Updated on 2023/02/05

写真a

 
MATSUDA Yasunobu
 
Organization
Academic Assembly Institute of Medicine and Dentistry Health Sciences Associate Professor
Faculty of Medicine School of Health Sciences Associate Professor
Graduate School of Health Sciences Health Sciences Associate Professor
Title
Associate Professor
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Degree

  • 医学博士 ( 1998.4   新潟大学 )

Research Interests

  • 腫瘍再増殖

  • 代償性増殖

  • oncology

  • gastroenterologym

  • エクソソーム

Research Areas

  • Life Science / Gastroenterology

Research History (researchmap)

  • Niigata University   Graduate School of Health Sciences Health Sciences   Associate Professor

    2007.10

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  • Niigata University   Faculty of Medicine School of Health Sciences   Associate Professor

    2007.10

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  • Niigata University   University Medical and Dental Hospital   Assistant Professor

    2007.4 - 2007.9

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  • Niigata University   University Medical and Dental Hospital   Research Assistant

    2003.10 - 2007.3

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  • Niigata University   Faculty of Medicine   Research Assistant

    2001.9 - 2003.9

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  • Osaka University   Faculty of Medicine   Researcher

    1993.5 - 1994.3

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Research History

  • Niigata University   Faculty of Medicine School of Health Sciences   Associate Professor

    2007.10

  • Niigata University   Graduate School of Health Sciences Health Sciences   Associate Professor

    2007.10

  • Niigata University   Graduate School of Health Sciences Health Sciences   Associate Professor

    2007.10

  • Niigata University   University Medical and Dental Hospital   Assistant Professor

    2007.4 - 2007.9

  • Niigata University   University Medical and Dental Hospital   Research Assistant

    2003.10 - 2007.3

  • Niigata University   Faculty of Medicine   Research Assistant

    2001.9 - 2003.9

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Education

  • Niigata University   Faculty of Medicine   School of Medicine

    1982.4 - 1998.3

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Professional Memberships

 

Papers

  • Exosomal p38 Mitogen-activated Protein Kinase Promotes Tumour Repopulation in TP53-mutated Bile Duct Cancer Cells. International journal

    Mami Osawa, Yasunobu Matsuda, Jun Sakata, Toshifumi Wakai

    Anticancer research   42 ( 2 )   745 - 757   2022.2

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    BACKGROUND/AIM: Tumour repopulation is a major obstacle for successful cancer treatment. This study investigated whether anticancer agents contribute to tumour repopulation in TP53-mutated bile duct cancer cells. MATERIALS AND METHODS: TP53-mutated HuCCT1 and HuH28 cells were exposed to anticancer agents, and recipient cells were exposed to their conditioned media or exosomes. The effect of inhibitors and siRNA-mediated gene silencing of p38 mitogen-activated protein kinase (MAPK) and of TP53 was analyzed by cell proliferation assays and western blotting. RESULTS: Conditioned media from genotoxic agent-treated cells promoted proliferation of recipient cells (p<0.05), and this effect was abrogated by exosome inhibitors. Exosomes from gemcitabine- or cisplatin-treated cells increased cell proliferation by 1.6- to 2.2-fold (p<0.05) through p38 MAPK signalling. These effects of exosomes were inhibited by inhibition/silencing of p38 MAPK but not by TP53 silencing. CONCLUSION: Exosomal p38 MAPK plays a pivotal role in tumour repopulation in a TP53-independent manner.

    DOI: 10.21873/anticanres.15533

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  • [Retracted] Alteration of p53-binding protein 1 expression as a risk factor for local recurrence in patients undergoing resection for extrahepatic cholangiocarcinoma. International journal

    Toshifumi Wakai, Yoshio Shirai, Jun Sakata, Pavel V Korita, Yasunobu Matsuda, Masaaki Takamura, Riuko Ohashi, Masayuki Nagahashi, Yoichi Ajioka, Katsuyoshi Hatakeyama

    International journal of oncology   59 ( 4 )   2021.10

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    Following the publication of this paper, the Journal was alerted by an investigation committee of Niigata University to the fact that the paper had been identified as a duplicate publication, which had already been published. Therefore, in accordance with the rules of Niigata University Fraud Investigation committee, a request was made that the paper be retracted. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in International Journal of Oncology 38: 1227-1236, 2011; DOI: 10.3892/ijo.2011.959].

    DOI: 10.3892/ijo.2021.5258

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  • Dysregulation of sphingolipid metabolic enzymes leads to high levels of sphingosine-1-phosphate and ceramide in human hepatocellular carcinoma. Reviewed International journal

    Kohei Miura, Masayuki Nagahashi, Pankaj Prasoon, Yuki Hirose, Takashi Kobayashi, Jun Sakata, Manabu Abe, Kenji Sakimura, Yasunobu Matsuda, Ali L Butash, Eriko Katsuta, Kazuaki Takabe, Toshifumi Wakai

    Hepatology research : the official journal of the Japan Society of Hepatology   51 ( 5 )   614 - 626   2021.5

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    AIM: Sphingosine-1-phosphate (S1P) and ceramide are bioactive sphingolipids known to be important in regulating numerous processes involved in cancer progression. The aim of this study was to determine the absolute levels of sphingolipids in hepatocellular carcinoma (HCC) utilizing data obtained from surgical specimens. In addition, we explored the clinical significance of S1P in patients with HCC and the biological role of S1P in HCC cells. METHODS: Tumors and normal liver tissues were collected from 20 patients with HCC, and sphingolipids were measured by mass spectrometry. The Cancer Genome Atlas (TCGA) cohort was utilized to evaluate gene expression of enzymes related to sphingolipid metabolism. Immunohistochemistry of phospho-sphingosine kinase 1 (SphK1), an S1P-producing enzyme, was performed for 61 surgical specimens. CRISPR/Cas9-mediated SphK1 knockout cells were used to examine HCC cell biology. RESULTS: S1P levels were substantially higher in HCC tissue compared with normal liver tissue. Levels of other sphingolipids upstream of S1P in the metabolic cascade, such as sphingomyelin, monohexosylceramide and ceramide, were also considerably higher in HCC tissue. Enzymes involved in generating S1P and its precursor, ceramide, were found in higher levels in HCC compared with normal liver tissue. Immunohistochemical analysis found that phospho-SphK1 expression was associated with tumor size. Finally, in vitro assays indicated that S1P is involved in the aggressiveness of HCC cells. CONCLUSIONS: Sphingolipid levels, including S1P and ceramide, were elevated in HCC compared with surrounding normal liver tissue. Our findings suggest S1P plays an important role in HCC tumor progression, and further examination is warranted.

    DOI: 10.1111/hepr.13625

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  • Changes in disease characteristics of primary biliary cholangitis: An observational retrospective study from 1982 to 2016. Reviewed International journal

    Masaaki Takamura, Yasunobu Matsuda, Naruhiro Kimura, Masafumi Takatsuna, Toru Setsu, Atsunori Tsuchiya, Akihiko Osaki, Nobuo Waguri, Masahiko Yanagi, Toru Takahashi, Soichi Sugitani, Yuka Kobayashi, Akira Yoshikawa, Toru Ishikawa, Toshiaki Yoshida, Toshiaki Watanabe, Hitoshi Bannai, Tomoyuki Kubota, Kazuhiro Funakoshi, Hiroto Wakabayashi, So Kurita, Norio Ogata, Masashi Watanabe, Yuhsaku Mita, Shigeki Mori, Motoya Sugiyama, Toru Miyajima, Sumio Takahashi, Shuichi Sato, Kisei Ishizuka, Hironobu Ohta, Yutaka Aoyagi, Shuji Terai

    Hepatology research : the official journal of the Japan Society of Hepatology   51 ( 2 )   166 - 175   2021.2

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    AIM: Disease characteristics of primary biliary cholangitis have changed recently. However, detailed studies on the subject have been limited. Therefore, we aimed to clarify disease characteristics of patients with recent primary biliary cholangitis using the cohort from Niigata University and 21 affiliated hospitals. METHODS: Overall, 508 patients were enrolled in this study from 1982 to 2016, divided into three cohorts according to their year of diagnosis: ≤1999, 2000-2009 and ≥2010. We compared differences in clinical characteristics, response to ursodeoxycholic acid and prognosis. RESULTS: The male-to-female ratio increased incrementally from 1:16.4 (≤1999) to 1:3.8 (≥2010) (P < 0.001). In women, the median age at diagnosis increased incrementally from 54.0 years (≤1999) to 60.5 years (≥2010) (P < 0.001) and serum albumin decreased gradually (P = 0.001), which might have affected the increase in the Fibrosis-4 Index and albumin-bilirubin score. The ursodeoxycholic acid response rate according to the Barcelona criteria increased incrementally from 26.7% (≤1999) to 78.4% (≥2010) (P < 0.010), and those according to other criteria (Paris-I, Rotterdam and Toronto) were approximately ≥80% in all cohorts. Ten-year survival rate in the ≤1999 and 2000-2009 cohorts were 98.6% and 95.6%, respectively. These earlier cohorts were also characterized by a higher rate of asymptomatic state and mild histology (83.5% [≤1999] and 84.7% [2000-2009], and 93.6% [≤1999] and 91.1% [2000-2009]). CONCLUSIONS: Patients with primary biliary cholangitis were characterized by older age at diagnosis and an increase in male to female ratio as well as higher response rates of ursodeoxycholic acid and longer survival, resulting from the early recognition of primary biliary cholangitis.

    DOI: 10.1111/hepr.13586

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  • Urokinase-type Plasminogen Activator Is a Therapeutic Target for Overcoming Sorafenib Resistance in Hepatoma Cells. Reviewed International journal

    Mami Osawa, Yasunobu Matsuda, Yoshiaki Kinoshita, Toshifumi Wakai

    Anticancer research   41 ( 2 )   645 - 660   2021.2

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    BACKGROUND/AIM: Sorafenib is a multikinase inhibitor approved as a first-line therapy for hepatocellular carcinoma. This study examined the sorafenib resistance mechanism. MATERIALS AND METHODS: Hepatoma HepG2 cells were exposed to sorafenib, and the biological activity of the conditioned media was analyzed using cell proliferation/apoptosis assays, multiplex immunoassays, ELISA, and western blot analyses. The effect of urokinase-type plasminogen activator (uPA) inhibitors or siRNA-mediated gene silencing was examined in culture experiments and a mouse xenograft tumor model. RESULTS: Sorafenib increased uPA secretion, which was abrogated by an Akt inhibitor. The growth-inhibitory effect of sorafenib was significantly enhanced by the uPA inhibitors UK122 and amiloride. Sorafenib-induced apoptosis was increased 2.4-fold in uPA siRNA-transduced cells (p<0.05). Combined therapy with sorafenib and amiloride significantly decreased tumor volumes [mean volume: 759 mm3 (sorafenib) vs. 283 mm3 (sorafenib plus amiloride), p<0.05]. CONCLUSION: uPA may play a critical role in sorafenib resistance.

    DOI: 10.21873/anticanres.14816

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  • Activin a Receptor Type 2A Mutation Affects the Tumor Biology of Microsatellite Instability-High Gastric Cancer. Reviewed International journal

    Kizuki Yuza, Masayuki Nagahashi, Hiroshi Ichikawa, Takaaki Hanyu, Masato Nakajima, Yoshifumi Shimada, Takashi Ishikawa, Jun Sakata, Shiho Takeuchi, Shujiro Okuda, Yasunobu Matsuda, Manabu Abe, Kenji Sakimura, Kazuaki Takabe, Toshifumi Wakai

    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract   25 ( 9 )   2231 - 2241   2021.1

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    BACKGROUND: Activin A receptor type 2A (ACVR2A) is one of the most frequently mutated genes in microsatellite instability-high (MSI-H) gastric cancer. However, the clinical relevance of the ACVR2A mutation in MSI-H gastric cancer patients remains unclear. The aims of this study were to explore the effect of ACVR2A mutation on the tumor behavior and to identify the clinicopathological characteristics of gastric cancer patients with ACVR2A mutations. METHODS: An in vitro study was performed to investigate the biological role of ACVR2A via CRISPR/Cas9-mediated ACVR2A knockout MKN74 human gastric cancer cells. One hundred twenty-four patients with gastric cancer were retrospectively analyzed, and relations between MSI status, ACVR2A mutations, and clinicopathological factors were evaluated. RESULTS: ACVR2A knockout cells showed less aggressive tumor biology than mock-transfected cells, displaying reduced proliferation, migration, and invasion (P < 0.05). MSI mutations were found in 10% (13/124) of gastric cancer patients, and ACVR2A mutations were found in 8.1% (10/124) of patients. All ACVR2A mutations were accompanied by MSI. The 5-year overall survival rates of ACVR2A wild-type patients and ACVR2A-mutated patients were 57% and 90%, respectively (P = 0.048). Multivariate analysis revealed that older age (P = 0.015), distant metastasis (P < 0.001), and ACVR2A wild-type status (P = 0.040) were independent prognostic factors for overall survival. CONCLUSIONS: Our study demonstrated that gastric cancer patients with ACVR2A mutation have a significantly better prognosis than those without. Dysfunction of ACVR2A in MKN74 human gastric cancer cells caused less aggressive tumor biology, indicating the importance of ACVR2A in the progression of MSI-H tumors.

    DOI: 10.1007/s11605-020-04889-9

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  • Epidermal growth factor receptor/heme oxygenase-1 axis is involved in chemoresistance to cisplatin and pirarubicin in HepG2 cell lines and hepatoblastoma specimens. Reviewed International journal

    Takashi Kobayashi, Masayuki Kubota, Yoshiaki Kinoshita, Yuki Arai, Toshiyuki Oyama, Naoki Yokota, Koichi Saito, Yasunobu Matsuda, Mami Osawa

    Pediatric surgery international   35 ( 12 )   1369 - 1378   2019.12

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    PURPOSE: To investigate the possibility that the antioxidant stress protein Heme oxygenase-1 (HO-1) is involved in the acquisition of chemoresistance in cisplatin and pirarubicin (CITA) therapy. METHODS: Human hepatoblastoma-derived cell line (HepG2) was used to generate a knockdown cell line of HO-1 by small interfering RNA (siRNA). Expression of HO-1, epidermal growth factor receptor (EGFR), Akt, and extracellular signal-regulated kinase1/2 (ERK1/2) was examined by Western blot. The cytotoxic effect of cisplatin, pirarubicin, and EGFR inhibitor was examined by trypan blue staining. In human hepatoblastoma specimens (n = 5), changes of HO-1 expression were examined immunohistochemically before and after CITA therapy. RESULTS: HO-1 expression in HepG2 cells was increased by the treatment of cisplatin (CDDP) and pirarubicin (THP) dose-dependently. In HO-1 knockdown HepG2 cells, the HO-1 was not expressed and the percentage of trypan blue-positive cells (dead cells) was significantly increased after treatment of CDDP and THP. The EGFR inhibitor decreased the levels of HO-1, phospho-Akt and phospho-ERK1/2 in HepG2 cells. Combination treatment of EGFR inhibitor with CDDP and THP increased the cytotoxic effect in HepG2 cells. In human hepatoblastoma specimens, 4 of the 5 patients (80%) showed HO-1 expression changed much stronger in the viable tumor cells after CITA therapy. CONCLUSION: The cytotoxic effects of CDDP and THP were both enhanced under HO-1 knockdown conditions as well as under conditions that inhibit the activation pathway of HO-1 by EGFR inhibitors. EGFR/HO-1 axis may be involved in acquiring chemoresistance in HepG2 cell lines as well as in human hepatoblastoma.

    DOI: 10.1007/s00383-019-04563-5

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  • Overexpression of a disintegrin and metalloproteinase 21 is associated with motility, metastasis, and poor prognosis in hepatocellular carcinoma. Reviewed International journal

    Hiroki Honda, Masaaki Takamura, Satoshi Yamagiwa, Takuya Genda, Ryoko Horigome, Naruhiro Kimura, Toru Setsu, Kentaro Tominaga, Hiroteru Kamimura, Yasunobu Matsuda, Toshifumi Wakai, Yutaka Aoyagi, Shuji Terai

    Scientific reports   7 ( 1 )   15485 - 15485   2017.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:NATURE PUBLISHING GROUP  

    Cell motility plays an important role in intrahepatic metastasis of hepatocellular carcinoma (HCC), and predicts poor prognosis in patients. The present study investigated the role of a disintegrin and metalloproteinases (ADAMs) in HCC, since these proteins are known to be associated with cell motility. We confirmed the expression of 12 ADAMs with putative metalloproteinase activity in HCC cells, and established a KYN-2 HCC cell line stably expressing short interfering RNA against ADAM21 to investigate the effect of ADAM21 deficiency on HCC cell motility and metastasis in vitro and in vivo. We also examined ADAM21 expression in a cohort of 119 HCC patients by immunohistochemistry. ADAM21 was overexpressed in KYN-2 cells, and its knockdown reduced invasion, migration, proliferation, and metastasis relative to controls. In clinical specimens, ADAM21 positivity was associated with vascular invasion, large tumor size, high histological grade, and lower overall and recurrence-free survival as compared to cases that were negative for ADAM21 expression. A multivariate analysis revealed that ADAM21 positivity was an independent risk factor for overall (P = 0.003) and recurrence-free (P = 0.001) survival. These results suggest that ADAM21 plays a role in HCC metastasis and can serve as a prognostic marker for disease progression.

    DOI: 10.1038/s41598-017-15800-z

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  • Clinical significance of NQO1 expression in KRAS wild-type colorectal cancer Reviewed

    Hitoshi Kameyama, Yuki Hirose, Yasunobu Matsuda, Masayuki Nagahashi, Hiroshi Ichikawa, You Sato, Saki Yamada, Shinnosuke Hotta, Yosuke Tajima, Takuma Okamura, Mae Nakano, Masato Nakano, Yoshifumi Shimada, Jun Sakata, Takashi Kobayashi, Toshifumi Wakai

    INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY   10 ( 5 )   5841 - 5849   2017

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:E-CENTURY PUBLISHING CORP  

    NAD(P)H: quinone oxidoreductase-1 (NQO1) protects cells against redox cycling and oxidative stress; however, in cancer cells, NQO1 confers resistance against anticancer agents. The aim of this study was to evaluate the association between NQO1 expression and prognosis in patients with advanced (locally advanced or metastatic/recurrent) colorectal cancer (CRC). A retrospective analysis of 47 patients [28 male and 19 female; median age: 62 years (range, 17-78)] with advanced CRC was conducted. Immunohistochemical examination of tumor tissue specimens was performed using monoclonal anti-NQO1 antibody. The association of NQO1 expression with patient characteristics, chemotherapeutic response, and clinical prognosis was assessed. Therapeutic efficacy (complete response, partial response, stable disease, and progressive disease) was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. We compared the therapeutic efficacy in KRAS wild and mutant CRC because epidermal growth factor receptor (EGFR)-signaling pathway plays a pivotal role in CRC. Of the 47 patients, 31 (66.0%) had KRAS wild CRC and 16 (34.0%) had KRAS mutant CRC. Moreover, 37 (78.7%) had NQO1-positive tumors and 10 (21.3%) had NQO1-negative tumors. Among the patients with KRAS wild CRC, NQO1-negative patients showed significantly better disease control rate (complete response + partial response + stable disease) than NQO1-positive patients (P = 0.028). Moreover, NQO1-negative patients had longer progression-free survival and overall survival than NQO1-positive patients (P = 0.041 and P = 0.043, respectively). NQO1 expression in the tumor may be a predictor of therapeutic efficacy and prognosis in patients with KRAS wild advanced CRC.

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  • Biological significance of a disintegrin and metalloproteinase 21 expression in hepatocellular carcinoma Reviewed

    Masaaki Takamura, Hiroki Honda, Satoshi Yamagiwa, Naruhiro Kimura, Toru Setsu, Kentaro Tominaga, Hiroteru Kamimura, Takuya Genda, Yasunobu Matsuda, Toshifumi Wakai, Shuji Terai

    HEPATOLOGY   64   639A - 639A   2016.10

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  • DNA damage response and sphingolipid signaling in liver diseases. Reviewed

    Masayuki Nagahashi, Yasunobu Matsuda, Kazuki Moro, Junko Tsuchida, Daiki Soma, Yuki Hirose, Takashi Kobayashi, Shin-Ichi Kosugi, Kazuaki Takabe, Masaaki Komatsu, Toshifumi Wakai

    Surgery today   46 ( 9 )   995 - 1005   2016.9

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

    Patients with unresectable hepatocellular carcinoma (HCC) cannot generally be cured by systemic chemotherapy or radiotherapy due to their poor response to conventional therapeutic agents. The development of novel and efficient targeted therapies to increase their treatment options depends on the elucidation of the molecular mechanisms that underlie the pathogenesis of HCC. The DNA damage response (DDR) is a network of cell-signaling events that are triggered by DNA damage. Its dysregulation is thought to be one of the key mechanisms underlying the generation of HCC. Sphingosine-1-phosphate (S1P), a lipid mediator, has emerged as an important signaling molecule that has been found to be involved in many cellular functions. In the liver, the alteration of S1P signaling potentially affects the DDR pathways. In this review, we explore the role of the DDR in hepatocarcinogenesis of various etiologies, including hepatitis B and C infection and non-alcoholic steatohepatitis. Furthermore, we discuss the metabolism and functions of S1P that may affect the hepatic DDR. The elucidation of the pathogenic role of S1P may create new avenues of research into therapeutic strategies for patients with HCC.

    DOI: 10.1007/s00595-015-1270-8

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  • Comparison of Number Versus Ratio of Positive Lymph Nodes in the Assessment of Lymph Node Status in Extrahepatic Cholangiocarcinoma. Reviewed International journal

    Jun Sakata, Toshifumi Wakai, Yasunobu Matsuda, Taku Ohashi, Yuki Hirose, Hiroshi Ichikawa, Takashi Kobayashi, Masahiro Minagawa, Shin-Ichi Kosugi, Yu Koyama, Kouhei Akazawa, Yoichi Ajioka

    Annals of surgical oncology   23 ( 1 )   225 - 34   2016.1

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    This study aimed to compare the utility of the number of positive lymph nodes with the lymph node ratio (LNR) in predicting survival after resection of extrahepatic cholangiocarcinoma.
    A retrospective analysis of 142 consecutive patients who underwent radical resection of extrahepatic cholangiocarcinoma was performed. A total of 3066 regional lymph nodes were resected. The median number of nodes per patient was 21. The optimal cutoff values for the number of positive nodes and the LNR were determined using the Chi square scores calculated by the Cox proportional hazards regression model.
    Nodal disease was found in 59 patients (42 %). In the subsequent analysis of the impact that nodal status has on survival, 18 patients with R1/2 resection and 6 patients with paraaortic nodal disease who did not survive for more than 5 years after resection were excluded. The optimal cutoff value for the number of positive nodes was 1, and the optimal cutoff value for the LNR was 5 %. Univariate analysis identified both the number of positive nodes (0, 1, or a parts per thousand yen2; P = 0.005) and the LNR (0, 0-5, or &gt; 5 %; P = 0.007) as significant prognostic factors. Multivariate analysis identified the number of positive nodes but not the LNR as an independent prognostic factor (P = 0.012). The 5-year survival rates were 64 % for the patients with no positive nodes, 46 % for the patients with one positive node, and 28 % for the patients with two or more positive nodes.
    The number of positive lymph nodes predicts survival better than the LNR after resection of extrahepatic cholangiocarcinoma, provided that nodal evaluation is sufficient.

    DOI: 10.1245/s10434-015-4609-x

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  • Prognostic significance of NQO1 expression in esophageal squamous cell carcinoma after preoperative chemotherapy with cisplatin and 5-fluorouracil followed by curative esophagectomy Reviewed

    Hiroshi Ichikawa, Shin-ichi Kosugi, Yuki Hirose, Yasunobu Matsuda, Takashi Ishikawa, Takaaki Hanyu, Kenji Usui, Yusuke Muneoka, Masayuki Nagahashi, Jun Sakata, Takashi Kobayashi, Hitoshi Kameyama, Toshifumi Wakai

    INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY   9 ( 7 )   7393 - 7401   2016

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:E-CENTURY PUBLISHING CORP  

    NAD(P) H:quinone oxidoreductase-1 (NQO1) confers resistance to anticancer agents, particularly to oxidative stress inducers such as cisplatin or 5-fluorouracil in malignant tumors. Here we evaluated the association between NQO1 expression in esophageal squamous cell carcinoma (ESCC) cells and the patients' responses to preoperative chemotherapy with cisplatin and 5-fluorouracil (CF), and we elucidated the prognostic significance of NQO1 expression in ESCC patients. We retrospectively analyzed the cases of 40 patients who underwent preoperative CF therapy followed by curative esophagectomy with lymphadenectomy. Immunohistochemistry of the surgically resected specimens was conducted using the primary monoclonal antibody against NQO1. Eighteen of the 40 patients (45%) had tumors that showed high NQO1 expression (NQO1-high group). The poorer histological response to preoperative CF therapy was dominant in the NQO1-high group compared to the NQO1-low group (72% and 45%, respectively) but the difference was not significant (P=0.09). The 3-year recurrence-free survival rate after esophagectomy in the NQO1-high group was significantly lower compared to the NQO1-low group (39% vs. 76%; P&lt;0.01). A Cox proportional hazards model revealed that high NQO1 expression was an independent unfavorable prognostic factor (HR=3.53; P=0.02) as was pN3 (HR=14.7; P&lt;0.01). The immunohistochemical evaluation of NQO1 expression has potential to predict the treatment response and prognosis in patients who undergo preoperative CF therapy followed by esophagectomy for ESCC.

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  • Clinical significance of MED12 expression in colorectal cancer Reviewed

    Yoshifumi Shimada, Yosuke Tajima, Hitoshi Kameyama, Ryoma Yagi, Takuma Okamura, Yuki Hirose, Jun Sakata, Takashi Kobayashi, Yasunobu Matsuda, Yoichi Ajioka, Shin-ichi Kosugi, Toshifumi Wakai

    INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY   9 ( 7 )   6937 - 6944   2016

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:E-CENTURY PUBLISHING CORP  

    MED12 is a transcriptional mediator complex subunit, which negatively regulates the transforming growth factor beta (TGF-beta) pathway. The TGF-beta pathway plays a major role in the induction of epithelial-mesenchymal transition 9EMT). MED12 loss induces activation of the TGF-beta pathway, resulting in EMT and drug resistance to epidermal growth factor receptor (EGFR)-targeted therapy. We aimed to investigate the clinical significance of MED12 loss detected by immunohistochemistry in patients with colorectal cancer (CRC). A total of 100 patients diagnosed with stage I-IV CRC were enrolled in this retrospective study. MED12 expression was evaluated immunohistochemically, and classified as either positive (&gt;= 20%) or negative (&lt;20%) with regard to the percentage of immunoreactive cells. The relationships between MED12 loss and clinicopathological characteristics and RAS mutation status were analyzed. Overall, 79 and 21 patients were classified as MED12 positive and MED12 negative, respectively. MED12 negativity was significantly associated with tumor budding (P = 0.034), N category (P = 0.010), and M category (P = 0.031). Among stage IV CRC patients, 18 of 31 patients had the RAS wild-type gene; 6 of these patients were MED12 negative, and were considered to have the potential for resistance to EGFR-targeted therapy despite the presence of the wild-type gene. In conclusion, MED12 loss is associated with tumor budding, nodal metastasis, and distant metastasis in patients with CRC, suggesting that MED12 loss induces activation of the TGF-beta pathway resulting in EMT. Future treatment strategies focusing on patients MED12 loss may improve the prognosis of patients with CRC.

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  • Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy. Reviewed International journal

    Shogo Ohkoshi, Masahiko Yano, Yasunobu Matsuda

    World journal of gastroenterology   21 ( 42 )   12150 - 6   2015.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:BAISHIDENG PUBLISHING GROUP INC  

    A well-known tumor suppressor, p21, acts paradoxically by promoting tumor growth in some cellular conditions. These conflicting functions have been demonstrated in association with the HBx gene and in hepatocarcinogenesis. The molecular behavior of p21 depends on its subcellular localization. Nuclear p21 may inhibit cell proliferation and be proapoptotic, while cytoplasmic p21 may have oncogenic and anti-apoptotic functions. Because most typical tumor suppressive proteins also have different effects according to subcellular localization, elucidating the regulatory mechanisms underlying nucleo-cytoplasmic transport of these proteins would be significant and may lead to a new strategy for anti-hepatocellular carcinoma (HCC) therapy. Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor involved in transport of tumor suppressors from nucleus to cytoplasm. Expression of CRM1 is enhanced in a variety of malignancies and in vitro studies have shown the efficacy of specific inhibition of CRM1 against cancer cell lines. Interestingly, interferon may keep p21 in the nucleus; this is one of the mechanisms of its anti-hepatocarcinogenic function. Here we review the oncogenic property of p21, which depends on its subcellular localization, and discuss the rationale underlying a new strategy for HCC treatment and prevention.

    DOI: 10.3748/wjg.v21.i42.12150

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  • Increase of fucosylated alpha-fetoprotein fraction at the onset of autoimmune hepatitis and acute liver failure. Reviewed International journal

    Satoshi Yamagiwa, Yasushi Tamura, Masaaki Takamura, Takuya Genda, Takafumi Ichida, Toru Ishikawa, Tomoteru Kamimura, Toru Takahashi, Takeshi Suda, Yasunobu Matsuda, Minoru Nomoto, Yutaka Aoyagi

    Hepatology research : the official journal of the Japan Society of Hepatology   44 ( 14 )   E368-75 - E375   2014.12

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    AimIncreased serum -fetoprotein (AFP) has been associated with a good prognosis following acute liver failure (ALF), but the levels of the fucosylated fraction of AFP (Lens culinaris agglutinin-reactive fraction of AFP [AFP-L3]) following acute liver injury remain unknown. The aim of the present study was to investigate the clinical significance of AFP and AFP-L3 in patients with acute liver injury.
    MethodsWe investigated the serum levels of AFP and highly sensitive AFP-L3% in 27 patients with acute-onset autoimmune hepatitis (AIH), 28 patients with acute hepatitis (AH) and 22 patients with ALF at the onset using a highly sensitive immunoassay (micro-total analysis system).
    ResultsThe serum AFP levels were increased in patients with AIH, AH and ALF, but the levels did not significantly differ among them. However, the mean AFP-L3% level was significantly higher in patients with AIH than in patients with AH (P=0.0039). Moreover, significantly more patients with AIH demonstrated AFP-L3 positivity (10%) when compared with patients with AH (P=0.014). Although the percentage of AFP-L3 positivity increased with AFP levels, at low serum AFP levels (&lt;10ng/mL), significantly more patients with AIH demonstrated AFP-L3 positivity than did patients with AH (P=0.024) or ALF (P=0.038).
    ConclusionWe demonstrated for the first time that highly sensitive AFP-L3% levels were increased at the onset of AIH. The mechanism underlying the increase in AFP-L3 remains to be elucidated, but this finding may reflect an alteration of the glycosylation such as hyperfucosylation, which can influence the modifications of self-antigens in hepatocytes.

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  • Imbalance between CD56+bright and CD56+dim natural killer cell subsets in the liver of patients with recurrent hepatitis C after liver transplantation. Reviewed

    Satoshi Yamagiwa, Yoshinobu Sato, Takafumi Ichida, Toru Setsu, Kentaro Tominaga, Hiroteru Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Yasunobu Matsuda, Yutaka Aoyagi

    Biomedical research (Tokyo, Japan)   35 ( 3 )   177 - 84   2014.6

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    Progressive liver fibrosis remains a major problem for patients with recurrent chronic hepatitis C (CHC) after liver transplantation (LT). However, the involvement of natural killer (NK) and natural killer T (NKT) cells, which predominate in the liver, in recurrent CHC after LT remains unclear. In the present study, we investigated the status of NK and NKT cells in the liver and peripheral blood obtained from 10 patients with recurrent CHC after LT (LT-C), 15 patients with CHC, and 7 normal donors for living donor LT. CD56(+) NK cells were separated into two subsets: CD56(+bright) subset, which is identified as major NK cytokine producer, and CD56(+dim) subset, which has greater spontaneous cytotoxicity. We found a significant decrease in the CD56(+bright) subset in the liver of patients with LT-C compared to patients with CHC (P &lt; 0.01) and normal donors (P = 0.03). The expression of inhibitory NK cell receptor NKG2A was significantly increased on intrahepatic CD56(+bright) subset in LT-C patients, and activated CD69(+)CD56(+dim) NK cell subset was significantly increased. in the liver of LT-C patients. Our results suggest that a significant imbalance between CD56(+bright) and CD56(+dim) NK cell subsets in the liver may contribute to the progression of recurrent CHC after LT.

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  • Valproic acid overcomes transforming growth factor-β-mediated sorafenib resistance in hepatocellular carcinoma. Reviewed International journal

    Yasunobu Matsuda, Toshifumi Wakai, Masayuki Kubota, Mami Osawa, Yuki Hirose, Jun Sakata, Takashi Kobayashi, Shun Fujimaki, Masaaki Takamura, Satoshi Yamagiwa, Yutaka Aoyagi

    International journal of clinical and experimental pathology   7 ( 4 )   1299 - 313   2014

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    Sorafenib is a multi-kinase inhibitor approved for hepatocellular carcinoma, but rarely causes tumor regression in patients with chronic liver diseases. To investigate whether growth factor-mediated signaling is involved in sorafenib resistance, HepG2 and PLC/PRF/5 hepatoma cells were exposed to epidermal growth factor (EGF), hepatocyte growth factor (HGF) or transforming growth factor-beta (TGF-beta) prior to treatment with sorafenib. Furthermore, to identify an effective combination treatment with sorafenib, growth factor-sensitized cells were treated with sorafenib alone or in combination with celecoxib, lovastatin or valproic acid (VPA). Trypan blue staining and Annexin V assays showed that the cytotoxic effect of sorafenib was inhibited by 15-54% in cells sensitized to TGF-beta (P&lt;0.05). Western blotting analysis showed that TGF-beta significantly activated extracellular signal-regulated kinase (ERK)-mediated AKT signaling, and sorafenib failed to suppress both ERK and AKT in TGF-beta-sensitized cells. The decreased anti-tumor effect of sorafenib was rescued by chemical inhibition of ERK and AKT. When TGF-beta-sensitized cells were treated with sorafenib plus VPA, the levels of phosphorylated ERK and AKT were considerably suppressed and the numbers of dead cells were increased by 3.7-5.7-fold compared with those exposed to sorafenib alone (P&lt;0.05). Moreover, low dose sorafenib-induced cell migration was effectively suppressed by combination treatment with sorafenib and VPA. Collectively, TGF-beta/ERK/AKT signaling might play a critical role in sorafenib resistance in hepatoma cells, and combination treatment with VPA may be effective against this drug resistance.

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  • Hepatitis B virus X stimulates redox signaling through activation of ataxia telangiectasia mutated kinase. Reviewed International journal

    Yasunobu Matsuda, Ayumi Sanpei, Toshifumi Wakai, Masayuki Kubota, Mami Osawa, Yuki Hirose, Jun Sakata, Takashi Kobayashi, Shun Fujimaki, Masaaki Takamura, Satoshi Yamagiwa, Masahiko Yano, Shogo Ohkoshi, Yutaka Aoyagi

    International journal of clinical and experimental pathology   7 ( 5 )   2032 - 43   2014

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    Hepatitis B virus X (HBX) protein plays a crucial role in carcinogenesis, but its mechanism is unclear. The involvement of ataxia telangiectasia mutated (ATM) kinase in the enhanced redox system was investigated by examining the phosphorylation level of ATM in HBX gene-transfected cells and in transgenic mice following redox system manipulation by treatment with hydrogen peroxide (H2O2) or antioxidant. Western blotting and immunostaining showed that phospho-ATM was significantly increased by HBX both in vitro (3.2-fold; p&lt;0.05) and in vivo (4-fold; p&lt;0.05), and this effect was abrogated by antioxidant treatment. The level of PKC-delta in HBX-expressing cells was increased 3.5-fold compared to controls. Nuclear localized NF-E2-related factor 2 (Nrf2) was increased in HBX-expressing cells exposed to H2O2, but remained at lower levels after the treatment with rottlerin, KU55933, or caffeine. The levels of anti-oxidant molecules were increased in HBX expressing cells and in transgenic mice, indicating that HBX stimulates the Nrf2-mediated redox system. The levels of intracellular reactive oxygen species (ROS) were significantly increased in HBX-expressing cells treated with hydrogen peroxide in the presence of ATM inhibitor KU55933 or caffeine. Treatment of HBX-expressing cells with KU55933 or caffeine before the exposure to H2O2 increased the ratio of cell apoptosis to 33 +/- 4% (p&lt;0.05) and 22 +/- 4% (p&lt;0.05), respectively. Collectively, HBX stimulates the ATM-mediated PKC-delta/Nrf2 pathway, and maintains the enhanced activity of the redox system. Therefore, manipulating ATM kinase activity might be a useful strategy for treating HBX-induced carcinogenesis.

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  • Sphingosine-1-phosphate transporters as targets for cancer therapy. Reviewed International journal

    Masayuki Nagahashi, Kazuaki Takabe, Krista P Terracina, Daiki Soma, Yuki Hirose, Takashi Kobayashi, Yasunobu Matsuda, Toshifumi Wakai

    BioMed research international   2014   651727 - 651727   2014

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    Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival, migration, the recruitment of immune cells, angiogenesis, and lymphangiogenesis, all of which are involved in cancer progression. S1P is generated inside cancer cells by sphingosine kinases then exported outside of the cell into the tumor microenvironment where it binds to any of five G protein coupled receptors and proceeds to regulate a variety of functions. We have recently reported on the mechanisms underlying the "inside-out" signaling of S1P, its export through the plasma membrane, and its interaction with cell surface receptors. Membrane lipids, including S1P, do not spontaneously exchange through lipid bilayers since the polar head groups do not readily go through the hydrophobic interior of the plasma membrane. Instead, specific transporter proteins exist on the membrane to exchange these lipids. This review summarizes what is known regarding S1P transport through the cell membrane via ATP-binding cassette transporters and the spinster 2 transporter and discusses the roles for these transporters in cancer and in the tumor microenvironment. Based on our research and the emerging understanding of the role of S1P signaling in cancer and in the tumor microenvironment, S1P transporters and S1P signaling hold promise as new therapeutic targets for cancer drug development.

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  • Alcoholic liver disease complicated by deep bleeding into the muscles or retroperitoneum: report of three cases and a review of the literature. Reviewed

    Masaaki Takamura, Jun Watanabe, Akira Sakamaki, Yutaka Honda, Kenya Kamimura, Atsunori Tsuchiya, Satoshi Yamagiwa, Takeshi Suda, Yasunobu Matsuda, Yutaka Aoyagi

    Internal medicine (Tokyo, Japan)   53 ( 16 )   1763 - 8   2014

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    We herein report three cases of alcoholic cirrhosis complicated by deep bleeding. In two of the three cases, intramuscular or retroperitoneal hematomas developed spontaneously. In contrast, in the remaining case, an intramuscular hematoma developed after trauma. In the former two patients, the intramuscular hematomas recurred at other sites during hospitalization. All three patients received conservative therapy, and one patient with a retroperitoneal hematoma underwent transcatheter arterial embolization. All of the patients eventually died of liver failure. The occurrence of severe alcoholic liver disease with deep bleeding has recently been reported with increasing frequency, and clinicians should bear this condition in mind as a life-threatening complication of alcoholic liver disease.

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  • Effects of rapamycin on granulation formation in response to centrally doubled coiled stents as a tracheal substitute. Reviewed International journal

    Masayuki Kubota, Yasunobu Matsuda, Shun Fujimaki, Mami Osawa, Toshifumi Wakai, Kengo Nakaya

    Journal of pediatric surgery   48 ( 12 )   2416 - 24   2013.12

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    Introduction: In experiments involving tracheal wall defects in rabbits, metallic coil stents inevitably induce granulation formation in the defects. We examined the involvement of the mammalian target of rapamycin (mTOR) signaling pathway in granulation formation and examined the effects of rapamycin. Methods: The anterior half of the tracheal wall was removed for a longitudinal length of six tracheal rings. Metallic coils were placed into the tracheal lumen through a wall defect. The rabbits were sacrificed two months after undergoing an endoscopic examination, and the granulation tissue in the tracheal defects was removed for a Western blot analysis and immunohistochemical analysis. Rapamycin (0.5 mg kg- 1 day- 1) was administered three times per week intramuscularly. The data were expressed as the relative expression versus the expression of actin. Results: The level of mTOR phosphorylation in the resected trachea was 0.72 ± 0.45, and it significantly increased in the granulation tissue to 11.6 ± 5.2, with concomitant increases in the phosphorylation levels of p70S6K and S6RP in all five rabbits. Although the systemic administration of rapamycin significantly decreased the levels of phosphorylated mTOR to 4.0 ± 2.4 in the five treated rabbits, the clinical outcomes were unsatisfactory. Three of the five treated rabbits exhibited signs of wound complications, and wet granulation tissue that caused respiratory symptoms was found inside and outside of the coils in four rabbits. Conclusions: Although rapamycin effectively reduced the mTOR activity in the granulation tissue, the granulation formation process seemed to be disturbed, most likely owing to the immunosuppressive effects of rapamycin. © 2013 Elsevier Inc. All rights reserved.

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  • Clinical significance of cell cycle inhibitors in hepatocellular carcinoma. Reviewed

    Yasunobu Matsuda, Toshifumi Wakai, Masayuki Kubota, Masaaki Takamura, Satoshi Yamagiwa, Yutaka Aoyagi, Mami Osawa, Shun Fujimaki, Ayumi Sanpei, Takuya Genda, Takafumi Ichida

    Medical molecular morphology   46 ( 4 )   185 - 92   2013.12

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    It is well accepted that cell cycle regulators are strongly implicated in the progression of cancer development. p16 and p27 are potent cyclin-dependent kinase (CDK) inhibitors involved in G1 phase progression, and are regarded as adverse prognostic biomarkers for various types of cancers. It has been reported that the main mechanism for p16 inactivation is aberrant DNA methylation, while p27 is exclusively inactivated by proteasome-mediated protein degradation. We have found that p27 is decreased in around half of hepatocellular carcinomas (HCCs), and in some cases p27 is inactivated by inappropriate interaction with cyclin D1/CDK4 complexes. In such cases, p16 is concomitantly inactivated through DNA methylation. Taking into consideration the complex interaction between p16 and p27, a comprehensive analysis including p16 and p27 would be useful for predicting the prognosis of HCC patients. © 2013 The Japanese Society for Clinical Molecular Morphology.

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  • p27 Is a critical prognostic biomarker in non-alcoholic steatohepatitis-related hepatocellular carcinoma. Reviewed International journal

    Yasunobu Matsuda, Toshifumi Wakai, Yuki Hirose, Mami Osawa, Shun Fujimaki, Masayuki Kubota

    International journal of molecular sciences   14 ( 12 )   23499 - 515   2013.11

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    Non-alcoholic steatohepatitis (NASH) is a recently identified chronic liver disease, which progresses to liver cirrhosis and hepatocellular carcinoma (HCC). As the number of patients studied to date has been limited, clinically useful prognostic biomarkers of NASH-related HCC have not been available. In this study, we investigated the status of a cell-cycle regulator, p27, in NASH-related HCC. p27 has been regarded as a prognostic factor in various types of cancer patients. A total of 22 cases with NASH-related HCC were analyzed for p27 protein expression, and phosphorylation at threonine 157 (T157) and serine 10 (S10) by immunohistochemical analysis. The correlation of p27 with tumor characteristics, disease-free survival (DFS), and overall survival was analyzed. p27 expression was decreased in 13 HCCs (59%), and was significantly correlated with enlarged tumor size (p = 0.01) and increased cell proliferation (p &lt; 0.01). Phospho-p27 at T157 and S10 was detected in four (18%) and seven (32%) cases, respectively, and patients positive for phospho-p27 (S10) showed reduced DFS (hazard ratio 7.623, p = 0.016) by univariate analysis. Further studies with more patients are required to verify the usefulness of p27 as a biomarker for predicting tumor recurrence in NASH patients.

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  • Hepatitis B virus X induces cell proliferation in the hepatocarcinogenesis via up-regulation of cytoplasmic p21 expression Reviewed

    Masahiko Yano, Shogo Ohkoshi, Yo-Hei Aoki, Hiromichi Takahashi, Sou Kurita, Kazuhide Yamazaki, Kenta Suzuki, Satoshi Yamagiwa, Ayumi Sanpei, Shun Fujimaki, Toshifumi Wakai, Shin-Ei Kudo, Yasunobu Matsuda, Yutaka Aoyagi

    Liver International   33 ( 8 )   1218 - 1229   2013.9

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    Background: Hepatitis B virus X protein (HBx) has been shown to induce hepatocarcinogenesis by disrupting the functions of intracellular molecules. Cyclin-dependent kinase inhibitor p21 (Cip1/WAF1), known as a tumour-suppressor gene, has been reported to have paradoxical function, that is, acting as an oncogene, particularly when expressed in the cytoplasm. The effects of HBx on the expression and function of p21 also remain controversial. Aims: We attempted to investigate the role of HBx in the hepatocarcinogenic process, focusing on the association with this paradoxical function of p21. The results obtained were further verified with experiments using the antihepatocarcinogenic action of interferon (IFN)-β. Methods: HBx transgenic mice (Xg) and HBx-transfected hepatoma cell lines were used. Intracellular localization of p21 was determined by Western blot analysis and immunofluorescence. Results: Xg and HBx-transfected cells exhibited increased expression of p21. Up-regulation of p21 was positively correlated with the expression of cyclin D1 and inactive phosphorylation of retinoblastoma protein (pRb). These HBx-induced cell proliferative responses were cancelled by knockdown of p21, which resulted in growth reduction in HBx-expressing cells, suggesting the oncogenic properties of HBx-induced p21. HBx induced accumulation of p21 in the cytoplasm, and activation of PKCα was involved. Finally, IFN-β-treated Xg liver, as well as hepatoma cells, showed a shift of cytoplasmic p21 to the nucleus, accompanied by the abrogation of HBx-induced oncogenic modulation. Conclusions: Our results suggest that HBx induces hepatocarcinogenesis via PKCα-mediated overexpression of cytoplasmic p21 and IFN-β suppressed these molecular events by shifting p21 to the nucleus. © 2013 John Wiley &amp
    Sons A/S. Published by John Wiley &amp
    Sons Ltd.

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  • Mycotoxins are conventional and novel risk biomarkers for hepatocellular carcinoma. Reviewed International journal

    Yasunobu Matsuda, Toshifumi Wakai, Masayuki Kubota, Mami Osawa, Ayumi Sanpei, Shun Fujimaki

    World journal of gastroenterology   19 ( 17 )   2587 - 90   2013.5

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    Hepatocellular carcinoma (HCC) is a common malignant disease with poor prognosis. To improve the clinical outcome, early diagnosis of HCC arising from nonviral agents and hepatitis virus is important. Among several etiological factors, mycotoxins defined as carcinogens by the International Agency for Research in Cancer (IARC) might be one of the critical risk factors for nonviral HCC. Afatoxin B1 is the most well-known carcinogenic mycotoxin for HCC, but the role of the other types of mycotoxin remains unclear. Several studies have reported that a chromatographic separation technique based on high-performance liquid chromatography can successfully detect the concentration of mycotoxins in plasma. Recently, serum level of ochra-toxin A (OTA), a widely distributed mycotoxin classified as Group 2B by IARC, was evaluated in HCC patients in Egypt. The results suggested that serum OTA levels might be a good biomarker for HCC. In this article, we review recent studies of OTA, and discuss its possible significance as a biomarker of HCC. © 2013 Baishideng. All rights reserved.

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  • Involvement of liver-intestine cadherin in cancer progression. Reviewed

    Takamura M, Yamagiwa S, Matsuda Y, Ichida T, Aoyagi Y

    Medical Molecular Morphology   46 ( 1 )   1 - 7   2013.3

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  • Risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts Reviewed

    Taku Ohashi, Toshifumi Wakai, Masayuki Kubota, Yasunobu Matsuda, Yuhki Arai, Toshiyuki Ohyama, Kengo Nakaya, Naoki Okuyama, Jun Sakata, Yoshio Shirai, Yoichi Ajioka

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   28 ( 2 )   243 - 247   2013.2

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    Background and Aim The aim of this study was to elucidate the risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts. Methods A retrospective analysis of 94 patients who had undergone cyst excision for congenital choledochal cysts was conducted. The median age at the time of cyst excision and median follow-up time after cyst excision were 7 years and 181 months, respectively. Results Biliary tract cancer developed in four patients at 13, 15, 23, and 32 years after cyst excision. The cumulative incidences of biliary tract cancer at 15, 20, and 25 years after cyst excision were 1.6%, 3.9%, and 11.3%, respectively. The sites of biliary tract cancer were the intrahepatic (n?=?2), hilar (n?=?1), and intrapancreatic (n?=?1) bile ducts. Of the four patients with biliary tract cancer after cyst excision, three patients underwent surgical resection and one patient received chemo-radiotherapy. The overall cumulative survival rates after treatment in the four patients with biliary tract cancer were 50% at 2 years and 25% at 3 years, with a median survival time of 15 months. Conclusions The risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts seems to be relatively high in the long-term. The risk of biliary malignancy in the remnant bile duct increases more than 15 years after cyst excision. Despite an aggressive treatment approach for this condition, subsequent biliary malignancy following cyst excision for congenital choledochal cysts shows an unfavorable outcome.

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  • Risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts Reviewed

    Taku Ohashi, Toshifumi Wakai, Masayuki Kubota, Yasunobu Matsuda, Yuhki Arai, Toshiyuki Ohyama, Kengo Nakaya, Naoki Okuyama, Jun Sakata, Yoshio Shirai, Yoichi Ajioka

    Journal of Gastroenterology and Hepatology (Australia)   28 ( 2 )   243 - 247   2013

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    Background and Aim: The aim of this study was to elucidate the risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts. Methods: A retrospective analysis of 94 patients who had undergone cyst excision for congenital choledochal cysts was conducted. The median age at the time of cyst excision and median follow-up time after cyst excision were 7 years and 181 months, respectively. Results: Biliary tract cancer developed in four patients at 13, 15, 23, and 32 years after cyst excision. The cumulative incidences of biliary tract cancer at 15, 20, and 25 years after cyst excision were 1.6%, 3.9%, and 11.3%, respectively. The sites of biliary tract cancer were the intrahepatic (n=2), hilar (n=1), and intrapancreatic (n=1) bile ducts. Of the four patients with biliary tract cancer after cyst excision, three patients underwent surgical resection and one patient received chemo-radiotherapy. The overall cumulative survival rates after treatment in the four patients with biliary tract cancer were 50% at 2 years and 25% at 3 years, with a median survival time of 15 months. Conclusions: The risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts seems to be relatively high in the long-term. The risk of biliary malignancy in the remnant bile duct increases more than 15 years after cyst excision. Despite an aggressive treatment approach for this condition, subsequent biliary malignancy following cyst excision for congenital choledochal cysts shows an unfavorable outcome. © 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

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  • Involvement of liver-intestine cadherin in cancer progression Reviewed

    Masaaki Takamura, Satoshi Yamagiwa, Yasunobu Matsuda, Takafumi Ichida, Yutaka Aoyagi

    Medical Molecular Morphology   46 ( 1 )   1 - 7   2013

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    Cadherins constitute a superfamily of Ca2+-dependent cell adhesion molecules that play critical roles in the maintenance of tissue structure and morphogenesis. Their dysregulation is commonly observed in a variety of cancers. Liver-intestine cadherin (LI-cadherin), which was so named in view of its sole expression in the liver and intestine of the rat, is a structurally unique member of the cadherin superfamily, possessing seven cadherin repeats within the extracellular cadherin domain and only 25 amino acids in the cytoplasmic domain. Its adhesive property does not require any interaction with cytoplasmic components such as catenins, and it responds to small changes in extracellular Ca2+ below the physiological plasma concentration. In humans, the distribution of LI-cadherin is limited to the duodenum, jejunum, ileum, colon, and part of the pancreatic duct. Data accumulated from studies of the biological characteristics of LI-cadherin have shown that it plays an important role in the pathophysiology of human cancers. Here, we review recent information about LI-cadherin and its implications for cancer progression. © 2012 The Japanese Society for Clinical Molecular Morphology.

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  • p21-activated kinase-2 is a critical mediator of transforming growth factor-β-induced hepatoma cell migration Reviewed

    Munehiro Sato, Yasunobu Matsuda, Toshifumi Wakai, Masayuki Kubota, Mami Osawa, Shun Fujimaki, Ayumi Sanpei, Masaaki Takamura, Satoshi Yamagiwa, Yutaka Aoyagi

    Journal of Gastroenterology and Hepatology (Australia)   28 ( 6 )   1047 - 1055   2013

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    Background and Aim: Transforming growth factor-β (TGF-β) has been shown to play a central role in the promotion of cell motility, but its functional mechanism has remained unclear. With the aim of investigating the diagnostic and treatment modalities for patients with hepatocellular carcinoma (HCC), the signaling pathway that may contribute to TGF-β-mediated cell invasion in hepatoma cells was evaluated. Methods: Three hepatoma cell lines, HepG2, PLC/PRF/5, and HLF, were treated with TGF-β, and the involvement of the non-canonical TGF-β pathway was analyzed by cell migration assays. HepG2 cells were treated with a p21-activated kinase-2 (PAK2)-targeting small interfering RNA and analyzed for their cell motility. The relationships between the PAK2 status and the clinicopathological characteristics of 62 HCC patients were also analyzed. Results: The cell migration assays showed that Akt is a critical regulator of TGF-β-mediated cell migration. Western blotting analyses showed that TGF-β stimulated Akt and PAK2 in all three hepatoma cell lines, and phosphorylated PAK2 was blocked by Akt inhibitor. Suppression of PAK2 expression by small interfering RNA resulted in increased focal adhesions with significantly repressed cell migration in the presence of TGF-β. Clinicopathological analyses showed that the phosphorylation level of PAK2 was closely associated with tumor progression, metastasis, and early recurrence of HCC. Conclusions: PAK2 may be a critical mediator of TGF-β-mediated hepatoma cell migration, and may represent a potential target for the treatment of HCC. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

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  • DNA damage sensor γ-H2AX is increased in preneoplastic lesions of hepatocellular carcinoma Reviewed

    Yasunobu Matsuda, Toshifumi Wakai, Masayuki Kubota, Mami Osawa, Masaaki Takamura, Satoshi Yamagiwa, Yutaka Aoyagi, Ayumi Sanpei, Shun Fujimaki

    The Scientific World Journal   2013   597095 - 597095   2013

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    Background. Phosphorylated histone H2AX (γ-H2AX) is a potential regulator of DNA repair and is a useful tool for detecting DNA damage. To evaluate the clinical usefulness of γ-H2AX in hepatocellular carcinoma (HCC), we measured the level of γ-H2AX in HCC, dysplastic nodule, and nontumorous liver diseases. Methods. The level of γ-H2AX was measured by immunohistochemistry in fifty-eight HCC, 18 chronic hepatitis, 22 liver cirrhosis, and 19 dysplastic nodules. Appropriate cases were also examined by fluorescence analysis and western blotting. Results. All cases with chronic liver disease showed increased levels of γ-H2AX expression. In 40 (69.9%) of 58 cases with HCC, the labeling index (LI) of γ-H2AX was above 50% and was inversely correlated with the histological grade. Mean γ-H2AX LI was the highest in dysplastic nodule (74.1 ± 22.1 %), which was significantly higher than HCC (P &lt
    0.005). Moreover, γ-H2AX was significantly increased in nontumorous tissues of HCC as compared with liver cirrhosis without HCC (62.5 ± 24.7 %, from 5.1 to 96.0%, P &lt
    0.005). Conclusions. γ-H2AX was increased in the preneoplastic lesions of HCC and might be a useful biomarker for predicting the risk of HCC. © 2013 Yasunobu Matsuda et al.

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  • Blockade of ataxia telangiectasia mutated sensitizes hepatoma cell lines to sorafenib by interfering with Akt signaling Reviewed

    Shun Fujimaki, Yasunobu Matsuda, Toshifumi Wakai, Ayumi Sanpei, Masayuki Kubota, Masaaki Takamura, Satoshi Yamagiwa, Masahiko Yano, Shogo Ohkoshi, Yutaka Aoyagi

    Cancer Letters   319 ( 1 )   98 - 108   2012.6

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    Sorafenib is a multi-kinase inhibitor applicable to hepatocellular carcinoma (HCC), but its limited therapeutic effects are a major problem to be solved. Here, we show that blockade of ataxia telangiectasia mutated (ATM) improves the antitumor effects of sorafenib. When hepatoma cell lines HepG2 and PLC/PRF/5 were treated with sorafenib plus ATM small inhibitory RNAs, ATM inhibitor KU55933 or caffeine, Akt signaling was suppressed and the cytotoxic effects were significantly potentiated. Moreover, ATM inhibition effectively suppressed the sorafenib-induced cell migration. Taken together, manipulation of ATM activity might be a useful strategy for improving sorafenib treatment of HCC. © 2012 Elsevier Ireland Ltd.

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  • Plasma cells and the chronic nonsuppurative destructive cholangitis of primary biliary cirrhosis Reviewed

    Toru Takahashi, Tomofumi Miura, Junichiro Nakamura, Satoshi Yamada, Tsutomu Miura, Masahiko Yanagi, Yasunobu Matsuda, Hiroyuki Usuda, Iwao Emura, Koichi Tsuneyama, Xiao-Song He, M. Eric Gershwin

    Hepatology   55 ( 3 )   846 - 855   2012.3

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    There has been increased interest in the role of B cells in the pathogenesis of primary biliary cirrhosis (PBC). Although the vast majority of patients with this disease have anti-mitochondrial antibodies, there is no correlation of anti-mitochondrial antibody titer and/or presence with disease severity. Furthermore, in murine models of PBC, it has been suggested that depletion of B cells may exacerbate biliary pathology. To address this issue, we focused on a detailed phenotypic characterization of mononuclear cell infiltrates surrounding the intrahepatic bile ducts of patients with PBC, primary sclerosing cholangitis, autoimmune hepatitis, chronic hepatitis C, and graft-versus-host disease, including CD3, CD4, CD8, CD20, CD38, and immunoglobulin classes, as well as double immunohistochemical staining for CD38 and IgM. Interestingly, CD20 B lymphocytes, which are a precursor of plasma cells, were found in scattered locations or occasionally forming follicle-like aggregations but were not noted at the proximal location of chronic nonsuppurative destructive cholangitis. In contrast, there was a unique and distinct coronal arrangement of CD38 cells around the intrahepatic ducts in PBC but not controls
    the majority of such cells were considered plasma cells based on their expression of intracellular immunoglobulins, including IgM and IgG, but not IgA. Patients with PBC who manifest this unique coronal arrangement were those with significantly higher titers of anti-mitochondrial antibodies. Conclusion: These data collectively suggest a role for plasma cells in the specific destruction of intrahepatic bile ducts in PBC and confirm the increasing interest in plasma cells and autoimmunity. (HEPATOLOGY 2012) © 2011 American Association for the Study of Liver Diseases.

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  • Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence. Invited

    Kamimura Hiroteru, Yamagiwa Satoshi, Tsuchiya Atsunori, Takamura Masaaki, Matsuda Yasunobu, Ohkoshi Shogo, Inoue Makoto, Wakai Toshifumi, Shirai Yoshio, Nomoto Minoru, Aoyagi Yutaka

    J Hepatol   56 ( 2 )   381 - 388   2012.2

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    BACKGROUND &amp; AIMS: The activating receptor natural killer group 2, member D (NKG2D) and its ligands play a crucial role in immune response to tumors. NKG2D ligand expression in tumors has been shown to be associated with tumor eradication and superior patient survival, but the involvement of NKG2D ligands in the immune response against hepatocellular carcinoma (HCC) still remains to be elucidated. METHODS: We investigated the expression of NKG2D ligands in HCC tissues collected from 54 patients and HCC cell lines. We also examined the proteasome expression and the effect of inhibition of proteasome activity on NKG2D ligand expression in HCC tissues and cell lines. RESULTS: In dysplastic nodules (DN), well-differentiated (well-HCC), and moderately-differentiated HCCs (mod-HCC), UL16-binding protein (ULBP) 1 was expressed predominantly in tumor cells, but not in poorly-differentiated HCCs (poor-HCC). Remarkably, recurrence-free survival of patients with ULBP1-negative HCC was significantly shorter than that of patients with ULBP1-positive HCC (p=0.006). Cox regression analysis revealed that loss of ULBP1 expression was an independent predictor of early recurrence (p=0.008). We c

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  • Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence Reviewed

    Hiroteru Kamimura, Satoshi Yamagiwa, Atsunori Tsuchiya, Masaaki Takamura, Yasunobu Matsuda, Shogo Ohkoshi, Makoto Inoue, Toshifumi Wakai, Yoshio Shirai, Minoru Nomoto, Yutaka Aoyagi

    JOURNAL OF HEPATOLOGY   56 ( 2 )   381 - 388   2012.2

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    Background 82 Aims: The activating receptor natural killer group 2, member D (NKG2D) and its ligands play a crucial role in immune response to tumors. NKG2D ligand expression in tumors has been shown to be associated with tumor eradication and superior patient survival, but the involvement of NKG2D ligands in the immune response against hepatocellular carcinoma (HCC) still remains to be elucidated.
    Methods: We investigated the expression of NKG2D ligands in HCC tissues collected from 54 patients and HCC cell lines. We also examined the proteasome expression and the effect of inhibition of proteasome activity on NKG2D ligand expression in HCC tissues and cell lines.
    Results: In dysplastic nodules (DN), well-differentiated (well-HCC), and moderately-differentiated HCCs (mod-HCC), UL16-binding protein (ULBP) 1 was expressed predominantly in tumor cells, but not in poorly-differentiated HCCs (poor-HCC). Remarkably, recurrence-free survival of patients with ULBP1-negative HCC was significantly shorter than that of patients with ULBP1-positive HCC (p = 0.006). Cox regression analysis revealed that loss of ULBP1 expression was an independent predictor of early recurrence (p = 0.008). We confirmed that ULBP1 was expressed in the well- and mod-HCC cell lines, but not in the poor-HCC cell line KYN-2. However, inhibition of proteasome activity resulted in significant up-regulation of ULBP1 expression in KYN-2. Moreover, we found that 20S proteasome expression was more abundant in KYN-2 than that in the well- and mod-HCC cell lines.
    Conclusions: ULBP1 is prevalently expressed in DN to mod-HCC, but loss of its expression correlates with tumor progression and early recurrence. (C) 2011 European Association for the Study of the Liver. Published by Elsevier By. All rights reserved.

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  • Sorafenib: Complexities of Raf-dependent and Raf-independent signaling are now unveiled Reviewed

    Yasunobu Matsuda, Manabu Fukumoto

    Medical Molecular Morphology   44 ( 4 )   183 - 189   2011.12

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    Hepatocellular carcinoma (HCC) is the most common primary cancer worldwide. The only current drug available for clinical treatment of HCC is sorafenib, which inhibits multiple signaling kinases including Raf family members, platelet-derived growth factor receptor, vascular endothelial growth factor receptors 1 and 2, c-Kit, and Fms-like tyrosine kinase 3. Many studies have revealed that the mechanism underlying the antitumor effect of sorafenib is complex. Because sorafenib inhibits C-Raf more potently than B-Raf, the therapeutic efficacy of sorafenib is strongly influenced by the relative expression and activity of B-Raf and C-Raf and the complex interactions between these factors. Moreover, Rafindependent signaling mechanisms have recently emerged as important pathways of sorafenib-induced cell death. Basic research studies have suggested that using sorafenib as part of a combination therapy may improve its effect, although this has yet to be confirmed by clinical evidence. Further studies of the functional mechanism of sorafenib are required to advance the development of targeted therapy for HCC. To aid future work on sorafenib, we here review the current literature pertaining to sorafenib signaling and its clinical efficacy in both monotherapy and combination therapy. © The Japanese Society for Clinical Molecular Morphology 2011.

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  • REDUCED NKG2D LIGAND EXPRESSION IN HEPATOCELLULAR CARCINOMA CORRELATES WITH EARLY RECURRENCE Reviewed

    Satoshi Yamagiwa, Hiroteru Kamimura, Atsunori Tsuchiya, Masaaki Takamura, Yasunobu Matsuda, Yoshio Shirai, Yutaka Aoyagi

    HEPATOLOGY   54   1100A - 1101A   2011.10

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  • Ribonucleotide Reductase M1 Expression in Intrahepatic Cholangiocarcinoma Reviewed

    Toshifumi Wakai, Yoshio Shirai, Jun Sakata, Masaaki Takamura, Yasunobu Matsuda, Pavel V. Korita, Katsuki Muneoka, Masataka Sasaki, Yoichi Ajioka, Katsuyoshi Hatakeyama

    HEPATO-GASTROENTEROLOGY   58 ( 110 )   1659 - 1663   2011.9

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    Background/Aims: Ribonucleotide reductase M1 (RRM1) is a key molecule for gemcitabine resistance. This study evaluated the immunohistochemical expression of RRM1 in resected specimens of intrahepatic cholangiocarcinoma (ICC) and investigated the efficacy of gemcitabine-based neoadjuvant chemotherapy in relation to RRM1 expression in tumors.
    Methodology: A retrospective analysis was conducted on 34 consecutive Japanese patients who underwent resection of ICC. Of the 34 patients, 2 were treated with neoadjuvant chemotherapy consisting of gemcitabine 800mg/m(2) every 2 weeks to address extrahepatic tumor extension. Expression of RRM1 in tumor specimens was assessed using immunohistochemistry and was classified as either positive or negative.
    Results: RRM1-positive expression was detected in 19/34 (56%) tumor specimens. Two patients were treated with gemcitabine-based neoadjuvant chemotherapy; one had a tumor specimen showing RRM1-positive expression and showed a 14% tumor reduction rate (stable disease); another patient had a tumor showing RRM1-negative expression and showed a 68% tumor reduction rate (partial response). Surgical procedures planned before administration of neoadjuvant chemotherapy were performed in both patients.
    Conclusions: Neoadjuvant chemotherapy with gemcitabine for locally advanced ICC was well tolerated and did not impair planned surgical resections. Tumor expression of RRM1 may determine the efficacy of gemcitabine-based chemotherapy for patients with ICC.

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  • Hepatocellular carcinoma and liver transplantation: Clinical perspective on molecular targeted strategies Reviewed

    Yasunobu Matsuda, Takafumi Ichida, Manabu Fukumoto

    Medical Molecular Morphology   44 ( 3 )   117 - 124   2011.9

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    Hepatocellular carcinoma (HCC) has an aggressive clinical course with frequent recurrence and metastasis. Orthotopic liver transplantation has been the only curative tool for unresectable HCC
    therefore, recent advances in molecular targeted therapy may improve the prognosis of HCC. The multiple kinase inhibitor sorafenib and the macrolide antibiotic rapamycin are currently the most promising agents for treating unresectable HCC. A large population-based clinical trial revealed that sorafenib significantly prolonged the overall survival of HCC patients. However, subsequent clinical studies showed that sorafenib rarely reduced tumor volume and inadequately prolonged survival of patients with severe liver damage. To improve its therapeutic effect, the development of a predictive biomarker and a sorafenib-based combination is awaited. Another molecular targeting agent, rapamycin, has now been considered as a putative agent for preventing tumor recurrence in post-liver transplantation HCC patients, because it not only has immunosuppressive activity but also exerts an anti-tumor effect. In the near future, a combination of molecular targeting agents, such as sorafenib and rapamycin, may become a standard protocol for treating unresectable HCC. For specifying cases with more effective and less harmful modalities, further investigation in clinical and basic research to identify unexpected effects are needed. © The Japanese Society for Clinical Molecular Morphology 2011.

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  • Failure to Achieve 2-log(10) Viral Decrease in First Four Weeks of Peg-IFN alpha-2b Plus Ribavirin Therapy for Chronic Hepatitis C with Genotype 1b and High Viral Titer is Useful in Predicting Non-response: Evaluation of Response-guided Therapy Reviewed

    Shogo Ohkoshi, Satoshi Yamagiwa, Masahiko Yano, Hiromichi Takahashi, Yoh-hei Aoki, Nobuo Waguri, Kentaro Igarashi, Soh-ichi Sugitani, Tohru Takahashi, Tohru Ishikawa, Tomoteru Kamimura, Hiroto Wakabayashi, Toshiaki Watanabe, Yasunobu Matsuda, Yutaka Aoyagi

    HEPATO-GASTROENTEROLOGY   58 ( 107 )   965 - 970   2011.5

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    Background/Aims: To clarify clinical parameters predicting sustained viral response (SVR) during 48 weeks pegylated-interferon (peg-IFN)alpha-2b plus ribavirin therapy for Japanese patients with chronic hepatitis C [CH(C)] genotype 1b and high viral titers.
    Methodology: One hundred and fifty-one (151) patients receiving peg-IFN alpha-2b plus ribavirin therapy for 48 weeks were enrolled. SVR and clinical parameters were evaluated. The relationship between virological parameters (substitutions in the core and NS5A) and the degree of early viral decrease was also studied.
    Results: Seventy (46.4%) patients achieved SVR (per protocol analysis). Negative predictive value (NPV) of &lt;2-log(10), decrease after 4 weeks of therapy for SVR was 78.0%; similar to that for failing to achieve early viral response (EVR) at 12 weeks (82.2%).
    Conclusions: Failure to achieve 2-log(10)) decrease in the first 4 weeks may be an important predictor of non-SVR during 48 weeks of peg-IFN alpha-2b plus ribavirin therapy; thus, therapeutic plans should be reassessed at that point.

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  • Alteration of p53-binding protein 1 expression as a risk factor for local recurrence in patients undergoing resection for extrahepatic cholangiocarcinoma. International journal

    Toshifumi Wakai, Yoshio Shirai, Jun Sakata, Pavel V Korita, Yasunobu Matsuda, Masaaki Takamura, Riuko Ohashi, Masayuki Nagahashi, Yoichi Ajioka, Katsuyoshi Hatakeyama

    International journal of oncology   38 ( 5 )   1227 - 36   2011.5

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    P53-binding protein 1 (53BP1) is an early DNA damage response-protein that is rapidly recruited to sites of DNA double-strand breaks. The presence of 53BP1 nuclear foci can be considered as a cytologic marker for endogenous double-strand breaks reflecting genomic instability. This study aimed to clarify the early DNA damage response mediated by 53BP1 in tumor specimens of ductal resection margins and to elucidate its predictive value for clinically evident local recurrence at ductal stumps in 110 patients undergoing resection for extrahepatic cholangiocarcinoma. The ductal resection margin status was classified as negative (85 patients), positive with carcinoma in situ (14 patients), or positive with invasive carcinoma (11 patients). The nuclear staining pattern of 53BP1 was evaluated by immunofluorescence. TUNEL analysis was used to calculate apoptotic index. Ductal margin status was the only independent risk factor for local recurrence (P=0.001). The cumulative probability of local recurrence at 5 years was 10%, 40% and 100% in patients with negative ductal margins, positive with carcinoma in situ and positive with invasive carcinoma, respectively (P<0.001). Of the 14 tumor specimens of carcinoma in situ, 10 showed diffuse localization of 53BP1 in nuclei (53BP1 inactivation) and 4 showed discrete nuclear foci of 53BP1 (53BP1 activation). All 11 tumor specimens of invasive carcinoma showed 53BP1 inactivation. Apoptotic index was markedly decreased in tumor specimens with 53BP1 inactivation compared to those with 53BP1 activation (median index, 0% vs. 22%; P<0.001). Among 14 patients with residual carcinoma in situ, the cumulative probability of local recurrence was significantly higher in patients with 53BP1 inactivation than in patients with 53BP1 activation (60% vs. 0% at 5 years; P=0.020). In conclusion, after resection for extrahepatic cholangiocarcinoma, clinically evident local recurrence at ductal stumps is closely associated with 53BP1 inactivation and decreased apoptosis.

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  • A case with chronic hepatitis C who developed liver cirrhosis due to liver dysfunction caused by pegylated interferon plus ribavirin treatment despite negativity of serum HCV RNA, during therapy

    Shogo Ohkoshi, Shin-Ichi Morita, Yukari Tanaka, Masahiko Yano, Manabu Takeuchi, Hiromichi Takahashi, Haruo Ikeda, Satoshi Yamagiwa, Yasunobu Matsuda, Minoru Nomoto, Yutaka Aoyagi

    Journal of Japanese Society of Gastroenterology   108 ( 2 )   267 - 274   2011.2

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    We report a case of chronic hepatitis C in whom liver cirrhosis was later diagnosed following abnormality of ALT levels during pegylated interferon α2a and ribavirin treatment. A 62-year-old woman with chronic hepatitis C was treated with pegylated interferon α2a plus ribavirin for 72 weeks. Her HCV RNA became negative 16 weeks after the start of treatment and continued to be negative for most of the treatment duration. Her AST/ALT, ALP/γ-GTP levels became elevated soon after the initiation of treatment and thereafter remained unchanged. However, most of these levels normalized after the end of treatment. Posttreatment liver biopsy showed liver cirrhosis, probably due to the interferon treatment itself. This unusual therapeutic outcome should be considered if the levels of hepatic dysfunction during interferon treatment are severe.

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  • Characterization of elevated alanine aminotransferase levels during pegylated-interferon alpha-2b plus ribavirin treatment for chronic hepatitis C Reviewed

    Yo-hei Aoki, Shogo Ohkoshi, Satoshi Yamagiwa, Masahiko Yano, Hiromichi Takahashi, Nobuo Waguri, Kentaro Igarashi, Soh-ichi Sugitani, Toru Takahashi, Toru Ishikawa, Tomoteru Kamimura, Hiroto Wakabayashi, Toshiaki Watanabe, Yasunobu Matsuda, Minoru Nomoto, Yutaka Aoyagi

    HEPATOLOGY RESEARCH   41 ( 2 )   118 - 125   2011.2

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    Aim:
    Elevation of alanine aminotransferase (ALT) levels during pegylated-interferon (peg-IFN) plus ribavirin therapy in patients with chronic hepatitis C [CHC] is a problem that cannot be disregarded. The aim of this study is to assess the frequency and to characterize clinical parameters of this phenomenon.
    Methods:
    Two hundred and thirty-five (235) CHC patients with genotype 1b receiving peg-IFN alpha-2b plus ribavirin therapy were analyzed. Clinical parameters that may be associated with abnormal ALT values during treatment and therapy outcomes were evaluated statistically. One hundred and sixteen (116) patients treated with peg-IFN alpha-2a plus ribavirin were also included for partial analysis.
    Results:
    Abnormal ALT values during treatment were observed in 23.0% of patients. It was observed in 14.5% of those with sustained virological response (SVR) and 17.8% of those with relapse, in whom viral clearance was observed during therapy. Multivariate logistic regression analysis revealed that pretreatment ALT values, therapy outcome, and body mass index (BMI) were significant factors related to abnormal ALT values during treatment. Abnormal ALT values during treatment became normal in SVR patients at 6 months after the completion of treatment, but not in NR (non-response) patients. Mean ALT values were significantly higher at some time points during treatment in patients treated with alpha-2a when compared to those treated with alpha-2b.
    Conclusion:
    Abnormal ALT values during peg-IFN plus ribavirin treatment are observed relatively frequently, even in patients without detectable HCV RNA. Direct or indirect involvement of drugs is considered as one possible cause.

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  • Prognostic significance of NQO1 expression in intrahepatic cholangiocarcinoma Reviewed

    Toshifumi Wakai, Yoshio Shirai, Jun Sakata, Yasunobu Matsuda, Pavel V. Korita, Masaaki Takamura, Yoichi Ajioka, Katsuyoshi Hatakeyama

    INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY   4 ( 4 )   363 - 370   2011

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    This study aimed to evaluate the association between the immunohistochemical expression of NAD(P) H: quinone oxidoreductase-1 (NQO1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in resected specimens of intrahepatic cholangiocarcinoma (ICC) and to elucidate the prognostic value of NQO1 and Nrf2 expression. A retrospective analysis was conducted of 34 consecutive patients who underwent surgical resection for ICC. Immunohistochemistry of the resected specimens was conducted using each of the following primary monoclonal antibodies against NQO1 and Nrf2. Of the 34 patients, 23 were classified as having tumors with NQO1-positive expression and 11 had tumors with loss of NQO1 expression, whereas 22 patients had tumors with Nrf2-positive expression and 12 had tumors with loss of Nrf2 expression. NQO1 expression showed a positive association with Nrf2 expression (p=0.005). Loss of NQO1 expression was more frequent in tumor specimens that were moderately or poorly differentiated (11/26; 42%) than in well-differentiated tumors (0/8; 0%; p=0.034). Post-resection survival was significantly worse in patients with tumors with loss of NQO1 expression than in patients with NQO1-positive tumors (cumulative 5 -year survival rate of 0% and 51%, respectively; p=0.005). Nrf2 expression was not associated with survival after resection (p=0.287). The Cox proportional hazards regression analysis revealed that lymph node involvement (p&lt;0.001) and loss of NQO1 expression (p&lt;0.001) had an independent adverse effect on survival. Loss of NQO1 expression reflects dedifferentiation and thus indicates a poor prognosis for patients undergoing resection for ICC.

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  • Multicentric occurrence of hepatocellular carcinoma with nonalcoholic steatohepatitis Reviewed

    Hirokazu Kawai, Minoru Nomoto, Takeshi Suda, Kenya Kamimura, Atsunori Tsuchiya, Yasushi Tamura, Masahiko Yano, Masaaki Takamura, Masato Igarashi, Toshifumi Wakai, Satoshi Yamagiwa, Yasunobu Matsuda, Shogo Ohkoshi, Isao Kurosaki, Yoshio Shirai, Masahiko Okada, Yutaka Aoyagi

    World Journal of Hepatology   3 ( 1 )   15 - 23   2011

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    Aim: To reveal the manner of hepatocellular carcinoma (HCC) development in patients with nonalcoholic steatohepatitis (NASH) focusing on multicentric occurrence (MO) of HCC. Methods: We compared clinicopathological characteristics between patients with and without MO of HCC arising from NASH background. The clinical features were implicated with reference to the literature available. Results: MO of HCC was identified with histological proof in 4 out of 12 patients with NASH-related HCC (2 males and 2 females). One patient had synchronous MO
    an advanced HCC, two well-differentiated HCCs and a dysplastic nodule, followed by the development of metachronous MO of HCC. The other three patients had multiple advanced HCCs accompanied by a well-differentiated HCC or a dysplastic nodule. Of these three patients, one had synchronous MO, one had metachronous MO and the other had both synchronous and metachronous MO. There were no obvious differences between the patients with or without MO in terms of liver function tests, tumor markers and anatomical extent of HCC. On the other hand, all four patients with MO of HCC were older than 70 years old and had the comorbidities of obesity, type 2 diabetes mellitus (T2DM), hypertension and cirrhosis. Although these conditions were not limited to MO of HCC, all the conditions were met in only one of eight patients without MO of HCC. Thus, concurrence of these conditions may be a predisposing situation to synchronous MO of HCC. In particular, old age, T2DM and cirrhosis were suggested to be prerequisite for MO because these factors were depicted in common among two other cases with MO of HCC under NASH in the literature. Conclusion: The putative predisposing factors and necessary preconditions for synchronous MO of HCC in NASH were suggested in this study. Further investigations are required to clarify the accurate prevalence and predictors of MO to establish better strategies for treatment and prevention leading to the prognostic improvement in NASH. © 2011 Baishideng.

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  • Multidrug resistance-associated protein 2 determines the efficacy of cisplatin in patients with hepatocellular carcinoma Reviewed

    Pavel V. Korita, Toshifumi Wakai, Yoshio Shirai, Yasunobu Matsuda, Jun Sakata, Masaaki Takamura, Masahiko Yano, Ayumi Sanpei, Yutaka Aoyagi, Katsuyoshi Hatakeyama, Yoichi Ajioka

    Oncology Reports   23 ( 4 )   965 - 972   2010.4

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    We hypothesized that expression of multidrug resistance-associated protein 2 (MRP2), a major cisplatin transporter, may determine the efficacy of cisplatin as a treatment for patients with hepatocellular carcinoma (HCC). A prospective analysis was conducted of 49 consecutive patients who underwent resection for HCC (16 patients treated with cisplatin-based neoadjuvant chemotherapy and 33 patients treated without neoadjuvant chemotherapy). Expression of MRP2 in resected specimens was assessed by immunohistochemical and Western blot analyses. The extent of tumor necrosis was assessed histologically in the greatest dimension of the tumor specimen from each patient. The median percentage of tumor necrosis was 81% (range: 0-100%) and complete tumor necrosis was found in 3 patients. Over-expression of MRP2 was detected in 24/46 (52%) tumor specimens. In 16 patients treated with cisplatin, tumor size and dose of cisplatin did not correlate with tumor necrosis of the resected specimens (P=0.706 and P=0.555, respectively). Of 13 tumor specimens containing vivid tumor from 16 patients treated with cisplatin, 8 had overexpression of MRP2. Tumor specimens with overexpression of MRP2 showed a lower percentage of tumor necrosis than those with non-overexpression (median percentage of tumor necrosis, 19% vs. 99%, P=0.003). In conclusion, overexpression of MRP2 correlates with a lower percentage of tumor necrosis in patients treated with cisplatin-based neoadjuvant chemotherapy for HCC, whereas either tumor size or dose of cisplatin does not. Expression of MRP2 determines the efficacy of cisplatinbased chemotherapy in patients with HCC.

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  • Rectal administration of tranilast ameliorated acute colitis in mice through increased expression of heme oxygenase-1: Original Article Reviewed

    Xiaomei Sun, Kenji Suzuki, Masaki Nagata, Yusuke Kawauchi, Masahiko Yano, Shogo Ohkoshi, Yasunobu Matsuda, Hiroshi Kawachi, Kenichi Watanabe, Hitoshi Asakura, Yutaka Aoyagi

    Pathology International   60 ( 2 )   93 - 101   2010.2

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    Mast cells play a key role in the pathophysiology of inflammatory bowel disease (IBD). Tranilast, a mast cell stabilizer, has been empirically used for IBD in Japan, but its precise role in the treatment of IBD is largely unknown. To investigate the role of tranilast for the treatment of IBD, tranilast was administered intrarectally to mice with dextran sulfate sodium (DSS)-induced colitis. Tranilast ameliorated DSS colitis clinically and pathologically, as demonstrated by decreased number and degranulation of mast cells in the colon. mRNA expression was increased for tumor necrosis factor-α, interferon-γ and interleukin (IL)-6, and decreased for IL-10 in the colon of DSS colitis mice. In contrast, tranilast markedly decreased expression of mRNAs for the pro-inflammatory cytokines, and increased that of the anti-inflammatory cytokines. Moreover, tranilast increased heme oxygenase (HO)-1 expression on colonic epithelial cells as well as on colon-infiltrating cells of DSS colitis. In conclusion, tranilast ameliorated DSS colitis by regulating mast cell degranulation, decreasing inflammatory cytokines and increasing anti-inflammatory cytokines. Tranilast might exert these effects partly through enhanced HO-1 expression in the colon, suggesting a potential adjunctive therapy for IBD. © 2009 Japanese Society of Pathology.

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  • Loss of liver-intestine cadherin in human intrahepatic cholangiocarcinoma promotes angiogenesis by up-regulating metal-responsive transcription factor-1 and placental growth factor Reviewed

    Masaaki Takamura, Satoshi Yamagiwa, Toshifumi Wakai, Yasushi Tamura, Hiroteru Kamimura, Takashi Kato, Atsunori Tsuchiya, Yasunobu Matsuda, Yoshio Shirai, Takafumi Ichida, Yoichi Ajioka, Yutaka Aoyagi

    International Journal of Oncology   36 ( 1 )   245 - 254   2010.1

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    Liver-intestine cadherin (LI-cadherin) represents a novel type of cadherin within the cadherin superfamily that comprises seven cadherin repeats and a short cytoplasmic domain. In this study, we first examined LI-cadherin expression immunohistochemically in 34 specimens of human intrahepatic cholangiocarcinoma (ICC). LI-cadherin expression was positive (defined as positivity in ≥10% of cells) in 18 of the ICCs (52.9%). LI-cadherin negativity was significantly correlated with tumor dedifferentiation (P=0.026) and vascular invasion (P=0.015). The cumulative survival rate of patients with LI-cadherin-negative ICC was significantly shorter than that of patients with LI-cadherinpositive ICC (P=0.021). Multivariate analysis identified the extent of LI-cadherin staining as an independent prognostic factor for ICC survival (P=0.027). Next, to elucidate the mechanism of loss of LI-cadherin-mediated aggressiveness in ICC, we knocked down LI-cadherin expression in an ICC cell line using small interfering RNA (siRNA) technology, and screened for genes that were expressed differentially between these cells and ICC cells transfected with scrambled siRNA using microarray analysis with real-time polymerase chain reaction confirmation. Among 21 identified genes, we focused on metal-responsive transcription factor-1 (MTF-1), whose target genes might contribute to tumor aggressiveness. Expression of placental growth factor (PlGF), one of the MTF-1 target genes, was up-regulated in the ICC cells transfected with LI-cadherin siRNA. Likewise, PlGF expression was up-regulated in LI-cadherin-negative ICC specimens. There was a significant inverse relationship between these expressions (P=0.033). Furthermore, the microvessel density of LI-cadherin-negative ICC specimens was higher than that of LI-cadherin-positive specimens. These findings suggest that loss of LI-cadherin in ICC is associated with tumor dedifferentiation and vascular invasion, and thus poor prognosis. Loss of LI-cadherin results in up-regulation of MTF-1 and PlGF, thereby regulating angiogenesis in ICC.

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  • Very-low-dose pegylated interferon α2a plus ribavirin therapy for advanced liver cirrhosis type C: A possible therapeutic alternative without splenic intervention Reviewed

    Shogo Ohkoshi, Satoshi Yamagiwa, Masahiko Yano, Hiromichi Takahashi, Yo-Hei Aoki, Yasunobu Matsuda, Yutaka Aoyagi

    Case Reports in Gastroenterology   4 ( 2 )   261 - 266   2010

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    Despite the recent progress in interferon (IFN) therapies for chronic hepatitis C, liver cirrhosis remains refractory. One of the major obstacles to successful IFN therapy is low platelet count. Currently, splenic interventions, such as partial splenic embolization (PSE) or surgical splenectomy, have been applied effectively and make standard IFN therapy possible. However, there may be a group of patients with low platelet counts who can be treated without splenic intervention. We here report two patients with advanced type C liver cirrhosis who were successfully treated using very-low-dose pegylated interferon α2a plus ribavirin. One patient had a very low platelet count (2.5 × 104/μl) due to splenomegaly before treatment. However, pretreatment serum HCV titers were low in both patients and early viral responses were obtained in both. Because PSE or splenectomy may still have some safety concerns, this attenuated IFN treatment protocol can be an alternative therapeutic option for patients with advanced type C liver disease, but good virological factors for sustained virological response. © 2010 S. Karger AG, Basel.

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  • Clinicopathological analysis of CD133+and NCAM+ human hepatic stem/progenitor cells in damaged livers and hepatocellular carcinomas Reviewed

    Atsunori Tsuchiya, Hiroteru Kamimura, Masaaki Takamura, Satoshi Yamagiwa, Yasunobu Matsuda, Yoshinobu Sato, Minoru Nomoto, Takafumi Ichida, Yutaka Aoyagi

    HEPATOLOGY RESEARCH   39 ( 11 )   1080 - 1090   2009.11

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    Aim:
    Hepatic stem cells are capable of dramatically changing and differentiating to form mature hepatocytes in acute and chronically damaged livers; however, the clinicopathological characteristics of these heterogeneous cell populations have not been sufficiently analyzed.
    Methods:
    In this study, cells in tissue sections from 12 cases of acute damaged livers and 31 cases of hepatocellular carcinomas (HCC), and the surrounding chronically damaged liver tissues, were analyzed by immunohistochemistry using the previously reported hepatic stem/progenitor cell marker CD133 (AC133) and the neural cell adhesion molecule (NCAM) marker.
    Results:
    In both the acute and chronically damaged livers, CD133+ cells and NCAM+ cells were present in ductular reactions (DR), which include hepatic stem/progenitor cells, and became more apparent in proportion to the degree of fibrosis or histological damage. Analysis of their distribution and morphological similarities revealed that the NCAM+ cell population included cells that were closer to, and morphologically more similar to, hepatocytes than were CD133+ cells. Analysis of HCC using these markers revealed that 9.7% of HCC expressed NCAM (two cases had abundant NCAM+ cells), while CD133+ HCC were not detected.
    Conclusion:
    These results suggest that CD133 and NCAM can be employed to enrich for hepatic stem/progenitor cells and that DR can be distinguished in greater detail using these markers. NCAM+ HCC were detected, but their function remains unresolved. Expression of CD133, a potent stem cell marker, may be extremely rare in the common human HCC examined.

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  • Impact of hepatitis B virus X protein on the DNA damage response during hepatocarcinogenesis Reviewed

    Yasunobu Matsuda, Takafumi Ichida

    Medical Molecular Morphology   42 ( 3 )   138 - 142   2009.9

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    Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide. The main HCC-associated diseases are chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), and HBV-associated HCC is still prevalent in Asia. Many studies have suggested that HBV X protein (HBX), which is the most common ORF integrated into the host genome, plays a crucial role in hepatocarcinogenesis. However, the accumulated evidence regarding HBX-mediated signaling pathways is not concordant, and it is difficult to understand the mechanistic nature of HBX-associated hepatocarcinogenesis. For example, HBX was reported to inactivate the early responses to DNA damage via p53-dependent and -independent pathways by interacting with several DNA damage-binding proteins and was also reported to sensitize cells to p53-mediated apoptosis via ataxia-telangiectasia and Rad3-related (ATR)-dependent signaling. HBX also interferes with the centrosome replication process, resulting in rearrangement of chromosomes with micronuclei. Moreover, HBX was found to sensitize protein kinases such as Ras/Raf/mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), stress-activated protein kinase/NH2-terminal-Jun kinase (SAPK/JNK), protein kinase B (PKB/Akt), and Janus kinase/STAT (JAK/STAT), indicating that a variety of signaling pathways may be activated by HBX. In this review, we focus on the roles of HBX in DNA damage repair during HCC development, with a view to achieving a better understanding of the significance of HBX in the early steps of hepatocarcinogenesis. © 2009 The Japanese Society for Clinical Molecular Morphology.

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  • Loss of carcinoembryonic antigen-related cell adhesion molecule 1 expression predicts metachronous pulmonary metastasis and poor survival in patients with hepatoblastoma. Reviewed

    Tsukada Mami, Wakai Toshifumi, Matsuda Yasunobu, Korita Pavel V, Shirai Yoshio, Ajioka Yoichi, Hatakeyama Katsuyoshi, Kubota Masayuki

    J Pediatr Surg   44 ( 8 )   1522 - 1528   2009.8

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    PURPOSE: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a member of the carcinoembryonic antigen family of immunoglobulin-like adhesion molecules. The aim of this study was to test the hypothesis that loss of CEACAM1 expression in hepatoblastoma cells may promote hematogeneous metastasis and function as an adverse prognostic factor. METHODS: Immunohistochemical expression of CEACAM1 in surgically resected specimens from 19 patients with hepatoblastoma was examined retrospectively. The CEACAM1 expression in the epithelial area of the tumor was classified into 2 categories as follows: diffuse expression, characterized by positive staining throughout the tumor specimen, or loss of expression, in which there were distinct areas of negative staining within the tumor specimen. RESULTS: Of the 19 patients, 12 were classified as having tumors with diffuse expression, and 7 had loss-of-expression tumors. Survival after treatment was significantly worse in patients with tumors with loss of CEACAM1 expression (cumulative 5-year survival rate, 29%) than in patients with diffuse CEACAM1 expression (cumulative 5-year survival rate, 92%; P = .0062). Loss of CEACAM1 expr

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  • Blockade of Endogenous CD26 Activity Augments the Therapeutic Potential of Marrow Stem Cells for Mouse Liver Cirrhosis Reviewed

    Matsuda Yasunobu, Sanpei Ayumi, Wakai Toshifumi, Shirai Yoshio, Yano Masahiko, Sun Xiaomei, Tsuchiya Atsunori, Takamura Masaaki, Yamagiwa Satoshi, Suzuki Kenji, Ohkoshi Shogo, Suzuki Yutaka, Aoyagi Yutaka

    GASTROENTEROLOGY   136 ( 5 )   A817   2009.5

  • Progression of hypermethylation of the p16(INK4A) gene from normal liver to nontumorous liver and hepatocellular carcinoma: an evaluation using quantitative PCR analysis. Reviewed

    Kurita So, Ohkoshi Shogo, Yano Masahiko, Yamazaki Kazuhide, Suzuki Kenta, Aoki Yo-hei, Matsuda Yasunobu, Wakai Toshifumi, Shirai Yoshio, Ichida Takafumi, Aoyagi Yutaka

    Dig Dis Sci   54 ( 1 )   80 - 88   2009.1

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    The aim of this study was to determine to what extent hypermethylation of the p16(INK4A) (p16) gene promoter is increased in nontumorous liver tissues compared with in normal liver, using two quantitative methylation-specific polymerase chain reaction (MS-PCR) methods and a bisulfite sequencing method. Methylation of the p16 gene was detected more frequently in nontumorous liver than in normal liver using the TaqMan PCR method. Methylation indices also were significantly higher in nontumorous than in normal liver. However, the bisulfite sequencing method did not detect significantly more methylation of the p16 gene in nontumorous than normal liver, nor was there a significant difference in the level of p16 mRNA. There may be a greater proportion of cells which contain methylated p16 in nontumorous than in normal liver. However, the difference was so small that the functional relevance to hepatocarcinogenesis remains elusive.

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  • A case of extra-hepatic lymph node metastasis of hepatocellular carcinoma with no evident sign of intra-hepatic recurrence

    Shinichi Morita, Yasunobu Matsuda, Tomoko Oshima, Tomoyuki Kubota, Yusuke Kawauchi, Makoto Kobayashi, Minoru Nomoto, Yutaka Aoyagi

    Journal of Japanese Society of Gastroenterology   106 ( 3 )   397 - 404   2009

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    A 73-year-old man with chronic hepatitis C was Successfully treated for hepatocellular carcinoma (HCC) by localized treatment During the follow-up period, abdominal computed tomography (CT) revealed no HCC recurrence in the liver. However, 9 months after the treatment, abdominal lymph nodes appeared enlarged on CT. Laparoscopic biopsy of the lymph nodes showed that the lesion was HCC, and TS-1/cisplatin chemotherapy was performed. However, extra-hepatic lymph nodes rapidly grew, leading to obstructive jaundice and finally death 10 months after of HCC metastasis. Although abdominal lymph node metastasis of HCC has been widely considered to be rare, the confirmation of effective therapy is awaited because histological studies have suggested that this pathologic lesion may occur more often than expected.

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  • Successful Treatment in a Case of Massive Hepatocellular Carcinoma with Paraneoplastic Syndrome. Reviewed

    Tsuchiya Atsunori, Kubota Tomoyuki, Takizawa Kazuyoshi, Yamada Kazuki, Wakai Toshifumi, Matsuda Yasunobu, Honma Terasu, Watanabe Masashi, Shirai Yoshio, Maruyama Hiroki, Nomoto Minoru, Aoyagi Yutaka

    Case Rep Gastroenterol   3 ( 1 )   105 - 110   2009

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    Paraneoplastic syndromes of hepatocellular carcinoma (HCC) are not uncommon. However, the prognosis is poor and follow-up and improvement of paraneoplastic syndromes with treatment have been reported rarely. We report a successful case in an aged man of a massive HCC with paraneoplastic syndrome, treated by combined intraarterial chemotherapy and hepatic resection. Paraneoplastic syndrome (erythrocytosis and hyperlipidemia) was monitored throughout the treatment and erythropoietin (EPO) mRNA also was analyzed in the resected liver. The hemoglobin level and serum levels of EPO and total cholesterol (T-cho) decreased dramatically with treatment, along with a decrease in serum levels of alpha-fetoprotein and protein induced by vitamin vitamin K absence II (PIVKA-II). Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) revealed that the residual cancer expressed EPO RNA but the nontumor tissue did not. This was a rare case of paraneoplastic syndrome of HCC that was treated successfully. This case indicates that paraneoplastic syndrome reflected tumor progression and that serum levels of both EPO and T-cho might be used as tumor markers.

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  • Overexpression of osteopontin independently correlates with vascular invasion and poor prognosis in patients with hepatocellular carcinoma. Reviewed

    Korita Pavel V, Wakai Toshifumi, Shirai Yoshio, Matsuda Yasunobu, Sakata Jun, Cui Xing, Ajioka Yoichi, Hatakeyama Katsuyoshi

    Hum Pathol   39 ( 12 )   1777 - 1783   2008.12

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    This study retrospectively evaluated the immunohistochemical expression of 3 cell adhesion molecules (CAMs), E-cadherin, beta-catenin, and osteopontin, according to tumor grade in 125 surgically resected specimens of hepatocellular carcinoma (HCC). The aims of this study were to identify factors associated with vascular invasion and to elucidate the prognostic value of CAMs. The median follow-up time was 110 months. The levels of E-cadherin, beta-catenin, and osteopontin immunoreactivity were significantly associated with Edmondson-Steiner grade but not with tumor size. There was increased loss of E-cadherin, nonnuclear overexpression of beta-catenin, and overexpression of osteopontin in tumors of higher histologic grade. Vascular invasion was found in 44 (35%) of 125 resected specimens. Logistic regression analysis identified 3 tumor-related factors that were independently associated with vascular invasion-tumor size more than 3 cm, Edmondson-Steiner grades III to IV, and overexpression of osteopontin. Among the tested CAMs, osteopontin (P = .0110) and E-cadherin (P = .0287) were significant prognostic factors by univariate analysis. The Cox proportional hazard regression analy

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  • Expression of liver-intestine cadherin in intrahepatic cholangiocarcinoma: Its prognostic significance and relationship to vascular invasion Reviewed

    Takamura M, Tamura Y, Wakai T, Yamagiwa S, Kato T, Tsuchiya A, Matsuda Y, Shirai Y, Ichida T, Ajioka Y, Aoyagi Y

    Hepatology (supplement)   48 ( S1 )   945A - 945A   2008.10

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  • THE BALANCE BETWEEN CD56(+BRIGHT) AND CD56(+DlM) NATURAL KILLER CELL SUBSETS IN THE LIVER OF PATIENTS WITH RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTATION Reviewed

    Yamagiwa Satoshi, Kamimura Hiroteru, Tsuchiya Atsunori, Takamura Masaaki, Matsuda Yasunobu, Sato Yoshinobu, Ichida Takafumi, Aoyagi Yutaka

    HEPATOLOGY   48 ( 4 )   769A - 770A   2008.10

  • Successful treatment with lamivudine may correlate with reduction of serum ferritin levels in the patients with chronic hepatitis and liver cirrhosis type B Reviewed

    Shogo Ohkoshi, Akira Yoshimura, Satoshi Yamamoto, Masahiko Yano, So Kurita, Kazuhide Yamazaki, Yo-hei Aoki, Satoshi Yamagiwa, Hiroto Wakabayashi, Motoya Sugiyama, Tohru Takahashi, Tohru Ishikawa, Yasunobu Matsuda, Takafumi Ichida, Tomoteru Kamimura, Yutaka Aoyagi

    HEPATOLOGY INTERNATIONAL   2 ( 3 )   382 - 387   2008.9

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    Purpose To study the changes in serum ferritin levels in lamivudine (LAM)-treated patients with chronic hepatitis and liver cirrhosis type B and determine whether successful treatment with LAM results in a reduction of serum ferritin levels.
    Methods Thirty patients with chronic hepatitis B virus (HBV) infection were followed prospectively during their treatment with LAM for 12 months. Serum HBV DNA, ferritin levels, and emergence of YMDD mutants were monitored. A case of severe liver cirrhosis with hepatic hemosiderosis that was treated successfully with LAM also is shown as a representative case.
    Results Serum alanine aminotransferase and ferritin levels decreased significantly more in the patients treated with LAM without YMDD mutants (n = 23) than those with mutants (n = 7). Hepatic hemosiderosis along with serum iron markers improved greatly in the representative patient.
    Conclusion Successful treatment with LAM may reduce serum ferritin levels and improve hepatic siderosis in a subset of patients with chronic HBV infection.

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  • Sustained response to interferon-alpha plus ribavirin therapy for chronic hepatitis C is closely associated with increased dynamism of intrahepatic natural killer and natural killer T cells Reviewed

    Satoshi Yamagiwa, Yasunobu Matsuda, Takafumi Ichida, Yutaka Honda, Masaaki Takamura, Satoshi Sugahara, Toru Ishikawa, Shogo Ohkoshi, Yoshinobu Sato, Yutaka Aoyagi

    HEPATOLOGY RESEARCH   38 ( 7 )   664 - 672   2008.7

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    Aim: Previous studies have revealed that functional impairment of innate immune cells, including natural killer (NK) and natural killer T (NKT) cells, might be associated with the persistence of hepatitis C virus (HCV) infection. However, the involvement of innate immune cells, which predominate in the liver, in therapeutic HCV clearance is still unclear.
    Methods: To clarify the role of intrahepatic innate immune cells in the clinical outcome of patients with chronic hepatitis C (CHC) treated with interferon-alpha plus ribavirin (IFN/RBV), we prospectively investigated the status of NK and NKT cells in paired liver biopsy and peripheral blood (PB) samples obtained from 21 CHC patients before and immediately after IFN/RBV treatment by flow cytometry. Normal liver and PB samples were obtained from 10 healthy donors for living donor liver transplantation.
    Results: Before treatment, intrahepatic NK and NKT cells constituted a significantly lower proportion in CHC patients than in healthy individuals (P &lt; 0.05). After IFN/RBV treatment, the proportions and absolute numbers of CD3(-)CD161(+) NK and CD3(+)CD56(+) NKT cells in the liver, but not in PB, were significantly increased in sustained responders (SR) as compared with poor responders (P &lt; 0.05). The proportion of CD3(+)CD161(+) NKT cells was also increased in the liver of SR after the treatment. Moreover, there was a striking increase of activated CD152(+) cells among CD3(+)CD56(+) NKT cells in the liver of SR (P = 0.041).
    Conclusion: These findings demonstrate that sustained response to IFN/RBV treatment for patients with CHC is closely associated with increased dynamism of NK and NKT cells in the liver.

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  • Molecular mechanism underlying the functional loss of cyclindependent kinase inhibitors p16 and p27 in hepatocellular carcinoma Reviewed

    Yasunobu Matsuda

    WORLD JOURNAL OF GASTROENTEROLOGY   14 ( 11 )   1734 - 1740   2008.3

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    Hepatocellular carcinoma (HCC) is one of the most common human cancers, and its incidence is still increasing in many countries. The prognosis of HCC patients remains poor, and identification of useful molecular prognostic markers is required. Many recent studies have shown that functional alterations of cell-cycle regulators can be observed in HCC. Among the various types of cell-cycle regulators, p16 and p27 are frequently inactivated in HCC and are considered to be potent tumor suppressors. p16, a G1-specific cell-cycle inhibitor that prevents the association of cyclindependent kinase (CDK) 4 and CDK6 with cyclin D1, is frequently inactivated in HCC via CpG methylation of its promoter region. p16 may be involved in the early steps of hepatocarcinogenesis, since p16 gene methylation has been detected in subsets of pre-neoplastic liver cirrhosis patients. p27, a negative regulator of the G1-S phase transition through inhibition of the kinase activities of Cdk2/cyclin A and Cdk2/cyclin E complexes, is now considered to be an adverse prognostic factor in HCC. In some cases of HCC with increased cell proliferation, p27 is overexpressed but inactivated by sequestration into cyclin D1-CDK4-containing complexes. Since loss of p16 is closely related to functional inactivation of p27 in HCC, investigating both p16 and p27 may be useful for precise prognostic predictions in individuals with HCC. (c) 2008 WJG. All rights reserved.

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  • Temporal treatment with interferon-beta prevents hepatocellular carcinoma in hepatitis B virus X gene transgenic mice Reviewed

    Kazuhide Yamazaki, Kenta Suzuki, Shogo Ohkoshi, Masahiko Yano, So Kurita, Yo-Hei Aoki, Ken Toba, Masa-aki Takamura, Satoshi Yamagiwa, Yasunobu Matsuda, Yutaka Aoyagi

    JOURNAL OF HEPATOLOGY   48 ( 2 )   255 - 265   2008.2

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    Background/Aims: The preventive effect of interferon (IFN) against hepatocellular carcinoma (HCC) has been confirmed clinically. We sought to determine whether the temporal administration of IFN-beta prevents hepatocarcinogenesis in a mouse model where HCC develops without necroinflammation.
    Methods: Hepatocarcinogenic mice that are transgenic for the hepatitis B virus X gene (HBx-Tg) were treated with IFN-beta or saline (control) for three months, from 3 to 6 months of age, and the incidence of HCC was determined at 18 months of age. The effects of IFN-beta on DNA synthesis and apoptosis were tested.
    Results: The incidence of HCC was significantly lower in the IFN-beta-treated mice than the controls (0 vs. 50%, P &lt; 0.01). Inhibition of DNA synthesis in hepatocytes by IFN-beta was observed in the livers of HBx-Tg, without any significant induction of apoptosis. Although the treatment of IFN-beta was temporal, the number of hepatocytes with DNA synthesis remained lower 3 and 12 months later in life.
    Conclusions: Temporal administration of IFN-beta has a significant preventive effect on the occurrence of HCC in a mouse model where HCC develops without inflammation. The mechanisms are the inhibition of DNA synthesis and cell cycle progression of hepatocytes. (c) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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  • Sca-1+ endothelial cells (SPECs) reside in the portal area of the liver and contribute to rapid recovery from acute liver disease Reviewed

    A. Tsuchiya, T. Heike, S. Baba, H. Fujino, K. Umeda, Y. Matsuda, M. Nomoto, T. Ichida, Y. Aoyagi, T. Nakahata

    Biochemical and Biophysical Research Communications   365 ( 3 )   595 - 601   2008.1

  • Altered expression of TLR homolog RP105 on monocytes hypersensitive to LPS in patients with primary biliary cirrhosis Reviewed

    Yutaka Honda, Satoshi Yamagiwa, Yasunobu Matsuda, Masaaki Takamura, Takafumi Ichida, Yutaka Aoyagi

    JOURNAL OF HEPATOLOGY   47 ( 3 )   404 - 411   2007.9

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    Backgrounds/Aims: Toll-like receptors (TLRs) have emerged as a key component of the innate immune system that triggers antimicrobial responses. Altered monocyte responses to ligands for TLRs have been reported in patients with primary biliary cirrhosis (PBC), yet the precise mechanism remains unknown.
    Methods: We investigated in vitro responses to a TLR4 ligand, lipopolysaccharide (LPS), using peripheral blood mononuclear cells and monocytes from 25patients with PBC, 10 patients with chronic viral hepatitis(CVH), and 20 healthy individuals.
    Results: After stimulation with LPS, we found significantly higher amounts of IL-I beta, IL-6, and IL-8 production in PBC patients. Through the TLR4 signaling pathway, activation of NF-kappa B and expression of MyD88 mRNA were significantly increased in PBC patients, and the level of TLR4 expression was significantly increased on PBC monocytes as compared with CVH patients and controls. Of significance, the surface expression of RP105, which has recently been shown to be involved in negative regulation of TLR4 signaling, on PBC monocytes was significantly decreased in comparison with CVH patients (P = 0.016) and controls (P &lt; 0.001).
    Conclusions: These results suggest that expression of RP105 and TLR4 is altered on PBC monocytes, which appear to be hypersensitive to LPS, resulting in increased secretion of pro-inflammatory cytokines. (C). 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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  • Tumor suppressor carcinoembryonic antigen-related cell adhesion molecule 1 potentates the anchorage-independent growth of human hepatoma HepG2 cells Reviewed

    Mariko Hokari, Yasunobu Matsuda, Toshifumi Wakai, Yoshio Shirai, Munehiro Sato, Atsunori Tsuchiya, Masaaki Takamura, Satoshi Yamagiwa, Kenji Suzuki, Shogo Ohkoshi, Takafumi Ichida, Hiroshi Kawachi, Yutaka Aoyagi

    LIFE SCIENCES   81 ( 4 )   336 - 345   2007.7

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    Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), an adhesion molecule of the immunoglobulin superfamily, has been characterized as a putative tumor suppressor because it is frequently down-regulated in aggressive types of cancer cells. Recently, however, several studies have shown that CEACAM 1 actively contributes to malignant progression or migration in some types of tumor cells, suggesting that the role of CEACAM 1 might be diverse among different types of cancer cells. To investigate the functional consequences of CEACAM 1 expression in hepatocellular carcinoma, we analyzed the status of CEACAM 1 in hepatoma cell lines HLF, PLC/PRF/5, HepG2 and KYN-2. We found that CEACAM1 was only expressed in HepG2 cells, which show a unique property for enhanced anchorage-independent growth. When HepG2 cells were treated with small interfering RNA targeted against CEACAM1, the growth rate in monolayer culture was increased. In contrast, when HepG2 cells were cultured in suspension, inhibition of CEACAM1 expression significantly decreased the growth rate, and the speed of cell-cell attachment was repressed. Hyaluronidase treatment attenuated the growth rate of HepG2 cells in suspension culture, indicating that cell-cell attachment is a requisite for anchorage-independent growth. Our data may reveal the dual role of CEACAM1 on hepatocarcinogenesis, by showing that CEACAM1 acts as a tumor suppressor in HepG2 cells in anchorage-dependent growth conditions, while in anchorage-independent growth conditions, it augments cell proliferation by potentiating the cell-cell attachment. (c) 2007 Elsevier Inc. All rights reserved.

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  • Early upsurge in anti-HBs titer possibly caused by the immunomodulative, not by the mutagenetic effect of interferon and ribavirin Reviewed

    Kazuhide Yamazaki, Shogo Ohkoshi, Masaki Maruyama, Yo-hei Aoki, Masahiko Yano, So Kurita, Kenta Suzuki, Yasunobu Matsuda, Kazuhito Sugimura, Yutaka Aoyagi

    HEPATOLOGY RESEARCH   37 ( 6 )   477 - 481   2007.6

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    A patient with chronic hepatitis B and C undergoing treatment with interferon and ribavirin showed an upsurge in hepatitis B virus surface antibody (anti-HBs) titer, accompanied by a decrease in hepatitis B virus surface antigen (HBsAg) during the early treatment phase. Simultaneously, elevation of alanine aminotransferase (ALT) was observed. Subsequently, the hepatitis B virus (HBV) DNA titer decreased and HBV e antigen (HBeAg) to anti-HBe seroconversion occurred. The anti-HBs titer gradually returned to the pretreatment level after cessation of ribavirin treatment and HBV-DNA became undetectable. We found no nucleotide mutations in HBV-DNA that could explain the sudden elevation in anti-HBs titer. The appearance of anti-HBs was considered to be a break in immune tolerance against some epitopes in HBsAg, possibly the r epitope, stimulated by interferon/ribavirin treatment. The immunomodulatory effect of ribavirin might have caused this unexpected early immune response to HBsAg that preceded seroconversion to anti-HBe.

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  • An inhibitor of c-Jun NH2-terminal kinase, SP600125, protects mice from D-galactosamine/lipopolysaccharide-induced hepatic failure by modulating BH3-only proteins Reviewed

    Masaaki Takamura, Yasunobu Matsuda, Satoshi Yamagiwa, Yasushi Tamura, Yutaka Honda, Kenji Suzuki, Takafumi Ichida, Yutaka Aoyagi

    LIFE SCIENCES   80 ( 14 )   1335 - 1344   2007.3

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    Fulminant hepatic failure (FHF) is a dramatic clinical syndrome characterized by massive hepatocyte apoptosis and very high mortality. The c-Jun-N-terminal kinase (JNK) pathway is an important stress-responsive kinase activated by several forms of liver injury. The aim of this study is to assess the role of JNK during D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury, an experimental model of FHF, using SP600125. a small molecule JNK-specific inhibitor. Mice were given an intraperitoneal dose of GalN (800 mu g/g body weight)/LPS (100 ng/g body weight) with and without subcutaneous SP600125 (50 mg/kg body weight) treatment (at 6 and 2 h before and 2 h after GalN/LPS administration). GalN/LPS treatment induced sustained INK activation. Administration of SP600125 diminished INK activity, suppressed lethality and the elevation of both serum alanine aminotransferase and aspartate aminotransferase, but had no effect on serum tumor necrosis factor-alpha. and reduced hepatocyte apoptosis after GalN/LPS administration. In support of the role of JNK in promoting the mitochondria-mediated apoptosis pathway, SP600125 prevented cytochrome c release, caspase-9 and caspase-3 activity. Moreover, SP600125 downregulated the mRNA and protein expression of Bad in the early periods following GalN/LPS injection and prevented Bid cleavage in the late periods. These results confirm the role of JNK as a critical apoptotic mediator in GalN/LPS-induced FHF. SP600125 has the potential to protect FTF by downregulating Bad and inhibiting Bid cleavage. (c) 2007 Elsevier Inc. All rights reserved.

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  • Long-term culture of postnatal mouse hepatic stem/progenitor cells and their relative developmental hierarchy Reviewed

    Atsunori Tsuchiya, Toshio Heike, Shiro Baba, Hisanori Fujino, Katsutsugu Umeda, Yasunobu Matsuda, Minoru Nomoto, Takafumi Ichida, Yutaka Aoyagi, Tatsutoshi Nakahata

    STEM CELLS   25 ( 4 )   895 - 902   2007

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    Few studies on the long-term culture of postnatal mouse hepatic stem/progenitor cells have been reported. We successfully adapted a serum-free culture system that we employed previously to expand fetal mouse hepatic stem/progenitor cells and maintained them in culture over long periods. The expanded postnatal cells contained immature alpha-fetoprotein-positive cells along with hepatocytic and cholangiocytic lineage-committed cells. These cells expressed CD49f but not CD45, CD34, Thy-1, c-kit, CD31, or flk-1, and oncostatin M induced their differentiation. This heterogeneous population contained side population (SP) cells, which express the ATP-binding cassette transporter ABCG2, and sca-1+ cells. As mice aged, the frequency of SP and sca-1+ cells decreased along with the ability of cultured cells to expand. Approximately 20%-40% of the SP cells expressed sca-1, but only a few sca-1+ cells were also SP cells. Analysis of colonies derived from single SP or sca-1+ cells revealed that, although both cells had dual differentiation potential and self-renewal ability, SP cells formed colonies more efficiently and gave rise to SP and sca-1+ cells, whereas sca-1+ cells generated only sca-1+ progeny. Thus, SP cells are more characteristic of stem cells than are sca-1+ cells. In regenerating livers, ABCG2+ cells and sca-1+ cells were detected around or in the portal area (the putative hepatic stem cell niche). The expanded cells share many features of fetal hepatic stem/progenitor cells or oval cells and may be useful in determining the mechanisms whereby hepatic stem cells self-renew and differentiate.

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  • p16 and p27 are functionally correlated during the progress of hepatocarcinogenesis Reviewed

    Yasunobu Matsuda, Takafumi Ichida

    MEDICAL MOLECULAR MORPHOLOGY   39 ( 4 )   169 - 175   2006.12

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    The molecular mechanism of the cell-cycle machinery in hepatocellular carcinoma (HCC) has not yet been fully elucidated. Among the various types of cell-cycle regulators, p16 and p27 are now considered to be potent tumor suppressors. p16 is a G1-specific cell-cycle inhibitor that prevents the association of cyclin-dependent kinase (CDK) 4 and CDK6 with cyclin D, Many studies have reported that p16 is inactivated not only in aggressive types of HCC but also in preneoplastic liver cirrhosis. In many cases of HCC, p16 is mainly inactivated by extensive CpG methylation, suggesting that epigenetic changes in the p16 gene may be important events during hepatocarcinogenesis. p27, an inhibitor of CDK2, is presently regarded as a potent adverse prognostic factor in many aggressive cancers. It should be noted that some cases of HCC show increased cell proliferation despite the expression of considerable amounts of p27. In these cases, p27 is inactivated by sequestration kinto cyclin D-1-CDK4-containing complexes. Al, though the reason for the compositional changes in the p27-containing complexes is unclear, our experimental results indicate that loss of p16 following DNA methylation is closely related to the functional inactivation of p27 in HCC. We suggest that assessment of the p16 status may be useful for a precise prognostic prediction for individuals with HCCs expressing high levels of p27.

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  • Increase of CD4(+) CD25(+) regulatory T-cells in the liver of patients with hepatocellular carcinoma Reviewed

    Xiu Hua Yang, Satoshi Yamagiwa, Takafumi Ichida, Yasunobu Matsuda, Satoshi Sugahara, Hisami Watanabe, Yoshinobu Sato, Toru Abo, David A. Horwitz, Yutaka Aoyagi

    JOURNAL OF HEPATOLOGY   45 ( 2 )   254 - 262   2006.8

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    Background/Aims: The immune response to tumor-specific antigens is typically unable to control the growth and spread of malignant cells. Accumulating evidence indicates that the suppressive effects of CD4(+) CD25(+) regulatory T-cells are at least partially responsible for the failure of immune-mediated elimination of tumor cells.
    Methods: We have studied 25 patients with hepatocellular carcinoma (HCC). The liver tissues with HCC were separated into the marginal region of tumor (peri-tumor region) and the non-tumor region distant from the tumor. CD4(+) CD25(+) T-cells were quantified in the blood and the liver by flow cytometry and immunohistochemistry, and their effect on T-cell proliferation and activation was determined.
    Results: We found a significant increase in both the proportion and absolute numbers of CD4(+) CD25(+) T-cells in the peri-tumor regions, but not in unaffected areas (9.5 4.5 vs. 4.6 2.8%, P = 0.011). C134(+) CD25(+) T-cells isolated from peri-tumor regions displayed phenotype markers characteristic of regulatory T-cells, and expressed Foxp3 mRNA. CD8(+) T-cells in peri-tumor regions were inversely proportional to CD4(+) CD25(+) T-cells in the same region (P &lt; 0.001). Moreover, isolated C134(+) CD25(+) T-cells inhibited autologous C138(+) T-cell proliferation.
    Conclusions: Our results suggest that CD4(+) CD25(+) T-cells in the marginal region of HCC may play a critical role in controlling CD8(+) cytotoxic T-cell activity and, thereby, contribute to the progression of HCC. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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  • MEK/ERK signaling is a critical mediator for integrin-induced cell scattering in highly metastatic hepatocellular carcinoma cells Reviewed

    N Honma, T Genda, Y Matsuda, S Yamagiwa, M Takamura, T Ichida, Y Aoyagi

    LABORATORY INVESTIGATION   86 ( 7 )   687 - 696   2006.7

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    The human hepatocellular carcinoma (HCC)-derived cell line KYN-2 is thought to provide a good model for studying the molecular basis of invasion and metastasis of human HCC, because it often shows cell scattering in vitro and intrahepatic metastasis in vivo. We previously found that integrin-mediated extracellular signals inactivated E-cadherin in KYN-2, and caused loss of cell-cell contact with gain of cell motility, which is considered to be a critical step in the process of cancer cell invasion and metastasis. To further understand molecular mechanisms involved in biological aggressiveness of HCC, we investigated intracellular signaling involved in integrin-mediated scattering of KYN-2 cells. Cultured KYN-2 cells formed trabecular aggregates in suspension, but when adhering to integrin-stimulating substrata, they scattered according to phosphorylation of extracellular signal-regulated kinase (ERK). Upon treatment with ERK kinase (MEK) inhibitor PD98059, adhered KYN-2 cell scattering was inhibited, tight cell-to-cell contact was recovered, and both E-cadherin and actin filaments accumulated in the area of intercellular contact zone. In contrast, constitutively active MEK1-transfected KYN-2 cells showed reduced E-cadherin and actin filaments in the intercellular contact zone, showing a flattened phenotype with broad lamellipodia. Enforced signaling of MEK-ERK pathway in KYN-2 cells suppressed cadherin-mediated homotypic adhesion and increased the potential of cell motility. An antibody-based protein microarray analysis revealed that the cytoplasmic protein c-Cbl was significantly downregulated in MEK1-transfected KYN-2 cells, suggesting that c-Cbl might be a candidate downstream mediator of integrin/MEK/ERK-mediated cell scattering. In conclusion, cell scattering of the highly metastatic cell line KYN-2 is regulated through the integrin-MEK-ERK signaling cascade, suggesting that this molecular pathway may be critical in intrahepatic metastasis of human HCC.

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  • A primary follicular lymphoma of the duodenum treated successfully with radiation therapy Reviewed

    Masaaki Takamura, Rintaro Narisawa, Yudzuru Maruyama, Junji Yokoyama, Yasuo Fukuhara, Hirokazu Kawai, Satoshi Yamagiwa, Yuichi Sato, Yasunobu Matsuda, Kazuhito Sugimura, Takafumi Ichida, Yutaka Aoyagi

    Internal Medicine   45 ( 5 )   309 - 311   2006.4

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    A 48-year-old man was admitted to our hospital because of repeated episodes of epigastralgia. Endoscopy showed multiple whitish granules extending from the 2nd to 3rd portion of the duodenum. Biopsy specimens showed well circumscribed follicles with a monotonous population of predominantly small cleaved cells that were positive for CD20, CD10 and BCL-2, but negative for CD5. A full staging study showed no abnormalities. The tumor was finally diagnosed according to the WHO classification as a stage I follicular lymphoma (FL), grade 1, of the duodenum and subsequently received irradiation to the involved area. After 3 years of follow-up, he is still in complete remission. Because FL arising in the duodenum has recently reported with increasing frequency, patients with multiple granules in the duodenum should be examined carefully. © 2006 The Japanese Society of Internal Medicine.

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  • Long-term outcomes of hepatectomy vs percutaneous ablation for treatment of hepatocellular carcinoma &lt;= 4 cm Reviewed

    Toshifumi Wakai, Yoshio Shirai, Takeshi Suda, Naoyuki Yokoyama, Jun Sakata, Pauldion V. Cruz, Hirokazu Kawai, Yasunobu Matsuda, Masashi Watanabe, Yutaka Aoyagi, Katsuyoshi Hatakeyama

    WORLD JOURNAL OF GASTROENTEROLOGY   12 ( 4 )   546 - 552   2006.1

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    AIM: To determine which treatment modality hepatectomy or percutaneous ablation - is more beneficial for patients with small hepatocellular carcinoma (HCC) (&lt;= 4 cm) in terms of long-term outcomes.
    METHODS: A retrospective analysis of 149 patients with HCC &lt;= 4 cm was conducted. Eighty-five patients underwent partial hepatectomy (anatomic in 47 and non-anatomic in 38) and 64 underwent percutaneous ablation (percutaneous ethanol injection in 37, radiofrequency ablation in 21, and microwave coagulation in 6). The median follow-up period was 69 mo.
    RESULTS: Hepatectomy was associated with larger tumor size (P&lt;0.001), whereas percutaneous ablation was significantly associated with impaired hepatic functional reserve. Local recurrence was less frequent following hepatectomy (P&lt;0.0001). Survival was better following hepatectomy (median survival time: 122 mo) than following percutaneous ablation (median survival time: 66 mo; P = 0.0123). When tumor size was divided into &lt;= 2 cm vs &gt; 2 cm, the favorable effects of hepatectomy on long-term survival was seen only in patients with tumors &gt;2 cm (P=0.0001). The Cox proportional hazards regression model revealed that hepatectomy (P=0.006) and tumors &lt;= 2 cm (P=0.017) were independently associated with better survival.
    CONCLUSION: Hepatectomy provides both better local control and better long-term survival for patients with HCC &lt;= 4 cm compared with percutaneous ablation. Of the patients with HCC &lt;= 4 cm, those with tumors &gt; 2 cm are good candidates for hepatectomy, provided that the hepatic functional reserve of the patient permits resection. (C) 2006 The WJG Press. All rights reserved.

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  • Overexpressed Id-1 is associated with a high risk of hepatocellular carcinoma development in patients with cirrhosis without transcriptional repression of p16 Reviewed

    Y Matsuda, S Yamagiwa, M Takamura, Y Honda, Y Ishimoto, T Ichida, Y Aoyagi

    CANCER   104 ( 5 )   1037 - 1044   2005.9

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    BACKGROUND. Inhibitor of differentiation/ DNA binding protein 1 (Id-1) plays a pivotal role in the regulation of cell proliferation and carcinogenesis via inhibiting basic helix-loop -helix (HLH) transcription factors. Recently, Id-1 was found to repress p16 in tumorous tissue specimens including hepatocellular carcinoma (HCC), but its relevance in precancerous liver tissues is unknown.
    METHODS. Id-1 expression in the liver tissue specimens of 112 patients with cirrhosis without HCC was studied by immunohistochemical analysis. Correlations were investigated between Id-1 expression and clinicopathologic features, the status of p16, and the risk of HCC occurrence.
    RESULTS. A high expression of Id-1 was observed in 42 patients (38%). The level of Id-1 expression was not associated with clinical standard parameters or the status of p16 in cirrhotic tissue specimens. The cumulative incidence of HCC development was significantly higher in a group of patients with high Id-1 expression (P 0.0008). Multivariate analysis revealed that increased Id-1 expression is an independent significant factor for the risk of HCC development in patients with cirrhosis (relative risk = 2.75, P = 0.003).
    CONCLUSIONS. The results of the current study suggested that increased expression of Id-1 may play an important role in the early step of hepatocarcinogenesis, and might serve as a useful marker for determining patients with cirrhosis with a high risk of HCC occurrence.

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  • Long-term extensive expansion of mouse hepatic stem/progenitor cells in a novel serum-free culture system Reviewed

    Atsunori Tsuchiya, Toshio Heike, Hisanori Fujino, Mitsutaka Shiota, Katsutsugu Umeda, Momoko Yoshimoto, Yasunobu Matsuda, Takafumi Ichida, Yutaka Aoyagi, Tatsutoshi Nakahata

    Gastroenterology   128 ( 7 )   2089 - 2104   2005.6

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    Background &amp
    Aims: The liver has high regenerative potential. We attempted to establish a novel culture system for extensive expansion of fetal mouse hepatic stem/progenitor cells and to characterize cultured cells. Methods: Hepatic spheroids collected from 6-day floating cultures were cultured on collagen-coated dishes in serum-free conditions in medium containing growth factors. Cultured cells were mainly characterized by immunocytochemistry and flow cytometry or transplanted into adult mice. Results: Approximately 400 expanding hepatic spheroids were generated from every 1 × 106 fetal liver cells. Subsequently, highly replicative colonies were subcultured with maintaining colony formation on collagen-coated dishes. These colonies consisted of small immature α-fetoprotein-positive cells and hepatocytic and cholangiocytic lineage-committed cells. The immature α-fetoprotein- positive cells could be expanded in a reproducible manner at least 5 × 105-fold (which involved at least 30 passages over &gt
    6 months) without losing differentiation potential. Flow cytometric analysis showed that all cultured cells expressed CD49f, but not CD34, Thy-1, c-kit, or CD45. Nearly 15% of the cells expressed Sca-1, and approximately 5%-20% of the cells were side population cells. Both sorted side population cells and Sca-1-positive cells (especially side population cells) produced a large number of α-fetoprotein-positive cells and lineage-committed cells. Expanded cells had bidirectional differentiation potential and improved serum albumin levels in mice with severe liver damage. Conclusions: Long-term extensive expansion of transplantable hepatic stem/progenitor cells was reproducibly achieved in a novel serum-free culture system. Moreover, this culture system yielded side population and Sca-1-positive cell populations that included hepatic stem/progenitor cells with differentiation and proliferation properties. © 2005 by the American Gastroenterological Association.

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  • Complete disappearance of pulmonary metastases in a case of hepatocellular carcinoma treated with docetaxel-based systemic chemotherapy Reviewed

    T Ishikawa, T Ichida, J Yokoyama, Y Matsuda, T Watanabe, H Asakura

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   19 ( 12 )   1423 - 1426   2004.12

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    A case of the complete shrinkage of pulmonary metastases from multiple hepatocellular carcinomas (HCC) after administration of docetaxel, cisplatin and enteric-coated tegafur/uracil is reported. A 54-year-old Japanese man was diagnosed with recurrent multiple HCC associated with pulmonary metastases and compensated liver cirrhosis. Docetaxel, cisplatin and enteric-coated tegafur/uracil were given to this patient. After 2 months of treatment, there was a decrease in tumor markers and a shrinkage of the pulmonary metastases. Image analyses such as chest X-rays and chest computed tomography scans showed a disappearance of the pulmonary metastases, although the multiple HCC did not disappear completely. This was evaluated as a complete remission of metastatic lesions or a partial remission of primary lesions according to the World Health Organization criteria. No recurrence of pulmonary metastasis was seen for 10 months. This combination therapy was well-tolerated for lung cancer and could represent an effective treatment for pulmonary metastases from HCC. (C) 2004 Blackwell Publishing Asia Pty Ltd.

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  • Overexpression of extracellular signal-regulated protein kinase and its correlation with proliferation in human hepatocellular carcinoma Reviewed

    Y Tsuboi, T Ichida, S Sugitani, T Genda, J Inayoshi, M Takamura, Y Matsuda, M Nomoto, Y Aoyagi

    LIVER INTERNATIONAL   24 ( 5 )   432 - 436   2004.10

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    Background: Dysregulation of cell proliferation is one of the most important features of human cancers including hepatocellular carcinoma (HCC). However, the molecular basis underlying the proliferation of HCC has not been fully clarified. Because a previous study reported that overexpression of extracellular signal-regulated protein kinase (ERK), which transduces extracellular growth stimuli to the nuclei, was frequently observed in several human cancers, this study was performed to analyze the expression of ERK in human HCC and its correlation with HCC proliferation. Methods: Twenty-four paired samples of primary HCCs and corresponding noncancerous liver tissues, and six samples of histologically normal liver tissue were obtained from surgically resected materials. The expression of ERK was examined by immunoblotting and immunohistochemical analysis. Proliferative activity of each HCC was examined by immunohistochemical demonstration of proliferative cell nuclear antigen (PCNA). Results: The ERK1 and ERK2 expression in HCCs was significantly higher than that in noncancerous liver tissues, and the ERK1 expression in noncancerous liver tissues from patients with HCC was higher than that in tissue from normal liver. Immunohistochemical examination revealed enhanced accumulation of ERK1 in the nuclei of HCC cells. Regression analysis revealed a significant correlation between ERK expression and PCNA labeling index in HCC. Conclusions: Our findings suggest that ERK overexpression contributes to the proliferation of HCC.

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  • Reduced expression of liver-intestine cadherin is associated with progression and lymph node metastasis of human colorectal carcinoma Reviewed

    M Takamura, T Ichida, Y Matsuda, M Kobayashi, S Yamagiwa, T Genda, K Shioji, S Hashimoto, M Nomoto, K Hatakeyama, Y Ajioka, M Sakamoto, S Hirohashi, Y Aoyagi

    CANCER LETTERS   212 ( 2 )   253 - 259   2004.8

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    Liver-intestine cadherin (LI-cadherin) is a recently identified member of the cadherin superfamily. We examined LI-cadherin expression in four human colorectal carcinoma cell lines and 45 human primary colorectal carcinomas using a monoclonal antibody against LI-cadherin. We also investigated the correlation between LI-cadherin expression and clinicopathologic parameters. Among the cell lines, LI-cadherin expression was detected in a differentiated phenotype, but not in dedifferentiated phenotypes. Among the 45 tumor samples, LI-cadherin expression was preserved in 28 (62%) and reduced in 17 (38%). Reduced LI-cadherin expression was significantly associated with a high tumor grade (P = 0.015), lymphatic invasion (P = 0.033), lymph node metastasis (P = 0.015), and an advanced pTNM stage (P 0.033). These results suggest that analysis of LI-cadherin expression may help to indicate the biological aggressiveness of this malignancy. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

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  • Recurrence of hepatocellular carcinoma 102 months after successful eradication and removal of membranous obstruction of the inferior vena cava Reviewed

    M Takamura, T Ichida, J Yokoyama, Y Matsuda, M Nomoto, Y Aoyagi

    JOURNAL OF GASTROENTEROLOGY   39 ( 7 )   681 - 684   2004.7

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    We report a 54-year-old Japanese woman who developed liver tumors 102 months after hepatic resection for hepatocellular carcinoma (HCC) and percutaneous transluminal angioplasty (PTA) for membranous obstruction of the inferior vena cava (MOVC), which is one form of Budd-Chiari syndrome. In the present admission workup showed no evidence of co-infection with hepatitis B and C viruses. Dynamic computed tomography (CT) and magnetic resonance imaging showed an enhanced lesion, 1.5 cm in diameter, in segment 3 of the liver, and no obstruction of the inferior vena cava after PTA. CT during both arterial portography and hepatic arteriography revealed another lesion, showing different hemodynamics, in segment 2. The patient therefore underwent hepatic resection, and the tumors were diagnosed histologically as HCC. The two tumors differed in their morphological features, one containing abundant fibrous stroma, whereas the other did not. The nontumorous liver tissue showed central zonal fibrosis, i.e., reversed lobulation, and partial expansion of nodule-like formations, indicating lack of progression since the situation seen at the initial hepatectomy. The presence of nontumorous liver tissue showing the above features suggests that, even after successful treatment for relief of congestion, patients who have had MOVC should be followed closely for as long as possible because of the risk of HCC recurrence. This is the first reported case of HCC recurrence after successful treatment of MOVC.

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  • Loss of p16 contributes to p27 sequestration by cyclin D-1-cyclindependent kinase 4 complexes and poor prognosis in hepatocellular carcinoma Reviewed

    Y Matsuda, T Ichida, T Genda, S Yamagiwa, Y Aoyagi, H Asakura

    CLINICAL CANCER RESEARCH   9 ( 9 )   3389 - 3396   2003.8

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    Purpose: p27(Kipl) (p27) might act as an adverse prognostic marker for various types of cancers. However, its clinical usefulness remains uncertain, because it is sometimes overexpressed in aggressive types.
    Experimental Design: To precisely evaluate the practical significance of p27 in hepatocellular carcinoma (HCC), we immunohistochemically compared the level of p27 expression with Ki-67 labeling in 74 HCCs and focused on tumors in which cell proliferation increased despite a high level of p27 expression. We then analyzed the status of p27 and related cell-cycle regulators using kinase and immuno-precipitation assays, Western blotting, and methylation-specific PCR to understand the rationale for the functional inactivation of p27 in HCC. We also evaluated relationships between the key biological characteristics of HCC and survival.
    Results: Immunohistochemical studies showed that 40 (54%) of 74 HCCs expressed high levels of p27 (&gt;50% of the tumor cells). Of these, the Ki-67 labeling index was low (&lt;20%) in 26 (65%) and high (&gt;20%) in 14 (35%). Increased proliferative activities were closely correlated with elevated kinase activities, sequestration of p27 protein, and p16 gene methylation. The association between a loss of p16 and poor prognosis was significant when p27 expression was high (P &lt; 0.01).
    Conclusions: The loss of p16 appears to be closely related to the functional inactivation of p27, and assessment of p16 status may be useful for a precise prognostic prediction of individuals with HCC expressing high levels of p27.

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  • Association between K469E allele of intercellular adhesion molecule 1 gene and inflammatory bowel disease in a Japanese population Reviewed

    J Matsuzawa, K Sugimura, Y Matsuda, M Takazoe, K Ishizuka, T Mochizuki, SS Seki, O Yoneyama, H Bannnai, K Suzuki, T Honma, H Asakura

    GUT   52 ( 1 )   75 - 78   2003.1

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    Background and aims: The genetic contribution to inflammatory bowel disease (IBD) is under investigation. Recent evidence indicates a significant linkage between a locus on chromosome 19p13 and IBD. We investigated the association between an intercellular adhesion molecule 1 gene (ICAM-1) polymorphism located on chromosome 19p13 and IBD in a Japanese population.
    Methods: We compared 207 Japanese patients who had IBD (79 with Crohn's disease (CD); 128 with ulcerative colitis (UC)) with 103 unrelated Japanese controls. We determined R241G and K469E polymorphisms of the ICAM-1 gene using polymerase chain reaction (PCR) techniques.
    Results: Both frequency and carriage rate of the K469 allele were significantly higher in IBD patients than in controls (allelic frequency, p(c)=0.0026; carriage rate, p(c)=0.0034; odds ratio 2.59; 95% confidence interval 1.42-4.68). Furthermore, the frequency of the K469 allele was significantly increased in both CD and UC. Subgroup analysis demonstrated that both K469 allelic frequency and K469 carriage rate were significantly higher in patients with the small bowel and colon type of CD and entire colitis compared with healthy controls.
    Conclusions: We identified an overall association between IBD and ICAM-1 K469 in a Japanese population. Further studies of this chromosome region are required to elucidate the gene responsible for IBD.

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  • Thrombopoietin receptor (c-Mpl) is constitutively expressed on platelets of patients with liver cirrhosis, and correlates with its disease progression Reviewed

    T Ishikawa, T Ichida, S Sugahara, S Yamagiwa, Y Matsuda, K Uehara, T Kato, H Miyazaki, H Asakura

    HEPATOLOGY RESEARCH   23 ( 2 )   115 - 121   2002.6

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    Thrombocytopenia is one of the major complications of liver cirrhosis. Except for hypersplenism associated with portal hypertension, it is not known which abnormalities of thrombopoiesis cause thrombocytopenia. To evaluate thrombopoiesis in liver cirrhosis, we analyzed thrombopoietin (TPO) and its receptor c-Mpl levels in cirrhotic patients. Expression of c-Mpl on platelets and the serum level of TPO were investigated from 38 patients with various stages of liver cirrhosis by flow-cytometric analysis and enzyme-immuno assay. Samples obtained from 22 individuals without evidence of liver disease were used as controls. Neither platelet counts nor TPO levels correlated with disease progression defined by the Child-Pugh classification. c-Mpl was constitutively expressed on the platelets of cirrhotic patients, and its expression level was reduced with disease progression defined by the Child-Pugh classification. In this study, serum TPO did not fluctuate according to the grade of cirrhosis. However, its receptor c-Mpl, which is expressed on platelets, was decreased significantly in severely cirrhotic patients with thrombocytopenia. Thus, a correlation between reduced c-Mpl expression and the progression of liver cirrhosis was demonstrated. We conclude that, in addition to hypersplenism, the reduced expression of c-Mpl may play a significant role in the thrombocytopenia observed in severe liver cirrhosis. (C) 2002 Elsevier Science B.V. All rights reserved.

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  • Expression of hepatic thrombopoietin mRNA in primary cultured hepatocytes and in rats with acute liver injury or bone marrow suppression with or without cirrhosis Reviewed

    T Ishikawa, T Ichida, Y Matsuda, S Sugitani, M Sugiyama, T Kato, H Miyazaki, H Asakura

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   15 ( 6 )   647 - 653   2000.6

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    Background and Aims: The main causes of thrombocytopenia in cirrhosis are thought to be platelet destruction and the reduction of thrombopoietin (TPO) expression in the liver. The mechanisms by which levels of TPO mRNA are regulated in cirrhosis have not been elucidated. In this study, we investigated some possible mechanisms.
    Methods: We used three experimental models: bone marrow suppression, acute liver injury and primary cultured hepatocytes. We used northern blots to assess the kinetics of TPO mRNA expression in the livers of irradiated rats (with and without cirrhosis) in acute liver injury and in primary cultured hepatocytes treated with hepatotoxin or cytokines.
    Results: Although the bone marrow was hypocellular, there was no apparent enhancement of TPO mRNA expression in the irradiated rats with cirrhotic livers compared with the unirradiated rats with cirrhotic livers. There were no conspicuous changes in hepatic TPO mRNA expression between the livers of the control rats and the three models of acute liver injury. There were no conspicuous changes in the levels of TPO mRNA between control hepatocytes and hepatocytes treated with hepatotoxin or cytokines.
    Conclusions: Our results suggest that bone marrow is not a regulator of hepatic TPO production in cirrhosis. The reduced TPO mRNA expression found in cirrhotic rats may not result merely from serious cellular damage; it may be associated with cirrhosis-specific regulatory mechanisms for the expression of the TPO gene. Further studies are needed to search for other factors that may induce reduced TPO expression. (C) 2000 Blackwell Science Asia Pty Ltd.

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  • Nuclear translocation of beta-catenin in colorectal cancer Reviewed

    M Kobayashi, T Honma, Y Matsuda, Y Suzuki, R Narisawa, Y Ajioka, H Asakura

    BRITISH JOURNAL OF CANCER   82 ( 10 )   1689 - 1693   2000.5

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    Post-translational stabilization of beta-catenin through mutation of the adenomatous polyposis coli (APC) gene has been proposed as an early step in colorectal carcinogenesis. Beta-catenin may translocate from the cytoplasm to the nucleus, where it might serve as a transcriptional factor to stimulate tumour formation. We investigated intracellular localization of beta-catenin in sporadic colorectal adenomas and cancers as well as familial adenomatous polyposis (FAP). Nuclear over-expression of beta-catenin was observed in 35% (7/20) of intramucosal cancers and 42% (23/55) of invasive cancers but was not seen in any adenomas from sporadic or FAP cases. Cytoplasmic beta-catenin in adenomas was significantly higher than that of normal mucosa in both sporadic and FAP cases. The cytoplasmic intensity index of cancers was significantly higher than that of sporadic adenomas, but the index was not correlated with nuclear expression in cancers. These findings suggest that nuclear translocation of beta-catenin is involved in development of intramucosal cancer rather than adenoma, independent of APC mutations. Cytoplasmic accumulation of beta-catenin may occur in adenomas, but it remains to be determined whether this is a cause or a consequence of colorectal cancer. (C) 2000 Cancer Research Campaign.

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  • Interaction between hyaluronan and CD44 in the development of dimethylnitrosamine-induced liver cirrhosis Reviewed

    T Satoh, T Ichida, Y Matsuda, M Sugiyama, K Yonekura, T Ishikawa, H Asakura

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   15 ( 4 )   402 - 411   2000.4

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    Background: A significant increase in serum hyaluronan (HA) levels has been reported in patients with liver cirrhosis. This mechanism is not yet clear, and receptors for HA have not been characterized. In this study, we examined the expression of both HA and its receptors, CD44 and intercellular adhesion molecule-1 (ICAM-1), in dimethylnitrosamine-induced liver cirrhosis.
    Methods and Results: Using biotinylated HA binding protein, HA was detected in the area of periportal fibrosis and around the sinusoidal wall where hepatic fibrosis was developing. Electron microscopy revealed that HA was localized on Ito cells and sinusoidal endothelial cells (SEC). Conversely, CD44, which was only expressed weakly in normal liver, was present in large amounts in cirrhotic liver. The distribution pattern of CD44 was similar to that of HA, however, CD44 was mainly localized on the infiltrating lymphocytes and Kupffer cells. Moreover, CD44 was detected on part of factor VIII-positive SEC. intercellular adhesion molecule-1, another receptor for HA, was detected on the surface of hepatocytes and around the sinusoidal wall in cirrhotic liver, but its distribution was not accompanied by expression of HA. With respect to CD44 isoforms, the standard form m-RNA predominated in both normal and cirrhotic liver. Variant pMeta-1 mRNA was detected at low levels.
    Conclusions: An interaction between HA and CD44 may play a role in the recruitment of numerous infiltrating cells and HA accumulation in hepatic sinusoids. Together with phenotypic changes in the SEC, these results may lead to a disturbance in the elimination of HA during the progression of liver cirrhosis. (C) 2000 Blackwell Science Asia Pty Ltd.

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  • p16(INK4) is inactivated by extensive CpG methylation in human hepatocellular carcinoma Reviewed

    Y Matsuda, T Ichida, J Matsuzawa, K Sugimura, H Asakura

    GASTROENTEROLOGY   116 ( 2 )   394 - 400   1999.2

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    Background & Aims: The molecular status of the p16(INK4) tumor-suppressor gene has not been fully elucidated in hepatocellular carcinoma. The aim of this study was to clarify the mechanism that gives rise to inactivation of p16(INK4) in hepatocellular carcinoma. Methods: The status of p16(INK4) was evaluated in 60 hepatocellular carcinomas by immunohistochemical staining, differential polymerase chain reaction, single-strand conformational polymorphism, methylation-specific polymerase chain reaction, and methylation-sensitive single nucleotide primer extension. Results: Immunohistochemical staining showed that 29 of the 60 tumors exhibited complete toss of p16(INK4) expression. High levels of DNA methylation were detected in 24 of 29 cases of hepatocellular carcinoma with negative p16(INK4) expression, with methylation of 60%-85% of the CpG islands. In contrast, the level of methylation was &lt;25% in tumors with faint p16(INK4) staining and no methylation was detected in tumors with positive immunostaining. Intragenic alteration of p16(INK4) was detected in 4 cases. Conclusions: A strong correlation was found between the extent of methylation and the degree of expression of p16(INK4) in tumor tissues, indicating that epigenetic change due to extensive CpG methylation is the main cause of inactivation of p16(INK4) in hepatocellular carcinoma.

    DOI: 10.1016/S0016-5085(99)70137-X

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  • Areas of sinusoidal surface hepatocyte nuclear predominance in type C chronic hepatitis Reviewed

    Y Tanaka, T Ichida, M Nomoto, Y Matsuda, H Asakura

    LIVER   18 ( 6 )   383 - 390   1998.12

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    Aims/Background: Thick hepatic plates have been considered one of the morphological characteristics of hepatocyte regeneration in cirrhotic nodules. They can be recognized by the sinusoidal surface predominance of their nuclei. We have investigated the prevalence of this in HBV and HCV infections. Methods and Results: This feature was more frequently present in type C chronic hepatitis with low activity of inflammation and low grade of fibrosis, than with type B chronic hepatitis. Additionally, this area of sinusoidal surface hepatocyte nuclear predominance (ASSHNP) was seen in zone II, rather than in periportal zones, in type C chronic hepatitis. Clinical data were analyzed statistically. Immunohistochemical reactivity of type IV collagen, laminin, Ulex europaeus agglutinin 1 lectin (UEA-1), and factor VIII-related antigen were increased in ASSHNP. Immunohistochemical staining of Ki-67 antigen was performed in order to assess the regenerative capacity of this area and showed a low level of regeneration. Ultrastructure of this area in type C chronic hepatitis showed a decrease in the number of mitochondria and an increase of nuclear pleomorphism together with basement membrane formation in the space of Disse. Conclusion. Although the cause of these abnormalities was not clarified in this study, it is suggested that they are related to chronic hepatitis C virus (HCV) infection per se, rather than regeneration or inflammatory activity. These changes may be significant in HCV-associated hepatocarcinogenesis.

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  • Reduced expression of thrombopoietin is involved in thrombocytopenia in human and rat liver cirrhosis Reviewed

    T Ishikawa, T Ichida, Y Matsuda, S Sugitani, M Sugiyama, T Kato, H Miyazaki, H Asakura

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   13 ( 9 )   907 - 913   1998.9

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    It is widely accepted that thrombocytopenia associated with liver cirrhosis is caused by increased platelet destruction in the enlarged spleen, but this issue has not yet been analysed sufficiently in terms of platelet production. Thrombopoietin is produced mainly in the liver and strongly promotes platelet production. We studied serum thrombopoietin and the levels of its mRNA in liver tissue of cirrhotic patients and also in a rat model of liver cirrhosis. Furthermore, to clarify the influence of the spleen, we investigated thrombopoietin mRNA in splenectomized rats. The serum thrombopoietin level in humans with liver cirrhosis was not significantly reduced instead of thrombocytopenia. The expression of thrombopoietin mRNA in liver tissue decreased with the progression of liver cirrhosis in both patients and the rat model and no compensatory expression was observed in other organs or nonparenchymal cells. The level of thrombopoietin mRNA did not differ significantly in splenectomized cirrhotic rats before or after administration of dimethylnitrosamine, but was lower than that in splenectomized rats without cirrhosis. We conclude that thrombocytopenia in liver cirrhosis is caused not only by platelet destruction but also by decreased platelet production, perhaps due to reduction of thrombopoietin mRNA in the liver.

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  • Hepatocyte growth factor suppresses the onset of liver cirrhosis and abrogates lethal hepatic dysfunction in rats. Reviewed

    Matsuda Y, Matsumoto K, Ichida T, Nakamura T

    J Biochem   118 ( 3 )   643 - 649   1998.4

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  • Autoantibodies against a 210 kDa glycoprotein of the nuclear pore complex as a prognostic marker in patients with primary biliary cirrhosis Reviewed

    S Itoh, T Ichida, T Yoshida, A Hayakawa, M Uchida, T Tashiro-Itoh, Y Matsuda, K Ishihara, H Asakura

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   13 ( 3 )   257 - 265   1998.3

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    It has been reported that the presence of anti-nuclear antibody against a 210 kDa glycoprotein of nuclear pore complex (anti-gp210) is highly specific for primary biliary cirrhosis (PBC). The aim of the present study was to investigate the significance of anti-gp210, especially as a prognostic marker. The presence of anti-gp210 was ascertained in 113 patients with PBC and 162 controls by indirect immunofluorescence assay using HepG2. cells and immunoblotting analysis using nuclear extracts from HeLa cells. Anti-gp210 was detected in 25 of the 113 (22.1%) patients. None of the 162 controls was positive for anti-gp210. The appearance and titre of anti-gp210 in the patients with PBC did not vary from the time of diagnosis and through their clinical course. Anti-mitochondrial antibodies (AMA), including antibodies against pyruvate dehydrogenase complex, branched chain a-ketoacid dehydrogenase complex and or-ketoglutarate dehydrogenase complex, were not detected by enzyme-linked immunosorbent assay in five of the 113 (4.4%) patients with PBC. However, anti-gp210 alone was positive in one of these five patients. The difference in prognosis was statistically significant; patients with PBC positive for anti-gp210 died from hepatic failure more frequently than those who were negative (P &lt; 0.01), although there were no statistically significant differences in the frequency of jaundice and the histological stage at the time of diagnosis between the two groups. We suggest that the presence of anti-gp210 is one of the independent prognostic markers able to predict, at the time of diagnosis, a poor outcome in patients with PBC.

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  • Expression of activin A is increased in cirrhotic and fibrotic rat livers Reviewed

    M Sugiyama, T Ichida, T Sato, T Ishikawa, Y Matsuda, H Asakura

    GASTROENTEROLOGY   114 ( 3 )   550 - 558   1998.3

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    Background & Aims: Activin A, a member of the transforming growth factor (TGF)-beta superfamily, recently has been reported to suppress DNA synthesis and to induce apoptosis of hepatocytes. These biological functions are similar to those of TGF-beta 1, which is overexpressed in liver cirrhosis. The aim of this study was to examine whether activin A is involved in liver cirrhosis and fibrosis. Methods: Liver cirrhosis or fibrosis was induced by intraperitoneal injections of dimethylnitrosamine or porcine serum into rats. The kinetics of activin A messenger RNA (mRNA) expression in cirrhotic and fibrotic livers and primary cultured rat hepatocytes were assessed by Northern blotting, and the localization of activin A was determined immunohistochemically. Modulation of type 1 collagen mRNA expression by activin A in rat cultured Ito/fat-storing cells and fibroblasts was also examined. Results: Northern blotting showed that activin A mRNA expression was enhanced in fibrotic livers. The numbers of hepatocytes expressing immunoreactive activin A were significantly greater, especially around the fibrotic areas. Activin A mRNA expression in cultured hepatocytes was increased significantly by TGF-beta 1 and by activin A itself. Furthermore, type 1 collagen mRNA expression in cultured cells was enhanced by activin A and TGF-beta 1 in a synergistic manner. Conclusions: Activin A is overexpressed in rat cirrhotic and fibrotic livers and may contribute to hepatic fibrogenesis.

    DOI: 10.1016/S0016-5085(98)70539-6

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  • Selective depletion of neutrophils by a monoclonal antibody, RP-3, suppresses dextran sulphate sodium-induced colitis in rats Reviewed

    M Natsui, K Kawasaki, H Takizawa, SI Hayashi, Y Matsuda, K Sugimura, K Seki, R Narisawa, F Sendo, H Asakura

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   12 ( 12 )   801 - 808   1997.12

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    Administration of dextran sulphate sodium to animals induces acute colitis characterized by infiltration of large numbers of neutrophils into the colonic mucosa, which histologically resembles human active ulcerative colitis. It has been reported that neutrophils and the reactive oxygen metabolites produced by them are involved in the progress of ulcerative colitis. This study was intended to clarify their roles by using this animal model. First, possible sources and species of reactive oxygen metabolites were determined using luminol-dependent chemiluminescence with addition of enzyme inhibitors and reactive oxygen metabolite scavengers. Next, to examine whether neutrophils and hypochlorous acid derived from them contribute to tissue injury, we administered RP-3, a monoclonal antibody capable of selectively depleting neutrophils, and taurine, a hypochlorous acid scavenger, to rats treated with dextran sulphate sodium. Addition of azide, taurine, catalase, superoxide dismutase and dimethyl sulphoxide into colonic mucosal scrapings significantly inhibited chemiluminescence production, but allopurinol and indomethacin had no effects. These results suggest that excessive hypochlorous acid, hydrogen peroxide, superoxide anion and hydroxyl radical are generated by the inflamed colonic mucosa. Intraperitoneal injections of RP-3 significantly suppressed bleeding, tissue myeloperoxidase activity, chemiluminescence production and erosion formation. On the other hand, administration of taurine tended to inhibit bleeding and erosion formation to some extent, although it could not significantly suppress them. These data suggest that neutrophils play an important role in the development of this colitis and that hypochlorous acid might be one of the causes of tissue injury induced by neutrophils.

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  • Metallothionein expression and concentrations of copper and zinc are associated with tumor differentiation in hepatocellular carcinoma Reviewed

    T Tashiro-Itoh, T Ichida, Y Matsuda, T Satoh, M Sugiyama, Y Tanaka, T Ishikawa, S Itoh, M Nomoto, H Asakura

    LIVER   17 ( 6 )   300 - 306   1997.12

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    Metallothionein is the carrier protein of heavy metal ions, such as copper (Cu) and zinc (Zn). In this study, the relationships among immunohistochemical expression of metallothionein, concentrations of Cu and Zn, histological differentiation and proliferative activity of hepatocellular carcinoma were investigated in 51 cases. The concentrations of Cu and Zn in both tumor and non-tumor tissues were determined using electron probe microanalysis. Immunohistochemical expression of metallothionein in tumor tissues decreased with the degree of differentiation, whereas the number of hepatocytes positive for Ki-67 increased. Furthermore, the concentrations of Cu and Zn in tumor tissues decreased with the degree of histological differentiation in human hepatocellular carcinoma.

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  • Preventive and therapeutic effects in rats of hepatocyte growth factor infusion on liver fibrosis/cirrhosis Reviewed

    Yasunobu Matsuda, Kunio Matsumoto, Akira Yamada, Takafumi Ichida, Hitoshi Asakura, Yasunobu Komoriya, Eiji Nishiyama, Toshikazu Nakamura

    Hepatology   26 ( 1 )   81 - 89   1997

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    Liver fibrosis/cirrhosis is characterized by hyper-accumulation of fibrous tissue components and is commonly observed in later or terminal states of chronic hepatic diseases. In ongoing work, we found that the administration of human recombinant hepatocyte growth factor (hrHGF) suppressed the onset of liver fibrosis/cirrhosis in several distinct models and accelerated the recovery from liver fibrosis/cirrhosis in rats. Repeated administration of porcine serum for 10 weeks to rats induced liver fibrosis without any accompanying hepatocellular injuries
    in addition, the intravenous (i.v.) administration of hepatocyte growth factor (HGF) to these rats suppressed increases in fibrous components and hydroxyproline contents in the liver, thus preventing the onset of liver fibrosis. Repeated administration of dimethylnitrosamine (DMN) for four weeks induced liver cirrhosis, as characterized by the hyperaccumulation of fibrous components, infiltration of mononuclear leukocytes, and hepatic dysfunction. When HGF was injected daily for four weeks along with DMN-treatment, the onset of DMN- induced hepatic fibrosis/cirrhosis was suppressed
    the numbers of infiltrating mononuclear cells, fibrous tissue components, and hydroxyproline content in the liver were decreased. When HGF was injected for two weeks following four weeks of DMN-treatment, HGF accelerated the recovery from liver cirrhosis and prevented death due to hepatic dysfunction. Likewise, HGF-injection suppressed the onset of liver fibrosis, when liver fibrosis had been induced by long-term treatment with carbon tetrachloride (CCl4). Thus, the administration of HGF holds great promise for treating subjects with liver fibrosis/cirrhosis as a result of chronic hepatic injury.

    DOI: 10.1002/hep.510260111

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  • Localization of hyaluronan in human liver sinusoids: A histochemical study using hyaluronan-binding protein Reviewed

    T Ichida, S Sugitani, T Satoh, Y Matsuda, M Sugiyama, K Yonekura, T Ishikawa, H Asakura

    LIVER   16 ( 6 )   365 - 371   1996.12

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    Circulating hyaluronan is mostly derived from lymph, fibroblast and Ito cells in the liver; and more than 90% of hyaluronan is degraded in hepatic sinusoidal endothelial cells. Thus, elevated serum hyaluronan is regarded as an indication of hepatic fibrosis with activated Ito cells and dysfunctional sinusoidal endothelial cells. We studied the distribution of hyaluronan in human liver sinusoids to determine the influences on elevated hyaluronan levels in sera. Histochemical examination was made using hyaluronan-binding protein (HABP) and serial sections of liver tissue for staining of alpha-smooth muscle actin (ASMA) (an indicator of activated Ito cells) and of ulex europaeus agglutinin I lectin (UEA-1) (closely related to hepatic sinusoidal capillarization). Positive staining, indicating the presence of hyaluronan, was noted in fibrous regions around the portal tracts, areas of focal necrosis in the liver parenchyma, and walls of the sinusoids in chronic hepatitis. In this group, hyaluronan-positive areas corresponded to positive ASMA staining and faint staining of UEA-1. On the contrary, in liver cirrhosis, UEA-1-positive areas were essentially identical to hyaluronan-positive areas and to ASMA-negative areas in sinusoidal walls. Hyaluronan and ASMA could be detected in the same areas of sinusoidal walls in chronic hepatitis, but not in liver cirrhosis. Hyaluronan appears to be mainly related to the staining of activated Ito cells in chronic hepatitis. Therefore, we concluded that in chronic hepatitis, the production of hyaluronan was accelerated in Ito cells; however, degradation of hyaluronan by sinusoidal endothelial cells continued. On the contrary, in liver cirrhosis, hyaluronan production decreased in Ito cells, and a marked transformation of sinusoidal endothelial cells with hepatic sinusoidal capillarization indicated loss of the ability to degrade hyaluronan. These different mechanisms in chronic hepatitis and liver cirrhosis may operate in the sinusoidal walls and may cause the elevation of hyaluronan in sera.

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  • Hepatocyte growth factor suppresses the onset of liver cirrhosis and abrogates lethal hepatic dysfunction in rats Reviewed

    Yasunobu Matsuda, Kunio Matsumoto, Toshikazu Nakamura, Takafumi Ichida

    Journal of Biochemistry   118 ( 3 )   643 - 649   1995

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    Hepatic fibrosis/cirrhosis is a common hepatic disease characterized by the hyper-accumulation of connective tissue components, and hepatic necrosis. Chronic alcohol inges-tion, viral infection, and metabolic disorders are contributing factors and there has been no effective treatment. Hepatocyte growth factor (HGF), originally identified as a potent mitogen for mature hepatocytes, is a long-sought hepatotrophic factor for liver regeneration. Administration of human recombinant HGF into rats with hepatic fibrosis/cirrhosis caused by dimethylnitrosamine (DMN) elicited mitogenic action for hepatocytes, stimulated hepatic collagenase activity, and prevented the onset and progression of hepatic fibrosis/cirrhosis. Accumulation of fibrous tissue components in the liver due to DMN-treatment were markedly decreased in HGF-injected rats. Moreover, HGF completely abrogated death caused by severe hepatic cirrhosis and dysfunction. We postulate that HGF may prove to be an effective treatment for human liver fibrosis/cirrhosis and for chronic hepatic failure. © 1995 by the Journal of Biochemistry.

    DOI: 10.1093/oxfordjournals.jbchem.a124958

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  • [Molecular biology of hepatocyte growth factor (HGF)].

    Matsuda Y, Nakamura T

    Nihon Rinsho   51 ( 2 )   435 - 445   1993.2

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    Hepatocyte growth factor (HGF) is the most potent mitogen of mature hepatocytes in primary culture, and is a molecule composed of 69 kD alpha-chain and 34 kD beta-chain. HGF predominantly acts on various epithelial cells as a mitogen, motogen and a morphogen. HGF mRNA and HGF protein increases rapidly in the liver and plasma of rats with liver injury such as hepatitis, ischemia, physical crush and partial hepatectomy. Production of HGF in the liver occurs in Kupffer cells, sinusoidal endothelial cells, and Ito cells, but not in hepatocytes. HGF mRNA is also rapidly increased in the intact organs such as lung, kidney and spleen. Thus, HGF may act as a hepatotrophic factor for liver regeneration through two mechanisms: a paracrine mechanism and an endocrine mechanism. Moreover, intravenously injected HGF enhances liver regeneration and protects hepatitis in vivo. Consequently, HGF may prove to be useful for the clinical treatment of patients with liver disease. Recently, we found a factor which specially appears in the blood of rats with organ injury and increases the synthesis of HGF, and it was named &quot;injurin&quot;. IL-1 alpha and IL-1 beta are also positive regulators for the exp

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  • [Molecular biology of hepatocyte growth factor (HGF)].

    Matsuda Y, Nakamura T

    Nihon Rinsho   51 ( 2 )   435 - 445   1993.2

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    Hepatocyte growth factor (HGF) is the most potent mitogen of mature hepatocytes in primary culture, and is a molecule composed of 69 kD alpha-chain and 34 kD beta-chain. HGF predominantly acts on various epithelial cells as a mitogen, motogen and a morphogen. HGF mRNA and HGF protein increases rapidly in the liver and plasma of rats with liver injury such as hepatitis, ischemia, physical crush and partial hepatectomy. Production of HGF in the liver occurs in Kupffer cells, sinusoidal endothelial cells, and Ito cells, but not in hepatocytes. HGF mRNA is also rapidly increased in the intact organs such as lung, kidney and spleen. Thus, HGF may act as a hepatotrophic factor for liver regeneration through two mechanisms: a paracrine mechanism and an endocrine mechanism. Moreover, intravenously injected HGF enhances liver regeneration and protects hepatitis in vivo. Consequently, HGF may prove to be useful for the clinical treatment of patients with liver disease. Recently, we found a factor which specially appears in the blood of rats with organ injury and increases the synthesis of HGF, and it was named &quot;injurin&quot;. IL-1 alpha and IL-1 beta are also positive regulators for the exp

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  • TENASCIN EXPRESSION IN HUMAN CHRONIC LIVER-DISEASE AND IN HEPATOCELLULAR-CARCINOMA Reviewed

    S YAMADA, T ICHIDA, Y MATSUDA, Y MIYAZAKI, T HATANO, K HATA, H ASAKURA, N HIROTA, A GEERTS, E WISSE

    LIVER   12 ( 1 )   10 - 16   1992.2

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    Tenascin is an oligomeric glycoprotein of the extracellular matrix synthesized during embryonic development. It is prominently expressed in a variety of tumors. The role of tenascin in liver tissue is, however, unknown. We used immunocytochemistry to define the localization of tenascin and compare this with the localization of non-collagenous proteins, such as laminin and fibronectin, in normal human liver and pathological liver from patients with chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. In normal liver, tenascin expression was localized along the sinusoidal and vascular wall. In fibrotic liver, tenascin was also observed in the region between the hepatic parenchyma and the fibrosing portal tracts, especially in areas of piecemeal necrosis in chronic hepatitis. Immuno-EM study of liver tissue in chronic hepatitis strongly suggested the synthesis and secretion of tenascin by fat-storing cells into the space of Disse. In hepatocellular carcinoma, tenascin was expressed in both the capsule and lobular septa, but not in the sinusoidal walls of the tumors. These results led us to postulate a close relationship between the occurrence of this protein and disease processes such as fibrosis and cancer invasion.

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  • p27

    MATSUDA Yasunobu( Role: Sole author)

    “Encyclopedia of Cancer” Springer Publishing  2014.1 

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  • Sorafenib

    MATSUDA Yasunobu( Role: Sole author)

    “Encyclopedia of Cancer” Springer Publishing  2014.1 

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  • Sorafenib-Inhibited Signaling: Emerging Evidence of RAF Independent Pathways as Potential Therapeutic Targets in Hepatocellular Carcinoma.

    MATSUDA Yasunobu( Role: Sole author)

    InTech publisher  2013.10  ( ISBN:9789535112020

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    Responsible for pages:239-253   Language:English Book type:Scholarly book

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  • Molecular Mechanism of DNA Damage Response Pathway During Hepatic Carcinogenesis.

    MATSUDA Yasunobu( Role: Sole author)

    InTech publisher  2012.2  ( ISBN:9789535100232

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    Responsible for pages:313-324   Language:English Book type:Scholarly book

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  • Hepatocellular carcinoma – etiology, risk factors and prevention

    MATSUDA Yasunobu( Role: Sole author)

    “Encyclopedia of Cancer” Springer Publishing  2012.1 

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  • NAFLD/NAFLD関連肝細胞癌におけるDNA損傷修復因子pATMおよびpCHK2発現の意義

    廣瀬 雄己, 小林 隆, 松田 康伸, 若井 俊文

    肝臓   60 ( Suppl.2 )   A682 - A682   2019.10

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  • 肝癌薬剤耐性におけるエクソソームの有用性および課題

    松田 康伸, 寺井 崇二

    BIO Clinica   34 ( 7 )   737 - 740   2019.7

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    エクソソームは、細胞-細胞間コミュニケーションを司る機能をもつ不溶性粒子である。近年ではエクソソームががん診断・治療に有用な生体ツールであることが明らかにされて以降、その実用性に関する注目が集まっている。肝がんは化学療法耐性を伴う、予後不良な悪性疾患であり、エクソソームを用いた治療への期待は高い。肝がん由来のエクソソームはがん進展や転移能を促進し、薬剤耐性獲得にも関与しているため、今後はエクソソーム分泌阻害剤による肝がん治療法の開発が待たれている。(著者抄録)

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  • 当院における高齢発症原発性胆汁性胆管炎患者の予後予測マーカーについて

    高村 昌昭, 木村 成宏, 薛 徹, 上村 博輝, 坂牧 僚, 横尾 健, 土屋 淳紀, 上村 顕也, 松田 康伸, 寺井 崇二

    肝臓   60 ( Suppl.1 )   A407 - A407   2019.4

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  • 当院における高齢発症原発性胆汁性胆管炎患者の予後予測マーカーについて

    高村 昌昭, 木村 成宏, 薛 徹, 上村 博輝, 坂牧 僚, 横尾 健, 土屋 淳紀, 上村 顕也, 松田 康伸, 寺井 崇二

    肝臓   60 ( Suppl.1 )   A407 - A407   2019.4

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  • 家兎気管大欠損モデルにおける代用気管と欠損部再生様式

    窪田 正幸, 小林 隆, 松田 康伸

    日本小児外科学会雑誌   54 ( 2 )   356 - 356   2018.4

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  • NAFLDにおけるイベント発生の前方視的検討

    川合 弘一, 松田 康伸, 阿部 聡司, 坂牧 僚, 上村 顕也, 土屋 淳紀, 高村 昌昭, 石川 達, 山際 訓, 杉谷 想一, 渡辺 雅史, 寺井 崇二

    日本消化器病学会雑誌   114 ( 臨増大会 )   A769 - A769   2017.9

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  • uPA/FGF-2経路は肝がん細胞におけるソラフェニブ耐性因子である

    大澤 まみ, 松田 康伸, 窪田 正幸, 若井 俊文

    日本癌学会総会記事   76回   P - 3295   2017.9

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  • 肝癌薬剤耐性におけるエクソソームの有用性および課題

    松田 康伸, 寺井 崇二

    Medical Science Digest   43 ( 7 )   334 - 337   2017.6

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    Language:Japanese   Publisher:(株)ニュー・サイエンス社  

    エクソソームは、細胞・細胞間コミュニケーションを司る機能をもつ不溶性粒子である。近年ではエクソソームががん診断・治療に有用な生体ツールであることが明らかにされて以降、その実用性に関する注目が集まっている。肝がんは化学療法耐性を伴う、予後不良な悪性疾患であり、エクソソームを用いた治療への期待は高い。肝がん由来のエクソソームはがん進展や転移能を促進し、薬剤耐性獲得にも関与しているため、今後はエクソソーム分泌阻害剤による肝がん治療法の開発が待たれている。(著者抄録)

    J-GLOBAL

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  • 肝細胞癌におけるa disintegrin and metalloprotease(ADAM)21発現の意義:in vivoでの検討と切除症例での臨床病理学的意義の検討

    高村昌昭, 本田博樹, 山際訓, 玄田拓哉, 松田康伸, 若井俊文, 寺井崇二

    肝臓   58 ( Supplement 1 )   A289 - A289   2017.4

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  • ベザフィブラート投与原発性胆汁性胆管炎症例におけるUDCA投与量の検討

    山際訓, 松田康伸, 寺井崇二

    肝臓   57 ( Supplement 3 )   A664   2016.10

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    J-GLOBAL

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  • 自己免疫性肝疾患における基礎と臨床 新たな臨床試験の可能性まで ベザフィブラート投与原発性胆汁性胆管炎症例におけるUDCA投与量の検討

    山際 訓, 松田 康伸, 寺井 崇二

    肝臓   57 ( Suppl.3 )   A664 - A664   2016.10

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  • 原発性胆汁性肝硬変に対するUDCA至適投与量の再検討

    山際訓, 松田康伸, 寺井崇二

    肝臓   57 ( Supplement 2 )   A505   2016.9

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  • 自己免疫性肝疾患 これからの課題 原発性胆汁性肝硬変に対するUDCA至適投与量の再検討

    山際 訓, 松田 康伸, 寺井 崇二

    肝臓   57 ( Suppl.2 )   A505 - A505   2016.9

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  • 肝細胞癌におけるa disintegrin and metalloprotease 21発現の生物学的意義に関する検討

    本田 博樹, 高村 昌昭, 山際 訓, 玄田 拓哉, 木村 成宏, 薛 徹, 冨永 顕太郎, 上村 博輝, 松田 康伸, 若井 俊文, 寺井 崇二

    肝臓   57 ( Suppl.1 )   A247 - A247   2016.4

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  • ラジオ波焼灼術を施行した肝細胞癌患者に対するNomogramを用いた生命予後予測モデルの開発と術前ICG‐PDR測定の臨床的意義

    安住基, 須田剛士, 横尾健, 上村博輝, 土屋淳紀, 上村顕也, 高村昌昭, 川合弘一, 松田康伸, 山際訓, 寺井崇二

    肝臓   57 ( Supplement 1 )   A158 - A158   2016.4

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  • 各種肝疾患における肝細胞ロゼット形成の臨床的意義

    野本実, 上村博輝, 土屋淳紀, 寺井崇二, 松田康伸

    新潟医学会雑誌   129 ( 10 )   632‐633 - 633   2015.10

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  • 44 各種肝疾患における肝細胞ロゼット形成の臨床的意義(Ⅰ.一般演題, 第39回リバーカンファレンス)

    野本 実, 上村 博輝, 土屋 淳紀, 寺井 崇二, 松田 康伸

    新潟医学会雑誌   129 ( 10 )   632 - 632   2015.10

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  • DJ-1 labeling index is a novel diagnostic biomarker for predicting progression of nonalcoholic steatohepatitis

    Masaaki Takamura, Satoshi Yamagiwa, Yasunobu Matsuda, Minoru Nomoto, Toshifumi Wakai, Shuji Terai

    HEPATOLOGY   62   1263A - 1263A   2015.10

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  • 肝がん細胞株におけるオーロラキナーゼ阻害剤・ソラフェニブ併用療法の解析

    大澤 まみ, 松田 康伸, 若井 俊文, 廣瀬 雄己, 永橋 昌幸, 坂田 純, 小林 隆, 藤巻 隼, 窪田 正幸

    新潟大学保健学雑誌   12 ( 1 )   57 - 63   2015.9

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    【目的】肝細胞癌(肝がん)は、化学療法の効果が乏しい予後不良な悪性疾患である。本研究では、新規の分子標的薬オーロラキナーゼ阻害剤の肝がんに対する作用機序を解析した。【方法】肝がん細胞株HepG2にオーロラキナーゼ阻害剤AZD1152を添加し、細胞シグナルをウエスタン・ブロットで解析した。また分子標的薬ソラフェニブをAZD1152と併用して、アポトーシス誘導率や細胞増殖を観察した。【結果】AZD1152単剤は、がん細胞の増殖は抑制するものの、細胞殺傷効果は認められなかった。AZD1152添加後のがん細胞では、ストレスキナーゼERKが著明に活性化しており、ERK阻害剤やソラフェニブを併用するとアポトーシス細胞数がAZD1152単剤に比べ約20倍に増加した(p&lt;0.01)。【総括】AZD1152は肝がんに対する殺傷効果が極めて弱く、ERK活性化がその原因であることが示唆された。ソラフェニブはERK阻害作用を有しており、有意にオーロラキナーゼ阻害剤の効果を増強した。(著者抄録)

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  • 「細胞間相互作用からみた胆管系腫瘍進展の分子機構」

    松田康伸

    日本膵・胆管合流異常研究会プロシーディングス   38th   16 - 17   2015.9

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  • 非アルコール性脂肪肝炎におけるDJ‐1核内発現および血清DJ‐1濃度測定の有用性

    高村昌昭, 山際訓, 松田康伸, 野本実, 青柳豊, 若井俊文, 寺井崇二

    肝臓   56 ( Supplement 1 )   A353 - A353   2015.4

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  • 肝胆膵 非アルコール性脂肪肝疾患関連肝細胞癌における肝切除の術後成績およびp27発現の臨床的意義

    廣瀬 雄己, 松田 康伸, 油座 築, 相馬 大輝, 岡部 康之, 森本 悠太, 三浦 宏平, 佐藤 良平, 滝沢 一泰, 永橋 昌幸, 坂田 純, 小林 隆, 亀山 仁史, 皆川 昌広, 小杉 伸一, 小山 諭, 若井 俊文

    日本外科学会定期学術集会抄録集   115回   YIA - 1   2015.4

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  • 46 当院における他科依頼肝疾患の現状(Ⅰ.一般演題, 第38回リバーカンファレンス)

    安住 基, 須田 剛士, 横尾 健, 山本 幹, 土屋 淳紀, 五十嵐 正人, 田村 康, 高村 昌昭, 川合 弘一, 山際 訓, 野本 実, 青柳 豊, 松田 康伸

    新潟医学会雑誌   128 ( 9 )   484 - 484   2014.9

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  • 当院における他科依頼肝疾患の現状

    安住 基, 須田 剛士, 横尾 健, 山本 幹, 土屋 淳紀, 五十嵐 正人, 田村 康, 高村 昌昭, 川合 弘一, 山際 訓, 野本 実, 青柳 豊, 松田 康伸

    新潟医学会雑誌   128 ( 9 )   484 - 484   2014.9

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  • TGF-BETAはソラフェニブ薬剤耐性の促進因子である(TGF-beta Is a Critical Mediator Of Sorafenib Resistance In Hepatocellular Carcinoma)

    松田 康伸, 大澤 まみ, 若井 俊文, 窪田 正幸

    日本癌学会総会記事   73回   P - 1405   2014.9

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  • Akt-FGF経路は肝がん細胞におけるソラフェニブ耐性機構に関与する(Hepatoma Cells Acquire Sorafenib Resistance through Akt-Fibroblast Growth Factor Signaling)

    大澤 まみ, 松田 康伸, 若井 俊文, 窪田 正幸

    日本癌学会総会記事   73回   P - 1391   2014.9

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  • 非アルコール性脂肪肝炎におけるDJ-1発現の有用性の検討

    高村 昌昭, 許 波, 山際 訓, 松田 康伸, 野本 実, 若井 俊文, 山本 格, 青柳 豊

    肝臓   55 ( Suppl.2 )   A628 - A628   2014.9

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  • 食道癌術前補助化学療法抵抗性におけるNQO1発現の関与

    市川 寛, 小杉 伸一, 松田 康伸, 皆川 昌広, 小林 隆, 亀山 仁史, 坂田 純, 羽入 隆晃, 石川 卓, 若井 俊文

    日本食道学会学術集会プログラム・抄録集   68回   107 - 107   2014.7

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  • 細胞周期調節因子p27はNASH関連肝細胞癌再発の予測因子である

    廣瀬 雄己, 松田 康伸, 滝沢 一泰, 島田 能史, 石川 卓, 亀山 仁史, 坂田 純, 小林 隆, 皆川 昌広, 小杉 伸一, 若井 俊文

    日本肝胆膵外科学会・学術集会プログラム・抄録集   26回   488 - 488   2014.6

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  • Molecular mechanism of compensatory proliferation

    Osawa Mami, Matsuda Yasunobu, Wakai Toshifumi, Hirose Yuki, Sakata Jun, Kobayashi Takashi, Fujimaki Shun, Kubota Masayuki

    新潟大学保健学雑誌 = Journal of health sciences of Niigata University   11 ( 1 )   1 - 6   2014.3

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    近年,アポトーシス細胞が周囲の細胞に生存・増殖を促す「代償性増殖作用」をもつことが明らかとなったが,そのメカニズムについては未だ不明な点が多い。最近の研究報告により,アポトーシスを進行させる因子であるカスパーゼが,ストレスキナーゼJNKやプロスタグランジンE2を介して,細胞増殖を誘導させる作用を併せ持つことが明らかになった。また酸化ストレスに関与するインターロイキン-11も,代償性増殖に関与する可能性が報告されており,本機構が多彩な因子によって調節されている可能性が推測されている。今後,さらなる研究の発展により,代償性増殖を利用した医療の発展に期待がもたれる。Recent studies have suggested that dying apoptotic cells are involved in various types of extracellular stimuli, termed compensatory proliferation. For example, caspase-9 (Dronc), a type of enzyme which induced cell apoptosis, stimulates JNK or prostaglandin E2, leading to the pronounced cell proliferation. Moreover, interleukin-11, which is produced by reactive oxygen stress, has been also found to be involved in the compensatory proliferation. For more understanding the mechanism of cell death and proliferation, further investigation of the compensatory proliferation is awaited.

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  • p70S6 kinase is activated in non-alcoholic steatohepatitis-related hepatocellular carcinoma

    Matsuda Yasunobu, Wakai Toshifumi, Hirose Yuki, Sakata Jun, Kobayashi Takashi, Osawa Mami, Fujimaki Shun, Kubota Masayuki

    新潟大学保健学雑誌 = Journal of health sciences of Niigata University   11 ( 1 )   51 - 56   2014.3

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    【目的】非アルコール性脂肪肝炎(NASH)は,近年急速に増加している原因不明の肝疾患である。本研究では,肝がん治療に有効とされる分子標的薬ラパマイシンの標的シグナルp70S6キナーゼが,NASH肝がんの病態に関与している可能性について検討した。 【方法】根治的外科手術療法を施行したNASH肝がん22例の病変組織に対して,リン酸化型(活性型)p70S6キナーゼの免疫組織化学染色を行い,臨床因子・予後の比較検討を行った。 【結果】NASH肝がん22例中12例(54.5%)がリン酸化型p70S6キナーゼを高発現しており,組織未分化度と相関した(p = 0.047)。リン酸化型P70S6キナーゼ高発現群は,外科切除後3年以内再発率が有意に増加していた(p = 0.045)。 【総括】p70S6キナーゼを高発現しているNASH肝がんは,再発頻度が高い傾向がある。同シグナルを阻害する分子標的薬ラパマイシンは,本疾患の再発防止に有効である可能性が示唆された。Objective: Non-alcoholic steatohepatitis(NASH)is a recently identified liver disease which causes hepatocellular carcinoma(HCC). In this study, we addressed whether p70S6 kinase(p70S6K), a main target of the anti-cancer agent rapamycin, is involved in the clinicopathological factors in NASH-related HCC. Methods: HCC tissue samples were obtained from 22 NASH patients with radical surgical treatment. Phosphorylation level of p70S6K was analyzed by immunohistochemical analysis, and the correlation with the clinicopathological factors were examined. Results: Phosphorylated p70S6K was detected in 54.5%(12/22)of NASH-related HCCs. The levels of phosphop70S6K were correlated with histological grade of HCC(p = 0.047), but not with clinical factors. Phosphorylation of p70S6K was correlated with increased cancer recurrence after 3 years of the treatment(p= 0.045). Conclusion: Phosphorylation level of p70S6K was correlated with cancer recurrence of NASH-related HCC. Rapamycin might be a useful agent for treating NASH-associated HCC.

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  • Blockade of CD26 Augments the Therapeutic Potential of Marrow Stem Cells in the Liver

    Matsuda Yasunobu, Wakai Toshifumi, Hirose Yuki, Sakata Jun, Kobayashi Takashi, Osawa Mami, Fujimaki Shun, Kubota Masayuki

    11 ( 1 )   39 - 49   2014.3

  • 42 当科におけるsorafenib治療の検討(Ⅰ.一般演題, 第37回リバーカンファレンス)

    長島 藍子, 須田 剛士, 倉岡 直亮, 罇 陽介, 山本 幹, 横山 純二, 五十嵐 正人, 川合 弘一, 山際 訓, 青柳 豊, 松田 康伸, 大越 省吾, 小林 真

    新潟医学会雑誌   127 ( 10 )   580 - 580   2013.10

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  • 39 全生存期間からみたTACEとchemolipiodolizationの比較検討(Ⅰ.一般演題, 第37回リバーカンファレンス)

    兼藤 努, 吉川 成一, 上村 顕也, 田村 康, 高村 昌昭, 五十嵐 正人, 川合 弘一, 山際 訓, 須田 剛士, 野本 実, 青柳 豊, 松田 康伸, 和栗 暢生

    新潟医学会雑誌   127 ( 10 )   578 - 579   2013.10

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  • 40 APM2は肝細胞癌に対するシスプラチンの効果予測マーカー候補である(Ⅰ.一般演題, 第37回リバーカンファレンス)

    上村 顕也, 吉川 成一, 兼藤 努, 田村 康, 高村 昌昭, 五十嵐 正人, 川合 弘一, 山際 訓, 須田 剛士, 松田 康伸, 野本 実, 青柳 豊

    新潟医学会雑誌   127 ( 10 )   579 - 579   2013.10

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  • 44 音響放射圧を用いた肝内せん断弾性波速度測定による肝細胞癌発癌リスク評価(Ⅰ.一般演題, 第37回リバーカンファレンス)

    高村 昌昭, 須田 剛士, 兼藤 努, 吉川 成一, 上村 顕也, 田村 康, 五十嵐 正人, 川合 弘一, 山際 訓, 野本 実, 青柳 豊, 松田 康伸

    新潟医学会雑誌   127 ( 10 )   580 - 580   2013.10

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  • 当科におけるsorafenib治療の検討

    長島 藍子, 須田 剛士, 倉岡 直亮, もたい 陽介, 山本 幹, 横山 純二, 五十嵐 正人, 川合 弘一, 山際 訓, 青柳 豊, 松田 康伸, 大越 省吾, 小林 真

    新潟医学会雑誌   127 ( 10 )   580 - 580   2013.10

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  • APM2は肝細胞癌に対するシスプラチンの効果予測マーカー候補である

    上村 顕也, 吉川 成一, 兼藤 努, 田村 康, 高村 昌昭, 五十嵐 正人, 川合 弘一, 山際 訓, 須田 剛士, 松田 康伸, 野本 実, 青柳 豊

    新潟医学会雑誌   127 ( 10 )   579 - 579   2013.10

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  • 全生存期間からみたTACEとchemolipiodolizationの比較検討

    兼藤 努, 吉川 成一, 上村 顕也, 田村 康, 高村 昌昭, 五十嵐 正人, 川合 弘一, 山際 訓, 須田 剛士, 野本 実, 青柳 豊, 松田 康伸, 和栗 暢生

    新潟医学会雑誌   127 ( 10 )   578 - 579   2013.10

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  • 音響放射圧を用いた肝内せん断弾性波速度測定による肝細胞癌発癌リスク評価

    高村 昌昭, 須田 剛士, 兼藤 努, 吉川 成一, 上村 顕也, 田村 康, 五十嵐 正人, 川合 弘一, 山際 訓, 野本 実, 青柳 豊, 松田 康伸

    新潟医学会雑誌   127 ( 10 )   580 - 580   2013.10

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  • A disintegrin and metalloprotease 21発現は肝細胞癌の細胞運動に関与し術後再発に影響を与える

    高村 昌昭, 玄田 拓哉, 山際 訓, 松田 康伸, 若井 俊文, 青柳 豊

    肝臓   54 ( Suppl.2 )   A593 - A593   2013.9

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  • 化学療法により根治的切除可能となった肝・リンパ節転移を伴う胃内分泌細胞癌の1例

    渡辺 庄治, 富所 隆, 高綱 将史, 外池 祐子, 堂森 浩二, 佐藤 明人, 福原 康夫, 佐藤 知巳, 北見 智恵, 川原 聖佳子, 牧野 成人, 西村 淳, 河内 保之, 新国 恵也, 松田 康伸, 五十嵐 俊彦, 吉川 明

    ENDOSCOPIC FORUM for digestive disease   29 ( 1 )   21 - 27   2013.5

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    症例は67歳男性。食欲不振と体重減少を主訴に受診、上部消化管内視鏡検査で進行胃癌、腹部computed tomography(CT)にてリンパ節および肝転移を認めた。当初、リンパ節および肝転移を伴う胃中分化管状腺癌と診断、S-1+シスプラチン(CDDP)併用療法、つぎにS-1+パクリタキセル(PTX)併用療法による化学療法が奏功、肝転移巣が消失したため、胃原発巣切除術を行ったところ切除標本は胃内分泌細胞癌であった。おそらく腺癌が先行発生し、癌細胞の分化により出現する増殖能の高い腫瘍性内分泌細胞が、腺癌粘膜深部から塊状増殖し、内分泌細胞癌が形成されたと考えられた。胃内分泌細胞癌は非常にまれな疾患で、かつ悪性度の高い予後不良な疾患であるが、発症から約3年経過、現在無再発生存中である。予後不良といわれる胃内分泌細胞癌であっても化学療法が奏功する可能性があり、かつ外科的手術の時期を判断することが重要である。(著者抄録)

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  • 非アルコール性脂肪性肝疾患モデルマウス肝組織のプロテオーム解析による新規バイオマーカーの探索

    高村 昌昭, 許 波, 山際 訓, 松田 康伸, 野本 実, 山本 格, 青柳 豊

    日本臨床分子医学会学術総会プログラム・抄録集   50回   64 - 64   2013.4

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  • 深部出血を合併した肝硬変症例における生存例と死亡例の比較検討

    高村 昌昭, 渡邊 順, 坂牧 僚, 本田 穣, 兼藤 努, 吉川 成一, 上村 顕也, 田村 康, 五十嵐 正人, 川合 弘一, 山際 訓, 須田 剛士, 松田 康伸, 野本 実, 青柳 豊

    肝臓   54 ( Suppl.1 )   A328 - A328   2013.4

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  • Presence of antibodies against self-HLA class II molecules in autoimmune hepatitis

    Satoshi Yamagiwa, Masaaki Takamura, Yasunobu Matsuda, Takuya Genda, Toru Takahashi, Takafumi Ichida, Yutaka Aoyagi

    HEPATOLOGY   56   989A - 989A   2012.10

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  • Comparative proteomic analysis of the liver in a murine model of non-alcoholic steatohepatitis

    Masaaki Takamura, Bo Xu, Satoshi Yamagiwa, Yasunobu Matsuda, Shuichiro Shimada, Ying Zhang, Yutaka Yoshida, Eishin Yaoita, Minoru Nomoto, Tadashi Yamamoto, Yutaka Aoyagi

    HEPATOLOGY   56   855A - 855A   2012.10

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  • An insulin resistance-inducing factor, RBP4, is a negative predictor of outcome of Peg-IFN plus ribavirin therapy for patients with chronic heatitis C

    Masahiko Yano, Shogo Ohkoshi, Hiromichi Takahashi, Satoshi Yamagiwa, Yasunobu Matsuda, Masanori Ikeda, Nobuyuki Kato, Yutaka Aoyagi

    HEPATOLOGY   56   269A - 269A   2012.10

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  • C型肝炎基礎 C型慢性肝炎とインスリン抵抗性因子RBP4 RBP4はインターフェロン治療抵抗性をもたらす

    高橋 弘道, 大越 章吾, 矢野 雅彦, 山際 訓, 松田 康伸, 池田 正徳, 加藤 宣之, 青柳 豊

    肝臓   53 ( Suppl.1 )   A342 - A342   2012.4

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  • p21細胞内局在制御によるIFN-βのシスプラチン制癌効果増強機構

    矢野 雅彦, 大越 章吾, 高橋 弘道, 藤巻 隼, 松田 康伸, 青柳 豊, 工藤 進英

    肝臓   53 ( Suppl.1 )   A427 - A427   2012.4

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  • 実験的NASHモデルマウス肝組織のプロテオーム解析

    高村 昌昭, 許 波, 嶋田 修一郎, 張 瑩, 吉田 豊, 矢尾板 永信, 山際 訓, 松田 康伸, 野本 実, 山本 格, 青柳 豊

    日本消化器病学会雑誌   109 ( 臨増総会 )   A325 - A325   2012.3

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  • Sorafenib: complexities of Raf-dependent and Raf-independent signaling are now unveiled

    Yasunobu Matsuda, Manabu Fukumoto

    MEDICAL MOLECULAR MORPHOLOGY   44 ( 4 )   183 - 189   2011.12

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    Hepatocellular carcinoma (HCC) is the most common primary cancer worldwide. The only current drug available for clinical treatment of HCC is sorafenib, which inhibits multiple signaling kinases including Raf family members, platelet-derived growth factor receptor, vascular endothelial growth factor receptors 1 and 2, c-Kit, and Fms-like tyrosine kinase 3. Many studies have revealed that the mechanism underlying the antitumor effect of sorafenib is complex. Because sorafenib inhibits C-Raf more potently than B-Raf, the therapeutic efficacy of sorafenib is strongly influenced by the relative expression and activity of B-Raf and C-Raf and the complex interactions between these factors. Moreover, Rafindependent signaling mechanisms have recently emerged as important pathways of sorafenib-induced cell death. Basic research studies have suggested that using sorafenib as part of a combination therapy may improve its effect, although this has yet to be confirmed by clinical evidence. Further studies of the functional mechanism of sorafenib are required to advance the development of targeted therapy for HCC. To aid future work on sorafenib, we here review the current literature pertaining to sorafenib signaling and its clinical efficacy in both monotherapy and combination therapy.

    DOI: 10.1007/s00795-011-0558-z

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  • Long-term Outcome of Surgical Resection for Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

    Wakai Toshifumi, Sakata Jun, Shirai Yoshio, Hatakeyama Katsuyoshi, Ajioka Yoichi, Kawai Hirokazu, Nomoto Minoru, Suda Takeshi, Tamura Yasushi, Takamura Masaaki, Yamagiwa Satoshi, Matsuda Yasunobu, Aoyagi Yutaka

    新潟医学会雑誌   125 ( 10 )   557 - 565   2011.10

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    【目的】非アルコール怪脂肪性肝疾患 (nonalcoholic fatty liver disease, 以下NAFLD) における肝細胞癌に対する外科治療成績を明らかにする. 【対象・方法】肝細胞癌に対して肝切除を施行した225例を対象とし, HBs抗原単独陽性群 (以下, B群) 61例, HCV抗体単独陽性群 (以下, C群) 147例, NAFLD群17例の3群に分類した. 3群間における臨床病理学的背景因子, 術後遠隔成績を比較検討した. 【結果】NAFLD群はB群, C群と比較して有意に高齢であり (P &lt;0.001), body mass index は高く (P &lt;0.001), 腫瘍径が大きかった (P =0.002). NAFLD群17例中8例は組織学的に非アルコール性脂肪肝炎 (nonalcoholic steatohepatitis, 以下NASH) と診断された. 術後合併症発生率, 在院死亡率は, B群 (各々28%, 8%), C群 (各々31%, 1.4%) と比較してNAFLD群 (各々59%, 12%) で有意に高かった (各々P =0.043, P =0.030). NAFLD群での在院死亡は2例であり, NASHに関連した肝硬変に合併した肝細胞癌に対して肝右葉切除が施行されていた. 術後累積5年無再発生存率は, B群39%, C群29%, NAFLD群66%であった. 術後累積無再発生存率はNAFLD群が単変量解析 (P =0.048), 多変量解析 (P =0.020) の両者で有意に良好な成績であった. 【結論】NAFLD関連肝細胞癌に対する外科治療は予後を改善する. NASH関連肝硬変患者に対して肝葉切除を行う際には細心の注意が必要である.

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  • 肝細胞癌におけるNK細胞活性化レセプターリガンド発現低下とその臨床的意義

    山際 訓, 上村 博輝, 土屋 淳紀, 高村 昌昭, 松田 康伸, 白井 良夫, 野本 実, 青柳 豊

    肝臓   52 ( Suppl.2 )   A624 - A624   2011.9

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  • Hepatocellular carcinoma and liver transplantation: clinical perspective on molecular targeted strategies

    Yasunobu Matsuda, Takafumi Ichida, Manabu Fukumoto

    MEDICAL MOLECULAR MORPHOLOGY   44 ( 3 )   117 - 124   2011.9

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    Hepatocellular carcinoma (HCC) has an aggressive clinical course with frequent recurrence and metastasis. Orthotopic liver transplantation has been the only curative tool for unresectable HCC; therefore, recent advances in molecular targeted therapy may improve the prognosis of HCC. The multiple kinase inhibitor sorafenib and the macrolide antibiotic rapamycin are currently the most promising agents for treating unresectable HCC. A large population-based clinical trial revealed that sorafenib significantly prolonged the overall survival of HCC patients. However, subsequent clinical studies showed that sorafenib rarely reduced tumor volume and inadequately prolonged survival of patients with severe liver damage. To improve its therapeutic effect, the development of a predictive biomarker and a sorafenib-based combination is awaited. Another molecular targeting agent, rapamycin, has now been considered as a putative agent for preventing tumor recurrence in post-liver transplantation HCC patients, because it not only has immunosuppressive activity but also exerts an anti-tumor effect. In the near future, a combination of molecular targeting agents, such as sorafenib and rapamycin, may become a standard protocol for treating unresectable HCC. For specifying cases with more effective and less harmful modalities, further investigation in clinical and basic research to identify unexpected effects are needed.

    DOI: 10.1007/s00795-011-0547-2

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  • 5 部分的膵動脈塞栓術後の血小板数予測の試み(I.一般演題,第63回新潟画像医学研究会)

    大崎 暁彦, 須田 剛士, 石川 達, 和栗 暢生, 川合 弘一, 土屋 淳紀, 上村 顕也, 矢野 雅彦, 田村 康, 高村 昌昭, 五十嵐 正人, 山際 訓, 松田 康伸, 大越 章吾, 野本 実, 青柳 豊

    新潟医学会雑誌   125 ( 6 )   339 - 340   2011.6

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  • 部分的脾動脈塞栓術後の血小板数予測の試み

    大崎 暁彦, 須田 剛士, 石川 達, 和栗 暢生, 川合 弘一, 土屋 淳紀, 上村 顕也, 矢野 雅彦, 田村 康, 高村 昌昭, 五十嵐 正人, 山際 訓, 松田 康伸, 大越 章吾, 野本 実, 青柳 豊

    新潟医学会雑誌   125 ( 6 )   339 - 340   2011.6

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  • ウイルス肝炎・肝癌制圧の分子基盤 B型肝炎ウイルスX遺伝子によるDNA酸化傷害機構の解析および制御方法の検討

    松田 康伸, 大越 章吾, 青柳 豊

    肝臓   52 ( Suppl.1 )   A26 - A26   2011.4

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  • 肝細胞癌におけるLiver-intestine(LI)-cadherinの発現とその臨床病理学的意義

    高村 昌昭, 山際 訓, 若井 俊文, 上村 博輝, 土屋 淳紀, 松田 康伸, 白井 良夫, 青柳 豊

    肝臓   52 ( Suppl.1 )   A324 - A324   2011.4

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  • DNA傷害修復因子ATMによる肝癌細胞の細胞死抑制機構の解析

    藤巻 隼, 松田 康伸, 矢野 雅彦, 大越 章吾, 若井 俊文, 白井 良夫, 三瓶 歩, 平野 茂樹

    肝臓   52 ( Suppl.1 )   A194 - A194   2011.4

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  • INTERFERON-beta PREVENTS HBX-TRIGGERED HEPATOCARCINOGENESIS BY DOWN-REGULATING CYTOPLASMIC P21 OVEREXPRESSION

    M. Yano, S. Ohkoshi, Y. Aoki, K. Yamazaki, S. Kurita, K. Suzuki, S. Fujimaki, A. Sanpei, Y. Matsuda, Y. Aoyagi

    JOURNAL OF HEPATOLOGY   54   S448 - S448   2011.3

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  • TRANSFORMING GROWTH FACTOR-beta/P38 MAP KINASE SIGNALING CONTRIBUTES TO SORAFENIB RESISTANCE IN HEPATOMA

    Y. Matsuda, T. Wakai, Y. Shirai, M. Yano, S. Ohkoshi, Y. Aoyagi, S. Fujimaki, A. Sanpei, S. Hirano

    JOURNAL OF HEPATOLOGY   54   S272 - S273   2011.3

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  • ペグインターフェロンとリバビリンの併用療法中HCV RNAの陰性化にもかかわらず肝機能障害が継続し組織学的に肝硬変への進展が確認されたC型慢性肝炎の1例

    大越 章吾, 森田 慎一, 田中 由佳里, 矢野 雅彦, 竹内 学, 高橋 弘道, 池田 晴夫, 山際 訓, 松田 康伸, 野本 実, 青柳 豊

    日本消化器病学会雑誌   108 ( 2 )   267 - 274   2011.2

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    症例は62歳女性。1型高ウイルス量のC型慢性肝炎に対し、ペグインターフェロン(PEG-IFN)α2aとリバビリンの併用療法を行った。治療開始後より肝酵素値の上昇が見られた。治療終了後の肝生検では結節形成を認め肝硬変の所見であった。PEG-IFN治療中に観察されるALT上昇の多くは軽度であり臨床的な問題点にはなりにくいが、長期に継続した場合、このような転帰をとる例があることは認知されるべきあると考え報告する。(著者抄録)

    DOI: 10.11405/nisshoshi.108.267

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  • HEPATITIS B VIRUS X PROTEIN ACTIVATES MAMMALIAN TARGET OF RAPAMYCIN MTOR VIA REACTIVE OXYGEN SPECIES GENERATION

    Ayumi Sanpei, Yasunobu Matsuda, Toshifumi Wakai, Jun Sakata, Yoshio Shirai, Masahiko Yano, Shogo Ohkoshi, Syun Fujimaki, Katsuyoshi Hatakeyama

    HEPATOLOGY   52 ( 4 )   591A - 592A   2010.10

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  • 肝細胞癌に対する術前CDDP肝動注施行例における組織学的腫瘍壊死率とmultidrug resistant-associated protein 2過剰発現との関連

    若井 俊文, 白井 良夫, 坂田 純, 松田 康伸, 高村 昌昭, 青柳 豊, 味岡 洋一, 畠山 勝義

    日本消化器病学会雑誌   107 ( 臨増大会 )   A891 - A891   2010.9

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  • 1型高ウイルス量C型慢性肝炎に対するPEG-IFNα2b+Rib併用療法の治療効果予測因子及びにフルバスタチン、テプレノンの上乗せ療法の検討

    大越 章吾, 山際 訓, 矢野 雅彦, 高橋 弘道, 和栗 暢生, 五十嵐 健太郎, 杉谷 想一, 高橋 達, 石川 達, 上村 朝輝, 渡辺 庄治, 武井 伸一, 津端 俊介, 若林 博人, 渡辺 俊明, 前田 裕伸, 松田 康伸, 青柳 豊

    肝臓   51 ( Suppl.2 )   A593 - A593   2010.9

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  • HBx遺伝子誘導性肝発癌に対するインターフェロンβの分子学的制御機構(Molecular mechanism of interferon-beta on prevention of HBx-induced hepatocarcinogenesis)

    矢野 雅彦, 大越 章吾, 青木 洋平, 山崎 和秀, 栗田 聡, 鈴木 健太, 三瓶 歩, 松田 康伸, 青柳 豊

    日本癌学会総会記事   69回   91 - 91   2010.8

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  • 肝細胞癌における分子標的としてのNK細胞活性化レセプターリガンドとその発現調節による抗腫瘍効果

    上村 博輝, 山際 訓, 土屋 淳紀, 高村 昌昭, 松田 康伸, 井上 真, 若井 俊文, 白井 良夫, 野本 実, 青柳 豊

    肝臓   51 ( Suppl.1 )   A167 - A167   2010.4

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  • 非蛋白性呼吸商の治療侵襲に対する耐容性指標としての有用性

    山田 一樹, 須田 剛士, 大崎 暁彦, 上村 博輝, 土屋 淳紀, 矢野 雅彦, 田村 康, 高村 昌昭, 五十嵐 正人, 川合 弘一, 山際 訓, 松田 康伸, 大越 章吾, 野本 実, 青柳 豊

    肝臓   51 ( Suppl.1 )   A306 - A306   2010.4

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  • HBx誘導性肝発癌に対するIFN-βの制御機構の分子学的解析

    矢野 雅彦, 大越 章吾, 青木 洋平, 山崎 和秀, 栗田 聡, 鈴木 健太, 三瓶 歩, 松田 康伸, 青柳 豊

    肝臓   51 ( Suppl.1 )   A212 - A212   2010.4

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  • 肝内胆管癌におけるLI-cadherinの発現消失はMTF-1およびPlGFの発現を上昇することにより血管新生を誘導する

    高村 昌昭, 山際 訓, 若井 俊文, 田村 康, 井上 真, 上村 博輝, 加藤 卓, 土屋 淳紀, 松田 康伸, 白井 良夫, 市田 隆文, 味岡 洋一, 青柳 豊

    日本消化器病学会雑誌   107 ( 臨増総会 )   A266 - A266   2010.3

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  • 慢性DSS腸炎に対するPlasmid-IL-10注腸治療効果の検討

    野々村 頼子, 孫 暁梅, 鈴木 健司, 大坪 亜矢, 遠藤 悠, 河内 裕介, 横山 純二, 串田 良裕, 大根田 輝, 細野 正道, 丸山 弘樹, 渡辺 賢一, 松田 康伸, 青柳 豊

    消化器と免疫   ( 46 )   140 - 144   2010.3

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    炎症性腸疾患(IBD)は炎症の再発、寛解を繰り返し、腸管の線維化に伴う腸管の狭窄をもたらす。われわれは、B6マウスに3% Dextran Sulfate Sodium(DSS)を自由飲水させ慢性DSS腸炎を惹起しIL-10遺伝子発現プラスミドの注腸治療を検討した。治療群では、無治療群に比べ、腸炎は臨床的、組織学的に改善し、腸管線維化の抑制が見られた。治療群において慢性DSS腸炎が改善したことより、IL-10遺伝子発現プラスミド注腸は、IBDの慢性腸管炎症と線維化に対する新たな治療法になり得ると考えた。(著者抄録)

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  • マウス肝発癌モデルを用いたインターフェロン-βによる肝発癌予防効果

    矢野 雅彦, 大越 章吾, 青木 洋平, 山崎 和秀, 鈴木 健太, 栗田 聡, 松田 康伸, 青柳 豊

    日本内科学会雑誌   99 ( Suppl. )   209 - 209   2010.2

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  • OXIDATIVE STRESS INDUCES ANTI-HCV STATUS VIA THE ACTIVATION OF MEK-ERK1/2 SIGNALING PATHWAY

    Masahiko Yano, Masanori Ikeda, Ken-ichi Abe, Yoshinari Kawai, Misao Kuroki, Kyoko Mori, Hiromichi Dansako, Yasuo Ariumi, Yasunobu Matsuda, Shougo Ohkoshi, Yutaka Aoyagi, Nobuyuki Kato

    HEPATOLOGY   50 ( 4 )   965A - 965A   2009.10

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  • 音響放射圧刺激に基づく肝硬度測定の臨床的意義

    窪田 智之, 須田 剛士, 土屋 淳紀, 田村 康, 矢野 雅彦, 高村 昌昭, 五十嵐 正人, 川合 弘一, 山際 訓, 松田 康伸, 大越 章吾, 野本 実, 青柳 豊

    肝臓   50 ( Suppl.2 )   A553 - A553   2009.9

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  • 胆管癌における53BP1を介したDNA損傷修復機構の解明及びその臨床的意義

    若井 俊文, 白井 良夫, 松田 康伸, 坂田 純, 味岡 洋一, 畠山 勝義

    日本消化器病学会雑誌   106 ( 臨増大会 )   A907 - A907   2009.9

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  • C型慢性肝炎関連非アルコール性脂肪性肝炎(NASH)の検討

    野本 実, 吉川 成一, 五十嵐 正人, 青柳 豊, 松田 康伸

    肝臓   50 ( Suppl.2 )   A551 - A551   2009.9

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  • ラジオ波焼灼術における硬膜外麻酔の鎮痛効果の検討

    五十嵐 聡, 川合 弘一, 窪田 智之, 土屋 淳紀, 矢野 雅彦, 田村 康, 高村 昌昭, 五十嵐 正人, 山際 訓, 須田 剛士, 松田 康伸, 大越 章吾, 岡本 学, 野本 実, 青柳 豊

    肝臓   50 ( Suppl.2 )   A576 - A576   2009.9

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  • Impact of hepatitis B virus X protein on the DNA damage response during hepatocarcinogenesis

    Yasunobu Matsuda, Takafumi Ichida

    MEDICAL MOLECULAR MORPHOLOGY   42 ( 3 )   138 - 142   2009.9

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    Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide. The main HCC-associated diseases are chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), and HBV-associated HCC is still prevalent in Asia. Many studies have suggested that HBV X protein (HBX), which is the most common ORF integrated into the host genome, plays a crucial role in hepatocarcinogenesis. However, the accumulated evidence regarding HBX-mediated signaling pathways is not concordant, and it is difficult to understand the mechanistic nature of HBX-associated hepatocarcinogenesis. For example, HBX was reported to inactivate the early responses to DNA damage via p53-dependent and -independent pathways by interacting with several DNA damage-binding proteins and was also reported to sensitize cells to p53-mediated apoptosis via ataxia-telangiectasia and Rad3-related (ATR)-dependent signaling. HBX also interferes with the centrosome replication process, resulting in rearrangement of chromosomes with micronuclei. Moreover, HBX was found to sensitize protein kinases such as Ras/Raf/mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), stress-activated protein kinase/NH2-terminal-Jun kinase (SAPK/JNK), protein kinase B (PKB/Akt), and Janus kinase/STAT (JAK/STAT), indicating that a variety of signaling pathways may be activated by HBX. In this review, we focus on the roles of HBX in DNA damage repair during HCC development, with a view to achieving a better understanding of the significance of HBX in the early steps of hepatocarcinogenesis.

    DOI: 10.1007/s00795-009-0457-8

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  • 劇症肝炎に対する生体部分肝移植におけるMELDスコアの意義

    山本 智, 佐藤 好信, 大矢 洋, 小林 隆, 小海 秀央, 山際 訓, 松田 康伸, 大越 章吾, 野本 実, 青柳 豊, 畠山 勝義

    肝臓   50 ( Suppl.1 )   A200 - A200   2009.4

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  • 慢性DSS腸炎におけるリザベン注腸治療効果の検討

    孫 暁梅, 鈴木 健司, 河内 裕介, 横山 純二, 斉藤 翼, 熊谷 さやか, 串田 良裕, 大根田 輝, 細野 正道, 渡辺 賢一, 松田 康伸, 永田 昌毅, 青柳 豊

    消化器と免疫   ( 45 )   139 - 143   2009.3

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    腸管狭窄の原因である腸管線維化は炎症性腸疾患(IBD)の重篤な合併症であり、いまだ有効な治療法を欠いている。我々はB6マウスに3% Dextran sulfate sodium(DSS)を自由飲水させ慢性DSS腸炎を惹起し、肥満細胞膜安定剤トラニラストの注腸治療を検討した。無治療群に比べ、治療群において腸炎は臨床的、組織学的に改善し、腸管線維化の抑制効果もみられた。治療群で腸炎が有意に改善したことより、トラニラスト注腸がIBDの慢性腸管炎症と線維化の有効な治療戦略となりうると示唆された。(著者抄録)

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  • DSS腸炎におけるplasmid-IL-10注腸治療効果の検討

    河合 裕子, 孫 暁梅, 鈴木 健司, 河内 裕介, 横山 純二, 北澤 侑恵, 斉藤 翼, 大根田 輝, 熊谷 さやか, 串田 良裕, 細野 正道, 丸山 弘樹, 渡辺 賢一, 松田 康伸, 青柳 豊

    消化器と免疫   ( 45 )   144 - 148   2009.3

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    IL-10遺伝子治療は炎症性腸疾患(IBD)の有力な治療法として注目されてきたが、IL-10の全身投与による副作用が問題となっている。我々はB6マウスに3% Dextran sulfate sodium(DSS)を自由飲水させ腸炎を惹起し、IL-10遺伝子発現プラスミドの注腸投与による治療効果を検討した。無治療群に比し、治療群では腸炎は臨床的、組織学的に改善がみられた。IL-10遺伝子発現プラスミド注腸により、DSS腸炎を改善できた。IL-10遺伝子注腸治療はIBD治療法になり得ると考えられた。(著者抄録)

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  • A case of extra-hepatic lymph node metastasis of hepatocellular carcinoma with no evident sign of intra-hepatic recurrence

    Shinichi Morita, Yasunobu Matsuda, Tomoko Oshima, Tomoyuki Kubota, Yusuke Kawauchi, Makoto Kobayashi, Minoru Nomoto, Yutaka Aoyagi

    Journal of Japanese Society of Gastroenterology   106 ( 3 )   397 - 404   2009

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    A 73-year-old man with chronic hepatitis C was Successfully treated for hepatocellular carcinoma (HCC) by localized treatment During the follow-up period, abdominal computed tomography (CT) revealed no HCC recurrence in the liver. However, 9 months after the treatment, abdominal lymph nodes appeared enlarged on CT. Laparoscopic biopsy of the lymph nodes showed that the lesion was HCC, and TS-1/cisplatin chemotherapy was performed. However, extra-hepatic lymph nodes rapidly grew, leading to obstructive jaundice and finally death 10 months after of HCC metastasis. Although abdominal lymph node metastasis of HCC has been widely considered to be rare, the confirmation of effective therapy is awaited because histological studies have suggested that this pathologic lesion may occur more often than expected.

    DOI: 10.11405/nisshoshi.106.397

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  • 術前CDDP肝動注療法にて、肝機能を保ちかつ著効し狭心症加療後切除し長期生存した多血症、高脂血症の腫瘍随伴症候群を伴う高齢者巨大肝細胞癌の一例

    土屋 淳紀, 窪田 智之, 滝澤 一休, 山田 一樹, 松田 康伸, 本間 照, 渡辺 雅史, 丸山 弘樹, 野本 実, 青柳 豊

    肝臓   49 ( Suppl.3 )   A717 - A717   2008.10

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  • 29 生体肝移植後に急速に進行したC型肝硬変症の1例(I.一般演題,第29回リバーカンファレンス)

    山際 訓, 松田 康伸, 杉村 一仁, 野本 実, 青柳 豊, 佐藤 好信, 畠山 勝義, 市田 隆文

    新潟医学会雑誌   122 ( 10 )   599 - 599   2008.10

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  • 31 アルコール性肝硬変に合併し, マロリー体の集簇を認めた結節性病変の1例(I.一般演題,第29回リバーカンファレンス)

    大崎 暁彦, 津端 俊介, 佐藤 俊大, 福原 康夫, 矢野 雅彦, 石本 結子, 横山 純二, 川合 弘一, 山際 訓, 松田 康伸, 杉村 一仁, 野本 実, 青柳 豊

    新潟医学会雑誌   122 ( 10 )   599 - 600   2008.10

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  • 原発巣の切除約5年後に肺転移を認めたbiliary mucinous cystadenocarcinomaの1例

    山際 訓, 松田 康伸, 野本 実, 須田 剛士, 白井 良夫, 青柳 豊

    肝臓   49 ( Suppl.3 )   A776 - A776   2008.10

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  • 生体肝移植後に急速に進行したC型肝硬変症の1例

    山際 訓, 松田 康伸, 杉村 一仁, 野本 実, 青柳 豊, 佐藤 好信, 畠山 勝義, 市田 隆文

    新潟医学会雑誌   122 ( 10 )   599 - 599   2008.10

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  • アルコール性肝硬変に合併し、マロリー体の集簇を認めた結節性病変の1例

    大崎 暁彦, 津端 俊介, 佐藤 俊大, 福原 康夫, 矢野 雅彦, 石本 結子, 横山 純二, 川合 弘一, 山際 訓, 松田 康伸, 杉村 一仁, 野本 実, 青柳 豊

    新潟医学会雑誌   122 ( 10 )   599 - 600   2008.10

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  • 8 セクタ型探触子使用により腹腔鏡下RFA術が可能であった被膜下肝細胞癌の1経験例(I.一般演題,第28回リバーカンファレンス)

    矢野 雅彦, 松田 康伸, 三浦 隆義, 大嶋 智子, 福原 康夫, 本間 信之, 小林 真, 五十嵐 正人, 玄田 拓哉, 和栗 暢生, 川合 弘一, 山際 訓, 青柳 豊

    新潟医学会雑誌   122 ( 9 )   530 - 530   2008.9

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  • 非アルコール性脂肪性肝炎を背景に多中心性発生したと思われる肝細胞癌の3例

    川合 弘一, 野本 実, 窪田 智之, 田村 康, 高村 昌昭, 五十嵐 正人, 山際 勲, 須田 剛士, 松田 康伸, 大越 章吾, 岡田 正彦, 青柳 豊

    日本消化器病学会雑誌   105 ( 臨増大会 )   A857 - A857   2008.9

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  • セクタ型探触子使用により腹腔鏡下RFA術が可能であった被膜下肝細胞癌の1経験例

    矢野 雅彦, 松田 康伸, 三浦 隆義, 大嶋 智子, 福原 康夫, 本間 信之, 小林 真, 五十嵐 正人, 玄田 拓哉, 和栗 暢生, 川合 弘一, 山際 訓, 青柳 豊

    新潟医学会雑誌   122 ( 9 )   530 - 530   2008.9

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  • 3 新規超音波造影剤ソナゾイドの肝細胞癌診療における有用性(I.一般演題,第56回新潟画像医学研究会)

    津端 俊介, 川合 弘一, 窪田 智之, 栗田 聡, 田村 康, 高村 昌昭, 五十嵐 正人, 山際 訓, 松田 康信, 大越 章吾, 野本 実, 青柳 豊, 渡辺 雅史

    新潟医学会雑誌   122 ( 5 )   292 - 292   2008.5

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  • 当科における肝硬変の成因別分類

    野本 実, 五十嵐 正人, 松田 康伸, 青柳 豊

    肝臓   49 ( Suppl.1 )   A85 - A85   2008.4

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  • p21はHBxトランスジェニックマウスモデルにおけるIFN-βの肝発癌予防効果に関与する

    青木 洋平, 大越 章吾, 栗田 聡, 山崎 和秀, 高村 昌昭, 山際 訓, 松田 康伸, 青柳 豊

    肝臓   49 ( Suppl.1 )   A359 - A359   2008.4

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  • 肝移植後C型慢性肝炎再発における肝内NK細胞の関与

    山際 訓, 松田 康伸, 土屋 淳紀, 高村 昌昭, 佐藤 好信, 大越 章吾, 市田 隆文, 青柳 豊

    肝臓   49 ( Suppl.1 )   A346 - A346   2008.4

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  • 肝内胆管癌におけるLiver-intestine(LI)-cadherinの発現の検討

    高村 昌昭, 田村 康, 若井 俊文, 山際 訓, 加藤 卓, 土屋 淳紀, 松田 康伸, 白井 良夫, 市田 隆文, 味岡 洋一, 青柳 豊

    肝臓   49 ( Suppl.1 )   A167 - A167   2008.4

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  • 当科で経験した薬物性肝障害の実態

    野本 実, 五十嵐 正人, 松田 康伸, 青柳 豊

    肝臓   49 ( Suppl.1 )   A116 - A116   2008.4

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  • アンジオテンシンII受容体拮抗薬の抗ウイルス療法非適応C型慢性肝炎・肝硬変に対する臨床効果の検討

    松田 康伸, 佐藤 宗弘, 土屋 淳紀, 高村 昌昭, 山際 訓, 大越 章吾, 野本 実, 青柳 豊

    日本消化器病学会雑誌   105 ( 臨増総会 )   A306 - A306   2008.3

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  • 若年性皮膚筋炎に合併し、5年の経過で線維化の進行を肝組織像にて確認し得た非アルコール性脂肪性肝炎(NASH)の一例

    窪田 智之, 小林 真, 高村 昌昭, 五十嵐 正人, 川合 弘一, 松田 康伸, 野本 実, 青柳 豊

    日本消化器病学会雑誌   105 ( 臨増総会 )   A265 - A265   2008.3

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  • 抗ウイルス療法非適応C型慢性肝疾患に対するアンギオテンシンII受容体拮抗薬少量長期投与の臨床効果

    松田 康伸, 佐藤 宗広, 土屋 淳紀, 高村 昌昭, 山際 訓, 大越 章吾, 野本 実, 青柳 豊

    日本内科学会雑誌   97 ( Suppl. )   180 - 180   2008.2

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  • 原発性胆汁性肝硬変におけるToll-like receptor homolog RP105の発現低下

    山際 訓, 松田 康伸, 高村 昌昭, 土屋 淳紀, 野本 実, 青柳 豊

    日本内科学会雑誌   97 ( Suppl. )   179 - 179   2008.2

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  • 原発性胆汁性肝硬変合併筋炎の3例 臨床的特徴の検討

    津端 俊介, 青柳 智也, 田村 康, 川合 弘一, 山際 訓, 松田 康伸, 大越 章吾, 野本 実, 青柳 豊

    日本消化器病学会雑誌   104 ( 臨増大会 )   A686 - A686   2007.9

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  • 皮膚筋炎を合併した抗ミトコンドリア抗体陰性無症候性原発性胆汁性肝硬変の一例

    津端 俊介, 川合 弘一, 山際 訓, 松田 康伸, 大越 章吾, 野本 実, 青柳 豊

    ENDOSCOPIC FORUM for digestive disease   23 ( 1 )   72 - 72   2007.6

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  • 原発性胆汁性肝硬変におけるToll-like receptor homolog RP105の発現とLPS高反応性

    山際 訓, 本田 穣, 高村 昌昭, 松田 康伸, 市田 隆文, 青柳 豊

    肝臓   48 ( Suppl.1 )   A38 - A38   2007.4

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  • IFN-βによる肝発癌予防効果とその機序

    青木 洋平, 山崎 和秀, 鈴木 健太, 大越 章吾, 矢野 雅彦, 栗田 聡, 高村 昌昭, 山際 訓, 松田 康伸, 青柳 豊

    肝臓   48 ( Suppl.1 )   A280 - A280   2007.4

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  • ヘパリン置換療法下にESDを施行した早期胃癌の1例

    廣野 玄, 東海林 俊之, 竹内 学, 佐藤 祐一, 大嶋 智子, 河内 裕介, 塩路 和彦, 横山 純二, 佐々木 俊哉, 小林 正明, 松田 康伸, 杉村 一仁, 成澤 林太郎, 青柳 豊, 曽川 正和, 林 純一

    ENDOSCOPIC FORUM for digestive disease   22 ( 2 )   152 - 152   2006.11

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  • 細胞周期調節因子Id-1/p16/p27を指標にした肝硬変患者の発癌リスク予測診断システムの確立

    松田 康伸

    新潟県医師会報   ( 679 )   2 - 7   2006.10

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  • Early treatment by beta-IFN prevents the occurrence of HCC by inhibition of DNA synthesis and cell cycle progression: A study using a hepatocarcinogenic mouse model

    Kazuhide Yamazaki, Shogo Ohkoshi, Kenta Suzuki, Masahiko Yano, So Kurita, Yohhei Aoki, Masa-aki Takamura, Satoshi Yamagiwa, Yasunobu Matsuda, Yutaka Aoyagi

    HEPATOLOGY   44 ( 4 )   619A - 619A   2006.10

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  • 新潟大学関連施設におけるC型慢性肝炎に対するPEG-IFNα-2a療法の現状と血清CXCL10による治療効果予測

    山際 訓, 松田 康伸, 大越 章吾, 和栗 暢生, 杉山 幹也, 杉谷 想一, 宮島 透, 若林 博人, 高橋 達, 渡辺 俊明, 上村 朝輝, 青柳 豊

    肝臓   47 ( Suppl.2 )   A401 - A401   2006.9

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  • 肝内血流の不均衡によって興味深い画像及び組織所見を呈した原因不明の肝静脈血栓症の1例

    塙 孝泰, 青木 洋平, 橋本 哲, 竹内 学, 山際 訓, 松田 康伸, 大越 章吾, 野本 実, 青柳 豊

    ENDOSCOPIC FORUM for digestive disease   22 ( 1 )   72 - 72   2006.6

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  • 検査値の読み方 比較的若年の女性に起こった原因不明の肝静脈閉塞症の1例

    塙 孝泰, 大越 章吾, 青木 洋平, 竹内 学, 山際 訓, 松田 康伸, 野本 実, 青柳 豊

    臨床消化器内科   21 ( 8 )   1197 - 1202   2006.6

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  • 【レジデントのための内視鏡診療マニュアル】 「肝」 各肝疾患における腹腔鏡所見の特徴

    渡辺 俊明, 坂内 均, 瀧本 光弘, 高橋 達, 松田 康伸

    消化器内視鏡   18 ( 5 )   888 - 892   2006.5

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  • インターフェロンβによる肝発癌抑制効果へのアプローチ 正常肝細胞に対するインターフェロンβの効果について

    山崎 和秀, 大越 章吾, 鈴木 健太, 栗田 聡, 矢野 雅彦, 高村 昌昭, 山際 訓, 松田 康伸, 青柳 豊

    肝臓   47 ( Suppl.1 )   A263 - A263   2006.4

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  • マウス急性肝不全モデルにおけるc-Jun N-terminal kinase(JNK)阻害剤による肝細胞のアポトーシス抑制効果

    高村 昌昭, 松田 康伸, 山際 訓, 本田 穣, 市田 隆文, 青柳 豊

    肝臓   47 ( Suppl.1 )   A100 - A100   2006.4

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  • 生体肝移植症例における肝内樹状細胞の経時的検討

    山際 訓, 富山 智香子, 渡部 久実, 市田 隆文, 松田 康伸, 高村 昌昭, 本田 穣, 佐藤 好信, 青柳 豊

    消化器と免疫   ( 42 )   146 - 149   2006.4

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    生体肝移植症例の移植肝生着とDCとの関連性について検討することを目的とし,移植前後で経時的に肝臓内樹状細胞(DC)の変動を解析した.生体肝移植を施行したレシピエント12例,およびそのドナー12例を対象とした.移植後の拒絶反応の有無は,血液生化学的データと肝生検による病理組織学的検討により診断した.肝組織および末梢血よりFicoll比重遠心法でリンパ球を分離後,各種蛍光モノクローナル抗体で染色しフローサイトメトリーで解析した.正常肝内DCは成熟あるいは活性化型が多く,未熟型が多い末梢血中DCとは異なるフェノタイプを示した.拒絶反応の有無により移植肝内DCの違いを認め,移植肝生着に関与していることが示唆された

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  • 【Innate immunityと肝病態】 各種肝疾患と自然免疫 PBC病態における自然免疫の関与

    山際 訓, 松田 康伸, 石本 結子, 高村 昌昭, 本田 穣, 市田 隆文

    肝・胆・膵   52 ( 4 )   563 - 570   2006.4

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  • CEACAM1発現調節による肝癌細胞株の足場非依存性増殖能の獲得

    小林 万李子, 松田 康伸, 青柳 豊, 若井 俊文, 白井 良夫

    肝臓   47 ( Suppl.1 )   A80 - A80   2006.4

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  • C型慢性肝炎症例のNK細胞におけるNKG 2A高発現とその機序

    山際 訓, 松田 康伸, 本田 穣, 高村 昌昭, 市田 隆文, 青柳 豊

    肝臓   47 ( Suppl.1 )   A217 - A217   2006.4

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  • CXCL10によるC型慢性肝炎に対するPEG化インターフェロン治療効果予測

    山際 訓, 松田 康伸, 本田 穣, 高村 昌昭, 大越 章吾, 野本 実, 青柳 豊

    日本内科学会雑誌   95 ( Suppl. )   215 - 215   2006.2

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  • 肝臓 肝細胞癌の病態と診断

    山際 訓, 松田 康伸, 青柳 豊

    Annual Review消化器   2006   276 - 282   2006.1

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  • 【胆管系と自然免疫:生体防御と病態形成への関与】 胆管系の自然免疫 生体防御因子 Toll-like receptors PBC病態形成への関与

    山際 訓, 本田 穣, 高村 昌昭, 松田 康伸, 市田 隆文

    肝・胆・膵   51 ( 4 )   565 - 572   2005.10

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  • C型慢性肝炎に対するPEG-IFN治療効果と血清CXCL10及び肝臓内NK細胞を中心としたCXCR3陽性リンパ球との関連

    山際 訓, 松田 康伸, 本田 穣, 高村 昌昭, 市田 隆文, 青柳 豊

    肝臓   46 ( Suppl.2 )   A409 - A409   2005.9

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  • 肝硬変組織におけるId-1過剰発現と肝癌発症リスクの相互関係

    松田 康伸, 山際 訓, 高村 昌昭, 本田 譲, 市田 隆文, 青柳 豊

    日本癌学会総会記事   64回   176 - 176   2005.9

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  • 肝再生医療の研究と臨床応用 G-CSF-CD26/DPPIV時間差調節を介した骨髄幹細胞による肝障害治療

    松田 康伸, 山際 訓, 青柳 豊

    日本消化器病学会雑誌   102 ( 臨増大会 )   A611 - A611   2005.9

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  • マウス胎児肝幹前駆細胞の無血清長期継代培養およびその階層性の解析

    土屋 淳紀, 平家 俊男, 藤野 寿典, 塩田 光隆, 梅田 雄嗣, 吉本 桃子, 松田 康伸, 市田 隆文, 青柳 豊, 中畑 龍俊

    炎症・再生   25 ( 4 )   304 - 304   2005.7

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  • マウス急性肝傷害モデルにおける予防的HGF遺伝子治療の検討

    塙 孝泰, 鈴木 健司, 河内 裕介, 松田 康伸, 丸山 弘樹, 韓 基東, 河内 裕, 清水 不二雄, 宮崎 純一, 朝倉 均, 青柳 豊

    消化器と免疫   ( 41 )   172 - 175   2005.5

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    四塩化炭素によるマウス急性肝障害モデルに対し,ハイドロダイナミクス法を用いて肝臓にHGF(肝細胞増殖因子)遺伝子導入を行った群とControl gene導入群を作製し,治療効果を比較した.HGF遺伝子導入群は血清ALT値が有意に低く,組織学的には傷害がより軽度であり,免疫組織学的にはBrdU陽性細胞数の増加と炎症細胞の肝浸潤抑制がより顕著であった.また,Control gene導入群でTUNEL陽性細胞数が増加したのに対してHGF遺伝子導入群では有意に減少した

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  • C型慢性肝炎における末梢血単核球レクチン結合能の特性

    山際 訓, 松田 康伸, 青柳 豊, 市田 隆文, 本田 穣, 高村 昌昭, 富山 智香子, 渡部 久実

    肝臓   46 ( Suppl.1 )   A227 - A227   2005.5

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  • 原発性胆汁性肝硬変におけるtoll様レセプターを介した単核球活性化の検討

    本田 穣, 山際 訓, 青柳 豊, 松田 康伸, 石本 結子, 高村 昌明, 野本 実, 市田 隆文

    肝臓   46 ( Suppl.1 )   A170 - A170   2005.5

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  • 消化器領域におけるプロテオーム研究の現状と新しい展開 肝癌周囲組織のプロテオーム解析により推定されたoval cell由来肝細胞の発現蛋白異常

    松田 康伸, 市田 隆文, 青柳 豊

    日本消化器病学会雑誌   102 ( 臨増総会 )   A67 - A67   2005.3

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  • 大腸癌におけるliver-intestine cadherin(LI-cadherin)発現の臨床病理学的意義の検討

    高村 昌昭, 市田 隆文, 松田 康伸, 小林 正明, 山際 訓, 玄田 拓哉, 塩路 和彦, 橋本 哲, 野本 実, 畠山 勝義, 味岡 洋一, 坂元 亨宇, 広橋 説雄, 青柳 豊

    日本消化器病学会雑誌   102 ( 臨増総会 )   A284 - A284   2005.3

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  • 肝癌周囲組織に発現上昇するferritin light chain(FLC)の発癌危険因子としての臨床学的検討

    松田 康伸, 山際 訓, 高村 昌昭, 石本 結子, 本田 穣, 青柳 豊

    日本内科学会雑誌   94 ( Suppl. )   121 - 121   2005.2

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  • 多彩な内視鏡像を呈したサルコイドーシス胃病変の一例

    大嶋 智子, 三浦 隆義, 佐藤 祐一, 松田 康伸, 杉村 一仁, 本間 照, 小林 正明, 味岡 洋一, 稲庭 謙一, 成澤 林太郎, 青柳 豊

    ENDOSCOPIC FORUM for digestive disease   20 ( 2 )   172 - 172   2004.11

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  • 薬物性肝障害の実態と今後の課題 薬剤性肝障害の診断と予後予測における組織学的検討の意義と自己免疫性肝炎急性型との比較

    野本 実, 松田 康伸, 青柳 豊

    肝臓   45 ( Suppl.3 )   A542 - A542   2004.11

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  • 検査値の読み方 抗ミトコンドリア抗体陰性原発性胆汁性肝硬変の1例

    大越 章吾, 小林 久里子, 見田 有作, 山際 訓, 松田 康伸, 野本 実, 青柳 豊

    臨床消化器内科   19 ( 13 )   1806 - 1810   2004.11

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  • セクタ型超音波探触子により腹腔鏡下ラジオ波焼灼術(LRFA)が可能であった表在性肝細胞癌の1例

    矢野 雅彦, 松田 康伸, 三浦 隆義, 大嶋 智子, 福原 康夫, 本間 信之, 小林 真, 五十嵐 正人, 玄田 拓哉, 和栗 暢生, 川合 弘一, 山際 訓, 青柳 豊

    ENDOSCOPIC FORUM for digestive disease   20 ( 2 )   151,162 - 157,162   2004.11

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    78歳男.肝被膜下表面のS3-4およびS3に存在する径12mm大と5mm大の肝細胞癌再発巣に対し,制癌剤動注療法後にLRFAを施行した.腹腔鏡下に病変を直視することはできなかったが,トロカールから挿入したセクタ型超音波探触子によって2つの病変が確認でき,正確な焼灼が行えた

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  • Increase of regulatory CD4(+)CD25(+) T cells in the liver of patients with hepatocellular carcinoma.

    S Yamagiwa, XH Yang, S Sugahara, Y Honda, Y Matsuda, Y Aoyagi, DA Horwitz, T Ichida

    HEPATOLOGY   40 ( 4 )   311A - 311A   2004.10

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  • G-CSF/SDF-1系を介した骨髄細胞の肝細胞分化

    松田 康伸, 市田 隆文, 青柳 豊

    肝臓   45 ( Suppl.2 )   A358 - A358   2004.9

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  • 肝癌周囲正常組織における肝細胞のプロテオーム解析

    松田 康伸, 市田 隆文, 山際 訓, 高村 昌昭, 青柳 豊

    日本癌学会総会記事   63回   451 - 451   2004.9

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  • 薬剤性肝障害の診断と予後推定に対する組織学的検討の意義

    野本 実, 松田 康伸, 青柳 豊

    肝臓   45 ( Suppl.2 )   A416 - A416   2004.9

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  • 再生医療は移植医療にとってかわるか? G-CSF/SDF-1系を介した骨髄細胞の肝細胞分化

    松田 康伸, 市田 隆文, 青柳 豊

    日本消化器病学会雑誌   101 ( 臨増大会 )   A421 - A421   2004.9

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  • 薬物性肝障害をめぐる諸問題 薬剤性肝障害の診断と予後推定に対する組織学的検討の意義

    野本 実, 松田 康伸, 青柳 豊

    日本消化器病学会雑誌   101 ( 臨増大会 )   A605 - A605   2004.9

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  • マウス胎児肝幹前駆細胞の長期継代培養の試み

    土屋 淳紀, 平家 俊男, 藤野 寿典, 塩田 光隆, 梅田 雄嗣, 吉本 桃子, 松田 康伸, 市田 隆文, 青柳 豊, 中畑 龍俊

    炎症・再生   24 ( 4 )   500 - 500   2004.7

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  • 【内視鏡ことわざ・寸言集】 肝 豹紋はPBCを疑え

    渡辺 俊明, 坂内 均, 瀧本 光弘, 松田 康伸

    消化器内視鏡   16 ( 6 )   1019 - 1020   2004.6

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  • p27強発現肝癌組織におけるCDK2活性及び関連細胞周期調節因子の解析

    松田 康伸, 市田 隆文, 山際 訓, 玄田 拓也, 青柳 豊

    肝臓   45 ( Suppl.1 )   A158 - A158   2004.4

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  • 肝炎ウイルス増殖機構の解明と治療戦略 C型慢性肝炎に対するInterferonとRibavirin併用療法の治療反応性の違いにおける肝臓内リンパ球及び肝臓発現遺伝子の変動

    山際 訓, 市田 隆文, 青柳 豊, 松田 康伸

    肝臓   45 ( Suppl.1 )   A18 - A18   2004.4

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  • Attenuation of acute liver injury of mice by hepatocyte growth factor gene transfer to the liver via tail vein

    T Hanawa, K Suzuki, Y Kawauchi, Y Matsuda, H Yoneyama, H Maruyama, GD Han, H Kawachi, F Shimizu, JI Miyazaki, H Asakura, Y Aoyagi

    GASTROENTEROLOGY   126 ( 4 )   A492 - A492   2004.4

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  • 8 画像学的に診断し得なかった肝腫瘍の一例(I.一般演題,第26回リバーカンファレンス総会)

    藤村 健夫, 佐藤 明人, 松田 康伸, 小林 真, 和栗 暢生, 須田 剛士, 高橋 達, 野本 実, 青柳 豊, 朝倉 均, 山本 哲史, 加村 毅

    新潟医学会雑誌   117 ( 11 )   2003.11

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  • 37 当科における自己免疫性肝炎に合併した肝細胞癌の検討(I.一般演題,第27回リバーカンファレンス総会)

    大橋 和政, 土屋 淳紀, 松田 康伸, 市田 隆文, 野本 実, 青柳 豊

    新潟医学会雑誌   117 ( 11 )   2003.11

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  • 19 PIVKA-II高値を呈した肝限局性結節性過形成の一例(I.一般演題,第27回リバーカンファレンス総会)

    東海林 俊之, 丸山 弦, 松田 康伸, 市田 隆文, 野本 実, 青柳 豊, 畑 耕治郎

    新潟医学会雑誌   117 ( 11 )   2003.11

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  • 22 好酸球増多と類上皮肉芽腫を認めた原発性硬化性胆管炎の一例(I.一般演題,第26回リバーカンファレンス総会)

    浦川 佳美, 江部 和人, 松田 康伸, 高橋 達, 野本 実, 市田 隆文, 青柳 豊, 朝倉 均

    新潟医学会雑誌   117 ( 11 )   2003.11

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  • 当科における自己免疫性肝炎に合併した肝細胞癌の検討

    大橋 和政, 土屋 淳紀, 松田 康伸, 市田 隆文, 野本 実, 青柳 豊

    新潟医学会雑誌   117 ( 11 )   674 - 674   2003.11

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  • PIVKA-II高値を呈した肝限局性結節性過形成の一例

    東海林 俊之, 丸山 弦, 松田 康伸, 市田 隆文, 野本 実, 青柳 豊, 畑 耕治郎

    新潟医学会雑誌   117 ( 11 )   668 - 668   2003.11

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  • 好酸球増多と類上皮肉芽腫を認めた原発性硬化性胆管炎の一例

    浦川 佳美, 江部 和人, 松田 康伸, 高橋 達, 野本 実, 市田 隆文, 青柳 豊, 朝倉 均

    新潟医学会雑誌   117 ( 11 )   658 - 658   2003.11

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  • 画像学的に診断し得なかった肝腫瘍の一例

    藤村 健夫, 佐藤 明人, 松田 康伸, 小林 真, 和栗 暢生, 須田 剛士, 高橋 達, 野本 実, 青柳 豊, 朝倉 均, 山本 哲史, 加村 毅

    新潟医学会雑誌   117 ( 11 )   653 - 653   2003.11

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  • 【偶発症とその対策 こんな時どうする】 腹腔鏡 前処置・診断 気腹操作による腹腔内出血

    松田 康伸, 高橋 達, 渡辺 俊明

    消化器内視鏡   15 ( 10 )   1450 - 1451   2003.10

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  • 【偶発症とその対策 こんな時どうする】 腹腔鏡 前処置・診断 腹腔鏡下肝生検による出血

    松田 康伸, 高橋 達, 渡辺 俊明

    消化器内視鏡   15 ( 10 )   1452 - 1453   2003.10

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  • Integrin-stimulated cell scattering is regulated by extracellular signal-regulated kinase (ERK) pathways in highly metastatic hepatocellular carcinoma cells.

    N Honma, T Genda, Y Matsuda, T Ichida, Y Aoyagi

    HEPATOLOGY   38 ( 4 )   567A - 567A   2003.10

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  • Serial phenotypic profiling of intrahepatic lymphocytes in patients with chronic hepatitis C before and after combination interferon alpha-2b and ribavirin therapy.

    S Yamagiwa, T Ichida, S Okoshi, XH Yang, Y Ishimoto, T Genda, Y Matsuda, T Abo, Y Aoyagi, H Watanabe

    HEPATOLOGY   38 ( 4 )   460A - 460A   2003.10

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  • 生体肝移植症例における原発性胆汁性肝硬変の肝内リンパ球解析

    石本 結子, 山際 訓, 市田 隆文, 菅原 聡, 佐藤 好信, 松田 康伸, 青柳 豊

    肝臓   44 ( Suppl.1 )   A111 - A111   2003.4

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  • CDC25Aホスファターゼの発現は肝細胞癌の脱分化と悪性度に強い関連性を示す

    栗田 聡, 市田 隆文, 松田 康伸, 玄田 拓哉, 山際 訓, 青柳 豊

    肝臓   44 ( Suppl.1 )   A174 - A174   2003.4

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  • MAPK pathwayの活性化は高転移性肝がん細胞のscatteringを誘導する

    本間 信之, 玄田 拓哉, 松田 康伸, 市田 隆文, 青柳 豊

    肝臓   44 ( Suppl.1 )   A163 - A163   2003.4

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  • Docetaxel/CDDP/UFT-E全身化学療法が奏効した肝細胞癌肺転移の1例

    石川 達, 市田 隆文, 横山 純二, 松田 康伸, 渡辺 俊明, 青柳 豊

    日本消化器病学会雑誌   100 ( 臨増総会 )   A268 - A268   2003.3

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  • <学会記事>23 CT・MRI で描出できず, CTA で腫瘤性病変を明瞭に描出可能であった膵癌の一治験例(一般演題)(第 71 回新潟消化器病研究会)

    渡辺 史郎, 杉谷 想一, 竹内 学, 和栗 暢生, 川合 弘一, 須田 剛士, 松田 康伸, 藤原 敬人, 本山 展隆, 渡辺 雅史, 高橋 達, 野本 実, 青柳 豊, 朝倉 均, 黒崎 功, 畠山 勝義, 加村 毅

    新潟医学会雑誌   116 ( 8 )   410 - 410   2002.8

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  • CT・MRIで描出できず,CTAで腫瘤性病変を明瞭に描出可能であった膵癌の一治験例

    渡辺 史郎, 杉谷 想一, 竹内 学, 和栗 暢生, 川合 弘一, 須田 剛士, 松田 康伸, 藤原 敬人, 本山 展隆, 渡辺 雅史, 高橋 達, 野本 実, 青柳 豊, 朝倉 均, 黒崎 功, 畠山 勝義, 加村 毅

    新潟医学会雑誌   116 ( 8 )   410 - 410   2002.8

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  • 肝臓癌におけるp27発現レベルと機能の相互関係の解析

    松田 康伸, 市田 隆文, 栗田 聡, 朝倉 均

    日本癌学会総会記事   60回   329 - 329   2001.9

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  • Nonalcoholic steatohepatitis(NASH)の3例

    和栗 暢生, 高橋 達, 川合 弘一, 塩路 和彦, 杉山 幹也, 小林 真, 渡辺 孝治, 五十嵐 正人, 稲吉 潤, 上原 一浩, 石川 達, 見田 有作, 松田 康伸, 市田 隆文, 野本 実, 朝倉 均

    ENDOSCOPIC FORUM for digestive disease   17 ( 1 )   88 - 88   2001.6

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  • 原発性胆汁性肝硬変と自己免疫性肝炎の境界症例と考えられた1例

    見田 有作, 高橋 達, 松田 康伸, 松井 茂, 瀧本 光弘, 石川 達, 川合 弘一, 坪井 康紀, 和栗 暢生, 山田 尚志, 黒岩 敬, 上原 一浩, 五十嵐 正人, 稲吉 潤, 渡辺 孝治, 市田 隆文, 青柳 豊, 朝倉 均

    ENDOSCOPIC FORUM for digestive disease   16 ( 2 )   158,173 - 164,173   2000.11

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    71歳女.胆道系優位の肝機能異常を認め,抗ミトコンドリア抗体は陰性であったが,抗核抗体および抗平滑筋抗体は陽性であり,自己免疫性肝炎の国際診断基準によるスコアは11点であった.腹腔鏡では溝状陥凹を有する起伏状変化の上に,大小不同の半球状結節が散在する肝表面像で,自己免疫性肝炎に近い像であった.組織では門脈域にpiecemeal necrosisを伴う細胞浸潤を認め,granulomaは認めないものの,ductpeniaと変性した隔壁胆管を認め,原発性胆汁性肝硬変も否定できない所見であった.これらの所見から,自己免疫性肝炎と原発性胆汁性肝硬変の境界に位置する症例と考え,ursodesoxycholic acid 300mg/日を投与し,経過をみているが,現在まで肝機能の悪化は認めていない

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  • 原発性胆汁性肝硬変(PBC)と自己免疫性肝炎(AIH)との境界症例と考えられた一例

    見田 有作, 高橋 達, 松田 康伸, 松井 茂, 瀧本 光弘, 石川 達, 川合 弘一, 菅原 聡, 坪井 康紀, 和栗 暢生

    ENDOSCOPIC FORUM for digestive disease   16 ( 2 )   187 - 187   2000.11

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  • 腹腔鏡下マイクロ波凝固療法(LMCT)を行った表在型肝癌3例

    松田 康伸, 高橋 達, 松井 茂, 朴 載広, 石川 達, 川合 弘一, 見田 有作, 和栗 暢生, 黒岩 敬, 上原 一浩, 市田 隆文, 青柳 豊, 朝倉 均

    ENDOSCOPIC FORUM for digestive disease   15 ( 2 )   199,238 - 204,238   1999.11

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    腹腔鏡下マイクロ波凝固治療(laparoscopic microwave coagulation therapy:LMCT)が有用であった表在型肝癌を3例(症例1:69歳女,症例2:70歳男,症例3:72歳女)を経験した.全例共にS3区域肝表面に存在する肝細胞癌であった.症例1の腫瘍は径6mmで肝表面に突出しており,腹腔鏡施行時に発見された.症例2の腫瘍は径2cmで,肝表面に腫瘍を視認できなかったが,腹腔鏡下超音波走査により描出可能であった.症例の3の腫瘍は径1cmで肝表面に突出しており,腹腔鏡で視認できたが,腹膜癒着のためLMCTのみでは十分なtreated marginを確保できず,LMCT施行時に経皮エタノール注入(PEIT)を追加した.いずれの症例も術後,画像検査で十分なtreated marginが得られた

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  • 腹腔鏡下マイクロ波凝固治療(LMCT)を行った表在型肝癌3例

    松田 康伸, 高橋 達, 松井 茂, 朴 載広, 石川 達, 川合 弘一, 見田 有作, 和栗 暢生, 黒岩 敬, 上原 一浩

    ENDOSCOPIC FORUM for digestive disease   15 ( 2 )   247 - 247   1999.11

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  • 血漿DNAを用いた膵・胆管癌スクリーニングの試み

    松田 康伸, 市田 隆文, 朝倉 均

    Gastroenterological Endoscopy   41 ( Suppl.2 )   1745 - 1745   1999.9

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  • 臨床応用可能な分子生物学 血漿DNAを用いた膵・胆管癌スクリーニングの試み

    松田 康伸, 市田 隆文, 朝倉 均

    胆道   13 ( 3 )   207 - 207   1999.9

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  • 肝癌におけるp16INK4遺伝子不活化機構の検討

    松田 康伸, 市田 隆文, 松澤 純, 杉村 一仁, 朝倉 均

    日本癌学会総会記事   58回   558 - 558   1999.8

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  • 【症候・病態の分子メカニズム】 消化器 主要疾患・症候群 膵・胆管癌

    松田 康伸, 朝倉 均

    Molecular Medicine   35 ( 臨増 )   167 - 168   1998.12

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  • 非B非C型肝疾患及び自己免疫性肝炎におけるTTV感染に関する検討

    高橋 達, 朴 載広, 松井 茂, 松田 康伸, 武田 康男, 大越 章吾, 市田 隆文, 朝倉 均

    肝臓   39 ( Suppl.3 )   82 - 82   1998.10

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  • 血漿DNAを用いた膵癌・胆管癌診断の試み

    松田 康伸, 小林 正明, 鈴木 裕, 新井 太, 坪井 康紀, 市田 隆文, 波多野 徹, 若井 俊文, 斎藤 英樹, 清水 武昭

    日本癌学会総会記事   57回   237 - 237   1998.8

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  • 18)多発性筋炎(PM)を合併した無症候性原発性胆汁性肝硬変(a-PBC)の2例(一般演題, 第65回新潟消化器病研究会 )

    丸山 貴広, 馬場 靖幸, 小柳 佳成, 松田 康伸, 鈴木 康史, 高橋 達, 野本 実, 青柳 豊, 朝倉 均, 高野 政彦, 広瀬 慎太郎, 小山 裕子, 粟森 和明, 姉崎 利治, 中野 亮一

    新潟医学会雑誌   112 ( 5 )   287 - 287   1998.5

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  • 多発性筋炎(PM)を合併した無症候性原発性胆汁性肝硬変(a-PBC)の2例

    丸山 貴広, 馬場 靖幸, 小柳 佳成, 松田 康伸, 鈴木 康史, 高橋 達, 野本 実, 青柳 豊, 朝倉 均, 高野 政彦

    新潟医学会雑誌   112 ( 5 )   287 - 287   1998.5

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  • 食塩水を併用した針電極組織内加温の検討

    斎藤 義明, 堀 潤一, 市田 隆文, 松田 康伸, 渡辺 雅史

    日本ハイパーサーミア学会誌   13 ( 4 )   245 - 245   1997.12

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  • 肝細胞癌におけるp16/INK4A/CDKN2遺伝子発現変動の検討

    松田 康伸

    肝臓   38 ( Suppl.2 )   157 - 157   1997.9

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  • Extention of Heating Range of Interstitial Needle RF Hyperthermia Using Saline

    SAITOH Yoshiaki, ICHIDA Takafumi, HORI Jun-ichi, MATSUDA Yasunobu, WATANABE Masafumi

    日本ハイパーサーミア学会誌 = Japanese journal of hyperthermic oncology   13 ( 2 )   68 - 74   1997.6

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    組織内癌温熱療法の一つである針電極によるRF加温の場合, 加温領域が狭いという問題があった.本研究では, 加温対象に食塩水を注入し, 導電率を高めることによって, 加温領域を拡大することを試みた.切離した豚の肝臓を対象として加温実験を行った結果, 食塩水の濃度が高いほど, また針電極の直径が太いほど加温領域が拡大した.Interstitial hyperthermia by using a needle electrode has problem that heating range is too narrow to apply for massive tissues. In this study, we tried to extend the heating range by using high-conductivity saline pouring into the heating object. In experiments of RF power heating using pig livers, the higher salt concentration or the thicker the diameter of the needle electrode, the wider the heating range.

    DOI: 10.3191/thermalmedicine.13.68

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  • Extention of heating range of interstitial needle RF hyperthermia using saline

    Yoshiaki Saitoh, Takafumi Ichida, Junichi Hori, Yasunobu Matsuda, Masafumi Watanabe

    Japanese Journal of Hyperthermia Oncology   13 ( 2 )   68 - 74   1997

  • 腹腔鏡アトラス アルコール性肝障害

    高橋 達, 松田 康伸, 佐藤 万成

    消化器内視鏡   8 ( 10 )   1414 - 1417   1996.10

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  • ラット肝硬変モデルにおけるアクチビンA発現変動の検討

    杉山 幹也, 松田 康信, 市田 隆文, 朝倉 均

    日本分子生物学会年会プログラム・講演要旨集   19   698 - 698   1996.8

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  • 31) 肝細胞癌に対する経皮的マイクロ波凝固療法(I. 一般演題, 第20回リバーカンファレンス総会)

    渡辺 雅史, 市田 隆文, 松田 康伸, 佐藤 知巳, 原田 武, 小柳 佳成, 五十嵐 広隆, 藤井 久一, 内田 守昭, 柳 雅彦, 青柳 豊, 朝倉 均

    新潟医学会雑誌   110 ( 8 )   358 - 358   1996.8

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  • 肝癌の治療 肝細胞癌に対する化学療法

    市田 隆文, 松田 康伸, 渡辺 雅史

    臨床成人病   26 ( 4 )   475 - 479   1996.4

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  • 肝癌治療症例のプロトコール 新潟大学医学部第3内科

    市田 隆文, 松田 康伸, 渡辺 雅史

    臨床成人病   26 ( 4 )   506 - 507   1996.4

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  • 28)特異な発育形態を示した大腸ポリープの1例(一般演題, 第61回新潟消化器病研究会)

    菅原 聡, 松田 康伸, 波田野 徹, 窪田 久, 富所 隆, 戸枝 一明, 杉山 一教

    新潟医学会雑誌   109 ( 9 )   439 - 439   1995.10

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  • ヒトリコンビナントHGF投与によるラット肝硬変の抑制および肝不全死の防止作用

    松田 康伸

    肝臓   36 ( Suppl.1 )   206 - 206   1995.6

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  • ヒトリコンビナントHFG投与によるラット肝線維症/肝硬変ならびに肝不全死の防止作用

    松田 康伸

    日本癌学会総会記事   53回   474 - 474   1994.10

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  • リコンビナントヒトHGF外因性投与はラット肝線維症/肝硬変および肝不全死を抑制する

    松田 康伸

    生化学   66 ( 7 )   748 - 748   1994.7

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  • 肝細胞増殖因子(HGF)による肝再生調節

    松田 康伸, 中村 敏一

    BIO Clinica   9 ( 4 )   243 - 249   1994.4

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  • 肝臓の分子病態生理学 肝再生 肝細胞増殖因子(HGF)の分子生物学

    松田 康伸, 中村 敏一

    日本臨床   51 ( 2 )   435 - 445   1993.2

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  • 7) 腹腔内にimplantationしたと思われた肝細胞癌の1例(I.一般演題, 第24回新潟画像医学研究会)

    尾崎 俊彦, 松田 康伸, 本間 明, 相場 哲朗, 川口 正樹

    新潟医学会雑誌   106 ( 5 )   455 - 455   1992.5

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  • 肝細胞癌初期病変におけるAgNOR染色による腫瘍細胞増殖能の検討

    松田 康伸, 市田 隆文, 宮崎 裕

    肝臓   33 ( 1 )   76 - 76   1992.1

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    核1個当りのAgNOR個数は,正常肝1.34±0.11 (mean±SD),慢性肝炎1.83±0.22,肝硬変1.93±0.40,細小肝癌2.64±0.52,進行性肝細胞癌3.93±0.60であった.細小肝癌は,肝硬変に比し,統計学的に有意差(p&lt;0.01)をもって個数の増加が認められた.進行性肝細胞癌との間にも有意差(p&lt;0.01)を認めた

    DOI: 10.2957/kanzo.33.76

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  • 経過中に尿崩症を呈した再膨脹性肺水腫(RPE)の1例

    松田 康伸, 星野 重幸, 八幡 和明

    日本胸部臨床   50 ( 12 )   1010 - 1015   1991.12

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    24歳男,ショック状態を呈したRPE.この時,経過中に一過性に尿崩症を併発し,その他に脳下垂体ホルモンの低下をきたした

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  • 肝細胞癌における5年以上長期生存例の臨床的検討

    松田 康伸

    肝臓   32 ( Suppl.3 )   87 - 87   1991.10

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  • 16) 腹腔内にimplantationしたと思われた肝細胞癌の1例(II.一般演題, 第15回リバーカンファレンス総会)

    松田 康伸, 本間 明, 尾崎 俊彦, 相場 哲朗, 川口 正樹

    新潟医学会雑誌   105 ( 8 )   567 - 567   1991.8

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  • 7) 穿孔性腹膜炎を来たした腸管ベーチェット病の1例(I.一般演題, 第232回新潟外科集談会)

    相場 哲朗, 川口 正樹, 前田 和夫, 尾崎 俊彦, 本間 明, 松田 康伸

    新潟医学会雑誌   105 ( 8 )   570 - 570   1991.8

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  • 16) 大腸におけるstrip biopsy症例の検討(一般演題, 第53回新潟消化器病研究会)

    本間 明, 松田 康伸, 尾崎 俊彦, 相場 哲朗, 川口 正樹, 太田 玉紀

    新潟医学会雑誌   105 ( 7 )   498 - 498   1991.7

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  • 腹腔内に発生した血管周被細胞腫の1例

    松田 康伸

    日本消化器病学会雑誌   88 ( 臨増 )   1038 - 1038   1991.3

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  • 腸結核瘢痕に合併した大腸癌の1例

    松田 康伸

    日本消化器病学会雑誌   88 ( 臨増 )   591 - 591   1991.2

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  • UEA-I染色を用いた肝内小結節性病変の組織化学的検討

    波田野 徹, 市田 隆文, 畑 耕治郎, 山田 慎二, 松田 康伸, 宮崎 裕, 上村 朝輝, 朝倉 均

    肝臓   32 ( 10 )   967 - 967   1991

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    DOI: 10.2957/kanzo.32.967

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  • 10)胃全摘後空腸重積症の1例(I.一般演題, 第23回新潟画像医学研究会)

    松田 康伸, 尾崎 俊彦, 本間 明, 相場 哲朗, 川口 正樹

    新潟医学会雑誌   104 ( 11 )   979 - 979   1990.11

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  • 胃全摘後空腸重積症の1例

    松田 康伸

    新潟医学会雑誌   104 ( 11 )   979 - 979   1990.11

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  • 3) ステロイド剤大量投与に起因するB型重症肝炎にインターフェロンが著効を奏した1例(一般演題, 第14回リバーカンファレンス総会)

    佐々木 亮, 小方 則夫, 田中 泰樹, 松田 康伸, 野本 実, 上村 朝輝, 朝倉 均, 須田 剛士, 宮武 正

    新潟医学会雑誌   104 ( 9 )   804 - 804   1990.9

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▶ display all

Awards

  • travel grant award

    2013.10   欧州消化器病学会  

    MATSUDA Yasunobu

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  • 奨励賞

    2011.10   日本臨床分子形態学会  

    松田 康伸

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  • 学術奨励賞

    2006.10   新潟県医師会  

    松田 康伸

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  • 市田賞

    2002.6   新潟大学医学部消化器内科学  

    松田 康伸

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  • JB論文賞

    1996.6   日本生化学会  

    松田 康伸

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Research Projects

  • 消化器癌のゲノム高次元データ解析システムを基盤とした深層学習による人工知能の開発

    Grant number:21H02998  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    若井 俊文, 奥田 修二郎, 諸 和樹, 島田 能史, 永橋 昌幸, 松田 康伸, 市川 寛, 坂田 純

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    Grant amount:\17420000 ( Direct Cost: \13400000 、 Indirect Cost:\4020000 )

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  • セラミドによる免疫制御機構を応用した膵島移植における膵島生着延長の試み

    Grant number:20K21628  2020.7 - 2023.3

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    小林 隆, 木下 義晶, 松田 康伸, 永橋 昌幸, 三浦 宏平, 廣瀬 雄己, 油座 築, 諸 和樹

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    Grant amount:\6500000 ( Direct Cost: \5000000 、 Indirect Cost:\1500000 )

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  • エクソソーム内包タンパク活性化機構に着目した胆道がん併用療法の確立

    Grant number:19K08365  2019.4 - 2022.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    松田 康伸, 高村 昌昭, 小林 隆

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    Grant amount:\4030000 ( Direct Cost: \3100000 、 Indirect Cost:\930000 )

    本研究の目的は、①胆道がんのエクソソームにおけるmTOR活性化機構を検討し、②mTOR以外のエクソソーム内部蛋白の活性化状態についても網羅的な解析を行い、エクソソームに拮抗する医薬品を用いた併用療法を確立することである。当初、本研究を進めるにあたって以下の実験計画を立案した。①胆道がんのエクソソーム内部におけるmTOR活性化の原因・機序を探る目的で、培養胆道がん細胞株にmTORシグナル阻害剤やmTOR siRNAを添加した後に、抗がん剤を投与してエクソソーム分泌量・活性を解析する。
    ②リン酸化抗体アレイを用いて、抗がん剤で活性化される胆道がんのエクソソーム内部蛋白を網羅的に解析する。
    本年度においては、上記の実験計画①を主に行った。具体的には、胆道がん細胞(胆管がんHuCCT1、胆のうがんNOZ)に抗がん剤(ゲムシタビン、シスプラチン)を投与し、エクソソーム量・活性(増殖/転移促進)を解析した。その結果、胆管がんのエクソソーム分泌量は抗がん剤刺激で有意に増加するするものの、正常コントロールの1.7-3倍程度にとどまることが明らかになった。一方、エクソソームの生物活性(細胞遊走能の促進・細胞増殖能の促進)は、抗がん剤刺激後では著明に増強していることが分かった。正常コントロールのがん細胞から分泌されるエクソソームは、僅かな細胞に対する遊走刺激しか示さないが(3/500細胞数)、抗がん剤刺激した細胞から得られたエクソソームは、約10数倍の細胞遊走能(20-35/500細胞数)を有していた。この理由をさぐるためにエクソソーム蛋白のリン酸化蛋白候補のウエスタン・ブロット解析を行った結果、予備実験で既に推測していたmTOR経路の活性化が関与していることが分かった。
    なお、上述の実験計画②は次年度以降に行う予定である。

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  • 消化器発癌における免疫老化による免疫監視不全の関与の解明と新規先制医療の開発

    Grant number:18K07965  2018.4 - 2021.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    山際 訓, 寺井 崇二, 高村 昌昭, 松田 康伸

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

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  • Creation of next-generation cell therapy for diabetes with focus on nesidioblastic change

    Grant number:17H04270  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    Kobayashi Takashi

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    Grant amount:\17160000 ( Direct Cost: \13200000 、 Indirect Cost:\3960000 )

    It was confirmed that stress protein expression was nesidioblastic changes observed in chronic pancreatitis tissue, and that similar proteins were also induced in drug induced pancreatitis models. Although stress proteins have been reported to promote graft engraftment, it is likely that stress-related proteins are also involved in graft engraftment with nesidioblastic changes. In addition, the usefulness of GLP-1 was suggested as a drug that may promote the regeneration of transplanted islets after engraftment of islets and improve blood glucose.

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  • Elucidation of clinical significance and chemotherapy resistance mechanism of NAD(P)H:quinone oxidoreductase 1 (NQO1) expression for colorectal liver metastasis

    Grant number:17K10663  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Nakano Mae

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    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

    NQO1 is an antioxidant stress protein. The expression of NQO1 is enhanced under stressed environment in vivo. We studied how NQO1 expression affects response of preoperative chemotherapy and prognosis in colorectal liver metastasis. In this study, immunohistochemistry using monoclonal antibody was performed on the resected specimen of colorectal liver metastasis, and the expression of NQO1 was analyzed. The NQO1 positive group had worse overall survival than the NQO1 negative group, and the presence of NQO1 polymorphism was associated with a better response to preoperative chemotherapy. The expression pattern of NQO1 can predict the prognosis and the response of preoperative chemotherapy in patients with colorectal liver metastasis.

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  • Regenetative medicine using decidouous teeth preparing for future diseases

    Grant number:17K08966  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Shogo Ohkoshi

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    Grant amount:\4810000 ( Direct Cost: \3700000 、 Indirect Cost:\1110000 )

    Dental pulp-derived mesenchymal stem cells were differentiated into polygonal hepatocyte-like cells(HLCs) under the presence of Activin A, FGF and HGF in culture media. These cells could convert ammonium into urea and expressed HGFd HGF-4, that revealed mature hepatocyte function of the cells. We observed the suppression of severity of experimental chemical hepatitis by infusing cells via tail veins.We also developed specific PCR primers that could specifically differentiate human cells from rat cells. We clarified the dynamic changes of HLCs in nude-rat livers when infused directly into portal veins.

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  • The mechanism of exosome-mediated drug resistance in hepatoma cells

    Grant number:16K09347  2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Yasunobu MATSUDA

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    Grant amount:\4810000 ( Direct Cost: \3700000 、 Indirect Cost:\1110000 )

    Recently, it has been regarded that cells secret exosome (nano-sized vesicles (20-100 nm)), which participate in various types of cell-cell communication. In this study, we examined the mechanism of exosome secretion in hepatoma cells, and found that exosome exert drug resistance to anticancer drugs. Our obtained results showed that anticancer drugs (cisplatin and 5-fluorouracil) stimulate the secretion of exosome in human hepatoma cells. When cells were incubated with anticancer drug-treated cells-derived exosome, they acquired strong resistance to anticancer drugs. We found that activated type of mTOR, a serine-threonine kinase which plays a pivotal role in the cell survival, was significantly increased in exosome. Collectively, exosome exerts drug resistance through mTOR signaling in hepatoma cells.

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  • Histochemical analysis and modification of the natural healing process of the large defect of rabbit trachea.

    Grant number:16K11343  2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Kubota Masayuki

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    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    The purpose of the present study is to establish a technique to induce more physiological healing process without a granulation formation in the large tracheal defect of rabbits. Firstly, a natural healing process was examined histochemically. Tracheal defect was covered with inflammatory tissue one week after operation, and granulation tissue created inside was covered with tracheal epithelium two weeks after operation. Exogenous application of TNFα monoclonal antibody induced general and local inflammatory responses probably due to suppression of natural immune system. Then, combined application of somatostatin analog (an inhibitor of growth hormone) and rapamycin (an inhibitor of intracellular mTOR signal pathway for fibrosis) were tried with a careful consideration of their dosages and timing of application. As a result, more physiological healing process without granulation formation could be induced.

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  • Elucidation of the signal expression mechanism in the mTOR cell and development of the rapamycin treatment in the hepatoblastoma

    Grant number:16K11341  2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Arai Yuhki

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    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    After examining 27 hepatoblastoma cases in our hospital for the past 30 years, I compared the clinical data such as the prognosis and the biological malignancy with the result of the immunostaining due to the mTOR (Ser2448) antibody of the preparation, and the tendency that a value of provided Labeling index related to was recognized by a malignancy and immunostaining. It did not lead to number of cases before finding enough significant difference, but, in the expression of hepatoblastoma, it is thought that PI3K/Akt/mTOR course participates, and the possibility that the drug which inhibited mTOR signaling course could become the therapeutic agent of the hepatoblastoma in the future was suggested.

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  • Establishment of new treatment strategy for NASH by elucidating the mechanisms of fibrosis progression due to nocturnal intermittent hypoxia.

    Grant number:16K09564  2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    HIRONO Haruka, WATANABE kazuhiko

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    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    The fatty liver disease which is not related to drinking is so called NAFLD(non-alcoholic fatty liver disease). Most of it is the simple fatty liver, not resulting in a big trouble. However, a part of it could be NASH(non-alcoholic steatohepatitis), which has mimicking pathology of alcoholic liver injury and has a potential of progression to liver cirrhosis. Though the most important cause of NAFLD is obesity, chronic intermittent nocturnal hypoxia in OSAS(obstructive sleep apnea syndrome) patients is regarded as one of the causes for NAFLD independently without obese factor.The first choice of the treatment of OSAS is CPAP(continuous positive airway pressure), resulting in improvement of nocturnal hypoxia. We demonstrated the effectiveness of CPAP therapy for hypoxic liver injury by using 50 OSAS patients with NAFLD.

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  • Elucidation of molecular mechanism of lipid mediator involved in metastatic ability of biliary tract cancer / pancreatic cancer and clinical application

    Grant number:15H04927  2015.4 - 2018.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    WAKAI TOSHIFUMI, Komatsu Masaaki, Sarah Spiegel, Hylemon Phillip B., Takabe Kazuaki

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    Grant amount:\16640000 ( Direct Cost: \12800000 、 Indirect Cost:\3840000 )

    We have developed a method to measure sphingosine-1-phosphate levels in the interstitial fluid that bathes cancer cells in the tumor microenvironment, and reported that high levels of sphingosine-1-phosphate exist in the tumor interstitial fluid. Importantly, sphingosine-1-phosphate can be secreted from cancer cells and non-cancer components such as immune cells and vascular/lymphatic endothelial cells in the tumor microenvironment. We elucidate the roles of sphingosine-1-phosphate in the interaction between cancer and non-cancer cells in tumor microenvironment, and discuss future possibilities for targeted therapies against sphingosine-1-phosphate signaling for cancer patients.

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  • 肝内免疫監視不全の回復と抗体関連型拒絶反応を応用した肝癌に対する新規治療法の開発

    Grant number:15K08991  2015.4 - 2018.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    山際 訓, 高村 昌昭, 松田 康伸

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    Grant amount:\4810000 ( Direct Cost: \3700000 、 Indirect Cost:\1110000 )

    ナチュラルキラー(NK)細胞と自然リンパ球(ILCs)およびNK細胞機能に影響する液性免疫に着目して,肝細胞癌(HCC)発癌・再発に関与する免疫病態,特に肝内免疫監視不全を分子・細胞レベルで解明することを目的とした研究を当初の研究計画に沿って実施した。
    1.研究対象の選定,同意を得た上での肝組織と末梢血の採取,臨床データのまとめ → HCC症例とHCC非合併慢性ウイルス性肝炎症例,および対照群として自己免疫性肝疾患症例より適切に肝組織と末梢血の採取を行い,研究に使用するとともにHCC再発の有無など臨床データのまとめと経過観察を継続中である。
    2.肝組織と末梢血より分離したNK細胞やILCsにおける細胞傷害性リガンド,サイトカイン・ケモカインレセプターの発現解析 → フローサイトメトリーと免疫組織染色によりNK細胞機能に関与する分子を中心に検討するとともに,液性免疫に対する重要な調節作用を持つ濾胞性ヘルパーT(Tfh)細胞にも着目して解析を追加し,Tfh細胞分画の中でCCR7陰性PD-1陽性Tfh分画が自己免疫性肝炎の病態と関連することを見出し,現在,英文論文を投稿中である。
    3.肝細胞癌株と血管内皮細胞株に対する細胞傷害活性,特に抗体添加による効果の解析 → 末梢血から磁気ビーズにて分離したNK細胞を用いて,各種肝癌細胞株に対する細胞傷害活性と抗MHC class I-related chain A(MICA)抗体の添加による作用を確認するとともに,血管内皮細胞株を用いて同様の実験を進めている。
    4.抗MICA抗体のallele解析 → 血清中に抗MICA抗体が陽性となるHCC症例について,抗体が認識するallele解析済みの症例では自己のMICA以外のalleleに対する抗体が多く認められた。

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  • Elucidation of the mechanism of drug resistance in colorectal cancer by p62-Keap 1-Nrf2 pathway

    Grant number:26462006  2014.4 - 2017.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    KAMEYAMA Hitoshi, KOMATSU Masaaki

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    Grant amount:\4940000 ( Direct Cost: \3800000 、 Indirect Cost:\1140000 )

    p62-Keap1-Nrf2 pathway induce the antioxidants like NQO1. In cancer cells, NQO1 confers resistance against anticancer agents. The aim of this study was to evaluate the association between NQO1 expression and prognosis in patients with advanced colorectal cancer (CRC). Among the patients with KRAS wild CRC, NQO1-negative patients showed significantly better disease control rate than NQO1-positive patients. Moreover, NQO1-negative patients had longer progression-free survival and overall survival than NQO1-positive patients. NQO1 expression in the tumor may be a predictor of therapeutic efficacy and prognosis in patients with KRAS wild advanced CRC.

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  • Discovery of new insulin-resistance marker which determines the effect of IFN for chronic hepatitis C

    Grant number:25461012  2013.4 - 2016.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Ohkoshi Shogo, MATSUDA Yasunobu, YAMAGIWA Satoshi, YANO Masahiko

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    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

    We examined whether RBP4(Retinol binding protein 4) was a significant factor which determined the outcome of the CH C patients with genotype 1b who were treated with PEG-IFN plus ribavirin.
    Because RBP4 was a marker of insulin resistance, we speculated that this might be the key molecule which determined the association between IFN therapy and insulin resistance. We performed in vitro experiments to examine whether RBP4 suppressed IFN signalling, resulting in the resistance of HCV replication against IFN. As a result, in RBP4-knockdown hepatoma cell, ISG genes were activatied and HCV replication was enhanced when compared to RBP4 (+) cells. Thus we found that RBP4 interfered the action of IFN against HCV and result in IFN resistance.
    However, RBP4 was not proved to be a significant factor for the prediction of clinical data from more number of patients. In conclusion, we could not verify the significance of RBP4 levels for the prediction of IFN therapy.

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  • Importance of NK cell function in the mechanisms responsible for tumor evasion of immune surveillance against hepatocellular carcinoma after liver transplantation

    Grant number:24590963  2012.4 - 2015.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    YAMAGIWA Satoshi, TAKAMURA Masaaki, MATSUDA Yasunobu

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    Grant amount:\5330000 ( Direct Cost: \4100000 、 Indirect Cost:\1230000 )

    We analysed mainly the function of natural killer (NK) cells in the liver and blood of patients with hepatocellular carcinoma (HCC) before and after liver transplantation (LT), but any specific immune markers associated with the recurrence of HCC after LT could not be defined. However, we revealed that anti-NK cell activation ligand antibody and soluble immune checkpoint molecule were detected in the blood of patients with HCC. Our results may help unveiling the mechanisms responsible for tumor evasion of immune surveillance against HCC.

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  • Effects of rapamycin on granulation formation in response to centrally-doubled coiled stents as a tracheal substitute.

    Grant number:24659773  2012.4 - 2015.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research  Grant-in-Aid for Challenging Exploratory Research

    KUBOTA Masayuki, MATSUDA Yasunobu

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    Grant amount:\3900000 ( Direct Cost: \3000000 、 Indirect Cost:\900000 )

    In order to prevent a formation of granulation tissue around the original artificial trachea, made of super-elastic wire, mTOR signal system in the granulation tissue was examined using rabbit tracheal defect model. In granulation tissue, mTOR activity was increased up to 20―40 folds in comparison with tracheal epithelium. Application of rapamycin, which blocked the mTOR signal system, partially blocked the mTOR activation. At the same time, the granulation tissue changed into the pathological condition, which induced respiratory infection. We have examined the proper method of application of rapamycin and it was found that the application of rapamycin starting from the 2 weeks after operation induced the favorable results. It is also suggested that the natural healing process of the tracheal wall defect is compromised and obtaining an improvement in this healing process should be one of the treatment strategies for tracheal pathologies.

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  • Early DNA damage response in residual carcinoma in situ at ductal stumps and local recurrence in patients undergoing resection for extrahepatic cholangiocarcinoma

    Grant number:24592021  2012.4 - 2015.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    WAKAI Toshifumi, MATSUDA Yasunobu, AJIOKA Yoichi, KOYAMA Yu, NAGAHASHI Masayuki

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    Grant amount:\5330000 ( Direct Cost: \4100000 、 Indirect Cost:\1230000 )

    Clinically evident local recurrence of residual carcinoma in situ at ductal stumps is closely associated with 53BP1 inactivation and decreased apoptosis. In contrast, apoptosis associated with early 53BP1-mediated DNA damage response is one of the molecular biological mechanisms that permit a small proportion of patients with residual carcinoma in situ at ductal stumps to survive in the long term with no evidence of local recurrence. Based on the Early DNA damage response, 50% of patients with formation of intraepithelial spread of invasive carcinoma, whereas 50% of patients with formation of field carcinogenesis. The formation of superficial intraepithelial spread results from both intraepithelial spread of invasive carcinoma and field carcinogenesis.

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  • Molecular Analysis of Cytokine-mediated Sorafenib Resistance

    Grant number:24590962  2012.4 - 2015.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    MATSUDA YASUNOBU, WAKAI Toshifumi, TKAMURA Masaaki, YAMAGIWA Satoshi

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    Sorafenib is a multi-kinase inhibitor for hepatocellular carcinoma. To address whether cytokine-mediated signaling is involved in the drug resistance, hepatoma cells were treated with sorafenib in the presence of several cytokines/growth factors. Obtained results showed that the effect of sorafenib on cell growth was significantly inhibited by TGF-beta. When TGF-beta-treated cells were treated with sorafenib and valproic acid, apoptotic cell numbers were increased as compared with those treated with sorafenib alone. Collectively, combination treatment of valproic acid and sorafenib might improve the efficacy of sorafenib.

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  • DNA障害の修復機構をマーカーとした新しいインターフェロン治療の開発

    2010.4 - 2013.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    大越章吾

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  • 肝がんにおける分子標的薬耐性機構の解析

    2010.1 - 2010.12

    その他の研究制度 

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  • Development of new IFN-strategy that based on DNA repair mechanism

    Grant number:22590722  2010 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    OHKOSHI Shogo, MATSUDA Yasunobu, YAMAGIWA Satoshi, YANO Masahiko

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    Grant amount:\4810000 ( Direct Cost: \3700000 、 Indirect Cost:\1110000 )

    The aim of this study is to clarify the molecular mechanisms of preventive effect of IFN-beta for the occurrence of hepatocellular carcinoma (HCC) and to establish the strategy of chemoprevention of HCC. We found that aberrant expression of p21, that was a known cyclin-dependent kinase (CDK) inhibitor, was a key mechanism for hepatocarcinogenesis and it’s prevention. IFN-beta shifted cytoplasmic p21, which was oncogenic, to nucleus, making them to exert original anti-proliferative function. We may explore this anti-cancer mechanism of IFN-beta in order to apply to clinical studies.

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  • 臓器移植における再生間葉系肝幹細胞門脈内投与による新たな免疫寛容誘導法の確立

    2009.4 - 2013.3

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    佐藤好信

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  • 胆管癌における53BP1を介したDNA損傷修復機構の解明及びその臨床的意義

    2009.4 - 2011.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    若井俊文

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  • Development of New Strategy of Immunological Tolerance Inductionby Intraportal administration of donor specific Mesenchymal hepatic stem cell in OrganTransplantation

    Grant number:21390356  2009 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    SATO Yoshinobu, ABO Toru, MATSUDA Yasunobu, TOMIYAMA Chikako

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    Grant amount:\17420000 ( Direct Cost: \13400000 、 Indirect Cost:\4020000 )

    The purpose of this study was to analyze the mechanisms of theinduction of operational tolerance in clinical liver transplantation by the intra-portaladministration of donor specific antigen and make the new method of induction of toleranceby hepatic stem cell. In the basic examination, the CD133+ NCAM+ human hepaticstem/progenitor cell was recognized around the region with existence of ductular reactionin the human liver with chronic or acute hepatitis. Especially, its existence was moreclearly in the human liver with higher hepatic injury. However, it was not recognizedin the normal human liver. In the immunological analysis of intra-portal administrationof super donor antigens, the population of FoxP3^+/CD4^+CD25^+ regulatory T cells increasedin the transplant patients with no immunosuppressants.
    Treg. cells increased in the patients above MELD score 20. It was proved that the graspof preoperative immunological situation of transplant patients take the betteradministration of immunosuppressants.

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  • Prospective analysis of DNA damage and repair markers in the patients with high risk of hepatocellular cancer

    Grant number:21590835  2009 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    MATSUDA Yasunobu

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    Background : It has been widely considered that the DNA damage response is strongly involved in the step of early carcinogenesis. In case of hepatocellular carcinoma(HCC), however, it has been remained unclear whether DNA damage response molecules are useful for the tumor markers of the patients with high risk of HCC.
    Methods : We evaluated the phosphorylation levels of DNA damage response markers in animal models with HCC by Western blotting or immunohistochemical staining. Based on the animal model experiments, we addressed whether any of the DNA-damage response molecules are involved in the cancer development of the patients with high risk of HCC.
    Results : Western blotting and immunohistochemical analysis showed that the levels of gamma-H2A were significantly increased in HCC-prone mice. Interestingly, increase in the levels of gamma-H2AX was observed from several months before the development of HCC. The increase in the levels of gamma-H2AX and Wip1 activity was also observed in human liver tissues adjacent to HCC.
    Conclusion : DNA damage response molecules gamma-H2AX and Wip1 might be useful markers for predicting the development of HCC.

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  • Development of a new endoscopic therapy using RNAi for intestinal fibrosis of Crohn's disease

    Grant number:21590807  2009 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    SUZUKI Kenji

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    Grant type:Competitive

    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    We have developed a new siRNA medicine, STNM-01 with Stelic Institute. In this project, we studied the therapeutic effects and the mechanism of endoscopic submucosal injection of the STNM-01 for the treatment of intestinal fibrosis using animal models. We have successfully developed a novel endoscopic injection therapy of STNM-01 for the treatment of intestinal fibrosis of Crohn's disease. Using this technique, we have started a phase I clinical trial for patients with Crohn's disease in Japan since January, 2012.

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  • Importance of NK cells and intrahepatic immune responses for the acceleration of hepatitis C after liver transplantation

    Grant number:21590834  2009 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    YAMAGIWA Satoshi, TAKAMURA Masaaki, MATSUDA Yasunobu, SATO Yoshinobu

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    Grant type:Competitive

    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

    The activating receptor natural killer group 2, member D(NKG2D) and its ligands play a crucial role in immune response to infections and tumors. Among the human NKG2D ligands, ULBP1 is prevalently expressed in hepatocellular carcinoma(HCC), but loss of its expression correlates with tumor progression and early recurrence. Although we could not find any significant changes in the gene expression profiles among the recurrent hepatitis C patients and chronic hepatitis C patients yet, our results suggest that the status of intrahepatic NK cell subsets and NK cell receptor ligand expressions might be associated with the rapid progression of recurrent hepatitis C infection.

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  • Manipulating the stromal-derived factor 1 function in mouse liver cirrhosis

    Grant number:19590753  2007 - 2008

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    MATSUDA Yasunobu

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

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  • Analysis of the innate immune responses in the liver of patients with chronic hepatitis C following liver transplantation to develop a novel immunotherapy for the recurrent hepatitis C infection

    Grant number:18590723  2006 - 2007

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    YAMAGIWA Satoshi, MATSUDA Yasunobu, TAKAMURA Masaaki, SATO Yoshinobu

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    Grant type:Competitive

    Grant amount:\3920000 ( Direct Cost: \3500000 、 Indirect Cost:\420000 )

    (1) Natural killer (NK) cell subsets in the liver of patients with recurrent hepatitis C following liver transplantation
    Human NK cells can be divided into two subsets based on their cell-surface density of CD56 - CD56^(+bright) and CD56^(+dim) - each with distinct phenotypic properties. We investigated the NK cell subsets in the liver of patients with recurrent hepatitis C following living-donor liver transplantation (LDLT). The patients with chronic hepatitis C (CHC) and the donors for LDLT were also investigated as controls. We revealed that the CD56^(+bright) subset was significantly decreased in the liver of patients with recurrent hepatitis C than that in the patients with CHC and the normal donors. The expression of an activation marker CD69 on the CD56^(+dim) subset was significantly increased in the liver of LDLT. Our results suggest that further examination of the status of intrahepatic NK cell subsets might provide a new insight into the mechanism of rapid progression of recurrent hepatitis C infection.
    (2) Gene expression profiles in the liver of patients with recurrent hepatitis C following liver transplantation
    We investigated the gene expression profiles in the liver of patients with recurrent hepatitis C after LDLT using liver biopsy samples. However, we could not find any significant changes in the gene expression profiles among the recurrent hepatitis C patients and CHC patients yet.
    (3) NK and NKT cells in the liver of patients with chronic hepatitis C before and after interferon plus ribavirin therapy
    Previous studies have revealed that functional impairment of NK and NKT cells might be associated with the persistence of hepatitis C virus (HCV). However, the involvement of these cells, which predominate in the liver, in therapeutic HCV clearance is still unclear. We found a close relationship between the significant increase of intrahepatic NK/NKT cells and sustained HCV clearance in CHC patients treated with interferon-a plus ribavirin therapy.

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  • C型肝炎に対するインターフェロン・リバビリン併用療法の治療マーカーの探索同定

    2005.1 - 2005.3

    株式会社バイオマーカーサイエンス  共同研究 

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    Grant amount:\100000

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  • 糖鎖を標的とした肝癌遺伝子治療戦略

    2004.4 - 2006.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    青柳豊

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  • Development of a new cell therapy by adoptive transfer of regulatory T cells to induce immunological tolerance for the transplanted liver

    Grant number:14570455  2002 - 2003

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    ICHIDA Takafumi, YAMAGIWA Satoshi, WATANABE Hisami, MATSUDA Yasunobu

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    Grant type:Competitive

    Grant amount:\3400000 ( Direct Cost: \3400000 )

    (1)Generation of human regulatory CD4^+CD25^+ T cells
    We confirmed that naive CD4^+ cells stimulated with alloantigens in the presence of TGF-β(transforming growth factor-β) differentiate into suppressor cells with a phenotype and functional properties similar if not identical with natural regulatory CD4^+CD25^+ T cells. We also studied the regulatory properties of other cytokines, separately or together with TGF-β, on CD4^+CD25^+ T cells generated by allo-stimulation. Although it has been reported that CD4^+ cells become regulatory T cells ('Tr1 cells') when repeatedly stimulated with IL-10,IL-10 inhibited CD25 expression on CD4^+* cells. Moreover, when naive CD4^+ cells were stimulated with alloantigens in the presence of both IL-10 and TGF-β,IL-10 inhibited the effect of TGF-β on the generation of CD4^+CD25^+ T cells.
    (2)Generation of murine regulatory CD4^+CD25^+ T cells
    We found that treatment of murine alio-activated CD4^+ T cells with TGF-β and IL-2 also enhanced expression of CD25 and enabled these cells to develop potent suppressive activity. We are planning to use those CD4^+CD25^+ T cells generated ex vivo in skin transplantation model to examine whether transfer of those cells can prevent graft rejection.
    (3)CD4^+CD25^+ T cells in the human liver
    We also investigated CD4^+CD25^+ T cells in human livers. Although the proportion of CD4^+CD25^+ T cells in the liver was lower than in the peripheral blood, we found a significant increase of CD4^+CD25^+ T cells in the marginal regions of hepatocellular carcinoma(HCC), but not in unaffected areas of the liver. CD4^+CD25^+ T cells isolated from peri-tumor regions of HCC displayed phenotype markers characteristic of regulatory T cells, and inhibited autologous CD8^+ cell proliferation. Our results suggest that CD4^+*CD25^+ T cells in the peri-tumor region of HCC inhibit the generation of tumor-specific CD8^+ cytotoxic T cell activity and, thereby, contribute to the progression of HCC.

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  • 肝がんにおける細胞周期調節機構の解析

    1999.1 - 1999.12

    その他の研究制度 

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  • Development of a new system identifying mutated DNA in the plasma

    Grant number:11670483  1999 - 2000

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    TAKAHASHI Toru, ICHIDA Takafumi, MATSUDA Yasunobu

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    Grant type:Competitive

    Grant amount:\3500000 ( Direct Cost: \3500000 )

    It is now being described that detection of mutated DNA using MutS protein is highly sensitive and accurate. because MutS can specifically bind mis-matched double strand of DNA, identifying mutated DNA(e.g., point mutation, deletion and insertion)is capable by referring to the amount of DNA-bound MutS.We addressed whether MutS could be useful in the detection of mutated DNA in the plasma, and examined its usefulness in case of patients affected with pancreatic/bile duct cancers.
    We obtained plasma DNA from 25 of patients with pancreatic cancers and 33 with bile duct cancers. PCR was performed using primers specific for p53(exon 5-8)and p16(exon 1-2), and mis-matched heteroduplex was examined using MutS-binding reaction. Consequently, we could detect mutated DNA in 18 and 33 patients with pancreatic cancers and bile duct cancers, respectively. Thus, we surmise that detecting mutated DNA in the plasma using MutS is useful for identifying the ptients who are suffered from solid cancers.

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  • 原発性胆汁性肝硬変の肝移植後の再発機序に関する研究

    1996.4 - 1997.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    市田隆文

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  • 原発性胆汁性肝硬変の肝移植後の再発機序に関する研究

    Grant number:08670567  1996

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    市田 隆文, 松田 康伸, 杉村 一仁

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    Grant amount:\1300000 ( Direct Cost: \1300000 )

    今回の研究に基ずく全国調査ではわが国の成人肝移植レシピエントは83例で54例が海外での脳死肝移植、28例がわが国における生体肝移植で1例が心臓死ドナー肝移植であることが判明した。その中の原発性胆汁性肝硬変症例は脳死肝移植例が10例、生体肝移植例が11例であった。この症例を対象に原発性胆汁性肝硬変の肝移植後の再発機序に関する研究を試みた。以下に今回の研究で明らかになったことを列挙する。
    原発性胆汁性肝硬変症例の肝移植成績として生体肝移植11例は最長3年3ヶ月の観察期間で生存率100%であり、脳死肝移植症例11例中9例が生存し最長8年6ヶ月である(生存率81%)ことが判明した。
    原発性胆汁性肝硬変の原疾患の再発に関する検索では脳死肝移植症例と生体肝移植症例の肝移植後の血中アルカリフォスファターゼ値の再上昇はそれぞれ7例中1例と9例中5例に、抗糸粒体抗体の再陽性化は8例中2例と10例中7例に、IgM値の再上昇は7例中1例と9例中6例にそれぞれ認められた。
    さらに組織学的観察では胆管病変を認めた脳死肝移植例では5例中、1例も認めていないが生体肝移植例では6例中2例に観察された。この原発性胆汁性肝硬変の再発に関してはすでに国際的な論争があるが、本研究では症例数には限りがあるが脳死肝移植に比例して生体肝移植例の方が血清学的マーカーの肝移植後の推移ならびに組織学的検索から再発の可能性が示唆された。しかしながら、術後の肝生検での胆管病変に関して慢性拒絶反応と原発性胆汁性肝硬変との組織学的鑑別が困難であるため、未だ明確な組織学的確診が得られないことも事実である。
    この要因を探るためにHLAのmatchingとHLADNAタイピングを検索中であるが、少なくとも生体肝移植例では親子間のドナー、レシピエントの関連よりHLAクラスIIのmatchingが何らかの要因になっている可能性が考えられた。
    今後、レシピエントリンパ球を用いたHLADNAタイピングの検索が必要と考えている。

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  • 肝細胞増殖因子 (hepatocyte growth factor)による肝再生機構

    1990.1 - 1990.12

    その他の研究制度 

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Teaching Experience

  • 保健学特定研究(検査技術科学)

    2021
    Institution name:新潟大学

  • 病態生理機能学実習

    2021
    Institution name:新潟大学

  • 保健学特別研究(検査技術科学)

    2021
    Institution name:新潟大学

  • 保健学総合

    2021
    Institution name:新潟大学

  • 生体システム機能検査科学特講

    2020
    Institution name:新潟大学

  • 生体システム機能検査科学特講演習

    2020
    Institution name:新潟大学

  • 医療英語ベーシック(検査)

    2020
    Institution name:新潟大学

  • 臨床検査管理概論

    2018
    Institution name:新潟大学

  • 入門医療英語

    2018
    Institution name:新潟大学

  • 医療安全管理学

    2018
    Institution name:新潟大学

  • 臨床検査実習

    2016
    Institution name:新潟大学

  • 医学検査管理総論

    2016
    Institution name:新潟大学

  • 成人・老年看護学演習Ⅱ

    2016
    Institution name:新潟大学

  • フィジカルアセスメント

    2015
    Institution name:新潟大学

  • 臨床薬理学

    2015
    Institution name:新潟大学

  • 病態生理学

    2015
    Institution name:新潟大学

  • 保健学特別研究(検査技術科学)

    2014
    Institution name:新潟大学

  • 保健学特定研究(検査技術科学)

    2014
    Institution name:新潟大学

  • 疾患と臨床検査

    2011
    Institution name:新潟大学

  • 病気の成り立ちⅡ

    2010
    -
    2016
    Institution name:新潟大学

  • 臨床生体情報検査科学特別研究

    2010
    -
    2013
    Institution name:新潟大学

  • 疾病の予防と治療

    2009
    Institution name:新潟大学

  • 医療英語(検査)

    2008
    Institution name:新潟大学

  • 卒業研究

    2008
    Institution name:新潟大学

  • 病態生理機能学特論

    2008
    Institution name:新潟大学

  • 画像検査科学

    2008
    Institution name:新潟大学

  • 画像検査科学実習

    2008
    Institution name:新潟大学

  • 医療と画像技術

    2008
    Institution name:新潟大学

  • 病態解析学概論

    2008
    Institution name:新潟大学

  • 生活習慣と健康

    2008
    Institution name:新潟大学

  • スタディスキルズ (検査)

    2008
    Institution name:新潟大学

  • 病気の成り立ちⅠ

    2008
    Institution name:新潟大学

  • 生理機能検査科学実習

    2008
    -
    2021
    Institution name:新潟大学

  • 病態生理機能学実習

    2008
    -
    2018
    Institution name:新潟大学

  • 生体システム機能検査学特講

    2008
    -
    2016
    Institution name:新潟大学

  • 生体システム機能検査学特講演習

    2008
    -
    2014
    Institution name:新潟大学

  • 筋電図検査科学

    2008
    -
    2013
    Institution name:新潟大学

  • 医用写真技術実習

    2008
    -
    2010
    Institution name:新潟大学

  • 疾患と臨床検査Ⅰ

    2008
    -
    2010
    Institution name:新潟大学

▶ display all