Faculty Profiles - NAGATSUKA Hitoshi

Papers - NAGATSUKA Hitoshi

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Comprehensive loss of heterozygosity analysis and identification of a novel hotspot at 3p21 in salivary gland neoplasms

Noriyasu Honjo, Mehmet Gunduz, Kunihiro Fukushima, Beyhan Cengiz, Levent B. Beder, Esra Gunduz, Hitoshi Nagatsuka, Jing Xiao, Kenji Shimizu, Kazunori Nishizaki

Otolaryngology - Head and Neck Surgery 137 ( 1 ) 119 - 125 2007.7

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY-ELSEVIER

Objectives: We sought to assess loss of heterozygosity (LOH) profiles of 3p, 6q, 8q, 10q, 12q, 13q, and 17p and to identify the tumor suppressor genes involved in salivary gland neoplasms. Study Design: LOH analysis was performed using 26 microsatellite markers by polymerase chain reaction-polyacrylamide gel electrophoresis method in 20 benign and 6 malignant salivary gland tumors. Results: Overall, LOH was detected in at least one informative locus in 18 of 20 (90%) of benign tumors and in all of 6 cases of malignant tumors. High LOH frequencies were revealed at the loci D3S1307 (22%, 3p26), D3S966 (41%, 3p21), D6S255 (27%, 6q25), D8S166 (25%, 8q12), D8S199 (21%, 8q24), and D10S1765 (28%, 10q23) in benign tumors, defining the hotspot regions for putative tumor suppressor genes. Conclusions and Significance: The hotspot regions defined by the present study suggest that new tumor suppressor genes related to the development of salivary gland tumors may reside at several chromosomal loci, including loci at 3p, 6q, 8q and 10q. © 2007 American Academy of Otolaryngology-Head and Neck Surgery Foundation.

DOI： 10.1016/j.otohns.2007.01.017

Depletion of O⁶-methylguanine-DNA methyltransferase by O ⁶-benzylguanine enhances 5-FU cytotoxicity in colon and oral cancer cell lines

Jun Murakami, You Jin Lee, Susumu Kokeguchi, Hidetsugu Tsujigiwa, Jun Ichi Asaumi, Hitoshi Nagatsuka, Kazuhiro Fukui, Masahiro Kuroda, Noriaki Tanaka, Nagahide Matsubara

Oncology Reports 17 ( 6 ) 1461 - 1467 2007.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PROFESSOR D A SPANDIDOS

O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme whose expression is controlled by its promoter methylation. A cell that expresses a low amount of MGMT is known to be more sensitive to the antiproliferative effects of alkylating agents. We have previously shown that the colorectal cancer patients treated with 5-fluorouracil (5-FU) as adjuvant chemotherapy had a better prognosis when the tumor revealed hypermethylation in its MGMT promoter. Therefore, we sought to investigate the relationship between the expression levels of MGMT and the antitumor effect of 5-FU in vitro by using two colon adenocarcinoma and four oral cancer cell lines with a variety of MGMT expression. We also investigated the effects of MGMT depletion by O 6-benzylguanine (O6-BG), a potent inhibitor of MGMT. The 5-FU treatment uniformly depleted protein and mRNA expression of MGMT in all cell lines examined. Cell lines expressing low levels of MGMT were sensitive to 5-FU. On the other hand, cells expressing high levels of MGMT were less sensitive to 5-FU. The 5-FU treatment exhibited a better antiproliferative effect on the cells expressing high levels of MGMT by the pretreatment of O 6-BG. Depletion of MGMT by O6-BG enhanced the antitumor effect of 5-FU. Assessment of the levels of MGMT expression in cancer cells and the control of its expression could contribute to the effective chemotherapy by 5-FU especially in patients who previously were considered as low-responsive individuals whose tumors have high levels of MGMT.

DOI： 10.3892/or.17.6.1461

Translocation of heparanase into nucleus results in cell differentiation

Tetsuji Nobuhisa, Yoshio Naomoto, Takaomi Okawa, Munenori Takaoka, Mehmet Gunduz, Takayuki Motoki, Hitoshi Nagatsuka, Hidetsugu Tsujigiwa, Yasuhiro Shirakawa, Tomoki Yamatsuji, Minoru Haisa, Junji Matsuoka, Junichi Kurebayashi, Motowo Nakajima, Shun'ichiro Taniguchi, Junji Sagara, Jian Dong, Noriaki Tanaka

Cancer Science 98 ( 4 ) 535 - 540 2007.4

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

We recently reported that heparanase, one of the extracellular matrix-degrading enzymes, which plays a critical role in cancer progression, is located not only in the cytoplasm but also in the nucleus. Here we identified nuclear translocation of heparanase as a key step in cell differentiation. We applied an in vitro differentiation model of HL-60 cells with 12-0-tetradecanoylphorbol-13-acetate (TPA), in which nuclear translocation of heparanase was observed using immunohistochemical analysis. In this system, nuclear translocation of heparanase was abolished by inhibitors of heat shock protein 90 (HSP90), suggesting the involvement of HSP90 in translocation of heparanase. We further confirmed that overexpression of active form of heparanase induced differentiation of HL-60 cells, although the catalytic negative form of heparanase did not. Therefore we speculate that nuclear translocation of enzymatically active heparanase may be involved in cellular differentiation. Our results suggest that a novel function of heparanase upon cell differentiation would raise a potential new strategy for cancer therapy of promyeloid leukemia and other types of cancer. © 2007 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2007.00420.x

An immunohistochemical evaluation of BMP-2, -4, osteopontin, osteocalcin and PCNA between ossifying fibromas of the jaws and peripheral cemento-ossifying fibromas on the gingiva

Akiko Ono, Goichi Tsukamoto, Hitoshi Nagatsuka, Yasuto Yoshihama, Rosario Santos Rivera, Miki Katsurano, Mayumi Yao, Akira Sasaki

Oral Oncology 43 ( 4 ) 339 - 344 2007.4

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

The present study examined histological difference between ossifying fibromas (OF, n = 5) and peripheral cemento-ossifying fibromas (PCOF, n = 7). Bone morphogenetic proteins (BMP)-2 and -4, osteopontin (OPN), osteocalcin (OCN) and proliferating cell nuclear antigen (PCNA) were used for the immunohistochemical examinations. Oxytalan fibers present at the periodontal tissue were stained to determine the tumor cell origin. Many OFs showed high immunohistochemical reactions for BMP-2, -4 and OPN compared to those of PCOFs. PCNA index (IP) of OFs was significantly higher than that of PCOFs. All the PCOFs showed a high expression of oxytalan fibers. Only two OFs exhibited a small number of oxytalan fibers. These results suggest that PCOF has only little ability to form hard tissue and seems to be a reactive lesion. The expression of oxytalan fibers reveals that OF does not only originate from periodontal tissue. © 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.oraloncology.2006.03.017

Fine deletion mapping of chromosome 2q21-37 shows three preferentially deleted regions in oral cancer

Beyhan Cengiz, Mehmet Gunduz, Hitoshi Nagatsuka, Levent Beder, Esra Gunduz, Ryo Tamamura, Naila Mahmut, Kunihiro Fukushima, Mahmoud Al Sheikh Ali, Yoshio Naomoto, Kenji Shimizu, Noriyuki Nagai

Oral Oncology 43 ( 3 ) 241 - 247 2007.3

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

We analysed the loss of heterozygosity (LOH) of long arm of chromosome 2 by using 16 polymorphic microsatellite markers in 39 matched oral normal and cancer tissues, and defined the deletional mapping of the region with putative tumor suppressor genes. LOH was detected at least one location in 33 of 39 (85%) tumor tissues. Frequent deletions were detected at the locations of microsatellite markers, D2S2304 (35%), D2S111 (40%), D2S155 (35%), D2S1327 (29%), D2S164 (29%), D2S125 (68%) and D2S140 (32%). Three preferentially deleted regions at 2q21-24, 2q33-35 and 2q37.3 were observed. Several candidate tumor suppressor genes in these regions such as LRP1B, CASP8, CASP10, BARD1, ILKAP, PPP1R7, and ING5, are located. Further molecular analysis of each gene should be performed to clarify their roles in oral carcinogenesis. © 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.oraloncology.2006.03.004

Mechanism of bone induction by KUSA/A1 cells using atelocollagen honeycomb scaffold International journal

Tsujigiwa Hidetsugu, Rodriguez Andrea Paola, Nagatsuka Hitoshi, Gunduz Mehmet, Lee You Jin, Silvia S. Borkosky, Missana Liliana, Nagai Noriyuki

Journal of Biomedical Science 14 ( 2 ) 255 - 263 2007.3

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

In order to induce new bone formation, mesenchymal stem cells were seeded onto atelocollagen honeycomb scaffold. We evaluated the mechanism of bone induction by KUSA/A1 cells combined with honeycomb atelocollagen scaffold. Scaffold alone, KUSA/A1 cells alone and with scaffold were implanted in the subcutaneous pockets of 4-week-old male SCID mice. The transplants were subjected to radiographical, histological and immunohistochemical examinations after 2 and 4 weeks of implantation. Radiographically, both KUSA/A1 cells alone and KUSA/A1-Scaffold showed some radiopaque areas formation but the latter disclosed a larger amount. Scaffold alone did not show any radiopacity. Histologically, Scaffold alone demonstrated only fibrous connective tissues in the periphery of the scaffold. KUSA/A1 cells alone showed few small islands of new bone formation surrounded by a thin layer of cellular proliferation. On the other hand, KUSA/A1-Scaffold revealed abundant new bone formation as well as cellular proliferation. We also determined the immunolocalization of type I collagen, CD34, Osteocalcin and PCNA in this newly formed bone. Our results indicated that less amount of stem cells are capable to induce the more amount of new bone in tissue engineering. This study support that atelocollagen honeycomb scaffold plays an important role in cellular anchorage and in vessel invasion, giving the precise shape and size for the new bone formation. © 2006 National Science Council Taipei.

DOI： 10.1007/s11373-006-9124-4

Original: Wnt5a Overexpression in Thick Primary Oral Mucosal Melanomas: Implications for its Role in Tumor Progression

Jing Xiao, Hitoshi Nagatsuka, Ryo Tamamura, Rosario Santos Rivera, Naoki Katase, Noriyuki Nagai, Chong Huat Siar, Kok Han Ng, Keisuke Nakano, Toshiyuki Kawakami, Masashi Inoue, Kojun Setsu

Journal of Hard Tissue Biology 16 ( 2 ) 79 - 86 2007

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

Wnt genes encode a large family of secreted cysteine-rich signaling molecules involved in cell growth, differentiation and tumorigenesis. Wnt5a, a non-transforming member of the Wnt family behaves as a putative oncogene in many cancers including melanomas. The aim of our study was to determine Wnt5a expression in primary oral mucosal melanomas (OMM) and correlate it with tumor thickness. Archival tissues from 18 OMM cases were subjected to immunohistochemical detection of Wnt5a by the streptavidin-biotin method. These were categorized into tumors of &lt
4 mm (thin and intermediate thickness lesions) and &gt
4 mm (thick lesions) thickness. Most OMM cases (17/18
94.4%) stained positive for Wnt5a, though heterogeneously. Seven thick (7/11
64%) and one intermediate thickness (1/7, 14%) OMM demonstrated strongly positive Wnt5a staining (P&lt
0.05). The only Wnt5a-negative case was a thick OMM without local recurrence after treatment. Strong Wnt5a expression at tumor advancing sites suggests a role in local tumor spread. Identification of pleomorphic epithelioid and spindle cells as melanoma cell populations with the most pronounced Wnt5a staining suggests that Wnt5a overexpression influences cellular phenotype. These results taken together suggest that Wnt5a is upregulated in OMM and may play a role in tumor progression. © 2007, THE SOCIETY FOR HARD TISSUE REGENERATIVE BIOLOGY. All rights reserved.

DOI： 10.2485/jhtb.16.79

Deletion mapping OF 2q21-37 region in oral cancer

Cengiz, M. Gunduz, H. Nagatsuka, L. B. Beder, E. Gunduz, N. Nagai

CHROMOSOME RESEARCH 15 202 - 202 2007

The Study of Palatal Cell Proliferation and Apoptosis in Retinoic Acid Induced Mouse Cleft Palate Varied with Different Developmental Stage

Xiao Jing, Cong Wei, Wang Ru, Wang Bo, Wang Fu, Zhu En-xin, Hu Hailong, Katase Naoki, Nagatsuka Hitoshi

Journal of hard tissue biology 16 ( 3 ) 125 - 130 2007

Language：English Publisher：The Society of Hard Tissue Biology

To determine the mechanisms and patterns of cleft palate induced by varied retinoic acid (RA) in different developmental stages of secondary palate, we detected the cell proliferation and apoptosis of palatal shelves by BrdU and TUNEL labeling on gestation day (GD) 10 and GD12 which RA was exposed, respectively. In GD 10 RA treated group, the percentage of BrdU positive cells of embryonic palatal mesenchyme were lower than control group, while TUNEL expression was higher than control group. No significant difference was detected in GD12 RA treated group and in control group either in embryonic palatal mesenchyme or medial edge epithelium by BrdU and TUNEL labeling. Our data indicated that the mechanisms of RA induced cleft palate in the early developmental stage were the inhibition of proliferation of palatal mesenchymal cells and medial edge epithelium cells, as well as excessive induction of apoptosis.

DOI： 10.2485/jhtb.16.125

Other Link： http://search.jamas.or.jp/link/ui/2008174217

Role of Heparanase in the Release of Heparan Sulphate Binding Growth Factors in Odontogenic Tumors

Hanu Phuu Pwint, Nagatsuka Hitoshi, Tamamura Ryo, Katase Naoki, Bernard Lefeuvre Mathieu, Hu Hailong, Takagi Shin, Ishida Nobuhisa, Nakano Keisuke, Kawakami Toshiyuki, Gunduz Mehmet

Journal of hard tissue biology 16 ( 1 ) 23 - 30 2007

Language：English Publisher：The Society of Hard Tissue Biology

Immunolocalization of heparan sulphate(HS) and heparanase was evaluated in benign and malignant odontogenic tumors in order to know whether these molecules have potential roles in odontogenic tumorigenesis. Archival formalin-fixed, paraffin-embedded tissues of 6 human tooth germs, 7 adenomatoid odontogenic tumors, 10 ameloblastic fibromas, 20 ameloblastomas and 4 ameloblastic carcinomas were subjected to immunohistochemical staining using antibodies to HS, heparanase and BMP-4. HS was ubiquitously localized in tooth germ but heparanase and BMP-4 were observed in limited areas only. In benign epithelial tumors such as ameloblastoma and adenomatoid odontogenic tumor, these molecules were localized in neoplastic epithelium but in ameloblastic fibroma, positive reactions were observed in both epithelial and mesenchymal cells. Stromal localization of HS and BMP-4 accompanied by intense immunoexpression of epithelial heparanase was observed in ameloblastic carcinoma,and this may represent the malignant progression of ameloblastoma to ameloblastic carcinoma. Stronger intensity and more diffuse localization of heparanase in odontogenic tumors compare to that of human tooth germ was the most significant finding. Taken together, the results inferred that heparanase may be responsible for the growth and progression of odontogenic tumors by modulating the availability and function of HS binding growth factors and the derangement in immunoexpression and localization of HS and heparanase molecules may have important roles in progression of malignant odontogenic tumors.

DOI： 10.2485/jhtb.16.23

Other Link： http://search.jamas.or.jp/link/ui/2007329823

Characterization and Gene Expression Profiling of Human Mesenchymal Stem Cells

Mori Hiroki, Itano Yoshitaro, Kobayashi Naoya, Kosaka Yoshikazu, Tanaka Noriaki, Nagatsuka Hitoshi, Inoues Masahisa, Setsu Kojun, Nakanishi Tohru

Journal of hard tissue biology 16 ( 1 ) 36 - 41 2007

Language：English Publisher：The Society of Hard Tissue Biology

Human bone marrow mesenchymal stem cells (hMSCs), one of the tissue stem cells, have the ability to differentiate into adipocytes, osteoblasts or chondrocytes, leading to the attempt to apply these stem cells to regeneration of bone and cartilage. To analyze characteristics of these cells and explain pluripotency of hMSCs, we analyzed gene expression profiles of hMSC clones by using DNA chips that contain over 10,000 genes per chip. We also analyzed their proliferation rates and cell surface markers. As a result, these hMSC clones showed various proliferation rates indicating that hMSCs contains multiple types of cells in their population. Furthermore, analysis of surface markers, especially analysis of CD34 and CD44 showed that these stem cells are not hematopoietic stem cells but mesenchymal origin. Profiling of gene expression by using DNA chip showed that several genes were specifically expressed in hMSCs, and the highest expression was observed in clone no. 12 showing that this clone possesses unique characters as a MSC applicable to regeneration research and regenerative medicine.

DOI： 10.2485/jhtb.16.36

Other Link： http://search.jamas.or.jp/link/ui/2007329825

Original: Origin of Osteoblasts Involved in the Mechanism of Ectopic Bone Formation Induced by KUSA/A1 Cells with Honeycomb Carrier

Andrea Rodriguez, Silvia Borkosky, Hitoshi Nagatsuka, Hidetsugu Tsujigiwa, Phuu Pwint Han, Mika Okauchi, Ryo Tamamura, Noriyuki Nagai, Hailong Hu, Keisuke Nakano, Toshiyuki Kawakami

Journal of Hard Tissue Biology 16 ( 2 ) 75 - 78 2007

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

The basic principle of bone tissue engineering is to use seeded stem cells in porous scaffold. Stem cells can proliferate and differentiate into various types of mature cells. A kind of stem cell called KUSA/A1 is a marrow stromal cell, capable of differentiating into three mesenchymal phenotypes: osteocyte, adipocyte, and myocyte by treating with 5-azacytidine in cell culture. Moreover, it has been reported that the mechanism of bone induction by KUSA/A1 cells is similar to intramembranous ossification. In order to clarify the origin of osteoblasts implicated in new bone formation, KUSA/A1 cells alone and combined with Honeycomb carrier were implanted in Transgenic Green Fluorescent Protein mice (GFP) mice. The presence of GFP positive host cells with osteoblastic morphology as well as GFP negative cells, clearly of KUSA/A1 cells in origin were observed around the bony trabeculae. These results indicated that the new bone was not only produced by KUSA/A1 cells but also by host cells from the surrounding connective tissues. To our knowledge, this is the first study to describe that host cells play an important role in ectopic bone induced by implanted marrow stromal cells, which would need special attention in bone tissue engineering. © 2007, THE SOCIETY FOR HARD TISSUE REGENERATIVE BIOLOGY. All rights reserved.

DOI： 10.2485/jhtb.16.75

Microcystic adnexal carcinoma with mandibular bone marrow involvement: A case report with immunohistochemistry International journal

Hitoshi Nagatsuka, Rosario Santos Rivera, Mehmet Gunduz, Chong Huat Siar, Ryo Tamamura, Nobuyoshi Mizukawa, Junichi Asaumi, Noriyuki Nagai

American Journal of Dermatopathology 28 ( 6 ) 518 - 522 2006.12

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Microcystic adnexal carcinoma is a rare, locally aggressive cutaneous neoplasm with a high probability of persistence locally but a low probability of metastasis. We report a case of a 69-year-old female patient with an indurated plaque at the mental region. Histologically, the tumor cells invaded the subcutaneous tissue and mandibular bone. The tumor consisted mainly of squamous and basaloid epithelial nests and cords embedded in a desmoplastic stroma. A few keratin-filled microcysts and ductal structures were also observed. Perineural encroachment was also noted but there was no mitosis, cytologic features of malignancy, or metastasis. The epithelial nests were positive to various cytokeratins except for CK20 and the lumina of the ductal structures were positive to carcinoembryonic antigen. Our results indicate that microcystic adnexal carcinoma consists of tumor cells capable of both follicular and eccrine differentiation. It is locally aggressive, extends far beyond its clinical presentation and may involve the bone. It may persist and remain asymptomatic for so many years without metastasis. A lifetime postsurgery monitoring is mandatory to ensure early and proper management. © 2006 Lippincott Williams & Wilkins, Inc.

DOI： 10.1097/01.dad.0000211511.52489.aa

Differential expression of basement membrane collagen-IV α1 to α6 chains during oral carcinogenesis International journal

Ryo Tamamura, Hitoshi Nagatsuka, Chong Huat Siar, Naoki Katase, Ichiro Naito, Yoshikazu Sado, Noriyuki Nagai

Virchows Archiv 449 ( 3 ) 358 - 366 2006.9

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

This study aimed to resolve if basement membrane (BM) collagen α chains undergo remodeling during oral carcinogenesis. Using immunohistochemistry and transmission electron microscopy, we found that BMs in oral epithelial dysplasias (OED: mild, n=10; moderate, n=10; severe, n=10) and carcinoma in situ (CIS) (n=10) differed from normal mucosa (n=6) and oral epithelial hyperplasia (n=5) in showing: (1) excessive lamina densa-like material ultrastructurally, and (2) stronger immunoexpression for α5(IV) than for α1(IV), α2(IV), and α6(IV) chains-findings that implicate these molecules' role as an adhesive template for the attachment and persistence of basal dysplastic cells. Incipient loss of BM integrity in CIS, where α5(IV)/α6(IV) chains were more frequently absent than α1(IV)/α2(IV) chains, suggests that α(IV) network disruption is crucial for progression of dysplastic cells into the extracellular compartment, marking transition into the invasive phase. In carcinomatous BM, the disappearance of α(IV) chains was more severe in poorly differentiated oral squamous cell carcinoma (OSCC) (n=10) than in well-differentiated OSCC (n=10). In all samples examined, α3(IV) and α4(IV) chains were absent. These findings taken together suggest that BM collagen-IV α chains undergo remodeling where selective increase and loss of these molecules are probably early and late events, respectively, during progression of oral dysplasia to cancer. © Springer-Verlag 2006.

DOI： 10.1007/s00428-006-0260-z

The close relationship between heparanase and cyclooxygenase-2 expressions in signet-ring cell carcinoma of the stomach International journal

Yasuyuki Ohtawa, Yoshio Naomoto, Yasuhiro Shirakawa, Munenori Takaoka, Toshihiro Murata, Ryotaro Sonoda, Kazufumi Sakurama, Tomoki Yamatsuji, Mehmet Gunduz, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Norihiko Terada, Satoshi Itano, Sadayuki Horiki, Kazuyoshi Yanagihara, Motowo Nakajima, Noriaki Tanaka

Human Pathology 37 ( 9 ) 1145 - 1152 2006.9

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

Signet-ring cell carcinoma (SRC) of the stomach exhibits diffuse growth and invasion without forming ducts. Destruction of the surrounding basal membrane and angiogenesis appear to be required for SRC to exhibit marked invasion and growth. We recently reported that heparanase (HPA) and cyclooxygenase-2 (COX-2) were strongly correlated with microvessel density, and that COX-2 expression is up-regulated by HPA in esophageal cancer. In this study, we examined the relationship between HPA expression and that of COX-2 in SRC of the stomach. We examined HPA and COX-2 expression in 3 cell lines derived from SRC of the stomach and in 50 SRC lesions of stomach by immunohistochemistry (IHC), in situ hybridization, and reverse transcriptase-polymerase chain reaction (RT-PCR). We also examined the relationships among HPA expression, COX-2 expression, and the clinicopathologic features of SRC, mean age, sex, invasion depth, regional lymph node metastasis, lymphatic invasion, and venous blood vessel invasion. Of the 3 cell lines, 2 exhibited both HPA and COX-2 mRNA expression on RT-PCR. Of the 3 cell lines, 1 exhibited only HPA mRNA expression on RT-PCR. Heparanase expression was confirmed in 23 (46%) of 50 tumor samples by IHC. COX-2 expression was confirmed in 25 (50%) of the 50 tumor samples by IHC. In situ hybridization revealed messenger RNA expression in the same area as in that revealed by IHC. A close correlation was noted between HPA and COX-2 expressions (P < .0001). The present study thus elucidated the biologic features of SRC of the stomach related to growth and angiogenesis. © 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2006.04.005

MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma International journal

Mitsukuni Okabe, Satoru Miyabe, Hitoshi Nagatsuka, Akihiro Terada, Nobuhiro Hanai, Motoo Yokoi, Kazuo Shimozato, Tadaaki Eimoto, Shigeo Nakamura, Noriyuki Nagai, Yasuhisa Hasegawa, Hiroshi Inagaki

Clinical Cancer Research 12 ( 13 ) 3902 - 3907 2006.7

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

Purpose: Mucoepidermoid carcinoma is the most common primary malignancy of the salivary gland. Mucoepidermoid carcinoma translocated gene 1-mastermind-like gene family (MECT1-MAML2) gene fusion was identified from a recurring t(11;19)(q21;p13) translocation, which is often the sole cytogenetic alteration in this disease. This fusion transcript has been frequently detected in nnucoepidermoid carcinoma and shown to be involved in the transformation of epithelial cells. However, its clinicopathologic significance remains unclear. Experimental Design: Seventy-one cases of mucoepidermoid carcinoma and 51 cases of nonmucoepidermoid carcinoma salivary gland tumors (including 26 Warthin tumor cases) were retrospectively analyzed. RNA was extracted from archival materials: histologic paraffin specimens in all cases and cytologic specimens in 10 mucoepidermoid carcinoma cases. The MECT1-MAML2 fusion transcript was detected by a reverse transcription-PCR assay, which can be applied to both histologic and cytologic specimens. The presence of the fusion transcript was correlated with relevant clinicopathologic and survival data of the mucoepidermoid carcinoma patients. Results: The MECT1-MAML2 fusion transcript was detected in 27 of the 71 (38%) mucoepidermoid carcinoma cases but not in any case of nonmucoepidermoid carcinoma tumors. The reverse transcription-PCR results showed no difference between histologic and cytologic specimens. Detection of the MECT1-MAML2 fusion transcript was associated with a less advanced clinical stage and a low-grade tumor histology. The presence of the transcript was associated with longer disease-free and overall survivals on univariate analysis and emerged as an independent prognostic factor for longer overall survival on multivariate analysis. Conclusions: The MECT1-MAML2 fusion transcript may be specific to mucoepidermoid carcinoma and associated with a distinct mucoepidermoid carcinoma subset that exhibits favorable clinicopathologic features and an indolent clinical course. © 2006 American Association for Cancer Research.

DOI： 10.1158/1078-0432.CCR-05-2376

Efficacy of atelocollagen honeycomb scaffold in bone formation using KUSA/A1 cells International journal

Andrea Paola Rodriguez, Liliana Missana, Hitoshi Nagatsuka, Mehmet Gunduz, Hidetsugu Tsujigiwa, Rosario Rivera, Noriyuki Nagai

Journal of Biomedical Materials Research - Part A 77 ( 4 ) 707 - 717 2006.6

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

To induce new bone formation, mesenchymal stem cells were seeded onto atelocollagen honeycomb scaffold. We evaluated the efficacy of this scaffold combined with KUSA/A1 cells in vivo. KUSA/A1 cells alone and with atelocollagen were implanted in the subcutaneous pockets of 4-week-old male SCID mice. The transplants were subjected to radiographical, histological, and immunohistochemical examinations after 2 and 4 weeks of implantation. Radiographically, both KUSA/A1 cells alone and KUSA/A1-atelocollagen showed some radiopaque areas formation but the latter disclosed a larger amount. Histologically, KUSA/A1 cells alone showed few small islands of new bone formation surrounded by a thin layer of cellular proliferation. On the other hand, KUSA/A1-atelocollagen revealed abundant new bone formation as well as cellular proliferation. We also determined the immunolocalization of type I collagen, CD34, osteocalcin, osteopontin, and PCNA in this newly formed bone. Our results indicated that collagen scaffold plays an important role allowing vessel formation and cell anchorage, especially through the proliferation and differentiation process in a confined space. This study supports tissue engineering as an alternative for treating different target diseases, such as trauma or congenital defects, and enhances existing therapeutic applications. © 2006 Wiley Periodicals, Inc.

DOI： 10.1002/jbm.a.30645

Immobilized rhBMP-2/succinylated type I atelocollagen gene expression of intracellular signaling molecules on ST2 cells International journal

Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Jin Lee You, Pwint Han Phuu, Mehmet Gunduz, Racquel Z. LeGeros, Masahisa Inoue, Masao Yamada, Noriyuki Nagai

Journal of Biomedical Materials Research - Part A 77 ( 3 ) 507 - 511 2006.6

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

Recombinant human bone morphogenetic protein-2 (rhBMP-2) chemically-bonded to succinylated type I atelocollagen, a biomaterial carrier with a porous structure, was reported to augment cellular activity of ST2 cells. The Smad protein family has been suggested to play an important role in the intracellular signaling pathway of BMP by its binding to receptors on target cells. However, there has been no study analyzing the downstream genes of the rhBMP-2 induced intracellular signal transduction pathway. The purpose of this study was to examine the effect of immobilized rhBMP-2 on gene expression of intracellular signaling molecules on ST2 cells. Our study showed two expression patterns of downstream genes of rhBMP-2 intracellular signal transduction pathway. In the first pattern, BMPR-IA, Smad 1, and Smad 5 genes showed high basic expression before the addition of rhBMP, and the high level of gene expression continued for long period and decreased in the late stage when rhBMP-2 was immobilized. In the second pattern, Smad 6, Smad 7, and Smad 8 genes showed low basic expression before the addition of rhBMP-2 and a continuous increase from the beginning was followed by a decrease in the late stage when rhBMP-2 was immobilized. Our results also showed that intracellular signaling continued for prolonged period when rhBMP-2 was immobilized to succinylated type I atelocollagen. This study indicated that immobilizing rhBMP-2 is an efficient method to increase bone induction. © 2006 Wiley Periodicals, Inc.

DOI： 10.1002/jbm.a.30661

Expression of Notch1 and Hes5 in the developing olfactory epithelium International journal

Yorihisa Orita, Hitoshi Nagatsuka, Hidetsugu Tsujigiwa, Junko Yoshinobu, Yukihide Maeda, Masashi Kakiuchi, Saeko Orita, Ayako Takeuchi, Yasushi Takeda, Kunihiro Fukushima, Noriyuki Nagai, Kazunori Nishizaki

Acta Oto-Laryngologica 126 ( 5 ) 498 - 502 2006.5

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

Conclusion. Notch signaling pathway may play an important role in the development of the olfactory epithelium (OE). Objectives. To elucidate whether the Notch signaling pathway mediates the developmental processes in the developing OE. Materials and methods. The expression of Notch1 and Hes5 in the developing OE of mice with ages ranging from embryonic day (E) 11 to postnatal day (PN) 14 was examined. Results. As detected by in situ hybridization, Notch1 was expressed in scattered cells located in the basal portion of the embryonic OE and later in the cell layer adjacent to the basal lamina from E11 to PN14. Hes5 was expressed in scattered cells located in the basal portion of the embryonic OE from E11. However, at the late embryonic stage, the number of Hes5-positive cells decreased and after birth distinct Hes5-positive cells were not observed in the OE. © 2006 Taylor & Francis.

DOI： 10.1080/00016480500437419

Heparanase and COX-2 expression in Barrett's esophagus and its carcinogenesis

Ryotaro Sonoda, Yoshio Naomoto, Yasuhiro Shirakawa, Tomoki Yamatsuji, Junji Matsuoka, Minoru Haisa, Mehmet Gunduz, Hitoshi Nagatsuka, Motowo Nakajima, Kaiyo Takubo, Michael Vieth, Noriaki Tanaka

CANCER RESEARCH 66 ( 8 ) 2006.4

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23
24