Kazuya Shimoda

Publications (83)287.98 Total impact

• Article: Impact of antibody to hepatitis B core antigen on the clinical course of hepatitis C virus carriers in a hyperendemic area in Japan: A community-based cohort study.

  Naoko Tsubouchi, Hirofumi Uto, Kotaro Kumagai, Fumisato Sasaki, Shuji Kanmura, Masatsugu Numata, Akihiro Moriuchi, Makoto Oketani, Akio Ido, Katsuhiro Hayashi, Kazunori Kusumoto, Kazuya Shimoda, Sherri O Stuver, Hirohito Tsubouchi
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  ABSTRACT: AIM: Subjects positive for antibody to hepatitis B core antigen (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are considered to have occult hepatitis B virus (HBV) infection. The aim of this study was to determine the impact of occult HBV infection on aggravation of the clinical course in hepatitis C virus (HCV) carriers. METHODS: A prospective cohort study was performed in 400 subjects who were positive for anti-HCV antibody and negative for HBsAg. Among these subjects, 263 were HCV core antigen positive or HCV RNA positive (HCV carriers). We examined whether the presence of HBcAb affected the clinical course in these HCV carriers from 1996-2005. RESULTS: The HBcAb positive rates were 53.6% and 52.6% in HCV carriers and HCV RNA negative subjects, respectively. There were no differences in the incidence of hepatocellular carcinoma (HCC) and cumulative mortality associated with liver-related death between HCV carriers who were positive and negative for HBcAb. In multivariate analysis, age (≥65 years) and alanine aminotransferase level (≥31 IU/L) emerged as independent risk factors for HCC development and liver-related death, but the HBcAb status was not a risk factor. In addition, increased serum hepatic fibrosis markers (measured from 2001-2004) were not associated with HBcAb status. CONCLUSION: In our cohort study, the presence of HBcAb had no impact on HCC development, liver-related death and hepatic fibrosis markers in HCV carriers. Thus, our results indicate that occult HBV infection has no impact on the clinical course in HCV carriers.
  Hepatology Research 02/2013; · 2.20 Impact Factor
• Article: Contribution of bone marrow-derived hematopoietic stem/progenitor cells to the generation of donor-marker(+) cardiomyocytes in vivo.

  Mitsuhiro Fukata, Fumihiko Ishikawa, Yuho Najima, Takuji Yamauchi, Yoriko Saito, Katsuto Takenaka, Kohta Miyawaki, Hideki Shimazu, Kazuya Shimoda, Takaaki Kanemaru, Kei-Ichiro Nakamura, Keita Odashiro, Koji Nagafuji, Mine Harada, Koichi Akashi
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  ABSTRACT: BACKGROUND: Definite identification of the cell types and the mechanism relevant to cardiomyogenesis is essential for effective cardiac regenerative medicine. We aimed to identify the cell populations that can generate cardiomyocytes and to clarify whether generation of donor-marker(+) cardiomyocytes requires cell fusion between BM-derived cells and recipient cardiomyocytes. METHODOLOGYPRINCIPAL FINDINGS: Purified BM stem/progenitor cells from green fluorescence protein (GFP) mice were transplanted into C57BL/6 mice or cyan fluorescence protein (CFP)-transgenic mice. Purified human hematopoietic stem cells (HSCs) from cord blood were transplanted into immune-compromised NOD/SCID/IL2rγ(null) mice. GFP(+) cells in the cardiac tissue were analyzed for the antigenecity of a cardiomyocyte by confocal microscopy following immunofluorescence staining. GFP(+) donor-derived cells, GFP(+)CFP(+) fused cells, and CFP(+) recipient-derived cells were distinguished by linear unmixing analysis. Hearts of xenogeneic recipients were evaluated for the expression of human cardiomyocyte genes by real-time quantitative polymerase chain reaction. In C57BL/6 recipients, Lin(-/low)CD45(+) hematopoietic cells generated greater number of GFP(+) cardiomyocytes than Lin(-/low)CD45(-) mesenchymal cells (37.0+/-23.9 vs 0.00+/-0.00 GFP(+) cardiomyocytes per a recipient, P = 0.0095). The number of transplanted purified HSCs (Lin(-/low)Sca-1(+) or Lin(-)Sca-1(+)c-Kit(+) or CD34(-)Lin(-)Sca-1(+)c-Kit(+)) showed correlation to the number of GFP(+) cardiomyocytes (P<0.05 in each cell fraction), and the incidence of GFP(+) cardiomyocytes per injected cell dose was greatest in CD34(-)Lin(-)Sca-1(+)c-Kit(+) recipients. Of the hematopoietic progenitors, total myeloid progenitors generated greater number of GFP(+) cardiomyocytes than common lymphoid progenitors (12.8+/-10.7 vs 0.67+/-1.00 GFP(+) cardiomyocytes per a recipient, P = 0.0021). In CFP recipients, all GFP(+) cardiomyocytes examined coexpressed CFP. Human troponin C and myosin heavy chain 6 transcripts were detected in the cardiac tissue of some of the xenogeneic recipients. CONCLUSIONSSIGNIFICANCE: Our results indicate that HSCs resulted in the generation of cardiomyocytes via myeloid intermediates by fusion-dependent mechanism. The use of myeloid derivatives as donor cells could potentially allow more effective cell-based therapy for cardiac repair.
  PLoS ONE 01/2013; 8(5):e62506. · 4.09 Impact Factor
• Article: Acute myeloid leukemia in clinical practice: a retrospective population-based cohort study in Miyazaki Prefecture, Japan.

  Takuya Matsunaga, Kiyoshi Yamashita, Yoko Kubuki, Takanori Toyama, Osamu Imataki, Kouichi Maeda, Noriaki Kawano, Seiichi Satou, Hiroshi Kawano, Junzo Ishizaki, [......], Keiko Katayose, Haruko K-Shimoda, Kotaro Shide, Shojiro Yamamoto, Hiroshi Moritake, Hiroyuki Nunoi, Shigeyoshi Makino, Akira Kitanaka, Hitoshi Matsuoka, Kazuya Shimoda
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  ABSTRACT: We performed a retrospective population-based cohort study of acute myeloid leukemia (AML) in Miyazaki Prefecture, Japan. Over 6 years, we diagnosed 221 patients (211 adults and 10 children) with AML, indicating an incidence of AML in Miyazaki Prefecture of 3.2 per 100,000 per year. In 193 adult patients with non-acute promyelocytic leukemia (APL), the proportion of patients with myelodysplasia, unfavorable risk karyotypes, antecedent hematologic diseases, prior chemotherapy for other malignancies, and small proportion of blasts in the marrow was higher in patients ≥65 years, and patients with poor performance status (PS) and higher WBC counts at diagnosis were more prevalent among patients ≥75 years. One-third of the adult non-APL patients met the inclusion criteria usually applied in clinical trials: de novo AML, age ≤64 years with PS 0-2 and no key organ dysfunction. The 5-year overall survival (OS) rate of adult non-APL patients was 21.1 % (patients ≤64 years, 33.8 %; 65-74 years, 21.6 %; ≥75 years, 0 %). Multivariate analysis revealed that French-American-British subtypes M0, M6, and M7, poor PS (3, 4), unfavorable risk karyotypes, and higher WBC counts at diagnosis were independent adverse prognostic factors associated with OS. This analysis provides real world data.
  International journal of hematology 07/2012; 96(3):342-9. · 1.17 Impact Factor
• Article: [Bone marrow failure syndrome (idiopathic hematopoietic disorders): progress in diagnosis and treatment. Topics: I. pathogenesis and pathophysiology of bone-marrow failure; 4. The molecular pathogenesis of myelofibrosis].

  Akira Kitanaka, Kazuya Shimoda
  Nihon Naika Gakkai Zasshi 07/2012; 101(7):1906-12.
• Article: Potentiated activation of VLA-4 and VLA-5 accelerates proplatelet-like formation.

  Takuya Matsunaga, Fumio Fukai, Takuro Kameda, Kotaro Shide, Haruko Shimoda, Eri Torii, Ayako Kamiunten, Masaaki Sekine, Shojirou Yamamoto, Tomonori Hidaka, [......], Makiko Uemura, Akihito Matsuoka, Fusako Waki, Kensuke Matsumoto, Nobuhiro Kanaji, Tomoya Ishii, Osamu Imataki, Hiroaki Dobashi, Shuji Bandoh, Kazuya Shimoda
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  ABSTRACT: Fibronectin (FN) plays important roles in the proliferation, differentiation, and maintenance of megakaryocytic-lineage cells through FN receptors. However, substantial role of FN receptors and their functional assignment in proplatelet-like formation (PPF) of megakaryocytes are not yet fully understood. Herein, we investigated the effects of FN receptors on PPF using the CHRF-288 human megakaryoblastic cell line, which expresses VLA-4 and VLA-5 as FN receptors. FN and phorbol 12-myristate 13-acetate (PMA) were essential for inducing PPF in CHRF-288 cells. Blocking experiments using anti-β1-integrin monoclonal antibodies indicated that the adhesive interaction with FN via VLA-4 and VLA-5 were required for PPF. PPF induced by FN plus PMA was accelerated when CHRF-288 cells were enforced adhering to FN by TNIIIA2, a peptide derived from tenascin-C, which we recently found to induce β1-integrin activation. Adhesion to FN enhanced PMA-stimulated activation of extracellular signal-regulated protein kinase 1 (ERK1)/2 and enforced adhesion to FN via VLA-4 and VLA-5 by TNIIIA2-accelerated activation of ERK1/2 with FN plus PMA. However, c-Jun amino-terminal kinase 1 (JNK1), p38, and phosphoinositide-3 kinase (PI3K)/Akt were not stimulated by FN plus PMA, even with TNIIIA2. Thus, the enhanced activation of ERK1/2 by FN, PMA plus TNIIIA2 was responsible for acceleration of PPF with FN plus PMA.
  Annals of Hematology 05/2012; 91(10):1633-43. · 2.62 Impact Factor
• Article: Difference in serum complement component C4a levels between hepatitis C virus carriers with persistently normal alanine aminotransferase levels or chronic hepatitis C.

  Kazuyuki Imakiire, Hirofumi Uto, Yuko Sato, Fumisato Sasaki, Seiichi Mawatari, Akio Ido, Kazuya Shimoda, Katsuhiro Hayashi, Sherri O Stuver, Yoshito Ito, Takeshi Okanoue, Hirohito Tsubouchi
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  ABSTRACT: Certain hepatitis C virus (HCV) carriers exhibit persistently normal alanine aminotransferase (ALT) levels (PNALT) (≤ 30 IU/l) accompanied by normal platelet counts (≥ 15 x 10(4)/µl); these individuals show milder disease activity and slower progression to cirrhosis. This study aimed to elucidate the characteristics of HCV carriers with PNALT using serum proteomics. The first group of subjects, who underwent clinical evaluation in the hospital, consisted of 19 HCV carriers with PNALT (PNALT-1) and 20 chronic hepatitis C (CHC-1) patients. The second group of subjects was part of a cohort study on the natural history of liver disease, and included 37 PNALT (PNALT-2) and 30 CHC (CHC-2) patients. Affinity bead-purified serum protein was subjected to matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis. Serum proteomics showed that 6 protein peaks with mass-to-charge ratios ranging from 1,000 to 3,000 differed significantly between the PNALT-1 and CHC-1 groups. Among these peaks, a 1738-m/z peak protein was identified as a fragment of complement component 4 (C4) and correlated significantly with serum C4a concentrations as determined by enzyme immunoassay. Serum C4a levels were also significantly higher in the PNALT-2 group compared to the CHC-2 group and healthy volunteers. Furthermore, in the PNALT-2 group, serum C4a levels negatively correlated with transaminase levels, but not with other biochemical tests, HCV core antigen levels, peripheral blood cell counts or serum hepatic fibrosis markers. This study indicates that host factors such as C4a not only differ between HCV carriers with PNALT and CHC, but that proteomic approaches could also contribute to the elucidation of factors in PNALT as more differences are discovered.
  Molecular Medicine Reports 05/2012; 6(2):259-64. · 0.42 Impact Factor
• Article: ticlopidine-Associated Thrombotic Thrombocytopenic Purpura With an IgG-Type Inhibitor to von Willebrand Factor-Cleaving Protease Activity

  Yasuhiro Sugio, Takashi Okamura, Kazuya Shimoda, Masanori Matsumoto, Hideo Yagi, Hiromichi Ishizashi, Yoshiyuki Niho, Shoichi Inaba, Yoshihiro Fujimura
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  ABSTRACT: A 41-year-old Japanese man complained of a left-sided visual disturbance. Imaging by magnetic resonance angiography revealed A 41-year-old Japanese man complained of a left-sided visual disturbance. Imaging by magnetic resonance angiography revealed a narrowing of the left internal cervical artery. Thus, ticlopidine (Tc) administration was started at a daily dose of 300 a narrowing of the left internal cervical artery. Thus, ticlopidine (Tc) administration was started at a daily dose of 300 mg. However, 2 weeks later, severe thrombocytopenia, fever, nausea, and psychiatric symptoms developed; Tc was therefore discontinued. mg. However, 2 weeks later, severe thrombocytopenia, fever, nausea, and psychiatric symptoms developed; Tc was therefore discontinued. Based on the diagnostic hallmark of 5 clinical signs, the patient’s disease was diagnosed as thrombotic thrombocytopenic purpura Based on the diagnostic hallmark of 5 clinical signs, the patient’s disease was diagnosed as thrombotic thrombocytopenic purpura (TTP). Daily plasmapheresis was performed for the first 4 days, and the patient’s clinical signs gradually improved. Von Willebrand (TTP). Daily plasmapheresis was performed for the first 4 days, and the patient’s clinical signs gradually improved. Von Willebrand factor-cleaving protease (vWF-CPase) activity in his plasma was less than 3% of that of the control sample at diagnosis, butthe control sample at diagnosis, but that value recovered steadily following plasmapheresis. In addition, immunoglobulin G purified from the patient plasma inhibited that value recovered steadily following plasmapheresis. In addition, immunoglobulin G purified from the patient plasma inhibited vWF-CPase activity in normal plasma with a specific activity of 0.8 Bethesda units/mg. No sign of TTP relapse has been noted vWF-CPase activity in normal plasma with a specific activity of 0.8 Bethesda units/mg. No sign of TTP relapse has been noted following cessation of Tc. Thus, it was concluded that the patient developed TTP by producing an inhibitory autoantibody against following cessation of Tc. Thus, it was concluded that the patient developed TTP by producing an inhibitory autoantibody against vWF-CPase activity that was presumably triggered by Tc administration. vWF-CPase activity that was presumably triggered by Tc administration.
  International Journal of Hematology 04/2012; 74(3):347-351. · 1.27 Impact Factor
• Article: [Molecular pathology and treatment for primary myelofibrosis].

  Akira Kitanaka, Kazuya Shimoda
  Nippon rinsho. Japanese journal of clinical medicine 04/2012; 70 Suppl 2:321-5.
• Article: Clinical features and treatment outcomes of isolated secondary central nervous system lymphomas in Miyazaki Prefecture.

  Noriaki Kawano, Hidenobu Ochiai, Shuro Yoshida, Kiyoshi Yamashita, Kotaro Shide, Haruko Shimoda, Tomonori Hidaka, Yoko Kubuki, Keiko Katayose, Takanori Toyama, [......], Junzo Ishizaki, Koichi Maeda, Seiichi Satou, Tatsuhiko Yano, Kenichiro Yamaguchi, Katsuto Takenaka, Yoshiya Shimao, Koichi Oshima, Akira Ueda, Kazuya Shimoda
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  ABSTRACT: Secondary central nervous system lymphoma (SCNSL) without extra-central nervous system (CNS) involvement is characterized by isolated secondary CNS relapse in malignant lymphoma patients. SCNSL is a rare disease, and no standard treatment has yet been established. To elucidate the clinical characteristics and outcomes of SCNSL, we retrospectively analyzed 12 patients (median age 67 years) in Miyazaki prefecture for the last 5 years. The initial histological diagnoses of the patients were diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma, and adult T-cell lymphoma in 9, 2, and 1 patient, respectively. We focused on analysis of the 9 SCNSL cases originating from DLBCL. The locations of CNS relapse were the cerebral hemisphere, basal ganglia, and cerebellum in 7, 1, and 1 patient, respectively. Three patients were treated with high-dose methotrexate (HD-MTX) therapy; 4 with whole-brain radiation therapy (WBRTX); and 1 with both HD-MTX and WBRTX. The remaining patients were treated with rituximab. Partial remission was achieved in 6 out of 9 patients (67%); the other 3 patients (33%) did not respond to therapy. Median survival of the 9 patients with CNS relapse was 253 days; 6 of the 9 patients survived for more than 6 months. As of March 2011, 2 HD-MTX group patients but none of the WBRTX group patients were alive. In this retrospective study, 6 of 9 patients with SCNSL originating from DLBCL survived for more than 6 months. Both HD-MTX and WBRTX had clinical benefits in the treatment of SCNSL.
  International Journal of Clinical Oncology 09/2011; 17(4):336-40. · 1.41 Impact Factor
• Article: Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice.

  Masayuki Ishizaki, Ryuta Muromoto, Toshihiko Akimoto, Yuya Ohshiro, Miki Takahashi, Yuichi Sekine, Hiroaki Maeda, Kazuya Shimoda, Kenji Oritani, Tadashi Matsuda
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  ABSTRACT: Tyrosine kinase-2 (Tyk2) participates in the signaling pathways of multiple cytokines in innate and acquired immunity. In the present study, we investigated the in vivo involvement of Tyk2 in anti-type II collagen antibody-induced arthritis (CAIA) using Tyk2-deficient mice. Hind paws of wild-type mice showed massive swelling and erythema by arthritogenic antibody injection, whereas Tyk2-deficient mice did not show any signs of arthritis. Indeed, neither the infiltration of inflammatory cells nor the fibrillation of articular cartilages was observed in Tyk2-deficient mice. Tyk2 deficiency also reduced the production of T(h)1/T(h)17-related cytokines, the other proinflammatory cytokines and matrix metalloproteases, which are induced in the CAIA paw. Our results demonstrate a critical contribution of Tyk2 in the development of arthritis, and we propose that Tyk2 might be an important candidate for drug development.
  International Immunology 09/2011; 23(9):575-82. · 3.41 Impact Factor
• Article: Involvement of tyrosine kinase-2 in both the IL-12/Th1 and IL-23/Th17 axes in vivo.

  Masayuki Ishizaki, Toshihiko Akimoto, Ryuta Muromoto, Mika Yokoyama, Yuya Ohshiro, Yuichi Sekine, Hiroaki Maeda, Kazuya Shimoda, Kenji Oritani, Tadashi Matsuda
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  ABSTRACT: Tyrosine kinase-2 (Tyk2), a member of the Jak family of kinases, mediates the signals triggered by various cytokines, including type I IFNs, IL-12, and IL-23. In the current study, we investigated the in vivo involvement of Tyk2 in several IL-12/Th1- and IL-23/Th17-mediated models of experimental diseases, including methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis. In these disease models, Tyk2 deficiency influenced the phenotypes in immunity and/or inflammation. Our findings demonstrate a somewhat broader contribution of Tyk2 to immune systems than previously expected and suggest that Tyk2 may represent an important candidate for drug development by targeting both the IL-12/Th1 and IL-23/Th17 axes.
  The Journal of Immunology 07/2011; 187(1):181-9. · 5.79 Impact Factor
• Article: R723, a selective JAK2 inhibitor, effectively treats JAK2V617F-induced murine myeloproliferative neoplasm.

  Kotaro Shide, Takuro Kameda, Vadim Markovtsov, Haruko K Shimoda, Elizabeth Tonkin, Shuling Fang, Chian Liu, Marina Gelman, Wayne Lang, Jason Romero, [......], Stacey Siu, Polly Pine, Gary Park, Allan Torneros, Matt Duan, Rajinder Singh, Donald G Payan, Takuya Matsunaga, Yasumichi Hitoshi, Kazuya Shimoda
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  ABSTRACT: The activating mutations in JAK2 (including JAK2V617F) that have been described in patients with myeloproliferative neoplasms (MPNs) are linked directly to MPN pathogenesis. We developed R723, an orally bioavailable small molecule that inhibits JAK2 activity in vitro by 50% at a concentration of 2nM, while having minimal effects on JAK3, TYK2, and JAK1 activity. R723 inhibited cytokine-independent CFU-E growth and constitutive activation of STAT5 in primary hematopoietic cells expressing JAK2V617F. In an anemia mouse model induced by phenylhydrazine, R723 inhibited erythropoiesis. In a leukemia mouse model using Ba/F3 cells expressing JAK2V617F, R723 treatment prolonged survival and decreased tumor burden. In V617F-transgenic mice that closely mimic human primary myelofibrosis, R723 treatment improved survival, hepatosplenomegaly, leukocytosis, and thrombocytosis. R723 preferentially targeted the JAK2-dependent pathway rather than the JAK1- and JAK3-dependent pathways in vivo, and its effects on T and B lymphocytes were mild compared with its effects on myeloid cells. Our preclinical data indicate that R723 has a favorable safety profile and the potential to become an efficacious treatment for patients with JAK2V617F-positive MPNs.
  Blood 06/2011; 117(25):6866-75. · 9.90 Impact Factor
• Article: Noncanonical K27-linked polyubiquitination of TIEG1 regulates Foxp3 expression and tumor growth.

  Dong-Jun Peng, Minghui Zeng, Ryuta Muromoto, Tadashi Matsuda, Kazuya Shimoda, Malayannan Subramaniam, Thomas C Spelsberg, Wei-Zen Wei, K Venuprasad
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  ABSTRACT: Earlier, we demonstrated the essential role of Kruppel-like transcription factor, TIEG1, in TGF-β-induced regulatory T cell (Treg) development. In this article, we demonstrate that IL-6, which promotes Th17 development, abrogated TIEG1 nuclear translocation and inhibited TGF-β-induced Treg development. Tyrosine kinase Tyk2-mediated phosphorylation of TIEG1 at Tyr179 promoted noncanonical K-27-linked polyubiquitination, which inhibited TIEG1 nuclear translocation. To test the role of TIEG1-regulated Treg/Th17 development in antitumor immunity, we analyzed TRAMP-C2 tumor growth in TIEG1(-/-) mice. The defective Treg development and elevated Th17 response resulted in enhanced immune reactivity in the tumor and inhibition of TRAMP-C2 tumor growth in TIEG1(-/-) mice. Thus, our results uncovered a novel regulatory mechanism that modulates Tregs and may regulate tumor progression.
  The Journal of Immunology 04/2011; 186(10):5638-47. · 5.79 Impact Factor
• Article: Clinical features and outcomes of 35 disseminated intravascular coagulation cases treated with recombinant human soluble thrombomodulin at a single institution.

  Noriaki Kawano, Shuro Yoshida, Nobuyuki Ono, Daisuke Himeji, Yuri Nagahiro, Sayaka Kawano, Kiyoshi Yamashita, Naoko Ikeda, Shigehiro Uezono, Hidenobu Ochiai, Fumiko Kawano, Ikuo Kikuchi, Fumihiko Ishikawa, Kazuya Shimoda, Akira Ueda, Koichi Akashi
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  ABSTRACT: Disseminated intravascular coagulation (DIC) is a clinical entity with high mortality and is characterized by multiple organ failure caused by activation of systemic intravascular coagulation. Although a standard treatment for DIC has not been established owing to the absence of randomized controlled trials, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC. To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 35 DIC patients treated with rTM at our institution over a 2-year period (infectious disease: 21 cases; hematological disease: 14 cases). Diagnosis of DIC was based on the diagnostic criteria for DIC of the Japanese Ministry of Health and Welfare. In addition to the treatment of underlying diseases, we administered rTM for 6 consecutive days. Twenty-one (60.0%) of the DIC patients attained resolution of DIC at 7 days after administration (infectious disease: 61.9%; hematological disease: 57.1%). Furthermore, 7 of the remaining 14 DIC patients (who did not attain resolution at 7 days) attained resolution at an average of 12.1 days. Consequently, 28 (80.0%) of the 35 patients were alive with resolution of DIC after a 28-day observation period (infectious disease: 76.2%; hematological disease: 85.7%). Among them, for 7 (70%) of the 10 DIC patients with severe life-threatening bleeding symptoms without hemorrhagic shock, treatment with heparin was contraindicated; these patients were successfully treated with rTM without the progression of hemorrhage. In the majority of DIC patients, rTM administration may be an effective, safe, and feasible therapeutic modality producing a good outcome.
  Journal of Clinical and Experimental Hematopathology 01/2011; 51(2):101-7.
• Article: Improvement of rheumatoid arthritis and autoimmune hepatitis in a patient treated with the tumor necrosis factor inhibitor, etanercept.

  Kunihiko Umekita, Shunichi Miyauchi, Shiro Ueno, Ichiro Takajo, Kazunori Kusumoto, Satoru Hasuike, Yoshiko Umekita, Hiroyuki Tanaka, Kenji Nagata, Yasuhiro Nagatomo, Hiroaki Kataoka, Kazuya Shimoda, Akihiko Okayama
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  ABSTRACT: We report a case of rheumatoid arthritis (RA) with autoimmune hepatitis (AIH) and Sjogren syndrome (SjS) that was treated with the tumor necrosis factor (TNF) inhibitor, etanercept (ETN). Both RA activity and transaminase levels improved as a result of treatment. Follow-up liver biopsy showed improvement of hepatitis. Although the efficacy of anti-TNF for RA patients with AIH remains controversial, this case suggests that treatment with ETN may result in a favorable clinical course in a certain subset of patients with RA and AIH.
  Internal Medicine 01/2011; 50(11):1245-9. · 0.94 Impact Factor
• Source

  Available from: hokudai.ac.jp

  Article: Functional involvement of Daxx in gp130-mediated cell growth and survival in BaF3 cells.

  Ryuta Muromoto, Makoto Kuroda, Sumihito Togi, Yuichi Sekine, Asuka Nanbo, Kazuya Shimoda, Kenji Oritani, Tadashi Matsuda
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  ABSTRACT: Death domain-associated protein (Daxx) is a multifunctional protein that modulates both cell death and transcription. Several recent studies have indicated that Daxx is a mediator of lymphocyte death and/or growth suppression, although the detailed mechanism is unclear. Previously, we reported that Daxx suppresses IL-6 family cytokine-induced gene expression by interacting with STAT3. STAT3 is important for the growth and survival of lymphocytes; therefore, we here examined the role of Daxx in the gp130/STAT3-dependent cell growth/survival signals. We found that Daxx suppresses the gp130/STAT3-dependent cell growth and that Daxx endogenously interacts with STAT3 and inhibits the DNA-binding activity of STAT3. Moreover, small-interfering RNA-mediated knockdown of Daxx enhanced the expression of STAT3-target genes and accelerated the STAT3-mediated cell cycle progression. In addition, knockdown of Daxx-attenuated lactate dehydrogenase leakage from cells, indicating that Daxx positively regulates cell death during gp130/STAT3-mediated cell proliferation. Notably, Daxx specifically suppressed the levels of Bcl2 mRNA and protein, even in cytokine-unstimulated cells, indicating that Daxx regulates Bcl2 expression independently of activated STAT3. These results suggest that Daxx suppresses gp130-mediated cell growth and survival by two independent mechanisms: inhibition of STAT3-induced transcription and down-regulation of Bcl2 expression.
  European Journal of Immunology 12/2010; 40(12):3570-80. · 5.10 Impact Factor
• Article: Tyrosine kinase 2 interacts with the proapoptotic protein Siva-1 and augments its apoptotic functions.

  Haruko K Shimoda, Kotaro Shide, Takuro Kameda, Takuya Matsunaga, Kazuya Shimoda
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  ABSTRACT: Siva-1 is a molecule that has the potential to induce both extrinsic (receptor-mediated) and intrinsic (non-receptor-mediated) apoptosis. Siva-1 binds to CD27, a member of the tumor necrosis factor receptor (TNFR) family, Abl-related gene (ARG), and BCL-X(L), and these partner molecules reportedly enhance the apoptotic properties of Siva-1. In this study, we show that Siva-1 also interacts with a member of the Jak family protein kinases, tyrosine kinase 2 (Tyk2). Siva-1 bound to Tyk2 via its N-terminal region, and Tyk2 phosphorylated Siva-1 at tyrosines 53 and 162. In murine pro-B cells, Ba/F3 cells, expression of Tyk2 augmented Siva-1-induced apoptosis. This augmentation of Siva-1-induced apoptosis was retained regardless of the phosphorylation of Siva-1, but was almost completely prevented by the abrogation of the Tyk2-Siva-1 association. These findings indicate that the interaction between Siva-1 and Tyk2 directly augments the apoptotic activity of Siva-1. Our novel observations suggest that Siva-1 forms a functional complex with Tyk2 and participates in the transduction of signals that inhibit B lymphocyte growth.
  Biochemical and Biophysical Research Communications 09/2010; 400(2):252-7. · 2.48 Impact Factor
• Article: Successful treatment of cryoglobulinemic glomerulonephritis derived from Waldenström's macroglobulinemia by rituximab-CHOP and tandem high-dose chemotherapy with autologous peripheral blood stem cell transplantation.

  Noriaki Kawano, Naoko Ikeda, Shuro Yoshida, Yasuhiro Sugio, Kiyoshi Yamashita, Shigehiro Uezono, Toru Hayashi, Seiichiro Hara, Shigeyoshi Makino, Kazuya Shimoda, Akira Ueda
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  ABSTRACT: Waldenström's macroglobulinemia (WM) is a slowly progressive, low-grade B cell lymphoproliferative disorder. In contrast to the indolent progression, the development of cryoglobulinemic glomerulonephritis associated with WM is a rare, aggressive, and life-threatening complication. We describe the case of a 53-year-old man who suffered from WM, which was accompanied by cryoglobulinemic glomerulonephritis. WM was diagnosed on the basis of an increase in monoclonal IgM kappa and infiltration of abnormal lymphoplasmacytic cells in the bone marrow. Moreover, the case was complicated by increase in the levels of urinary protein, serum creatinine, and serum cryoglobulin. Histological findings showed endocapillary glomerulonephritis with hyaline plugs. Electron microscopy demonstrated the accumulation of electron-dense deposits in the subepithelial, subendothelial, intramembranous, and mesangial areas, which revealed cryoglobulinemic proliferative glomerulonephritis. The patient received four courses of rituximab therapy followed by four courses of R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) in combination with cryofiltration. Subsequently, the patient underwent high-dose chemotherapy (melphalan [L-PAM]) followed by tandem autologous peripheral blood stem cell transplantation. After these treatments, the patient remained disease-free for 26 months. Histological findings of cryoglobulinemic glomerulonephritis were markedly improved after these treatments. Our case suggests that these treatments may be a feasible, safe, and effective strategy for critical cryoglobulinemic glomerulonephritis derived from WM.
  International journal of hematology 09/2010; 92(2):391-7. · 1.17 Impact Factor
• Article: JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation.

  Seido Oku, Katsuto Takenaka, Takuro Kuriyama, Kotaro Shide, Takashi Kumano, Yoshikane Kikushige, Shingo Urata, Takuji Yamauchi, Chika Iwamoto, Haruko K Shimoda, Toshihiro Miyamoto, Koji Nagafuji, Junji Kishimoto, Kazuya Shimoda, Koichi Akashi
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  ABSTRACT: The acquired JAK2 V617F mutation is observed in the majority of patients with BCR-ABL1 negative chronic myeloproliferative neoplasms (MPN). BCR-ABL1 negative MPN displays myeloproliferation with an elevated leucocyte alkaline phosphatase (LAP) activity, a neutrophil activation marker. We tried to separate the downstream signalling of JAK2 V617F to stimulate myeloproliferation and LAP activity. NB4, a myeloid lineage cell line, was transduced with Jak2 V617F mutation or wild-type Jak2. We found that Jak2 V617F mutation, but not wild-type Jak2 enhanced LAP expression in NB4-derived neutrophils and proliferation of NB4 cells. JAK2 V617F induces constitutive phosphorylation of STAT3 and STAT5, and uses signalling targets such as Ras/MEK/ERK and PI3K/Akt pathways. By using MEK1/2 inhibitor U0126, PI3K inhibitor LY294002, and STAT3 or STAT5 siRNAs, JAK2 V617F was found to specifically use the STAT3 pathway to enhance LAP expression, while STAT5, Ras/MEK/ERK and PI3K/Akt, but not STAT3 pathways, were able to stimulate cell proliferation. These data strongly suggest that JAK2 V617F uses distinct signalling pathways to induce typical pathological features of MPN, such as high LAP activity and enhanced cell proliferation.
  British Journal of Haematology 08/2010; 150(3):334-44. · 4.94 Impact Factor
• Article: [Antiphospholipid syndrome with autoimmune hemolytic anemia which mimics thrombotic thrombocytopenic purpura].

  Naoki Karasawa, Yasuhiro Taniguchi, Tomonori Hidaka, Keiko Katayose, Takuro Kameda, Kotaro Side, Haruko Shimoda, Kenji Nagata, Yoko Kubuki, Takuya Matsunaga, Kazuya Shimoda
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  ABSTRACT: A 67-year-old woman was admitted to the hospital for lethargy, fever, hemolytic anemia, thrombocytopenia, and consciousness disturbance. Direct Coombs test was positive, and anti-cardiolipin beta2-glycoprotein I antibody was detected. She was diagnosed with antiphospholipid syndrome complicated with autoimmune hemolytic anemia (AIHA). She demonstrated variable consciousness disturbance, inability to distinguish right from left, dysgraphia and dyscalculia. Multiple cerebral infarctions, especially dominant cerebral hemisphere infarctions, were observed on magnetic resonance imaging. A ventilation-perfusion scan demonstrated the presence of a ventilation-perfusion mismatch in both lung fields, and multiple veinous embolisms in the right femoral, bilateral the great saphenous and popliteal veins. Therefore, pulmonary embolism and thrombophlebitis were diagnosed. Based on these findings, it was necessary to distinguish this diagnosis from thrombotic thrombocytopenic purpura (TTP). As ADAMTS-13 activity was within the normal range, TTP was denied. Thereafter, the patient was treated with 1 mg/kg of prednisolone for AIHA, 3 mg of warfarin, and 3500 units of low-molecular-weight heparin for thrombosis, and her condition improved.
  [Rinshō ketsueki] The Japanese journal of clinical hematology 04/2010; 51(4):275-80.