Faculty Profiles - FUJIWARA Toshiyoshi

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Hepatitis C Virus-specific T-cell Response Correlates with Hepatitis Activity and Donor IL28B Genotype Early after Liver Transplantation

Ryuichiro Tsuzaki, Akinobu Takaki, Takahito Yagi, Fusao Ikeda, Kazuko Koike, Yoshiaki Iwasaki, Hidenori Shiraha, Yasuhiro Miyake, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Masashi Utsumi, Eiichi Nakayama, Toshiyoshi Fujiwara, Kazuhide Yamamoto

ACTA MEDICA OKAYAMA 68 ( 5 ) 291 - 302 2014.10

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

It is not known how the immune system targets hepatitis C virus (HCV)-infected HLA-mismatched hepatocytes under immune-suppressed conditions after orthotopic liver transplantation (OLT). In addition, the relationship between the HCV-specific immune response and IL28B variants as predictors of HCV clearance has not been well-characterized. We determined the IL28B polymorphisms for 57 post-OLT HCV carriers, and we assessed the HCV-specific immune responses by measuring the peripheral blood mononuclear cell-derived HCV-specific interferon-gamma (IFN-gamma) response using an enzyme-linked immunospot assay. At 1-3 years after OLT, patients with no active hepatitis showed higher total spots on the immunospot assay. At > 3 years after OLT, patients with resolved HCV showed higher levels of core, NS3, NS5A, and total spots compared to the chronic hepatitis patients. The IL28B major genotype in the donors correlated with higher spot counts for NS5A and NS5B proteins at 1-3 years after OLT. In the post-OLT setting, the HCV-specific immune response could be strongly induced in patients with no active hepatitis with an IL28B major donor or sustained virological response. Strong immune responses in the patients with no active hepatitis could only be maintained for 3 years and diminished later. It may be beneficial to administer IFN treatment starting 3 years after OLT, to induce the maximum immunological effect.

DOI： 10.18926/AMO/52898

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Early detection of metachronous bile duct cancer in Lynch syndrome: report of a case

Kunitoshi Shigeyasu, Kohji Tanakaya, Takeshi Nagasaka, Hideki Aoki, Toshiyoshi Fujiwara, Kokichi Sugano, Hideki Ishikawa, Teruhiko Yoshida, Yoshihiro Moriya, Yoichi Furukawa, Ajay Goel, Hitoshi Takeuchi

SURGERY TODAY 44 ( 10 ) 1975 - 1981 2014.10

Language：English Publisher：SPRINGER

Lynch syndrome is an autosomal dominant disease associated with a high incidence of colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, bile duct and brain tumors. The syndrome can also include sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel. The lifetime risk for bile duct cancer in patients with Lynch syndrome is approximately 2 %. The present report describes a case of Lynch syndrome with metachronous bile duct cancer diagnosed at an early stage. The patient was a 73-year-old Japanese male who underwent a successful left lobectomy of the liver, and there was no sign of recurrence for 2 years postoperative. However, this patient harbored a germline mutation in MLH1, which prompted diagnostic examinations for noncolorectal tumors when a periodic surveillance blood examination showed abnormal values of hepatobiliary enzymes. Although most patients with bile duct cancer are diagnosed at an advanced stage, the bile duct cancer was diagnosed at an early stage in the present patient due to the observation of the gene mutation and the preceding liver tumor. This case illustrates the importance of continuous surveillance for extracolonic tumors, including bile duct cancer, in patients with Lynch syndrome.

DOI： 10.1007/s00595-013-0669-3

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Virus-guided fluorescence imaging of intraperitoneal free gastric cancer cells as a potential clinical biomarker

Megumi Watanabe, Shunsuke Kagawa, Michihiro Ishida, Naoto Hori, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Hiroshi Tazawa, Toshiyoshi Fujiwara

CANCER RESEARCH 74 ( 19 ) 2014.10

Novel combination therapy of adenoviral gene transfer of HER2-extracellular domain and trastuzumab-based photoimmunotherapy for HER2 negative cancer cells

Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Kiyoto Takehara, Kazuhiro Noma, Shunsuke Tanabe, Hiroshi Tazawa, Junji Matsuoka, Hisataka Kobayashi, Toshiyoshi Fujiwara

CANCER RESEARCH 74 ( 19 ) 2014.10

Combination strategy of endoscopic resection and telomerase-targeting oncolytic virus for eradicating lymph node metastasis of submucosal invasive colorectal cancer

Naoto Hori, Satoru Kikuchi, Hiroyuki Kishimoto, Hiroshi Tazawa, Yuuri Hashimoto, Shinji Kuroda, Shunsuke Kagawa, Yasuo Urata, Robert M. Hoffman, Toshiyoshi Fujiwara

CANCER RESEARCH 74 ( 19 ) 2014.10

Development of systemically-deliverable telomerase-specific oncolytic adenovirus

Katsuyuki Aoyama, Shinji Kuroda, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER RESEARCH 74 ( 19 ) 2014.10

Selective methioninase-induced trap of cancer cells in S/G(2) phase visualized by FUCCI imaging confers chemosensitivity

Shuya Yano, Shukuan Li, Qinghong Han, Yuying Tan, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

ONCOTARGET 5 ( 18 ) 8729 - 8736 2014.9

Language：English Publisher：IMPACT JOURNALS LLC

A major impediment to the response of tumors to chemotherapy is that the large majority of cancer cells within a tumor are quiescent in G(0)/G(1), where cancer cells are resistant to chemotherapy. To attempt to solve this problem of quiescent cells in a tumor, cancer cells were treated with recombinant methioninase (rMETase), which selectively traps cancer cells in S/G(2). The cell cycle phase of the cancer cells was visualized with the fluorescence ubiquitination cell cycle indicator (FUCCI). At the time of rMETase-induced S/G(2)-phase blockage, identified by the cancer cells' green fluorescence by FUCCI imaging, the cancer cells were administered S/G(2)-dependent chemotherapy drugs, which interact with DNA or block DNA synthesis such as doxorubicin, cisplatin, or 5-fluorouracil. Treatment of cancer cells with drugs only, without rMETase-induced S/G(2) phase blockage, led to the majority of the cancer-cell population being blocked in G(0)/G(1) phase, identified by the cancer cells becoming red fluorescent in the FUCCI system. The G(0)/G(1) blocked cells were resistant to the chemotherapy. In contrast, trapping of cancer cells in S/G(2) phase by rMETase treatment followed by FUCCI-imaging-guided chemotherapy was highly effective in killing the cancer cells.

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Intussusception due to rectal adenocarcinoma in a young adult: A case report

Ryo Inada, Takeshi Nagasaka, Toshiaki Toshima, Yoshiko Mori, Yoshitaka Kondo, Hiroyuki Kishimoto, Toshiyoshi Fujiwara

WORLD JOURNAL OF GASTROENTEROLOGY 20 ( 35 ) 12678 - 12681 2014.9

Language：English Publisher：BAISHIDENG PUBLISHING GROUP INC

An intussusception due to colonic adenocarcinoma has sometimes been reported. However, to the best of our knowledge, reports of intussusception due to rectal adenocarcinoma are extremely rare. In this report, the case of a young man with rectal adenocarcinoma causing intussusception is described. A 24-year-old man visited a hospital complaining of abdominal pain, and an upper rectal cancer was diagnosed by colonoscopy. Computed tomography showed intussusception caused by a large tumor in the pelvis and absence of distant metastases. Locally advanced rectal cancer causing intussusception was diagnosed, and a low anterior resection was performed. Intraoperatively, repair of the invagination could not be accomplished easily; therefore, the repair was abandoned. Instead, the tumor was removed en bloc to avoid dissemination of the cancer. Histopathologically, the tumor was diagnosed as a poorly differentiated adenocarcinoma, pStage. A. The patient has no evidence of recurrence at 10 mo after the operation. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

DOI： 10.3748/wjg.v20.i35.12678

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MafA Is Required for Postnatal Proliferation of Pancreatic beta-Cells

Koki Eto, Wataru Nishimura, Hisashi Oishi, Haruhide Udagawa, Miho Kawaguchi, Masaki Hiramoto, Toshiyoshi Fujiwara, Satoru Takahashi, Kazuki Yasuda

PLOS ONE 9 ( 8 ) e104184 2014.8

Language：English Publisher：PUBLIC LIBRARY SCIENCE

The postnatal proliferation and maturation of insulin-secreting pancreatic beta-cells are critical for glucose metabolism and disease development in adults. Elucidation of the molecular mechanisms underlying these events will be beneficial to direct the differentiation of stem cells into functional beta-cells. Maturation of beta-cells is accompanied by increased expression of MafA, an insulin gene transcription factor. Transcriptome analysis of MafA knockout islets revealed MafA is required for the expression of several molecules critical for beta-cell function, including Glut2, ZnT8, Granuphilin, Vdr, Pcsk1 and Urocortin 3, as well as Prolactin receptor (Prlr) and its downstream target Cyclin D2 (Ccnd2). Inhibition of MafA expression in mouse islets or beta-cell lines resulted in reduced expression of Prlr and Ccnd2, and MafA transactivated the Prlr promoter. Stimulation of beta-cells by prolactin resulted in the phosphorylation and translocation of Stat5B and an increased nuclear pool of Ccnd2 via Prlr and Jak2. Consistent with these results, the loss of MafA resulted in impaired proliferation of beta-cells at 4 weeks of age. These results suggest that MafA regulates the postnatal proliferation of beta-cells via prolactin signaling.

DOI： 10.1371/journal.pone.0104184

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Spatial-temporal FUCCI imaging of each cell in a tumor demonstrates locational dependence of cell cycle dynamics and chemoresponsiveness

Shuya Yano, Yong Zhang, Shinji Miwa, Yasunori Tome, Yukihiko Hiroshima, Fuminari Uehara, Mako Yamamoto, Atsushi Suetsugu, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 13 ( 13 ) 2110 - 2119 2014.7

Language：English Publisher：LANDES BIOSCIENCE

The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We report here on the results of monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI) before, during, and after chemotherapy. In nascent tumors in nude mice, approximately 30% of the cells in the center of the tumor are in G(0)/G(1) and 70% in S/G(2)/M. In contrast, approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G(0)/G(1) phase. Similarly, approximately 75% of cancer cells far from (>100 mu m) tumor blood vessels of an established tumor are in G(0)/G(1). Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Our results suggest why most drugs currently in clinical use, which target cancer cells in S/G(2)/M, are mostly ineffective on solid tumors. The results also suggest that drugs that target quiescent cancer cells are urgently needed.

DOI： 10.4161/cc.29156

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MECHANISM OF RESISTANCE TO TRASTUZUMAB AND MOLECULAR SENSITIZATION VIA ADCC ACTIVATION BY EXOGENOUS EXPRESSION OF HER2 EXTRACELLULAR DOMAIN

Ryosuke Yoshida, Hiroshi Tazawa, Yuuri Hashimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

JOURNAL OF GENE MEDICINE 16 ( 7-8 ) 277 - 278 2014.7

肝細胞癌治療における外科手術の位置づけ再発肝細胞癌の治療方針再肝切除の有効性とSalvage transplantationの可能性

藤智和, 楳田祐三, 貞森裕, 篠浦先, 吉田龍一, 信岡大輔, 内海方嗣, 杭瀬崇, 八木孝仁, 藤原俊義

日本消化器外科学会総会 69回 WS - 5 2014.7

MiCRORNA-7 INHIBITS THE STEM-LIKE PROPERTIES OF CD133(+) HUMAN GASTRIC CANCER CELLS

Teppei Onishi, Hiroshi Tazawa, Shuya Yano, Yuuri Hashimoto, Ryosuke Yoshida, Shunsuke Kagawa, Toshiyoshi Fujiwara

JOURNAL OF GENE MEDICINE 16 ( 7-8 ) 266 - 266 2014.7

Frequency of regulatory T-cell and hepatitis C viral antigen-specific immune response in recurrent hepatitis C after liver transplantation

Masashi Utsumi, Akinobu Takaki, Yuzo Umeda, Kazuko Koike, Stephanie C. Napier, Nobukazu Watanabe, Hiroshi Sadamori, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Tetsuya Yasunaka, Eiichi Nakayama, Kazuhide Yamamoto, Toshiyoshi Fujiwara, Takahito Yagi

TRANSPLANT IMMUNOLOGY 31 ( 1 ) 33 - 41 2014.6

Language：English Publisher：ELSEVIER SCIENCE BV

Introduction: Regulatory T (Treg) and type 1 regulatory T (Tr1) cells facilitate hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT). However, their frequencies and effects on HCV-specific immune responses have not been well investigated.
Methods: We determined Treg and Tr1 frequencies in OLT patients with hepatitis C and assessed their associations with HCV-specific T cell responses. These patients comprised the following groups: an early post-transplantation group (n = 14); an OLT-chronic active hepatitis C group (n = 14) with active hepatitis C (alanine aminotransferase of > upper limit of normal/positive for HCV-RNA); an OLT-persistently normal alanine aminotransferase group (n = 12) without active hepatitis C (not interferon/positive for HCV-RNA); and an OLT-sustained viral response group (n = 6) with sustained viral responses using interferon treatment (negative for HCV-RNA). The frequencies of HCV-specific CD4+ T cells that secreted interferon-gamma were determined by enzyme-linked immunosorbent spot assay (except for the OLT early group).
Results: Treg and Tr1 frequencies were low during the early post-transplantation period. OLT patients with sustained viral responses had lower Treg frequencies than those with chronic hepatitis C, whereas Tr1 frequencies were significantly reduced in OLT patients with persistently normal alanine aminotransferase levels compared to those with chronic hepatitis C (p < 0.05). Treg frequencies positively correlated with HCV NS3 antigen-specific interferon-gamma responses, which corresponded to HCV clearance.
Conclusions: Increased Treg frequencies and reduced HCV-NS3 antigen-specific responses recovered after viral eradication in post-OLT chronic hepatitis C patients. Reduced Tr1 frequencies were associated with hepatitis activity control, which may facilitate controlling chronic hepatitis C in patients after OLT. (C) 2014 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.trim.2014.05.006

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手術手技食道癌手術における用手補助的腹腔鏡下胃管作成の工夫

白川靖博, 前田直見, 田辺俊介, 大原利章, 野間和広, 藤原俊義

手術 68 ( 7 ) 951 - 954 2014.6

腫瘍縮小にて膵頭十二指腸切除術を回避できた膵Solid-pseudopapillary neoplasmの1例

信岡大輔, 八木孝仁, 篠浦先, 高木弘誠, 杭瀬崇, 内海方嗣, 吉田龍一, 楳田祐三, 貞森裕, 藤原俊義

日本癌治療学会誌 49 ( 3 ) 2101 - 2101 2014.6

Establishment of a pancreatic stem cell line from fibroblast-derived induced pluripotent stem cells

Takashi Kuise, Hirofumi Noguchi, Hiroshi Tazawa, Takashi Kawai, Masaya Iwamuro, Issei Saitoh, Hitomi Usui Kataoka, Masami Watanabe, Yasufumi Noguchi, Toshiyoshi Fujiwara

BIOMEDICAL ENGINEERING ONLINE 13 doi:10.1186/1475-925X-13-64 2014.5

Language：English Publisher：BIOMED CENTRAL LTD

Background: For cell therapies to treat diabetes, it is important to produce a sufficient number of pancreatic endocrine cells that function similarly to primary islets. Induced pluripotent stem (iPS) cells represent a potentially unlimited source of functional pancreatic endocrine cells. However, the use of iPS cells for laboratory studies and cell-based therapies is hampered by their high tumorigenic potential and limited ability to generate pure populations of differentiated cell types in vitro. The purpose of this study was to establish a pancreatic stem cell line from iPS cells derived from mouse fibroblasts.
Methods: Mouse iPS cells were induced to differentiate into insulin-producing cells by a multi-step differentiation protocol, which was conducted as described previously with minor modifications. Selection of the pancreatic stem cell was based on morphology and Pdx1 expression. The pancreatic potential of the pancreatic stem cells was evaluated using a reverse transcription PCR, real-time PCR, immunofluorescence, and a glucose challenge test. To assess potential tumorigenicity of the pancreatic stem cells, the cells were injected into the quadriceps femoris muscle of the left hindlimb of nude mice.
Results: The iPS-derived pancreatic stem cells expressed the transcription factor -Pdx1- a marker of pancreatic development, and continued to divide actively beyond passage 80. Endocrine cells derived from these pancreatic stem cells expressed insulin and pancreatic genes, and they released insulin in response to glucose stimulation. Mice injected with the pancreatic stem cells did not develop tumors, in contrast to mice injected with an equal number of iPS cells.
Conclusion: This strategy provides a new approach for generation of insulin-producing cells that is more efficient and safer than using iPS cells. We believe that this approach will help to develop a patient-specific cell transplantation therapy for diabetes in the near future.

DOI： 10.1186/1475-925X-13-64

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Molecular surgery using a novel biological agent, OBP-301, for lymph node micrometastasis in human colorectal cancer.

Satoru Kikuchi, Hiroyuki Kishimoto, Hiroshi Tazawa, Shunsuke Kagawa, Yasuo Urata, Robert M. Hoffman, Toshiyoshi Fujiwara

JOURNAL OF CLINICAL ONCOLOGY 32 ( 15 ) 2014.5

Assistant-Based Standardization of Prone Position Thoracoscopic Esophagectomy

Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Ryoichi Katsube, Shunsuke Tanabe, Toshiaki Ohara, Kazufumi Sakurama, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 68 ( 2 ) 111 - 117 2014.4

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Thoracoscopic esophagectomy in the prone position (TEPP) might enable solo-surgery in cases requiring resection of the esophagus and the surrounding lymph nodes due to the associated advantages of good exposure of the surgical field and ergonomic considerations for the surgeon. However, no one approach can be for all patients requiring extensive lymphadenectomy. We recently developed an assistant-based procedure to standardize exposure of the surgical field. Patients were divided into 1 of 2 groups: a pre-standardization group (n = 37) and a post-standardization group (n = 28). The thoracoscopic operative time was significantly shorter (p= 0.0037)) in the post-standardization group (n = 28; 267 +/- 31min) than in the pre-standardization group (n = 37; 301 +/- 53 min). Further, learning curve analysis using the moving average method showed stabilization of the thoracoscopic operative time after the standardization. No significant differences were found in the number of mediastinal lymph nodes dissected or intraoperative blood loss between the 2 groups. There were also no significant differences in the complication rate. Assistant-based surgery and standardization of the procedure resulted in a well-exposed and safe surgical field. TEPP decreased the operative time, even in patients requiring extensive lymphadenectomy.

DOI： 10.18926/AMO/52407

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術前DCF療法が著効した食道原発内分泌細胞癌の1切除例

前田直見, 白川靖博, 國府島健, 大原利章, 田邊俊輔, 野間和広, 櫻間教文, 藤原俊義

岡山医学会雑誌 126 ( 1 ) 39 - 43 2014.4

Language：Japanese Publisher：岡山医学会

66歳男。心窩部痛を主訴とした。上部消化管造影検査所見で胸部中部食道(Mt)左-前壁に70mm大の周堤隆起明瞭な2型病変が認められた。上部消化管内視鏡検査所見で切歯より25cm〜33cmの食道左-前壁に半周性の2型病変を認められた。同部位の生検を施行し、内分泌細胞癌(小細胞型)と診断された。造影CT検査所見およびPET/CT検査より、胸部食道内分泌細胞癌(小細胞型)cT3cN1cM0:cStage IIIと診断し、術前補助化学療法2コースの後、手術の方針とした。化学療法は、docetaxel、cisplatin、5-fluorouracilの三剤を併用した。手術は腹臥位胸腔鏡下食道亜全摘、用手補助的腹腔鏡下胃管作製、3領域リンパ節郭清、胸骨後経路再建、頸部吻合を施行した。組織所見にて潰瘍部では加療による影響と考えられる線維化とヘモジデリンの沈着を認め、Grade 3と判定した。

DOI： 10.4044/joma.126.39

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J00175&link_issn=&doc_id=20140415220008&doc_link_id=10.4044%2Fjoma.126.39&url=https%3A%2F%2Fdoi.org%2F10.4044%2Fjoma.126.39&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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