T Hirano

Kitakyushu University, Kitakyūshū, Fukuoka-ken, Japan

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Publications (195)1132.07 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The base excision repair system for 8-hydroxyguanine (8-OH-Gua) is believed to play a role in the prevention of mutations, such as GC-to-TA transversion, which leads to cancer development. However, the exact repair mechanism is still unclear. In this study, we examine whether the repair activity level for 8-hydroxyguanine, one of the major forms of oxidative DNA damage, depends on the sequence of the substrate DNA. We prepared six different oligonucleotides containing 8-hydroxyguanine as substrates and reacted them with crude extracts from the livers and kidneys of 8-week-old Sprague-Dawley rats. As a result, up to a 10-fold difference in the repair activity levels was observed, depending on the substrates used. Based on this observation, we suggest that the repair systems may act with sequence specificity on the damaged DNA.
    Journal of Radiation Research 10/2001; 42(3):247-54. · 1.69 Impact Factor
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    ABSTRACT: We report the isolation of two novel zebrafish mix-type homeobox genes, mtx1 and mtx2. The homeodomains of both Mtx1 and Mtx2 exhibited a 50% amino acid identity to other Mix-family protein homeodomains. mtx1 was expressed throughout the yolk syncytial layer (YSL), an extraembryonic structure in teleosts, from the late-blastula to the mid-gastrula period. mtx2 was first expressed in the dorsal blastomeres soon after the mid-blastula transition, and slightly later in the entire blastoderm margin. After the late blastula period, mtx2 transcripts were detected in the YSL, and they were restricted to the dorsal YSL by the early gastrula period. The expression of mtx2 was dependent on Wnt signals but not on Nodal signals. mtx1 expression was not regulated by either Wnt or Nodal signals. This is in complete contrast to the Nodal signal-dependent expression of mixer. These results indicate the complexity of the regulation of mix-type homeobox genes.
    Biochemical and Biophysical Research Communications 06/2000; 271(3):603-9. · 2.28 Impact Factor
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    ABSTRACT: In vertebrates, specification of the dorso-ventral axis requires Wnt signaling, which leads to formation of the Nieuwkoop center and the Spemann organizer (dorsal organizer), through the nuclear accumulation of beta-catenin. Zebrafish bozozok/dharma (boz) and squint (sqt), which encode a homeodomain protein and a Nodal-related protein, respectively, are required for the formation of the dorsal organizer. The zygotic expression of boz and sqt in the dorsal blastoderm and dorsal yolk syncytial layer (YSL) was dependent on the maternally derived Wnt signal, and their expression at the late blastula and early gastrula stages was dependent on the zygotic expression of their own genes. The dorsal organizer genes, goosecoid (gsc) and chordin (din), were ectopically expressed in wild-type embryos injected with boz or sqt RNA. The expression of gsc strictly depended on both boz and sqt while the expression of din strongly depended on boz but only partially depended on sqt and cyclops (cyc, another nodal-related gene). Overexpression of boz in embryos defective in Nodal signaling elicited the ectopic expression of din but not gsc and resulted in dorsalization, implying that boz could induce part of the organizer, independent of the Nodal proteins. Furthermore, boz; sqt and boz;cyc double mutants displayed a severely ventralized phenotype with anterior truncation, compared with the single mutants, and boz;sqt;cyc triple mutant embryos exhibited an even more severe phenotype, lacking the anterior neuroectoderm and notochord, suggesting that Boz/Dharma and the Nodal-related proteins cooperatively regulate the formation of the dorsal organizer.
    Mechanisms of Development 04/2000; 91(1-2):293-303. · 2.24 Impact Factor
  • Toshio Hirano
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    ABSTRACT: Cytokines and growth factors play pivotal roles in cell growth, differentiation, and cell survival. Ligand binding to the receptors induces dimerization or oligomerization of the receptors, resulting in the activation of a variety of signal transduction pathways. The interplay among these multiple signals is critically involved in the biological activities of cytokines and growth factors. In this minireview, I discuss two models. One is the "receptor conversion model": The complex of cytokine and its soluble form of receptor acts like a cytokine with novel target specificity. The other is the "orchestrating model": Cytokines can simultaneously generate contradictory signals in the same target cells and the balance of each contradictory signal may determine the final output of cytokine signals to express unified biological activity. These mechanisms are part of the molecular basis underlying functional pleiotropy of cytokines and growth factors.
    Biochemical and Biophysical Research Communications 08/1999; 260(2):303-8. · 2.28 Impact Factor
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    ABSTRACT: Asbestos and man-made-mineral fibers are known to increase one type of oxidative DNA damage, 8-hydroxyguanine (8-OH-(Gua), in vitro. In this study, we analyzed the 8-OH-Gua level in DNA and its repair activity after a single intratracheal instillation of fibers (crocidolite or glass) or saline to Syrian hamsters or Wistar rats. The 8-OH-Gua level was measured with a high-performance liquid chromatography-electrochemical detector (HPLC-ECD) system. The 8-OH-Gua repair enzyme activity was determined with an endonuclease nicking assay using a 32P-labeled or fluorescently labeled 22mer DNA that contains 8-OH-Gua at a specific position. A significant increase in the 8-OH-Gua level in the lung DNA was observed 1 day after the exposure to crocidolite, as compared to the saline control. The repair activity was increased significantly at 7 days. On the other hand, after exposure to glass fibers, little or no increase of these carcinogenicity indicators was detected. These assays of 8-OH-Gua and its repair activity in short-term animal experiments will be useful for evaluating the carcinogenicity of fibers. This is the first report of the increase of 8-OH-Gua and its repair activity in the animal lung after the instillation of asbestos fibers.
    Japanese journal of cancer research: Gann 06/1999; 90(5):505-9.
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    ABSTRACT: We investigated the effect of physical exercise on the level of 8-hydroxyguanine (8-OH-Gua), a form of oxidative DNA damage, and its repair activity in human peripheral leukocytes. Whole blood samples were collected by venipuncture from 21 healthy male volunteers (10 trained athletes and 13 untrained men), aged 19-50 years, both before and after physical exercise. Trained athletes showed a lower level of 8-OH-Gua (2.4+/-0.5/10(6) Gua, p = 0.0032) before exercise when compared to that of untrained men (6.2+/-3.5). The mean levels of 8-OH-Gua of untrained subjects decreased significantly (p = 0.0057) from 6.2+/-3.5/10(6) Gua (mean+/-SD/10(6) Gua) to 3.3+/-1.4/10(6) Gua after physical exercise. On the other hand, the mean levels of repair activity of untrained subjects significantly increased after exercise (p = 0.0093) from 0.037+/-0.024 (mean DNA cleavage ratio+/-SD) to 0.056+/-0.036. In the trained athletes 8-OH-Gua level and its repair activity were not changed before and after the exercise. We also observed inter-individual differences in 8-OH-Gua levels and its repair activities. These results suggest that physical exercise causes both rapid and long-range reduction of oxidative DNA damage in human leukocytes, with individually different efficiencies.
    Free Radical Research 01/1999; 29(6):581-4. · 2.99 Impact Factor
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    ABSTRACT: Oxygen radicals are known to play a role in causing cellular DNA damage, which is involved in carcinogenesis. 8-Hydroxyguanine (8-OH-Gua) is a major form of oxidative DNA damage and is known as a useful marker of DNA oxidation. Recently, we found another type of oxidative DNA damage, 2-hydroxyadenine (2-OH-Ade), which has a mutation frequency comparable to that of 8-OH-Gua. We compared the repair activities for two types of oxidative DNA damage, 8-OH-Gua and 2-OH-Ade, in 7-week-old male Sprague-Dawley (SD) rat organs. The repair activities were measured by an endonuclease nicking assay using 22 mer [32P]-end-labeled double-stranded DNA substrates, which contained either 8-OH-Gua (opposite C) or 2-OH-Ade (opposite T or C). In all of the SD rat organs we studied, the nicking activity for 2-OH-Ade was not detected, while that for 8-OH-Gua was clearly detected with the same conditions. Moreover, the 2-OH-Ade nicking activity was not induced in Wistar rat kidney extracts prepared after ferric nitrilotriacetate (Fe-NTA) treatment, which is known to increase 8-OH-Gua repair activity. These results suggest that 2-OH-Ade might not be repaired by the glycosylase type mechanism in mammalian cells.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 09/1998; 408(2):121-7. · 4.44 Impact Factor
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    ABSTRACT: Carcinogen-resistant inbred DRH rats developed from the Donryu strain showed a remarkably low incidence of liver tumors when they were fed diets containing hepatocarcinogens such as 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). In this work, we examined various characteristics of male DRH and Donryu rats during 3'-Me-DAB administration for 8 weeks. 32P-Postlabeling analysis showed that essentially similar levels of DNA-adducts were generated by the metabolites of 3'-Me-DAB in the livers of these two strains of rats at several time points. However, both GADD45 (growth arrest and DNA damage-inducible) and O6-methylguanine methyltransferase (putatively DNA damage-inducible) mRNA levels were increased significantly in Donryu rat livers, but were increased to a lesser extent in DRH rats. [3H]Thymidine incorporation into hepatic DNA began to increase around 10 to 20 days after the start of 3'-Me-DAB administration in Donryu rats probably due to DNA repair, while no significant change occurred in DRH rats under the same conditions. Furthermore, inductions of heme oxygenase (due to degradation of heme-proteins) and hepatocyte growth factor (HGF; cell death and regeneration of hepatocytes) mRNAs were greater in Donryu rat livers than those of DRH, suggesting that the former were more sensitive to cytotoxic effects of 3'-Me-DAB than the latter. Another remarkable difference observed between these two strains was the significant induction of cytochrome P-450 2E1 mRNA in Donryu rat livers; this may contribute to the generation of reactive oxygen intermediates. Finally, increases of glutathione S-transferase (P-form) and gamma-glutamyltranspeptidase mRNAs as marker enzymes of preneoplastic changes of hepatocytes were clearly seen only in Donryu rat livers at 6 to 8 weeks after the start of 3'-Me-DAB administration. These results indicate that the different susceptibility to hepatocarcinogenesis between these two strains of rats may arise from events other than the DNA adduct formation.
    Japanese journal of cancer research: Gann 09/1998; 89(8):806-13.
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    ABSTRACT: We investigated the effects of forced and spontaneous exercise on the levels of 8-hydroxydeoxyguanosine (8-OH-dG), a form of oxidative DNA damage, in rat organs (heart, lung, and liver). Rats were randomly assigned to one of three groups: forced exercise group (F), spontaneous exercise group (S), and sedentary control group (C). The mean levels of 8-OH-dG in the F group were 1.9-, 2.1-, and 2.4-fold higher in the heart, lung, and liver DNA, respectively, than in the S group. In the S group of rats, the distance run was not significantly correlated to the 8-OH-dG levels in the heart, lung, and liver DNA. These results demonstrate that the intensity of exercise is an important determinant in DNA damage, and suggest that spontaneous physical exercise is beneficial for maintaining a low level of oxidative DNA damage.
    Biochemical and Biophysical Research Communications 02/1998; 243(3):678-82. · 2.28 Impact Factor
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    ABSTRACT: Tec/Btk tyrosine kinases are members of a subgroup of Src tyrosine kinase family. They are reported to be activated in response to cytokines, such as IL-3 and IL-6. Janus kinases (JAKs) are known to associate with certain cytokine receptors, e.g. gp130, the signal transducing subunit of IL-6 receptor, and the common beta chain of IL-3 receptor, which can be activated upon receptor dimerization in response to cytokines. Here we show the association between Jak1/Jak2 and Tec or Jak1 and Btk. Furthermore, Jak1 but not Jak2 induces tyrosine phosphorylation of Btk, but not Tec. These observations suggest that upon cytokine stimulation JAKs activate Tec/Btk or induce their dimerization resulting in endogenous tyrosine phosphorylation. Furthermore using a yeast two-hybrid system we have identified the target molecules for Tec, the p85 and p55PIK subunits of PI-3 kinase, and Vav. Tec associated with Vav through its SH2 domain independently of its kinase activity. In contrast the p85 and p55PIK subunits of PI-3 kinase associated with the SH2-kinase domain of Tec, dependent on Tec kinase activity. Consistent with these, IL-6 or IL-3 induced the association between Tec and the p85 subunit of PI-3 kinase in mammalian cells. These findings suggest that Tec tyrosine kinase links cytokine receptors to PI-3 kinase probably through JAKs.
    Oncogene 06/1997; 14(19):2273-82. · 8.56 Impact Factor
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    ABSTRACT: BST-1 is an ectoenzyme expressed on human bone marrow Stromal cells and myeloid lineage cells, having both ADP-ribosyl cyclase and cyclic ADP-ribose (cADPR) hydrolase activities. In mouse, BST-1 is also expressed on lymphoid progenitors. We isolated chromosomal DNA segments of the human BST-1 gene. The human BST-1 gene consisted of nine exons and eight introns. The length of each exon was very similar to that of the Aplysia ADP-ribosyl cyclase gene. The flanking region of the BST-1 gene contained several potential binding sites for nuclear factors, NF-kappa B, p53, NF-IL6, CREB, PEA3, E2A, C/EBP, AP3, AP2 and SP1 and consensus sequences for gamma-IRE and ISRE like element.
    Immunology Letters 01/1997; 54(1):1-4. · 2.37 Impact Factor
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    ABSTRACT: We have previously identified and cloned BST-1 as a molecule which is overexpressed on the bone marrow stromal cell lines derived from patients with rheumatoid arthritis and which has the ability to support the pre-B cell growth. BST-1 is a glycosylphosphatidylinositol-anchored ectoenzyme having ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase activities. In this report, we demonstrate that human BST-1 was expressed on monocytes, granulocytes in the peripheral blood of healthy donors, and macrophages matured in vitro. Cross-linking of BST-1 with a polyclonal anti-BST-1 antibody induced tyrosine phosphorylation of a 130-kDa protein (p130) in the human myeloid cell lines U937 and THP-1. Cross-linking of BST-1 overexpressed on a transfectant induced tyrosine phosphorylation of p130, dephosphorylation of the 100-kDa protein, and growth inhibition. These results suggest that BST-1 can deliver signals into cells and function as a receptor.
    Biochemical and Biophysical Research Communications 12/1996; 228(3):838-45. · 2.28 Impact Factor
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    ABSTRACT: Profilin is a cytoplasmic protein that binds to actin monomer and regulates actin polymerization. In a number of experimental and human glomerular diseases, the mesangial cell expresses alpha-smooth muscle actin and undergoes a phenotypic change to myofibroblast. We used a rat model of mesangial proliferative nephritis induced with antibody to the Thy 1 antigen present on mesangial cells to investigate whether profilin is upregulated. We amplified and sequenced rat profilin cDNA by the reverse-transcribed-polymerase chain reaction (RT-PCR). The nucleotide and amino acid sequences were highly conserved across the mammalian profilins. We raised affinity purified antibody to rat profilin in rabbits immunized with a synthetic profilin peptide (EFTMDLRTKS). At 7 days after disease induction, enhanced expression in both profilin mRNA and protein was demonstrated in the isolated glomeruli by RT-PCR and Western blot analysis. These results suggest that profilin may be involved in the pathogenesis of glomerulonephritis by reorganizing actin cytoskeleton.
    Biochemical and Biophysical Research Communications 06/1996; 222(3):683-7. · 2.28 Impact Factor
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    ABSTRACT: Interleukin 6 (IL-6) and related cytokines, such as leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF) and IL-11 exhibit multiple functions and redundancy in biological activities and play important roles in the immune response, hematopoiesis, the nervous system and acute phase reactions. These IL-6 family cytokines exhibit a similar helical structure, and their receptors are structurally similar and constitute a cytokine receptor super family. In addition, a receptor subunit is shared among these IL-6 related cytokine subfamily receptors, contributing to one of the mechanisms of functional redundancy of cytokine activities and suggesting the presence of a common signal transduction pathway among these receptors. In this review, we describe the structure of the receptors for IL-6 and its related cytokine subfamily members. Furthermore, we propose a novel mechanism for the generation of cytokine diversity, i.e. the complex of a cytokine and one of its receptor subunits act as a novel cytokine on the cells that express the other receptor subunit(s) capable of acting as a receptor for the complex. Finally, we describe a Ras-independent novel signal transduction pathway that utilizes Jak tyrosine kinase family, Stat protein family and yet unidentified H-7-sensitive pathway. This signal transduction pathway is commonly generated through the receptors for a wide range of cytokines and growth factors.
    Stem Cells 06/1994; 12(3):262-77. · 7.13 Impact Factor
  • Toshio Hirano
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    ABSTRACT: Interleukin 6 (IL-6) is a multifunctional cytokine regulating immune response acute phase reaction and hematopoiesis. IL-6 plays a critical role in B cell differentiation to plasma cells and is a potent growth factor for plasmacytoma and myeloma. Abnormal production of IL-6 has been suggested to be involved in polyclonal plasma cell abnormalities and plasma cell neoplasias. The deregulated expression of the IL-6 gene in transgenic mice resulted in the generation of malignant plasmacytoma. Based on these findings, it could be considered that continuous IL-6 gene expression plays an essential role in a multistep oncogenesis of plasma cell neoplasias. The role of IL-6 and its receptor in the generation of plasma cell neoplasias and the mechanisms of the IL-6 gene expression and IL-6 receptor-mediated signal transduction are described.
    International journal of cell cloning 06/1991; 9(3):166-84.
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    ABSTRACT: Activation of c-myc by juxtaposition to an immunoglobulin locus and introduction of the v-abl oncogene act synergistically in generating a mouse plasmacytoma (PC). The question arose whether the effect of v-abl could be attributed to a deregulation of interleukin-6 (IL-6) production or responsiveness, in view of the fact that IL-6 exerts potent growth-stimulatory activity on PC cells. We studied the effect of IL-6 on the in vitro growth of primary PCs induced by pristane alone (TEPCs) or by pristane + A-MuLV (ABPCs). Five of 13 TEPCs and 3 of 7 ABPCs responded to IL-6. Macrophage supernatants prepared from both TEPCs and ABPCs had similar stimulatory effects on PC cells. From 30 primary PCs (including both TEPCs and ABPCs), we established 9 in vitro lines, 2 of which expressed v-abl. All were able to grow on macrophage feeder layers. Three types of behavior could be distinguished on the basis of growth in feeder-free cultures in the presence and absence of IL-6. Group I contained 4 IL-6-dependent lines. Group II contained 2 IL-6-independent lines (one v-abl expressor) that grew faster in the presence of IL-6. Group III consisted of 3 feeder-dependent lines (one v-abl expressor) that were not significantly stimulated by IL-6. These findings indicate that v-abl expression does not influence IL-6 dependence or responsiveness by itself. The supernatant of one line in group II was able to stimulate PC cells. All 6 lines of Groups I and II carried a typical (12;15) translocation, while all 3 lines in group III had a variant (6;15) or (15;16) translocation.
    International Journal of Cancer 06/1991; 48(2):234-8. · 5.01 Impact Factor
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    ABSTRACT: Interleukin-6 (IL-6) signal is transduced through a membrane glycoprotein, gp130, which associates with IL-6 receptor (IL-6-R). A cDNA encoding human gp130 has been cloned, revealing that it consists of 918 amino acids with a single transmembrane domain. The extracellular region comprises six units of a fibronectin type III module, and part of this region of approximately 200 amino acids has features typical of a cytokine receptor family. A cDNA-expressed gp130 showed no binding property to IL-6 or several other cytokines. Although a transfectant with an IL-6-R cDNA expressed mainly low affinity IL-6 binding sites, an increase in high affinity binding sites was observed after cotransfection with a gp130 cDNA. This confirmed that a gp130 is involved in the formation of high affinity IL-6 binding sites. A cloned gp130 could associate with a complex of IL-6 and soluble IL-6-R and transduce the growth signal when expressed in a murine IL-3-dependent cell line.
    Cell 01/1991; 63(6):1149-57. · 33.12 Impact Factor
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    ABSTRACT: Interleukin-6 mediates pleiotropic functions in various types of cells through its specific receptor (IL-6-R), the cDNA of which has already been cloned. We report here that an 80 kd single polypeptide chain (IL-6-R) is involved in IL-6 binding and that IL-6 triggers the association of this receptor with a non-ligand-binding membrane glycoprotein, gp130. The association takes place at 37 degrees C within 5 min and is stable for at least 40 min in the presence of IL-6, but does not occur at 0 degree C. Human IL-6-R can associate with a murine gp130 homolog and is functional in murine cells. Mutant IL-6-R lacking the intracytoplasmic portion is functional, suggesting that the two polypeptide chains interact to involve their extracellular portion. In fact, a soluble IL-6-R lacking the transmembrane and intracytoplasmic domains can associate with gp130 in the presence of IL-6 and mediate its function. These findings indicate that the complex of IL-6 and IL-6-R can interact with a non-ligand-binding membrane glycoprotein, gp130, extracellularly and can provide the IL-6 signal.
    Cell 09/1989; 58(3):573-81. · 33.12 Impact Factor
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    ABSTRACT: Interleukin 6 (IL-6) production from synovial tissues of various diseases was examined. Augmented IL-6 production was found in inflammatory synovium not only in RA but also in other kinds of synovitis, including psoriatic arthritis and Behçet's disease. Increased amounts of IL-6-mRNA were detected in rheumatoid synovium using a dot blot hydridization technique. Furthermore, there was a positive correlation between IL-6 production and accumulation of plasma cells in the synovium. These findings suggest that IL-6 plays an important role not only in immune response but also in active inflammation in various kinds of synovitis.
    Clinical Immunology and Immunopathology 09/1989; 52(2):238-47.
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    ABSTRACT: Interleukin-6 (IL-6) was found to be a growth factor of renal cell carcinomas Furthermore, renal cell carcinomas freshly isolated from the patients expressed mRNA of IL-6 and secreted biologically active IL-6 under the culture conditions where the tumor cells could grow, but they did not produce IL-6 nor proliferate in the absence of fetal calf serum. The production of IL-6 by the tumor cells was also demonstrated by immunostaining of the IL-6-producing cells utilizing anti-IL-6 antiserum. Moreover, anti-IL-6 antiserum specifically inhibited the in vitro tumor growth. All data indicated that IL-6 functions as an in vitro autocrine growth factor of renal cell carcinomas.
    FEBS Letters 08/1989; 250(2):607-10. · 3.34 Impact Factor

Publication Stats

17k Citations
1,132.07 Total Impact Points


  • 2009
    • Kitakyushu University
      • Graduate School of Environmental Engineering
      Kitakyūshū, Fukuoka-ken, Japan
  • 1999–2009
    • Osaka City University
      • Department of Neurosurgery
      Ōsaka, Ōsaka, Japan
    • Kyushu University
      • Graduate School of Information Science and Electrical Engineering
      Hukuoka, Fukuoka, Japan
  • 1993–2009
    • University of Occupational and Environmental Health
      • • Department of Environmental Oncology
      • • Department of Biochemistry
      • • Department of Orthopedics
      Kitakyūshū, Fukuoka, Japan
    • Nara Medical University
      • Department of Internal Medicine
      Nara-shi, Nara, Japan
  • 1987–2003
    • Osaka University
      • • Department of Integrated Medicine
      • • Immunology Division
      • • Division of Cellular and Molecular Biology
      Ōsaka-shi, Osaka-fu, Japan
  • 1997–1998
    • Kyushu Institute of Technology
      • Faculty of Computer Science & Systems Engineering
      Иидзука, Fukuoka, Japan
  • 1995
    • University of Washington Seattle
      • Department of Microbiology
      Seattle, WA, United States
  • 1991
    • RWTH Aachen University
      Aachen, North Rhine-Westphalia, Germany
  • 1990
    • The University of Tokyo
      • Department of Internal Medicine
      Tokyo, Tokyo-to, Japan
    • University of California, Los Angeles
      • Division of Hematology and Medical Oncology
      Los Angeles, CA, United States
  • 1988–1990
      Edo, Tōkyō, Japan
    • Osaka Minami Medical Center
      Ōsaka, Ōsaka, Japan
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1989
    • Shinshu University
      • Department of Pediatrics
      Matsumoto, Nagano-ken, Japan
    • University of Alabama at Birmingham
      • Department of Microbiology
      Birmingham, AL, United States