Updated on 2021/07/12

写真a

 
KANO Mitsunobu
 
Organization
Interdisciplinary Science and Engineering in Health Systems Professor
Position
Professor
Profile
臨床医の経験を通じて、身近に見出した課題を、基礎科学的に解き明かしていく研究やマネジメントを進めています。臨床、すなわち、身体症状という課題を抱えた方々を、科学という新しい知恵を確実にする方法を通じて、どうして差し上げたらよいか、という経験が原点にあるためです。現在の大きな柱は、主に研究面では1)膵がんをはじめとする薬物治療不応性の原因を、病巣組織構築に関連させナノテクノロジーや三次元培養等の新技術を応用し解析していく研究、2)医療ビッグデータを活用して、医療や疾病の全国的な状況を記述していく研究、そして主にマネジメント面では3)身近な疑問の集合体ともいえる国連のSDGs(持続可能な発展のための目標)を今後の研究活動の原動力としていくための大学運営、4)さらにこうした発想での研究活動も支援していくような政策の在り方を考える公的活動、などを進めています。
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Research Interests

  • Science and Technology Policy

  • Issue-driven sciences

  • Epidemiology

  • Nano-pathophysiology

Research Areas

  • Life Science / Experimental pathology

  • Life Science / Medical management and medical sociology

  • Life Science / Biomedical engineering

  • Life Science / General internal medicine

  • Life Science / Pharmacology

  • Life Science / Tumor diagnostics and therapeutics

  • Life Science / Biomaterials

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Education

  • The University of Tokyo   Graduate School of Medicine  

    2002 - 2005

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  • The University of Tokyo   Faculty of Medicine   School of Medicine

    1995 - 1999

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  • The University of Tokyo   College of Arts and Sciences  

    1993 - 1995

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Research History

  • Science and Technology Co-Advisor to the Minister for Foreign Affairs of Japan (Concurrent post)

    2019.4

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  • Okayama University Graduate School of Interdisciplinary Sciences and Engineering in Health Systems   Department of Pharmaceutical Biomedicine   Professor

    2018.4

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  • 岡山大学 副理事(企画・評価・総務担当)・SDGs推進企画会議 議長 (併任)

    2018

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  • Okayama University

    2017 - 2018

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  • 岡山大学医歯薬学総合研究科 副研究科長

    2016 - 2017

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  • 岡山大学医歯薬学総合研究科 教授

    2012 - 2018.3

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

    2012

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  • 東京大学 医学部 MD研究者育成プログラム室・分子病理学 講師

    2008 - 2012

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  • Senior Assistant Professor

    2008 - 2012

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  • Assistant Professor

    2007 - 2008

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  • 東京大学 ナノバイオ・インテグレーション研究拠点・医学系研究科分子病理学 特任教員(助手・助教)

    2006 - 2008

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  • Research Associate

    2006 - 2007

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  • The University of Tokyo   Graduate School of Medicine

    2005 - 2006

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  • 東京大学医学部附属病院 (老年病学) 診療登録医

    2002 - 2005

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  • St. Luke's International University   St.Luke's International Hospital

    2002 - 2003

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  • St. Luke's International University   St.Luke's International Hospital

    1999 - 2002

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Professional Memberships

Committee Memberships

  • 日本DDS学会   理事  

    2018   

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    Committee type:Academic society

    日本DDS学会

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  •   JST 自己評価委員会 外部委員  

    2018   

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  •   文部科学省 科学技術・学術政策局 科学技術イノベーション政策における「政策のための科学」アドバイザリー委員会 委員  

    2018   

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    Committee type:Government

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  •   外務省 科学技術外交委員会 SDGsスタディグループ メンバー(2018)  

    2018   

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  •   文部科学省 科学技術・学術審議会 臨時委員  

    2017   

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    Committee type:Government

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  •   政策研究大学院大学 客員研究員  

    2017   

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  •   文部科学省 ゲノム医療実現のための研究基盤の充実・強化に関する検討会(研究振興局ライフサイエンス課) 委員 (2017-2018)  

    2017 - 2018   

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  •   東北大学 学際科学フロンティア研究所 客員教授  

    2017 - 2018   

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  •   文部科学省 基礎研究医養成活性化プログラム ペーパーレフェリー(2017-2018)  

    2017 - 2018   

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  •   - 科学と社会研究会(日本学術協力財団) 会員(2017-)  

    2017   

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  •   「学術の動向」誌(日本学術協力財団) 編集委員 (2017-)  

    2016   

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  •   公益財団法人国際高等研究所 基幹プログラム「将来の地球社会を考えたときの科学技術の在り方」 参加研究員(2015-2018)  

    2015 - 2018   

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  •   熊本大学大学院生命科学研究部 柴三郎プログラム 外部評価委員(2015-2017)  

    2015 - 2017   

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  •   JST 研究戦略開発センター(CRDS) 特任フェロー  

    2014   

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  •   厚生労働省 戦略研究モニタリング 委員(2014-2017)  

    2014 - 2017   

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  •   日本学術会議 特任連携会員 ・若手アカデミー 副代表(2014-2017)  

    2014 - 2017   

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  •   JST バイオデータベースセンター(NDBC) 統合化推進プログラム 研究アドバイザー  

    2014 - 2017   

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  • 日本癌学会   評議員  

    2013   

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    Committee type:Academic society

    日本癌学会

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  •   文部科学省 未来医療研究人材養成推進委員会 ペーパーレフェリー(2013-2014)  

    2013 - 2014   

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  •   PLoS One アカデミックエディター(2012-2016)  

    2012 - 2016   

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  •   内閣府総合科学技術会議 ライフイノベーション戦略協議会 構成員  

    2012 - 2014   

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  •   文部科学省 新学術領域研究専門委員会 ナノメディシン専門委員会 委員(2012-2013)  

    2012 - 2013   

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  •   日本学術会議 連携会員  

    2011   

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  •   Global Young Academy 委員(2014 執行委員)(2011-2017)  

    2011 - 2017   

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  •   Global Young Academy Member(2014 Member of the Executive Committee)(2011-2017)  

    2011 - 2017   

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  •   日本学術会議 特任連携会員 ・ 若手アカデミー委員会 副委員長 (2011-2014)  

    2011 - 2014   

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  • 日本DDS学会   評議員  

    2011   

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    Committee type:Academic society

    日本DDS学会

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  •   日本学術会議 特任連携会員 ・ 若手アカデミー委員会 若手アカデミー活動検討分科会幹事(2010-2011)  

    2010 - 2011   

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Papers

  • Trends in the nontuberculous mycobacterial disease mortality rate in Japan: A nationwide observational study, 1997-2016. Reviewed International journal

    Ko Harada, Hideharu Hagiya, Tomoko Funahashi, Toshihiro Koyama, Mitsunobu R Kano, Fumio Otsuka

    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America   2020.6

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

    BACKGROUND: The incidence of nontuberculous mycobacterial (NTM) infections has been increasing worldwide, becoming a significant healthcare burden especially among elderly people. This study aimed to evaluate the trends in NTM-associated mortality in Japan. METHODS: This study used vital statistics data and data on all NTM-associated deaths (N=18,814) among individuals aged ≥40 years in Japan from 1997 to 2016. We calculated the crude and age-adjusted mortality rates by age and sex and used joinpoint regression to analyze trends and estimate the average annual percentage change (AAPC). We compared crude NTM- and tuberculosis (TB)-associated mortality rates by sex. RESULTS: The overall crude annual mortality rate increased from 0.63/100,000/year in 1997 to 1.93/100,000/year in 2016 and was the highest among individuals aged 80-84 years. The AAPC of the crude mortality rates among males of all ages and females aged 40-59 years were stable but increased among females aged 60-79 years (3.5%, 95% confidence interval [CI]: 2.8-4.3%) and ≥80 years (4.3%, 95% CI: 3.7-4.9%). Among males, the age-adjusted mortality rates did not show a significant trend, while among females, the rates increased over the study period (AAPC: 4.6%, 95% CI: 2.7-6.6%). In females, the crude NTM-associated mortality rate exceeded the TB mortality rate in 2014, 2015, and 2016. CONCLUSIONS:  NTM mortality increased in Japan between 1997 and 2016, especially among the elderly female population. Given the increasing NTM-associated mortality and susceptible aging population, public health authorities in Japan should pay greater attention to NTM infections.

    DOI: 10.1093/cid/ciaa810

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  • Heterotypic 3D pancreatic cancer model with tunable proportion of fibrotic elements. Reviewed International journal

    Hiroyoshi Y Tanaka, Tsuyoshi Kurihara, Takuya Nakazawa, Michiya Matsusaki, Atsushi Masamune, Mitsunobu R Kano

    Biomaterials   251   120077 - 120077   2020.4

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    Pancreatic ductal adenocarcinoma (PDAC) is an often lethal disease characterized by a dense, fibrotic stroma. However, the lack of relevant preclinical models that recapitulate the characteristic histopathology of human PDAC in vitro impedes the development of novel therapies. The amount of stromal elements differ largely within and between patients, but in vitro models of human PDAC often do not account for this heterogeneity. Indeed, analyses of human PDAC histopathology revealed that the proportion of stroma ranged from 40 to 80% across patients. We, therefore, generated a novel 3D model of human PDAC, consisting of co-cultured human PDAC tumor cells and fibroblasts/pancreatic stellate cells, in which the proportion of fibrotic elements can be tuned across the clinically observed range. Using this model, we analyzed the signaling pathways involved in the differentiation of myofibroblasts, a characteristic subpopulation of fibroblasts seen in PDAC. We show that both YAP and SMAD2/3 in fibroblasts are required for myofibroblastic differentiation and that both shared and distinct signaling pathways regulate the nuclear localization of these factors during this process. Our novel model will be useful in promoting the understanding of the complex mechanisms by which the fibrotic stroma develops and how it might be therapeutically targeted.

    DOI: 10.1016/j.biomaterials.2020.120077

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  • Antibiotic prescriptions for Japanese outpatients with acute respiratory tract infections (2013-2015): A retrospective Observational Study. Reviewed International journal

    Toshihiro Koyama, Hideharu Hagiya, Yusuke Teratani, Yasuhisa Tatebe, Ayako Ohshima, Mayu Adachi, Tomoko Funahashi, Yoshito Zamami, Hiroyoshi Y Tanaka, Ken Tasaka, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   2020.3

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    OBJECTIVES: Appropriate antibiotic prescriptions for outpatients with acute respiratory tract infections (ARTIs) are urgently needed in Japan. However, the empirical proof of this need is under-documented. Therefore, we aimed to determine antibiotic prescription rates, and the proportions of antibiotic classes prescribed for Japanese patients with ARTIs. METHODS: We analysed health insurance claims data over 2013-2015 among Japanese patients aged <75 years and determined the following indicators: 1) visit rates for patients with ARTIs and antibiotic prescription rates per 1000 person-years, and 2) proportion of visits by antibiotic-prescribed patients with ARTIs. We defined broad-spectrum antibiotics using the WHO Anatomical Therapeutic Chemical classification 4 level codes. RESULTS: Among 8.65 million visits due to ARTIs at 6859 hospitals and 62,024 physicians' offices, the visit rate and antibiotic prescription rate per 1000 person-years were 990.6 (99% confidence interval [CI], 989.4-991.7) and 532.4 (99% CI, 531.6-533.3), respectively. The visit rates for patients aged 0-17, 18-59, and 60-74 years were 2410.0 (99% CI, 2407.2-2412.9), 683.6 (99% CI, 682.7-684.6), and 682.1 (99% CI, 678.2-686.0), and antibiotic prescription rates were 1093.3 (99% CI, 1091.4-1095.2), 434.1 (99% CI, 433.4-434.9), and 353.4 (99% CI, 350.7-356.1), respectively. The overall proportion of antibiotic prescriptions for ARTI visits was 52.7% and 91.3% of the antibiotics prescribed were broad-spectrum. CONCLUSIONS: Both the visit rates and antibiotic prescription rates for ARTIs were high in this Japanese cohort. The proportion of antibiotic prescriptions exceeded that recommended in the clinical guidelines. Thus, there might be a scope for reducing the current antibiotic prescription rate in Japan.

    DOI: 10.1016/j.jiac.2020.02.001

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  • Trends in Place of Death in a Super-Aged Society: A Population-Based Study, 1998-2017. Reviewed International journal

    Toshihiro Koyama, Hideharu Hagiya, Tomoko Funahashi, Yoshito Zamami, Miyu Yamagishi, Hiroshi Onoue, Yusuke Teratani, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

    Journal of palliative medicine   2020.2

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    Background:
    Globally, the number of deaths is estimated to increase to 74 million per year by 2030. Place of death (PoD) is increasingly being recognized as an important aspect of end-of-life care. However, recent trends in PoD in Japan, one of the super-aged societies, are unknown.
    Objective:
    To analyze trends in PoD in Japan over two decades.
    Design:
    Population-based retrospective observational study.
    Setting:
    All deaths reported in Japan, 1998-2017. PoD was defined as hospital, nursing home, or own home.
    Results:
    All Japanese decedents (∼22.6 million) over the past 20 years were analyzed. The proportion of hospital deaths was consistently high (>80%), with a significant decreasing trend from the mid-2000s. Although the proportion of deaths at home decreased in the first half of the study period, they later increased. There was a low proportion of deaths in nursing homes compared to other places of death; however, the proportion increased continually throughout the study period, particularly among women. In 2015, more women died in nursing homes than at home. Although the proportion of hospital deaths declined in the second half of the study period, their overall number continued to increase, reflecting an increase in total deaths in Japan.
    Conclusions:
    This study highlighted rapid changes in trends in PoD in Japan, and the need to consider affordable end-of-life care in Japan as well as other countries with aging populations. The findings from this long-term epidemiological study provide important insights on this issue.

    DOI: 10.1089/jpm.2019.0445

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  • Place of death trends among patients with dementia in Japan: a population-based observational study. Reviewed International journal

    Toshihiro Koyama, Misato Sasaki, Hideharu Hagiya, Yoshito Zamami, Tomoko Funahashi, Ayako Ohshima, Yasuhisa Tatebe, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

    Scientific reports   9 ( 1 )   20235 - 20235   2019.12

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    Dementia is a major public health concern in ageing societies. Although the population of Japan is among the most aged worldwide, long-term trends in the place of death (PoD) among patients with dementia is unknown. In this Japanese nationwide observational study, we analysed trends in PoD using the data of patients with dementia who were aged ≥65 years and died during 1999-2016. Trends in the crude death rates and PoD frequencies were analysed using the Joinpoint regression model. Changes in these trends were assessed using the Joinpoint regression analysis in which significant change points, the annual percentage change (APC) and average APCs (AAPC) in hospitals, homes, or nursing homes were estimated. During 1999-2016, the number of deaths among patients with dementia increased from 3,235 to 23,757 (total: 182,000). A trend analysis revealed increased mortality rates, with an AAPC of 8.2% among men and 9.3% among women. Most patients with dementia died in the hospital, although the prevalence of hospital deaths decreased (AAPC: -1.0%). Moreover, the prevalence of nursing home deaths increased (AAPC: 5.6%), whereas the prevalence of home deaths decreased (AAPC: -5.8%). These findings support a reconsideration of the end-of-life care provided to patients with dementia.

    DOI: 10.1038/s41598-019-56388-w

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  • Fall-related mortality trends in older Japanese adults aged ≥65 years: a nationwide observational study. Reviewed International journal

    Hideharu Hagiya, Toshihiro Koyama, Yoshito Zamami, Yasuhisa Tatebe, Tomoko Funahashi, Kazuaki Shinomiya, Yoshihisa Kitamura, Shiro Hinotsu, Toshiaki Sendo, Hiromi Rakugi, Mitsunobu R Kano

    BMJ open   9 ( 12 )   e033462   2019.12

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    OBJECTIVES: Fall-related mortality among older adults is a major public health issue, especially for ageing societies. This study aimed to investigate current trends in fall-related mortality in Japan using nationwide population-based data covering 1997-2016. DESIGN: We analysed fall-related deaths among older persons aged ≥65 years using the data provided by the Japanese Ministry of Health, Labour and Welfare. RESULTS: The crude and age-standardised mortality rates were calculated per 100 000 persons by stratifying by age (65-74, 75-84 and ≥85 years) and sex. To identify trend changes, a joinpoint regression model was applied by estimating change points and annual percentage change (APC). The total number of fall-related deaths in Japan increased from 5872 in 1997 to 8030 in 2016, of which 78.8% involved persons aged ≥65 years. The younger population (65-74 years) showed continuous and faster-decreasing trends for both men and women. Average APC among men aged ≥75 years did not decrease. Among middle-aged and older women (75-84 and ≥85 years) decreasing trends were observed. Furthermore, the age-adjusted mortality rate of men was approximately twice that of women, and it showed a faster decrease for women. CONCLUSIONS: Although Japanese healthcare has shown improvement in preventing fall-related deaths over the last two decades, the crude mortality for those aged over 85 years remains high, indicating difficulty in reducing fall-related deaths in the super-aged population. Further investigations to uncover causal factors for falls in older populations are required.

    DOI: 10.1136/bmjopen-2019-033462

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  • Oral anticoagulants usage in Japanese patients aged 18-74 years with non-valvular atrial fibrillation: a retrospective analysis based on insurance claims data. Reviewed International journal

    Ayako Ohshima, Toshihiro Koyama, Aiko Ogawa, Yoshito Zamami, Hiroyoshi Y Tanaka, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Michael W Miller, Mitsunobu R Kano

    Family practice   36 ( 6 )   685 - 692   2019.11

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    BACKGROUND: Oral anticoagulants use has increased rapidly, internationally. Here we look at risks and benefits, based on Japanese data, of therapy with low risk non-valvular atrial fibrillation patients. OBJECTIVES: Using a health insurance claims data set we assessed: (i) oral anticoagulants usage in Japan, and (ii) efficacy and safety of dabigatran compared with warfarin, in Japanese patients with non-valvular atrial fibrillation, aged 18-74 years. METHODS: We identified 4380 non-valvular atrial fibrillation patients treated with anticoagulants between 1 January 2005, and 28 February 2014, and estimated the adjusted hazard ratio for stroke or systemic embolism, and any hemorrhagic event (Cox proportional hazards regression model with stabilized inverse probability treatment weighting). RESULTS: The data included 101 989 anticoagulant prescriptions for 4380 patients, of which direct oral anticoagulants increased to 40.0% of the total by the end of the study. After applying exclusion criteria, 1536 new non-valvular atrial fibrillation patients were identified, including 1071 treated with warfarin and 465 with dabigatran. Mean ages were 56.11 ± 9.70 years for warfarin, and 55.80 ± 9.65 years for dabigatran. The adjusted hazard ratio (95% confidence interval), comparing dabigatran with warfarin, was 0.48 (0.25-0.91) for stroke or systemic embolism, and 0.91 (0.60-1.39) for any hemorrhage including intracranial and gastrointestinal. CONCLUSIONS: Number of patients prescribed direct oral anticoagulants steadily increased, and incidence of all-cause bleeding related to dabigatran was similar to warfarin, in our study population of younger non-valvular atrial fibrillation patients. Dabigatran, compared with warfarin, generally reduced risk of all-cause stroke and systemic embolism.

    DOI: 10.1093/fampra/cmz016

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  • Pattern of antibiotic prescriptions for outpatients with acute respiratory tract infections in Japan, 2013-15: a retrospective observational study. Reviewed International journal

    Yusuke Teratani, Hideharu Hagiya, Toshihiro Koyama, Mayu Adachi, Ayako Ohshima, Yoshito Zamami, Hiroyoshi Y Tanaka, Yasuhisa Tatebe, Ken Tasaka, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Mitsunobu R Kano, Shiro Hinotsu, Toshiaki Sendo

    Family practice   36 ( 4 )   402 - 409   2019.7

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    BACKGROUND: In this age of antimicrobial resistance, unnecessary use of antibiotics to treat non-bacterial acute respiratory tract infections (ARTIs) and inappropriate use of antibiotics in treating bacterial ARTIs are public health concerns. PURPOSE: Our aim is to identify the pattern of oral antibiotic prescriptions for outpatients with ARTIs in Japan. METHODS: We analysed health insurance claims data of patients (aged ≤74 years) from 2013 to 2015, to determine the pattern of antibiotic prescriptions for outpatient ARTIs and calculated the proportion of each antibiotic. RESULTS: Data on 4.6 million antibiotic prescriptions among 1559394 outpatients with ARTIs were analysed. The most commonly prescribed classes of antibiotics included cephalosporins (41.9%), macrolides (32.8%) and fluoroquinolones (14.7%). The proportion of first-, second- and third-generation cephalosporins was 1.0%, 1.7% and 97.3%, respectively. Fluoroquinolones accounted for a quarter of the prescriptions for ARTIs in patients aged >20 years. In contrast, penicillins accounted for just 8.0% of the total number of antibiotic prescriptions for ARTIs. CONCLUSIONS: According to clinical guidelines, penicillins are first-line antibiotics against ARTIs. However, third-generation cephalosporins, macrolides and fluoroquinolones are more frequently prescribed in Japan. Although we could not assess the extent to which appropriate antibiotics are selected, our results support the necessity of improving antibiotic choices in the treatment of ARTIs.

    DOI: 10.1093/fampra/cmy094

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  • In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers. Reviewed International journal

    Sumiyo Watanabe, Kotaro Hayashi, Kazuko Toh, Hyun Jin Kim, Xueying Liu, Hiroyuki Chaya, Shigeto Fukushima, Keisuke Katsushima, Yutaka Kondo, Satoshi Uchida, Satomi Ogura, Takahiro Nomoto, Hiroyasu Takemoto, Horacio Cabral, Hiroaki Kinoh, Hiroyoshi Y Tanaka, Mitsunobu R Kano, Yu Matsumoto, Hiroshi Fukuhara, Shunya Uchida, Masaomi Nangaku, Kensuke Osada, Nobuhiro Nishiyama, Kanjiro Miyata, Kazunori Kataoka

    Nature communications   10 ( 1 )   1894 - 1894   2019.4

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    Stabilisation of fragile oligonucleotides, typically small interfering RNA (siRNA), is one of the most critical issues for oligonucleotide therapeutics. Many previous studies encapsulated oligonucleotides into ~100-nm nanoparticles. However, such nanoparticles inevitably accumulate in liver and spleen. Further, some intractable cancers, e.g., tumours in pancreas and brain, have inherent barrier characteristics preventing the penetration of such nanoparticles into tumour microenvironments. Herein, we report an alternative approach to cancer-targeted oligonucleotide delivery using a Y-shaped block catiomer (YBC) with precisely regulated chain length. Notably, the number of positive charges in YBC is adjusted to match that of negative charges in each oligonucleotide strand (i.e., 20). The YBC rendezvouses with a single oligonucleotide in the bloodstream to generate a dynamic ion-pair, termed unit polyion complex (uPIC). Owing to both significant longevity in the bloodstream and appreciably small size (~18 nm), the uPIC efficiently delivers oligonucleotides into pancreatic tumour and brain tumour models, exerting significant antitumour activity.

    DOI: 10.1038/s41467-019-09856-w

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  • Association between rapid antigen detection tests and antibiotics for acute pharyngitis in Japan: A retrospective observational study. Reviewed International journal

    Yusuke Teratani, Hideharu Hagiya, Toshihiro Koyama, Ayako Ohshima, Yoshito Zamami, Yasuhisa Tatebe, Ken Tasaka, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R Kano

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   25 ( 4 )   267 - 272   2019.4

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    The application and clinical impact of rapid antigen detection test (RADT) in the treatment of acute pharyngitis is unknown in Japan. We aimed to examine the proportions of RADT usage to identify Group A β-hemolytic Streptococcus (GAS) in outpatients with acute pharyngitis and evaluate the association between RADT and antibiotic treatment. We analyzed health insurance claims data from 2013 to 2015. Logistic regression models were used to analyze associated factors with RADT, overall antibiotic prescription, or penicillin use. We analyzed 1.27 million outpatient visits with acute pharyngitis, in which antibiotics were prescribed in 59.3% of visits. Of the total visits, 5.6% of patients received RADT, and 10.8% of the antibiotics were penicillin. Penicillin selection rates were higher in cases with RADT (25.4%) than those without RADT (9.7%). Compared to large-scale facilities, antibiotic prescription rates were higher in physicians' offices. For factor analysis, age (3-15 years), diagnosis code (streptococcal pharyngitis), size of the medical facility (large-scale hospitals), and physician's specialty (pediatrics) were associated with RADT use. Penicillin selection rate increased with RADT implementation (25.4% vs. 9.7%: adjusted odds ratio 1.55; 95% CI, 1.50-1.60). At 63% of the facilities, the RADT implementation rate was <5% of acute pharyngitis visits prescribed antibiotics. In conclusion, the proportion of RADT usage for outpatients with acute pharyngitis was low in Japan. With appropriate indication and evaluation, we expect that more utilization of RADT can help promote antimicrobial stewardship for outpatients with acute pharyngitis by prompting penicillin therapy. Further investigation with detailed clinical data are warranted.

    DOI: 10.1016/j.jiac.2018.12.005

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  • Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness. Reviewed International journal

    Hiroyoshi Y Tanaka, Kentaro Kitahara, Naoki Sasaki, Natsumi Nakao, Kae Sato, Hirokazu Narita, Hiroshi Shimoda, Michiya Matsusaki, Hiroshi Nishihara, Atsushi Masamune, Mitsunobu R Kano

    Biomaterials   192   355 - 367   2019.2

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    Desmoplasia is a hallmark of pancreatic cancer and consists of fibrotic cells and secreted extracellular matrix (ECM) components. Various in vitro three-dimensional (3D) models of desmoplasia have been reported, but little is known about the relevant thickness of the engineered fibrotic tissue. We thus measured the thickness of fibrotic tissue in human pancreatic cancer, as defined by the distance from the blood vessel wall to tumor cells. We then generated a 3D fibrosis model with a thickness reaching the clinically observed range using pancreatic stellate cells (PSCs), the main cellular constituent of pancreatic cancer desmoplasia. Using this model, we found that Collagen fiber deposition was increased and Fibronectin fibril orientation drastically remodeled by PSCs, but not normal fibroblasts, in a manner dependent on Transforming Growth Factor (TGF)-β/Rho-Associated Kinase (ROCK) signaling and Matrix Metalloproteinase (MMP) activity. Finally, by targeting Secreted Protein, Acidic and Rich in Cysteine (SPARC) by siRNA, we found that SPARC expression in PSCs was necessary for ECM remodeling. Taken together, we developed a 3D fibrosis model of pancreatic cancer with a clinically relevant thickness and observed aberrant SPARC-dependent ECM remodeling in cancer-derived PSCs.

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  • Search for Therapeutic Agents for Cardiac Arrest Using a Drug Discovery Tool and Large-Scale Medical Information Database. Reviewed International journal

    Yoshito Zamami, Takahiro Niimura, Toshihiro Koyama, Yuta Shigemi, Yuki Izawa-Ishizawa, Mizuki Morita, Ayako Ohshima, Keisaku Harada, Toru Imai, Hiromi Hagiwara, Naoto Okada, Mitsuhiro Goda, Kenshi Takechi, Masayuki Chuma, Yutaka Kondo, Koichiro Tsuchiya, Shiro Hinotsu, Mitsunobu R Kano, Keisuke Ishizawa

    Frontiers in pharmacology   10   1257 - 1257   2019

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    The survival rate of cardiac arrest patients is less than 10%; therefore, development of a therapeutic strategy that improves their prognosis is necessary. Herein, we searched data collected from medical facilities throughout Japan for drugs that improve the survival rate of cardiac arrest patients. Candidate drugs, which could improve the prognosis of cardiac arrest patients, were extracted using "TargetMine," a drug discovery tool. We investigated whether the candidate drugs were among the drugs administered within 1 month after cardiac arrest in data of cardiac arrest cases obtained from the Japan Medical Data Center. Logistic regression analysis was performed, with the explanatory variables being the presence or absence of the administration of those candidate drugs that were administered to ≥10 patients and the objective variable being the "survival discharge." Adjusted odds ratios for survival discharge were calculated using propensity scores for drugs that significantly improved the proportion of survival discharge; the influence of covariates, such as patient background, medical history, and treatment factors, was excluded by the inverse probability-of-treatment weighted method. Using the search strategy, we extracted 165 drugs with vasodilator activity as candidate drugs. Drugs not approved in Japan, oral medicines, and external medicines were excluded. Then, we investigated whether the candidate drugs were administered to the 2,227 cardiac arrest patients included in this study. The results of the logistic regression analysis showed that three (isosorbide dinitrate, nitroglycerin, and nicardipine) of seven drugs that were administered to ≥10 patients showed significant association with improvement in the proportion of survival discharge. Further analyses using propensity scores revealed that the adjusted odds ratios for survival discharge for patients administered isosorbide dinitrate, nitroglycerin, and nicardipine were 3.35, 5.44, and 4.58, respectively. Thus, it can be suggested that isosorbide dinitrate, nitroglycerin, and nicardipine could be novel therapeutic agents for improving the prognosis of cardiac arrest patients.

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  • Trends in Polypharmacy in Japan: A Nationwide Retrospective Study. Reviewed International journal

    Hiroshi Onoue, Toshihiro Koyama, Yoshito Zamami, Hideharu Hagiya, Yasuhisa Tatebe, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Shiro Hinotsu, Toshiaki Sendo, Yasuyoshi Ouchi, Mitsunobu R Kano

    Journal of the American Geriatrics Society   66 ( 12 )   2267 - 2273   2018.12

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    OBJECTIVES: To describe and examine trends in polypharmacy according to age in Japan from 2010 to 2016. DESIGN: Retrospective observational study. SETTING: Outpatient settings. PARTICIPANTS: Japanese individuals aged 20 and older. MEASUREMENTS: We analyzed pharmacy claims data that the Japanese Ministry of Health, Labor, and Welfare provided in the Survey of Medical Care Activities in Public Health Insurance from 2010 to 2016. The use of 5 or more oral prescription medications per month was defined as polypharmacy and of 10 or more as excessive polypharmacy. Regression analysis was used to estimate trends in polypharmacy with annual percentage changes. Using number of medications (polypharmacy vs excessive polypharmacy), trends in polypharmacy and crude and age-adjusted rates of polypharmacy per 1,000 persons were calculated according to year and age group (20-34, 35-49, 50-64, 65-79, ≥ 80). RESULTS: We analyzed 240 million pharmacy claims data. The age-adjusted monthly prevalence rate of polypharmacy increased from 85.2 to 93.8 per 1,000 persons per month and of excessive polypharmacy from 13.6 to 14.0 per 1,000 persons per month from 2010 to 2016 in the entire study population. The highest rate of polypharmacy (per 1,000 persons) was observed in 2016 in those aged 80 and older (326.8), followed by those aged 65 to 79 (167.3). The polypharmacy rate increased by 6.3% (95% confidence interval (CI)=4.0-8.7) per year from 2010 to 2012, then decreased by 0.7% (95% CI=-1.3-0.0) per year from 2012 to 2016. The rate of excessive polypharmacy increased by 4.5% (95% CI=1.1-8.0) per year from 2010 to 2013 and then decreased by 3.7% (95% CI=-6.7 to -0.6) per year from 2013 to 2016. CONCLUSION: The overall trend of polypharmacy in Japan increased during the study period, although the increase ceased in 2013 and then declined from 2013 to 2016. Policy changes in Japan might be responsible for some of the changes. J Am Geriatr Soc 66:2267-2273, 2018.

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  • Trends in incidence and mortality of tuberculosis in Japan: a population-based study, 1997-2016. Reviewed

    H Hagiya, T Koyama, Yoshito Zamami, Y Minato, Y Tatebe, N Mikami, Y Teratani, A Ohshima, K Shinomiya, Y Kitamura, T Sendo, S Hinotsu, K Tomono, R M Kano

    Epidemiology and infection   2018.11

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    Japan is still a medium-burden tuberculosis (TB) country. We aimed to examine trends in newly notified active TB incidence and TB-related mortality in the last two decades in Japan. This is a population-based study using Japanese Vital Statistics and Japan Tuberculosis Surveillance from 1997 to 2016. We determined active TB incidence and mortality rates (per 100 000 population) by sex, age and disease categories. Joinpoint regression was applied to calculate the annual percentage change (APC) in age-adjusted mortality rates and to identify the years showing significant trend changes. Crude and age-adjusted incidence rates reduced from 33.9 to 13.9 and 37.3 to 11.3 per 100 000 population, respectively. Also, crude and age-adjusted mortality rates reduced from 2.2 to 1.5 and 2.8 to 1.0 per 100 000 population, respectively. Average APC in the incidence and mortality rates showed significant decline both in men (-6.2% and -5.4%, respectively) and women (-5.7% and -4.6%, respectively). Age-specific analysis demonstrated decreases in incidence and mortality rates for every age category, except for the incidence trend in the younger population. Although trends in active TB incidence and mortality rates in Japan have favourably decreased, the rate of decline is far from achieving TB elimination by 2035.

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  • Trends in Polypharmacy in Japan: A Nationwide Retrospective Study. Reviewed

    Onoue H, Koyama T, Zamami Y, Hagiya H, Tatebe Y, Mikami N, Shinomiya K, Kitamura Y, Hinotsu S, Sendo T, Ouchi Y, Kano MR

    Journal of the American Geriatrics Society   2018.10

  • In vitro 3D blood/lymph-vascularized human stromal tissues for preclinical assays of cancer metastasis. Reviewed International journal

    Akihiro Nishiguchi, Michiya Matsusaki, Mitsunobu R Kano, Hiroshi Nishihara, Daisuke Okano, Yoshiya Asano, Hiroshi Shimoda, Satoko Kishimoto, Soichi Iwai, Mitsuru Akashi

    Biomaterials   179   144 - 155   2018.10

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    Tumour models mimicking in vivo three-dimensional (3D) microenvironments are of increasing interest in drug discovery because of the limitations inherent to current models. For example, preclinical assays that rely on monolayer or spheroid cell cultures cannot easily predict 3D cancer behaviours because they have no vasculature. Furthermore, there are major differences in cancer behaviour between human and animal experiments. Here, we show the construction of 3D blood/lymph-vascularized human stromal tissues that can be combined with cancer cells to mimic dynamic metastasis for real-time throughput screening of secreted proteinases. We validated this tool using three human carcinoma cell types that are known to invade blood/lymph vessels and promote angiogenesis. These cell types exhibited characteristic haematogenous/lymphogenous metastasis and tumour angiogenesis properties. Importantly, these carcinoma cells selectively secreted different matrix metalloproteinases depending on their metastasis stage and target vasculature, suggesting the possibility of developing drugs that can target each secreted proteinase. We conclude that the 3D tissue tool will be a powerful throughput system for predicting cancer cell responses and time-dependent secretion of molecules in preclinical assays.

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  • Stromal barriers to nanomedicine penetration in the pancreatic tumor microenvironment Reviewed

    Hiroyoshi Y. Tanaka, Mitsunobu R. Kano

    Cancer Science   109 ( 7 )   2085 - 2092   2018.7

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    © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Pancreatic cancer is known for its dismal prognosis despite efforts to improve therapeutic outcome. Recently, cancer nanomedicine, application of nanotechnology to cancer diagnosis and treatment, has gained interest for treatment of pancreatic cancer. The enhanced permeability and retention (EPR) effect that promotes selective accumulation of nanometer-sized molecules within tumors is the theoretical rationale of treatment. However, it is clear that EPR may be insufficient in pancreatic cancer as a result of stromal barriers within the tumor microenvironment (TME). These limit intratumoral accumulation of macromolecules. The TME and stromal barriers inside it consist of various stromal cell types which interact both with each other and with tumor cells. We are only beginning to understand the complexities of the stromal barriers within the TME and its functional consequences for nanomedicine. Understanding the complex crosstalk between barrier stromal cells is challenging because of the difficulty of modeling pancreatic cancer TME. Here we provide an overview of stromal barriers within the TME. We also describe the preclinical models, both in vivo and in vitro, developed to study them. We furthermore discuss the critical gaps in our understanding, and how we might formulate a better strategy for using nanomedicine against pancreatic cancer.

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  • Stromal barriers to nanomedicine penetration in the pancreatic tumor microenvironment. Reviewed International journal

    Hiroyoshi Y Tanaka, Mitsunobu R Kano

    Cancer science   109 ( 7 )   2085 - 2092   2018.7

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    Pancreatic cancer is known for its dismal prognosis despite efforts to improve therapeutic outcome. Recently, cancer nanomedicine, application of nanotechnology to cancer diagnosis and treatment, has gained interest for treatment of pancreatic cancer. The enhanced permeability and retention (EPR) effect that promotes selective accumulation of nanometer-sized molecules within tumors is the theoretical rationale of treatment. However, it is clear that EPR may be insufficient in pancreatic cancer as a result of stromal barriers within the tumor microenvironment (TME). These limit intratumoral accumulation of macromolecules. The TME and stromal barriers inside it consist of various stromal cell types which interact both with each other and with tumor cells. We are only beginning to understand the complexities of the stromal barriers within the TME and its functional consequences for nanomedicine. Understanding the complex crosstalk between barrier stromal cells is challenging because of the difficulty of modeling pancreatic cancer TME. Here we provide an overview of stromal barriers within the TME. We also describe the preclinical models, both in vivo and in vitro, developed to study them. We furthermore discuss the critical gaps in our understanding, and how we might formulate a better strategy for using nanomedicine against pancreatic cancer.

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  • Okayama University's Collective Response to Advance the SDGs Reviewed

    KANO Mitsunobu, INO Hideo, YOKOI Atsufumi, SATO Norito, TAKAHASHI Kayo, MAKINO Hirofumi

    TRENDS IN THE SCIENCES   23 ( 1 )   1_44 - 1_47   2018

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  • Hydrocortisone administration was associated with improved survival in Japanese patients with cardiac arrest. Reviewed International journal

    Takahiro Niimura, Yoshito Zamami, Toshihiro Koyama, Yuki Izawa-Ishizawa, Masashi Miyake, Tadashi Koga, Keisaku Harada, Ayako Ohshima, Toru Imai, Yutaka Kondo, Masaki Imanishi, Kenshi Takechi, Keijo Fukushima, Yuya Horinouchi, Yasumasa Ikeda, Hiromichi Fujino, Koichiro Tsuchiya, Toshiaki Tamaki, Shiro Hinotsu, Mitsunobu R Kano, Keisuke Ishizawa

    Scientific reports   7 ( 1 )   17919 - 17919   2017.12

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    There are few reports on hydrocortisone administration after cardiac arrest, and those that have been published included few subjects. This study aimed to evaluate the effect of hydrocortisone administration on the outcomes of patients who experienced cardiac arrest. We investigated the survival discharge rates and the length of hospital stay from cardiac arrest to discharge, stratified by use of hydrocortisone, using a Japanese health-insurance claims dataset that covers approximately 2% of the Japanese population. The study included the data of 2233 subjects who experienced either in-hospital or out-of-hospital cardiac arrest between January 2005 and May 2014. These patients were divided into two groups, based on the administration of hydrocortisone. We adjusted the baseline characteristics, medical treatment, and drug administration data of the two groups using propensity scores obtained via the inverse probability of treatment weighted method. The hydrocortisone group had a significantly higher survival discharge rate (13/61 [21.1%] vs. 240/2172 [11.0%], adjusted odds ratio: 4.2, 95% CI: 1.60-10.98, p = 0.004). In addition, the administration of hydrocortisone was independent predictor of survival to discharge (hazard ratio: 4.6, p < 0.001). The results demonstrate a correlation between hydrocortisone administration and the high rates of survival to discharge.

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  • Desmoplastic Reaction in 3D-Pancreatic Cancer Tissues Suppresses Molecular Permeability. Reviewed International journal

    Michiya Matsusaki, Misaki Komeda, Simona Mura, Hiroyoshi Y Tanaka, Mitsunobu R Kano, Patrick Couvreur, Mitsuru Akashi

    Advanced healthcare materials   6 ( 15 )   739 - 744   2017.8

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    The survival rate of pancreatic ductal adenocarcinoma is still the lowest among all types of cancers, primarily as a consequence of an important desmoplastic reaction. Although the presence of thick stromal tissues in pancreatic tumors has been reported, in vivo animal studies do not enable a clear understanding of the crosstalk between cancer cells and fibroblasts. Accordingly, this paper reports the design and characterization of an in vitro pancreatic cancer-stromal 3D-tissue model, which enhances the understanding of the interactions between cancer cells and fibroblasts and their influence on the secretion of extracellular matrix (ECM). 3D-tissue models comprising fibroblasts and pancreatic cancer cells (MiaPaCa-2 cell line) or colon cancer cells (HT29 cell line, used as a control) show decreased molecular permeability with increased cancer cell ratios. The 3D-MiaPaCa-2 tissues display an increase in the secretion of collagen as a function of the cancer cell ratio, whereas 3D-HT29 tissues do not show a significant difference. Notably, the secretion of ECM proteins from single fibroblasts in 3D-tissue models containing 90% MiaPaCa-2 cells is ten times higher than that under 10% cancer cell conditions. In vitro pancreatic cancer 3D-tissues will be a valuable tool to obtain information on the interactions between cancer and stromal cells.

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  • Regulation of endothelial Fas expression as a mechanism of promotion of vascular integrity by mural cells in tumors

    Ryosuke Kamei, Hiroyoshi Y. Tanaka, Takao Kawano, Chiharu Morii, Sayaka Tanaka, Hiroshi Nishihara, Caname Iwata, Mitsunobu R. Kano

    Cancer Science   108 ( 5 )   1080 - 1088   2017.5

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    © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Angiogenesis is a multi-step process that culminates in vascular maturation whereby nascent vessels stabilize to become functional, and mural cells play an essential role in this process. Recent studies have shown that mural cells in tumors also promote and maintain vascular integrity, with wide-reaching clinical implications including the regulation of tumor growth, metastases, and drug delivery. Various regulatory signaling pathways have been hitherto implicated, but whether regulation of Fas-dependent apoptotic mechanisms is involved has not yet been fully investigated. We first compared endothelial FAS staining in human pancreatic ductal adenocarcinomas and colon carcinomas and show that the latter, characterized by lower mural cell coverage of tumor vasculature, demonstrated higher expression of FAS than the former. Next, in an in vitro coculture system of MS-1 and 10T1/2 cells as endothelial and mural cells respectively, we show that mural cells decreased endothelial Fas expression. Then, in an in vivo model in which C26 colon carcinoma cells were inoculated together with MS-1 cells alone or with the further addition of 10T1/2 cells, we demonstrate that mural cells prevented hemorrhage. Finally, knockdown of endothelial Fas sufficiently recapitulated the protection against hemorrhage seen with the addition of mural cells. These results together suggest that regulation of endothelial Fas signaling is involved in the promotion of vascular integrity by mural cells in tumors.

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  • Regulation of endothelial Fas expression as a mechanism of promotion of vascular integrity by mural cells in tumors. Reviewed International journal

    Ryosuke Kamei, Hiroyoshi Y Tanaka, Takao Kawano, Chiharu Morii, Sayaka Tanaka, Hiroshi Nishihara, Caname Iwata, Mitsunobu R Kano

    Cancer science   108 ( 5 )   1080 - 1088   2017.5

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    Angiogenesis is a multi-step process that culminates in vascular maturation whereby nascent vessels stabilize to become functional, and mural cells play an essential role in this process. Recent studies have shown that mural cells in tumors also promote and maintain vascular integrity, with wide-reaching clinical implications including the regulation of tumor growth, metastases, and drug delivery. Various regulatory signaling pathways have been hitherto implicated, but whether regulation of Fas-dependent apoptotic mechanisms is involved has not yet been fully investigated. We first compared endothelial FAS staining in human pancreatic ductal adenocarcinomas and colon carcinomas and show that the latter, characterized by lower mural cell coverage of tumor vasculature, demonstrated higher expression of FAS than the former. Next, in an in vitro coculture system of MS-1 and 10T1/2 cells as endothelial and mural cells respectively, we show that mural cells decreased endothelial Fas expression. Then, in an in vivo model in which C26 colon carcinoma cells were inoculated together with MS-1 cells alone or with the further addition of 10T1/2 cells, we demonstrate that mural cells prevented hemorrhage. Finally, knockdown of endothelial Fas sufficiently recapitulated the protection against hemorrhage seen with the addition of mural cells. These results together suggest that regulation of endothelial Fas signaling is involved in the promotion of vascular integrity by mural cells in tumors.

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  • Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery. Reviewed International journal

    Yu Matsumoto, Joseph W Nichols, Kazuko Toh, Takahiro Nomoto, Horacio Cabral, Yutaka Miura, R James Christie, Naoki Yamada, Tadayoshi Ogura, Mitsunobu R Kano, Yasuhiro Matsumura, Nobuhiro Nishiyama, Tatsuya Yamasoba, You Han Bae, Kazunori Kataoka

    Nature nanotechnology   11 ( 6 )   533 - 538   2016.6

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    Enhanced permeability in tumours is thought to result from malformed vascular walls with leaky cell-to-cell junctions. This assertion is backed by studies using electron microscopy and polymer casts that show incomplete pericyte coverage of tumour vessels and the presence of intercellular gaps. However, this gives the impression that tumour permeability is static amid a chaotic tumour environment. Using intravital confocal laser scanning microscopy we show that the permeability of tumour blood vessels includes a dynamic phenomenon characterized by vascular bursts followed by brief vigorous outward flow of fluid (named 'eruptions') into the tumour interstitial space. We propose that 'dynamic vents' form transient openings and closings at these leaky blood vessels. These stochastic eruptions may explain the enhanced extravasation of nanoparticles from the tumour blood vessels, and offer insights into the underlying distribution patterns of an administered drug.

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  • Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery

    Yu Matsumoto, Joseph W. Nichols, Kazuko Toh, Takahiro Nomoto, Horacio Cabral, Yutaka Miura, R. James Christie, Naoki Yamada, Tadayoshi Ogura, Mitsunobu R. Kano, Yasuhiro Matsumura, Nobuhiro Nishiyama, Tatsuya Yamasoba, You Han Bae, Kazunori Kataoka

    NATURE NANOTECHNOLOGY   11 ( 6 )   533 - +   2016.6

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    Enhanced permeability in tumours is thought to result from malformed vascular walls with leaky cell-to-cell junctions(1,2). This assertion is backed by studies using electron microscopy and polymer casts that show incomplete pericyte coverage of tumour vessels and the presence of intercellular gaps(3). However, this gives the impression that tumour permeability is static amid a chaotic tumour environment. Using intravital confocal laser scanning microscopy(4,5) we show that the permeability of tumour blood vessels includes a dynamic phenomenon characterized by vascular bursts followed by brief vigorous outward flow of fluid (named 'eruptions') into the tumour interstitial space. We propose that 'dynamic vents' form transient openings and closings at these leaky blood vessels. These stochastic eruptions may explain the enhanced extravasation of nanoparticles from the tumour blood vessels, and offer insights into the underlying distribution patterns of an administered drug(6,7).

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  • Increased fibrosis and impaired intratumoral accumulation of macromolecules in a murine model of pancreatic cancer co-administered with FGF-2. Reviewed International journal

    Satoshi Sakai, Caname Iwata, Hiroyoshi Y Tanaka, Horacio Cabral, Yasuyuki Morishita, Kohei Miyazono, Mitsunobu R Kano

    Journal of controlled release : official journal of the Controlled Release Society   230   109 - 15   2016.5

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    Pancreatic cancer is notorious for its poor prognosis. The histopathologic characteristic of pancreatic ductal adenocarcinoma (PDAC), which is the most common type of pancreatic cancer, is fibrosis within tumor tissue. Although fibrosis within tumor tissue is thought to impede drug therapy by interfering with the intratumoral accumulation of anti-tumor drugs, this hypothesis has yet to be proven directly in preclinical models. Here, we evaluated the effect of enhanced fibrosis on intratumoral accumulation of macromolecular drugs by increasing fibrosis in a murine tumor model of subcutaneously xenografted BxPC-3, a human PDAC cell line. When fibroblast growth factor-2 (FGF-2) was co-administered upon BxPC-3 inoculation, stromal fibrotic area was increased and was characterized by augmented murine collagen accumulation compared to inoculation of BxPC-3 alone, which correlated with increased monocyte/macrophage contents in the tumor tissues. We further discovered that the intratumoral accumulation of intravenously administrated fluorescein isothiocyanate-dextran of 2,000,000Da (2MDa) was significantly reduced in the FGF-2 co-administered tumors despite unaltered hyaluronan accumulation and pericyte coverage of the tumor neovasculature and increased lymphangiogenesis. Finally, we found that FGF-2 co-administered tumors are more refractory to macromolecular drug therapy using nab-paclitaxel (Abraxane). The model established and analyzed in this study, characterized by increased fibrotic component, provides a preclinical animal model suited to predict the intratumoral accumulation of macromolecular drugs and to evaluate the efficacy of drugs targeting the tumor stroma.

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  • Systemically Injectable Enzyme-Loaded Polyion Complex Vesicles as In Vivo Nanoreactors Functioning in Tumors. Reviewed International journal

    Yasutaka Anraku, Akihiro Kishimura, Mako Kamiya, Sayaka Tanaka, Takahiro Nomoto, Kazuko Toh, Yu Matsumoto, Shigeto Fukushima, Daiki Sueyoshi, Mitsunobu R Kano, Yasuteru Urano, Nobuhiro Nishiyama, Kazunori Kataoka

    Angewandte Chemie (International ed. in English)   55 ( 2 )   560 - 5   2016.1

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    The design and construction of nanoreactors are important for biomedical applications of enzymes, but lipid- and polymeric-vesicle-based nanoreactors have some practical limitations. We have succeeded in preparing enzyme-loaded polyion complex vesicles (PICsomes) through a facile protein-loading method. The preservation of enzyme activity was confirmed even after cross-linking of the PICsomes. The cross-linked β-galactosidase-loaded PICsomes (β-gal@PICsomes) selectively accumulated in the tumor tissue of mice. Moreover, a model prodrug, HMDER-βGal, was successfully converted into a highly fluorescent product, HMDER, at the tumor site, even 4 days after administration of the β-gal@PICsomes. Intravital confocal microscopy showed continuous production of HMDER and its distribution throughout the tumor tissues. Thus, enzyme-loaded PICsomes are useful for prodrug activation at the tumor site and could be a versatile platform for enzyme delivery in enzyme prodrug therapy.

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  • Systemically injectable enzyme-loaded polyion complex vesicles as in vivo nanoreactors functioning in tumors Reviewed

    Y. Anraku, A. Kishimura, M. Kamiya, S. Tanaka, T. Nomoto, K. Toh, Y. Matsumoto, S. Fukushima, D. Sueyoshi, M. R. Kano, Y. Urano, N. Nishiyama, K. Kataoka

    Angewandte Chemie International Edition   128 ( 2 )   570 - 575   2016.1

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  • Authentic Vascular and Stromal Structure in Animal Disease Model for Nanomedicine

    Hiroshi Nishihara, Mitsunobu R. Kano

    Intracellular Delivery III   149 - 160   2016

  • Density-tunable conjugation of cyclic RGD ligands with polyion complex vesicles for the neovascular imaging of orthotopic glioblastomas Reviewed

    Wataru Kawamura, Yutaka Miura, Daisuke Kokuryo, Kazuko Toh, Naoki Yamada, Takahiro Nomoto, Yu Matsumoto, Daiki Sueyoshi, Xueying Liu, Ichio Aoki, Mitsunobu R. Kano, Nobuhiro Nishiyama, Tsuneo Saga, Akihiro Kishimura, Kazunori Kataoka

    SCIENCE AND TECHNOLOGY OF ADVANCED MATERIALS   16 ( 3 )   035004   2015.6

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    Introduction of ligands into 100 nm scaled hollow capsules has great potential for diagnostic and therapeutic applications in drug delivery systems. Polyethylene glycol-conjugated (PEGylated) polyion complex vesicles (PICsomes) are promising hollow nano-capsules that can survive for long periods in the blood circulation and can be used to deliver water-soluble macromolecules to target tissues. In this study, cyclic RGD (cRGD) peptide, which is specifically recognized by alpha(V)beta(3) and alpha(v)beta(5) integrins that are expressed at high levels in the neovascular system, was conjugated onto the distal end of PEG strands on PICsomes for active neovascular targeting. Density-tunable cRGD-conjugation was achieved using PICsomes with definite fraction of end-functionalized PEG, to substitute 20, 40, and 100% of PEG distal end of the PICsomes to cRGD moieties. Compared with control-PICsomes without cRGD, cRGD-PICsomes exhibited increased uptake into human umbilical vein endothelial cells. Intravital confocal laser scanning microscopy revealed that the 40%-cRGD-PICsomes accumulated mainly in the tumor neovasculature and remained in the perivascular region even after 24 h. Furthermore, we prepared superparamagnetic iron oxide (SPIO)-loaded cRGD-PICsomes for magnetic resonance imaging (MRI) and successfully visualized the neovasculature in an orthotopic glioblastoma model, which suggests that SPIO-loaded cRGD-PICsomes might be useful as a MRI contrast reagent for imaging of the tumor microenvironment, including neovascular regions that overexpress alpha(V)beta(3) integrins.

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  • Systemic Targeting of Lymph Node Metastasis through the Blood Vascular System by Using Size-Controlled Nano carriers Reviewed

    Horacio Cabral, Jun Makino, Yu Matsumoto, Peng Mi, Hailiang Wu, Takahiro Nomoto, Kazuko Toh, Naoki Yamada, Yuriko Higuchi, Satoshi Konishi, Mitsunobu R. Kano, Hiroshi Nishihara, Yutaka Miura, Nobuhiro Nishiyama, Kazunori Kataoka

    ACS NANO   9 ( 5 )   4957 - 4967   2015.5

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    Occult nodal metastases increase the risk of cancer recurrence, demoting prognosis and quality of life of patients. While targeted drug delivery by using systemically administered nanocarriers can potentially control metastatic disease, lymph node metastases have been mainly dealt by locally injecting nanocarriers, which may not always be applicable. Herein, we demonstrated that sub-50 nm polymeric micelles incorporating platinum anticancer drugs could target lymph node metastases in a syngeneic melanoma model after systemic injection, even after removing the primary tumors, limiting the growth of the metastases. By comparing these micelles with clinically used doxorubicin-loaded liposomes (Doxil) having 80 nm, as well as a 70 nm version of the micelles, we found that the targeting efficiency of the nanocarriers against lymph node metastases was associated with their size-regulated abilities to extravasate from the blood vasculature in metastases and to penetrate within the metastatic mass. These findings indicate the potential of sub-50 nm polymeric micelles for developing effective conservative treatments against lymph node metastasis capable of reducing relapse and improving survival.

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  • Secretions from placenta, after hypoxia/reoxygenation, can damage developing neurones of brain under experimental conditions Reviewed

    Daniel J. Curtis, Aman Sood, Tom J. Phillips, Veronica H. L. Leinster, Akihiro Nishiguchi, Christopher Coyle, Lizeth Lacharme-Lora, Oliver Beaumont, Helena Kemp, Roberta Goodall, Leila Cornes, Michele Giugliano, Rocco A. Barone, Michiya Matsusaki, Mitsuru Akashi, Hiroyoshi Y. Tanaka, Mitsunobu Kano, Jennifer McGarvey, Nagaraj D. Halemani, Katja Simon, Robert Keehan, William Ind, Tracey Masters, Simon Grant, Sharan Athwal, Gavin Collett, Dionne Tannetta, Ian L. Sargent, Emma Scull-Brown, Xun Liu, Kristian Aquilina, Nicki Cohen, Jon D. Lane, Marianne Thoresen, Jon Hanley, Andrew Randall, C. Patrick Case

    EXPERIMENTAL NEUROLOGY   261   386 - 395   2014.11

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    Some psychiatric diseases in children and young adults are thought to originate from adverse exposures during foetal life, including hypoxia and hypoxia/reoxygenation. The mechanism is not understood. Several authors have emphasised that the placenta is likely to play an important role as the key interface between mother and foetus. Here we have explored whether a first trimester human placenta or model barrier of primary human cytotrophoblasts might secrete factors, in response to hypoxia or hypoxia/reoxygenation, that could damage neurones. We find that the secretions in conditioned media caused an increase of [Ca2+](i) and mitochondrial free radicals and a decrease of dendritic lengths, branching complexity, spine density and synaptic activity in dissociated neurones from embryonic rat cerebral cortex. There was altered staining of glutamate and GABA receptors. We identify glutamate as an active factor within the conditioned media and demonstrate a specific release of glutamate from the placenta/cytotrophoblast barriers in vitro after hypoxia or hypoxia/reoxygenation. Injection of conditioned media into developing brains of P4 rats reduced the numerical density of parvalbumin-containing neurones in cortex, hippocampus and reticular nucleus, reduced immunostaining of glutamate receptors and altered cellular turnover. These results show that the placenta is able to release factors, in response to altered oxygen, that can damage developing neurones under experimental conditions. (C) 2014 Elsevier Inc. All rights reserved.

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  • Polymeric micelles loaded with platinum anticancer drugs target preangiogenic micrometastatic niches associated with inflammation Reviewed

    Hailiang Wu, Horacio Cabral, Kazuko Toh, Peng Mi, Yi-Chun Chen, Yu Matsumoto, Naoki Yamada, Xueying Liu, Hiroaki Kinoh, Yutaka Miura, Mitsunobu R. Kano, Hiroshi Nishihara, Nobuhiro Nishiyama, Kazunori Kataoka

    JOURNAL OF CONTROLLED RELEASE   189   1 - 10   2014.9

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    Nanocarriers have been used for specific delivery of therapeutic agents to solid tumors based on the enhanced permeability and retention in cancerous tissues. Despite metastasis is the main reason of cancer-related death and a priority for nanocarrier-based therapies, the targeting ability of nanocarriers to the metastatic disease is poorly understood, especially for preangiogenic micrometastases as nanocarriers usually use the malignant neovasculature for enhancing their accumulation. Thus, herein, we studied the ability of micellar nanocarriers incorporating (1,2-diaminocyclohexane) platinum(II) (DACHPt) for treating liver metastases of bioluminescent murine colon adenocarcinoma C-26, during overt and preangiogenic metastatic stages. After intravenous injection, DACHPt-loaded micelles (DACHPt/m) effectively inhibited the tumor growth in both metastatic tumor models. While the anticancer activity of the micelles against overt metastases was associated with their selective accumulation in cancerous tissues having neovasculature, the ability of DACHPt/m to target preangiogenic metastases was correlated with the inflammatory microenvironment of the niche. This targeting capability of polymeric micelles to preangiogenic metastasis may provide a novel approach for early diagnosis and treatment of metastases. (C) 2014 Elsevier B.V. All rights reserved.

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  • Nanotechnology and tumor microcirculation Reviewed

    Mitsunobu R. Kano

    ADVANCED DRUG DELIVERY REVIEWS   74   2 - 11   2014.7

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    Though much progress has been made in the development of anti-tumor chemotherapeutic agents, refractoriness is still a major clinical difficulty because little is known about the non-autonomous mechanisms involved. Abnormal capillary structures in tumors, for example, are well documented, but a thorough characterization of microcirculation, including functional consequences with particular regard to drug delivery and intratumor accumulation, is still required for many kinds of tumor. In this review, we highlight how use of synthesized nanoparticles, themselves a product of emerging nanotechnology, are beginning to open up new perspectives in understanding the functional and therapeutic consequences of capillary structure within tumors. Furthermore, nanoparticles promise exciting new clinical applications. I also stress the urgent necessity of developing clinically relevant tumor models, both in vivo and in vitro. (C) 2013 Elsevier B.V. All rights reserved.

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  • Nano-pathophysiology: A novel integrated approach to disease through application of nanotechnology Preface Reviewed

    Mitsunobu R. Kano

    ADVANCED DRUG DELIVERY REVIEWS   74   1 - 1   2014.7

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  • SPIO-PICsome: Development of a highly sensitive and stealth-capable MRI nano-agent for tumor detection using SPIO-loaded unilamellar polyion complex vesicles (PICsomes) (vol 169, pg 220, 2013) Reviewed

    Daisuke Kokuryo, Yasutaka Anraku, Akihiro Kishimura, Sayaka Tanaka, Mitsunobu R. Kano, Jeff Kershaw, Nobuhiro Nishiyama, Tsuneo Saga, Ichio Aoki, Kazunori Kataoka

    JOURNAL OF CONTROLLED RELEASE   178   125 - 125   2014.3

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  • Targeted gene delivery by polyplex micelles with crowded PEG palisade and cRGD moiety for systemic treatment of pancreatic tumors Reviewed

    Zhishen Ge, Qixian Chen, Kensuke Osada, Xueying Liu, Theofilus A. Tockary, Satoshi Uchida, Anjaneyulu Dirisala, Takehiko Ishii, Takahiro Nomoto, Kazuko Toh, Yu Matsumoto, Makoto Oba, Mitsunobu R. Kano, Keiji Itaka, Kazunori Kataoka

    BIOMATERIALS   35 ( 10 )   3416 - 3426   2014.3

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    Adequate retention in systemic circulation is the preliminary requirement for systemic gene delivery to afford high bioavailability into the targeted site. Polyplex micelle formulated through self-assembly of oppositely-charged poly(ethylene glycol) (PEG)-polycation block copolymer and plasmid DNA has gained tempting perspective upon its advantageous core shell architecture, where outer hydrophilic PEG shell offers superior stealth behaviors. Aiming to promote these potential characters toward systemic applications, we strategically introduced hydrophobic cholesteryl moiety at the omega-terminus of block copolymer, anticipating to promote not only the stability of polyplex structure but also the tethered PEG crowdedness. Moreover, M-w of PEG in the PEGylated polyplex micelle was elongated up to 20 kDa for expecting further enhancement in PEG crowdedness. Furthermore, cyclic RGD peptide as ligand molecule to integrin receptors was installed at the distal end of PEG in order for facilitating targeted delivery to the tumor site as well as promoting cellular uptake and intracellular trafficking behaviors. Thus constructed cRGD conjugated polyplex micelle with the elevated PEG shielding was challenged to a modeled intractable pancreatic cancer in mice, achieving potent tumor growth suppression by efficient gene expression of antiangiogenic protein (sFlt-1) at the tumor site. (C) 2013 Elsevier Ltd. All rights reserved.

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  • Building Experimental System Modeling Fibrotic Tissue in Human Pancreatic Cancer by Three-Dimensional Layer-by-Layer Culture

    Mitsunobu R. Kano

    Engineered Cell Manipulation for Biomedical Application.   175 - 181   2014

  • Cyclic RGD-Linked Polymeric Micelles for Targeted Delivery of Platinum Anticancer Drugs to Glioblastoma through the Blood-Brain Tumor Barrier Reviewed

    Yutaka Miura, Tomoya Takenaka, Kazuko Toh, Shourong Wu, Hiroshi Nishihara, Mitsunobu R. Kano, Yasushi Ino, Takahiro Nomoto, Yu Matsumoto, Hiroyuki Koyama, Horacio Cabral, Nobuhiro Nishiyama, Kazunori Kataoka

    ACS NANO   7 ( 10 )   8583 - 8592   2013.10

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    Ligand-mediated drug delivery systems have enormous potential for improving the efficacy of cancer treatment. In particular, Arg-Gly-Asp peptides are promising ligand molecules for targeting alpha(gamma),beta(3)/alpha(gamma)beta(5) integrins, which are overexpressed in angiogenic sites and tumors, such as intractable human glioblastoma (U87MG). We here achieved highly efficient drug delivery to U87MG tumors by using a platinum anticancer drug-incorporating polymeric micelle (PM) with cyclic Arg-Gly-Asp (cRGD) ligand molecules. Intravital confocal laser scanning microscopy revealed that the cRGD-linked polymeric micelles (cRGD/m) accumulated rapidly and had high permeability from vessels into the tumor parenchyma compared with the PM having nontargeted ligand, "cyclic-Arg-Ala-Asp" (cRAD). As both cRGD/m- and cRAD-linked polymeric micelles have similar characteristics, including their size, surface charge, and the amount of incorporated drugs, it is likely that the selective and accelerated accumulation of cRGD/m into tumors occurred via an active internalization pathway, possibly transcytosis, thereby producing significant antitumor effects in an orthotopic mouse model of U87MG human glioblastoma.

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  • SPIO-PICsome: Development of a highly sensitive and stealth-capable MRI nano-agent for tumor detection using SPIO-loaded unilamellar polyion complex vesicles (PICsomes) Reviewed

    Daisuke Kokuryo, Yasutaka Anraku, Akihiro Kishimura, Sayaka Tanaka, Mitsunobu R. Kano, Jeff Kershaw, Nobuhiro Nishiyama, Tsuneo Saga, Ichio Aoki, Kazunori Kataoka

    JOURNAL OF CONTROLLED RELEASE   169 ( 3 )   220 - 227   2013.8

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    Size controllable polyion complex vesicles (PICsomes), composed of biocompatible poly(ethylene glycol) (PEG) and poly(amino acid) s, have an extremely prolonged lifetime in the bloodstream that enables them to accumulate effectively in tumors via the enhanced permeability and retention (EPR) effect. The purpose of this study was to use PICsomes to synthesize a highly sensitive MRI contrast agent for more precise tumor detection. We synthesized SPIO-Cy5-PICsomes (superparamagnetic iron oxide nanoparticle-loaded Cy5-cross-linked Nano-PICsomes) and characterized them using dynamic light scattering and transmission electron microscopy in vitro and evaluated their ability to detect subcutaneously grafted tumors in vivo with MRI. The transverse relaxivity (r(2)) of the SPIO-Cy5-PICsomes (r(2) = 663 +/- 28 mM(-1) s(-1)) was 2.54 times higher than that of bare clinically-used SPIO. In in vivo MRI experiments on mice subcutaneously grafted with colon-26 tumor cells, the tumor signal was significantly altered at 3 h after SPIO-Cy5-PICsome administration and persisted for at least 24 h. Small and early-stage in vivo tumors (3 days after grafting, approximately 4 mm(3)) were also clearly detected with MRI. SPIO-loaded PICsomes are sensitive MRI contrast agents that can act as a powerful nanocarrier to detect small tumors for early diagnosis. (C) 2013 Elsevier B. V. All rights reserved.

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  • Targeted therapy of spontaneous murine pancreatic tumors by polymeric micelles prolongs survival and prevents peritoneal metastasis Reviewed

    Horacio Cabral, Mami Murakami, Hironori Hojo, Yasuko Terada, Mitsunobu R. Kano, Ung-Il Chung, Nobuhiro Nishiyama, Kazunori Kataoka

    Proceedings of the National Academy of Sciences of the United States of America   110 ( 28 )   11397 - 11402   2013.7

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    Nanoscaled drug-loaded carriers are of particular interest for efficient tumor therapy as numerous studies have shown improved targeting and efficacy. Nevertheless, most of these studies have been performed against allograft and xenograft tumor models, which have altered microenvironment features affecting the accumulation and penetration of nanocarriers. Conversely, the evaluation of nanocarriers on genetically engineered mice, which can gradually develop clinically relevant tumors, permits the validation of their design under normal processes of immunity, angiogenesis, and inflammation. Therefore, considering the poor prognosis of pancreatic cancer, we used the elastase 1-promoted luciferase and Simian virus 40 T and t antigens transgenic mice, which develop spontaneous bioluminescent pancreatic carcinoma, and showed that long circulating micellar nanocarriers, incorporating the parent complex of oxaliplatin, inhibited the tumor growth as a result of their efficient accumulation and penetration in the tumors. The reduction of the photon flux from the endogenous tumor by the micelles correlated with the decrease of serum carbohydrate-associated antigen 19-9 marker. Micelles also reduced the incidence of metastasis and ascites, extending the survival of the transgenic mice.

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  • SPIO-loaded unilamellar polyion complex vesicles (SPIO-Cy5-PICsomes) as a high relaxivity contrast agent for tumor detection Reviewed

    D. Kokuryo, Y. Anraku, A. Kishimura, M. R Kano, S. Tanaka, T. Saga, I. Aoki, K. Kataoka

    Proc. 21th ISMRM Scientific Meeting and Exhibition   1869 - 1869   2013.4

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  • Transcription Factor YY1 Contributes to Tumor Growth by Stabilizing Hypoxia Factor HIF-1 alpha in a p53-Independent Manner Reviewed

    Shourong Wu, Vivi Kasim, Mitsunobu R. Kano, Sayaka Tanaka, Shinsuke Ohba, Yutaka Miura, Kanjiro Miyata, Xueying Liu, Ako Matsuhashi, Ung-il Chung, Li Yang, Kazunori Kataoka, Nobuhiro Nishiyama, Makoto Miyagishi

    CANCER RESEARCH   73 ( 6 )   1787 - 1799   2013.3

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    In response to hypoxic stress, hypoxia-inducible factor (HIF)-1 alpha is a critical transcription factor regulating fundamental cellular processes, and its elevated expression level and activity are associated with poor outcomes in most malignancies. The transcription factor Yin Yang 1 (YY1) is an important negative regulator of the tumor suppressor factor p53. However, the role of YY1 under tumor hypoxic condition is poorly understood. Herein, we show that inhibition of YY1 reduced the accumulation of HIF-1 alpha and its activity under hypoxic condition, and consequently downregulated the expression of HIF-1 alpha target genes. Interestingly, our results revealed that the downregulation of HIF-1 alpha by inhibiting YY1 is p53-independent. Functionally, the in vivo experiments revealed that inhibition of YY1 significantly suppressed growth of metastatic cancer cells and lung colonization and also attenuated angiogenesis in a p53-null tumor. Collectively, our findings unraveled a novel mechanism by which YY1 inhibition disrupts hypoxia-stimulated HIF-1 alpha stabilization in a p53-independent manner. Therefore, YY1 inhibition could be considered as a potential tumor therapeutic strategy to give consistent clinical outcomes independent of p53 status. Cancer Res; 73(6); 1787-99. (C)2012 AACR.

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  • PDGFR beta expression in tumor stroma of pancreatic adenocarcinoma as a reliable prognostic marker Reviewed

    Sayaka Yuzawa, Mitsunobu R. Kano, Takahiro Einama, Hiroshi Nishihara

    MEDICAL ONCOLOGY   29 ( 4 )   2824 - 2830   2012.12

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    Pancreatic adenocarcinoma is a lethal disease that often develops a desmoplastic reaction in tumor stroma. In general, desmoplasia is thought to promote tumor growth. However, its molecular pathology and prognostic potential have not been fully investigated. Here, we investigate 26 cases of pancreatic ductal adenocarcinoma and examine the clinicopathological association between survival and expression levels of several molecular markers for stromal cells. These include alpha-smooth muscle actin (SMA) and platelet-derived growth factor (PDGF) receptor beta (PDGFR beta). Both are markers of activated fibroblasts or pancreatic stellate cells (PSCs) that play an important role in desmoplasia. The staining patterns of both molecular markers were not uniform, so we categorized them into 3 grades (high, middle, and low) according to intensity. Interestingly, Kaplan-Meier analysis revealed that higher expression of PDGFR beta matched shorter prognosis (p = 0.0287, log-rank test) as well as lymphatic invasion and lymph node metastasis, whereas SMA did not (p = 0.6122). Our results suggest the prognostic potential of cancer stroma via PDGF-B signaling. Regulation of PDGF-B-associated signaling crosstalk between cancer cells and stroma cells, therefore, may indicate a possible therapeutic target for desmoplastic malignant tumors such as pancreatic adenocarcinoma.

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  • Homo-catiomer integration into PEGylated polyplex micelle from block-catiomer for systemic anti-angiogenic gene therapy for fibrotic pancreatic tumors Reviewed

    Qixian Chen, Kensuke Osada, Takehiko Ishii, Makoto Oba, Satoshi Uchida, Theofilus A. Tockary, Taisuke Endo, Zhishen Ge, Hiroaki Kinoh, Mitsunobu R. Kano, Keiji Itaka, Kazunori Kataoka

    BIOMATERIALS   33 ( 18 )   4722 - 4730   2012.6

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    Homo-poly(N'-[N-(2-aminoethyl)-2-aminoehtyljaspartamide) [PAsp(DET), HI was attempted to integrate into poly (ethylene glycol) (PEG)-b-PAsp(DET)] (B) formulated polyplex micelle with the aim of enhancing cell transfection efficiency for PEGylated polyplex micelle via H integration. In vitro evaluations verified H integration of potent stimulation in enhancing cell-transfecting activity of PEGylated polyplex micelles via promoted cellular uptake and facilitated endosome escape. In vivo anti-angiogenic tumor suppression evaluations validated the feasibility of H integration in promoting gene transfection to the affected cells via systemic administration, where loaded anti-angiogenic gene remarkably expressed in the tumor site, thereby imparting significant inhibitory effect on the growth of vascular endothelial cells, ultimately leading to potent tumor growth suppression. These results demonstrated potency of H integration for enhanced transfection activity and potential usage in systemic applications, which could have important implications on the strategic use of H integration in the non-viral gene carrier design. (C) 2012 Elsevier Ltd. All rights reserved.

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  • Pericyte-Coverage of Human Tumor Vasculature and Nanoparticle Permeability Reviewed

    Liuzhe Zhang, Hiroshi Nishihara, Mitsunobu R. Kano

    BIOLOGICAL & PHARMACEUTICAL BULLETIN   35 ( 5 )   761 - 766   2012.5

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    Nano drug delivery systems (nanoDDS) are a promising strategy for treatment of human tumors. As indicated by our previous work, the extent of pericyte-coverage of tumor vasculature is important to determining nanoDDS efficacy since intratumoral accumulation of nanoDDS is less in tumor models with pericyte-covered vasculature. Here we investigated the clinical relevance of our previous observations in animal models, by determining pericyte coverage using immunohistochemistry of smooth muscle actin (SMA) with CD34: a vascular endothelial marker, in human tumor tissue samples. The investigation revealed that tumor vasculature coverage by pericytes in pancreatic and diffuse-type gastric cancers was significantly greater than in ovarian, colon, and intestinal-type gastric cancers. The latter group of cancers is easier to treat clinically. These observations are consistent with our previous findings in animal models. On the basis of these findings we believe optimization of nanoDDS delivery should be done depend upon a clear understanding of the effects of pericyte vascular coverage.

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  • Polymeric micelles incorporating (1,2-diaminocyclohexane)platinum (II) suppress the growth of orthotopic scirrhous gastric tumors and their lymph node metastasis Reviewed

    Md Rafi, H. Cabral, M. R. Kano, P. Mi, C. Iwata, M. Yashiro, K. Hirakawa, K. Miyazono, N. Nishiyama, K. Kataoka

    JOURNAL OF CONTROLLED RELEASE   159 ( 2 )   189 - 196   2012.4

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    Nano-scaled drug carriers have great potential for the treatment of solid tumors. Nevertheless, hypovascularity and fibrosis in some types of solid tumors have been demonstrated to reduce the penetration and accumulation of nano-scaled drug carriers. Diffuse-type scirrhous gastric cancers present such characteristics as well as frequent metastasis to the lymph nodes; therefore, it remains a great challenge to eradicate scirrhous gastric cancers based on the drug targeting using nanocarriers. Herein, we demonstrated that polymeric micelles with 30-nm diameter incorporating (1,2-diaminocyclohexane) platinum(II) (DACHPt), the parent complex of the anticancer drug oxaliplatin, efficiently penetrated and accumulated in an orthotopic scirrhous gastric cancer model, leading to the inhibition of the tumor growth. Moreover, the elevated localization of systemically injected DACHPt-loaded micelles in metastastic lymph nodes reduced the metastatic tumor growth. These results suggest DACHPt-loaded micelles as a promising nanocarrier for the treatment of scirrhous gastric cancers and their lymphatic metastases. (C) 2012 Elsevier B.V. All rights reserved.

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  • Engineering fibrotic tissue in pancreatic cancer: A novel three-dimensional model to investigate nanoparticle delivery Reviewed

    Hitomi Hosoya, Koji Kadowaki, Michiya Matsusaki, Horacio Cabral, Hiroshi Nishihara, Hideaki Ijichi, Kazuhiko Koike, Kazunori Kataoka, Kohei Miyazono, Mitsuru Akashi, Mitsunobu R. Kano

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   419 ( 1 )   32 - 37   2012.3

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    Pancreatic cancer contains both fibrotic tissue and tumor cells with embedded vasculature. Therefore anti-cancer nanoparticles need to extravasate from tumor vasculature and permeate thick fibrotic tissue to target tumor cells. To date, permeation of drugs has been investigated in vitro using monolayer models. Since three-dimensional migration of nanoparticles cannot be analyzed in a monolayer model, we established a novel, three-dimensional, multilayered, in vitro model of tumor fibrotic tissue, using our hierarchical cell manipulation technique with K643f fibroblasts derived from a murine pancreatic tumor model. NIH3T3 normal fibroblasts were used in comparison. We analyzed the size-dependent effect of nanoparticles on permeation in this experimental model using fluorescent dextran molecules of different molecular weights. The system revealed permeation decreased as number of layers of cultured cells increased, or as molecule size increased. Furthermore, we showed changes in permeation depended on the source of the fibroblasts. Observations of this sort cannot be made in conventional monolayer culture systems. Thus our novel technique provides a promising in vitro means to investigate permeation of nanoparticles in fibrotic tissue, when both type and number of fibroblasts can be regulated. (C) 2012 Elsevier Inc. All rights reserved.

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  • NC-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo Reviewed

    Mitsunori Harada, Caname Iwata, Hiroyuki Saito, Kenta Ishii, Tatsuyuki Hayashi, Masakazu Yashiro, Kosei Hirakawa, Kohei Miyazono, Yasuki Kato, Mitsunobu R. Kano

    INTERNATIONAL JOURNAL OF NANOMEDICINE   7   2713 - 2727   2012

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    Drug release rate is an important factor in determining efficacy and toxicity of nanoscale drug delivery systems. However, optimization of the release rate in polymeric micellar nanoscale drug delivery systems has not been fully investigated. In this study NC-6301, a poly(ethylene glycol)-poly(aspartate) block copolymer with docetaxel (DTX) covalently bound via ester link, was synthesized with various numbers of DTX molecules bound to the polymer backbone. The number of DTX molecules was determined up to 14 to achieve an optimal release rate, based upon the authors' own pharmacokinetic model using known patient data. Efficacy and toxicity of the formulation was then tested in animals. When administered three times at 4-day intervals, the maximum tolerated doses of NC-6301 and native DTX were 50 and 10 mg/kg, respectively, in nude mice. Tissue distribution studies of NC-6301 in mice at 50 mg/kg revealed prolonged release of free DTX in the tumor for at least 120 hours, thus supporting its effectiveness. Furthermore, in cynomolgus monkeys, NC-6301 at 6 mg/kg three times at 2-week intervals showed marginal toxicity, whereas native DTX, at 3 mg/kg with the same schedule, induced significant decrease of food consumption and neutrophil count. NC-6301 at 50 mg/kg in mice also regressed a xenografted tumor of MDA-MB-231 human breast cancer. Native DTX, on the other hand, produced only transient and slight regression of the same tumor xenograft. NC-6301 also significantly inhibited growth of OCUM-2MLN human scirrhous gastric carcinoma in an orthotopic mouse model. Total weight of metastatic lymph nodes was also reduced. In conclusion, NC-6301 with an optimized release rate improved the potency of DTX while reducing its toxicity.

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  • NC-6301, a polymeric micelle rationally optimized for effective release of docetaxel, is potent but is less toxic than native docetaxel in vivo Reviewed

    Mitsunori Harada, Caname Iwata, Hiroyuki Saito, Kenta Ishii, Tatsuyuki Hayashi, Masakazu Yashiro, Kosei Hirakawa, Kohei Miyazono, Yasuki Kato, Mitsunobu R. Kano

    International Journal of Nanomedicine   7   2713 - 2727   2012

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    Drug release rate is an important factor in determining efficacy and toxicity of nanoscale drug delivery systems. However, optimization of the release rate in polymeric micellar nanoscale drug delivery systems has not been fully investigated. In this study NC-6301, a poly(ethylene glycol)-poly(aspartate) block copolymer with docetaxel (DTX) covalently bound via ester link, was synthesized with various numbers of DTX molecules bound to the polymer backbone. The number of DTX molecules was determined up to 14 to achieve an optimal release rate, based upon the authors' own pharmacokinetic model using known patient data. Efficacy and toxicity of the formulation was then tested in animals. When administered three times at 4-day intervals, the maximum tolerated doses of NC-6301 and native DTX were 50 and 10 mg/kg, respectively, in nude mice. Tissue distribution studies of NC-6301 in mice at 50 mg/kg revealed prolonged release of free DTX in the tumor for at least 120 hours, thus supporting its effectiveness. Furthermore, in cynomolgus monkeys, NC-6301 at 6 mg/kg three times at 2-week intervals showed marginal toxicity, whereas native DTX, at 3 mg/kg with the same schedule, induced significant decrease of food consumption and neutrophil count. NC-6301 at 50 mg/kg in mice also regressed a xenografted tumor of MDA-MB-231 human breast cancer. Native DTX, on the other hand, produced only transient and slight regression of the same tumor xenograft. NC-6301 also significantly inhibited growth of OCUM-2MLN human scirrhous gastric carcinoma in an orthotopic mouse model. Total weight of metastatic lymph nodes was also reduced. In conclusion, NC-6301 with an optimized release rate improved the potency of DTX while reducing its toxicity. 2012 Cárdenas et al, publisher and licensee Dove Medical Press Ltd.

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  • Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size Reviewed

    H. Cabral, Y. Matsumoto, K. Mizuno, Q. Chen, M. Murakami, M. Kimura, Y. Terada, M. R. Kano, K. Miyazono, M. Uesaka, N. Nishiyama, K. Kataoka

    NATURE NANOTECHNOLOGY   6 ( 12 )   815 - 823   2011.12

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    A major goal in cancer research is to develop carriers that can deliver drugs effectively and without side effects. Liposomal and particulate carriers with diameters of similar to 100 nm have been widely used to improve the distribution and tumour accumulation of cancer drugs, but so far they have only been effective for treating highly permeable tumours. Here, we compare the accumulation and effectiveness of different sizes of long-circulating, drug-loaded polymeric micelles ( with diameters of 30, 50, 70 and 100 nm) in both highly and poorly permeable tumours. All the polymer micelles penetrated highly permeable tumours in mice, but only the 30 nm micelles could penetrate poorly permeable pancreatic tumours to achieve an antitumour effect. We also showed that the penetration and efficacy of the larger micelles could be enhanced by using a transforming growth factor-beta inhibitor to increase the permeability of the tumours.

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  • High Expression of IL-22 Suppresses Antigen-Induced Immune Responses and Eosinophilic Airway Inflammation via an IL-10-Associated Mechanism Reviewed

    Kazuyuki Nakagome, Mitsuru Imamura, Kimito Kawahata, Hiroaki Harada, Katsuhide Okunishi, Taku Matsumoto, Oh Sasaki, Ryoichi Tanaka, Mitsunobu R. Kano, He Chang, Haruo Hanawa, Jun-ichi Miyazaki, Kazuhiko Yamamoto, Makoto Dohi

    JOURNAL OF IMMUNOLOGY   187 ( 10 )   5077 - 5089   2011.11

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    Allergic inflammation in the airway is generally considered a Th2-type immune response. However, Th17-type immune responses also play important roles in this process, especially in the pathogenesis of severe asthma. IL-22 is a Th17-type cytokine and thus might play roles in the development of allergic airway inflammation. There is increasing evidence that IL-22 can act as a proinflammatory or anti-inflammatory cytokine depending on the inflammatory context. However, its role in Ag-induced immune responses is not well understood. This study examined whether IL-22 could suppress allergic airway inflammation and its mechanism of action. BALB/c mice were sensitized and challenged with OVA-Ag to induce airway inflammation. An IL-22-producing plasmid vector was delivered before the systemic sensitization or immediately before the airway challenge. Delivery of the IL-22 gene before sensitization, but not immediately before challenge, suppressed eosinophilic airway inflammation. IL-22 gene delivery suppressed Ag-induced proliferation and overall cytokine production in CD4(+) T cells, indicating that it could suppress Ag-induced T cell priming. Antagonism of IL-22 by IL-22-binding protein abolished IL-22-induced immune suppression, suggesting that IL-22 protein itself played an essential role. IL-22 gene delivery neither increased regulatory T cells nor suppressed dendritic cell functions. The suppression by IL-22 was abolished by deletion of the IL-10 gene or neutralization of the IL-10 protein. Finally, IL-22 gene delivery increased IL-10 production in draining lymph nodes. These findings suggested that IL-22 could have an immunosuppressive effect during the early stage of an immune response. Furthermore, IL-10 plays an important role in the immune suppression by IL-22. The Journal of Immunology, 2011, 187: 5077-5089.

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  • Transforming growth factor-beta decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells Reviewed

    S. Ehata, E. Johansson, R. Katayama, S. Koike, A. Watanabe, Y. Hoshino, Y. Katsuno, A. Komuro, D. Koinuma, M. R. Kano, M. Yashiro, K. Hirakawa, H. Aburatani, N. Fujita, K. Miyazono

    ONCOGENE   30 ( 14 )   1693 - 1705   2011.4

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    Stem cells in normal tissues and cancer-initiating cells (CICs) are known to be enriched in side population (SP) cells. However, the factors responsible for the regulation of expression of ABCG2, involved in efflux of dyes, in SP cells have not been fully investigated. Here, we characterized the SP cells within diffuse-type gastric carcinoma, and examined the effects of transforming growth factor-beta (TGF-beta) on SP cells. Diffuse-type gastric carcinoma cells established from four independent patients universally contained SP cells between 1 and 4% of total cells, which displayed greater tumorigenicity than non-SP cells did. TGF-beta repressed the transcription of ABCG2 through direct binding of Smad2/3 to its promoter/enhancer, and the number of SP cells and the tumor-forming ability of cancer cells were decreased by TGF-beta, although ABCG2 is not directly involved in the tumor-forming ability of SP cells. Cancer cells from metastatic site expressed much higher levels of ABCG2 and included a greater percentage of SP cells than parental cancer cells did. SP cells are thus responsible for the progression of diffuse-type gastric carcinoma, and TGF-beta negatively contributes to maintain the CICs within the cancer. Oncogene (2011) 30, 1693-1705; doi:10.1038/onc.2010.546; published online 6 December 2010

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  • Antiangiogenic gene therapy of experimental pancreatic tumor by sFlt-1 plasmid DNA carried by RGD-modified crosslinked polyplex micelles Reviewed

    Yelena Vachutinsky, Makoto Oba, Kanjiro Miyata, Shigehiro Hiki, Mitsunobu R. Kano, Nobuhiro Nishiyama, Hiroyuki Koyama, Kohei Miyazono, Kazunori Kataoka

    JOURNAL OF CONTROLLED RELEASE   149 ( 1 )   51 - 57   2011.1

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    Disulfide crosslinked polyplex micelles with RGD peptides were formed through ion complexation of thiolated c(RGDfK)-poly(ethylene glycol)-block-poly(L-lysine) (c(RGDfK)-PEG-P(Lys-SH)) and plasmid DNA encoding sFlt-1 and tested for their therapeutic effect in BxPC3 pancreatic adenocarcinoma tumor bearing mice. These micelles, systemically injected, demonstrated significant inhibition of tumor growth up to day 18, as a result of the antiangiogenic effect that was confirmed by vascular density measurements. Significant therapeutic activity of the 15% crosslinked micelle (c(RGDfK)-PEG-P(Lys-SH15)) was achieved by combined effect of increased tumor accumulation, interaction with endothelial cells and enhanced intracellular uptake through receptor-mediated endocytosis. These results suggest that RGD targeted crosslinked polyplex micelles can be effective plasmid DNA carriers for antiangiogenic gene therapy. (C) 2010 Elsevier B.V. All rights reserved.

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  • Improving Drug Potency and Efficacy by Nanocarrier-Mediated Subcellular Targeting Reviewed

    Mami Murakami, Horacio Cabral, Yu Matsumoto, Shourong Wu, Mitsunobu R. Kano, Takao Yamori, Nobuhiro Nishiyama, Kazunori Kataoka

    SCIENCE TRANSLATIONAL MEDICINE   3 ( 64 )   64ra2   2011.1

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    Nanocarrier-mediated drug targeting is an emerging strategy for cancer therapy and is being used, for example, with chemotherapeutic agents for ovarian cancer. Nanocarriers are selectively accumulated in tumors as a result of their enhanced permeability and retention of macromolecules, thereby enhancing the antitumor activity of the nanocarrier-associated drugs. We investigated the real-time subcellular fate of polymeric micelles incorporating (1,2-diaminocyclohexane) platinum(II) (DACHPt/m), the parent complex of oxaliplatin, in tumor tissues by fluorescence-based assessment of their kinetic stability. These observations revealed that DACHPt/m was extravasated from blood vessels to the tumor tissue and dissociated inside each cell. Furthermore, DACHPt/m selectively dissociated within late endosomes, enhancing drug delivery to the nearby nucleus relative to free oxaliplatin, likely by circumvention of the cytoplasmic detoxification systems such as metallothionein and methionine synthase. Thus, these drug-loaded micelles exhibited higher antitumor activity than did oxaliplatin alone, even against oxaliplatin-resistant tumors. These findings suggest that nanocarriers targeting subcellular compartments may have considerable benefits in clinical applications.

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  • Polyplex micelles prepared from omega-cholesteryl PEG-polycation block copolymers for systemic gene delivery Reviewed

    Makoto Oba, Kanjiro Miyata, Kensuke Osada, R. James Christie, Mai Sanjoh, Weidong Li, Shigeto Fukushima, Takehiko Ishii, Mitsunobu R. Kano, Nobuhiro Nishiyama, Hiroyuki Koyama, Kazunori Kataoka

    BIOMATERIALS   32 ( 2 )   652 - 663   2011.1

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    Polyplex micelles formed with plasmic! DNA (pDNA) and poly(ethylene glycol) (PEG)-block-poly(N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide) [PAsp(DET)] exhibit effective endosomal escaping properties based on di-protonation of diamine side chains with decreasing pH which improves their transfection efficiency and thus are promising candidates for local in vivo gene transfer Here PEG-PAsp(DET) polyplex micelles were further Improved as in vivo systemic vectors by introduction of cholesterol (Chole) into the vi-terminus of PEG-PAsp(DET) to obtain PEG-PAsp(DET)-Chole Introduction of the cholesterol resulted in enhanced association of block copolymers with pDNA which led to increased stability in proteinous medium and also in the blood stream after systemic injection compared to PEG-PAsp(DET) micelles The synergistic effect between enhanced polymer association with pDNA and increased micelle stability of PEG-PAsp(DET)-Chole polyplex micelles led to high in vitro gene transfer even at relatively low concentrations due to efficient cellular uptake and effective endosomal escape of block copolymers and pDNA Finally PEG-PAsp(DET)-Chole micelles achieved significant suppression of tumor growth following Intravenous injection Into mice bearing a subcutaneous pancreatic tumor using therapeutic pDNA encoding an anti-angiogenic protein These results suggest that PEG-PAsp(DET)-Chole micelles can be effective systemic gene vectors for treatment of solid tumors (C) 2010 Elsevier Ltd All rights reserved

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  • LPA(4) regulates blood and lymphatic vessel formation during mouse embryogenesis Reviewed

    Hayakazu Sumida, Kyoko Noguchi, Yasuyuki Kihara, Manabu Abe, Keisuke Yanagida, Fumie Hamano, Shinichi Sato, Kunihiko Tamaki, Yasuyuki Morishita, Mitsunobu R. Kano, Caname Iwata, Kohei Miyazono, Kenji Sakimura, Takao Shimizu, Satoshi Ishii

    BLOOD   116 ( 23 )   5060 - 5070   2010.12

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    Lysophosphatidic acid (LPA) is a potent lipid mediator with a wide variety of biological actions mediated through G protein-coupled receptors (LPA(1-6)). LPA(4) has been identified as a G(13) protein-coupled receptor, but its physiological role is unknown. Here we show that a subset of LPA(4)-deficient embryos did not survive gestation and displayed hemorrhages and/or edema in many organs at multiple embryonic stages. The blood vessels of bleeding LPA(4)-deficient embryos were often dilated. The recruitment of mural cells, namely smooth muscle cells and pericytes, was impaired. Consistently, Matrigel plug assays showed decreased mural cell coverage of endothelial cells in the neovessels of LPA(4)-deficient adult mice. In situ hybridization detected Lpa(4) mRNA in the endothelium of some vasculatures. Similarly, the lymphatic vessels of edematous embryos were dilated. These results suggest that LPA(4) regulates establishment of the structure and function of blood and lymphatic vessels during mouse embryogenesis. Considering the critical role of autotaxin (an enzyme involved in LPA production) and G alpha(13) in vascular development, we suggest that LPA(4) provides a link between these 2 molecules. (Blood. 2010;116(23):5060-5070)

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  • Induction of Endothelial Nitric Oxide Synthase, SIRT1, and Catalase by Statins Inhibits Endothelial Senescence Through the Akt Pathway Reviewed

    Hidetaka Ota, Masato Eto, Mitsunobu R. Kano, Tomoaki Kahyo, Mitsutoshi Setou, Sumito Ogawa, Katsuya Iijima, Masahiro Akishita, Yasuyoshi Ouchi

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY   30 ( 11 )   2205 - U411   2010.11

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    Objective-Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) have pleiotropic vascular protective effects besides cholesterol lowering. Recently, experimental and clinical studies have indicated that senescence of endothelial cells is involved in endothelial dysfunction and atherogenesis. Therefore, the present study was performed to determine whether statins would reduce endothelial senescence and to clarify the molecular mechanisms underlying the antisenescent property of statins.
    Methods and Results-Senescent human umbilical vein endothelial cells were induced by hydrogen peroxide (H(2)O(2)), as judged by senescence-associated beta-galactosidase assay and cell morphological appearance. Atorvastatin, pravastatin, and pitavastatin inhibited the oxidative stress induced-endothelial senescence. These statins phosphorylated Akt at Ser473 and subsequently led to increased expression of endothelial nitric oxide synthase (eNOS), SIRT1, and catalase. Treatment with LY294002 or Akt short interfering RNA decreased the eNOS activation, SIRT1 expression, and antisenescent property of atorvastatin. Moreover, in streptozotocin-diabetic mice, administration of pitavastatin increased eNOS, SIRT1, and catalase expression and decreased endothelial senescence, but levels remained unaltered in Sirt1 knockout mice.
    Conclusion-Our results indicate that treatment with statins inhibits endothelial senescence and that enhancement of SIRT1 plays a critical role in prevention of endothelial senescence through the Akt pathway, a direct target of statins. (Arterioscler Thromb Vasc Biol. 2010; 30: 2205-2211.)

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  • Exogenous introduction of tissue inhibitor of metalloproteinase 2 reduces accelerated growth of TGF-beta-disrupted diffuse-type gastric carcinoma Reviewed

    Erik Johansson, Akiyoshi Komuro, Caname Iwata, Akifumi Hagiwara, Yuma Fuse, Akira Watanabe, Yasuyuki Morishita, Hiroyuki Aburatani, Keiko Funa, Mitsunobu R. Kano, Kohei Miyazono

    CANCER SCIENCE   101 ( 11 )   2398 - 2403   2010.11

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    Diffuse-type gastric carcinoma is characterized by rapid progression and poor prognosis. High expression of transforming growth factor (TGF)-beta and thick stromal fibrosis are observed in this type of gastric carcinoma. We have previously shown that disruption of TGF-beta signaling via introduction of a dominant negative form of the TGF-beta type II receptor (dnT beta RII) into diffuse-type gastric cancer cell lines, including OCUM-2MLN, caused accelerated tumor growth through induction of tumor angiogenesis in vivo. In the present study, we show that TGF-beta induces upregulation of expression of tissue inhibitor of metalloproteinase 2 (TIMP2) in the OCUM-2MLN cell line in vitro, and that expression of TIMP2 is repressed by dnT beta RII expression in vivo. Transplantation of the OCUM-2MLN cells to nude mice exhibited accelerated tumor growth in response to dnT beta RII expression, which was completely abolished when TIMP2 was coexpressed with dnT beta RII. Although the blood vessel density of TIMP2-expressing tumors was only slightly decreased, the degree of hypoxia in tumor tissues was significantly increased and pericytes covering tumor vasculature were decreased by TIMP2 expression in OCUM-2MLN cells, suggesting that the function of tumor vasculatures was repressed by TIMP2 and consequently tumor growth was reduced. These findings provide evidence that one of the mechanisms of the increase in angiogenesis in diffuse-type gastric carcinoma is the downregulation of the anti-angiogenic protein TIMP2. (Cancer Sci 2010; 101: 2398-2403).

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  • Exogenous introduction of tissue inhibitor of metalloproteinase 2 reduces accelerated growth of TGF-β-disrupted diffuse-type gastric carcinoma Reviewed

    Erik Johansson, Akiyoshi Komuro, Caname Iwata, Akifumi Hagiwara, Yuma Fuse, Akira Watanabe, Yasuyuki Morishita, Hiroyuki Aburatani, Keiko Funa, Mitsunobu R. Kano, Kohei Miyazono

    International Journal of Psychoanalysis   91 ( 5 )   2398 - 2403   2010.10

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    Diffuse-type gastric carcinoma is characterized by rapid progression and poor prognosis. High expression of transforming growth factor (TGF)-β and thick stromal fibrosis are observed in this type of gastric carcinoma. We have previously shown that disruption of TGF-β signaling via introduction of a dominant negative form of the TGF-β type II receptor (dnTβRII) into diffuse-type gastric cancer cell lines, including OCUM-2MLN, caused accelerated tumor growth through induction of tumor angiogenesis in vivo. In the present study, we show that TGF-β induces upregulation of expression of tissue inhibitor of metalloproteinase 2 (TIMP2) in the OCUM-2MLN cell line in vitro, and that expression of TIMP2 is repressed by dnTβRII expression in vivo. Transplantation of the OCUM-2MLN cells to nude mice exhibited accelerated tumor growth in response to dnTβRII expression, which was completely abolished when TIMP2 was coexpressed with dnTβRII. Although the blood vessel density of TIMP2-expressing tumors was only slightly decreased, the degree of hypoxia in tumor tissues was significantly increased and pericytes covering tumor vasculature were decreased by TIMP2 expression in OCUM-2MLN cells, suggesting that the function of tumor vasculatures was repressed by TIMP2 and consequently tumor growth was reduced. These findings provide evidence that one of the mechanisms of the increase in angiogenesis in diffuse-type gastric carcinoma is the downregulation of the anti-angiogenic protein TIMP2. (Cancer Sci 2010
    101: 2398-2403) © 2010 Japanese Cancer Association.

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  • Enhanced in vivo Magnetic Resonance Imaging of Tumors by PEGylated Iron-Oxide-Gold Core-Shell Nanoparticles with Prolonged Blood Circulation Properties Reviewed

    Michiaki Kumagai, Tridib Kumar Sarma, Horacio Cabral, Sachiko Kaida, Masaki Sekino, Nicholas Herlambang, Kensuke Osada, Mitsunobu R. Kano, Nobuhiro Nishiyama, Kazunori Kataoka

    MACROMOLECULAR RAPID COMMUNICATIONS   31 ( 17 )   1521 - 1528   2010.9

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    High-density poly(ethylene glycol) (PEG)-coated iron-oxide-gold core-shell nanoparticles (AuIONs) were developed as T(2)-weighted magnetic resonance imaging (MRI) contrast agents for cancer imaging. The PEG-coated iron-oxide-gold core-shell nanoparticles (PEG-AuIONs) were approximately 25 nm in diameter with a narrow distribution. Biodistribution experiments in mice bearing a subcutaneous colon cancer model prepared with C26 murine colon adenocarcinoma cells showed high accumulation of the PEG-AuIONs within the tumor mass and low nonspecific accumulation in the liver and spleen, resulting in high specificity to solid tumors. T(2)-weighted MR images following intravenous injection of PEG-AuIONs showed selective negative enhancement of tumor tissue in an orthotopic pancreatic cancer model prepared with Mia-PaCa-2 human pancreatic adenocarcinoma cells. These results indicate that PEG-AuIONs are a promising MRI contrast agent for diagnosis of malignant tumors, including pancreatic cancer.

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  • Antiangiogenic Gene Therapy of Solid Tumor by Systemic Injection of Polyplex Micelles Loading Plasmid DNA Encoding Soluble Flt-1 Reviewed

    Makoto Oba, Yelena Vachutinsky, Kanjiro Miyata, Mitsunobu R. Kano, Sorato Ikeda, Nobuhiro Nishiyama, Keiji Itaka, Kohei Miyazono, Hiroyuki Koyama, Kazunori Kataoka

    MOLECULAR PHARMACEUTICS   7 ( 2 )   501 - 509   2010.3

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    In this study, a polyplex micelle was developed as a potential formulation for antiangiogenic gene therapy of subcutaneous pancreatic tumor model. Poly(ethylene glycol)-poly(L-lysine) block copolymers (PEG-PLys) with thiol groups in the side chain of the PLys segment were synthesized and applied for preparation of disulfide cross-linked polyplex micelles through ion complexation with plasmid DNA (pDNA) encoding the soluble form of vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), which is a potent antiangiogenic molecule. Antitumor activity and gene expression of polyplex micelles with various cross-linking rates were evaluated in mice bearing subcutaneously xenografted BxPC3 cell line, derived from human pancreatic adenocarcinoma, and polyplex micelles with optimal cross-linking rate achieved effective suppression of tumor growth. Significant gene expression of this micelle was detected selectively in tumor tissue, and its antiangiogenic effect was confirmed by decreased vascular density inside the tumor. Therefore, the disulfide cross-linked polyplex micelle loading sFlt-1 pDNA has a great potential for antiangiogenic therapy against subcutaneous pancreatic tumor model by systemic application.

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  • Treating "intractable" tumours using nanoDDS and TGF-beta inhibitor Reviewed

    Kano M.R, Nishihara H, Kataoka K, Miyazono K

    European Cells and Materials   20 ( SUPPL.3 )   2010

  • Autophagy Is Activated by TGF-beta and Potentiates TGF-beta-Mediated Growth Inhibition in Human Hepatocellular Carcinoma Cells Reviewed

    Kunihiko Kiyono, Hiroshi I. Suzuki, Hironori Matsuyama, Yasuyuki Morishita, Akiyoshi Komuro, Mitsunobu R. Kano, Koichi Sugimoto, Kohei Miyazono

    CANCER RESEARCH   69 ( 23 )   8844 - 8852   2009.12

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    Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates cell growth, differentiation, and apoptosis of various types of cells. Autophagy is emerging as a critical response of normal and cancer cells to environmental changes, but the relationship between TGF-beta signaling and autophagy has been poorly understood. Here, we showed that TGF-beta activates autophagy in human hepatocellular carcinoma cell tines. TGF-beta induced accumulation of autophagosomes and conversion of microtubule-associated protein I light chain 3 and enhanced the degradation rate of long-lived proteins. TGF-beta increased the mRNA expression levels of BECLIN1, ATG5, ATG7, and death-associated protein kinase (DAPK). Knockdown of Smad2/3, Smad4, or DAPK, or inhibition of c-Jun NH(2)-terminal kinase, attenuated TGF-beta-induced autophagy, indicating the involvement of both Smad and non-Smad pathway(s). TGF-beta activated autophagy earlier than execution of apoptosis (6-12 versus 48 h), and reduction of autophagy genes by small interfering RNA attenuated TGF-beta-mediated growth inhibition and induction of proapoptotic genes Bim and Bmf, suggesting the contribution of autophagy pathway to the growth-inhibitory effect of TGF-beta. Additionally, TGF-beta also induced autophagy in some mammary carcinoma cells, including MDA-MB-231 cells. These findings show that TGF-beta signaling pathway activates autophagy in certain human cancer cells and that induction of autophagy is a novel aspect of biological functions of TGF-beta. [Cancer Res 2009;69(23):8844-52]

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  • Enhanced magnetic resonance imaging of experimental pancreatic tumor in vivo by block copolymer-coated magnetite nanoparticles with TGF-beta inhibitor Reviewed

    Michiaki Kumagai, Mitsunobu R. Kano, Yasuyuki Morishita, Motomi Ota, Yutaka Imai, Nobuhiro Nishiyama, Masaki Sekino, Shoogo Ueno, Kohei Miyazono, Kazunori Kataoka

    JOURNAL OF CONTROLLED RELEASE   140 ( 3 )   306 - 311   2009.12

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    Early detection of solid tumors, particularly pancreatic cancer, is of substantial importance in clinics. Enhanced magnetic resonance imaging (MRI) with iron oxide nanoparticles is an available way to detect the cancer. The effective and selective accumulation of these nanoparticles in the tumor tissue is needed for improved imaging, and in this regard, their longevity in the blood circulation time is crucial. We developed here block copolymer-coated magnetite nanoparticles for pancreatic cancer imaging, by means of a chelation between the carboxylic acid groups in poly(ethylene glycol)-poly(aspartic acid) block copolymer (PEG-PAsp) and Fe on the surface of the iron oxide nanoparticles. These nanoparticles had considerably narrow distribution, even upon increased ionic strength or in the presence of fetal bovine serum. The PEG-PAsp-coated nanoparticles were further shown to be potent as a contrast agent for enhanced MRI for an experimental pancreatic cancer, xenografts of the human-derived BxPC3 cell line in BALB/c nude mice, with combined administration of TGF-beta inhibitor. Iron staining of tumor tissue confirmed the accumulation of the nanoparticles in tumor tissue. Use of the PEG-PAsp-coated magnetite nanoparticles, combined with the TGF-beta inhibitor, is of promising clinical importance for the detection of intractable solid cancers, including pancreatic cancer. (C) 2009 Elsevier B.V. All rights reserved.

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  • c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-beta signaling in diffuse-type gastric carcinoma Reviewed

    Kunihiko Kiyono, Hiroshi I. Suzuki, Yasuyuki Morishita, Akiyoshi Komuro, Caname Iwata, Masakazu Yashiro, Kosei Hirakawa, Mitsunobu R. Kano, Kohei Miyazono

    CANCER SCIENCE   100 ( 10 )   1809 - 1816   2009.10

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    c-Ski, originally identified as a proto-oncogene product, is an important negative regulator of transforming growth factor (TGF)-beta family signaling through interaction with Smad2, Smad3, and Smad4. High expression of c-Ski has been found in some cancers, including gastric cancer. We previously showed that disruption of TGF-beta signaling by dominant-negative TGF-beta type II receptor in a diffuse-type gastric carcinoma model accelerated tumor growth through induction of tumor angiogenesis by decreased expression of the anti-angiogenic factor thrombospondin (TSP)-1. Here, we examined the function of c-Ski in human diffuse-type gastric carcinoma OCUM-2MLN cells. Overexpression of c-Ski inhibited TGF-beta signaling in OCUM-2MLN cells. Interestingly, c-Ski overexpression resulted in extensive acceleration of the growth of subcutaneous xenografts in BALB/c nu/nu female mice (6 weeks of age). Similar to tumors expressing dominant-negative TGF-beta type II receptor, histochemical studies revealed less fibrosis and increased angiogenesis in xenografted tumors expressing c-Ski compared to control tumors. Induction of TSP-1 mRNA by TGF-beta was attenuated by c-Ski in vitro, and expression of TSP-1 mRNA was decreased in tumors expressing c-Ski in vivo. These findings suggest that c-Ski overexpression promotes the growth of diffuse-type gastric carcinoma through induction of angiogenesis. (Cancer Sci 2009; 100: 1809-1816).

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  • Enhanced Percolation and Gene Expression in Tumor Hypoxia by PEGylated Polyplex Micelles Reviewed

    Muri Han, Makoto Oba, Nobuhiro Nishiyama, Mitsunobu R. Kano, Shinae Kizaka-Kondoh, Kazunori Kataoka

    MOLECULAR THERAPY   17 ( 8 )   1404 - 1410   2009.8

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    In regard to gene vectors for cancer gene therapy, their percolation into the tumor tissue should be essential for successful outcome. Here, we studied the tumor penetrability of nonviral vectors (polyplexes) after incubation with the multicellular tumor spheroid (MCTS) models and intratumoral (i.t.) injection into subcutaneous tumors. As a result, polyethylene glycolated (PEGylated), core-shell type polyplexes (polyplex micelles) showed facilitated percolation and improved transfection inside the tumor tissue, whereas conventional polyplexes from cationic polymers exhibited limited percolation and localized transfection. Furthermore, the transfection of hypoxia-responsive plasmid demonstrated that polyplex micelles allowed the transfection to the hypoxic region of the tumor tissue in both in vitro and in vivo experiments. To the best of our knowledge, our results demonstrated for the first time that polyplex micelles might show improved tumor penetrability over cationic polyplexes, thereby achieving transfection into the inside of the tumor tissue.

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  • Diffuse-Type Gastric Carcinoma: Progression, Angiogenesis, and Transforming Growth Factor beta Signaling Reviewed

    Akiyoshi Komuro, Masakazu Yashiro, Caname Iwata, Yasuyuki Morishita, Erik Johansson, Yoshiko Matsumoto, Akira Watanabe, Hiroyuki Aburatani, Hiroyuki Miyoshi, Kunihiko Kiyono, Yo-taro Shirai, Hiroshi I. Suzuki, Kosei Hirakawa, Mitsunobu R. Kano, Kohei Miyazono

    JOURNAL OF THE NATIONAL CANCER INSTITUTE   101 ( 8 )   592 - 604   2009.4

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    Diffuse-type gastric carcinoma is a cancer with poor prognosis that has high levels of transforming growth factor beta (TGF-beta) expression and thick stromal fibrosis. However, the association of TGF-beta signaling with diffuse-type gastric carcinoma has not been investigated in detail.
    We used a lentiviral infection system to express a dominant-negative TGF-beta type II receptor (dnT beta RII) or green fluorescent protein (GFP) as a control in the diffuse-type gastric carcinoma cell lines, OCUM-2MLN and OCUM-12. These infected cells and the corresponding parental control cells were subcutaneously or orthotopically injected into nude mice. Angiogenesis was inhibited by infecting cells with a lentivirus carrying the gene for angiogenic inhibitor thrombospondin-1 or by injecting mice intraperitoneally with the small-molecule angiogenic inhibitor sorafenib or with anti-vascular endothelial growth factor (VEGF) neutralizing antibody (six or eight mice per group). Expression of phospho-Smad2 and thrombospondin-1 was investigated immunologically in human gastric carcinoma tissues from 102 patients. All statistical tests were two-sided.
    Expression of dnT beta RII into OCUM-2MLN cells did not affect their proliferation in vitro, but it accelerated the growth of subcutaneously or orthotopically transplanted tumors in vivo (eg, for mean volume of subcutaneous tumors on day 10 relative to that on day 0: dnT beta RII tumors = 3.49 and GFP tumors = 2.46, difference = 1.02, 95% confidence interval [CI] = 0.21 to 1.84; P = .003). The tumors expressing dnT beta RII had higher levels of angiogenesis than those expressing GFP because of decreased thrombospondin-1 production. Similar results were obtained with OCUM-12 cells. Expression of thrombospondin-1 in the dnT beta RII tumor or treatment with sorafenib or anti-VEGF antibody reduced tumor growth, whereas knockdown of thrombospondin-1 expression resulted in more accelerated growth of OCUM-2MLN tumors than of GFP tumors (eg, mean tumor volumes on day 14 relative to those on day 0: thrombospondin-1-knockdown tumors = 4.91 and GFP tumors = 3.79, difference = 1.12, 95% CI = 0.80 to 1.44; P &lt; .001). Positive association between phosphorylated Smad2 and thrombospondin-1 immunostaining was observed in human gastric carcinoma tissues.
    Disruption of TGF-beta signaling in diffuse-type gastric carcinoma models appeared to accelerate tumor growth, apparently through increased tumor angiogenesis that was induced by decreased expression of thrombospondin-1.

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  • Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-beta receptor inhibitor on extravasation of nanoparticles from neovasculature Reviewed

    Mitsunobu R. Kano, Yukari Komuta, Caname Iwata, Masako Oka, Yo-taro Shirai, Yasuyuki Morishita, Yasuyoshi Ouchi, Kazunori Kataoka, Kohei Miyazono

    CANCER SCIENCE   100 ( 1 )   173 - 180   2009.1

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    There are a number of kinase inhibitors that regulate components of the neovasculature. We previously reported the use of transforming growth factor (TGF)-beta inhibitor on neovasculature in stroma-rich tumor models to increase the intratumoral distribution of nanoparticles. Here, we compared the effects of two other kinase inhibitors, imatinib and sorafenib, with TGF-beta inhibitor (LY364947) on extravasation of a modeled nanoparticle, 2 MDa dextran. We first used a mouse model of neoangiogenesis, the Matrigel plug assay, to compare neovasculature formed inside of and around Matrigel plugs (intraplug and periplug regions, respectively). Intraplug vasculature was more strongly pericyte covered, whereas periplug vasculature was less covered. In this model, TGF-beta inhibitor exhibited the most potent effect on intraplug vasculature in increasing the extravasation of dextran, whereas sorafenib had the strongest effect on periplug vasculature. Although imatinib and TGF-beta inhibitor each reduced pericyte coverage, imatinib also reduced the density of endothelium, resulting in a decrease in overall delivery of nanoparticles. These findings were confirmed in two tumor models, the CT26 colon cancer model and the BxPC3 pancreatic cancer model. The vasculature phenotype in the CT26 model resembled that in the periplug region, whereas the latter resembled that in the intraplug region. Consistent with this, sorafenib most potently enhanced the accumulation of nanoparticles in the CT26 model, whereas TGF-beta inhibitor did in the BxPC3 model. In conclusion, the appropriate strategy for optimization of tumor vasculature for nanoparticles may differ depending on tumor type, and in particular on the degree of pericyte coverage around the vasculature. (Cancer Sci 2009; 100: 173-180).

    DOI: 10.1111/j.1349-7006.2008.01003.x

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  • Angiogenesis through Silencing Prolyl Hydroxylase Domain-2 Using Biocompatible Polyplex Nanocarrier Reviewed

    Wu Shourong, Nishiyama Nobuhiro, Itaka Keiji, Kano Mitsunobu R, Morishita Yasuyuki, Miyazono Kohei, Chung Ung-Il, Kataoka Kazunori

    Molecular Therapy   17   S390   2009

  • Polyplex Micelles from Triblock Copolymers Composed of Tandemly Aligned Segments with Biocompatible, Endosomal Escaping, and DNA-Condensing Functions for Systemic Gene Delivery to Pancreatic Tumor Tissue Reviewed

    Kanjiro Miyata, Makoto Oba, Mitsunobu R. Kano, Shigeto Fukushima, Yelena Vachutinsky, Muri Han, Hiroyuki Koyama, Kohei Miyazono, Nobuhiro Nishiyama, Kazunori Kataoka

    PHARMACEUTICAL RESEARCH   25 ( 12 )   2924 - 2936   2008.12

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    For systemic gene delivery to pancreatic tumor tissues, we prepared a three-layered polyplex micelle equipped with biocompatibility, efficient endosomal escape, and pDNA condensation functions from three components tandemly aligned; poly(ethylene glycol) (PEG), a poly(aspartamide) derivative with a 1,2-diaminoethane moiety (PAsp(DET)), and poly(l-lysine).
    The size and in vitro transfection efficacy of the polyplex micelles were determined by dynamic light scattering (DLS) and luciferase assay, respectively. The systemic gene delivery with the polyplex micelles was evaluated from enhanced green fluorescence protein (EGFP) expression in the tumor tissues.
    The polyplex micelles were approximately 80 nm in size and had one order of magnitude higher in vitro transfection efficacy than that of a diblock copolymer as a control. With the aid of transforming growth factor (TGF)-beta type I receptor (T beta R-1) inhibitor, which enhances accumulation of macromolecular drugs in tumor tissues, the polyplex micelle from the triblock copolymer showed significant EGFP expression in the pancreatic tumor (BxPC3) tissues, mainly in the stromal regions including the vascular endothelial cells and fibroblasts.
    The three-layered polyplex micelles were confirmed to be an effective gene delivery system to subcutaneously implanted pancreatic tumor tissues through systemic administration.

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  • Cilostazol inhibits oxidative stress-induced premature senescence via upregulation of Sirt1 in human endothelial cells Reviewed

    Hidetaka Ota, Masato Eto, Mitsunobu R. Kano, Sumito Ogawa, Katsuya Iijima, Masahiro Akishita, Yasuyoshi Ouchi

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY   28 ( 9 )   1634 - 1639   2008.9

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    Objective-Cilostazol, a selective inhibitor of PDE3, has a protective effect on endothelium after ischemic vascular damage, through production of nitric oxide (NO). The purpose of the present study was to clarify the molecular mechanisms underlying the preventive effect of treatment with cilostazol on oxidative stress-induced premature senescence in human endothelial cells.
    Methods and Results-Prematurely senescent human umbilical vein endothelial cells (HUVECs) were induced by treatment with hydrogen peroxide (H2O2) as judged by senescence-associated beta-galactosidase assay (SA-beta gal), cell morphological appearance, and plasminogen activator inhibitor-1 (PAI-1) expression. Treatment with H2O2 caused 93% of the cells to be SA-beta gal positive, whereas 46% of cilostazol (100 mu mol/L)-treated cells were positive. HUVECs treated with other cAMP-elevating agents and DETA-NO showed a reduction of SA-beta gal-positive cells as well. Cilostazol increased phosphorylation of Akt at Ser(473) and of endothelial nitric oxide synthase (eNOS) at Ser(1177), with a dose-dependent increase in Sirt1 expression. Moreover, the effect of cilostazol on premature senescence was abrogated through inhibition of Sirt1.
    Conclusions-Our results indicated that cilostazol exerted protective effects against endothelial senescence and dysfunction, and enhancement of NO production is a key mediator in upregulation of Sirt1.

    DOI: 10.1161/ATVBAHA.108.164368

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  • Enhancement of angiogenesis through stabilization of hypoxia-inducible factor-1 by silencing prolyl hydroxylase domain-2 gene Reviewed

    Shourong Wu, Nobuhiro Nishiyama, Mitsunobu R. Kano, Yasuyuki Morishita, Kohei Miyazono, Keiji Itaka, Ung-il Chung, Kazunori Kataoka

    MOLECULAR THERAPY   16 ( 7 )   1227 - 1234   2008.7

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    Hypoxia-inducible factor-1 (HIF-1) plays a central role in cellular response to hypoxia by activating vascular endothelial growth factor (VEGF) and other angiogenic factors. Prolyl hydroxylase domain-2 (PHD2) protein induces the degradation of HIF-1 by hydroxylating specific prolyl residues. Therefore gene silencing of PHD2 by RNA interference (RNAi) might increase the expression of angiogenic growth factors and, consequently, neoangiogenesis through the stabilization of HIF-1 alpha. In this study we have shown that the specific silencing of PHD2 is sufficient for stabilizing HIF-1a and increasing its transcriptional activity, resulting in the increased expression of angiogenic factors including VEGF and fibroblast growth factor-2 (FGF2). Moreover, when PHD2-siRNA vector was used, the increase in VEGF secretion was observed for as long as 18 days after transfection. In vitro treatment of human umbilical vein endothelical cells with conditioned medium from PHD2-siRNA vector-transfected NIH3T3 cells was shown to increase cell proliferation. Also, in vivo angiogenesis was observed in mice implanted with Matrigel plugs mixed with NIH3T3 cells transfected with PHD2-siRNA vector. These results indicate that PHD2 silencing induces expressions of multiple angiogenic growth factors by stabilizing HIF-1 alpha, and that the implantation of cells transfected with PHD2-siRNA vector is sufficient to enhance angiogenesis in vivo. In the light of these findings, PHD2 silencing by RNAi might offer a potential tool for angiogenic therapy.

    DOI: 10.1038/mt.2008.90

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  • Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis Reviewed

    Masako Oka, Caname Iwata, Hiroshi I. Suzuki, Kunihiko Kiyono, Yasuyuki Morishita, Tetsuro Watabe, Akiyoshi Kornuro, Mitsunobu R. Kano, Kohei Miyazono

    BLOOD   111 ( 9 )   4571 - 4579   2008.5

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    Lymphangiogenesis is induced by various growth factors, including VEGF-C. Although TGF-beta plays crucial roles in angiogenesis, the roles of TGF-beta signaling in lymphangiogenesis are unknown. We show here that TGF-beta transduced signals in human dermal lymphatic microvascular endothelial cells (HDLECs) and inhibited the proliferation, cord formation, and migration toward VEGF-C of HDLECs. Expression of lymphatic endothelial cell (LEC) markers, including LYVE-1 and Prox1 in HDLECs, as well as early lymph vessel development in mouse embryonic stem cells in the presence of VEGF-A and C, were repressed by TGF-beta but were induced by TGF-beta type I receptor (T beta R-I) inhibitor. Moreover, inhibition of endogenous TGF-beta signaling by T beta R-I inhibitor accelerated lymphangiogenesis in a mouse model of chronic peritonitis. Lymphanglogenesis was also induced by T beta R-I inhibitor in the presence of VEGF-C in pancreatic adenocarcinoma xenograft models inoculated in nude mice. These findings suggest that TGF-beta transduces signals in LECs and plays an important role in the regulation of lymphangiogenesis in vivo.

    DOI: 10.1182/blood-2007-10-120337

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  • Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis Reviewed

    Caname Iwata, Mitsunobu R. Kano, Akiyoshi Komuro, Masako Oka, Kunihiko Kiyono, Erik Johansson, Yasuyuki Morishita, Masakazu Yashiro, Kosei Hirakawa, Michio Kaminishi, Kohei Miyazono

    CANCER RESEARCH   67 ( 21 )   10181 - 10189   2007.11

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    Cyclooxygenase-2 (COX-2) inhibitor has been reported to suppress tumor progression. However, it is unclear whether this inhibitor can also prevent lymphatic metastasis. To determine the effects of COX-2 inhibitor on lymphatic metastasis, etodolac, a COX-2 inhibitor, was given p.o. to mice bearing orthotopic xenografts or with carcinomatous peritonitis induced with a highly metastatic human diffuse-type gastric carcinoma cell line, OCUM-2MLN. Tumor lymphangiogenesis was significantly decreased in etodolac-treated mice compared with control mice. Consistent with this decrease in lymphangiogenesis, the total weight of metastatic lymph nodes was less in etodolac-treated mice than in control mice. Immunohistochemical analysis revealed that the major source of vascular endothelial growth factor-C (VEGF-C) and VEGF-D was F4/80-positive macrophages in our models. The mRNA levels of VEGF-C in mouse macrophage-like RAW264.7 cells, as well as those in tumor tissues, were suppressed by etodolac. The growth of human dermal lymphatic microvascular endothelial cells was also suppressed by etodolac. Supporting these findings, etodolac also inhibited lymphangiogenesis in a model of chronic aseptic peritonitis, suggesting that COX-2 can enhance lymphangiogenesis in the absence of cancer cells. Our findings suggest that COX-2 inhibitor may be useful for prophylaxis of lymph node metastasis by reducing macrophage-mediated tumor lymphangiogenesis.

    DOI: 10.1158/0008-5472.CAN-07-2366

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  • IL-5-induced hypereosinophilia suppiresses the antigen-induced immune response via a TGF-beta-dependent mechanism Reviewed

    Kazuyuki Nakagome, Makoto Dohi, Katsuhide Okunishi, Ryoichi Tanaka, Taku Kouro, Mitsunobu R. Kano, Kohei Miyazono, Jun-ichi Miyazaki, Kiyoshi Takatsu, Kazuhiko Yamamoto

    JOURNAL OF IMMUNOLOGY   179 ( 1 )   284 - 294   2007.7

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    Although eosinophils play an essential role in allergic inflammation, their role has recently been under controversy. Epidemic studies suggest that hypereosinophilia induced by parasite infection could suppress subsequent Ag sensitization, although the mechanism has not been fully clarified. In this study, we investigated whether eosinophils could suppress the Ag-specific immune response in the airway. BALB/c mice were sensitized and airway challenged with OVA. Systemic hypereosinophilia was induced by delivery of an IL-5-producing plasmid. IL-5 gene delivery suppressed the Ag-specific proliferation and cytokine production of CD4(+) T cells in the spleen. IL-5 gene delivery before OVA sensitization significantly suppressed airway eosinophilia and hyperresponsiveness provoked by subsequent OVA airway challenge, while delivery during the OVA challenge did not suppress them. This IL-5-induced immune suppression was abolished in eosinophil-ablated mice, suggesting an essential role of eosinophils. IL-5 treatment increased the production of TGF-ss 1 in the spleen, and we demonstrated that the main cellular source of TGF-ss 1 production was eosinophils, using eosinophil-ablated mice and depletion study. TGF-ss 1, but not IL-5 itself, suppressed the Ag-specific immune response of CD4(+) T cells in vitro. Furthermore, IL-5 treatment enhanced phosphorylation of Smad2 in CD4(+) T cells. Finally, a TGF-ss type I receptor kinase inhibitor restored this IL-5-induced immune suppression both in vitro and in vivo. These results suggest that IL-5-induced hypereosinophilia could suppress sensitization to Ag via a TGF-ss-dependent mechanism, thus suppressed allergic airway inflammation. Therefore, hypereosinophilia could reveal an immunosuppressive effect in the early stage of Ag-induced immune response.

    DOI: 10.4049/jimmunol.179.1.284

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  • IL-5-induced hypereosinophilia suppiresses the antigen-induced immune response via a TGF-beta-dependent mechanism Reviewed

    Kazuyuki Nakagome, Makoto Dohi, Katsuhide Okunishi, Ryoichi Tanaka, Taku Kouro, Mitsunobu R. Kano, Kohei Miyazono, Jun-ichi Miyazaki, Kiyoshi Takatsu, Kazuhiko Yamamoto

    JOURNAL OF IMMUNOLOGY   179 ( 1 )   284 - 294   2007.7

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    Although eosinophils play an essential role in allergic inflammation, their role has recently been under controversy. Epidemic studies suggest that hypereosinophilia induced by parasite infection could suppress subsequent Ag sensitization, although the mechanism has not been fully clarified. In this study, we investigated whether eosinophils could suppress the Ag-specific immune response in the airway. BALB/c mice were sensitized and airway challenged with OVA. Systemic hypereosinophilia was induced by delivery of an IL-5-producing plasmid. IL-5 gene delivery suppressed the Ag-specific proliferation and cytokine production of CD4(+) T cells in the spleen. IL-5 gene delivery before OVA sensitization significantly suppressed airway eosinophilia and hyperresponsiveness provoked by subsequent OVA airway challenge, while delivery during the OVA challenge did not suppress them. This IL-5-induced immune suppression was abolished in eosinophil-ablated mice, suggesting an essential role of eosinophils. IL-5 treatment increased the production of TGF-ss 1 in the spleen, and we demonstrated that the main cellular source of TGF-ss 1 production was eosinophils, using eosinophil-ablated mice and depletion study. TGF-ss 1, but not IL-5 itself, suppressed the Ag-specific immune response of CD4(+) T cells in vitro. Furthermore, IL-5 treatment enhanced phosphorylation of Smad2 in CD4(+) T cells. Finally, a TGF-ss type I receptor kinase inhibitor restored this IL-5-induced immune suppression both in vitro and in vivo. These results suggest that IL-5-induced hypereosinophilia could suppress sensitization to Ag via a TGF-ss-dependent mechanism, thus suppressed allergic airway inflammation. Therefore, hypereosinophilia could reveal an immunosuppressive effect in the early stage of Ag-induced immune response.

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  • IL-5-induced hypereosinophilia suppiresses the antigen-induced immune response via a TGF-beta-dependent mechanism Reviewed

    Kazuyuki Nakagome, Makoto Dohi, Katsuhide Okunishi, Ryoichi Tanaka, Taku Kouro, Mitsunobu R. Kano, Kohei Miyazono, Jun-ichi Miyazaki, Kiyoshi Takatsu, Kazuhiko Yamamoto

    JOURNAL OF IMMUNOLOGY   179 ( 1 )   284 - 294   2007.7

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    Although eosinophils play an essential role in allergic inflammation, their role has recently been under controversy. Epidemic studies suggest that hypereosinophilia induced by parasite infection could suppress subsequent Ag sensitization, although the mechanism has not been fully clarified. In this study, we investigated whether eosinophils could suppress the Ag-specific immune response in the airway. BALB/c mice were sensitized and airway challenged with OVA. Systemic hypereosinophilia was induced by delivery of an IL-5-producing plasmid. IL-5 gene delivery suppressed the Ag-specific proliferation and cytokine production of CD4(+) T cells in the spleen. IL-5 gene delivery before OVA sensitization significantly suppressed airway eosinophilia and hyperresponsiveness provoked by subsequent OVA airway challenge, while delivery during the OVA challenge did not suppress them. This IL-5-induced immune suppression was abolished in eosinophil-ablated mice, suggesting an essential role of eosinophils. IL-5 treatment increased the production of TGF-ss 1 in the spleen, and we demonstrated that the main cellular source of TGF-ss 1 production was eosinophils, using eosinophil-ablated mice and depletion study. TGF-ss 1, but not IL-5 itself, suppressed the Ag-specific immune response of CD4(+) T cells in vitro. Furthermore, IL-5 treatment enhanced phosphorylation of Smad2 in CD4(+) T cells. Finally, a TGF-ss type I receptor kinase inhibitor restored this IL-5-induced immune suppression both in vitro and in vivo. These results suggest that IL-5-induced hypereosinophilia could suppress sensitization to Ag via a TGF-ss-dependent mechanism, thus suppressed allergic airway inflammation. Therefore, hypereosinophilia could reveal an immunosuppressive effect in the early stage of Ag-induced immune response.

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  • Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling Reviewed

    Mitsunobu R. Kano, Younsoo Bae, Caname Iwata, Yasuyuki Morishita, Masakazu Yashiro, Masako Oka, Tomoko Fujii, Akiyoshi Komuro, Kunihiko Kiyono, Michio Kaminishi, Kosei Hirakawa, Yasuyoshi Ouchi, Nobuhiro Nishiyama, Kazunori Kataoka, Kohei Miyazono

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   104 ( 9 )   3460 - 3465   2007.2

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    Transforming growth factor (TGF)-beta plays a pivotal role in regulation of progression of cancer through effects on tumor microenvironment as well as on cancer cells. TGF-beta inhibitors have recently been shown to prevent the growth and metastasis of certain cancers. However, there may be adverse effects caused by TGF-beta signaling inhibition, including the induction of cancers by the repression of TGF-beta-mediated growth inhibition. Here, we present an application of a short-acting, small-molecule TGF-beta type I receptor (T beta R-1) inhibitor at a low dose in treating several experimental intractable solid tumors, including pancreatic adenocarcinoma and diffuse-type gastric cancer, characterized by hypovascularity and thick fibrosis in tumor microenvironments. Low-dose T beta R-1 inhibitor altered neither TGF-beta signaling in cancer cells nor the amount of fibrotic components. However, it decreased pericyte coverage of the endothelium without reducing endlothelial area specifically in tumor neovasculature and promoted accumulation of macromolecules, including anticancer nanocarriers, in the tumors. Compared with the absence of T beta R-1 inhibitor, anticancer nanocarriers exhibited potent growth-inhibitory effects on these cancers in the presence of T beta R-1 inhibitor. The use of TiSR-1 inhibitor combined with nanocarriers; may thus be of significant clinical and practical importance in treating intractable solid cancers.

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  • VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFR beta signaling Reviewed

    MR Kano, Y Morishita, C Iwata, S Iwasaka, T Watabe, Y Ouchi, K Miyazono, K Miyazawa

    JOURNAL OF CELL SCIENCE   118 ( 16 )   3759 - 3768   2005.8

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    Combined stimulation with VEGF-A, FGF-2, or PDGF-BB has emerged as a potent strategy for therapeutic angiogenesis, although the mechanisms underlying the synergism of these factors are not well understood. In the present study, we investigated the mechanism of synergism between VEGF-A and FGF-2 by using Matrigel plug assay in vivo and embryonic stem cell (ESC)-derived VEGF receptor 2 (VEGFR2)-positive cells in vitro. Experiments in vitro revealed that, in addition to having direct mitogenic effects, these molecules enhance intercellular PDGF-B signaling in a cell-type specific manner: VEGF-A enhances endothelial PDGF-B expression, whereas FGF-2 enhances mural PDGF receptor P (PDGFR,6) expression. Co-stimulation with VEGF-A and FGF-2 caused significant mural cell recruitment in vitro and formation of functional neovasculature in vivo, compared with single-agent stimulation. These effects were abrogated not only by anti-PDGFR beta neutralizing antibody, but also by exogenous; PDGF-BB, which could overwhelm the endogenous PDGF-BB distribution. These findings indicated the importance of preservation of the periendothelial PDGF-BB gradient. Thus, we demonstrated that the directional enhancement of endogenous PDGF-B-PDGFR beta signaling is indispensable for the synergistic effect of VEGF-A and FGF-2 on neoangiogenesis in adults. The findings provide insights into the mechanisms underlying the effects of co-stimulation by growth factors, which could lead to rational design of therapeutic angiogenic strategies.

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  • 論理的な考え方 伝え方 根拠に基づく正しい議論のために

    慶應義塾大学出版会  2015 

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  • Practice in Fundamental Pharmaceutical Sciences III (2021academic year) Second semester  - その他6~9

  • Practice in Fundamental Pharmaceutical Sciences III (2021academic year) Second semester  - その他6~9

  • Pharmacotherapeutic 1 (2021academic year) 1st semester  - 水1~2

  • Pharmacotherapeutic 1 (2021academic year) 1st semester  - 水1~2

  • Pharmacotherapeutic 2 (2021academic year) Second semester  - 水1~2

  • Pharmacotherapeutic 2 (2021academic year) Second semester  - 水1~2

  • Pharmacotherapeutic 3 (2021academic year) 1st semester  - 水3~4

  • Pharmacotherapeutic 3 (2021academic year) 1st semester  - 水3~4

  • Pharmacotherapeutic 4 (2021academic year) Second semester  - 水3~4

  • Pharmacotherapeutic 4 (2021academic year) Second semester  - 水3~4

  • Scientific investigation of human beings (2020academic year) Third semester  - 月1,月2

  • Introduction to Human Care Innovation and Health Care (2020academic year) Prophase  - 金5,金6

  • Big Data (2020academic year) Late  - 水1,水2

  • Advanced Internship for Interdisciplinary Medical Sciences and Engineering (2020academic year) Year-round  - その他

  • Internship for Interdisciplinary Medical Sciences and Engineering (2020academic year) Year-round  - その他

  • Technical English for Interdisciplinary Medical Sciences and Engineering (2020academic year) Late  - その他

  • Exercises for Interdisciplinary Medical Sciences and Engineering (2020academic year) Late  - その他

  • Research Works for Interdisciplinary Medical Sciences and Engineering (2020academic year) Year-round  - その他

  • Advanced Interdisciplinary Medical Sciences and Engineering (2020academic year) Prophase  - その他

  • General Exercises for Interdisciplinary Medical Sciences and Engineering (2020academic year) Late  - その他

  • Applying medical sciences and technologies to clinical practice (2020academic year) Late  - その他

  • Pharmaceutical Biomedicine (2020academic year) special  - その他

  • Research Projects & Practicals: Clinical Evaluation of Pharmaceutical care A I (2020academic year) special  - その他

  • Lecture & Research Projects: Clinical Evaluation of Pharmaceutical care A I (2020academic year) special  - その他

  • Research Projects & Practicals: Clinical Evaluation of Pharmaceutical care A II (2020academic year) special  - その他

  • Lecture & Research Projects: Clinical Evaluation of Pharmaceutical care A II (2020academic year) special  - その他

  • Research Projects & Practicals: Clinical Evaluation of Pharmaceutical care B I (2020academic year) special  - その他

  • Lecture & Research Projects: Clinical Evaluation of Pharmaceutical care B I (2020academic year) special  - その他

  • Research Projects & Practicals: Clinical Evaluation of Pharmaceutical care B II (2020academic year) special  - その他

  • Lecture & Research Projects: Clinical Evaluation of Pharmaceutical care B II (2020academic year) special  - その他

  • Research Projects & Practicals: Clinical Evaluation of Pharmaceutical care C I (2020academic year) special  - その他

  • Lecture & Research Projects: Clinical Evaluation of Pharmaceutical care C I (2020academic year) special  - その他

  • Research Projects & Practicals: Clinical Evaluation of Pharmaceutical care C II (2020academic year) special  - その他

  • Lecture & Research Projects: Clinical Evaluation of Pharmaceutical care C II (2020academic year) special  - その他

  • Practical Internship (2020academic year) Year-round  - その他

  • Practical Interdisciplinary Medical Sciences and Engineering (2020academic year) Late  - その他

  • Technical Writing and Presentation (2020academic year) Late  - その他

  • Life Science 3 (2020academic year) special  - その他

  • Introduction to clinical therapeutics (2020academic year) 1st and 2nd semester  - 木1,木2

  • Introduction to clinical sciences (2020academic year) Summer concentration  - その他

  • Practice in Fundamental Pharmaceutical Sciences III (2020academic year) Second semester  - その他

  • Practice in Fundamental Pharmaceutical Sciences III (2020academic year) Second semester  - その他

  • Pharmacotherapeutic 1 (2020academic year) 1st semester  - 水1,水2

  • Pharmacotherapeutic 1 (2020academic year) 1st semester  - 水1,水2

  • Pharmacotherapeutic 2 (2020academic year) Second semester  - 水1,水2

  • Pharmacotherapeutic 2 (2020academic year) Second semester  - 水1,水2

  • Pharmacotherapeutic 3 (2020academic year) 1st semester  - 水3,水4

  • Pharmacotherapeutic 3 (2020academic year) 1st semester  - 水3,水4

  • Pharmacotherapeutic 4 (2020academic year) Second semester  - 水3,水4

  • Pharmacotherapeutic 4 (2020academic year) Second semester  - 水3,水4

  • Pharmacotherapeutic I (2020academic year) 1st and 2nd semester  - 水1,水2

  • Pharmacotherapeutic II (2020academic year) 1st and 2nd semester  - 水3,水4

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