Takashi Saku

Niigata University, Niahi-niigata, Niigata, Japan

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Publications (169)295.76 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We have reported that neutrophilic infiltration was associated with round-shaped dyskeratosis foci, a kind of keratin pearl, of oral carcinoma in situ and that those inflammatory cells are recruited from intra-epithelially entrapped blood vessels. Based on these lines of evidence, we have formulated a hypothesis that keratin pearls are terminally degraded by neutrophils. To confirm this hypothesis, we investigated immunohistochemically stepwise degradation of keratin pearls in oral squamous cell carcinoma (SCC) to clarify any other type scavenger cells in addition to neutrophils are involved in this particular degradation process.
    Journal of Oral Pathology and Medicine 06/2014; · 2.06 Impact Factor
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    ABSTRACT: Background We have demonstrated the induction of perlecan-rich stroma of oral squamous cell carcinoma (SCC) on and after its start of invasion. However, it remains unknown how such a neoplastic stroma is actually arranged in tumor tissues.Methods To this end, tissue microarray samples, in which keratin and perlecan were contrastively labeled by immunohistochemistry, were three-dimensionally analyzed using digital images and image analysis software to demonstrate the relationship between SCC foci and the perlecan-positive stromal space or that between carcinoma in situ (CIS) and invasive SCC foci.ResultsThe three-dimensional (3D) reconstruction demonstrated three kinds of perlecan profiles for inside (I) and outside (O) areas of the carcinoma cell focus: mode 1, I+/O−; mode 2, I+/O+; and mode 3, I−/O+. Mode 1 was seen in CIS as well as SCC tumor massifs in the surface part. Mode 2 was seen in small SCC foci, which seemed isolated in 2D sections but were mostly continuous with the tumor massif in 3D reconstructions. Mode 3 was limited to small SCC foci, which were truly segregated from the tumor massif.Conclusions The results indicated that the 2D SCC focus isolation could not be regarded as invasion but that the SCC foci surrounded by perlecan-positive stroma (modes 2 and 3) could be regarded as a more objective measure for invasion of SCC. This is the first 3D tissue-level demonstration of the neoplastic stroma space induced with oral SCC invasion, the presence of which we have predicted based on our previous 2D and tissue culture evidence.
    Journal of Oral Pathology and Medicine 04/2014; · 2.06 Impact Factor
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    ABSTRACT: Periodontitis involves periodontal tissue destruction and is associated with chronic inflammation and ageing. Periodontitis has recently been recognised as a risk factor for Alzheimer's disease (AD). We showed upregulation of molecules in the AD pathway including amyloid beta (A4) precursor protein (APP), a key gene in AD, interleukin-1 beta (IL-1β), and complement component 1 (q subcomponent, A chain) (C1QA) in periodontitis compared to healthy tissues. Here, we quantitatively analysed the expression levels of APP, IL-1β, and C1QA and determined the localisation of APP in gingival tissues. Fourteen chronic periodontitis patients and 14 healthy participants were enrolled. Six samples of total RNA from two distinct sites of healthy and periodontitis-affected gingival tissues from three randomly selected patients were used for microarray analyses, and significant biological pathways in periodontitis were identified. Differential gene expression of APP, IL-1β, and C1QA, which belong to the AD pathway, were analysed with quantitative reverse transcription real-time polymerase chain reaction (qRT-PCR) using samples from these 14 chronic periodontitis patients and 14 healthy controls. APP localisation was analysed with immunohistochemistry. APP, IL-1β, and C1QA mRNA levels were significantly upregulated in periodontitis-affected gingival tissues. APP was mainly localised in macrophages in gingival connective tissues underneath the epithelial layers. An association between AD and periodontitis was detected with microarray and computer-aided data mining analyses. qRT-PCR identified differential gene expression in periodontitis-affected gingival tissue that may be related to AD pathogenesis. Elevated APP, IL-1β, and C1QA transcripts and APP-expressing macrophages in periodontitis-affected gingival tissues were observed, suggesting a relationship between periodontitis and AD pathogenesis.
    Archives of oral biology 03/2014; 59(6):586-594. · 1.65 Impact Factor
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    ABSTRACT: The aim of this study was to demonstrate the presence of intraepithelial stroma represented by extracellular matrix (ECM) deposits in the junctional epithelium to clarify its function as a scaffold for leukocyte migration through epithelial cells. Twenty-three biopsy specimens from the gingiva including the junctional epithelium were examined to determine comparative protein and gene level expression profiles for keratin and ECM molecules between the junctional epithelium and the gingival epithelium using immunohistochemistry and in situ hybridization. Intraepithelial leukocyte types and frequencies were also determined and compared between the junctional and gingival epithelia. In the junctional epithelium, which was positive for keratin 19, perlecan was strongly deposited in intercellular space of the whole epithelial layer, while it was faintly positive around the parabasal layer of the gingival epithelium. Perlecan mRNA signals were enhanced to a greater degree in both epithelial and inflammatory cells within the junctional epithelium. In the junctional epithelium, greater numbers of neutrophils and macrophages were found as compared with the gingival epithelium. Our results showed that perlecan is the primary ECM molecule comprising intraepithelial stroma of the junctional epithelium, in which leukocytes may migrate on ECM scaffolds in intercellular space toward the surface of the gingival sulci or pockets.
    Histochemie 02/2014; · 2.61 Impact Factor
  • Takashi Saku
    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology. 01/2014;
  • Takashi Saku
    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology. 01/2014;
  • Takashi Saku
    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology. 01/2014;
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    ABSTRACT: We report a rare case of radiation-induced undifferentiated high-grade pleomorphic sarcoma (UPS) (malignant fibrous histiocytoma, MFH) in the right mandible of a 44-year-old woman. The patient had suffered from osteomyelitis of the same region of the mandible for several years, which was considered to be due to radiotherapy for a malignant lymphoma in her right neck 19 years before. The tumor appeared as an exophytic and invasive growth in the molar region of the mandible. Histopathologically, the tumor consisted of an interlacing proliferation of vimentin-immunopositive spindle-shaped fibroblastic cells with bizarre nuclei with high Ki-67 labeling scores, and tumor cells showed storiform patterns mixed with pleomorphic cells. Taking the history of radiation into consideration, we diagnosed the lesion as radiation-induced UPS. Including the present case, there have been only 14 documented cases of radiation-induced UPS in the jawbone, and this is the first case arising in the follow-up period of long-standing osteomyelitis.
    Pathology - Research and Practice 01/2014; · 1.21 Impact Factor
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    ABSTRACT: Background. Local recurrence remains a challenging clinical issue for the treatment of oral squamous cell carcinoma (SCC). We analyzed retrospectively how effective the frozen section technique (FS) was against recurrences of oral SCC. Methods. We screened 343 surgical samples from 236 patients who had oral SCC, carcinoma in situ (CIS), or epithelial dysplasia, and we followed up their clinical outcomes for at least 5 years. Histopathological states of surgical margins were compared between FS and surgical materials in relapse and relapse-free groups, respectively. Results. Among the 236 patients, 191 were classified into the relapse-free group, and 45 into the relapse group. FS was more frequently performed in the relapse-free group (128/191) than in the relapse group (83/152). Histopathologically, moderate dysplasia or CIS (borderline malignancies) and SCC were recognized in 55 samples of the relapse-free group and in 57 of the relapse group. For those surgical margins with borderline malignancies, additional incisions were performed in 38 of the 55 relapse-free cases, which reduced to 20 from the 38 margins with borderline malignancies (47.4% reduction), and in 39 of the 57 relapse cases, which reduced to only 3 of 39 (7.7% reduction). Conclusions. The intraoperative assessment of surgical margins by FS is essential in preventing recurrences of oral mucosal malignancies.
    BioMed Research International 01/2014; 2014:823968. · 2.88 Impact Factor
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    ABSTRACT: Hybrid odontogenic tumors including 2 or more different histologic types have been documented, but their occurrences are not very common. We present a case of hybrid odontogenic tumor composed of ameloblastoma and adenomatoid odontogenic tumor (AOT) arising in the mandibular molar region of a 31-year-old Japanese woman who had a history of familial adenomatous polyposis. The tumor, measuring 10 mm in diameter, was surgically removed from the alveolar bone. Histopathologically, the tumor consisted of both follicular and plexiform types of ameloblastoma in which multiple and smaller foci of AOT were intermingled. There have been 3 reported cases of hybrid ameloblastoma and AOT, all of which presented unicystic types as ameloblastoma components. This, however, is the first report of a hybrid tumor containing an authentic solid-type ameloblastoma compartment and an AOT compartment in a patient with a background of familial adenomatous polyposis.
    Oral surgery, oral medicine, oral pathology and oral radiology. 11/2013;
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    ABSTRACT: Keratocystic odontogenic tumor (KCOT), a developmental jaw cyst previously referred to as odontogenic keratocyst (OKC), typically arises in the jawbone. In this article, however, we report a case of KCOT located within the temporalis muscle. We compared its immunohistochemical profiles with those of authentic jaw KCOT, orthokeratinized odontogenic cyst, and epidermoid cyst in order to consider whether a soft tissue counterpart of KCOT could be a separate disease entity. The patient was a 46-year-old man with a well-defined cystic lesion within the left temporalis muscle. On computed tomographic images, the lesion was recognized as a cystic lesion, although KCOT was not included in the clinical differential diagnoses. The location of the lesion was not within bone but, rather, within the temporalis muscle that was attached to the jawbones. Our review of the literature has disclosed more than 20 peripheral KCOT cases of the oral mucosa and more than 10 cases of the skin, but only 1 case arising in muscle. Immunohistochemical investigation of the present intramuscular case reveals KCOT-characteristic profiles distinct from the other 3 types of cysts investigated. The results indicate that KCOT-like lesions can arise within soft tissues, although use of the term odontogenic might seem inappropriate in those cases.
    Human pathology 10/2013; · 3.03 Impact Factor
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    ABSTRACT: To examine the histopathological characteristics of inflammatory lesions containing Actinomyces based on DNA sequencing. Furthermore, case reports of actinomycosis in the maxillofacial region are summarized by a review of the literature. The study comprised 12 cases of inflammatory lesions containing Actinomyces as diagnosed by DNA analysis. The average age of the subjects was 59 ± 15 years (6 males; 6 females). The distribution of causative bacteria was: Actinomyces israelii in 9 cases, Actinomyces gerencseriae in 2 cases, and Actinomyces naeslundii in 1 case. Four cases diagnosed by DNA sequencing were positive for "Druse," a known morphological diagnostic characteristic of actinomycosis, and 8 cases lacked typical colony formation. DNA analysis using paraffin-embedded samples is effective for both early and accurate diagnosis of oral lesions containing Actinomyces.
    Oral surgery, oral medicine, oral pathology and oral radiology. 10/2013; 116(4):485-91.
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    ABSTRACT: IL-17RA, a member of the interleukin (IL)-17 receptor family, is a single membrane-spanning protein that ubiquitously expressed on the cell surface. IL-17RA transduces IL-17A, IL-17F, and IL-17A/F heterodimer-mediated signals by forming a complex with IL-17RC, and also signals the IL-17E (also known as IL-25) response in combination with IL-17RB (also known as IL-25R). Previously, soluble isoforms of human IL-17RC and IL-17RB have been reported, but the existence of a soluble isoform of human IL-17RA has remained unclear. Here, we report the identification of a soluble isoform of human IL-17RA at the mRNA and protein levels. Reverse transcribed PCR experiments showed that the IL-17RA variant is generated by spliced out of exon 11 encoding the transmembrane region in a variety of human tissues. The soluble IL-17RA isoform was detected in the culture media of human cell lines by Western blotting. The existence of the soluble IL-17RA isoform sheds new light on the regulation of IL-17RA mediated responses.
    Cytokine 09/2013; · 2.52 Impact Factor
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    ABSTRACT: Podoplanin (PDPN), one of the representative mucin-like type-I transmembrane glycoproteins specific to lymphatic endothelial cells, is expressed in various cancers including squamous cell carcinoma (SCC). On the basis of our previous studies, we have developed the hypothesis that PDPN functions in association with the extracellular matrix (ECM) from the cell surface side. The aim of this study was to elucidate the molecular role of PDPN in terms of cell adhesion, proliferation, and migration in oral SCC cells. Forty-four surgical specimens of oral SCC were used for immunohistochemistry for PDPN, and the expression profiles were correlated with their clinicopathological properties. Using ZK-1, a human oral SCC cell system, and five other cell systems, we examined PDPN expression levels by immunofluorescence, western blotting, and real-time PCR. The effects of transient PDPN knockdown by siRNA in ZK-1 were determined for cellular functions in terms of cell proliferation, adhesion, migration, and invasion in association with CD44 and hyaluronan. Cases without PDPN-positive cells were histopathologically classified as less-differentiated SCC, and SCC cells without PDPN more frequently invaded lymphatics. Adhesive properties of ZK-1 were significantly inhibited by siRNA, and PDPN was shown to collaborate with CD44 in cell adhesion to tether SCC cells with hyaluronan-rich ECM of the narrow intercellular space as well as with the stromal ECM. There was no siRNA effect in migration. We have demonstrated the primary function of PDPN in cell adhesion to ECM, which is to secondarily promote oral SCC cell proliferation.Laboratory Investigation advance online publication, 1 July 2013; doi:10.1038/labinvest.2013.86.
    Laboratory Investigation 07/2013; · 3.96 Impact Factor
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    ABSTRACT: Signals of perlecan, an extracellular matrix molecule, which accumulates within the intercellular spaces of the stellate reticulum of the enamel organ, are mediated by at least two receptors, dystroglycan (DG) and integrin β1, in a case-dependent manner in various events in embryogenesis and pathogenesis. This study aims to understand the expression profiles of these two perlecan receptors at both protein and gene levels in murine enamel organ development. Before birth, α-DG was immunolocalized in stellate reticulum cells, in which perlecan was colocalized, while integrin β1 was mainly distributed in the peripheral enamel organ cells as well as the dental mesenchymal cells. On and after postnatal Day 1, the expression of α-DG was dramatically decreased in the stellate reticulum, while integrin β1 was enhanced around blood vessels within the enamel organ. Furthermore, biosyntheses of α-DG and integrin β1 by dental epithelial and pulp mesenchymal cells were confirmed in-vitro by using immunofluorescence and reverse-transcriptase polymerase chain reaction. The results suggest that DG is a perlecan receptor that specifically functions in the stellate reticulum of the embryonic stage, but that dental epithelial and mesenchymal cells are maturated by capturing perlecan signals differentially through integrin β1.
    Gene Expression Patterns 05/2013; · 1.64 Impact Factor
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    ABSTRACT: In previous studies, we have shown several lines of evidence that podoplanin (PDPN) plays an important role in cell adhesion via its association with extracellular components in neoplastic conditions, though there has been no trial for searching PDPN-interaction molecules in the extracellular milieu. To screen for those molecules, we performed proteomics-based analysis using liquid chromatography-tandem mass spectrometry followed by co-immunoprecipitation for PDPN in ZK-1, an oral squamous cell carcinoma (SCC) cell system whose cell membrane molecules were cross-linked each other in their extracellular compartments, and we identified heat shock protein (HSP) A9 as one of the extracellular PDPN bound molecules. Effects of transient PDPN knockdown by siRNA in ZK-1 were also comparatively examined for cellular behaviors in terms of HSPA9 expression and secretion. Finally, HSPA9 expression modes were immunohistochemically visualized in oral SCC tissue specimens. HSPA9 was secreted from ZK-1 cells, and the expression and secretion levels of HSPA9 gene and protein were well coordinated with those of PDPN. Immunohistochemically, HSPA9 and PDPN were co-localized in ZK-1 cells and oral SCC foci, especially in the peripheral zone. In conclusion, the results indicate that HSPA9 secreted by oral SCC cells interacts with PDPN on their cell surface in an autocrine manner and regulates their growth and invasiveness.
    Biochemical and Biophysical Research Communications 03/2013; · 2.41 Impact Factor
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    ABSTRACT: Although the histopathogenetic process of keratin pearls is still poorly understood, acceleration of keratinization in squamous cell carcinoma (SCC) cells may represent one possible therapeutic avenue. Based on our histopathological observations, we have hypothesized that SCC cells are keratinized by phagocytosis of extravasated erythrocytes. To confirm this hypothesis, we firstly examined immature keratin pearls in oral carcinoma in-situ (CIS) and mature ones in SCC by immunohistochemistry. Concentric dyskeratotic cells in CIS keratin pearls became positive for keratin (K) 10, K17, heme oxygenase-1 (HO-1), or protease activated receptor-2 (PAR-2), a candidate regulator for hemophagocytosis. When ZK-1 cells, a SCC cell system, were incubated with human peripheral blood erythrocytes, or with crude and purified hemoglobins (Hbs), their erythro-hemophagocytotic activities were confirmed by immunofluorescence. Immunofluorescence signals for K10, K17 and HO-1 were enhanced due to hemophagocytosis in time-dependent manners. mRNA expression levels for the three molecules were most enhanced by purified Hb, followed by crude Hb and erythrocytes. K17/K10 mRNA expression levels were more elevated when PAR-2 was activated in ZK-1 cells. The results indicated that immature and mature keratin pearls in CIS and SCC were generated by oxidative stresses derived from erythro-hemophagocytosis, which might mediate HO-1 expression and be regulated by PAR-2. Thus, hemorrhage from the rupture of blood vessels can be one of the triggers for keratin pearl formation in oral CIS and SCC. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 03/2013; · 4.22 Impact Factor
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    ABSTRACT: OBJECTIVE: It is known that tumour necrosis factor (TNF)-α converting enzyme (TACE) plays a crucial role in fibrotic inflammatory diseases, and is specifically inhibited by tissue inhibitor of metalloproteinase (TIMP)-3. Fibrotic drug-induced gingival overgrowth (GO) is often combined with periodontitis. However, neither TACE nor TIMP-3 has been thoroughly examined in periodontal tissues to date. The aim of the present study was to analyse mRNA expression of TACE and TIMP-3, and protein localisation of TACE in gingival tissues removed from drug-(calcium-channel blocker) induced GO and periodontitis. METHODS: A total of 30 gingival tissue samples were taken from 15 GO and 15 periodontitis patients. The mRNA expression levels were analysed by quantitative reverse transcription polymerase chain-reaction (qRT-PCR) and the protein localisation was investigated by immunohistochemistry. Statistical analysis was performed using the Mann-Whitney U-test. RESULTS: TACE and TIMP-3 mRNA levels were significantly higher in GO compared to the periodontitis groups, as revealed by qRT-PCR (p<0.05). TACE-producing cells were immunohistochemically detected among monocytes/macrophages, plasma cells and some epithelial cells. TACE immunoreactivity was shown to be more intense in GO than in periodontitis-gingival tissue. CONCLUSIONS: We have demonstrated TACE expression in cells such as macrophages, plasma cells and epithelial cells, and its predominant expression in GO tissues. This data suggests that TACE expression in GO-gingiva could be involved in the pathogenesis of disease.
    Archives of oral biology 03/2013; · 1.65 Impact Factor
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    ABSTRACT: A case of solitary central neurofibroma of the mandible arising in a 70-year-old man is reported. The patient had a radiolucent lesion, measuring 16 mm in diameter, with central radiopaque freckles in the right incisor–canine region of the mandible, which was discovered incidentally during routine dental check-up. The lesion was persisted for 10 years without any symptoms or complication. It was clinically diagnosed as benign tumor and surgically removed under general anesthesia. Histologically, the removed tumor was relatively well demarcated and composed of a sparse proliferation of elongated spindleshaped cells with wavy nuclei in loosely textured connective tissue stroma, which was associated with bone formation. Clinicopathological features of central neurofibroma of the jaw bone are reviewed from the literature. This is the first report of central neurofibroma arising in the anterior part of the mandible.
    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology. 01/2013;
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    ABSTRACT: Objectives Oral lichen planus (OLP) is characterized by a subepithelial lymphocytic infiltration. To find the correlation between vascular and inflammatory reaction, the expressions of vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), CD34, and CD68 were investigated. Materials and methods 30 cases of OLP and 20 normal oral tissues samples were subjected to immunohistochemistry for VEGF, iNOS, CD34 and CD68. CD34-positive (+) blood vessels (microvessel density, MVD), degree of lymphocytic infiltration, and CD68+ macrophages were correlated with the expression of VEGF and iNOS. OLP cases were histopathologically subdivided into active (non erosive and erosive/ulcerative) and non-active stages. Results Expression of VEGF was observed in all epithelial layers of OLP while iNOS was in basal and parabasal layers. They were significantly higher (P < 0.001) than those in controls. The mean MVD (CD34+) was significantly increased in all cases of OLP (P < 0.05), especially in the active (erosive/ulcerative) stage (P < 0.01) compared with controls. The mean number of CD68+ cells was significantly increased (P < 0.01) in OLP, especially higher in the active (erosive/ulcerative) OLP (P < 0.001). The expressions of VEGF (P < 0.05) and iNOS (P < 0.01) were significantly correlated in OLP. There was significant positive correlations between the lymphocytic infiltration and the expressions of VEGF and iNOS (P < 0.05), MVD (P < 0.01), and CD68 counts (P < 0.001) in OLP. Conclusion The present results indicated that the upregulation of VEGF and iNOS plays an important role in pathogenesis of OLP through activated angiogenesis and chronic inflammatory cell infiltrates. Novel strategies directed to inhibition of these markers could be developed for OLP treatment.
    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology. 01/2013;

Publication Stats

2k Citations
295.76 Total Impact Points

Institutions

  • 1994–2014
    • Niigata University
      • • Department of Tissue Regeneration and Reconstruction
      • • Division of Oral Pathology
      • • Division of Oral and Maxillofacial Radiology
      • • Division of Oral and Maxillofacial Surgery
      • • Department of Pathology
      Niahi-niigata, Niigata, Japan
  • 2011
    • Ministry of Health - Myanmar
      Nay Pyi Taw, Mandalay, Myanmar
    • University of Aberdeen
      Aberdeen, Scotland, United Kingdom
  • 2009
    • King Faisal University
      Al Hadā, Makkah, Saudi Arabia
    • University of Peradeniya
      • Department of Oral Pathology
      Kandy, Central Province, Sri Lanka
  • 2007–2009
    • University of Jordan
      • Faculty of Dentistry
      Amman, Amman, Jordan
  • 2004–2009
    • Sichuan University
      • • West China School of Stomatology
      • • Department of Pathology
      Chengdu, Sichuan Sheng, China
  • 2002
    • The University of Tokyo
      • Department of Biotechnology
      Tokyo, Tokyo-to, Japan
  • 1992
    • Tokyo Medical and Dental University
      Edo, Tōkyō, Japan
  • 1984–1990
    • Nagasaki University
      • Department of Pathology
      Nagasaki-shi, Nagasaki-ken, Japan
  • 1989
    • Yale University
      • School of Medicine
      New Haven, CT, United States