Kazuyuki Tobe

University of Toyama, Тояма, Toyama, Japan

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Publications (276)1463.03 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have highlighted the renoprotective effect of sirtuin1 (SIRT1), a deacetylase that contributes to cellular regulation. However, the pathophysiologic role of SIRT1 in podocytes remains unclear. Here, we investigated the function of SIRT1 in podocytes. We first established podocyte-specific Sirt1 knockout (SIRT1(pod-/-)) mice. We then induced glomerular disease by nephrotoxic serum injection. The increase in urinary albumin excretion and BUN and the severity of glomerular injury were all significantly greater in SIRT1(pod-/-) mice than in wild-type mice. Western blot analysis and immunofluorescence showed a significant decrease in podocyte-specific proteins in SIRT1(pod-/-) mice, and electron microscopy showed marked exacerbation of podocyte injury, including actin cytoskeleton derangement in SIRT1(pod-/-) mice compared with wild-type mice. Protamine sulfate-induced podocyte injury was also exacerbated by podocyte-specific SIRT1 deficiency. In vitro, actin cytoskeleton derangement in H2O2-treated podocytes became prominent when the cells were pretreated with SIRT1 inhibitors. Conversely, this H2O2-induced derangement was ameliorated by SIRT1 activation. Furthermore, SIRT1 activation deacetylated the actin-binding and -polymerizing protein cortactin in the nucleus and facilitated deacetylated cortactin localization in the cytoplasm. Cortactin knockdown or inhibition of the nuclear export of cortactin induced actin cytoskeleton derangement and dissociation of cortactin from F-actin, suggesting the necessity of cytoplasmic cortactin for maintenance of the actin cytoskeleton. Taken together, these findings indicate that SIRT1 protects podocytes and prevents glomerular injury by deacetylating cortactin and thereby, maintaining actin cytoskeleton integrity. Copyright © 2014 by the American Society of Nephrology.
    Journal of the American Society of Nephrology : JASN. 11/2014;
  • American Journal of Respiratory and Critical Care Medicine 11/2014; 190(9):e30-1. · 11.04 Impact Factor
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    ABSTRACT: Although phenotypically polarized macrophages are now generally classified into two major subtypes termed proinflammatory M1 and anti-inflammatory M2 macrophages, a contributory role of lung M2 macrophages in the pathophysiological features of acute lung injury is not fully understood. Herein, we show in an endotoxemic murine model that M2 macrophages serve as key anti-inflammatory cells that play a regulatory role in the severity of lung injury. To study whether M2 macrophages can modify inflammation, we depleted M2 macrophages from lungs of CD206-diphtheria toxin (DT) receptor transgenic (Tg) mice during challenge with lipopolysaccharide. The i.p. administration of DT depleted CD206-positive cells in bronchoalveolar lavage fluid. The use of M2 macrophage markers Ym1 and arginase-1 identified pulmonary CD206-positive cells as M2 macrophages. A striking increase in neutrophils in bronchoalveolar lavage fluid cell contents was found in DT-treated CD206-DT receptor Tg mice. In CD206-DT receptor Tg mice given DT, endotoxin challenge exaggerated lung inflammation, including up-regulation of proinflammatory cytokines and increased histological lung damage, but the endotoxemia-induced increase in NF-κB activity was significantly reduced, suggesting that M2 phenotype-dependent counteraction of inflammatory insult cannot be attributed to the inhibition of the NF-κB pathway. Our results indicate a critical role of CD206-positive pulmonary macrophages in triggering inflammatory cascade during endotoxemic lung inflammation.
    The American Journal of Pathology. 10/2014;
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    ABSTRACT: Aims and background. It is reported that about 20% of patients with small cell lung cancer (SCLC) receive third-line chemotherapy. We conducted a retrospective study to investigate the outcome and prognostic factors of patients with SCLC who receive third-line chemotherapy. Methods and study design. The medical records of patients with SCLC who received third-line chemotherapy at our institution were reviewed. Overall survival (OS) from the initiation of third-line chemotherapy was evaluated, and the association between OS and patient characteristics was assessed by the log-rank test. Results. A total of 73 patients with SCLC were treated with cytotoxic drugs between 2004 and 2012, and 19 patients received third-line chemotherapy. Median OS from initiation of third-line chemotherapy was 8.5 months. Patients with higher body mass index (BMI) (P = 0.0071), lower levels of lactate dehydrogenase (LDH) (P = 0.0036), higher levels of hemoglobin (P = 0.048), longer time to progression (TTP) from the initiation of second-line treatment (P = 0.0036), and better response to second-line treatment (P = 0.029) had longer duration of OS. Conclusions. It is suggested that TTP and tumor response in second-line chemotherapy, serum levels of LDH and hemoglobin, and BMI at initiation of third-line chemotherapy could be possible prognostic factors.
    Tumori. 09/2014; 100(5):507-11.
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    ABSTRACT: The usefulness of the Palliative Prognostic Index (PPI) has been successfully validated in a variety of clinical settings. However, while lung cancer is the leading cause of death worldwide, patients with lung cancer accounted for only 6.9-25.8 % of the study populations in these previous studies. We conducted a retrospective study to evaluate the usefulness of the PPI for survival prediction in patients with lung cancer. Patients with lung cancer who were admitted to our hospital between 2009 and 2013 to receive palliative care were enrolled. The association between the Palliative Prognostic Index, determined based on the data recorded in the clinical charts at the last admission to our hospital, and survival was evaluated. The patient group with a PPI of >6 showed a significantly shorter survival time than the patient group with a PPI of ≤6 (P < 0.0001, log-rank test). The sensitivity and specificity of the PPI determined using the cutoff value of 6 for predicting less than 3 weeks of survival were 61.3 and 86.8 %, respectively. However, the sensitivity decreased to 50.0 % when the assessment was carried out in only patients with small cell lung carcinoma. Our findings suggest the existence of a close association between the PPI and survival in patients with lung cancer receiving palliative care. However, the sensitivity of the index for predicting less than 3 weeks of survival was relatively low in patients with small cell lung carcinoma.
    Medical oncology (Northwood, London, England). 09/2014; 31(9):154.
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    ABSTRACT: Central venous catheterization at the femoral site is associated with higher complication rates of infections and thrombosis than at the jugular or subclavian sites. However, the procedure of insertion at the femoral site is considered safer. We present a unique but dangerous positioning of a left femoral central venous catheter into the iliolumbar vein. We were aware of this accidental cannulation by chance when our patient underwent bone scintigraphy. Although a few cases were reported about accidental cannulation into the ascending lumbar vein, this is the first case where a femoral central venous catheter was misplaced into the iliolumbar vein.
    Clinical nuclear medicine. 08/2014;
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    ABSTRACT: The efficacy of docetaxel, vinorelbine, or gemcitabine monotherapy in previously untreated elderly patients with non-small cell lung cancer has been reported.Pemetrexed monotherapy has shown clinically equivalent efficacy to docetaxel, a standard therapeutic option, in patients with previously treated non-small cell lung cancer and in those with a lower incidence of toxicity such as febrile neutropenia.
    Gan to kagaku ryoho. Cancer & chemotherapy 07/2014; 41(7):849-52.
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    ABSTRACT: NAD biosynthesis is of substantial interest owing to its important roles in regulating various biological processes. Nicotinamide mononucleotide adenylyltransferase 3 (Nmnat3) is considered a mitochondria- localized NAD synthesis enzyme involved in de novo and salvage pathways. Although the biochemical properties of Nmnat3 are well documented, its physiological function in vivo remains unclear. In this study, we demonstrated that Nmnat3 was localized in the cytoplasm of mature erythrocytes and critically regulated their NAD pool. Deficiency of Nmnat3 in mice caused splenomegaly and hemolytic anemia, which was associated with the findings that Nmnat3-deficient erythrocytes had markedly lower ATP levels and shortened lifespans. However, NAD level in other tissues were not apparently affected by the deficiency of Nmnat3. LC-MS/MS based metabolomics revealed that the glycolysis pathway in Nmnat3-deficient erythrocytes was blocked at glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step because of the shortage of co-enzyme NAD. Stable isotope tracer analysis further demonstrated that deficiency of Nmnat3 resulted in glycolysis stall and a shift to pentose phosphate pathway. Our findings indicate the critical roles of Nmnat3 in maintenance of the NAD pool in mature erythrocytes and the physiological impacts at its absence in mice.
    Journal of Biological Chemistry 04/2014; · 4.65 Impact Factor
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    ABSTRACT: Orogenital ulcer is one of the clinical manifestations of Behçet's disease (BD). However, orogenital ulcer may be observed in various conditions, such as complex aphthous dermatitis and herpes simplex virus infections. Therefore, orogenital ulcer along with skin lesions, including acne or erythema nodosum, may be misdiagnosed as BD, but is actually pseudo-BD instead. We report here a case of pseudo-BD due to Mycobacterium tuberculosis infection in which anti-tuberculous treatment resulted in complete resolution. Furthermore, we review the literature regarding the association of BD and M. tuberculosis infection.
    Rheumatology International 03/2014; · 2.21 Impact Factor
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    ABSTRACT: In recent years, several oral antidiabetic drugs with new mechanisms of action have become available, expanding the number of treatment options. Sodium/glucose cotransporter-2 (SGLT2) inhibitors are a new class of oral antidiabetic drugs with an insulin-independent mechanism promoting urinary glucose excretion. We report the results of a combined Phase 2 and 3 clinical study (Japic CTI-101349) of the SGLT2 inhibitor tofogliflozin (CSG452, RG7201) in Japanese patients with type 2 diabetes mellitus. The efficacy and safety of tofogliflozin were assessed in this multicenter, placebo-controlled, randomized, double-blind parallel-group study involving 230 patients with type 2 diabetes mellitus with inadequate glycemic control on diet/exercise therapy. Between 30 October 2010 and 28 February 2012, patients at 33 centers were randomized to either placebo (n = 56) or tofogliflozin (10, 20, or 40 mg; n = 58 each) orally, once daily for 24 weeks. The primary efficacy endpoint was the change from baseline in HbA1c at week 24. Overall, 229 patients were included in the full analysis set (placebo: n = 56; tofogliflozin 10 mg: n = 57; tofogliflozin 20 and 40 mg: n = 58 each). The least squares (LS) mean change (95% confidence interval) from baseline in HbA1c at week 24 was -0.028% (-0.192 to 0.137) in the placebo group, compared with -0.797% (-0.960 to -0.634) in the tofogliflozin 10 mg group, -1.017% (-1.178 to -0.856) in the tofogliflozin 20 mg group, and -0.870% (-1.031 to -0.709) in the tofogliflozin 40 mg group (p < 0.0001 for the LS mean differences in all tofogliflozin groups vs placebo). There were also prominent decreases in fasting blood glucose, 2-h postprandial glucose, and body weight in all tofogliflozin groups compared with the placebo group. The main adverse events were hyperketonemia, ketonuria, and pollakiuria. The incidence of hypoglycemia was low. Furthermore, most adverse events were classified as mild or moderate in severity. Tofogliflozin 10, 20, or 40 mg administered once daily as monotherapy significantly decreased HbA1c and body weight, and was generally well tolerated in Japanese patients with type 2 diabetes mellitus. Phase 3 studies were recently completed and support the findings of this combined Phase 2 and 3 study.Trial registration: This study was registered in the JAPIC clinical trials registry (ID: Japic CTI-101349).
    Cardiovascular Diabetology 03/2014; 13(1):65. · 4.21 Impact Factor
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    ABSTRACT: Objective: To evaluate long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes as monotherapy or in combination with other oral antidiabetic agents, we conducted 52-week, open-label, randomized controlled trials. Research design and methods: The single-agent trial included patients with inadequate glycemic control on diet and exercise, whereas the add-on trial included those uncontrolled with any of the oral antidiabetic agents. In both trials, patients were randomly assigned to receive tofogliflozin 20 or 40 mg once daily orally for 52 weeks. Main outcome measures: Safety assessments. Results: A total of 194 patients (65, 20-mg group; 129, 40-mg group) were enrolled into the single-agent trial, whereas 602 (178 and 424, respectively) were enrolled into the add-on trial. Tofogliflozin was well tolerated for 52 weeks in both trials with < 6% of treatment discontinuation because of adverse events in each treatment group. It also reduced hemoglobin A1c. In the single-agent trial, mean reductions at 52 weeks were 0.67 and 0.66% in the 20- and 40-mg groups, respectively. In the add-on trial, mean reductions ranged from 0.71 to 0.93% across the subgroups by dose and background therapy. Conclusion: Tofogliflozin was well tolerated and showed sustained efficacy in both trials.
    Expert Opinion on Pharmacotherapy 03/2014; 15(6). · 2.86 Impact Factor
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    ABSTRACT: Diabetes mellitus is the leading cause of blindness and end-stage renal disease. To understand the pathogenesis of diabetic complications, suitable animal models for this disease have been needed. The activation of Ca2+/ calmodulin-dependent protein kinase II (CaMKII) in pancreatic β-cells has been thought to play a central role in Ca2+-mediated insulin secretion. We generated transgenic mice over expressing the constitutively active-type CaMKIIα (Thr286Asp) in β-cells, which showed very high plasma glucose levels and exhibited the features of diabetic nephropathy and retinopathy. In cDNA microarray analysis osteopontin mRNA increased in CaMKIIα transgenic mice. In quantitative real-time RT-PCR analyses, not only M1 macrophage marker genes but also M2 macrophage marker genes were over expressed in renal cortex of CaMKIIα transgenic mice. The mice were crossed with conditional knockout mice in which platelet-derived growth factor receptor-β gene (Pdgfr-β) was deleted postnatal. The increased oxidative stress in the kidneys of the CaMKII α transgenic mice, which was shown by the increased urinary 8-hydroxydeoxyguanosine excretion and the increased expression of NAD (P) H oxidase 4, was decreased by Pdgfr-β deletion. The CaMKIIα (Thr286Asp) transgenic mice will be valuable as a novel model of severe insulin-dependent diabetes accompanied by an early progression of diabetic micro vascular complications.
    Austin Journal of Endocrinology and Diabetes. 01/2014; 1(1):9.
  • Revue du Rhumatisme. 01/2014;
  • Joint Bone Spine. 01/2014;
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    ABSTRACT: Aims/IntroductionThe objective of the present study was to clarify the validity of β-cell function-related parameters for predicting the insulin requirement of Japanese type 2 diabetic patients. Materials and Methods In 188 patients with type 2 diabetes who had been admitted to the University of Toyama Hospital (Toyama, Japan) without receiving insulin therapy, we carried out a cross-sectional study examining the relationship between the homeostasis model assessment of β-cell function (HOMA-β) and C-peptide-based indices, and also carried out a retrospective study to examine the utility for predicting insulin requirement of several β -cell function-related indices using a receiver operating characteristic (ROC) curve analysis. ResultsThe secretory units of islets in transplantation index (SUIT) had the strongest correlation with HOMA-β, followed by the fasting serum C-peptide immunoreactivity index (CPI); the fasting serum C-peptide immunoreactivity itself (F-CPR) had the least correlation. The CPI, HOMA-β and SUIT were significantly lower in the insulin-requiring group than in the non-insulin-requiring group, even after adjustments for confounding factors (P < 0.01). The areas under the ROC curve for insulin requirement were 0.622, 0.774, 0.808, and 0.759 for F-CPR, CPI, SUIT, and HOMA-β, respectively. The cut-off values of SUIT, CPI, and HOMA-β for an over 80% specificity for the prediction of insulin therapy were 23.5, 1.00, and 14.9, respectively. Conclusions The present study shows that SUIT is the best predictor of insulin requirement among these β-cell function-related markers.
    Journal of Diabetes Investigation. 12/2013;
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    ABSTRACT: Objective:The objective of this study was to clarify the generation and gender differences in the association between central obesity and the accumulation of metabolic risk factors (RFs) in the Japanese population.Material and methods:A total of 12 389 subjects (age: 18-80 years) without receiving medication for diabetes, dyslipidemia or hypertension were enrolled in this study and divided according to age and gender. In each group, we performed analyses as follows: (1) a receiver operating characteristic (ROC) analysis to evaluate the utility of the waist circumference (WC) for detecting subjects with multiple RFs of metabolic syndrome (MS); (2) a cross-sectional study to examine the relationship between the WC and the odds ratio (OR) for detecting those subjects and (3) a longitudinal study to examine how longitudinal changes (Δ) in WC over a 1-year period affected the values of each metabolic RF.Results:With age, the WC cutoff values yielding the maximum Youden index for detecting subjects with multiple RFs increased only in women, and the areas under the curves of the ROC analysis of WC for detecting those subjects decreased in both genders. The positive correlation between the WC and the OR for detecting subjects with multiple RFs became weaker with age, especially in women. In the longitudinal study, the significant correlation between ΔWC and Δ each metabolic RF, except for hypertension, and between ΔWC and Δ the number of RFs became weaker with age in women, whereas the significant correlation between ΔWC and Δ the number of RFs was not affected with age in men. In women aged 60 years, none of the changes in each metabolic RF were significantly associated with ΔWC.Conclusions:Aging attenuates the association of central obesity with the accumulation of metabolic RFs, especially in women.
    Nutrition & Diabetes 11/2013; 3:e96.
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    ABSTRACT: East Asian genome-wide association studies (GWAS) for type 2 diabetes identified 8 loci with genome-wide significance, and 2 loci with a borderline association. However, the associations of these loci except MAEA locus with type 2 diabetes have not been evaluated in independent East Asian cohorts. We performed a replication study to investigate the association of these susceptibility loci with type 2 diabetes in an independent Japanese population. We genotyped 7,379 Japanese participants (5,315 type 2 diabetes and 2,064 controls) for each of the 9 single nucleotide polymorphisms (SNPs), rs7041847 in GLIS3, rs6017317 in FITM2-R3HDML-HNF4A, rs6467136 near GCCI-PAX4, rs831571 near PSMD6, rs9470794 in ZFAND3, rs3786897 in PEPD, rs1535500 in KCNK16, rs16955379 in CMIP, and rs17797882 near WWOX. Because the sample size in this study was not sufficient to replicate single SNP associations, we constructed a genetic risk score (GRS) by summing a number of risk alleles of the 9 SNPs, and examined the association of the GRS with type 2 diabetes using logistic regression analysis. With the exception of rs1535500 in KCNK16, all SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. The GRS constructed from the 9 SNPs was significantly associated with type 2 diabetes in the Japanese population (p = 4.0 × 10(-4), OR = 1.05, 95% confidence interval: 1.02-1.09). In quantitative trait analyses, rs16955379 in CMIP was nominally associated with a decreased homeostasis model assessment of β-cell function and with increased fasting plasma glucose, but neither the individual SNPs nor the GRS showed a significant association with the glycemic traits. These results indicate that 9 loci that were identified in the East Asian GWAS meta-analysis have a significant effect on the susceptibility to type 2 diabetes in the Japanese population.
    PLoS ONE 09/2013; 8(9):e76317. · 3.53 Impact Factor
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    ABSTRACT: ContextGenome-wide association studies (GWAS) have identified over 60 susceptibility loci for type 2 diabetes (T2D). Although the ability of previous genetic information (∼40 loci) to discriminate between susceptible and non-susceptible individuals is limited, the added benefit of updated genetic information has not been evaluated.Objective We assessed the clinical utility of GWAS-derived T2D susceptibility variants in a Japanese population.Design and settingA cross-sectional case-control study.ParticipantsT2D cases (n = 2,613) and controls (n = 1,786) with complete genotype data for 49 SNPs were selected for analyses.Outcome MeasuresWe constructed genetic risk scores (GRSs) by summing the susceptibility alleles of 49 SNP loci for T2D (GRS-49) or 10 SNP loci with genome-wide significant association in previous Japanese studies (GRS-10), and examined the association of the GRSs with the disease by receiver operating characteristic (ROC) analyses using a logistic regression model.ResultsThe GRS-49 was significantly associated with T2D (p = 8.75 × 10(-45)). The area under the curve (AUC) for GRS-49 alone (model-1) and for age, sex, and BMI (model-2) was 0.624 and 0.743, respectively. Addition of the GRS-49 to model-2 resulted in a small but significant increase in the AUC (ΔAUC = 0.03, p = 7.99 × 10(-15)). ROC-AUC was greater for GRS-49 than for GRS-10 (0.624 vs. 0.603, p = 0.019), whereas the odds ratio per risk allele was smaller for GRS-49 than for GRS-10 (GRS-49; 1.13, 95% confidence interval (CI) 1.11-1.15, GRS-10; 1.26, 95% CI 1.22-1.31, p = 7.31 × 10(-10)). The GRS-49 was significantly associated with age at diagnosis in 1,591 cases (β = -0.199, p = 0.0069) and with fasting plasma glucose in 804 controls (β = 0.009, p = 0.021).Conclusions Updated genetic information slightly improves disease prediction ability, but is not sufficiently robust for translation into clinical practice.
    The Journal of Clinical Endocrinology and Metabolism 08/2013; · 6.31 Impact Factor
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    Journal of the American Geriatrics Society 06/2013; 61(6):1043-4. · 4.22 Impact Factor
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    ABSTRACT: Pituitary adenylate cyclase-activating polypeptide (PACAP) has been known as a neuroprotectant agent in several retinal injury models. However, a detailed mechanism of this effect is still not well understood. In this study, we examined the retinoprotective effects and associated underlying mechanisms of action of PACAP in the mouse N-methyl-D-aspartic acid (NMDA)-induced retinal injury model, focusing on the relationship between PACAP and retinal microglia/macrophage (MG/MΦ) status. Adult male C57BL/6 mice received an intravitreal injection of NMDA to induce retinal injury. Three days after NMDA injection, the number of MG/MΦ increased significantly in the retinas. The concomitant intravitreal injection of PACAP suppressed NMDA-induced cell loss in the ganglion cell layer (GCL) and significantly increased the number of MG/MΦ. These outcomes associated with PACAP were attenuated by cotreatment with PACAP6-38, while the beneficial effects of PACAP were not seen in interleukin-10 (IL-10) knockout mice. PACAP significantly elevated the messenger RNA levels of anti-inflammatory cytokines such as transforming growth factor beta 1 and IL-10 in the injured retina, with the immunoreactivities seen to overlap with markers of MG/MΦ. These results suggest that PACAP enhances the proliferation and/or infiltration of retinal MG/MΦ and modulates their status into an acquired deactivation subtype to favor conditions for neuroprotection.
    Journal of Molecular Neuroscience 05/2013; · 2.89 Impact Factor

Publication Stats

15k Citations
1,463.03 Total Impact Points

Institutions

  • 2011–2014
    • University of Toyama
      • Department of Internal Medicine 3
      Тояма, Toyama, Japan
  • 2012–2013
    • St. Marianna University School of Medicine
      • Department of Internal Medicine
      Kawasaki, Kanagawa-ken, Japan
  • 1987–2013
    • The University of Tokyo
      • • Department of Diabetes and Metabolic Diseases
      • • Faculty & Graduate School of Medicine
      • • Department of Internal Medicine
      • • Division of Internal Medicine
      Edo, Tōkyō, Japan
  • 2009–2012
    • Toyama University
      Тояма, Toyama, Japan
  • 2010
    • Asahi General Hospital
      Asahi, Chiba, Japan
  • 2006–2008
    • Central Institute for Experimental Animals
      Kawasaki Si, Kanagawa, Japan
  • 2001
    • Tokyo Medical University
      • Animal Research Center
      Edo, Tōkyō, Japan
  • 1999–2001
    • Okayama University
      Okayama, Okayama, Japan
    • Osaka City University
      • Graduate School of Medicine
      Ōsaka-shi, Osaka-fu, Japan
  • 2000
    • Chiba University
      Tiba, Chiba, Japan
  • 1996
    • Kyoto University
      • Institute for Virus Research
      Kyoto, Kyoto-fu, Japan
  • 1992
    • Gifu Pharmaceutical University
      • Department of Biology
      Gihu, Gifu, Japan