Development of a novel therapy and assessment method for NASH targeting glycosylation modification
Project/Area Number |
15H04810
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Gastroenterology
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Research Institution | Osaka University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
真鍋 良幸 大阪大学, 理学研究科, 助教 (00632093)
三善 英知 大阪大学, 医学系研究科, 教授 (20322183)
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Research Collaborator |
Ono Masafumi
Sumida Yoshio
Hyogo Hideyuki
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Project Period (FY) |
2015-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2018: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2017: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2016: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2015: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
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Keywords | NAFLD/NASH / バイオマーカー / フコシル化ハプトグロビン / Mac-2 binding protein / Fut8 / NASH/NAFLD / NASH / Mac-2bp / NAFLD / 肝臓学 / 糖鎖 / fucosylation |
Outline of Final Research Achievements |
We found that liver fucosylation increased during the progression of nonalcoholic fatty liver disease (NAFLD). Using biopsy-proven 510 NAFLD patients and 2122 health checkpup subjects, we developed two glyco-biomarkers, fucosylated haptoglobin (Fuc-Hpt) and Mac-2 binding protein (Mac-2bp). These glyco-biomarkers were superior than other conventional biomarkers, and well-diagnosed NAFLD disease severity. We found that Fuc-Hpt is a useful for the prediction of ballooning hepatocyte presence, and Mac-2bp is useful for the diagnosis of liver fibrosis progression in NAFLD patients. Combination of these biomarkers can be used as a superior NAFLD biomarker. Among fucosylation, core-fucosylation specially increased in NAFLD liver. We previously found core-fucose specific lectin, PhoSL, from Japanese mushroom. PhoSL administration improved NAFLD development in mouse NAFLD model. This result suggested the utility of PhoSL lectin as a “glyco-therapy” for NAFLD.
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Academic Significance and Societal Importance of the Research Achievements |
NAFLD診断はこれまで確立した方法が肝生検による組織診断しかなかった。治療効果判定のために頻回に肝生検を行うことは困難であるため、非侵襲的に病態進展を評価する方法の開発が喫緊の課題となっている。本研究によって糖鎖バイオマーカーにより、血液を用いてNAFLD病態進展を評価することが可能となった。またマウスを用いた基礎的研究によってPhoSLというキノコから抽出したタンパク質がNAFLD病態進展を抑制することがわかった。PhoSLはコアフコースという糖鎖に結合するタンパク質である。本研究の成果は糖鎖を標的とした新しいヒトNAFLD治療法の開発につながるものと期待される。
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Report
(5 results)
Research Products
(77 results)
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[Journal Article] A Data Mining-based Prognostic Algorithm for NAFLD-related Hepatoma Patients: A Nationwide Study by the Japan Study Group of NAFLD2018
Author(s)
Kawaguchi T, Tokushige K, Hyogo H, Aikata H, Nakajima T, Ono M, Kawanaka M, Sawada K, Imajo K, Kamada Y, Saibara T, Karino Y, Chayama K, Hashimoto E, George J, Torimura T
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Journal Title
Scientific Reports
Volume: 8
Issue: 1
Pages: 10434-10434
DOI
Related Report
Peer Reviewed
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[Journal Article] Targeting the mevalonate pathway is a novel therapeutic approach to inhibit oncogenic FoxM1 transcription factor in human hepatocellular carcinoma2018
Author(s)
Ogura S, Yoshida Y, Kurahashi T, Egawa M, Furuta K, Kiso S, Kamada Y, Hikita H, Eguchi H, Ogita H, Doki Y, Mori M, Tatsumi T, Takehara T.
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Journal Title
Oncotarget
Volume: 9
Issue: 30
Pages: 21022-21035
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Establishment of an antibody specific for cancer-associated haptoglobin: A possible implication of clinical investigation.2018
Author(s)
Nishino K, Koda S, Kataoka N, Takamatsu S, Nakano M, Ikeda S, Kamamatsu Y, Morishita K, Moriwaki K, Eguchi H, Yamamoto E, Kikkawa F, Tomita Y, Kamada Y, Miyoshi E.
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Journal Title
Oncotarget
Volume: 9
Issue: 16
Pages: 12732-12744
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Targeting the mevalonate pathway is a novel therapeutic approach to inhibit oncogenic FoxM1 transcription factor in human hepatocellular carcinoma.2018
Author(s)
Ogura S, Yoshida Y, Kurahashi T, Egawa M, Furuta K, Kiso S, Kamada Y, Hikita H, Eguchi H, Ogita H, Doki Y, Mori M, Tatsumi T, Takehara T.
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Journal Title
Oncotarget
Volume: in press
Related Report
Peer Reviewed / Open Access
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[Journal Article] Fatty Acid-Mediated Stromal Reprogramming of Pancreatic Stellate Cells Induces Inflammation and Fibrosis That Fuels Pancreatic Cancer.2017
Author(s)
Hata T, Kawamoto K, Eguchi H, Kamada Y, Takamatsu S, Maekawa T, Nagaoka S, Yamada D, Iwagami Y, Asaoka T, Noda T, Wada H, Gotoh K, Masamune A, Miyoshi E, Mori M, Doki Y.
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Journal Title
Pancreas
Volume: 46
Issue: 10
Pages: 1259-1266
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Use of Mac-2 binding protein as a biomarker for nonalcoholic fatty liver disease diagnosis.2017
Author(s)
Kamada Y, Ono M, Hyogo H, Fujii H, Sumida Y, Yamada M, Mori K, Tanaka S, Maekawa T, Ebisutani Y, Yamamoto A, Takamatsu S, Yoneda M, Kawada N, Chayama K, Saibara T, Takehara T, Miyoshi E.; Japan Study Group of NAFLD (JSG-NAFLD)
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Journal Title
Hepatol Commun.
Volume: 1
Issue: 8
Pages: 780-791
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Development of alpha1,6-fucosyltransferase inhibitors through the diversity-oriented syntheses of GDP-fucose mimics using the coupling between alkyne and sulfonyl azide.2017
Author(s)
Manabe, Y., Kasahara, S., Takakura, Y., Yang, X., Takamatsu, S., Kamada Y., Miyoshi, M., Yoshidome, D., Fukasea, K.
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Journal Title
Bioorg. Med. Chem.
Volume: in press
Issue: 11
Pages: 2844-2850
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Increased expression of Forkhead box M1 transcription factor is associated with clinicopathological features and confers a poor prognosis in human hepatocellular carcinoma.2017
Author(s)
Egawa M, Yoshida Y, Ogura S, Kurahashi T, Kizu T, Furuta K, Kamada Y, Chatani N, Hamano M, Kiso S, Hikita H, Tatsumi T, Eguchi H, Nagano H, Doki Y, Mori M, Takehara T
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Journal Title
Hepatol Res.
Volume: 印刷中
Issue: 11
Pages: 1196-1205
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Establishment of mouse Mac-2 binding protein enzyme-linked immunosorbent assay and its application for mouse chronic liver disease models.2016
Author(s)
Iwata A, Kamada Y, Ebisutani Y, Yamamoto A, Ueda Y, Arai H, Fujii H, Takamatsu S, Maruyama N, Maeda M, Takehara T, Miyoshi E.
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Journal Title
Hepatology Research
Volume: 47
Issue: 9
Pages: 1-11
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Hepatic aberrant glycosylation by N-acetylglucosaminyltransferase V accelerates HDL assembly.2016
Author(s)
Kamada Y, Kida S, Hirano KI, Yamaguchi S, Suzuki A, Hashimoto C, Kimura A, Sato M, Fujii H, Sobajima T, Yamamoto A, Ebisutani Y, Takamatsu S, Shinzaki S, Yoshida Y, Yamada M, Nagasaka H, Takehara T, Miyoshi E.
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Journal Title
Am J Physiol Gastrointest Liver Physiol
Volume: 311
Issue: 5
Pages: G859-G868
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Core-fucosylation plays a pivotal role in hepatitis B pseudo virus infection: a possible implication for HBV glycotherapy.2016
Author(s)
Takamatsu S, Shimomura M, Kamada Y, Maeda H, Sobajima T, Hikita H, Iijima M, Okamoto Y, Misaki R, Fujiyama K, Nagamori S, Kanai Y, Takehara T, Ueda K, Kuroda S, Miyoshi E.
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Journal Title
Glycobiology.
Volume: 26
Pages: 1180-1189
DOI
Related Report
Peer Reviewed
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[Journal Article] Serum Mac-2 binding protein is a novel biomarker for chronic pancreatitis.2016
Author(s)
Maekawa T*, Kamada Y* (equally contributed), Ebisutani Y, Ueda M, Hata T, Kawamoto K, Takamatsu S, Mizutani K, Shimomura M, Sobajima T, Fujii H, Nakayama K, Nishino K, Yamada M, Kumada T, Ito T, Eguchi H, Nagano H, Miyoshi E.
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Journal Title
World J Gastroenterol
Volume: 22
Issue: 17
Pages: 4403-10
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Specific increase in serum core-fucosylated haptoglobin in patients with chronic pancreatitis.2016
Author(s)
Ueda M, Kamada Y, Takamatsu S, Shimomura M, Maekawa T, Sobajima T, Fujii H, Nakayama K, Nishino K, Yamada M, Kobayashi Y, Kumada T, Ito T, Eguchi H, Nagano H, Miyoshi E.
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Journal Title
Pancreatology
Volume: 16
Issue: 2
Pages: 238-243
DOI
Related Report
Peer Reviewed
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[Journal Article] Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice.2016
Author(s)
Furuta K, Yoshida Y, Ogura S, Kurahashi T, Kizu T, Maeda S, Egawa M, Chatani N, Nishida K, Nakaoka Y, Kiso S, Kamada Y, Takehara T.
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Journal Title
Hepatology
Volume: 63
Issue: 4
Pages: 1340-1355
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Elevation of CA19-9-Related Novel Marker, Core 1 Sialyl Lewis A, in Sera of Adenocarcinoma Patients Verified by a SRM-Based Method.2016
Author(s)
Tanaka-Okamoto M, Yabu M, Mukai M, Takahashi H, Fujiwara Y, Ohue M, Kamada Y, Miyoshi E, Miyamoto Y.
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Journal Title
Journal of Proteome Research
Volume: 15
Issue: 1
Pages: 152-165
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease and alcoholic liver disease: multicenter survey.2016
Author(s)
Tokushige K, Hyogo H, Nakajima T, Ono M, Kawaguchi T, Honda K, Eguchi Y, Nozaki Y, Kawanaka M, Tanaka S, Imajo K, Sumida Y, Kamada Y, Fujii H, Suzuki Y, Kogiso T, Karino Y, Munekage K, Kuromatsu R, Oeda S, Yanase M, Mori K, Ogawa Y, Seko Y, Takehara T, Itoh Y, Nakajima A, Kanemasa K, Saibara T
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Journal Title
J Gastroenterol
Volume: 印刷中
Issue: 6
Pages: 586-96
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] N-Acetylglucosaminyltransferase V exacerbates murine colitis with macrophage dysfunction and enhances colitic tumorigenesis.2016
Author(s)
Shinzaki S, Ishii M, Fujii H, Iijima H, Wakamatsu K, Kawai S, Shiraishi E, Hiyama S, Inoue T, Hayashi Y, Kuwahara R, Takamatsu S, Kamada Y, Morii E, Tsujii M, Takehara T, Miyoshi E.
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Journal Title
J Gastroenterol.
Volume: 51
Issue: 4
Pages: 357-369
DOI
Related Report
Peer Reviewed
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[Journal Article] Ectopic expression of N-acetylglucosaminyltransferase V accelerates hepatic triglyceride synthesis.2016
Author(s)
Kamada Y, Ebisutani Y, Kida S, Mizutani K, Akita M, Yamamoto A, Fujii H, Sobajima T, Terao N, Takamatsu S, Yoshida Y, Takehara T, Miyoshi E
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Journal Title
Hepatol Res.
Volume: 46
Issue: 3
Pages: 1189-129
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] A novel noninvasive diagnostic method for nonalcoholic steatohepatitis using two glycobiomarkers.2015
Author(s)
Kamada Y, Ono M, Hyogo H, Fujii H, Sumida Y, Mori K, Tanaka S, Yamada M, Akita M, Mizutani K, Fujii H, Yamamoto A, Takamatsu S, Yoshida Y, Itoh Y, Kawada N, Chayama K, Saibara T, Takehara T, Miyoshi E
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Journal Title
Hepatology.
Volume: 62
Issue: 5
Pages: 1433-1443
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Establishment of a novel lectin-antibody ELISA system to determine core-fucosylated haptoglobin.2015
Author(s)
Shimomura M, Nakayama K, Azuma K, Terao N, Nishino K, Takamatsu S, Nakano M, Takahashi S, Kobayashi Y, Murata K, Kamada Y, Miyoshi E.
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Journal Title
Clin Chim Acta
Volume: in press
Pages: 30-6
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Loss of α1,6-fucosyltransferase suppressed liver regeneration: implication of core fucose in the regulation of growth factor receptor-mediated cellular signaling.2015
Author(s)
Wang Y, Fukuda T, Isaji T, Lu J, Gu W, Lee HH, Ohkubo Y, Kamada Y, Taniguchi N, Miyoshi E, Gu J.
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Journal Title
Sci Rep
Volume: in press
Issue: 1
Pages: 925-35
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice.2015
Author(s)
Kizu T, Yoshida Y, Furuta K, Ogura S, Egawa M, Chatani N, Hamano M, Takemura T, Ezaki H, Kamada Y, Nishida K, Nakaoka Y, Kiso S, Takehara T.
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Journal Title
Am J Physiol Gastrointest Liver Physiol
Volume: 308
Issue: 7
Pages: 613-624
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Secreted frizzled-related protein 5 (Sfrp5) decreases hepatic stellate cell activation and liver fibrosis.2015
Author(s)
Chatani N, Kamada Y, Kizu T, Ogura S, Furuta K, Egawa M, Hamano M, Ezaki H, Kiso S, Shimono A, Ouchi N, Yoshida Y, Takehara T.
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Journal Title
Liver Int
Volume: in press
Issue: 8
Pages: 2017-26
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] N-Acetylglucosaminyltransferase V exacerbates concanavalin A‑induced hepatitis in mice.2015
Author(s)
Kamada Y, Sato M, Kida S, Akita M, Mizutani K, Fujii H, Sobajima T, Yoshida Y, Shinzaki S, Takamatsu S, Takehara T, Miyoshi E.
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Journal Title
Mol Med Rep.
Volume: 5
Issue: 5
Pages: 3573-84
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Serum fucosylated haptoglobin in chronic liver diseases as a potential biomarker of hepatocellular carcinoma development.2015
Author(s)
Kamada Y*, Asazawa H* (equally contributed), Takeda Y, Takamatsu S, Shinzaki S, Kim Y, Nezu R, Kuzushita N, Mita E, Kat M, Miyoshi E.
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Journal Title
Clin Chem Lab Med
Volume: 53
Issue: 1
Pages: 95-102
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Fetuin-A negatively correlates with liver and vascular fibrosis in nonalcoholic fatty liver disease subjects.2015
Author(s)
Kamada Y*, Sato M* (equally contributed), Takeda Y, Kida S, Ohara Y, Fujii H, Akita M, Mizutani K, Yoshida Y, Yamada M, Hougaku H, Takehara T, Miyoshi E.
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Journal Title
Liver Int
Volume: 35
Issue: 3
Pages: 925-35
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Presentation] Biomarkers for NAFLD/NASH2017
Author(s)
Yoshihiro Kamada, Tetsuo Takehara, Eiji Miyoshi
Organizer
The 103rd General Meeting of the Japanese Society of Gastroenterology
Related Report
Int'l Joint Research / Invited
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[Presentation] Establishment of mouse Mac-2 binding protein ELISA and its application for mouse chronic liver disease models.2017
Author(s)
Yoshihiro Kamada, Ayumi Iwata, Yusuke Ebisutani, Akiko Yamamoto, Yui Ueda, Hitomi Arai, Hironobu Fujii, Shinji Takamatsu, Nobuhiro Maruyama, Masahiro Maeda, Tetsuo Takehara, Eiji Miyoshi
Organizer
The 68 th Annual Meeting of the American Association for the Study of Liver Diseases
Related Report
Int'l Joint Research
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[Presentation] A novel noninvasive diagnostic method for nonalcoholic steatohepatitis (NASH) using two glycobiomarkers2015
Author(s)
Yoshihiro Kamada, Masafumi Ono, Hideyuki Hyogo, Hideki Fujii, Yoshio Sumida, Kojiroh Mori, Saiyu Tanaka, Makoto Yamada, Maaya Akita, Kayo Mizutani, Hironobu Fujii, Akiko Yamamoto, Shinji Takamatsu, Yuichi Yoshida, Yoshito Ito, Norifumi Kawada, Kazuaki Chayama, Toshiji Saibara, Tetsuo Takehara, and Eiji Miyoshi
Organizer
AASLD The Liver Meeting 2015
Place of Presentation
San Francisco
Year and Date
2015-11-13
Related Report
Int'l Joint Research
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[Presentation] Ectopic expression of N-acetylglucosaminyltransferase V (GnT-V) accelerates hepatic triglyceride synthesis2015
Author(s)
Yusuke Ebisutani, Yoshihiro Kamada, Sachiho Kida, Kayo Mizutani, Maaya Akita, Akiko Yamamoto, Hironobu Fujii, Tomoaki Sobajima, Naoko Terao, Shinji Takamatsu, Yuichi Yoshida, Tetsuo Takehara, Eiji Miyoshi
Organizer
AASLD The Liver Meeting 2015
Place of Presentation
San Francisco
Year and Date
2015-11-13
Related Report
Int'l Joint Research
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