The impact of viral sequence on the pathological status of the post-antiviral therapeutic liver analyzed by single molecular sequencing.

• Project/Area Number: 20K08281
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: University of Yamanashi
• Principal Investigator: Maekawa Shinya 山梨大学, 大学院総合研究部, 特任教授 (70397298)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肝炎ウイルス制御後 / 原発性肝癌 / HCV / 次世代シークエンサー / 自然免疫 / ウイルスゲノム / 宿主遺伝子 / 1分子シークエンシング / HBV / ウイルス制御後の病態進展 / ウイルスゲノム1分子シークエンシング

Outline of Research at the Start

本研究では、ウイルス制御時代における肝病態進展の問題について、一分子シークエンサーにより 得られる大量な直列ウイルスゲノムのquasispecies情報を機械学習AIのプログラムを導入すること により迅速に処理し、precision medicineとしてのウイルスゲノムの意義について明らかとしてゆ く。さらにウイルスゲノム変異に対応した宿主因子についても、血液等を用いてmiRNA、体細胞変異 等を中心に解析、簡便なバイオマーカーの開発を目指してゆく。

Outline of Final Research Achievements

In this study, the Nanopore system, a single molecule sequencer, has been improved to analyze the genomic information of HCV as quasispecies of the full-length viral genome, whereas conventional next-generation sequencers can only detect genomic information as quasispecies of viral fragments, making it possible to clarify the relationship between the pathogenesis and the virus. This system has made it possible to elucidate the relationship between the pathogenesis and the virus more thoroughly. Using this system, mutations in the E1/E2 and NS5A regions at distant locations on the viral genome were shown to be synchronized with each other and related to disease progression.

Academic Significance and Societal Importance of the Research Achievements

従来断片的なウイルスゲノム解析以外は不可能であったウイルス変異体解析において、近年の技術革新で登場した高精度にロングリード可能な1分子シークエンシングシステムを導入し、完全長肝炎ウイルスゲノムの変異・quasispecies情報を取得することにより、ウイルス制御後の病態進展におけるウイルスゲノムの意義を嘗てないレベルで明らかにすることが可能となった。

Research Products

• [Journal Article] Significance of serum IP-10/CXCL10 measurement in predicting post-direct acting antiviral treatment liver function in patients with HCV-decompensated liver cirrhosis. (2023)
  • Author(s): Katoh R, Maekawa S, Osawa L, Komiyama Y, Nakakuki N, Takada H, Matsuda S, Muraoka M, Suzuki Y, Sato M, Tatsumi A, Takano S, Fukasawa M, Yamaguchi T, Nakayama Y, Inoue T, Enomoto N.
  • Journal Title: Hepatol Res Volume: 53 Pages: 280-288
  • Peer Reviewed
• [Journal Article] Early diagnosis of hepatic inflammation in Japanese nonalcoholic fatty liver disease patients using 3D MR elastography. (2023)
  • Author(s): Komiyama Y, Motosugi U, Maekawa S, Osawa L, Nakakuki N, Takada H, Muraoka M, Suzuki Y, Sato M, Takano S, Fukasawa M, Yamaguchi T, Onishi H, Yin M, Enomoto N.
  • Journal Title: Hepatol Res Volume: 53 Pages: 208-218
  • Peer Reviewed
• [Journal Article] Effect of a combination of pemafibrate and a mild low-carbohydrate diet on obese and non-obese patients with metabolic-associated fatty liver disease. (2023)
  • Author(s): Suzuki Y, Maekawa S, Yamashita K, Osawa L, Komiyama Y, Nakakuki N, Takada H, Muraoka M, Sato M, Takano S, Fukasawa M, Yamaguchi T, Funayama S, Morisaka H, Onishi H, Enomoto N.
  • Journal Title: J Gastroenterol Hepatol Volume: in press Issue: 6 Pages: 921-929
  • DOI: 10.1111/jgh.16154
  • Peer Reviewed
• [Journal Article] Prediction of Therapeutic Response Using Contrast-Enhanced Ultrasound in Japanese Patients Treated with Atezolizumab and Bevacizumab for Unresectable Hepatocellular Carcinoma. (2023)
  • Author(s): Takada H, Yamashita K, Osawa L, Komiyama Y, Nakakuki N, Muraoka M, Suzuki Y, Sato M, Takano S, Fukasawa M, Yamaguchi T, Maekawa S, Enomoto N.
  • Journal Title: Oncology Volume: 101 Pages: 173-184
  • Peer Reviewed
• [Journal Article] Analysis of direct-acting antiviral-resistant hepatitis C virus haplotype diversity by single-molecule and long-read sequencing. (2022)
  • Author(s): Yamauchi K, Sato M, Osawa L, Matsuda S, Komiyama Y, Nakakuki N, Takada H, Katoh R, Muraoka M, Suzuki Y, Tatsumi A, Miura M, Takano S, Amemiya F, Fukasawa M, Nakayama Y, Yamaguchi T, Inoue T, Maekawa S, Enomoto N.
  • Journal Title: Hepatol Commun Volume: 6 Pages: 1634-1651
  • Peer Reviewed
• [Journal Article] Analysis of direct-acting antiviral-resistant hepatitis C virus haplotype diversity by single-molecule and long-read sequencing (2022)
  • Author(s): Yamauchi K, Sato M, Osawa L, Matsuda S, Komiyama Y, Nakakuki N, Takada H, Katoh R, Muraoka M, Suzuki Y, Tatsumi A, Miura M, Takano S, Amemiya F, Fukasawa M, Nakayama Y, Yamaguchi T, Inoue T, Maekawa S, Enomoto N.
  • Journal Title: Hepatol Commun Volume: in press Issue: 7 Pages: 1634-1651
  • DOI: 10.1002/hep4.1929
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory effect of a novel thiazolidinedione derivative on hepatitis B virus entry (2021)
  • Author(s): Tanaka Tomohisa、Okuyama-Dobashi Kaori、Motohashi Ryoji、Yokoe Hiromasa、Takahashi Kazunori、Wiriyasermkul Pattama、Kasai Hirotake、Yamashita Atsuya、Maekawa Shinya、Enomoto Nobuyuki、Ryo Akihide、Nagamori Shushi、Tsubuki Masayoshi、Moriishi Kohji
  • Journal Title: Antiviral Research Volume: 194 Pages: 105165-105165
  • DOI: 10.1016/j.antiviral.2021.105165
  • Peer Reviewed / Open Access
• [Journal Article] Usefulness of Circulating CYFRA21-1 in Patients as a Biomarker in Patients Taking Sorafenib or Lenvatinib for Unresectable Hepatocellular Carcinoma. (2021)
  • Author(s): Takada H, Osawa L, Komiyama Y, Kato R, Nakakuki N, Muraoka M, Suzuki Y, Tatsumi A, Sato M, Takahashi E. Maekawa S, Enomoto N.
  • Journal Title: Reports Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Usefulness of Cell-Free Human Telomerase Reverse Transcriptase Mutant DNA Quantification in Blood for Predicting Hepatocellular Carcinoma Treatment Efficacy. (2021)
  • Author(s): Muraoka M, Maekawa S, Katoh R, Komiyama Y, Nakakuki N, Takada H, Matsuda S, Suzuki Y, Sato M, Tatsumi A, Miura M, Amemiya F, Shindo H, Takano S, Fukasawa M, Yamauchi K, Yamaguchi T, Nakayama Y, Inoue T, Enomoto N.
  • Journal Title: Hepatol Commun. Volume: 5(11) Issue: 11 Pages: 1927-1938
  • DOI: 10.1002/hep4.1762
  • Peer Reviewed / Open Access
• [Journal Article] The impact of antiviral therapy for hepatitis C virus on the survival of patients after hepatocellular carcinoma treatment. (2021)
  • Author(s): Mori Y, Matsuda S, Sato M, Muraoka M, Suzuki Y, Tatsumi A, Nakayama Y, Inoue T, Maekawa S, Enomoto N.
  • Journal Title: Internal Medicine Volume: Online ahead of print.
  • Peer Reviewed / Open Access
• [Journal Article] Deep sequencing analysis of serum hepatitis B virus-RNA during nucleot(s)ide analogue therapy (2021)
  • Author(s): Shuya Matsuda, Shinya Maekawa, Yasuyuki Komiyama, Natsuko Nakakuki, Tatsuya Yamaguchi, Yasuhiro Nakayama, Taisuke Inoue, Tadashi Sato, Atsuya Yamashita, Kohji Moriishi, Nobuyuki Enomoto
  • Journal Title: Hepatology Research Volume: 51 Issue: 1 Pages: 39-50
  • DOI: 10.1111/hepr.13574
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between presarcopenia and event occurrence in patients with primary hepatocellular carcinoma (2020)
  • Author(s): Takada H, Amemiya F, Yasumura T, Yoda H, Okuwaki T, Imagawa N, Shimamura N, Tanaka K, Kadokura M, Maekawa S, Enomoto N.
  • Journal Title: Sci Rep. Volume: 1 Issue: 1 Pages: 10186-10186
  • DOI: 10.1038/s41598-020-67147-7
  • Peer Reviewed / Open Access
• [Journal Article] Cancer-related genetic changes in multistep hepatocarcinogenesis and their correlation with imaging and histological findings (2020)
  • Author(s): Masaru Muraoka, Shinya Maekawa, Yuichiro Suzuki , Mitsuaki Sato, Tatsuya Yamaguchi, Taisuke Inoue, Tadashi Sato, Atsuya Yamashita, Kohji Moriishi, Masanori Matsuda, Nobuyuki Enomoto
  • Journal Title: Hepatology Research Volume: 50 Issue: 9 Pages: 1071-1082
  • DOI: 10.1111/hepr.13529
  • Peer Reviewed / Open Access