Angiogenesis and Ultrasound-Anti-Angiogenesis Therapy in Combination with Ultrasound Irradiation for Human Cancer Evaluated by Contrast Color2007

    • Author(s)
      Makoto Emoto, Katsuro Tachibana
    • Organizer
      The 9th International Symposium on Ultrasound Contrast Imaging
    • Place of Presentation
      大阪
    • Year and Date
      2007-12-15
    • Related Report
      2007 Annual Research Report
  • [Presentation] Emerging Technologies Using Ultrasound for Drug Delivery2007

    • Author(s)
      立花克郎、フェリル ロリト
    • Organizer
      International Symposium on Sonochemistry and Sonoprocessing 2007 - New horizons in Sonochemistry and Sonoprocessing
    • Place of Presentation
      京都
    • Year and Date
      2007-12-08
    • Related Report
      2008 Final Research Report
  • [Presentation] In vivo gene delivery by sonoporation with liposomal bubbles2007

    • Author(s)
      Ryo Suzuki, Eisuke Nanami, yusuke Oda, Tomoko Takizawa, Naoki Utoguchi, Yoichi Negishi, Katsuro Tachibana, Kazuo Maruyama
    • Organizer
      International Symposium on Sonochemistry and Sonoprocessing 2007-New horizonsin Sonochemistry and Sonoprocessing-
    • Place of Presentation
      京都
    • Year and Date
      2007-12-07
    • Related Report
      2007 Annual Research Report
  • [Presentation] Ultrasound-induced mechanical damage on cells enchanced by hypotoniainduced cell swelling2007

    • Author(s)
      FERIL Loreto, Tachibana Katsuro, Kondo T, Yamaguchi K
    • Organizer
      19th International Congress on Acoustics
    • Place of Presentation
      Madrid Spain
    • Year and Date
      2007-09-02
    • Related Report
      2007 Annual Research Report
  • [Presentation] Effect of low-intensity ultrasound on humang astric carcinoma in nude mice2007

    • Author(s)
      Endo Hitomi, Tachibana Katsuro, Kondo T, Yamaguchi K
    • Organizer
      19th International Congress on Acoustics
    • Place of Presentation
      Madrid Spain
    • Year and Date
      2007-09-02
    • Related Report
      2007 Annual Research Report
  • [Presentation] HIFU(強力集束超音波療法)2007

    • Author(s)
      立花 克郎
    • Organizer
      第26回日本脳神経超音波学会
    • Place of Presentation
      横浜市 パシフィコ横浜
    • Year and Date
      2007-07-10
    • Related Report
      2007 Annual Research Report
  • [Presentation] Enhanced Gene Transfer by Echo Contrast Agents : Comparison between BR1 and BR14 in Vitro and in Vivo2007

    • Author(s)
      遠藤日富美、立花克郎、フェリル ロリト
    • Organizer
      10th Annual Meeting American Society of GENE THERAPY
    • Place of Presentation
      Seattle Washingon USA
    • Year and Date
      2007-06-02
    • Related Report
      2008 Final Research Report
  • [Presentation] Sonotrans fection as a potential alternative Gene Therapy Method in treating pregnant women:A study using Gamma Interferon Gene against Neurofibromav2007

    • Author(s)
      FERIL Loreto, NAKAYAMA Juichiro, Tachibana Katsuro
    • Organizer
      The23rd Fetus as a Patient International Congress
    • Place of Presentation
      Manila,philippines
    • Year and Date
      2007-05-15
    • Related Report
      2007 Annual Research Report
  • [Presentation] 超音波血栓溶解療法2007

    • Author(s)
      立花 克郎
    • Organizer
      日本超音波医学会第80回学術集会
    • Place of Presentation
      鹿児島
    • Related Report
      2007 Annual Research Report
  • [Book] Gene Transfer delivery and Expression of DNA and RNA Edited by Theodore Friedmann John Rossi2007

    • Author(s)
      Ohta S, Ogino Y, Suzuki K, Kamimuea M, Tachibana K, Yamada G.
    • Publisher
      Sonoporation:An Efficient Technique for the Introduction of Genes into Chick Embryos
    • Related Report
      2007 Annual Research Report
  • [Book] Emerging Therapeutic Ultrasound Emerging technologies using ultrasound for drag delivery2006

    • Author(s)
      Tachibana K, Tachibana S
    • Publisher
      World Scientific and Imperial College Press
    • Related Report
      2006 Annual Research Report
  • [Remarks]

    • URL

      http://resweb2.jhk.adm.fukuoka-u.ac.jp/FukuokaUniv/R101J_Action.do

    • Related Report
      2008 Annual Research Report
  • [Remarks]

    • URL

      http://resweb2.jhk.adm.fukuoka-u.ac.jp/FukuokaUniv/R101J_Action.do

    • Related Report
      2007 Annual Research Report

URL: 

Published: 2006-04-01   Modified: 2016-04-21  

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