次世代肺がんチロシンキナーゼ阻害薬の感受性マーカーの同定と治療標的分子の探索

• 研究課題/領域番号: 23390147
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 病態検査学
• 研究機関: 東京大学
• 研究代表者: 高井 大哉 東京大学, 医学部附属病院, 講師 (90361493)
• 研究期間 (年度): 2011-04-01 – 2014-03-31
• 研究課題ステータス: 完了 (2013年度)
• 配分額: 18,850千円 (直接経費: 14,500千円、間接経費: 4,350千円); 2013年度: 4,550千円 (直接経費: 3,500千円、間接経費: 1,050千円); 2012年度: 6,370千円 (直接経費: 4,900千円、間接経費: 1,470千円); 2011年度: 7,930千円 (直接経費: 6,100千円、間接経費: 1,830千円)
• キーワード: 肺がん / チロシンキナーゼ / ＦＥＲ / ＲＥＴ / 腫瘍検査学 / 個別化医療

研究概要

原発性肺がんは現在毎年6万人以上が命を落とす，がん死における最も多いがんである．申請者らは，最近の分子標的薬開発の状況に鑑み，ALKチロシンキナーゼと相同性の高いチロシンキナーゼの発現状況を網羅的に解析し，新たな治療標的となる分子ＦＥＲを同定した．FERを過剰に発現する肺がん細胞株NCI-H661細胞において，FERをsiRNAベクターによって発現抑制すると，細胞はアポトーシスに至ることが明らかになった．また肺がん切除例における病理標本での検討から，FER過剰発現例は原発性肺がんの約10%で過剰発現を認め，予後が不良であった．これらの結果を論文にて報告した．

研究成果

• [雑誌論文] Combined Large Cell Neuroendocrine Carcinoma and Adenocarcinoma with Epidermal Growth Factor Receptor Mutation in a Female Patient Who Never Smoked (2014)
  • 著者名/発表者名: Yoshida Y, Ota S, Murakawa T, Takai D
  • 雑誌名: Annals of Thoracic and Cardiovascular Surgery 巻: 20 号: Supplement ページ: 582-584
  • DOI: 10.5761/atcs.cr.12.02217
  • NAID: 130003377861
  • ISSN: 1341-1098, 2186-1005
  • 査読あり
• [雑誌論文] Growth-associated hyperphosphatemia in young recipients accelerates aortic allograft calcification in a rat model (2013)
  • 著者名/発表者名: Yamauchi H, Motomura N, Chung UI, Sata M, Takai D, Saito A, Ono M, Takamoto S
  • 雑誌名: J Thorac Cardiovasc Surg 巻: 145(2) ページ: 522-530
• [雑誌論文] Uridine diphosphate glucuronosyl transferase 1 family polypeptide A1 gene (UGT1A1) polymorphisms are associated with toxicity and efficacy in irinotecan monotherapy for refractory pancreatic cancer (2013)
  • 著者名/発表者名: Takahara N, Nakai Y, Isayama H, Sasaki T, Satoh Y, Takai D, Hamada T, Uchino R, Mizuno S, Miyabayashi K, Mohri D, Kawakubo K, Kogure H, Yamamoto N, Sasahira N, Hirano K, Ijichi H, Tada M, Yatomi Y, Koike K
  • 雑誌名: Cancer Chemother Pharmacol 巻: 71(1) ページ: 85-92
• [雑誌論文] High-grade lung adenocarcinoma with fetal-lung-like morphology - Clinicopathological, immunohistochemical, and molecular analyses of 17 cases (2013)
  • 著者名/発表者名: Morita S, Yoshida A, Goto A, Ota S, Tsuta K, Yokozawa K, Asamura H, Nakajima J, Takai D, Mori M, Oka T, Tamaru J, Itoyama S, Furuta K, Fukayama M, Tsuda H
  • 雑誌名: American J of Surg. Pathology 巻: 37(6) ページ: 924-932
• [雑誌論文] FER overexpression is associated with poor postoperative prognosis and cancer-cell survival in non-small cell lung cancer (2013)
  • 著者名/発表者名: Kawakami M, Morita S, Sunohara M, Amano Y, Ishikawa R, Watanabe K, Hamano E, Ohishi N, Nakajima J, Yatomi Y, Nagase T, Fukayama M, Takai D
  • 雑誌名: Int J Clin Exp Pathol 巻: 6(4) ページ: 598-612
• [雑誌論文] A pilot study of salvage irinotecan monotherapy for advanced biliary tract cancer (2013)
  • 著者名/発表者名: Sasaki T, Isayama H, Nakai Y, Takahara N, Satoh Y, Takai D, Kogure H, Yamamoto N, Hirano K, Tada M, Yatomi Y, Koike K
  • 雑誌名: Anticancer Res 巻: 33(6) ページ: 2619-2622
• [雑誌論文] Combined Large Cell Neuroendocrine Carcinoma and Adenocarcinoma with Epidermal Growth Factor Receptor Mutation in a Female Patient Who Never Smoked (2013)
  • 著者名/発表者名: Yoshida Y, Ota S, Murakawa T, Takai D, Nakajima J
  • 雑誌名: Ann Thorac Cardiovasc Surg
  • NAID: 130003377861
• [雑誌論文] Detection of novel paraja ring finger 2-fer tyrosine kinase mRNA chimeras is associated with poor postoperative prognosis in non-small cell lung cancer (2013)
  • 著者名/発表者名: Kawakami M, Ishikawa R, Amano Y, Sunohara M, Watanabe K, Ohishi N, Yatomi Y, Nakajima J, Fukayama M, Nagase T, Takai D
  • 雑誌名: Cancer Sci 巻: 104(11) ページ: 1447-1454
• [雑誌論文] Successful Treatment of Mediastinal Unicentric Castleman's Disease Using Video-Assisted Thoracoscopic Surgery with Preoperative Embolization (2013)
  • 著者名/発表者名: Amano Y, Takai D, Ohishi N, Shinozaki-Ushiku A, Fukayama M, Akahane M, Nakajima J, Nagase T
  • 雑誌名: Case Rep Med 巻: 2013 ページ: 354507-354507
• [雑誌論文] Disruption of the expression and function of microRNAs in lung cancer as a result of epigenetic changes (2013)
  • 著者名/発表者名: Watanabe K & Takai D
  • 雑誌名: Frontiers in Genetics 巻: 4 ページ: 275-275
• [雑誌論文] Disruption of the expression and function of microRNAs in lung cancer as a result of epigenetic changes. (2013)
  • 著者名/発表者名: Watanabe K, Takai D.
  • 雑誌名: Frontiers in Genetics 巻: 4 ページ: 275-275
  • 査読あり
• [雑誌論文] Successful Treatment of Mediastinal Unicentric Castleman's Disease Using Video-Assisted Thoracoscopic Surgery with Preoperative Embolization. (2013)
  • 著者名/発表者名: Amano Y, Takai D, Ohishi N, Shinozaki-Ushiku A, Fukayama M, Akahane M, Nakajima J, Nagase T.
  • 雑誌名: Case Reports in Medicine 巻: 2013 ページ: 354507-354507
  • 査読あり
• [雑誌論文] Detection of novel paraja ring finger 2-fer tyrosine kinase mRNA chimeras is associated with poor postoperative prognosis in non-small cell lung cancer. (2013)
  • 著者名/発表者名: Kawakami M, Ishikawa R, Amano Y, Sunohara M, Watanabe K, Ohishi N, Yatomi Y, Nakajima J, Fukayama M, Nagase T, Takai D.
  • 雑誌名: Cancer Sci 巻: 104 号: 11 ページ: 1447-1454
  • DOI: 10.1111/cas.12250
  • 査読あり
• [雑誌論文] A pilot study of salvage irinotecan monotherapy for advanced biliary tract cancer. (2013)
  • 著者名/発表者名: Sasaki T, Isayama H, Nakai Y, Takahara N, Satoh Y, Takai D, Kogure H, Yamamoto N, Hirano K, Tada M, Yatomi Y, Koike K.
  • 雑誌名: Anticancer Research 巻: 33 ページ: 2619-2622
  • 査読あり
• [雑誌論文] High-grade Lung Adenocarcinoma With Fetal Lung-like Morphology: Clinicopathologic, Immunohistochemical, and Molecular Analyses of 17 Cases (2013)
  • 著者名/発表者名: Morita S, Yoshida A, Goto A, Ota S, Tsuta K, Yokozawa K, Asamura H, Nakajima J, Takai D, Mori M, Oka T, Tamaru J, Itoyama S, Furuta K, Fukayama M, Tsuda H.
  • 雑誌名: Am J Surg Pathol 巻: 37(6) 号: 6 ページ: 924-932
  • DOI: 10.1097/pas.0b013e31827e1e83
  • 査読あり
• [雑誌論文] FER overexpression is associated with poor postoperative prognosis and cancer-cell survival in non-small cell lung cancer. (2013)
  • 著者名/発表者名: Kawakami M, Morita S, Sunohara M, Amano Y, Ishikawa R, Watanabe K, Hamano E, Ohishi N, Nakajima J, Yatomi Y, Nagase T, Fukayama M, Takai D.
  • 雑誌名: International Journal of Clinical & Experimental Pathology 巻: 6 ページ: 598-612
  • 査読あり
• [雑誌論文] Combined Large Cell Neuroendocrine Carcinoma and Adenocarcinoma with Epidermal Growth Factor Receptor Mutation in a Female Patient Who Never Smoked. (2013)
  • 著者名/発表者名: Yoshida Y, Ota S, Murakawa T, Takai D, Nakajima J.
  • 雑誌名: Annals of Thoracic and Cardiovascular Surgery 巻: Epub ahead
  • NAID: 130003377861
  • 査読あり
• [雑誌論文] Growth-associated hyperphosphatemia in young recipients accelerates aortic allograft calcification in a rat model. (2013)
  • 著者名/発表者名: Yamauchi Haruo
  • 雑誌名: The Journal of Thoracic and Cardiovascular Surgery 巻: 145 号: 2 ページ: 522-530
  • DOI: 10.1016/j.jtcvs.2012.03.010
  • 査読あり
• [雑誌論文] Uridine diphosphate glucuronosyl transferase 1 family polypeptide A1 gene (UGT1A1) polymorphisms are associated with toxicity and efficacy in irinotecan monotherapy for refractory pancreatic cancer (2013)
  • 著者名/発表者名: Takahara N, Nakai Y, Isayama H, Sasaki T, Satoh Y, Takai D, Miyabayashi K, Mohri D, Kawakubo K, Kogure H, Yamamoto N, Sasahira N, Hirano K, Ijichi H, Tada M, Yatomi Y, Koike K
  • 雑誌名: Cancer Chemotherapy and Pharmacology 巻: 71 号: 1 ページ: 85-92
  • DOI: 10.1007/s00280-012-1981-0
  • 査読あり
• [雑誌論文] FER overexpression is associated with poor postoperative prognosis and cancer-cell survival in non-small cell lung cancer (2013)
  • 著者名/発表者名: Kawakami M, Morita S, Sunohara M, Amano Y, Ishikawa R, Watanabe K, Hamano E, Ohishi N, Nakajima J, Yatomi Y, Nagase T, Fukayama M, Takai D
  • 雑誌名: International Journal of Clinical and Experimental Pathology 巻: 6 ページ: 598-612
  • 査読あり
• [雑誌論文] High-grade lung adenocarcinoma with fetal-lung-like morphology ? Clinicopathological, immunohistochemical, and molecular analyses of 17 cases (2013)
  • 著者名/発表者名: Morita S, Yoshida A, Goto A, Ota S, Tsuta K, Yokozawa K, Asamura H, Nakajima J, Takai D, Mori M, Oka T, Tamaru J, Itoyama S, Furuta K, Fukayama M, Tsuda H
  • 雑誌名: American Journal of Surgical Pathology 巻: in press
  • 査読あり
• [雑誌論文] Genome structure-based screening identified epigenetically silenced microRNA associated with invasiveness in non-small-cell lung cancer (2012)
  • 著者名/発表者名: Watanabe K, Emoto N, Hamano E, Sunohara M, Kawakami M, Kage H, Kitano K, Nakajima J, Goto A, Fukayama M, Nagase T, Yatomi Y, Ohishi N, Takai D
  • 雑誌名: Int J Cancer 巻: 130(11) ページ: 2580-2590
• [雑誌論文] Pulmonary Venous Invasion, Determined by Chest Computed Tomographic Scan, as a Potential Early Indicator of Zygomycosis Infection : A Case Series (2012)
  • 著者名/発表者名: Kitagawa H, Watanabe K, Kage H, Inoh S, Goto A, Fukayama M, Nagase T, Ohishi N, Takai D
  • 雑誌名: J Thorac Imaging 巻: 27(4)
• [雑誌論文] Analysis for the combination expression of CK20, FABP1 and MUC2 is sensitive for the prediction of peritoneal recurrence in gastric cancer (2012)
  • 著者名/発表者名: Satoh Y, Mori K, Kitano K, Kitayama J, Yokota H, Sasaki H, Uozaki H, Fukayama M, Seto Y, Nagawa H, Yatomi Y, Takai D
  • 雑誌名: Jpn J Clin Oncol 巻: 42(2) ページ: 148-152
• [雑誌論文] Genome structure-based screening identifiedepigenetically silenced microRNA associated with invasiveness in non-small-cell lung cancer. (2012)
  • 著者名/発表者名: Watanabe K, Goto A, Takai D.
  • 雑誌名: Int J Cancer. 巻: 130 号: 11 ページ: 2580-2590
  • DOI: 10.1002/ijc.26254
  • 査読あり
• [雑誌論文] Pulmonary Venous Invasion, Determined by Chest Computed Tomographic Scan, as a Potential Early Indicator of Zygomycosis Infection: A Case Series (2012)
  • 著者名/発表者名: Kitagawa H, Watanabe K, Kage H, Inoh S, Goto A, Fukayama M, Nagase T, Ohishi N, Takai D
  • 雑誌名: J Thorac Imaging 巻: 27 号: 4 ページ: W97-W99
  • DOI: 10.1097/rti.0b013e3182282d17
  • 査読あり
• [雑誌論文] Analysis for the Combination Expression of CK20, FABP1 and MUC2 is Sensitive for the Prediction of Peritoneal Recurrence in Gastric Cancer (2012)
  • 著者名/発表者名: Satoh Y, Mori K, Kitano K, Kitayama J, Yokota H, Sasaki H, Uozaki H, Fukayama M, Seto Y, Nagawa H, Yatomi Y, Takai D
  • 雑誌名: Jpnease Journal of Clinical Oncology 巻: 42 号: 2 ページ: 148
  • DOI: 10.1093/jjco/hyr179
  • 査読あり
• [雑誌論文] Analysis for the combination expression of CK20, FABP1 and MUC2 is sensitive for the prediction of peritoneal recurrence in gastric cancer (2012)
  • 著者名/発表者名: Satoh Y, Takai D, et al.
  • 雑誌名: Jpn J Clin Oncol. 巻: 42 号: 2 ページ: 148-152
  • DOI: 10.1093/jjco/hyr204
  • 査読あり
• [雑誌論文] Suppression of Tgf・1 in lung alveolar epithelium-derived cells using adeno-associated virus type 2/5 vectors to carry short hairpin RNA (2011)
  • 著者名/発表者名: Kage H, Sugimoto K, Sano A, Kitagawa H, Nagase T, Ohishi N, Takai D
  • 雑誌名: Experimental Lung Research 巻: 37(3) ページ: 175-185
• [雑誌論文] Polymerase reaction without primers throughout for the reconstruction of full-length cDNA from products of rapid amplification of cDNA ends (RACE) (2011)
  • 著者名/発表者名: Sunohara M, Kawakami M, Kage H, Watanabe K, Emoto N, Nagase T, Ohishi N, Takai D
  • 雑誌名: Biotechnol Lett 巻: 33(7) ページ: 1301-1307
• [雑誌論文] CpG island methylation of microRNAs is associated with tumor size and recurrence of non-small-cell lung cancer (2011)
  • 著者名/発表者名: Kitano K, Watanabe K, Emoto N, Kage H, Hamano E, Nagase T, Sano A, Murakawa T, Nakajima J, Goto A, Fukayama M, Yatomi Y, Ohishi N, Takai D
  • 雑誌名: Cancer Sci 巻: 102(12) ページ: 2126-2131
  • NAID: 10030245653
• [雑誌論文] CpG island methylation of microRNAs is associated with tumor size and recurrence of non-small-cell lung cancer (2011)
  • 著者名/発表者名: Kitano K, Watanabe K, Emoto N, Kage H, Hamano E, Nagase T, Sano A, Murakawa T, Nakajima J, Goto A, Fukayama M, Yatomi Y, Ohishi N, Takai D.
  • 雑誌名: Cancer Sci 巻: 102 号: 12 ページ: 2126-2131
  • DOI: 10.1111/j.1349-7006.2011.02101.x
  • NAID: 10030245653
  • 査読あり
• [雑誌論文] Polymerase reaction without primers throughout for the reconstruction of full-length cDNA from products of rapid amplification of cDNA ends (RACE) (2011)
  • 著者名/発表者名: Sunohara M, Takai D, et al.
  • 雑誌名: Biotechnol Lett. 巻: 33 号: 7 ページ: 1301-1307
  • DOI: 10.1007/s10529-011-0580-1
  • 査読あり
• [雑誌論文] Suppression of transforming growth factor β1 in lung alveolar epithelium-derived cells using adeno-associated virus type 2/5 vectors to carry short hairpin RNA (2011)
  • 著者名/発表者名: Kage H, Takai D, et al.
  • 雑誌名: Exp Lung Res. 巻: 37 号: 3 ページ: 175-185
  • DOI: 10.3109/01902148.2010.529985
  • 査読あり
• [学会発表] Loss of PABPN1 and alternative polyadenylation yield poor prognosis in non-small cell lung cancer (2014)
  • 著者名/発表者名: Ichinose J, Watanabe K, Sano A, Nagase T, Nakajima J, Fukayama M, Yatomi Y, Ohishi N, Takai D
  • 学会等名: AACR-IASLC Joint Conference on The Molecular Origins of Lung Cancer
  • 発表場所: San Diego, CA, USA
• [学会発表] Can lung cancer with overexpression of RET-proto oncogene be a good candidate for vandetanib treatment? (2014)
  • 著者名/発表者名: Sunohara M, Morita S, Kawakami M, Watanabe K, Kage H, Amano Y, Ishikawa R, Fukayama M, Nagase T, Ohishi N, Takai D
  • 学会等名: AACR-IASLC Joint Conference on The Molecular Origins of Lung Cancer
  • 発表場所: San Diego, CA, USA
• [学会発表] Histone methylation-mediated silencing of mir-139 enhances an aggressive phenotype of non-small cell lung cancer (2014)
  • 著者名/発表者名: Watanabe K, Sunohara M, Amano Y, Ishikawa R, Ichinose J, Nakajima J, Fukayama M, Yatomi Y, Nagase T, Ohishi N, Takai D
  • 学会等名: AACR-IASLC Joint Conference on The Molecular Origins of Lung Cancer
  • 発表場所: San Diego, CA, USA
• [学会発表] Loss of PABPN1 and alternative polyadenylation yield poor prognosis in non-small cell lung cancer. (2014)
  • 著者名/発表者名: Ichinose J, Watanabe K, Sano A, Nagase T, Nakajima J, Fukayama M, Yatomi Y, Ohishi N, Takai D
  • 学会等名: AACR-IASLC Joint Conference on The Molecular Origins of Lung Cancer
  • 発表場所: San Diego, CA, USA
• [学会発表] Can lung cancer with overexpression of RET-proto oncogene be a good candidate for vandetanib treatment ? (2014)
  • 著者名/発表者名: Sunohara M, Morita S, Kawakami M, Watanabe K, Kage H, Amano Y, Ishikawa R, Fukayama M, Nagase T, Ohishi N, Takai D
  • 学会等名: AACR-IASLC Joint Conference on The Molecular Origins of Lung Cancer
  • 発表場所: San Diego, CA, USA
• [学会発表] Histone methylation-mediated silencing of mir-139 enhances an aggressive phenotype of non-small cell lung cancer. (2014)
  • 著者名/発表者名: Watanabe K, Sunohara M, Amano Y, Ishikawa R, Ichinose J, Nakajima J, Fukayama M, Yatomi Y, Nagase T, Ohishi N, Takai D
  • 学会等名: AACR-IASLC Joint Conference on The Molecular Origins of Lung Cancer
  • 発表場所: San Diego, CA, USA
• [学会発表] Genome sturucture-based screeening identified epigenetically silenced microRNA associated with invasiveness in non-small cell lung cancer (2012)
  • 著者名/発表者名: Watanabe K, Takai D, et al.
  • 学会等名: AACR-IASLC Joint Conference on THE MOLECULAR ORIGINS OF LUNG CANCER
  • 発表場所: San Diego, CA, USA
  • 年月日: 2012-01-10
• [学会発表] CpG island methylation of microRNAs is associated with tumor size and the recurrence of non-small cell lung cancer (2012)
  • 著者名/発表者名: Kitano K, Takai D, et al.
  • 学会等名: AACR-IASLC Joint Conference on THE MOLECULAR ORIGINS OF LUNG CANCER
  • 発表場所: San Diego, CA, USA
  • 年月日: 2012-01-09
• [学会発表] CpG island methylation of microRNAs is associated with tumor size and the recurrence of non-small cell lung cancer (2012)
  • 著者名/発表者名: Kitano K, Goto A, Fukayama M, Watanabe K, Emoto N, Kage H, Hamano H, Nagase T, Sano A, Murakawa T, Nakajima J, Yatomi Y, Ohishi N, Takai D
  • 学会等名: AACR-IASLC Joint Conference on The Molecular Origins of Lung Cancer
  • 発表場所: San Diego, CA, USA
• [学会発表] Genome structure-based screening identified epigenetically silenced microRNA associated with invasiveness in non-small cell lung cancer (2012)
  • 著者名/発表者名: Watanabe K, Goto A, Fukayama M, Nagase T, Emoto N, Hamano E, Amano Y, Ishikawa R, Sunohara M, Kawakami M, Kitano K, Nakajima J, Yatomi Y, Ohishi N, Takai D
  • 学会等名: AACR-IASLC Joint Conference on The Molecular Origins of Lung Cancer
  • 発表場所: San Diego, CA, USA
• [学会発表] Vandetanib Can Overcome the Acquired Resistance to Gefitinib Due to RET Overexpression in Lung Cancer (2012)
  • 著者名/発表者名: Sunohara M, Kawakami K, Watanabe K, Morita S, Kage H, Amano Y , Fukayama M, Nagase T, N. Ohishi N, Takai D
  • 学会等名: The 24th EORTC-NCI-AACR Symposium on 'Molecular Targets and Cancer Therapeutics
  • 発表場所: Dublin, Island
• [学会発表] Identification of FER as a New Molecular Target in Non-small Cell Lung Cancer (2012)
  • 著者名/発表者名: Kawakami M, Sunohara M, Amano Y, Ishikawa R, Watanabe K, Hamano E, Ohishi N, Nagase T, Yatomi Y, Takai D
  • 学会等名: The 24th EORTC-NCIAACR Symposium on 'Molecular Targets and Cancer Therapeutics
  • 発表場所: Dublin, Island
• [学会発表] Identification of FER as a New Molecular Target in Non-small Cell Lung Cancer (2012)
  • 著者名/発表者名: Kawakami M, Sunohara M, Amano Y, Ishikawa R, Watanabe K, Hamano E, Ohishi N, Nagase T, Yatomi Y, Takai D
  • 学会等名: The 24th EORTC-NCI-AACR Symposium on ‘Molecular Targets and Cancer Therapeutics'
  • 発表場所: Dublin, Ireland
• [学会発表] Vandetanib Can Overcome the Aquired Resistance to Gefitinib Due to RET Overexpression in Lung Cancer (2012)
  • 著者名/発表者名: Sunohara M, Kawakami M, Watanabe K, Morita S, Kage H, Amano Y, Fukayama M, T. Nagase T, Ohishi N, Takai D
  • 学会等名: The 24th EORTC-NCI-AACR Symposium on ‘Molecular Targets and Cancer Therapeutics'
  • 発表場所: Dublin, Ireland
• [学会発表] Crosstalk Between Alveolar Epithelial Cells And Fibroblasts Through Transforming Growth Factor ・1 And Prostaglandin Synthase 2 Results In Suppression Of Fibroblast Growth (2011)
  • 著者名/発表者名: Kage H, Amano Y, Ishikawa R, Sunohara M, Kawakami M, Emoto N, Watanabe K, Hamano E, Ohishi N, Nagase T, Takai D
  • 学会等名: American Thoracic Society International Conference
  • 発表場所: Denver, CO, USA
• [備考]
  • URL: http://kokyuki.umin.jp/305.html
• [備考]
  • URL: http://kokyuki.umin.jp/305.html