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Minimally invasive therapy for the lymph node metastasis of oral cancer using the gold nanoparticles and near-infrared light

Research Project

Project/Area Number 26670856
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Surgical dentistry
Research InstitutionTohoku University

Principal Investigator

MORI SHIRO  東北大学, 大学病院, 講師 (80230069)

Co-Investigator(Kenkyū-buntansha) OKAJIMA Junnosuke  東北大学, 流体科学研究所, 助教 (70610161)
Project Period (FY) 2014-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords口腔癌 / リンパ節転移 / 転移モデル / 金ナノロッド / 近赤外線レーザー
Outline of Final Research Achievements

Irradiation of near-infrared laser light to the gold nanorods (GNRs) induces the surface plasmon resonance heating. To develop a minimally invasive therapy for the metastatic lymph node (LN) of oral cancer, photothermal therapy by using the surface plasmon resonance heating was tested. In this study, we used MXH10/Mo/lpr mice whose LNs enlarged to about 10 mm in diameter as a model for LN metastasis. When the GNRs were injected into the metastatic LN of the mouse model, and then a near-infrared laser light were irradiated to the LN, anti-cancer effect was observed. However, burn of skin on the LN was induced by the irradiation of a near-infrared laser light. To overcome the side effect, we developed cooling system using circulation of cold water to suppress increasing temperature of the skin during the irradiation. Under the control of skin temperature by using this cooling system, burn of the skin after the laser irradiation was completely suppressed.

Report

(3 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • Research Products

    (48 results)

All 2016 2015 2014

All Journal Article (10 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 10 results,  Open Access: 9 results,  Acknowledgement Compliant: 8 results) Presentation (38 results) (of which Int'l Joint Research: 10 results)

  • [Journal Article] Early diagnosis of lymph node metastasis: importance of intranodal pressures2016

    • Author(s)
      Miura Y, Mikada M, Ouchi T, Horie S, Takeda K, Yamaki T, Sakamoto M, Mori S, Kodama T
    • Journal Title

      Cancer Sci.

      Volume: 107 Issue: 3 Pages: 224-32

    • DOI

      10.1111/cas.12873

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A Novel Treatment Method for Lymph Node Metastasis Using a Lymphatic Drug Delivery System with Nano/Microbubbles and Ultrasound2015

    • Author(s)
      Kato S, Mori S, Kodama T
    • Journal Title

      J Cancer

      Volume: 6 Issue: 12 Pages: 1282-94

    • DOI

      10.7150/jca.13028

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Photothermal therapy of tumors in lymph nodes using gold nanorods and near-infrared laser light with controlled surface cooling2015

    • Author(s)
      Sugiura T, Matsuki D, Okajima J, Komiya A, Mori S, Maruyama S, Kodama T
    • Journal Title

      Nano Research

      Volume: 8 Issue: 12 Pages: 2842-52

    • DOI

      10.1007/s12274-015-0884-x

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Delivery of Molecules to the Lymph Node via Lymphatic Vessels Using Ultrasound and Nano/Microbubbles.2015

    • Author(s)
      Kato S, Shirai Y, Kanzaki H, Sakamoto M, Mori S, Kodama T
    • Journal Title

      Ultrasound Med Biol.

      Volume: 41 Issue: 5 Pages: 1411-1421

    • DOI

      10.1016/j.ultrasmedbio.2014.12.014

    • Related Report
      2015 Annual Research Report 2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Activation of latent metastases in the lung after resection of a metastatic lymph node in a lymph node metastasis mouse model.2015

    • Author(s)
      Shao L, Ouchi T, Sakamoto M, Mori S, Kodama T
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 460 Issue: 3 Pages: 543-548

    • DOI

      10.1016/j.bbrc.2015.03.066

    • Related Report
      2015 Annual Research Report 2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Direct delivery of a cytotoxic anticancer agent into the metastatic lymph node using nano/microbubbles and ultrasound2015

    • Author(s)
      Takuma Sato, Shiro Mori, Maya Sakamoto, Yoichi Arai, Tetsuya Kodama
    • Journal Title

      PLOS ONE.

      Volume: 10 Issue: 4 Pages: e0123619-e0123619

    • DOI

      10.1371/journal.pone.0123619

    • Related Report
      2015 Annual Research Report 2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Communication between lymphatic and venous systems in mice2015

    • Author(s)
      Shao L, Takeda K, Kato S, Mori S, Kodama T
    • Journal Title

      J Immunol Methods

      Volume: 424 Pages: 100-5

    • DOI

      10.1016/j.jim.2015.05.007

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] High-Accuracy Ultrasound Contrast Agent Detection Method for Diagnostic Ultrasound Imaging Systems.2015

    • Author(s)
      Ito K, Noro K, Yanagisawa Y, Sakamoto M, Mori S, Shiga K, Kodama T, Aoki T.
    • Journal Title

      Ultrasound Med Biol.

      Volume: 41 Issue: 12 Pages: 3120-3130

    • DOI

      10.1016/j.ultrasmedbio.2015.07.032

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Visualization of flow fields in lymphatic vessels and lymph nodes using a mouse model to test a lymphatic drug delivery system2015

    • Author(s)
      Kodama T, Hatakeyama Y, Kato S, Mori S
    • Journal Title

      Biomedical Optics Express

      Volume: 6 Issue: 1 Pages: 124-134

    • DOI

      10.1364/boe.6.000124

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Epigallocatechin gallate stimulates the neuroreactive salivary secretomotor system in autoimmune sialadenitis of MRL-Faslpr mice via activation of cAMP-dependent protein kinase A and inactivation of nuclear factor κB.2015

    • Author(s)
      Saito K, Mori S, Date F, Hong G
    • Journal Title

      Autoimmunity

      Volume: - Issue: 6 Pages: 1-10

    • DOI

      10.3109/08916934.2015.1030617

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] 担がんリンパ節へのリンパ行性薬剤送達法に関する研究2016

    • Author(s)
      吉羽正太,加藤茂樹,松木大輔,森士朗,小玉哲也
    • Organizer
      第28回バイオエンジニアリング講演会
    • Place of Presentation
      東京工業大学大岡山キャンパス(東京都目黒区)
    • Year and Date
      2016-01-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] マイクロ CTを用いた転移リンパ節内の管構造解析2016

    • Author(s)
      岩村亮,八巻哲平,森士朗,小玉哲也
    • Organizer
      第28回バイオエンジニアリング講演会
    • Place of Presentation
      東京工業大学 大岡山キャンパス(東京都目黒区)
    • Year and Date
      2016-01-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] マウスリンパ節周囲の循環系に関する研究2016

    • Author(s)
      武田航,森士朗,小玉哲也
    • Organizer
      第28回バイオエンジニアリング講演会
    • Place of Presentation
      東京工業大学 大岡山キャンパス(東京都目黒区)
    • Year and Date
      2016-01-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] 転移リンパ節に対する行性薬剤送達法に関する研2016

    • Author(s)
      多田明日香,吉羽正太,加藤茂樹,森士朗,小玉哲也
    • Organizer
      第28回バイオエンジニアリング講演会
    • Place of Presentation
      東京工業大学 大岡山キャンパス(東京都目黒区)
    • Year and Date
      2016-01-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] Intranodal chemotherapy for tumor-bearing lymph node and its evaluation by using intranodal pressure2015

    • Author(s)
      Takeda K, Mori S, Kodama T
    • Organizer
      South Africa / Japan Bilateral Sympossium
    • Place of Presentation
      Cape Penunsula University of Technology, Capetown, South Africa
    • Year and Date
      2015-11-04
    • Related Report
      2015 Annual Research Report
  • [Presentation] Lymphatic Delivery of Exogenous Molecules into Lymph Nodes via Lymphatic Vessels with ano/microbubbles and Ultrasound2015

    • Author(s)
      Yoshiba S, Kato S, Mori S, Kodama T
    • Organizer
      South Africa / Japan Bilateral Sympossium
    • Place of Presentation
      Cape Penunsula University of Technology, Capetown, South Africa
    • Year and Date
      2015-11-04
    • Related Report
      2015 Annual Research Report
  • [Presentation] Evaluation Methods of Metastatic Lymph Node and Its Treatment using Intranodal Pressures2015

    • Author(s)
      Takeda K, Mori S, Kodama T
    • Organizer
      12th International Confefence on Flow Dynamics
    • Place of Presentation
      仙台国際センター(宮城県仙台市)
    • Year and Date
      2015-10-27
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Lymphatic Delivery of Exogenous Molecules into Lymph Nodes via Lymphatic Vessels with ano/microbubbles and Ultrasound2015

    • Author(s)
      Yoshiba S, Kato S, Mori S, Kodama T
    • Organizer
      12th International Confefence on Flow Dynamics
    • Place of Presentation
      仙台国際センター(宮城県仙台市)
    • Year and Date
      2015-10-27
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Drug Delivery System via Lymphatic Network using Nano/microbubbles and Ultrasound2015

    • Author(s)
      Tada A, Yoshiba S, Kato S, Mori S, Kodama T
    • Organizer
      12th International Confefence on Flow Dynamics
    • Place of Presentation
      仙台国際センター(宮城県仙台市)
    • Year and Date
      2015-10-27
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Photo-thermal therapy of tumors in lymph nodes using gold nanorods and near-infrared laser light with controlled surface cooling2015

    • Author(s)
      Matsuki D, Okajima J, Komiya A, Mori S, Maruyama S, Kodama T
    • Organizer
      13th International Symposium on Advanced Biomedical Ultrasound
    • Place of Presentation
      東北大学カ青葉山キャンパス(宮城県仙台市)
    • Year and Date
      2015-10-19
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Perfusion defect in metastatic lymph node using micro CT2015

    • Author(s)
      Yamaki T, Sakamoto M, Mori S, Shiga K, Kodama T
    • Organizer
      13th International Symposium on Advanced Biomedical Ultrasound
    • Place of Presentation
      東北大学カ青葉山キャンパス(宮城県仙台市)
    • Year and Date
      2015-10-19
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Intranodal chemotherapy for tumor-bearing lymph node and its evaluation by using intranodal pressure2015

    • Author(s)
      Takeda K, Mori S, Kodama T
    • Organizer
      13th International Symposium on Advanced Biomedical Ultrasound
    • Place of Presentation
      東北大学カ青葉山キャンパス(宮城県仙台市)
    • Year and Date
      2015-10-19
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Lymphatic Delivery of Exogenous Molecules into Lymph Nodes via Lymphatic Vessels with Sonoporation2015

    • Author(s)
      Yoshiba S, Kato S, Mori S, Kodama T
    • Organizer
      13th International Symposium on Advanced Biomedical Ultrasound
    • Place of Presentation
      東北大学カ青葉山キャンパス(宮城県仙台市)
    • Year and Date
      2015-10-19
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Visualization of Flow Dynamics in Lymphatic Channels in Lymph Node2015

    • Author(s)
      Tada A, Takeda K, Mori S, Kodama T
    • Organizer
      13th International Symposium on Advanced Biomedical Ultrasound
    • Place of Presentation
      東北大学カ青葉山キャンパス(宮城県仙台市)
    • Year and Date
      2015-10-19
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] フォトサーマル効果と表面冷却による低侵襲加熱法を利用したリンパ節転移治療法の開発2015

    • Author(s)
      松木大輔,阪本真弥,森士朗,小玉哲也
    • Organizer
      第74回日本癌学会学術総会
    • Place of Presentation
      名古屋国際会議場(愛知県名古屋市)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] リンパ節転移の新たな診断指標の提案2015

    • Author(s)
      八巻哲平,阪本真弥,森士朗,志賀清人,小玉哲也
    • Organizer
      第74回日本癌学会学術総会
    • Place of Presentation
      名古屋国際会議場(愛知県名古屋市)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] ドキソルビシン内封リポソームを用いたリンパ節内における薬剤分布に関する研究2015

    • Author(s)
      吉羽正太,阪本真弥,森士朗,小玉哲也
    • Organizer
      第74回日本癌学会学術総会
    • Place of Presentation
      名古屋国際会議場(愛知県名古屋市)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] 郭清外リンパ節治療のための超音波と微小気泡を用いたリンパ行性薬剤送達法の開発2015

    • Author(s)
      多田明日香,吉羽正太,武田航,森士朗,小玉哲也
    • Organizer
      第74回日本癌学会学術総会
    • Place of Presentation
      名古屋国際会議場(愛知県名古屋市)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] リンパ節内圧によるリンパ節担癌の進行とその化学療法の評価方法の検討2015

    • Author(s)
      武田航,森士朗,阪本真弥,小玉哲也
    • Organizer
      第74回日本癌学会学術総会
    • Place of Presentation
      名古屋国際会議場(愛知県名古屋市)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] がんの診断治療の現状と疾患モデルの開発2015

    • Author(s)
      森士朗
    • Organizer
      日本機械学会2015年度年次大会
    • Place of Presentation
      北海道大学工学部(北海道札幌市)
    • Year and Date
      2015-09-13
    • Related Report
      2015 Annual Research Report
  • [Presentation] リンパネットワークを介した転移リンパ節の治療法に関する研究2015

    • Author(s)
      多田明日香,武田航,加藤茂樹,森士朗,小玉哲也
    • Organizer
      日本機械学会2015年度年次大会
    • Place of Presentation
      北海道大学工学部(北海道札幌市)
    • Year and Date
      2015-09-13
    • Related Report
      2015 Annual Research Report
  • [Presentation] リンパ節内圧を用いたリンパ節内腫瘍の評価とその治療2015

    • Author(s)
      武田航,多田明日香,森士朗,小玉哲也
    • Organizer
      日本機械学会2015年度年次大会
    • Place of Presentation
      北海道大学工学部(北海道札幌市)
    • Year and Date
      2015-09-13
    • Related Report
      2015 Annual Research Report
  • [Presentation] ナノ・マイクロバブルと超音波を用いたリンパネットワークによるリンパ節内への高分子導入に関する研究2015

    • Author(s)
      吉羽正太,加藤茂樹,多田明日香,森士朗,小玉哲也
    • Organizer
      日本機械学会2015年度年次大会
    • Place of Presentation
      北海道大学工学部(北海道札幌市)
    • Year and Date
      2015-09-13
    • Related Report
      2015 Annual Research Report
  • [Presentation] Intraymphatic chemotherapy for metastatic lymph node: evaluation by intranodal pressure2015

    • Author(s)
      Takeda K, Mori S, Kodama T
    • Organizer
      The 10th Anniversary International Workshop on Biomaterials in Interface Science
    • Place of Presentation
      Togatta-onsen Baden-ya Soho, Miyagi Zao, Japan
    • Year and Date
      2015-08-04
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] リンパ行性薬剤投与とソノポレーションによる腫瘍リンパ節治療法開発2015

    • Author(s)
      加藤茂樹,森士朗,阪本真弥,小玉哲也
    • Organizer
      第31回日本DDS学会学術集会
    • Place of Presentation
      京王プラザホテル(東京都新宿区)
    • Year and Date
      2015-07-02
    • Related Report
      2015 Annual Research Report
  • [Presentation] ソノポレーション法によるリンパ球への遺伝子導入2015

    • Author(s)
      加藤茂樹,森士朗,阪本真弥,小玉哲也
    • Organizer
      第31回日本DDS学会学術集会
    • Place of Presentation
      京王プラザホテル(東京都新宿区)
    • Year and Date
      2015-07-02
    • Related Report
      2015 Annual Research Report
  • [Presentation] Evaluation of Cisplatin-Induced Anti-Tumor Effect with Interstitial Fluid Pressure2015

    • Author(s)
      Takeda K, Ouchi T, Mori S, Kodama T
    • Organizer
      2015 International Congress on Chemical, Biological and Environmental Sciences (ICCBES)
    • Place of Presentation
      Kyoto Research Park, Japan
    • Year and Date
      2015-05-07
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 間質液圧を用いた転移リンパ節に対する抗腫瘍効果の検討2015

    • Author(s)
      武田航,吉羽正太,森士朗,小玉哲也
    • Organizer
      第54回日本生体医工学会大会
    • Place of Presentation
      名古屋国際会議場(愛知県名古屋市)
    • Year and Date
      2015-05-07
    • Related Report
      2015 Annual Research Report
  • [Presentation] 金ナノロッドと近赤外レーザー光を用いたリンパ節転移治療法の開発2015

    • Author(s)
      松木大輔,大内友貴,阪本真弥,森士朗,小玉哲也
    • Organizer
      日本機械学会第27回バイオエンジニアリング講演会
    • Place of Presentation
      朱鷺メッセ:新潟コンベンションセンター(新潟県新潟市)
    • Year and Date
      2015-01-09 – 2015-01-10
    • Related Report
      2014 Research-status Report
  • [Presentation] リンパ節切除にともなう肺転移を阻害する薬剤送達法の開発2015

    • Author(s)
      大内友貴,邵楽南,松木大輔,阪本真弥,森士朗,小玉哲也
    • Organizer
      日本機械学会第27回バイオエンジニアリング講演会
    • Place of Presentation
      朱鷺メッセ:新潟コンベンションセンター(新潟県新潟市)
    • Year and Date
      2015-01-09 – 2015-01-10
    • Related Report
      2014 Research-status Report
  • [Presentation] ナノ・マイクロバブルと超音波を用いた疑似転移リンパ節への薬剤送達法の開発2015

    • Author(s)
      吉羽正太,加藤茂樹,白井優子,寺川貴樹,森士朗,小玉哲也
    • Organizer
      日本機械学会第27回バイオエンジニアリング講演会
    • Place of Presentation
      朱鷺メッセ:新潟コンベンションセンター(新潟県新潟市)
    • Year and Date
      2015-01-09 – 2015-01-10
    • Related Report
      2014 Research-status Report
  • [Presentation] 間質液圧を用いたリンパ節転移早期診断法の開発2015

    • Author(s)
      武田航,大内友貴,森士朗,小玉哲也
    • Organizer
      日本機械学会第27回バイオエンジニアリング講演会
    • Place of Presentation
      朱鷺メッセ:新潟コンベンションセンター(新潟県新潟市)
    • Year and Date
      2015-01-09 – 2015-01-10
    • Related Report
      2014 Research-status Report
  • [Presentation] マイクロCTを用いた転移リンパ節内の血管構造解析2015

    • Author(s)
      八巻哲平,柳沢ゆかり,阪本真弥,森士朗,小玉哲也
    • Organizer
      日本機械学会第27回バイオエンジニアリング講演会
    • Place of Presentation
      朱鷺メッセ:新潟コンベンションセンター(新潟県新潟市)
    • Year and Date
      2015-01-09 – 2015-01-10
    • Related Report
      2014 Research-status Report
  • [Presentation] 口腔外科手術におけるPGAシートと自己血フィブリン糊を用いた創部処置に関する検討2014

    • Author(s)
      纐纈 衆,野上晋之介,橋元 亘,森 士朗,山内健介,栗原 淳,宮下 仁,高橋 哲
    • Organizer
      第59回公益社団法人 日本口腔外科学会総会・学術大会
    • Place of Presentation
      幕張メッセ(千葉県千葉市)
    • Year and Date
      2014-10-17 – 2014-10-19
    • Related Report
      2014 Research-status Report
  • [Presentation] 診断に苦慮した節外性NK/T細胞リンパ腫の経験に基づいた初動対応に関する提言2014

    • Author(s)
      小田島健二 ,森 士朗,大泉丈史,川井 忠,栗原 淳,橋元 亘,宮下 仁,熊本裕行,高橋 哲
    • Organizer
      第59回公益社団法人 日本口腔外科学会総会・学術大会
    • Place of Presentation
      幕張メッセ(千葉県千葉市)
    • Year and Date
      2014-10-17 – 2014-10-19
    • Related Report
      2014 Research-status Report
  • [Presentation] 東北大学病院歯科顎口腔外科における口腔粘膜表在癌と前癌病変患者の臨床統計学的検討2014

    • Author(s)
      齋藤 悠,橋元 亘,栗原 淳,野上晋之介,宮下 仁,山内健介,森 士朗,纐纈 衆, 熊本裕行,高橋 哲
    • Organizer
      第59回公益社団法人 日本口腔外科学会総会・学術大会
    • Place of Presentation
      幕張メッセ(千葉県千葉市)
    • Year and Date
      2014-10-17 – 2014-10-19
    • Related Report
      2014 Research-status Report
  • [Presentation] Combined Application of Doxorubicin-Encapsulated Thermosensitive Liposomes and Photothermal Therapy for Treatment of Tumor-Bearing Lymph Nodes2014

    • Author(s)
      Matsuki D, Ouchi T, Mori S, Kodama T
    • Organizer
      9th East Asian Consortium on Biomedical Engineering
    • Place of Presentation
      National Cheng Kung University, Tainan, Taiwan
    • Year and Date
      2014-10-11 – 2014-10-12
    • Related Report
      2014 Research-status Report
  • [Presentation] Diagnosis of Early-stage Lymph Node Metastasis using Interstitial Fluid Pressure2014

    • Author(s)
      Takeda K, Ouchi T, Mori S, Kodama T
    • Organizer
      9th East Asian Consortium on Biomedical Engineering
    • Place of Presentation
      National Cheng Kung University, Tainan, Taiwan
    • Year and Date
      2014-10-11 – 2014-10-12
    • Related Report
      2014 Research-status Report

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Published: 2014-04-04   Modified: 2017-05-10  

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