Shigeru Chiba

Asahikawa Medical University, Асахикава, Hokkaidō, Japan

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Publications (344)1667.32 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Adult T-cell leukemia/lymphoma (ATLL) is a distinct form of peripheral T-cell lymphoma (PTCL) with poor prognosis which is caused by human T-lymphotropic virus type 1 (HTLV-1). In contrast to the unequivocal importance of HTLV-1 infection in the pathogenesis of ATLL, the role of acquired mutations in HTLV-1 infected T-cells has not been fully elucidated with a handful of genes known to be recurrently mutated. In this study, we identified unique RHOA mutations in ATLL through whole genome sequencing of an index case, followed by deep sequencing of 203 ATLL samples. RHOA mutations showed distinct distribution and function from those found in other cancers. Involving 15% (30/203) of ATLL cases, RHOA mutations were widely distributed across the entire coding sequence but almost invariably located at the GTP-binding pocket, with Cys16Arg being most frequently observed. Unexpectedly, depending on mutation types and positions, these RHOA mutants showed different or even opposite functional consequences in terms of GTP/GDP-binding kinetics, regulation of actin fibers, and transcriptional activation. The Gly17Val mutant did not bind GTP/GDP and act as a dominant negative molecule, whereas other mutants (Cys16Arg and Ala161Pro) showed fast GTP/GDP cycling with enhanced transcriptional activation. These findings suggest that both loss- and gain-of-RHOA functions could be involved in ATLL leukemogenesis. In summary, our study not only provides a novel insight into the molecular pathogenesis of ATLL but also highlights a unique role of variegation of heterologous RHOA mutations in human cancers.
    Blood 11/2015; DOI:10.1182/blood-2015-06-644948 · 10.45 Impact Factor
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    ABSTRACT: We have previously shown the clinical usefulness of Wilms' tumor 1 gene (WT1) mRNA expression in peripheral blood (PB) as a minimal residual disease (MRD) monitoring marker in 191 acute myeloid leukemia (AML) patients using the WT1 mRNA assay kit "Otsuka" (Otsuka Pharmaceutical Co., Ltd.; "former kit"). In contrast, the usefulness of WT1 mRNA expression in bone marrow (BM) has been investigated in only a limited number of subjects using former kit. Following that previous study, a next-generation kit, WT1 mRNA assay kit II "Otsuka" (Otsuka Pharmaceutical Co., Ltd.; "new kit") has been newly developed. In the present study, we aimed to evaluate the performance of the new kit and to investigate the clinical usefulness of WT1 mRNA expression in BM. The PB and BM were collected on the same day from 164 blood disease patients, including 118 AML patients. WT1 mRNA expression was determined using the new and former kits and the values obtained were compared. The performance of new kit was shown to be equivalent to that of former kit. As reported in PB, WT1 mRNA expression in BM was found to be a useful marker for monitoring disease status as well as for a diagnosis of early stage relapse in AML patients.
    International journal of hematology 11/2015; DOI:10.1007/s12185-015-1882-1 · 1.92 Impact Factor
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    ABSTRACT: Acute graft-versus-host disease (aGVHD) represents one of the major complications in allogeneic stem cell transplantation and is primarily caused by genetic disparity between the donor and recipient. In human leukocyte antigen (HLA)-matched transplants, the disparity is thought to be determined by loci encoding minor histocompatibility antigens (minor H antigens), which are presented by specific HLA molecules. We performed a genome-wide association study (GWAS) to identify minor H antigen loci associated with aGVHD. A total of 500,568 single nucleotide polymorphisms (SNPs) were genotyped for donors and recipients from 1,589 unrelated bone marrow transplants matched for HLA-A, B, C, DRB1, and DQB1, followed by the imputation of unobserved SNPs. We interrogated SNPs whose disparity between the donor and recipient was significantly associated with aGVHD development. Without assuming HLA unrestriction, we successfully captured a known association of HLA-DPB1 disparity (P = 4.50 × 10(-9)) with grade II-IV aGVHD development, providing a proof of the concept of the GWAS design aimed at discovering genetic disparity associated with aGVHD. In HLA-restricted analyses, where association tests were confined to major subgroups sharing common HLA alleles to identify putative minor H antigen loci, we identified three novel loci significantly associated with grade III-IV aGVHD. Among these, rs17473423 (P = 1.20 × 10(-11)) at 12p12.1 within the KRAS locus showed the most significant association in the subgroup sharing HLA DQB1*06:01. Our result suggested that GWAS can be successfully applied to identify allele mismatch associated with aGVHD development, contributing to the understanding of the genetic basis of aGVHD.
    Blood 10/2015; DOI:10.1182/blood-2015-03-630707 · 10.45 Impact Factor
  • Mamiko Sakata-Yanagimoto · Shigeru Chiba ·
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    ABSTRACT: Understanding the molecular pathogenesis of peripheral T cell lymphomas (PTCLs) has lagged behind that of B cell lymphomas due to disease rarity. However, novel approaches are gradually clarifying these mechanisms, and gene profiling has identified specific signaling pathways governing PTCL cell survival and growth. For example, genetic alterations have been discovered, including signal transducer and activator of transcription (STAT)3 and STAT5b mutations in several PTCLs, disease-specific ras homolog family member A (RHOA) mutations in angioimmunoblastic T cell lymphoma (AITL), and recurrent translocations at the dual specificity phosphatase 22 (DUSP22) locus in anaplastic lymphoma receptor tyrosine kinase (ALK)-negative anaplastic large cell lymphomas (ALCLs). Intriguingly, some PTCL-relevant mutations are seen in apparently normal blood cells as well as tumor cells, while others are confined to tumor cells. These data have dramatically changed our understanding of PTCL origins: once considered to originate from mature T lymphocytes, some PTCLs are now believed to emerge from immature hematopoietic progenitor cells.
    Current Hematologic Malignancy Reports 10/2015; DOI:10.1007/s11899-015-0289-7 · 2.20 Impact Factor
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    09/2015; 2:15031. DOI:10.1038/hgv.2015.31

  • Hideharu Muto · Mamiko Sakata-Yanagimoto · Shigeru Chiba ·
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    ABSTRACT: TET (Ten Eleven Translocation) family proteins are dioxygenases that convert methylcytosine to hydroxymethylcytosine, and play an important role in the DNA demethylation process. Most notably, TET2 mutations have frequently been identified in myeloid malignancies, such as myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia, and acute myeloid leukemias, as well as angioimmunoblastic T-cell lymphoma and a proportion of peripheral T-cell lymphomas. To date, various types of Tet2 knockout/knockdown mice have been generated. Tet2 mutations induce enhanced self-renewal ability and competitive repopulation capacity in hematopoietic stem cells, and various MPN/MDS-like diseases and T-cell lymphoma consequently develop in model mice. These findings appear to have a strong correlation with the recently identified TET2 mutations in a significant proportion of healthy elderly people, and suggest that TET2 mutations lead to a pre-cancer state in hematopoietic stem/progenitor cells. In conclusion, TET2 might play a major role as a gate keeper for hematopoietic stem/progenitor cells preventing them from developing into various hematologic malignancies by acquiring additional disease-specific gene mutations.
    [Rinshō ketsueki] The Japanese journal of clinical hematology 08/2015; 56(6):651-6. DOI:10.11406/rinketsu.56.651

  • Annals of Hematology 08/2015; 94(12). DOI:10.1007/s00277-015-2463-3 · 2.63 Impact Factor
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    ABSTRACT: Chronic kidney disease (CKD) is one of the major manifestations of paroxysmal nocturnal hemoglobinuria (PNH). CKD in PNH is induced mainly by intravascular hemolysis of PNH-affected red blood cells (RBC) missing the glycosylphosphatidylinositol-anchored proteins with complement-regulatory activities, CD55 and CD59. CKD develops by heme absorption in the proximal tubules resulting in the interstitial deposition of iron in the kidneys. We administered eculizumab to a patient with PNH, who was one of 29 patients enrolled in the AEGIS clinical trial, an open-label study of eculizumab in Japan. The patient was complicated by stage 3 CKD with impaired estimated glomerular filtration rate (eGFR), at grade G3b, and had obvious proteinuria (2-3+, 1-2 g/day). In a two-year extension to the 12-week AEGIS study, eGFR improved significantly, and the eGFR has since been maintained at grade G2 without proteinuria by sustained eculizumab treatment (>6 years). Renal function improved and maintained by long-term sustained eculizumab treatment, presumably by clearance of iron from the kidney as well as inhibition of the production of anaphylatoxin C5a, even in advanced stages of CKD, is one of the benefits of eculizumab treatment in PNH.
    06/2015; 2015:1-4. DOI:10.1155/2015/673195
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    ABSTRACT: Interdigitating dendritic cell sarcoma (IDCS) is a rare and aggressive neoplasm that is thought to arise from dendritic cells. This disease usually involves the lymph nodes and, rarely, extra-nodal sites. We report a 62-year-old man presenting skin nodules in the head, body, and extremities, as well as bone marrow involvement. Morphologic analysis of a biopsied specimen from the skin lesion was consistent with IDCS. Immunohistochemical staining demonstrated that the tumor cells were positive for IDCS-associated antigens such as CD4, CD45, CD68 (KP-1), and S-100 protein. Complete remission was achieved by treatment with 6 cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) chemotherapy. Although the optimal treatment of IDSC remains unknown, the experience in the current case supports the notion that ABVD chemotherapy may be effective for IDCS, and further extends this idea to rare patients presenting multiple skin lesions.
    Journal of Clinical and Experimental Hematopathology 06/2015; 55(1):33-7. DOI:10.3960/jslrt.55.33
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    ABSTRACT: Hydroxymethylcytosine (hmC) is a natural nucleobase, which is converted from methylcytosine (mC) by tet methylcytosine dioxygenase (TET) family (TET1-3) enzymes. Decrease of genomic hmC is postulated to confer a risk for myeloid-lineage as well as T-cell neoplasms, based on the fact that loss-of-function mutations in the TET2 gene were frequently identified in these diseases. The relationship between hmC and aging remains to be elucidated. Here, we demonstrated that hmC content decreased with age in the peripheral blood T cells of 53 human volunteers. We further identified that the mRNA expression levels of TET1 and TET3 decreased with age, while those of TET2 were not influenced by age. The genomic hmC content was correlated with the mRNA expression level of TET3, but not those of TET1 and TET2. Our study suggests the presence of new epigenetic regulatory mechanisms in aging T cells.
    Journal of Clinical and Experimental Hematopathology 06/2015; 55(1):1-6. DOI:10.3960/jslrt.55.1
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    ABSTRACT: RHOA is a member of RHO family small GTPases. Over the past 2 decades, numerous biochemical and cell biological studies on RHOA have demonstrated signalings such as activation of RHO-associated coiled-coil forming kinases through guanine nucleotide exchange and GTP hydrolysis, cellular responses such as actin fiber formation and myocin activation, biological consequences such as cell motility and cytokineses, etc. There have also been a plenty of active discussion on the roles of RHOA in tumorigenesis, primarily based on gain- and loss-of-function experiments. However, cell-type-specific functions of RHOA have only recently been delineated by conditional gene targeting strategies. Furthermore, very little information had been available on human cancer genetics until we and others recently reported frequent somatic RHOA mutations in a distinct subtype of T-cell-type malignant lymphoma called angioimmunoblastic T-cell lymphoma (AITL), and other T-cell lymphoma with AITL-like features. The RHOA mutations were very specific to these types of lymphoma among hematologic malignancies, and a single hotspot, glycine at the 17th position, was affected by the replacement with valine (G17V). Remarkably, G17V RHOA did not bind GTP, and moreover, it inhibited the GTP binding to wild-type RHOA. How G17V RHOA contributes to T-cell lymphomagenesis needs to be clarified. [199 words; 150-200].
    Small GTPases 06/2015; 6(2). DOI:10.4161/21541248.2014.988088
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    ABSTRACT: Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study ( NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100mg/day) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into 2 groups according to those calculated thresholds by receiver operating characteristic curve (407/μL for NK cells and 347/μL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    American Journal of Hematology 06/2015; 90(9). DOI:10.1002/ajh.24096 · 3.80 Impact Factor
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    ABSTRACT: Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 05/2015; 49. DOI:10.1016/j.bbi.2015.05.003 · 5.89 Impact Factor
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    ABSTRACT: A 52-year-old woman was diagnosed with BJP-λ multiple myeloma (MM) in November 2012. She was treated with six cycles of bortezomib and dexamethasone, resulting in a very good partial response. The patient underwent autologous peripheral blood stem cell transplantation (PBSCT) 6 months after the diagnosis, and clearly achieved a complete response thereafter. She again suffered chronic abdominal pain with spontaneous remission 9 months after the PBSCT, and, 2 months thereafter, was hospitalized due to intestinal obstruction. Two small intestinal intussusceptions and polyposis in the small intestine were found on abdominal computed tomography. As conservative treatment produced no improvement, partial resection of the small intestine was performed. The pathologic review clearly demonstrated the polyps to have atypical plasma cell infiltrates in the mucosa of the small intestine involving all layers. Immunohisto-chemistry and FISH analyses yielded positive results for CD138, CD79a, and λ light chain, consistent with extramedullary relapse of MM. It is very rare for MM to present with polyposis in the small intestine. There have been no reports describing such a case after autologous PBSCT.
    [Rinshō ketsueki] The Japanese journal of clinical hematology 05/2015; 56(4):400-5. DOI:10.11406/rinketsu.56.400

  • Annals of Hematology 05/2015; 94(8). DOI:10.1007/s00277-015-2391-2 · 2.63 Impact Factor
  • N Kurita · F Frassoni · S Chiba · M Podestà ·
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    ABSTRACT: As the history of the cord blood banking system has lengthened, the number of cord blood units (CBUs) cryopreserved for years has increased. The global expansion of cord blood banking resulted in active international exchange of CBUs. To determine whether long-term cryopreservation and international shipment of CBUs affect the quality of the units and outcome after transplantation, we retrospectively analyzed the quality of 95 CBUs and the hematologic recovery of 127 patients with hematological malignancy following single-unit cord blood transplantation. Of the 127 CBUs used to transplant, 42 units were cryopreserved for long periods (5-11.8 years), and 44 units were shipped from distant countries. We found that length of cryopreservation and origin of CBUs did not affect the ratio of viable total-nucleated cells after thawing. Also, neutrophil engraftment was not affected by long-term cryopreservation (> 5 years) or origin (from distant countries), (hazard ratio, 0.91 and 1.2; P=0.65 and 0.41; respectively). The number of CD34(+) cells before freezing (> 1.4 cells/kg recipient) was the only factor that enhanced neutrophil engraftment (hazard ratio, 1.8; P<0.01). This suggests that length of cryopreservation and origin need not be prioritized over the CD34(+) cell dose when selecting CBUs.Bone Marrow Transplantation advance online publication, 23 March 2015; doi:10.1038/bmt.2015.56.
    Bone marrow transplantation 03/2015; 50(6). DOI:10.1038/bmt.2015.56 · 3.57 Impact Factor
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    ABSTRACT: We report a 38-year-old Nigerian woman with sickle cell disease. Sickle cell disease had been diagnosed when she experienced her first sickle cell crisis episode at age 8 years. Thereafter, she had infrequent minor episodes. She visited a hospital presenting with fever, anemia, jaundice, and systemic pain, and was then transferred to our hospital. Together with rehydration and red blood cell transfusion, analgesics and antibiotics were prescribed, and produced gradual improvement of all symptoms and signs. The patient was discharged on day 9 of hospitalization. Sickle cell crisis is an acute painful episode caused by occlusion of arterioles. The degree of pain and accompanying symptoms, as well as the frequencies of crises, are variable. Moreover, one third of individuals with sickle cell disease never experience a crisis. As our society becomes increasingly globalized, the probabilities of encountering sickle cell disease patients will be higher.
    [Rinshō ketsueki] The Japanese journal of clinical hematology 03/2015; 56(1):30-4. DOI:10.11406/rinketsu.56.30
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    ABSTRACT: Recent identification of platelet/megakaryocyte-biased hematopoietic stem/repopulating cells requires revision of the intermediate pathway for megakaryopoiesis. Here, we show a unipotent megakaryopoietic pathway bypassing the bipotent megakaryocyte/erythroid progenitors (biEMP). Cells purified from mouse bone marrow by CD42b (GPIbα) marking were demonstrated to be unipotent megakaryocyte progenitors (MKP) by culture and transplantation. A subpopulation of CD41(+) cells in the lineage(-) Sca1(+) cKit(+) (LSK) fraction (subCD41(+) LSK) isolated from mouse bone marrow differentiated only into MKP and mature megakaryocytes in vitro culture. Although CD41(+) LSK cells as a whole were capable of differentiating into all myeloid and lymphoid cells in vivo, they produced unipotent megakaryocytic progenitors (MKP), mature megakaryocytes, and platelets in vitro and in vivo much more efficiently than Flt3(+) CD41(-) LSK cells, especially at the early phase after transplantation. In single cell PCR and thrombopoietin (TPO) signaling analyses, the MKP and a fraction of CD41(+) LSK, but not the biEMP, showed the similarities in mRNA expression profile and visible TPO mediated phosphorylation. On increased demand of platelet production after 5-FU treatment, a part of CD41(+) LSK population expressed CD42b on the surface, and 90% of them showed unipotent megakaryopoietic capacity in single cell culture and predominantly produced platelets in vivo at the early phase after transplantation. These results suggest that the CD41(+) CD42b(+) LSK are straightforward progenies of megakaryocytes/platelet-biased stem/repopulating cells, but not progenies of biEMP. Consequently, we show a unipotent/highly-biased megakaryopoietic pathway interconnecting stem/repopulating cells and mature megakaryocytes, the one that may play physiologic roles especially in emergency megakaryopoiesis. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
    Stem Cells 03/2015; 33(7). DOI:10.1002/stem.1985 · 6.52 Impact Factor
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    ABSTRACT: To investigate prognosis and effects of first-line therapy in elderly primary central nervous system lymphoma (PCNSL) patients. A systematic review of studies about first-line therapy in immunocompetent patients≥60 years with PCNSL until 2014 and a meta-analysis of individual patient data from eligible studies and international collaborators were performed. We identified 20 eligible studies; from 13 studies we obtained individual data of 405 patients, which were pooled with data of 378 additional patients (N=783). Median age and Karnofsky Performance Score (KPS) was 68 years (range: 60 - 90) and 60% (range: 10% - 100%), respectively. Treatments varied greatly, 573 (73%) patients received high-dose methotrexate (HD-MTX)-based therapy. 276 patients received whole brain radiotherapy (median 36 Gy, range 28.5 - 70). KPS≥70% was the strongest prognostic factor for mortality (hazard ratio [HR] 0.50, 95% CI 0.41 - 0.62). After a median follow-up of 40 months, HD-MTX based therapy was associated with improved survival (HR 0.70, 95% CI 0.53 - 0.93). There was no difference between HD-MTX plus oral chemotherapy and more aggressive HD-MTX based therapies (HR 1.39, 95% CI 0.90 - 2.15). Radiotherapy was associated with an improved survival, but correlated with an increased risk for neurological side effects (odds ratio 5.23, 95% CI 2.33 - 11.74). Elderly PCNSL patients benefit from HD-MTX based therapy, especially if combined with oral alkylating agents. More aggressive HD-MTX protocols do not seem to improve outcome. WBRT may improve outcome, but is associated with increased risk for neurological side effects. Prospective trials for elderly PCNSL patients are warranted. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
    Annals of Oncology 02/2015; 26(7). DOI:10.1093/annonc/mdv076 · 7.04 Impact Factor

Publication Stats

10k Citations
1,667.32 Total Impact Points


  • 2012-2015
    • Asahikawa Medical University
      • Department of Psychiatry and Neurology
      Асахикава, Hokkaidō, Japan
  • 2008-2015
    • University of Tsukuba
      • Institute of Clinical Medicine
      Tsukuba, Ibaraki, Japan
  • 2000-2013
    • Tokyo Medical University
      • Division of Hematology
      Edo, Tōkyō, Japan
  • 1989-2011
    • The University of Tokyo
      • • Department of Hematology and Oncology
      • • Department of Cell Therapy and Transplantation Medicine
      • • Division of Internal Medicine
      • • Department of Pathology
      Tōkyō, Japan
  • 2007
    • Institute for Molecular Medicine and Cell Therapy
      Düsseldorf, North Rhine-Westphalia, Germany
  • 2006
    • Saiseikai Maebashi Hospital
      Edo, Tōkyō, Japan
  • 2004
    • Yale University
      New Haven, Connecticut, United States
  • 2000-2002
    • National Institute for Basic Biology
      Okazaki, Aichi, Japan
  • 1996-2002
    • Oita University
      • • Faculty of Medicine
      • • Department of Clinical Pharmacy
      Ōita, Ōita, Japan