Faculty Profiles - NAGATSUKA Hitoshi

Papers - NAGATSUKA Hitoshi

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Clinico-pathological evaluation of oral melanotic macule, oral pigmented nevus and oral mucosal melanoma

Rosario Rivera Buery, Chong Huat Siar, Naoki Katase, Masae Fujii, Han Liu, Midori Kubota, Ryo Tamamura, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka

Journal of Hard Tissue Biology 19 ( 1 ) 57 - 64 2010

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL HARD TISSUE BIOLOGY

Focal pigmented melanocytic lesions rarely occur in the oral cavity but should not be taken for granted for they may represent markers or risks for oral mucosal melanoma (OMM). The study investigated the clinical and pathological features of focal pigmented lesions of melanocytic origin focusing on oral melanotic macule (oral MM), oral pigmented nevus (OPN) and OMM. Immunohistochemistry was employed with S100, HMB-45, Melan A, c-kit and Ki-67. Oral MM mostly occurred on the gingiva and buccal mucosa while OPN mostly occurred on the buccal mucosa. OMM occurred on the palate and gingiva. A female gender predilection was observed in oral MM. Most of the benign lesions were less than 6 mm in diameter while OMM had greater than 10 mm in diameter. Benign lesions occurred in almost the same location as that of OMM. S100 and c-kit were detected in most benign cases while HMB-45 and Melan A were focally detected in some cases. S100, HMB-45 and Melan A expressions were detected in all cases of OMM. Ki-67 was only detected at the epithelial basal layer in oral MM and was completely negative in nevus cells. In OMM, Ki-67 was more than 80%. In conclusion, oral MM and OPN may not be markers of risk for OMM but excisional biopsy is highly recommended for clinically undefined lesions greater than 6 mm in diameter. The combination of S100, c-kit, HMB-45 and Melan A can be utilized to support the diagnosis of OMM. © 2010 The Hard Tissue Biology Network Association Printed in Japan.

DOI： 10.2485/jhtb.19.57

Clinicopathological significance of the CRTC3-MAML2 fusion transcript in mucoepidermoid carcinoma International journal

Takahisa Nakayama, Satoru Miyabe, Mitsukuni Okabe, Hidenori Sakuma, Kei Ijichi, Yasuhisa Hasegawa, Hitoshi Nagatsuka, Kazuo Shimozato, Hiroshi Inagaki

Modern Pathology 22 ( 12 ) 1575 - 1581 2009.12

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Mucoepidermoid carcinoma is the most common primary malignancy of the salivary gland. We and others showed that CRTC1-MAML2 gene fusion was associated with favorable clinicopathological tumor features. Recently, a novel gene fusion, CRTC3-MAML2, was reported as a rare gene alteration in a case of mucoepidermoid carcinoma. However, its frequency and clinicopathological significance remains unclear. In all, 101 cases of mucoepidermoid carcinoma and 89 cases of non-mucoepidermoid carcinoma of the salivary gland were analyzed, and RNA was extracted from formalin-fixed, paraffin-embedded specimens. In the CRTC family, there have been three genes, CRTC1, CRTC2, and CRTC3. We developed reverse transcription-polymerase chain reaction (RT-PCR) assays for CRTC1-MAML2, CRTC2-MAML2, and CRTC3-MAML2 fusions. Clinicopathological data of the patients were obtained from their clinical records. Of 101 cases of mucoepidermoid carcinoma, 34 (34%) and 6 (6%) were positive for CRTC1-MAML2 and CRTC3-MAML2 fusion transcripts. However, in the 89 cases of non-mucoepidermoid carcinoma, neither transcript was noted. In the former cases, CRTC1-MAML2 and CRTC3-MAML2 fusions were mutually exclusive. The other fusion, CRTC2-MAML2, was not detected. We confirmed that the clinicopathological features of CRTC1-MAML2-positive mucoepidermoid carcinomas indicated an indolent course. CRTC3-MAML2-positive mucoepidermoid carcinomas also had clinicopathologically favorable features; all cases showed a less advanced clinical stage, negative nodal metastasis, no high-grade tumor histology, and no recurrence or tumor-related death after surgical resection of the tumor. It is interesting to note that patients with CRTC3-MAML2-positive tumors (mean 36 years of age) were significantly younger that those with the CRTC1-MAML2 fusion (55 years) and those with fusion-negative tumors (58 years). In conclusion, CRTC3-MAML2 fusion, which is mutually exclusive with CRTC1-MAML2 fusion and specific to mucoepidermoid carcinoma, may be detected more frequently than previously expected. Mucoepidermoid carcinomas possessing CRTC3-MAML2 fusion may be associated with favorable clinicopathological features and patients may be younger than those with CRTC1-MAML2 fusion or those with no detectable gene fusion. © 2009 USCAP, Inc. All rights reserved.

DOI： 10.1038/modpathol.2009.126

Involvement of focal adhesion kinase in the progression and prognosis of gastrointestinal stromal tumors International journal

Nobuyuki Kamo, Yoshio Naomoto, Yasuhiro Shirakawa, Tomoki Yamatsuji, Seiichi Hirota, Yasuhiro Fujiwara, Kazuhiro Noma, Kazufumi Sakurama, Munenori Takaoka, Hitoshi Nagatsuka, Mehmet Gunduz, Junji Matsuoka, Noriaki Tanaka

Human Pathology 40 ( 11 ) 1643 - 1649 2009.11

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO-ELSEVIER INC

Gastrointestinal stromal tumors often express gene mutations to c-KIT and platelet-derived growth factor receptor-α, both of which result in constitutive activations of their signaling pathways that are quite essential for the proliferation and survival of tumor cells in most clinical gastrointestinal stromal tumors. Targeting these molecules provides a dramatic improvement to therapeutic strategy. To identify a new therapeutic target for gastrointestinal stromal tumor treatment, we focused on focal adhesion kinase, which is reported to be an up-regulated gene in clinical gastrointestinal stromal tumors, because so far no one has examined its expression status at the protein level. In this study, Western blot analysis revealed that all 10 of the examined gastrointestinal stromal tumor tissues strongly expressed focal adhesion kinase protein and that phosphorylated focal adhesion kinase was detected in 9 of them. Next, we assessed the expression status of focal adhesion kinase and phosphorylated focal adhesion kinase in 51 cases of gastrointestinal stromal tumor by immunohistochemistry. Positive stainings for focal adhesion kinase and phosphorylated focal adhesion kinase were confirmed in 44 (86.3%) and in 40 cases (78.4%) of the 51 gastrointestinal stromal tumors, respectively. We further found that the focal adhesion kinase-positive staining rate became higher along with the increased status of malignant behavior. Moreover, when the 51 gastrointestinal stromal tumors were divided into 2 groups based upon their focal adhesion kinase expression status, the 5-year overall survival of patients in the focal adhesion kinase-positive group (66.5%) was significantly poorer than that in the focal adhesion kinase-negative group (100%). These results indicate that the up-regulation of focal adhesion kinase protein may also contribute to the tumor progression of gastrointestinal stromal tumors and that focal adhesion kinase is a potential target for gastrointestinal stromal tumor treatment. © 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2009.05.004

Secreted frizzled related protein (sFRP)-2 inhibits bone formation and promotes cell proliferation in ameloblastoma International journal

Gulsan Ara Sathi, Miho Inoue, Hidemitsu Harada, Andrea P. Rodriguez, Ryo Tamamura, Hidetsugu Tsujigiwa, Silvia S. Borkosky, Mehmet Gunduz, Hitoshi Nagatsuka

Oral Oncology 45 ( 10 ) 856 - 860 2009.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Secreted frizzled related protein (sFRP)-2, a Wnt antagonist, was strongly expressed by both stromal and tumor cells of ameloblastoma. The aim of this study is to evaluate whether sFRP-2 secreted from tumor cells have any direct role in suppressed bone formation or not. A pre-osteoblastic cell line, KUSA/A1 cells, cultured in conditioned medium of an ameloblastoma-derived cell line (AM-1CM) was used in the study. Alkaline phosphatase (ALP) activity, alizarin red staining, mineral quantification and MTS assay was performed. Wnt-canonical pathway is a major pathway for osteoblasts. Antagonists of this pathway, sFRP-1, 2 and 3, were detected by immunohistochemistry and western blot analysis. KUSA/A1 cells cultured in AM-1CM showed high cell proliferation, low ALP activity without mineralized matrix deposition. sFRP-2 was strongly expressed in ameloblastoma tissue and AM-1 cells. After sFRP-2 depletion, the cells showed diffuse mineralization. In this study, it was confirmed that ameloblastoma cells have a major role in decreased bone formation by secreting sFRP-2 in cell culture model. Though, sFRP-2 has great effect on tumor progression, inhibition of sFRP-2's anti-bone formation activity and cell proliferative activity may reduce the invasive property of ameloblastoma and possibility of recurrence rate. © 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.oraloncology.2009.02.001

Localization of antimicrobial peptides human β-defensins in minor salivary glands with Sjögren's syndrome International journal

Yoshihiro Kaneda, Tomoichiro Yamaai, Nobuyoshi Mizukawa, Hitoshi Nagatsuka, Eiki Yamachika, Mehmet Gunduz, Koichi Sawaki, Yuji Yamanishi, Masakazu Matsubara, Naoki Katase, Shin Takagi

European Journal of Oral Sciences 117 ( 5 ) 506 - 510 2009.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

Sjögren's syndrome is a common systemic autoimmune disease associated with inflammatory cells that infiltrate exocrine glands. The antimicrobial peptides human β-defensin-1, human β-defensin-2, and human β-defensin-3 are expressed in various human epithelial cells and in normal salivary glands. Antimicrobial peptides provide local protection against infection and participate in inflammatory responses. Because of the presence of inflammation, we hypothesized that human β-defensin expression in minor salivary glands may be increased in subjects with Sjögren's syndrome. However, the expression of human β-defensins 1 and 2 was decreased in salivary glands affected by Sjögren's syndrome in comparison with the human β-defensin expression patterns in salivary glands from normal subjects. In addition, the reduction in expression of human β-defensin-2 was greater than the reduction in expression of human β-defensin-1. The aforementioned result suggests that the reduction in expression of human β-defensin-2 may occur earlier than the reduction in expression of human β-defensin-1, which may lead to a greater decrease in human β-defensin-2 than in human β-defensin-1 during disease progression. © 2009 Eur J Oral Sci.

DOI： 10.1111/j.1600-0722.2009.00667.x

Establishment of odontoblastic stem cells producing extracellular matrix under in vitro condition

Tsujigiwa H, Katase N, Yamachika E, Nagatsuka H, Rodriguez AP, Harada H, Yamada M

Journal of Hard Tissue Biology 18 ( 3 ) 165 2009.9

Expression of heparanase in odontogenic cystic lesions

Matsuda H, Katase N, Tsujigiwa H, Sathi GSA, Fujii M, Lefeuvre M, Liu H, Tamamura R, Nagatsuka H

Journal of Hard Tissue Biology 18 ( 3 ) 168 - 169 2009.9

Angiogenic squamous dysplasia-like phenomenon in oral epithelial precursor lesions

C. H. Siar, V. P.A. Oo, H. Nagatsuka, K. Nakano, K. H. Ng, T. Kawakami

European Journal of Medical Research 14 ( 7 ) 315 - 319 2009.7

Language：English Publishing type：Research paper (scientific journal) Publisher：I HOLZAPFEL VERLAG GMBH

Statement of the problem: Dysplasia, the morphological yardstick of epithelial precursor lesions, is the collective term for a variety of architectural and cytological changes within the altered oral epithelium. Angiogenic squamous dysplasia (ASD), a distinct morphological characteristic in pre-invasive bronchial lesions, describes the presence of capillary tufts that are closely juxtaposed to and projecting into the dysplastic bronchial epithelium. Objective: To determine whether ASD-like phenomenon occurs in oral epithelial precursor lesions, and to speculate on its relevance. Methods: Twenty cases each of mild, moderate and severe oral dysplasia (inclusive of carcinoma-in-situ), and 10 normal oral mucosa (normal controls) were serial sectioned for H and E staining, and for microvessel density (MVD) scoring with CD31, CD34 and CD105. Microcapillary pattern images were digitally captured for 3-D reconstruction. Results: Oral ASD foci consisting of CD31- and CD34-positive capillary loops abutting onto the overlying dysplastic oral epithelium (and causing it to assume an irregular or papillary surface configuration) were identified in moderate (3/20; 15%) and severe dysplasia (13/20; 65%), but not in normal oral mucosa and mild dysplasia. MVD score demonstrated increasing vascularity as epithelium progressed from normal to severe dysplasia (p<0.05). CD105 demonstrated increase neovascularization in all dysplasia grades (p<0.05). Conclusions: These preliminary findings taken together suggest that: 1. ASD-like phenomenon may be an important intermediary biomarker in oral precursor lesions; and 2. architectural alterations of the entire disturbed mucosa may be a more useful pre-malignancy index. © I. Holzapfel Publishers 2009.

DOI： 10.1186/2047-783x-14-7-315

Loss of heterozygosity at the 9p21-24 region and identification of BRM as a candidate tumor suppressor gene in head and neck squamous cell carcinoma International journal

Esra Gunduz, Mehmet Gunduz, Mahmoud Al Sheik Ali, Levent Beder, Ryo Tamamura, Naoki Katase, Susumu Tominaga, Noboru Yamanaka, Kenji Shimizu, Hitoshi Nagatsuka

Cancer Investigation 27 ( 6 ) 661 - 668 2009.7

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS INC

We have analyzed allelic loss of the short arm of chromosome 9 in 39 head and neck cancers using 13 polymorphic markers and found two deletions of hot spots at 9p21 and 9p24. Loss of heterozygosity was detected at least at one locus in 28 of 39 cases (71.8%). P16, a well-known tumor suppressor gene, is considered to be a target for deletion of the 9p21 region. However, novel frequent chromosomal deletion and a candidate tumor suppressor gene, BRM at the 9p24 region, were detected. Moreover, comparison of clinicopathological variables demonstrated that loss of heterozygosity at the BRM locus was associated with a worse prognosis. Copyright © Informa Healthcare USA, Inc.

DOI： 10.1080/07357900802563010

Dynamic contrast-enhanced magnetic resonance imaging for estimating tumor proliferation and microvessel density of oral squamous cell carcinomas International journal

Teruhisa Unetsubo, Hironobu Konouchi, Yoshinobu Yanagi, Jun Murakami, Masae Fujii, Hidenobu Matsuzaki, Miki Hisatomi, Hitoshi Nagatsuka, Jun ichi Asaumi

Oral Oncology 45 ( 7 ) 621 - 626 2009.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

We evaluated the relationship between histopathological prognostic factors, tumor proliferation microvessel density (MVD), and enhancement parameters in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in oral squamous cell carcinoma (SCC). Twenty-eight T2 and T3 patients with primary oral SCC underwent DCE-MRI using three-dimensional fast imaging with a steady-state precession sequence. Tumor cell proliferation and MVD of all surgical specimens were evaluated using immunohistochemical staining with CD34 and the antibody for proliferating cell nuclear antigen (PCNA). Regression analysis was used to statistically analyze the relationship between the PCNA labeling index or MVD and each of three DCE-MRI parameters: maximum CI (CI-max), maximum CI gain (CI-gain) and the CI-gain / CI-max ratio). The PCNA labeling index and MVD showed significant correlations with the CI-gain/CI-max ratio (P = 0.0012, r = 0.581 and P = 0.00141, r = 0.574, respectively). The assessment of DCE-MRI parameters may prove to be a valuable non-invasive method for assessing tumor cell proliferation and MVD of patients with oral cancer. © 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.oraloncology.2008.09.003

Prognostic Significance of p27^Kip1, Ki-67, and CRTC1-MAML2 Fusion Transcript in Mucoepidermoid Carcinoma: A Molecular and Clinicopathologic Study of 101 Cases International journal

Satoru Miyabe, Mitsukuni Okabe, Hitoshi Nagatsuka, Yasuhisa Hasegawa, Akira Inagaki, Kei Ijichi, Noriyuki Nagai, Tadaaki Eimoto, Motoo Yokoi, Kazuo Shimozato, Hiroshi Inagaki

Journal of Oral and Maxillofacial Surgery 67 ( 7 ) 1432 - 1441 2009.7

Language：English Publishing type：Research paper (scientific journal)

Purpose: Mucoepidermoid carcinoma (MEC) is the most frequently detected primary malignancy of the salivary gland and is characterized by a marked variation in prognosis. In the present study, we investigated the prognostic significance of p27Kip1, Ki-67, and CRTC1 (also called MECT1, TORC1, and WAMTP1)-MAML2 fusion in MEC. Materials and Methods: MEC cases (n = 101) were examined for p27Kip1 and Ki-67 expression using immunohistochemistry and for CRTC1-MAML2 fusion transcript using reverse transcriptase-polymerase chain reaction. Results: p27Kip1, Ki-67, and the CRTC1-MAML2 fusion transcript were expressed in 71, 31, and 34 of the 101 cases, respectively. p27Kip1 and CRTC1-MAML2 fusion were associated with favorable clinicopathologic tumor features and Ki-67 with aggressive clinicopathologic features. Multivariate survival analyses were performed that included the following 10 clinicopathologic factors: age, gender, tumor site, tumor size, nodal metastasis, clinical stage, histologic grade, p27 expression, Ki-67 expression, and CRTC1-MAML2 fusion. For disease-free survival, only p27Kip1 expression was significant as an independent prognostic factor. For overall survival, p27Kip1 expression, CRTC1-MAML2 fusion, and tumor size were significant. In each analysis, p27Kip1 and CRTC1-MAML2 fusion were independent of the clinical stage. Ki-67 expression was not selected in either multivariate analysis. Conclusions: p27Kip1 and CRTC1-MAML2 fusion were associated with favorable clinicopathologic tumor features, and both were useful in predicting the overall survival of patients with MEC. For disease-free survival, p27Kip1 might be the most useful prognostic factor. In contrast, Ki-67 might not be a very powerful prognostic indicator for either survival point. © 2009 American Association of Oral and Maxillofacial Surgeons.

DOI： 10.1016/j.joms.2009.03.021

Increased mRNA expression of ADAMTS metalloproteinases in metastatic foci of head and neck cancer International journal

Kadir Demircan, Esra Gunduz, Mehmet Gunduz, Levent Bekir Beder, Satoshi Hirohata, Hitoshi Nagatsuka, Beyhan Cengiz, Mehmet Zeynel Cilek, Noboru Yamanaka, Kenji Shimizu, Yoshifumi Ninomiya

Head and Neck 31 ( 6 ) 793 - 801 2009.6

Language：English Publishing type：Research paper (scientific journal) Publisher：JOHN WILEY & SONS INC

Background. Although contribution of matrix metalloproteinases in cancer progression and dissemination is now well known, roles of recently discovered metalloproteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), in cancer development and progression remain mostly unknown. Methods. Here we examined the mRNA expression pattern of 6 members of ADAMTS aggrecanases (1, 4, 5, 8, 9, and 15) in primary head and neck cancer with and without metastasis by real-time reverse transcriptase-polymerase chain reaction. Results. Expression levels of ADAMTS mRNAs were lower in the majority of the primary tumors as compared with the controls. On the other hand, the expression levels of all of the ADAMTS mRNAs except ADAMTS4 were higher in the metastatic foci than in their corresponding primary tumors, which suggest that characteristics of the cancer cell population are different in the primary tumor and metastatic focus. Conclusion. Our findings suggest a metastasis model proposing accumulation of a subtype of cancer cells with high metastatic capacity within heterogenous primary tumor cell population. © 2009 Wiley Periodicals, Inc.

DOI： 10.1002/hed.21045

Frequent deletion of ING2 locus at 4q35.1 associates with advanced tumor stage in head and neck squamous cell carcinoma International journal

Silvia S. Borkosky, Mehmet Gunduz, Hitoshi Nagatsuka, Levent Bekir Beder, Esra Gunduz, Mahmoud Al Sheikh Ali, Andrea P. Rodriguez, Mehmet Zeynel Cilek, Susumu Tominaga, Noboru Yamanaka, Kenji Shimizu, Noriyuki Nagai

Journal of Cancer Research and Clinical Oncology 135 ( 5 ) 703 - 713 2009.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Background: Loss of heterozygosity (LOH) in the ING family members has been shown in head and neck squamous cell carcinoma (HNSCC) except for ING2. Like all the other members of ING family, ING2, which is located at chromosome 4q35.1, is a promising tumor suppressor gene (TSG). In this study, we performed LOH analysis of ING2 in HNSCC and compared it with clinicopathological variables. Materials and methods: We performed LOH analysis in DNAs from 80 paired of normal and HNSCC tissues, using a specifically designed microsatellite marker on chromosome 4q35.1, which detects allelic loss of ING2. TP53 mutation analysis and its relationship with ING2 chromosomal deletion were also performed in available 68 of the samples. The correlation between LOH status and clinicopathological characteristics was evaluated by using statistical methods. The overall survival (OS) and disease free survival (DFS) were also determined. Results: LOH was detected in 54.6% (30/55) of the informative samples. Statistical significance was obtained between LOH and tumor (T) stage (P = 0.02), application of radiotherapy and chemotherapy. Positive node status (N) appeared to be the only independent prognostic factor for both OS (P = 0.031) and DFS (P = 0.044). Conclusions: Our study showed allelic loss of 4q35.1 in HNSCC. The high percentage of LOH suggests ING2 as a candidate TSG in HNSCC. High LOH frequency was statistically associated with advanced T stage, suggesting that ING2 LOH might occur in late stages during HNSCC progression. © 2008 Springer-Verlag.

DOI： 10.1007/s00432-008-0507-y

The upregulation of FAK contributes to tumor progression and a resistance to Imatinib in gastrointestinal stromal tumor

Xiaohong Bao, Nobuyuki Kamo, Huifang Hao, Kazufumi Sakurama, Kazuhiro Noma, Yasuhiro Shirakawa, Hitoshi Nagatsuka, Yasuko Tomono, Yasuhiro Fujiwara, Nobuyuki Watanabe, Seishi Nishitani, Toshiaki Ohara, Munenori Takaoka, Tomoki Yamatsuji, Junji Matsuoka, Seiichi Hirota, Shinji Hatakeyama, Osamu Omori, Zhigang Wang, Noriaki Tanaka, Yoshio Naomoto

CANCER RESEARCH 69 2009.5

Recombinant human bone morphogenetic protein-2/atelocollagen composite as a new material for ossicular reconstruction International journal

Ayako Takeuchi, Hidetsugu Tsujigiwa, Jun Murakami, Akihiro Kawasaki, Yasushi Takeda, Kunihiro Fukushima, Andrea P. Rodriguez, Hitoshi Nagatsuka, Masao Yamada, Kazunori Nishizaki

Journal of Biomedical Materials Research - Part A 89 ( 1 ) 36 - 45 2009.4

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Ossicular reconstruction is the rebuilding of the damaged middle ear. There are many different prosthesis and techniques used to reconstruct the middle ear ossicles. However, precision in the surgical procedures and prostheses used for ossiculoplasty are still imperfect. The objective of this study was to evaluate the potential of recombinant human bone morphogenetic protein-2 (rhBMP-2)/atelocollagen composite for ossicular reconstruction implanted in the tympanic cavity of rat. The ossicles were extirpated by perforating the tympanic membranes of rats. rhBMP-2/atelocollagen composite was implanted as substitute of ossicles in intimate contact with the tympanic membrane. Composites were subjected to histological, immunohistochemical, and radiological examination. To evaluate the auditory function, auditory brainstem response (ABR) was measured. rhBMP-2/atelocollagen composites showed good stability and durability without any inflammatory reaction within the tympanic cavity. The process of new bone formation was similar to intramembranous ossification. They also demonstrated that the hearing ability was re-established by ABR threshold shifts. rhBMP-2/atelocollagen composite exhibited excellent potential for ossicular reconstruction, maintaining their vibratory function. This ossicular tissue engineering may be considered as a future therapeutic strategy for ossiculoplasty. © 2008 Wiley Periodicals, Inc.

DOI： 10.1002/jbm.a.31971

Downregulation of TESTIN and its association with cancer history and a tendency toward poor survival in head and neck squamous cell carcinoma International journal

Esra Gunduz, Mehmet Gunduz, Levent Beder, Hitoshi Nagatsuka, Kunihiro Fukushima, Recep Sutcu, Namik Delibas, Noboru Yamanaka, Kenji Shimizu, Noriyuki Nagai

Archives of Otolaryngology - Head and Neck Surgery 135 ( 3 ) 254 - 260 2009.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER MEDICAL ASSOC

Objective: To examine the role of TESTIN as a candidate tumor suppressor gene in head and neck carcinogenesis. Design: Mutation and messenger RNA (mRNA) expression analyses. Setting: Academic research. Patients: Paired normal and tumor samples were obtained from 38 patients with primary head and neck squa- mous cell carcinoma. Main Outcome Measures: Analysis and comparison of TESTIN gene mRNA expression and its relationship to clinicopathologic variables. Results: Mutation analysis showed a nucleotide and amino acid change in 6 of the 38 tumor samples (16.0%). Semiquantitative mRNA expression analysis of TESTIN revealed a decreased expression in approximately 50% of the tumors compared with their matched normal controls. Interestingly, comparison of clinicopathologic vari ables to mRNA expression status of TESTIN revealed a significant difference in terms of cancer history (P = .03). Moreover, a higher smoking ratio and a family cancer history were also associated with downregulation of TESTIN, although the difference was not statistically significant (P =.43 and P =.16, respectively). Kaplan-Meier survival analysis demonstrated a worse survival rate among the patients with low TESTIN expression compared with the patients with normal-high TESTIN expression. Conclusions: Our findings suggest that inactivation of TESTIN is involved in head and neck carcinogenesis through its downregulation. Further studies in various human cancer tissues using a large sample size and in vitro functional studies as well as clinical comparison research studies would give us a better evaluation of TESTINs role and its possible future application in molecular diagnosis and treatment of different cancer types, including head and neck squamous cell carcinoma. © 2009 American Medical Association. All rights reserved.

DOI： 10.1001/archoto.2008.560

Erratum: Expression of human β-defensin -1, -2, and -3 in non-inflamed pseudocyst, mucoceles (Oral Diseases (2008) 7 (652-657))

M. K. Frederic, T. Yamaai, N. Mizukawa, Y. Kaneda, N. Katase, M. Gunduz, H. Nagatsuka, T. Sugahara

Oral Diseases 15 ( 2 ) 183 - 183 2009.3

IDENTIFICATION OF BRM AS A CANDIDATE TUMOR SUPPRESSOR FROM 9P24 REGION IN HEAD AND NECK SQUAMOUS CELL CARCINOMAS

Esra Gunduz, Mehmet Gunduz, Levent Beder, Kadir Dernircan, Ryo Tarnamura, Noboru Yamanaka, Hitoshi Nagatsuka

IUBMB LIFE 61 ( 3 ) 341 - 342 2009.3

The engraftment of transplanted bone marrow-derived cells into the inner ear International journal

Yorihisa Orita, Hidetsugu Tsujigiwa, Kazunori Nishizaki, Takanori Teshima, Junko Yoshinobu, Saeko Orita, Ayako Takeuchi, Yasushi Takeda, Hitoshi Nagatsuka, Noriyuki Nagai

European Archives of Oto-Rhino-Laryngology 266 ( 1 ) 59 - 63 2009.1

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

To investigate whether bone marrow-derived cells (BMC) would migrate and engraft into the sensory epithelium of the inner ear, BMC of green fluorescence protein (GFP) mice were transplanted into lethally irradiated recipient mice. Then the recipient mice were treated with streptomycin and immunohistochemical staining was performed to evaluate the migration and engraftment of donor BMC into the sensory epithelium of the inner ear. Immunohistochemical staining for GFP was found initially in the vascular epithelium and oral mucosa but not in the sensory epithelium of the inner ear. In the case of mouse, BMC may not migrate and be engrafted into the sensory epithelium of the inner ear. © 2008 Springer-Verlag.

DOI： 10.1007/s00405-008-0725-6

Fine deletion analysis of 1p36 chromosomal region in oral squamous cell carcinomas International journal

Mathieu Lefeuvre, Mehmet Gunduz, Hitoshi Nagatsuka, Esra Gunduz, Mahmoud Al Sheikh Ali, Levent Beder, Kunihiro Fukushima, Noboru Yamanaka, Kenji Shimizu, Noriyuki Nagai

Journal of Oral Pathology and Medicine 38 ( 1 ) 94 - 98 2009.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

Background: Squamous cell carcinoma is the most common cancer type of the oral cavity and approximately 50% of the patients succumb to the disease. Unfortunately, few are known about the molecular mechanisms involving in the formation of oral squamous cell carcinoma (OSCC). Recently, it has been reported that 1p36 chromosomal region is deleted in various cancer types and is suspected to harbor various tumor suppressor genes (TSGs). However, limited studies exist on genetics alteration on 1p36 in OSCC and the responsible TSG remained unidentified. Methods: To investigate area susceptible to harbor TSG(s) involved in OSCC on 1p36 region, paired normal and tumor tissues of 27 patients with diagnosis of OSCC have been analyzed for loss of heterozygosity (LOH) using nine microsatellite markers based on recent gene mapping. Results: LOH was found at least in one locus in 85% of the cases (23 of 27). Interestingly, microsatellite instability was also found in 7% (two of 27) of the cases analyzed. The higher LOH frequencies were found with the markers D1S243 (25%), D1S468 (22%), D1S450 (25%), D1S228 (38%), D1S199 (28%), and D1S1676 (23%). Conclusions: Three preferentially deleted regions have been identified in OSCC: region 1 (D1S468-D1S243), region 2 (D1S450-D1S228), and region 3 (D1S199-D1S1676). Multiple candidate TSGs, such as RIZ1, p73, UBE4B, Rap1GAP, EPHB2, and RUNX3, are located in these three areas. The data obtained in this study can be used for further functional analysis of these genes involved in OSCC carcinogenesis. © 2008 The Authors.

DOI： 10.1111/j.1600-0714.2008.00666.x

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