Updated on 2021/12/16

写真a

 
NAGATSUKA Hitoshi
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
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Degree

  • (BLANK) ( Okayama University )

Research Interests

  • 口腔病理学

  • Oral pathology

Research Areas

  • Life Science / Human pathology

  • Life Science / Oral biological science

Education

  • Okayama University   歯学研究科   歯学

    - 1991

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    Country: Japan

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  • Okayama University    

    - 1991

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  • Okayama University    

    - 1987

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  • Okayama University   歯学部   歯学科

    - 1987

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    Country: Japan

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Research History

  • Okayama University   Dental School   Dean

    2020.4 - 2022.3

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  • 岡山大学医歯薬学総合研究科 教授

    2008

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Professional Memberships

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Committee Memberships

  • 一般社団法人日本癌治療学会   領域横断的癌取扱い規約検討委員  

    2021.10   

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  • 歯科基礎医学会   評議員  

    2008   

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    Committee type:Academic society

    歯科基礎医学会

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  • 岡山歯学会   理事  

    2008   

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    Committee type:Academic society

    岡山歯学会

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  • 口腔科学会   編集査読委員  

    2008   

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    Committee type:Academic society

    口腔科学会

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  • 日本臨床口腔病理学会   教育委員長  

       

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  • 日本病理学会   将来構想検討委員  

       

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  • 硬組織再生生物学会   国際委員長  

       

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  • 日本組織細胞化学会   査読委員  

       

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  • 日本病理学会   口腔病理専門医試験委員  

       

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  • 日本病理学会   口腔病理専門医制度運営委員  

       

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  • 日本臨床口腔病理学会   口腔癌診断基準検討委員長  

       

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  • 日本病理学会   医療業務委員  

       

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  • 日本病理学会中四国支部   学術委員  

       

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  • 硬組織再生生物学会   編集副委員長  

       

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Papers

  • Extracellular vesicles of P. gingivalis-infected macrophages induce lung injury. International journal

    Kayo Yoshida, Kaya Yoshida, Natsumi Fujiwara, Mariko Seyama, Kisho Ono, Hotaka Kawai, Jiajie Guo, Ziyi Wang, Yao Weng, Yaqiong Yu, Yoko Uchida-Fukuhara, Mika Ikegame, Akira Sasaki, Hitoshi Nagatsuka, Hiroshi Kamioka, Hirohiko Okamura, Kazumi Ozaki

    Biochimica et biophysica acta. Molecular basis of disease   1867 ( 11 )   166236 - 166236   2021.11

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    Periodontal diseases are common inflammatory diseases that are induced by infection with periodontal bacteria such as Porphyromonas gingivalis (Pg). The association between periodontal diseases and many types of systemic diseases has been demonstrated; the term "periodontal medicine" is used to describe how periodontal infection/inflammation may impact extraoral health. However, the molecular mechanisms by which the factors produced in the oral cavity reach multiple distant organs and impact general health have not been elucidated. Extracellular vesicles (EVs) are nano-sized spherical structures secreted by various types of cells into the tissue microenvironment, and influence pathophysiological conditions by delivering their cargo. However, a detailed understanding of the effect of EVs on periodontal medicine is lacking. In this study, we investigated whether EVs derived from Pg-infected macrophages reach distant organs in mice and influence the pathophysiological status. EVs were isolated from human macrophages, THP-1 cells, infected with Pg. We observed that EVs from Pg-infected THP-1 cells (Pg-inf EVs) contained abundant core histone proteins such as histone H3 and translocated to the lungs, liver, and kidneys of mice. Pg-inf EVs also induced pulmonary injury, including edema, vascular congestion, inflammation, and collagen deposition causing alveoli destruction. The Pg-inf EVs or the recombinant histone H3 activated the NF-κB pathway, leading to increase in the levels of pro-inflammatory cytokines in human lung epithelial A549 cells. Our results suggest a possible mechanism by which EVs produced in periodontal diseases contribute to the progression of periodontal medicine.

    DOI: 10.1016/j.bbadis.2021.166236

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  • Dynamic contrast-enhanced MRI as a predictor of programmed death ligand-1 expression in patients with oral squamous cell carcinoma

    Nouha Tekiki, Mariko Fujita, Tatsuo Okui, Hotaka Kawai, May Oo, Toshiyuki Kawazu, Miki Hisatomi, Shunsuke Okada, Yohei Takeshita, Majd Barham, Hitoshi Nagatsuka, Yoshinobu Yanagi, Jun-Ichi Asaumi

    ONCOLOGY LETTERS   22 ( 5 )   2021.11

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    Immune checkpoint inhibitors (ICIs) targeting programmed death ligand-1 (PD-L1) are highly promising therapies for oral squamous cell carcinoma (OSCC). The assessment of PD-L1 expression may help predicting the therapeutic effect of ICIs and, thus, benefit patient selection. Contrast index (CI) parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) have been proven as efficient to assess microvessel density (MVD) in OSCC. The present study aimed to determine the correlation between DCE-MRI parameters and MVD and between DCE-MRI parameters and PD-L1 expression to determine whether DCE-MRI could be used non-invasively to evaluate PD-L1 expression in patients with OSCC. A total of 21 patients with primary OSCC who had undergone a 3T MRI scan, including DCE-MRI, were included in the present study, and CI curve-derived parameters were examined. The MVD and PD-L1 expression in the surgically resected specimens were analyzed using immunohistochemistry (IHC) staining for CD31 and IHC staining for PD-L1, respectively. The results demonstrated that the expression levels of these markers were correlated with DCE-MRI parameters. PD-L1 expression levels were found to be significantly correlated with the maximum CI (CI-max; P=0.007), peak CI (CI-peak; P=0.007), maximum CI gain (CI-gain; P=0.006) and MVD (P=0.001) values. The mean CI-max, CI-peak, CI-gain and MVD values were significantly higher in tumors with high PD-L1 expression (P<0.05). MVD levels were also significantly correlated with the time of CI-max (T-max; P=0.003) and CI-gain (P=0.037). The mean CI-gain was significantly increased, and the mean T-max was significantly shorter in high MVD tumors (P<0.05 and P<0.01, respectively). In summary, the findings from the present study confirmed the correlation between CI parameters, derived from DCE-MRI, and MVD, and suggested that these parameters may be correlated with PD-L1 expression in OSCC tumor cells.

    DOI: 10.3892/ol.2021.13039

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  • Stromal cells in the tumor microenvironment promote the progression of oral squamous cell carcinoma. International journal

    Qiusheng Shan, Kiyofumi Takabatake, Haruka Omori, Hotaka Kawai, May Wathone Oo, Keisuke Nakano, Soichiro Ibaragi, Akira Sasaki, Hitoshi Nagatsuka

    International journal of oncology   59 ( 3 )   2021.9

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    The stromal cells in the tumor microenvironment (TME) can influence the progression of multiple types of cancer; however, data on oral squamous cell carcinoma (OSCC) are limited. In the present study, the effects of verrucous squamous cell carcinoma‑associated stromal cells (VSCC‑SCs), squamous cell carcinoma‑associated stromal cells (SCC‑SCs) and human dermal fibroblasts (HDFs) on the tumor nest formation, proliferation, invasion and migration of HSC‑3 cells were examined in vitro using Giemsa staining, MTS, and Transwell (invasion and migration) assays, respectively. The results revealed that both the VSCC‑SCs and SCC‑SCs inhibited the tumor nest formation, and promoted the proliferation, invasion and migration of OSCC cells in vitro. Furthermore, the effects of VSCC‑SCs, SCC‑SCs and HDFs on the differentiation, proliferation, invasion and migration of OSCC cells in vivo were evaluated by hematoxylin and eosin staining, tartrate‑resistant acid phosphatase staining, immunohistochemistry and double‑fluorescent immunohistochemical staining, respectively. The results demonstrated that the VSCC‑SCs promoted the differentiation, proliferation, invasion and migration of OSCC cells, while the SCC‑SCs inhibited the differentiation, and promoted the proliferation, invasion and migration of OSCC cells in vivo. Finally, microarray data were used to predict genes in VSCC‑SCs and SCC‑SCs that may influence the progression of OSCC, and those with potential to influence the differential effects of VSCC‑SCs and SCC‑SCs on the differentiation of OSCC. It was found that C‑X‑C motif chemokine ligand (CXCL)8, mitogen‑activated protein kinase 3 (MAPK3), phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit alpha (PIK3CA), C-X-C motif chemokine ligand 1 (CXCL1) and C‑C motif chemokine ligand 2 (CCL2) may be involved in the crosstalk between VSCC‑SCs, SCC‑SCs and OSCC cells, which regulates the progression of OSCC. Intercellular adhesion molecule 1 (ICAM1), interleukin (IL)1B, Fos proto‑oncogene, AP‑1 transcription factor subunit (FOS), bone morphogenetic protein 4 (BMP4), insulin (INS) and nerve growth factor (NGF) may be responsible for the differential effects of VSCC‑SCs and SCC‑SCs on the differentiation of OSCC. On the whole, the present study demonstrates that both VSCC‑SCs and SCC‑SCs may promote the progression of OSCC, and SCC‑SCs were found to exert a more prominent promoting effect; this may represent a potential regulatory mechanism for the progression of OSCC.

    DOI: 10.3892/ijo.2021.5252

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  • Effect of Patient Clinical Variables in Osteoporosis Classification Using Hip X-rays in Deep Learning Analysis. International journal

    Norio Yamamoto, Shintaro Sukegawa, Kazutaka Yamashita, Masaki Manabe, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Toshifumi Ozaki, Keisuke Kawasaki, Hitoshi Nagatsuka, Yoshihiko Furuki, Takashi Yorifuji

    Medicina (Kaunas, Lithuania)   57 ( 8 )   2021.8

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    Background and Objectives: A few deep learning studies have reported that combining image features with patient variables enhanced identification accuracy compared with image-only models. However, previous studies have not statistically reported the additional effect of patient variables on the image-only models. This study aimed to statistically evaluate the osteoporosis identification ability of deep learning by combining hip radiographs with patient variables. Materials andMethods: We collected a dataset containing 1699 images from patients who underwent skeletal-bone-mineral density measurements and hip radiography at a general hospital from 2014 to 2021. Osteoporosis was assessed from hip radiographs using convolutional neural network (CNN) models (ResNet18, 34, 50, 101, and 152). We also investigated ensemble models with patient clinical variables added to each CNN. Accuracy, precision, recall, specificity, F1 score, and area under the curve (AUC) were calculated as performance metrics. Furthermore, we statistically compared the accuracy of the image-only model with that of an ensemble model that included images plus patient factors, including effect size for each performance metric. Results: All metrics were improved in the ResNet34 ensemble model compared with the image-only model. The AUC score in the ensemble model was significantly improved compared with the image-only model (difference 0.004; 95% CI 0.002-0.0007; p = 0.0004, effect size: 0.871). Conclusions: This study revealed the additional effect of patient variables in identification of osteoporosis using deep CNNs with hip radiographs. Our results provided evidence that the patient variables had additive synergistic effects on the image in osteoporosis identification.

    DOI: 10.3390/medicina57080846

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  • The Origin of Stroma Influences the Biological Characteristics of Oral Squamous Cell Carcinoma. International journal

    Haruka Omori, Qiusheng Shan, Kiyofumi Takabatake, Keisuke Nakano, Hotaka Kawai, Shintaro Sukegawa, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka

    Cancers   13 ( 14 )   2021.7

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    Normal stromal cells surrounding the tumor parenchyma, such as the extracellular matrix (ECM), normal fibroblasts, mesenchymal stromal cells, and osteoblasts, play a significant role in the progression of cancers. However, the role of gingival and periodontal ligament tissue-derived stromal cells in OSCC progression is unclear. In this study, the effect of G-SCs and P-SCs on the differentiation, proliferation, invasion, and migration of OSCC cells in vitro was examined by Giemsa staining, Immunofluorescence (IF), (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS), invasion, and migration assays. Furthermore, the effect of G-SCs and P-SCs on the differentiation, proliferation, and bone invasion by OSCC cells in vivo was examined by hematoxylin-eosin (HE) staining, immunohistochemistry (IHC), and tartrate-resistant acid phosphatase (TRAP) staining, respectively. Finally, microarray data and bioinformatics analyses identified potential genes that caused the different effects of G-SCs and P-SCs on OSCC progression. The results showed that both G-SCs and P-SCs inhibited the differentiation and promoted the proliferation, invasion, and migration of OSCC in vitro and in vivo. In addition, genes, including CDK1, BUB1B, TOP2A, DLGAP5, BUB1, and CCNB2, are probably involved in causing the different effects of G-SCs and P-SCs on OSCC progression. Therefore, as a potential regulatory mechanism, both G-SCs and P-SCs can promote OSCC progression.

    DOI: 10.3390/cancers13143491

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  • Biological Effects of Bioresorbable Materials in Alveolar Ridge Augmentation: Comparison of Early and Slow Resorbing Osteosynthesis Materials. International journal

    Hotaka Kawai, Shintaro Sukegawa, Keisuke Nakano, Kiyofumi Takabatake, Sawako Ono, Hitoshi Nagatsuka, Yoshihiko Furuki

    Materials (Basel, Switzerland)   14 ( 12 )   2021.6

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    The purpose of this study was to investigate the bone healing properties and histological environment of a u-HA/PLLA/PGA (u-HA-uncalcined and unsintered hydroxyapatite, PLLA-Poly L-lactic acid, PGA-polyglycolic acid) composite device in humans, and to understand the histological dynamics of using this device for maxillofacial treatments. Twenty-one subjects underwent pre-implant maxillary alveolar ridge augmentation with mandibular cortical bone blocks using u-HA/PLLA or u-HA/PLLA/PGA screws for fixation. Six months later, specimens of these screws and their adjacent tissue were retrieved. A histological and immunohistochemical evaluation of these samples was performed using collagen 1a, ALP (alkaline phosphatase), and osteocalcin. We observed that alveolar bone augmentation was successful for all of the subjects. Upon histological evaluation, the u-HA/PLLA screws had merged with the bone components, and the bone was directly connected to the biomaterial. In contrast, direct bone connection was not observed for the u-HA/PLLA/PGA screw. Immunohistological findings showed that in the u-HA/PLLA group, collagen 1a was positive for fibers that penetrated vertically into the bone. Alkaline phosphatase was positive only in the u-HA/PLLA stroma, and the stroma was negative for osteocalcin. In this study, u-HA/PLLA showed a greater bioactive bone conductivity than u-HA/PLLA/PGA and a higher biocompatibility for direct bone attachment. Furthermore, u-HA/PLLA was shown to have the potential for bone formation in the stroma.

    DOI: 10.3390/ma14123286

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  • Preparation of absorption-resistant hard tissue using dental pulp-derived cells and honeycomb tricalcium phosphate International journal

    Kiyofumi Takabatake, Keisuke Nakano, Hotaka Kawai, Yasunori Inada, Shintaro Sukegawa, Shan Qiusheng, Shigeko Fushimi, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka

    Materials   14 ( 12 )   2021.6

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    In recent years, there has been increasing interest in the treatment of bone defects using undifferentiated mesenchymal stem cells (MSCs) in vivo. Recently, dental pulp has been proposed as a promising source of pluripotent mesenchymal stem cells (MSCs), which can be used in various clinical applications. Dentin is the hard tissue that makes up teeth, and has the same composition and strength as bone. However, unlike bone, dentin is usually not remodeled under physiological conditions. Here, we generated odontoblast-like cells from mouse dental pulp stem cells and combined them with honeycomb tricalcium phosphate (TCP) with a 300 µm hole to create bone-like tissue under the skin of mice. The bone-like hard tissue produced in this study was different from bone tissue, i.e., was not resorbed by osteoclasts and was less easily absorbed than the bone tissue. It has been suggested that hard tissue-forming cells induced from dental pulp do not have the ability to induce osteoclast differentiation. Therefore, the newly created bone-like hard tissue has high potential for absorption-resistant hard tissue repair and regeneration procedures.

    DOI: 10.3390/ma14123409

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  • Expression of neurokinin b receptor in the gingival squamous cell carcinoma bone microenvironment International journal

    Shoko Yoshida, Tsuyoshi Shimo, Kiyofumi Takabatake, Yurika Murase, Kyoichi Obata, Tatsuo Okui, Yuki Kunisada, Soichiro Ibaragi, Hitoshi Nagatsuka, Akira Sasaki

    Diagnostics   11 ( 6 )   2021.6

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    Gingival squamous cell carcinoma (SCC) frequently invades the maxillary or mandibular bone, and bone destruction is known as a key prognostic factor in gingival SCCs. Recently, Neurokinin 3 receptor (NK-3R), the receptor ligand for NK-3, which is a member of the tachykinin family expressed in the central nervous system, was identified through pathway analysis as a molecule expressed in osteoclasts induced by the hedgehog signal. Although the expression of NK-3R has been detected in osteoclast and SCC cells at the bone invasion front, the relationship between NK-3R expression and the prognosis of gingival SCC patients remains unclear. In the present study, we retrospectively reviewed 27 patients with gingival SCC who had undergone surgery with curative intent. Significantly higher NK-3R expression in tumor cells was found in a case of jawbone invasion than in a case of exophytic poor jawbone invasion. On the other hand, no significant association was observed between NK-3R tumor-positive cases and tumor size, TNM stage, or tumor differentiation. The survival rate tended to be lower in NK-3R tumor-positive cases, but not significantly. However, the disease-specific survival rate was significantly lower in patients with a large number of NK-3Rpositive osteoclasts than in those with a small number of them at the tumor bone invasion front. Our results suggest that NK-3R signaling in the gingival SCC bone microenvironment plays an important role in tumor bone destruction and should be considered a potential therapeutic target in advanced gingival SCC with bone destruction.

    DOI: 10.3390/diagnostics11061044

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  • Multi-task deep learning model for classification of dental implant brand and treatment stage using dental panoramic radiograph images International journal

    Shintaro Sukegawa, Kazumasa Yoshii, Takeshi Hara, Tamamo Matsuyama, Katsusuke Yamashita, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

    Biomolecules   11 ( 6 )   2021.6

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    It is necessary to accurately identify dental implant brands and the stage of treatment to ensure efficient care. Thus, the purpose of this study was to use multi-task deep learning to investigate a classifier that categorizes implant brands and treatment stages from dental panoramic radiographic images. For objective labeling, 9767 dental implant images of 12 implant brands and treatment stages were obtained from the digital panoramic radiographs of patients who underwent procedures at Kagawa Prefectural Central Hospital, Japan, between 2005 and 2020. Five deep convolutional neural network (CNN) models (ResNet18, 34, 50, 101 and 152) were evaluated. The accuracy, precision, recall, specificity, F1 score, and area under the curve score were calculated for each CNN. We also compared the multi-task and single-task accuracies of brand classification and implant treatment stage classification. Our analysis revealed that the larger the number of parameters and the deeper the network, the better the performance for both classifications. Multi-tasking significantly improved brand classification on all performance indicators, except recall, and significantly improved all metrics in treatment phase classification. Using CNNs conferred high validity in the classification of dental implant brands and treatment stages. Furthermore, multi-task learning facilitated analysis accuracy.

    DOI: 10.3390/biom11060815

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  • A case of intramandibular neurofibroma resembling a radicular cyst in a neurofibromatosis type 1 patient International journal

    Yuki Kunisada, Norie Yoshioka, Soichiro Ibaragi, Tatsuo Okui, Hitoshi Nagatsuka, Akira Sasaki

    International Journal of Surgery Case Reports   82   105883 - 105883   2021.5

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    Introduction: Neurofibromatosis is a disease that causes various abnormalities such as neurofibroma, mainly in the skin and nerves. The common sites in the oral cavity are the palate, gingiva, tongue, buccal mucosa, and lips but, occurrence in the mandible is rare. Presentation of case: A 26-year-old woman was referred to our clinic because of percussion pain. Radiographic findings showed a radiolucent area. The patient was clinically diagnosed with a radicular cyst by a previous doctor. Multiple café-au-lait spots were found disseminated on her body, and she had already been prenatally diagnosed with neurofibromatosis type 1 (NF1). We performed a biopsy and suggested a neurofibroma. Tumor extirpation was performed under general anesthesia. The histopathological diagnosis showed a neurofibroma. Clinical discussion and conclusion: NF1 is a systemic nevus that causes abnormalities in melanocytes and Schwann cells, and various lesions appear, but intramandibular lesions are extremely rare. Diagnosis of NF1 and radicular cysts in the mandible is difficult due to their image resemblance. However, it should be kept in mind if the underlying disease is NF1. In our case, it was easy to detach and may have originated from small peripheral nerve endings in the mandible.

    DOI: 10.1016/j.ijscr.2021.105883

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  • General rules for clinical and pathological studies on oral cancer (2nd edition): a synopsis

    Yoshihide Ota, Tadahide Noguchi, Eiichiro Ariji, Chihiro Fushimi, Nobukazu Fuwa, Hiroyuki Harada, Takafumi Hayashi, Ryuichi Hayashi, Yoshitaka Honma, Masahiko Miura, Taisuke Mori, Hitoshi Nagatsuka, Masaya Okura, Michihiro Ueda, Narikazu Uzawa, Kazuhiro Yagihara, Hisao Yagishita, Masashi Yamashiro, Souichi Yanamoto, Tadaaki Kirita

    International Journal of Clinical Oncology   26 ( 4 )   623 - 635   2021.4

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    For doctors and other medical staff treating oral cancer, it is necessary to standardize the basic concepts and rules for oral cancer to achieve progress in its treatment, research, and diagnosis. Oral cancer is an integral part of head and neck cancer and is treated in accordance with the general rules for head and neck cancer. However, detailed rules based on the specific characteristics of oral cancer are essential. The objective of this article was to contribute to the development of the diagnosis, treatment, and research of oral cancer, based on the correct and useful medical information of clinical, surgical, pathological, and imaging findings accumulated from individual patients at various institutions. Our general rules were revised as the UICC was revised for the 8th edition and were published as the Japanese second edition in 2019. In this paper, the English edition of the “Rules” section is primarily presented.

    DOI: 10.1007/s10147-020-01812-9

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J04721&link_issn=&doc_id=20210422260001&doc_link_id=10.1007%2Fs10147-020-01812-9&url=https%3A%2F%2Fdoi.org%2F10.1007%2Fs10147-020-01812-9&type=Crossref&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00002_2.gif

  • Homeobox transcription factor engrailed homeobox 1 is a possible diagnostic marker for adenoid cystic carcinoma and polymorphous adenocarcinoma International journal

    Shunichi Baba, Takumi Akashi, Kou Kayamori, Tomoyuki Ohuchi, Ikuko Ogawa, Nobuhisa Kubota, Keisuke Nakano, Hitoshi Nagatsuka, Hiromasa Hasegawa, Kenichi Matsuzaka, Shohei Tomii, Keisuke Uchida, Noriko Katsuta, Takahiro Sekiya, Noboru Ando, Keiko Miura, Hironori Ishibashi, Yousuke Ariizumi, Takahiro Asakage, Yasuyuki Michi, Hiroyuki Harada, Kei Sakamoto, Yoshinobu Eishi, Kenichi Okubo, Tohru Ikeda

    Pathology International   71 ( 2 )   113 - 123   2021.2

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    Diagnostic utility of a homeobox transcription factor, engrailed homeobox 1 (En1) in the histopathology of salivary gland neoplasms was studied. The expression of En1 was immunohistochemically examined in 51 cases of adenoid cystic carcinoma (AdCC) and 143 cases of other salivary gland neoplasms. In all 51 AdCCs, En1 was expressed in 30–100% of tumor cells. In eight of nine polymorphous adenocarcinomas (PACs), En1 was expressed in 40–100% of tumor cells. Less than 5% of tumor cells expressed En1 in three of 12 epithelial–myoepithelial carcinomas, one of 17 basal cell adenomas (BCAs), and one of 34 pleomorphic adenomas (PAs). Among 55 other carcinoma cases, 1–30% of tumor cells expressed En1 in three salivary duct carcinomas (SDCs) ex PA. None of the myoepitheliomas and Warthin tumors expressed En1. When the cut-off value of the percentage of En1-expressing cells was set to 25%, all 51 AdCCs, eight of nine PACs and one SDC ex PA were En1-positive and the others were En1-negative. En1 is expressed consistently in AdCCs, frequently in PACs, but rarely in other salivary gland neoplasms. En1 is a possible diagnostic marker for AdCC and PAC in the histopathology of salivary gland neoplasms.

    DOI: 10.1111/pin.13050

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  • Potential role of myeloid-derived suppressor cells in transition from reaction to repair phase of bone healing process International journal

    Hotaka Kawai, May Wathone Oo, Hidetsugu Tsujigiwa, Keisuke Nakano, Kiyofumi Takabatake, Shintaro Sukegawa, Hitoshi Nagatsuka

    International Journal of Medical Sciences   18 ( 8 )   1824 - 1830   2021

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    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with immunosuppressive functions; these cells play a key role in infection, immunization, chronic inflammation, and cancer. Recent studies have reported that immunosuppression plays an important role in the healing process of tissues and that Treg play an important role in fracture healing. MDSCs suppress active T cell proliferation and reduce the severity of arthritis in mice and humans. Together, these findings suggest that MDSCs play a role in bone biotransformation. In the present study, we examined the role of MDSCs in the bone healing process by creating a bone injury at the tibial epiphysis in mice. MDSCs were identified by CD11b and GR1 immunohistochemistry and their role in new bone formation was observed by detection of Runx2 and osteocalcin expression. Significant numbers of MDSCs were observed in transitional areas from the reactionary to repair stages. Interestingly, MDSCs exhibited Runx2 and osteocalcin expression in the transitional area but not in the reactionary area. And at the same area, cllagene-1 and ALP expression level increased in osteoblast progenitor cells. These data is suggesting that MDSCs emerge to suppress inflammation and support new bone formation. Here, we report, for the first time (to our knowledge), the role of MDSCs in the initiation of bone formation. MDSC appeared at the transition from inflammation to bone making and regulates bone healing by suppressing inflammation.

    DOI: 10.7150/ijms.51946

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  • A case of large adenomatoid odontogenic tumor in the posterior region of the mandible showing root resorption

    Atsushi Fujita, Yoshiya Ueyama, Hitoshi Nagatsuka, Hitoshi Kawamata

    Journal of Oral Medicine and Oral Surgery   27 ( 2 )   2021

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    Introduction: Adenomatoid odontogenic tumor (AOT) is a rare tumor of epithelial origin, and usually presents as a unilocular radiolucency in the maxillary anterior region in adolescent females. Observation: A 31-year-old Japanese male, having a large adenomatoid odontogenic tumor from the right molar region to the left anterior region of the mandible showing root resorption of the neighboring teeth, was presented to the hospital. The lesion was totally resected under general anesthesia. Commentary: AOT may cause displacement of the neighboring teeth. But root resorption is a very rare finding. AOTs are relatively small in size. Conclusion: The patient was under follow-up and had not shown any signs of recurrence 12 months after surgery.

    DOI: 10.1051/mbcb/2020053

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  • Factors of successful treatment using the bone lid technique in maxillofacial surgery: A pilot study

    Shintaro Sukegawa, Norio Yamamoto, Tamamo Matsuyama, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

    Journal of Hard Tissue Biology   30 ( 2 )   193 - 198   2021

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    This study aimed to investigate the success factors of the bone lid surgery technique in the maxillofacial region. A retrospective cohort study was performed on 30 maxillofacial patients who underwent bone lid surgery between January 2014 and December 2019 at our hospital. The predictor variables consisted of clinical factors that were classified as attribute (age and sex), health status (smoking and alcohol intake), anatomical (maxillary/mandibular site, left/right side, and cortical bone thickness), lesion (lesion size, location, and pathological diagnosis), and treatment variables (differences in ab-sorbable osteosynthesis materials). The outcome variable was the incidence of bone lid necrosis after surgery. Various risk factors for postoperative bone lid necrosis were investigated statistically. A p value <0.05 was considered statistically signif-icant. Postoperative bone lid necrosis was observed in three patients (10.0%). No significant differences in the attribute, an-atomical, and treatment status variables were noted. Significant differences were observed between smoking (p=0.005) and alcohol intake (p=0.003) in the health status variables. There was a significant difference in the distance of the lesion from the alveolar bone crest in the lesion variables (p=0.037). Smoking and alcohol consumption were the health status variables found to be risk factors for bone lid necrosis. In addition, proximity to the alveolar crest was also a risk factor for lesion de-velopment.

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  • Endoscopic-assisted resection of pleomorphic adenoma in the accessory parotid gland.

    Kazuaki Hasegawa, Shintaro Sukegawa, Sawako Ono, Midori Ando, Akane Shibata, Yuka Sukegawa-Takahashi, Ai Fujimura, Tamamo Matsuyama, Soichiro Ibaragi, Hitoshi Nagatsuka, Koichi Mizobuchi, Akira Sasaki, Yoshihiko Furuki

    The journal of medical investigation : JMI   68 ( 3.4 )   376 - 380   2021

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    Background : An accessory parotid gland (APG) is a common anatomical structure that occurs in 10%-56% of individuals. Pleomorphic adenomas are the most common benign tumors of the APG, and their ideal treatment is surgical excision, although there is a risk for aesthetic disorders and facial nerve damage due to the site of origin. Moreover, despite being benign, these tumors are known to recur. Therefore, it is necessary to achieve both reliable excision and avoidance of facial nerve damage. Case presentation : We report a case of a 49-year-old Japanese man with a mass in his left cheek. The lesion was diagnosed as a benign salivary gland tumor derived from the APG by computed tomography imaging, magnetic resonance imaging and fine needle aspiration cytology. We resected the tumor using modified high submandibular incision under the endoscopic-assisted field of view. Discussion and Conclusions : The tumor was less invasive and reliably resected using an endoscope. In surgical treatment, the endoscopic-assisted technique is very useful to achieve complete tumor resection and prevent relapse while avoiding serious complications due to surgical procedures. J. Med. Invest. 68 : 376-380, August, 2021.

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  • A case of oral cancer with delayed occipital lymph node metastasis: Case report International journal

    Kisho Ono, Norie Yoshioka, Masanori Masui, Kyoichi Obata, Yuki Kunisada, Tatsuo Okui, Soichiro Ibaragi, Hotaka Kawai, Hitoshi Nagatsuka, Akira Sasaki

    Clinical Case Reports   8 ( 12 )   2469 - 2475   2020.12

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    Consideration of unexpected metastasis in patients who have undergone neck dissection with advanced tumors must be anticipated with careful follow-up.

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  • Geometrical structure of honeycomb TCP to control dental pulp-derived cell differentiation International journal

    Kiyofumi Takabatake, Hidetsugu Tsujigiwa, Keisuke Nakano, Yasunori Inada, Shan Qiusheng, Hotaka Kawai, Shintaro Sukegawa, Shigeko Fushimi, Hitoshi Nagatsuka

    Materials   13 ( 22 )   1 - 10   2020.11

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    Recently, dental pulp has been attracting attention as a promising source of multipotent mesenchymal stem cells (MSCs) for various clinical applications of regeneration fields. To date, we have succeeded in establishing rat dental pulp-derived cells showing the characteristics of odontoblasts under in vitro conditions. We named them Tooth matrix-forming, GFP rat-derived Cells (TGC). However, though TGC form massive dentin-like hard tissues under in vivo conditions, this does not lead to the induction of polar odontoblasts. Focusing on the importance of the geometrical structure of an artificial biomaterial to induce cell differentiation and hard tissue formation, we previously have succeeded in developing a new biomaterial, honeycomb tricalcium phosphate (TCP) scaffold with through-holes of various diameters. In this study, to induce polar odontoblasts, TGC were induced to form odontoblasts using honeycomb TCP that had various hole diameters (75, 300, and 500 µm) as a scaffold. The results showed that honeycomb TCP with 300-µm hole diameters (300TCP) differentiated TGC into polar odontoblasts that were DSP positive. Therefore, our study indicates that 300TCP is an appropriate artificial biomaterial for dentin regeneration.

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  • Effect of honeycomb β-TCP geometrical structure on bone tissue regeneration in skull defect International journal

    Toshiyuki Watanabe, Kiyofumi Takabatake, Hidetsugu Tsujigiwa, Satoko Watanabe, Ryoko Nakagiri, Keisuke Nakano, Hitoshi Nagatsuka, Yoshihiro Kimata

    Materials   13 ( 21 )   1 - 13   2020.11

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    The effect of the geometric structure of artificial biomaterials on skull regeneration remains unclear. In a previous study, we succeeded in developing honeycomb β-tricalcium phosphate (β-TCP), which has through-and-through holes and is able to provide the optimum bone microenvironment for bone tissue regeneration. We demonstrated that β-TCP with 300-µm hole diameters induced vigorous bone formation. In the present study, we investigated how differences in hole directions of honeycomb β-TCP (horizontal or vertical holes) influence bone tissue regeneration in skull defects. Honeycomb β-TCP with vertical and horizontal holes was loaded with BMP-2 using Matrigel and Collagen gel as carriers, and transplanted into skull bone defect model rats. The results showed that in each four groups (Collagen alone group, Matrigel alone group, Collagen + BMP group and Matrigel + BMP-2), vigorous bone formation was observed on the vertical β-TCP compared with horizontal β-TCP. The osteogenic area was larger in the Matrigel groups (with and without BMP-2) than in the Collagen group (with and without BMP-2) in both vertical β-TCP and horizontal β-TCP. However, when BMP-2 was added, the bone formation area was not significantly different between the Collagen group and the Matrigel group in the vertical β-TCP. Histological finding showed that, in vertical honeycomb β-TCP, new bone formation extended to the upper part of the holes and was observed from the dura side to the periosteum side as added to the inner walls of the holes. Therefore, we can control efficient bone formation by creating a bone microenvironment provided by vertical honeycomb β-TCP. Vertical honeycomb β-TCP has the potential to be an excellent biomaterial for bone tissue regeneration in skull defects and is expected to have clinical applications.

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  • Deep learning for osteoporosis classification using hip radiographs and patient clinical covariates International journal

    Norio Yamamoto, Shintaro Sukegawa, Akira Kitamura, Ryosuke Goto, Tomoyuki Noda, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Keisuke Kawasaki, Yoshihiko Furuki, Toshifumi Ozaki

    Biomolecules   10 ( 11 )   1 - 13   2020.11

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    This study considers the use of deep learning to diagnose osteoporosis from hip radiographs, and whether adding clinical data improves diagnostic performance over the image mode alone. For objective labeling, we collected a dataset containing 1131 images from patients who underwent both skeletal bone mineral density measurement and hip radiography at a single general hospital between 2014 and 2019. Osteoporosis was assessed from the hip radiographs using five convolutional neural network (CNN) models. We also investigated ensemble models with clinical covariates added to each CNN. The accuracy, precision, recall, specificity, negative predictive value (npv), F1 score, and area under the curve (AUC) score were calculated for each network. In the evaluation of the five CNN models using only hip radiographs, GoogleNet and EfficientNet b3 exhibited the best accuracy, precision, and specificity. Among the five ensemble models, EfficientNet b3 exhibited the best accuracy, recall, npv, F1 score, and AUC score when patient variables were included. The CNN models diagnosed osteoporosis from hip radiographs with high accuracy, and their performance improved further with the addition of clinical covariates from patient records.

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  • Impact of the stroma on the biological characteristics of the parenchyma in oral squamous cell carcinoma International journal

    Kiyofumi Takabatake, Hotaka Kawai, Haruka Omori, Shan Qiusheng, May Wathone Oo, Shintaro Sukegawa, Keisuke Nakano, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka

    International Journal of Molecular Sciences   21 ( 20 )   1 - 15   2020.10

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    Solid tumors consist of the tumor parenchyma and stroma. The standard concept of oncology is that the tumor parenchyma regulates the tumor stroma and promotes tumor progression, and that the tumor parenchyma represents the tumor itself and defines the biological characteristics of the tumor tissue. Thus, the tumor stroma plays a pivotal role in assisting tumor parenchymal growth and invasiveness and is regarded as a supporter of the tumor parenchyma. The tumor parenchyma and stroma interact with each other. However, the influence of the stroma on the parenchyma is not clear. Therefore, in this study, we investigated the effect of the stroma on the parenchyma in oral squamous cell carcinoma (OSCC). We isolated tumor stroma from two types of OSCCs with different invasiveness (endophytic type OSCC (ED-st) and exophytic type OSCC (EX-st)) and examined the effect of the stroma on the parenchyma in terms of proliferation, invasion, and morphology by co-culturing and co-transplanting the OSCC cell line (HSC-2) with the two types of stroma. Both types of stroma were partially positive for alpha-smooth muscle actin. The tumor stroma increased the proliferation and invasion of tumor cells and altered the morphology of tumor cells in vitro and in vivo. ED-st exerted a greater effect on the tumor parenchyma in proliferation and invasion than EX-st. Morphological analysis showed that ED-st changed the morphology of HSC-2 cells to the invasive type of OSCC, and EX-st altered the morphology of HSC-2 cells to verrucous OSCC. This study suggests that the tumor stroma influences the biological characteristics of the parenchyma and that the origin of the stroma is strongly associated with the biological characteristics of the tumor.

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  • Clinical study on primary screening of oral cancer and precancerous lesions by oral cytology International journal

    Shintaro Sukegawa, Sawako Ono, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

    Diagnostic Pathology   15 ( 1 )   107 - 107   2020.9

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    Background: This study was conducted to compare the histological diagnostic accuracy of conventional oral-based cytology and liquid-based cytology (LBC) methods. Methods: Histological diagnoses of 251 cases were classified as negative (no malignancy lesion, inflammation, or mild/moderate dysplasia) and positive [severe dysplasia/carcinoma in situ (CIS) and squamous cell carcinoma (SCC)]. Cytological diagnoses were classified as negative for intraepithelial lesion or malignancy (NILM), oral low-grade squamous intraepithelial lesion (OLSIL), oral high-grade squamous intraepithelial lesion (OHSIL), or SCC. Cytological diagnostic results were compared with histology results. Results: Of NILM cytology cases, the most frequent case was negative [LBC n = 50 (90.9%), conventional n = 22 (95.7%)]. Among OLSIL cytodiagnoses, the most common was negative (LBC n = 34; 75.6%, conventional n = 14; 70.0%). Among OHSIL cytodiagnoses (LBC n = 51, conventional n = 23), SCC was the most frequent (LBC n = 31; 60.8%, conventional n = 7; 30.4%). Negative cases were common (LBC n = 13; 25.5%, conventional n = 14; 60.9%). Among SCC cytodiagnoses SCC was the most common (LBC n = 16; 88.9%, conventional n = 14; 87.5%). Regarding the diagnostic results of cytology, assuming OHSIL and SCC as cytologically positive, the LBC method/conventional method showed a sensitivity of 79.4%/76.7%, specificity of 85.1%/69.2%, false-positive rate of 14.9%/30.7%, and false-negative rate of 20.6%/23.3%. Conclusions: LBC method was superior to conventional cytodiagnosis methods. It was especially superior for OLSIL and OHSIL. Because of the false-positive and false-negative cytodiagnoses, it is necessary to make a comprehensive diagnosis considering the clinical findings.

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  • 下顎臼後部歯肉に発生した周辺性エナメル上皮腫の1例

    武田 斉子, 山近 英樹, 高畠 清文, 中野 敬介, 長塚 仁, 飯田 征二

    日本口腔科学会雑誌   69 ( 3 )   239 - 240   2020.9

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  • ニコチンが口腔癌細胞に与える影響の検討

    伊原木 聰一郎, 清水 理恵子, 奥井 達雄, 高畠 清文, 河合 穂高, 小野 喜章, 長塚 仁, 佐々木 朗

    日本口腔科学会雑誌   69 ( 3 )   235 - 235   2020.9

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  • 深層学習を用いた歯科インプラントの分類

    吉位 和将, 助川 信太郎, 原 武史, 山下 勝督, 中野 敬介, 長塚 仁, 古木 良彦

    日本医用画像工学会大会予稿集   39回   241 - 245   2020.9

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    インプラントには多くのブランドがあり,メーカーごとに独自に開発されている.患者のインプラントのメンテナンスをする際にはブランドを特定する必要があるが,一人に対して異なるブランドのインプラントが異なる歯科医によって埋入されることが頻繁にあり,歯科医の間で共有される情報がなく特定するのは困難である.歯科パノラマX線画像からは特定に必要な情報を得ることができるが,これを行うには歯科医の努力と経験が必要になる.本研究の目的は,深層学習を用いて歯科パノラマX線画像からインプラントの分類を行い,歯科医や患者の負担軽減に寄与することである.畳み込み層が6つのCNNと,VGG16とVGG19の転移学習及びファインチューニングモデルでの分類精度を評価した.5つのモデルのうちVGG16のファインチューニングが94%と最も高い精度を示し,インプラントの分類において深層学習が有用である可能性が示唆された.(著者抄録)

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  • 深層学習を用いた歯科インプラントの分類

    吉位 和将, 助川 信太郎, 原 武史, 山下 勝督, 中野 敬介, 長塚 仁, 古木 良彦

    日本医用画像工学会大会予稿集   39回   35 - 35   2020.9

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  • ニコチンが口腔癌細胞に与える影響の検討

    伊原木 聰一郎, 清水 理恵子, 奥井 達雄, 高畠 清文, 河合 穂高, 小野 喜章, 長塚 仁, 佐々木 朗

    日本口腔科学会雑誌   69 ( 3 )   235 - 235   2020.9

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  • Risk Factors for Mandibular Fracture After Marginal Mandibular Resection

    Shintaro Sukegawa, Masato Saika, Ryo Tamamura, Norio Yamamoto, Keisuke Nakano, Hitoshi Nagatsuka, Yoshihiko Furuki

    The Journal of craniofacial surgery   31 ( 5 )   1430 - 1433   2020.7

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    PURPOSE: This study aimed to examine the relationship between post-operative mandibular fractures and its predictable risk factors in patients with marginal mandibular resection. Additionally, the timing of post-operative mandibular fractures was assessed. PATIENTS AND METHODS: Records of 37 patients with mandibular gingival carcinoma who underwent marginal mandibular resection at the Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, from April 2011 to March 2019 were retrospectively analyzed. The following variables were investigated: age, sex, location of carcinoma, tumor size, mandibular height on the surgical and healthy sides, surgical approach, number of residual teeth, post-operative radiotherapy, chemotherapy, and the presence or absence of diabetes and osteoporosis. Various risk factors for post-operative mandibular fractures were statistically investigated. RESULTS: Post-operative mandibular fracture was observed in 5 (13.5%) of the 37 mandibular marginal resection cases. The average residual mandibular height in patients with post-operative mandibular fracture was 8.5 mm. A significant difference in residual mandibular height (P = 0.013) was observed between patients with post-operative mandibular fracture and those with no fracture. The average time to post-operative fracture of the mandible was 305.4 days, and it was found to be correlated to the remaining height of the mandibular body. CONCLUSIONS: A decrease in mandibular height below 9 mm results in post-operative mandibular fracture. Furthermore, a correlation between the height of the mandibular bone and the period until the post-operative mandibular fracture was noted in this study. These findings contribute to the prediction and management of mandibular fractures after mandibular margin resection.

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  • Maxillofacial Trauma Surgery Patients With Titanium Osteosynthesis Miniplates: Remove or Not?

    Shintaro Sukegawa, Masanori Masui, Yuka Sukegawa-Takahashi, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

    The Journal of craniofacial surgery   31 ( 5 )   1338 - 1342   2020.7

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    The authors examined the timing and causes of titanium miniplate removal after maxillofacial trauma surgery. The authors performed a retrospective study of maxillofacial fracture patients in whom maxillofacial osteosynthesis miniplates were inserted or removed at the Kagawa Prefectural Central Hospital, between 2008 and 2017. Predictive variables were age, sex, fracture site distribution, and time to miniplate removal with or without complications in relation to primary outcome variables. Among 185 patients, 440 miniplates were inserted and 272 miniplates were removed. In total, 116 patients (73.4%) had 282 miniplates (64.1%) removed, of which 4.8% fracture sites and 5.7% miniplates were removed because of complications. The mean time to miniplate removal was 630.9 and 258.0 days in patients with and without complications, respectively. There was a statistically significant difference in miniplate removal and miniplate retention relative to age and sex. This difference was not related to the presence or absence of sex- or age-related complications. The miniplates as osteosynthesis material were safe and useful for a long period of time with relatively few complications. Because complications requiring miniplate removal occurred within 1 or after 5 years postoperatively, osteosynthesis miniplate treatments should be decided while considering the patient's age and sex. Long-term follow-up is recommended for miniplates that remain implanted for >1 year.

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  • Biomechanical loading comparison between titanium and bioactive resorbable screw systems for fixation of intracapsular condylar head fractures International journal

    Shintaro Sukegawa, Norio Yamamoto, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Takahiro Kanno, Hitoshi Nagatsuka, Yoshihiko Furuki

    Materials   13 ( 14 )   2020.7

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    Osteosynthesis resorbable materials made of uncalcined and unsintered hydroxyapatite (u-HA) particles, poly-L-lactide (PLLA), are bioresorbable, and these materials have feasible bioactive/osteoconductive capacities. However, their strength and stability for fixation in mandibular condylar head fractures remain unclear. This in vitro study aimed to assess the biomechanical strength of u-HA/PLLA screws after the internal fixation of condylar head fractures. To evaluate their biomechanical behavior, 32 hemimandible replicas were divided into eight groups, each consisting of single-screw and double-screw fixations with titanium or u-HA/PLLA screws. A linear load was applied as vertical and horizontal load to each group to simulate the muscular forces in condylar head fractures. Samples were examined for 0.5, 1, 2, and 3-mm displacement loads. Two screws were needed for stable fixation of the mandibular condylar head fracture during biomechanical evaluation. After screw fixation for condylar head fractures, the titanium screws model was slightly more resistant to vertical and horizontal movement with a load for a small displacement than the u-HA/PLLA screws model. There was no statistically significant difference with load for large displacements. The u-HA/PLLA screw has a low mechanical resistance under small displacement loading compared with titanium within the limits of the mandibular head fracture model study.

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  • Deep neural networks for dental implant system classification International journal

    Shintaro Sukegawa, Kazumasa Yoshii, Takeshi Hara, Katsusuke Yamashita, Keisuke Nakano, Norio Yamamoto, Hitoshi Nagatsuka, Yoshihiko Furuki

    Biomolecules   10 ( 7 )   1 - 13   2020.7

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    In this study, we used panoramic X-ray images to classify and clarify the accuracy of different dental implant brands via deep convolutional neural networks (CNNs) with transfer-learning strategies. For objective labeling, 8859 implant images of 11 implant systems were used from digital panoramic radiographs obtained from patients who underwent dental implant treatment at Kagawa Prefectural Central Hospital, Japan, between 2005 and 2019. Five deep CNN models (specifically, a basic CNN with three convolutional layers, VGG16 and VGG19 transfer-learning models, and finely tuned VGG16 and VGG19) were evaluated for implant classification. Among the five models, the finely tuned VGG16 model exhibited the highest implant classification performance. The finely tuned VGG19 was second best, followed by the normal transfer-learning VGG16. We confirmed that the finely tuned VGG16 and VGG19 CNNs could accurately classify dental implant systems from 11 types of panoramic X-ray images.

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  • 口腔扁平上皮癌の腫瘍微小環境における骨髄由来細胞の分化と役割

    高畠 清文, 河合 穂高, Oo May Wathone, 吉田 沙織, 大森 悠加, 中野 敬介, 辻極 秀次, 長塚 仁

    日本口腔科学会雑誌   69 ( 2 )   132 - 132   2020.7

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  • Patient-derived xenograftモデルを用いた腫瘍間質による腫瘍実質の生物学的性格制御の検討

    高畠 清文, 河合 穂高, 大森 悠加, Oo May Wathone, 吉田 沙織, 中野 敬介, 長塚 仁

    日本口腔科学会雑誌   69 ( 2 )   132 - 133   2020.7

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  • 口腔扁平上皮癌の腫瘍微小環境における骨髄由来細胞の分化と役割

    高畠 清文, 河合 穂高, Oo May Wathone, 吉田 沙織, 大森 悠加, 中野 敬介, 辻極 秀次, 長塚 仁

    日本口腔科学会雑誌   69 ( 2 )   132 - 132   2020.7

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  • Patient-derived xenograftモデルを用いた腫瘍間質による腫瘍実質の生物学的性格制御の検討

    高畠 清文, 河合 穂高, 大森 悠加, Oo May Wathone, 吉田 沙織, 中野 敬介, 長塚 仁

    日本口腔科学会雑誌   69 ( 2 )   132 - 133   2020.7

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  • Outer membrane vesicles of Porphyromonas gingivalis attenuate insulin sensitivity by delivering gingipains to the liver International journal

    Mariko Seyama, Kaya Yoshida, Kayo Yoshida, Natsumi Fujiwara, Kisho Ono, Takanori Eguchi, Hotaka Kawai, Jiajie Guo, Yao Weng, Yuan Haoze, Kenta Uchibe, Mika Ikegame, Akira Sasaki, Hitoshi Nagatsuka, Kuniaki Okamoto, Hirohiko Okamura, Kazumi Ozaki

    Biochimica et Biophysica Acta - Molecular Basis of Disease   1866 ( 6 )   165731 - 165731   2020.6

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    Outer membrane vesicles (OMVs) are nanosized particles derived from the outer membrane of gram-negative bacteria. Oral bacterium Porphyromonas gingivalis (Pg) is known to be a major pathogen of periodontitis that contributes to the progression of periodontal disease by releasing OMVs. The effect of Pg OMVs on systemic diseases is still unknown. To verify whether Pg OMVs affect the progress of diabetes mellitus, we analyzed the cargo proteins of vesicles and evaluated their effect on hepatic glucose metabolism. Here, we show that Pg OMVs were equipped with Pg-derived proteases gingipains and translocated to the liver in mice. In these mice, the hepatic glycogen synthesis in response to insulin was decreased, and thus high blood glucose levels were maintained. Pg OMVs also attenuated the insulin-induced Akt/glycogen synthase kinase-3 β (GSK-3β) signaling in a gingipain-dependent fashion in hepatic HepG2 cells. These results suggest that the delivery of gingipains mediated by Pg OMV elicits changes in glucose metabolisms in the liver and contributes to the progression of diabetes mellitus.

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  • Knockout of MMP3 weakens solid tumor organoids and cancer extracellular vesicles International journal

    Eman A. Taha, Chiharu Sogawa, Yuka Okusha, Hotaka Kawai, May Wathone Oo, Abdellatif Elseoudi, Yanyin Lu, Hitoshi Nagatsuka, Satoshi Kubota, Ayano Satoh, Kuniaki Okamoto, Takanori Eguchi

    Cancers   12 ( 5 )   2020.5

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    The tumor organoid (tumoroid) model in three-dimensional (3D) culture systems has been developed to reflect more closely the in vivo tumors than 2D-cultured tumor cells. Notably, extracellular vesicles (EVs) are efficiently collectible from the culture supernatant of gel-free tumoroids. Matrix metalloproteinase (MMP) 3 is a multi-functional factor playing crucial roles in tumor progression. However, roles of MMP3 within tumor growth and EVs have not unveiled. Here, we investigated the protumorigenic roles of MMP3 on integrities of tumoroids and EVs. We generated MMP3-knockout (KO) cells using the CRISPR/Cas9 system from rapidly metastatic LuM1 tumor cells. Moreover, we established fluorescent cell lines with palmitoylation signal-fused fluorescent proteins (tdTomato and enhanced GFP). Then we confirmed the exchange of EVs between cellular populations and tumoroids. LuM1-tumoroids released large EVs (200–1000 nm) and small EVs (50–200 nm) while the knockout of MMP3 resulted in the additional release of broken EVs from tumoroids. The loss of MMP3 led to a significant reduction in tumoroid size and the development of the necrotic area within tumoroids. MMP3 and CD9 (a category-1 EV marker tetraspanin protein) were significantly down-regulated in MMP3-KO cells and their EV fraction. Moreover, CD63, another member of the tetraspanin family, was significantly reduced only in the EVs fractions of the MMP3-KO cells compared to their counterpart. These weakened phenotypes of MMP3-KO were markedly rescued by the addition of MMP3-rich EVs or conditioned medium (CM) collected from LuM1-tumoroids, which caused a dramatic rise in the expression of MMP3, CD9, and Ki-67 (a marker of proliferating cells) in the MMP3-null/CD9-low tumoroids. Notably, MMP3 enriched in tumoroids-derived EVs and CM deeply penetrated recipient MMP3-KO tumoroids, resulting in a remarkable enlargement of solid tumoroids, while MMP3-null EVs did not. These data demonstrate that EVs can mediate molecular transfer of MMP3, resulting in increasing the proliferation and tumorigenesis, indicating crucial roles of MMP3 in tumor progression.

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  • Secretory Carcinoma of Salivary Gland with High-Grade Histology Arising in Hard Palate: A Case Report

    Kiyofumi Takabatake, Keisuke Nakano, Hotaka Kawai, Saori Yoshida, Haruka Omori, May Wathone Oo, Shan Qiusheng, Kenichiro Uchida, Katsuaki Mishima, Hitoshi Nagatsuka

    Reports — Medical Cases, Images, and Videos   3 ( 2 )   6 - 6   2020.3

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    Secretory carcinoma (SC) is a recently described salivary gland tumor reported in the fourth edition of World Health Organization classification of head and neck tumors. SC is characterized by strong S-100 protein, mammaglobin, and vimentin immunoexpression, and harbors a t(12;15)(p13;q25) translocation which leads to ETV6-NTRK3 fusion product. Histologically, SC displays a lobulated growth pattern and is often composed of microcystic, tubular, and solid structures with abundant eosinophilic homogenous or bubbly secretion. SC is generally recognized as low-grade malignancy with low-grade histopathologic features, and metastasis is relatively uncommon. In this case, we described a SC of hard palate that underwent high grade transformation and metastasis to the cervical lymph node in a 54-year-old patient. In addition, this case showed different histological findings between primary lesion and metastasis lesion. Therefore, the diagnosis was confirmed by the presence of ETV6 translocation. Here, we report a case that occurred SC with high-grade transformation in the palate, and a review of the relevant literature is also presented.

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  • エナメル上皮腫開窓術の適応に関する組織学的検討

    大森 悠加, 高畠 清文, 河合 穂高, 吉田 沙織, メイワト・ウ, 浜田 芽衣, 中野 敬介, 長塚 仁

    日本病理学会会誌   109 ( 1 )   316 - 316   2020.3

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  • 間葉系幹細胞由来新規幹細胞を用いたモデルラットの脊髄損傷治療

    山崎 勤, 中野 敬介, 長塚 仁, 杉野 哲造, 笹井 紀明, 中西 徹

    日本薬学会年会要旨集   140年会   28L - am11   2020.3

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  • 口腔癌間質細胞が骨髄由来細胞の動員に与える影響

    河合 穂高, メイワト・ウ, 辻極 秀次, 高畠 清文, 大森 悠加, 藤井 昌江, 中野 敬介, 長塚 仁

    日本病理学会会誌   109 ( 1 )   315 - 315   2020.3

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  • 腫瘍組織に動員される骨髄由来細胞へ腫瘍間質が及ぼす影響の検討

    Oo May Wathone, 河合 穂高, 吉田 沙織, 高畠 清文, 中野 敬介, 長塚 仁

    日本口腔診断学会雑誌   33 ( 1 )   116 - 116   2020.2

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  • 口腔扁平上皮癌における組織マイクロアレイ標本を用いたPD-L1発現傾向の解析

    大森 悠加, 吉田 沙織, 藤井 昌江, 浜田 芽衣, 安田 政実, 長塚 仁

    日本口腔診断学会雑誌   33 ( 1 )   115 - 115   2020.2

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  • 口腔扁平上皮癌が作り出す腫瘍微小環境における骨髄由来細胞の役割

    高畠 清文, 吉田 沙織, Oo May Wathone, 大森 悠加, 河合 穂高, 中野 敬介, 長塚 仁

    日本口腔診断学会雑誌   33 ( 1 )   114 - 114   2020.2

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  • CXCR4の阻害が口腔扁平上皮癌の腫瘍血管に与える影響 Reviewed

    吉田 沙織, 河合 穂高, メイ・ワトン・ウ, 常 安き, 浜田 芽衣, 高畠 清文, 中野 敬介, 長塚 仁

    日本口腔診断学会雑誌   33 ( 1 )   116 - 116   2020.2

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  • Triple knockdown of CDC37, HSP90-alpha and HSP90-beta diminishes extracellular vesicles-driven malignancy events and macrophage M2 polarization in oral cancer International journal

    Kisho Ono, Chiharu Sogawa, Hotaka Kawai, Manh Tien Tran, Eman A. Taha, Yanyin Lu, May Wathone Oo, Yuka Okusha, Hirohiko Okamura, Soichiro Ibaragi, Masaharu Takigawa, Ken Ichi Kozaki, Hitoshi Nagatsuka, Akira Sasaki, Kuniaki Okamoto, Stuart K. Calderwood, Takanori Eguchi

    Journal of Extracellular Vesicles   9 ( 1 )   1769373 - 1769373   2020.1

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    Evidence has been accumulating to indicate that extracellular vesicles (EVs), including exosomes, released by cancer cells can foster tumour progression. The molecular chaperones–CDC37, HSP90α and HSP90β play key roles in cancer progression including epithelial-mesenchymal transition (EMT), although their contribution to EVs-mediated cell–cell communication in tumour microenvironment has not been thoroughly examined. Here we show that triple depletion of the chaperone trio attenuates numerous cancer malignancy events exerted through EV release. Metastatic oral cancer-derived EVs (MEV) were enriched with HSP90α HSP90β and cancer-initiating cell marker CD326/EpCAM. Depletion of these chaperones individually induced compensatory increases in the other chaperones, whereas triple siRNA targeting of these molecules markedly diminished the levels of the chaperone trio and attenuated EMT. MEV were potent agents in initiating EMT in normal epithelial cells, a process that was attenuated by the triple chaperone depletion. The migration, invasion, and in vitro tumour initiation of oral cancer cells were significantly promoted by MEV, while triple depletion of CDC37/HSP90α/β reversed these MEV-driven malignancy events. In metastatic oral cancer patient-derived tumours, HSP90β was significantly accumulated in infiltrating tumour-associated macrophages (TAM) as compared to lower grade oral cancer cases. HSP90-enriched MEV-induced TAM polarization to an M2 phenotype, a transition known to support cancer progression, whereas the triple chaperone depletion attenuated this effect. Mechanistically, the triple chaperone depletion in metastatic oral cancer cells effectively reduced MEV transmission into macrophages. Hence, siRNA-mediated knockdown of the chaperone trio (CDC37/HSP90α/HSP90β) could potentially be a novel therapeutic strategy to attenuate several EV-driven malignancy events in the tumour microenvironment. Abbreviations: CDC37: cell division control 37; EMT: epithelial-mesenchymal transmission; EV: extracellular vesicles; HNSCC: head and neck squamous cell carcinoma; HSP90: heat shock protein 90; TAM: tumour-associated macrophage.

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  • Podoplanin is an efficient predictor of neck lymph node metastasis in tongue squamous cell carcinoma with low tumor budding grade International journal

    Mei Hamada, Yasuhiro Ebihara, Koji Nagata, Mitsutake Yano, Yasunao Kogashiwa, Mitsuhiko Nakahira, Masashi Sugasawa, Hitoshi Nagatsuka, Masanori Yasuda

    Oncology Letters   19 ( 4 )   2602 - 2608   2020

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    The current study investigated the efficacy of podoplanin expression in tumor budding cells as a predictor of neck lymph node metastasis (NLM) in patients with tongue squamous cell carcinoma (SCC) of low tumor budding grade (TBG). A total of 99 patients with early T-stage tongue SCC of any clinical N status who received the initial curative treatment were enrolled. The association between podoplanin expression and NLM was immunohistochemically analyzed, with a focus on tongue SCC with low TBG. The disease-specific survival (DSS) rate was 77% at 5 years, and a significant difference was observed between the NLM-positive and NLM-negative groups, and between the low (n=77) and high (n=22) TBG groups. In the low TBG group, there was a significant difference in DSS between the NLM-positive and NLM-negative groups. The multivariate analysis showed that lymphatic vessel invasion (ly) [odds ratio (OR)=11.5, 95% confidence interval (CI): 1.50-87.6; P=0.02] and podoplanin expression (OR=7.07, 95% CI: 1.80-27.7; P=0.005) were significantly correlated with NLM. Furthermore, negative predictive values (NPV) of ly and podoplanin expression for NLM were 75% and 88%, respectively. Considering the balance of stratification case number adding to ratio, NLM-negative prediction by podoplanin was more significant than that by ly for the low TBG group. The results of the present study demonstrated that podoplanin expression in tumor budding is an independent and efficient predictor of NLM in the tongue SCC with low TBG. The low TBG and podoplanin-negative cases may be candidates for the wait and watch policy, therefore, reducing inappropriate elective neck lymph node dissections.

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  • Clinical retrospective study of dental implant removal: Do patients who require implant removal desire implant prosthesis again?

    Shintaro Sukegawa, Masato Saika, Ryo Tamamura, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

    Medicina Oral Patologia Oral y Cirugia Bucal   25 ( 6 )   e784 - e790   2020

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    Background: This study investigated the causes of dental implant removal due to complications, and examined whether patients who had dental implant removal desired re-implant prosthesis treatments. Material and Methods: A retrospective case–control study was conducted on patients who had their dental implants removed. We investigated whether the removed dental implant was replaced with other implant prosthe-ses. Age, sex, diabetes, smoking, implant site distribution, reason for implant removal, and blade and root-form implants were categorized as predictive variables. The outcome variable was desire for re-implantation or use of other prosthetic methods after implant removal. A logistic regression model was created to identify patient factors that could predict the re-implantation of dental prostheses after implant removal. Results: A total of 215 dental implants were removed from 143 patients. The most common reason for implant removal was peri-implantitis that was identified in 165 implants. After implant removal, re-implantation was performed in 98 implants (45.6%). Bivariate analyses showed that age, diabetes, implant type, and reason for implant removal were associated with the desire for re-implanted prostheses. The multiple regression model revealed that age, implant type, and reason for implant removal were associated with an increased desire for re-implant prostheses after implant removal. Conclusions: Re-implantation of prostheses after the removal of dental implants was desired by patients who were younger, had implants placed in the root form, and had implants removed due to prosthetic-related complications.

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  • 口腔扁平上皮癌が作り出す腫瘍微小環境における骨髄由来細胞の役割

    高畠 清文, 吉田 沙織, Oo May Wathone, 大森 悠加, 河合 穂高, 中野 敬介, 長塚 仁

    日本口腔内科学会雑誌   25 ( 2 )   104 - 104   2019.12

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  • 口腔扁平上皮癌における組織マイクロアレイ標本を用いたPD-L1発現傾向の解析

    大森 悠加, 吉田 沙織, 藤井 昌江, 浜田 芽衣, 安田 政実, 長塚 仁

    日本口腔内科学会雑誌   25 ( 2 )   105 - 105   2019.12

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  • 腫瘍組織に動員される骨髄由来細胞へ腫瘍間質が及ぼす影響の検討

    Oo May Wathone, 河合 穂高, 吉田 沙織, 高畠 清文, 中野 敬介, 長塚 仁

    日本口腔内科学会雑誌   25 ( 2 )   106 - 106   2019.12

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  • ハニカムTCPの硬組織形成制御機構解明と臨床応用

    大森 悠加, 高畠 清文, 辻極 秀次, 河合 穂高, 吉田 沙織, Oo May Wathone, 中野 敬介, 長塚 仁

    岡山歯学会雑誌   38 ( 2 )   86 - 87   2019.12

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  • CXCR4の阻害が口腔扁平上皮癌の腫瘍血管に与える影響 Reviewed

    吉田 沙織, 河合 穂高, ウ・メイ・ワトン, 常 安き, 浜田 芽衣, 高畠 清文, 中野 敬介, 長塚 仁

    日本口腔内科学会雑誌   25 ( 2 )   106 - 106   2019.12

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  • The role of sonic hedgehog signaling in the tumor microenvironment of oral squamous cell carcinoma Reviewed International journal

    Kiyofumi Takabatake, Tsuyoshi Shimo, Jun Murakami, Chang Anqi, Hotaka Kawai, Saori Yoshida, May Wathone Oo, Omori Haruka, Shintaro Sukegawa, Hidetsugu Tsujigiwa, Keisuke Nakano, Hitoshi Nagatsuka

    International Journal of Molecular Sciences   20 ( 22 )   2019.11

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    Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of SHH expression appear to correlate with cancer progression. However, the role of SHH in the tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is still unclear. No studies have compared the expression of SHH in different subtypes of OSCC and focused on the relationship between the tumor parenchyma and stroma. In this study, we analyzed SHH and expression of its receptor, Patched-1 (PTCH), in the TME of different subtypes of OSCC. Fifteen endophytic-type cases (ED type) and 15 exophytic-type cases (EX type) of OSCC were used. H&E staining, immunohistochemistry (IHC), double IHC, and double-fluorescent IHC were performed on these samples. ED-type parenchyma more strongly expressed both SHH and PTCH than EX-type parenchyma. In OSCC stroma, CD31-positive cancer blood vessels, CD68-and CD11b-positive macrophages, and α-smooth muscle actin-positive cancer-associated fibroblasts partially expressed PTCH. On the other hand, in EX-type stroma, almost no double-positive cells were observed. These results suggest that autocrine effects of SHH induce cancer invasion, and paracrine effects of SHH govern parenchyma-stromal interactions of OSCC. The role of the SHH pathway is to promote growth and invasion.

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  • Advantage of Alveolar Ridge augmentation with bioactive/bioresorbable screws made of composites of unsintered hydroxyapatite and poly-L-lactide Reviewed International journal

    Shintaro Sukegawa, Hotaka Kawai, Keisuke Nakano, Kiyofumi Takabatake, Takahiro Kanno, Hitoshi Nagatsuka, Yoshihiko Furuki

    Materials   12 ( 22 )   2019.11

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    We studied human bone healing characteristics and the histological osteogenic environment by using devices made of a composite of uncalcined and unsintered hydroxyapatite (u-HA) and poly-L-lactide (PLLA). In eight cases of fixation, we used u-HA/PLLA screws for maxillary alveolar ridge augmentation, for which mandibular cortical bone block was used in preimplantation surgery. Five appropriate samples with screws were evaluated histologically and immunohistochemically for runt-related transcription factor 2 (RUNX2), transcription factor Sp7 (Osterix), and leptin receptor (LepR). In all cases, histological evaluation revealed that bone components had completely surrounded the u-HA/PLLA screws, and the bone was connected directly to the biomaterial. Inflammatory cells did not invade the space between the bone and the u-HA/PLLA screw. Immunohistochemical evaluation revealed that many cells were positive for RUNX2 or Osterix, which are markers for osteoblast and osteoprogenitor cells, in the tissues surrounding u-HA/PLLA. In addition, many bone marrow-derived mesenchymal stem cells were notably positive for both LepR and RUNX2. The u-HA/PLLA material showed excellent bioactive osteoconductivity and a highly biocompatibility with bone directly attached. In addition, our findings suggest that many bone marrow-derived mesenchymal stem cells and mature osteoblast are present in the osteogenic environment created with u-HA/PLLA screws and that this environment is suitable for osteogenesis.

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  • 高転移臓器における転移促進的微小環境の性質の検討

    河合 穂高, 信長 ひかり, Oo May Wathone, 吉田 沙織, 大森 悠加, 高畠 清文, 中野 敬介, 辻極 秀次, 長塚 仁

    Journal of Oral Biosciences Supplement   2019   261 - 261   2019.10

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  • Oropharyngeal adenoid cystic carcinoma invading the mandibular bone through the mandibular foramen Reviewed

    Yohei Takeshita, Shunsuke Okada, Miki Hisatomi, Hidenobu Matsuzaki, Hotaka Kawai, Yohei Noda, Jun Murakami, Mariko Fujita, Hitoshi Nagatsuka, Yoshinobu Yanagi, Junichi Asaumi

    Oral Radiology   35 ( 3 )   335 - 340   2019.9

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    Adenoid cystic carcinoma (ACC) is a rare epithelial tumor of the head and neck region, and one of the most common malignant tumors of the salivary glands. ACC is a slow-growing tumor characterized by perineural invasion and often has a high-recurrence rate. We describe a case of oropharyngeal ACC invading the mandibular bone through the mandibular foramen that showed a rare pattern of origin and invasion. A 70-year-old woman complained of noise and pain around the right temporomandibular joint. Osteomyelitis was suspected on the initial imaging examinations, although the findings were slightly atypical. However, a mass was observed in the right oropharyngeal wall on subsequent imaging examinations, and mandibular bone invasion, rather than osteomyelitis, was additionally suspected. The mass in the right oropharyngeal wall and right mandible was surgically excised. On postoperative histopathological examination, the mass was finally diagnosed as ACC. As tumor cells were also observed around the inferior alveolar nerve, mandibular bone invasion through the mandibular foramen was suspected. An oropharyngeal ACC invading the mandibular bone through the mandibular foramen is extremely rare. The present case suggests that bone invasion should be considered carefully with several imaging examinations when a malignant tumor such as ACC is observed around the jaw bone.

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  • 舌扁平上皮癌における新TNM分類(UICC:第8版)の実用性(第2報) 正誤表に準拠

    吉田 祥子, 岸本 晃治, 村瀬 友里香, 伊原木 聰一郎, 吉岡 徳枝, 奥井 達雄, 長塚 仁, 佐々木 朗

    日本口腔腫瘍学会誌   31 ( 3 )   151 - 156   2019.9

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    UICCのTNM分類は、口腔癌の進行度評価の基準として使用されている。2016年に公表された第8版TNM分類では、T分類に浸潤の深さ(DOI)、N分類に被膜外進展(ENE)が導入された。そして、われわれは、舌扁平上皮癌の手術症例を対象に、第7版と第8版TNM分類による評価を比較し、後者の実用性を本誌において報告した。さらに、2018年にUICCから正誤表が公表され、T2、T3、T4が訂正された。そこで本研究では、当科で手術を施行した舌扁平上皮癌107例について、正誤表に準拠して改めて検討を行った。正誤表に準拠して評価すると、1例がT3からT2に、3例がT3からT4aに変更された。第7版と比較すると、後発転移率がT1では低下し、T2では増加したが、第8版とは同様の結果であった。生存率は、第8版と同様に、Tの上昇とともに低下した。また、pTの変更に伴って、pStageが変更されたため、stageの上昇とともに生存率が低下した。訂正された第8版TNM分類は、進行度に即したTの細分化を舌扁平上皮癌においても実現し、細分化により進行度を的確に後発転移と生存率へ反映させており、実用的であると考えられた。(著者抄録)

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  • Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) in Oral Cancer Reviewed International journal

    Saori Yoshida, Hotaka Kawai, Takanori Eguchi, Shintaro Sukegawa, May Wathone Oo, Chang Anqi, Kiyofumi Takabatake, Keisuke Nakano, Kuniaki Okamoto, Hitoshi Nagatsuka

    CELLS   8 ( 7 )   2019.7

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    CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis, thereby supporting tumor survival in OSCC. Immunohistochemistry on human clinical specimens revealed that CXCR4 and a tumor vasculature marker CD34 were co-distributed in tumor vessels in human OSCC specimens. To uncover the effects of CXCR4 inhibition, we treated the OSCC-xenografted mice with AMD3100, so-called plerixafor, an antagonist of CXCR4. Notably, we found a unique pathophysiological structure defined as tumor angiogenic inhibition triggered necrosis (TAITN), which was induced by the CXCR4 antagonism. Treatment with AMD3100 increased necrotic areas with the induction of hypoxia-inducible factor-1a in the xenografted tumors, suggesting that AMD3100-induced TAITN was involved in hypoxia and ischemia. Taken together, we demonstrated that CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment.

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  • Locally injected ivabradine inhibits carrageenan-induced pain and inflammatory responses via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels Reviewed International journal

    Saki Miyake, Hitoshi Higuchi, Yuka Honda-Wakasugi, Maki Fujimoto, Hotaka Kawai, Hitoshi Nagatsuka, Shigeru Maeda, Takuya Miyawaki

    PLoS ONE   14 ( 5 )   e0217209   2019.5

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    Background Recently, attention has been focused on the role of hyperpolarization-activated cyclic nucleotide- gated (HCN) channels in the mechanism of and as a treatment target for neuropathic and inflammatory pain. Ivabradine, a blocker of HCN channels, was demonstrated to have an effect on neuropathic pain in an animal model. Therefore, in the present study, we evaluated the effect of ivabradine on inflammatory pain, and under the hypothesis that ivabradine can directly influence inflammatory responses, we investigated its effect in in vivo and in vitro studies. Methods After approval from our institution, we studied male Sprague-Dawley rats aged 8 weeks. Peripheral inflammation was induced by the subcutaneous injection of carrageenan into the hindpaw of rats. The paw-withdrawal threshold (pain threshold) was evaluated by applying mechanical stimulation to the injected site with von Frey filaments. Ivabradine was subcutaneously injected, combined with carrageenan, and its effect on the pain threshold was evaluated. In addition, we evaluated the effects of ivabradine on the accumulation of leukocytes and TNF-alpha expression in the injected area of rats. Furthermore, we investigated the effects of ivabradine on LPS-stimulated production of TNF-alpha in incubated mouse macrophage- like cells. Results The addition of ivabradine to carrageenan increased the pain threshold lowered by carrageenan injection. Both lamotrigine and forskolin, activators of HCN channels, significantly reversed the inhibitory effect of ivabradine on the pain threshold. Ivabradine inhibited thecarrageenan-induced accumulation of leukocytes and TNF-alpha expression in the injected area. Furthermore, ivabradine significantly inhibited LPS-stimulated production of TNFalpha in the incubated cells. Conclusion The results of the present study demonstrated that locally injected ivabradine is effective against carrageenan-induced inflammatory pain via HCN channels. Its effect was considered to involve not only an action on peripheral nerves but also an anti-inflammatory effect.

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  • Notch signaling affects oral neoplasm cell differentiation and acquisition of tumor-specific characteristics Reviewed International journal

    Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Saori Yoshida, Hatsuhiko Maeda, Toshiyuki Kawakami, Hitoshi Nagatsuka

    International Journal of Molecular Sciences   20 ( 8 )   2019.4

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    Histopathological findings of oral neoplasm cell differentiation and metaplasia suggest that tumor cells induce their own dedifferentiation and re-differentiation and may lead to the formation of tumor-specific histological features. Notch signaling is involved in the maintenance of tissue stem cell nature and regulation of differentiation and is responsible for the cytological regulation of cell fate, morphogenesis, and/or development. In our previous study, immunohistochemistry was used to examine Notch expression using cases of odontogenic tumors and pleomorphic adenoma as oral neoplasms. According to our results, Notch signaling was specifically associated with tumor cell differentiation and metaplastic cells of developmental tissues. Notch signaling was involved in the differentiation of the ductal epithelial cells of salivary gland tumors and ameloblast-like cells of odontogenic tumors. However, Notch signaling was also involved in squamous metaplasia, irrespective of the type of developmental tissue. In odontogenic tumors, Notch signaling was involved in epithelial–mesenchymal interactions and may be related to tumor development and tumorigenesis. This signaling may also be associated with the malignant transformation of ameloblastomas. Overall, Notch signaling appears to play a major role in the formation of the characteristic cellular composition and histological features of oral neoplasms, and this involvement has been reviewed here.

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  • Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma Reviewed International journal

    Rieko Shimizu, Soichiro Ibaragi, Takanori Eguchi, Daisuke Kuwajima, Shinichi Kodama, Takashi Nishioka, Tatsuo Okui, Kyoichi Obata, Kiyofumi Takabatake, Hotaka Kawai, Kisho Ono, Kuniaki Okamoto, Hitoshi Nagatsuka, Akira Sasaki

    International Journal of Oncology   54 ( 1 )   283 - 294   2019.1

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    Epidermal growth factor (EGF) is overexpressed in many cancers and is associated with worse prognosis. EGF binds to its cell surface receptor (EGFR), which induces EGFR phosphorylation. Phosphorylated EGFR (p-EGFR) is translocated into the nucleus, which increases cancer cell activity. Nicotine, which is one of the main components of tobacco, is absorbed through pulmonary alveoli and mucosal epithelia in the head and neck region by smoking and moves into the blood. Nicotine in blood binds to nicotinic acetylcholine receptor (nAChR) in the central nervous system and serves a crucial role in tobacco addiction. Although nAChR localization is thought to be limited in the nervous system, nAChR is present in a wide variety of non-neuronal cells, including cancer cells. Recent studies suggest that nicotine contributes to the metastasis and resistance to anti-cancer drugs of various cancer cells. However, it remains unknown whether head and neck squamous cell carcinoma (HNSCC) cells can utilize nicotine-nAChR signaling to metastasize and acquire resistance to anti-cancer drugs, even though the mucosal epithelia of the head and neck region are the primary sites of exposure to tobacco smoke. To the best of our knowledge, the present study is the first to demonstrate the role of nicotine in metastasis and anti-EGFR-therapy resistance of HNSCC. The present findings demonstrated that nicotine increased proliferation, migration, invasion, p-EGFR nuclear translocation and protein kinase B (Akt) phosphorylation in HNSCC cells. It was also demonstrated that nicotine restored cetuximab-inhibited proliferation, migration and invasion of HNSCC cells. Finally, an in vivo experiment revealed that nicotine increased lymph node metastasis of xenografted tumors, whereas an nAChR inhibitor suppressed lymph node metastasis and p-EGFR nuclear localization of xenografted tumors. Taken together, these results demonstrated that nicotine induced nuclear accumulation of p-EGFR, and activation of Akt signaling. These signaling pathways elevated the activities of HNSCC cells, causing lymph node metastasis and serving a role in cetuximab resistance.

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  • Immunohistochemistry of YAP and dNp63 and survival analysis of patients bearing precancerous lesion and oral squamous cell carcinoma Reviewed International journal

    Sawako Ono, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka

    International Journal of Medical Sciences   16 ( 5 )   766 - 773   2019

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    Background: Yes-associated protein (YAP) is a candidate oncogene in various human cancers, and recently, it has been reported that YAP expression and its activity was enhanced by ΔNp63. However, the role of YAP and ΔNp63 expression in carcinogenesis and progression of oral squamous cell carcinoma (OSCC) has been unknown. Therefore, we investigated how YAP and ΔNp63 influence carcinogenesis and progression of OSCC. Methods: We performed immunohistochemical analyses in whole tissue samples to investigate YAP and ΔNp63 expression in normal oral mucosa, epithelial hyperplasia, oral epithelial dysplasia (OED; low/high grade), carcinoma in situ (CIS), and OSCC. Furthermore, in OSCC, we analyzed clinical significance by using Kaplan-Meier survival analysis. Results: In normal oral mucosa and epithelial hyperplasia, YAP expression was primarily confined to the basal and parabasal layers, but YAP expression was elevated in OED, CIS, and OSCC. In OED, YAP and ΔNp63 expression levels were markedly higher in high grade than in low grade. In OSCC groups, YAP and ΔNp63 expression patterns tended to differ according to histopathological differentiation of OSCC. Furthermore, the YAP high expression group, which showed YAP staining in >50% positive cells with strong cytoplasmic staining or >10% positive cells with nuclear reactivity, showed a tendency to have a poor survival rate. Conclusion: YAP and ΔNp63 expression levels correlated with grade of oral OED. Additionally, YAP expression was associated with OSCC survival rate. Our results suggested that YAP and ΔNp63 expression might serve as predictive markers to distinguish OSCC development and progression.

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  • In vivo tissue response of endodontic bio-ceramic materials

    Teresita Romano, María Victoria Jammal, Keisuke Nakano, Ana García Rusco, Jorge Olmos Fassi, Silvia Kozuszko, Kiyofumi Takabatake, Hitoshi Nagatsuka, Liliana Raquel Missana

    Journal of Hard Tissue Biology   28 ( 1 )   1 - 6   2019

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    In order to evaluate the biocompatibility and mineral repair capacity, mineral trioxide aggregate (MTA), portland cement normal setting (PCn) and fast setting (PCf) and calcium hydroxide-based paste (Calen) filled silicone tube were implanted into the dorsal subcutaneous connective tissues of 25 Wistar rats. Animals were euthanized at 24, 72 hours, 7, 15 and 30 days. Implants with surrounding tissues were fixed with 10% buffer formaldehyde and processed for histological routine techniques. Slides (5 µm serial cuts) were stained with H&E and Von Kossa stains for morphological, qualitative and quantitative analysis by light microscopy. Calen showed severe and moderate inflammatory response and granuloma-tous reaction with psammoma body-like formation. PCn and MTA have similar behavior, with mild inflammatory reaction from 8% and 4%, respectively. Even though, PCn and MTA demonstrated analogous biological reaction, MTA developing thick artificial mineral precipitation (p = 0,007). All sealers demonstrated a similar inflammatory response at all time periods studied (p = 0.678).

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  • Whitish-Yellow Tumor on its Characteristic Cut Surface: A Case Report of Congenital Granular Cell Epulis

    Kenichi Mizutani, Munenori Mukai, Hitoshi Nagatsuka, Sohsuke Yamada

    Clinical Pathology   12   2019

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    Introduction: Congenital granular cell epulis is a rare and benign lesion in newborn. There are some papers of the entity; however, there are very few reports focusing on its macroscopic view. Case Presentation: A 0-day-old boy was noted to have a mass consisting of multiple nodules on maxillary gingiva, and it was excised. The mass was measured about 2 cm in its greatest diameter. Surface of cross-section was characteristically whitish-yellow and very smooth. Histopathologically, the lesion was composed of a proliferation of large polygonal cells with demarcated cell membrane, granular cytoplasm, and small uniform nuclei. Immunohistochemically, these cells were negative for S100. The diagnosis was concluded as congenital granular cell epulis. Discussion and Conclusion: We reported a typical case of congenital granular cell epulis. It is noteworthy that the cross-section observed in this case was very characteristically whitish-yellow and smooth.

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  • An in vitro three-dimensional co-culture system for ameloblastoma modelling Reviewed

    Soo Leng Lee, Zainal Ariff Abdul Rahman, Hidetsugu Tsujigiwa, Mei Hamada, Kiyofumi Takabatake, Keisuke Nakano, Hitoshi Nagatsuka, Chong Huat Siar

    Sains Malaysiana   48 ( 8 )   1697 - 1706   2019

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    Ameloblastoma, the most clinically significant odontogenic epithelial tumor, is a locally-invasive and destructive lesion in the jawbones. However, the nature of this infiltrativeness and destructive behavior remains ill-understood. To address this, we established an in vitro three-dimensional (3D) co-culture system to simulate an amelobastoma disease model aimed at investigating the interactions between tumor cells and osteoblasts. Osteoblastic cell lines (KUSA/A1 and MC3T3-E1) and one stromal cell line (ST2) were separately co-seeded with ameloblastoma-derived cell line (AM-1) in a collagen scaffold (representing the extracellular bone matrix) and incubated with mineralization medium. Immunohistochemistry, double immunofluorescence and mineralization assay were performed. Only AM-1/KUSA-A1 co-culture showed a significant increase in AM-1 cell count, suggesting that heterotypic cell-cell interaction promotes tumoral cell growth, while formation of visible AM-1 epithelial nest-like structures resembling ameloblastoma cells in their native state, suggest morphodifferentiation. A RANK-high, RANKL-low and osteoprotegerin-low immunoprofile in co-culture AM-1 cells implies deregulated osteoclastogenesis. Mineralization assays showed diminished calcification in AM-1/KUSA-A1 co-culture extracellular matrix suggesting an altered local bone metabolism. In contrast, KUSA/A1 monocultures showed abundant extracellular matrix calcification. Taken together, these results suggest that a 3D co-culture system as an amelobastoma disease model provides insights that bidirectional ameloblastoma-osteoblastic interactions might play a role in modulating tumor growth and osteoclastogenesis.

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  • Biomechanical loading comparison between titanium and unsintered hydroxyapatite/poly-L-lactide plate system for fixation of mandibular subcondylar fractures Reviewed International journal

    Shintaro Sukegawa, Takahiro Kanno, Norio Yamamoto, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

    Materials   12 ( 9 )   2019

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    Osteosynthesis absorbable materials made of uncalcined and unsintered hydroxyapatite (u-HA) particles, poly-l-lactide (PLLA), and u-HA/PLLA are bioresorbable, and these plate systems have feasible bioactive osteoconductive capacities. However, their strength and stability for fixation in mandibular subcondylar fractures remain unclear. This in vitro study aimed to assess the biomechanical strength ofu-HA/PLLAbioresorbable plate systems after internal fixation of mandibular subcondylar fractures. Tensile and shear strength were measured for each u-HA/PLLA and titanium plate system. To evaluate biomechanical behavior, 20 hemimandible replicas were divided into 10 groups, each comprising a titanium plate and a bioresorbable plate. A linear load was applied anteroposteriorly and lateromedially to each group to simulate the muscular forces in mandibular condylar fractures. All samples were analyzed for each displacement load and the displacement obtained by the maximum load. Tensile and shear strength of the u-HA/PLLA plate were each approximately 45% of those of the titanium plates. Mechanical resistance was worst in the u-HA/PLLA plate initially loaded anteroposteriorly. Titanium plates showed the best mechanical resistance during lateromedial loading. Notably, both plates showed similar resistance when a lateromedially load was applied. In the biomechanical evaluation of mandibular condylar fracture treatment, the u-HA/PLLA plates had sufficiently high resistance in the two-plate fixation method.

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  • Feasible advantage of bioactive/bioresorbable devices made of forged composites of hydroxyapatite particles and poly-L-lactide in alveolar bone augmentation: A preliminary study Reviewed International journal

    Shintaro Sukegawa, Hotaka Kawai, Keisuke Nakano, Takahiro Kanno, Kiyofumi Takabatake, Hitoshi Nagatsuka, Yoshihiko Furuki

    International Journal of Medical Sciences   16 ( 2 )   311 - 317   2019

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    Purpose: We aimed to document the clinical usefulness of uncalcined and unsintered hydroxyapatite (u-HA) particles and poly-L-lactide (PLLA) composite materials and their advantageous properties. Methods: Between April 2016 and March 2018, five patients required anterior maxillary alveolar ridge augmentation using fixation with u-HA/PLLA screws for an onlay block bone graft harvested from the mandibular ramus at our institute. Bone biopsies were obtained from the dental implantation site following bone healing for histomorphometric and immunohistochemical (IHC) measurements. Results: Many stromal cells were positive for Osterix, RUNX2, and SOX9 but were negative for CD68. On cell counting, based on IHC staining for Osterix, RUNX2, SOX9 and CD68 from peripheral u-HA/PLLA screw or bone areas, both areas consistently showed no significant difference in terms of Osterix, RUNX2, and SOX9. Hematoxylin-eosin staining revealed direct bone connection to the biomaterials, and no inflammatory cells infiltrated the areas surrounding the bone or artificial material. Area between the bone and u-HA/PLLA screw was seamless with no boundary. Round small cells and immature fibroblasts were noted. The new bone showed the presence of bone lamellae, normal osteocytes, and osteoblasts. Conclusion: The u-HA/PLLA materials showed excellent biodegradability and bioactive osteoconductivity. In addition, this material induced no apparent inflammatory or foreign body reactions following implantation, and it directly bonded to the human bone. Therefore, this u-HA/PLLA material seems ideal and most suitable for use as a substitute for osteosynthesis.

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  • Differentiation and roles of bone marrow-derived cells on the tumor microenvironment of oral squamous cell carcinoma Reviewed International journal

    Chang Anqi, Kiyofumi Takabatake, Hotaka Kawai, O. O. May Wathone, Saori Yoshida, Masae Fujii, Haruka Omori, Shintaro Sukegawa, Keisuke Nakano, Hidetsugu Tsujigiwa, Zheng Jinhua, Hitoshi Nagatsuka

    Oncology Letters   18 ( 6 )   6628 - 6638   2019

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    The stroma affects the properties and dynamics of the tumor. Previous studies have demonstrated that bone marrow-derived cells (BMDCs) possess the capability of differentiating into stromal cells. However, the characteristics and roles of BMDCs in oral squamous cell carcinoma remain unclear. The current study therefore investigated their locations and features by tracing green fluorescent protein (GFP)-labeled BMDCs in a transplantation mouse model. After irradiation, BALB-c nu-nu mice were injected with bone marrow cells from C57BL/6-BALB-C-nu/nu-GFP transgenic mice. These recipient mice were then injected subcutaneously in the head with human squamous cell carcinoma-2 cells. Immunohistochemistry for GFP, Vimentin, CD11b, CD31 and α-smooth muscle actin (SMA), and double-fluorescent immunohistochemistry for GFP-Vimentin, GFP-CD11b, GFP-CD31 and GFP-α-SMA was subsequently performed. Many round-shaped GFP-positive cells were observed in the cancer stroma, which indicated that BMDCs served a predominant role in tumorigenesis. Vimentin(+) GFP(+) cells may also be a member of the cancer-associated stroma, originating from bone marrow. Round or spindle-shaped CD11b(+) GFP(+) cells identified in the present study may be macrophages derived from bone marrow. CD31(+)GFP(+) cells exhibited a high tendency towards bone marrow-derived angioblasts. The results also indicated that spindle-shaped α-SMA(+) GFP(+) cells were not likely to represent bone marrow-derived cancer-associated fibroblasts. BMDCs gathering within the tumor microenvironment exhibited multilineage potency and participated in several important processes, such as tumorigenesis, tumor invasion and angiogenesis.

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  • Do the presence of mandibular third molar and the occlusal support affect the occurrencand the mode of mandibular condylar fractures? Reviewed

    Shintaro Sukegawa, Masato Saika, Takahiro Kanno, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

    Journal of Hard Tissue Biology   28 ( 4 )   377 - 382   2019

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    To investigate the influence of occlusal support and the presence and position of mandibular third molars on the incidence of mandibular condylar fractures. Records of 222 patients who presented with mandibular fracture at the Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, from 2006 to 2019 were retrospectively analyzed. The following variables were investigated: age, sex, cause of fracture, the presence and state (impaction and angula-tion) of mandibular third molars, the site of mandibular fracture, and the presence of occlusal support for molars. Various risk factors for mandibular condylar head and subcondylar fractures were investigated. The majority of fractures were caused by a fall. The risk of mandibular subcondylar fractures was significantly higher in patients with occlusal support and mandibular third molars. The risk of mandibular condylar head fractures was significantly higher in patients without occlusal support or mandibular third molars. The position and angulation of mandibular third molars did not show significant difference between occurrences of head or subcondylar fractures. This study demonstrated that occlusal support and the presence of mandibular third molars significantly increased the risk of subcondylar fractures. One the contrary, their absence increased the risk of condylar head fractures.

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  • 舌扁平上皮癌における新TNM分類(UICC:第8版)の実用性

    吉田 祥子, 岸本 晃治, 村瀬 友里香, 伊原木 聰一郎, 吉岡 徳枝, 奥井 達雄, 長塚 仁, 佐々木 朗

    日本口腔腫瘍学会誌   30 ( 4 )   151 - 157   2018.12

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    UICCのTNM分類は、口腔癌の進行度評価の基準にされているが、2016年に第8版へ改訂され、T分類では浸潤の深さ(Depth of Invasion:DOI)が、N分類では被膜外進展(Extra Nodal Extension:ENE)が導入された。本研究では、当科で手術を行った舌扁平上皮癌症例107例において、第7版と第8版TNM分類により評価を行い、TNM分類改訂と頸部リンパ節後発転移(以下後発転移)および生存率との関連について検討を行った。TNM分類改訂により、17例(15.9%)にcTの変更を、6例(5.6%)にpTの変更を認めた。後発転移数・後発転移率は、cT1とpT1では低下し、cT2とpT2では増加した。また、第7版でcT4a、pT4aの2例が、第8版ではcT3、pT3に変更されたため、第8版は第7版と比較してcT3、pT3の生存率が低下した。第7版でpN2bの3例が、第8版ではpN3bに分類され、3例とも経過不良であった。当科の舌扁平上皮癌症例におけるTNM分類の第7版から第8版への見直しは、主にStage上昇につながった。そして、第8版TNM分類は、舌扁平上皮癌の進行度をより的確に後発転移と生存率へ反映させるため、実用的であると考えられた。(著者抄録)

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  • ニコチンは口腔扁平上皮癌細胞のセツキシマブ耐性を促進する

    清水 理恵子, 伊原木 聰一郎, 江口 傑徳, 奥井 達雄, 高畠 清文, 河合 穂高, 小野 喜章, 岡元 邦彰, 長塚 仁, 佐々木 朗

    岡山歯学会雑誌   37 ( 2 )   80 - 81   2018.12

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  • Significance of PD-L1 expression in tongue cancer development Reviewed International journal

    Saori Yoshida, Hitoshi Nagatsuka, Keisuke Nakano, Yasunao Kogashiwa, Yasuhiro Ebihara, Mitsutake Yano, Masanori Yasuda

    International Journal of Medical Sciences   15 ( 14 )   1723 - 1730   2018.10

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    Aims: Immunohistochemistry of PD-L1 has been recently established as a surrogate method to predict if immunotherapy targeting PD-L1/PD-1 has a significant effect on suppression of cancers such as lung non-small cell carcinoma, melanoma, and renal cell carcinoma. Here we performed immunohistochemistry for PD-L1 expression in squamous cell carcinoma (SCC) of the tongue to investigate the potential correlation between PD-L1 expression and clinicopathological factors and whether PD-L1 expression would be associated with prognosis. Methods: Tissue microarray cores of paraffin-embedded blocks from 135 cases with surgically resected tongue SCC were immunohistochemically analysed for PD-L1 expression. Results: We observed a positive correlation between PD-L1 expression and tongue SCC pT1 and pT2 tumours, but a negative correlation with pT2, pT3 and pT4 tumours. We also observed a positive correlation with lymph node metastasis. However, no positive correlation was demonstrated between PD-L1 expression and overall survival. Conclusions: PD-L1 tends to be overexpressed at the early stage of tongue SCC, showing a close correlation with initial development of tongue. However, PD-L1 expression may not affect prognosis.

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  • Effects of the geometrical structure of a honeycomb TCP on relationship between bone/ cartilage formation and angiogenesis Reviewed International journal

    Hiroyuki Matsuda, Kiyofumi Takabatake, Hidetsugu Tsujigiwa, Satoko Watanabe, Satoshi Ito, Hotaka Kawai, Mei Hamada, Saori Yoshida, Keisuke Nakano, Hitoshi Nagatsuka

    International Journal of Medical Sciences   15 ( 14 )   1582 - 1590   2018.10

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    A number of biomaterials have been developed, some of which already enjoy widespread clinic use. We have devised a new honeycomb tricalcium phosphate (TCP) containing through-and-through holes of various diameters to control cartilage and bone formation. However, the way in which the geometric structure of the honeycomb TCP controls cartilage and bone tissue formation separately remains unknown. In addition, an association has been reported between bone formation and angiogenesis. Therefore, in the present study, we investigated the relationship between angiogenesis and various hole diameters in our honeycomb TCP over time in a rat ectopic hard tissue formation model. Honeycomb TCPs with hole diameters of 75, 300, and 500 µm were implanted into rat femoral muscle. Next, ectopic hard tissue formation in the holes of the honeycomb TCP was assessed histologically at postoperative weeks 1, 2, and 3, and CD34 immunostaining was performed to evaluate angiogenesis. The results showed that cartilage formation accompanied by thin and poor blood vessel formation, bone marrow-like tissue with a branching network of vessels, and vigorous bone formation with thick linear blood vessels occurred in the TCPs with 75-µm, 300-µm, and 500-µm hole diameters, respectively. These results indicated that the geometrical structure of the honeycomb TCP affected cartilage and bone tissue formation separately owing to the induced angiogenesis and altered oxygen partial pressure within the holes.

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  • A case of sublingual adenoid cystic carcinoma involving the mandible presenting as a “skip lesion”

    Mariko Fujita, Yoshinobu Yanagi, Arthur R.G. Cortes, Emiko Saito Arita, Tomoo Onoda, Hitoshi Nagatsuka, Jun ichi Asaumi

    Oral Radiology   34 ( 3 )   281 - 287   2018.9

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    Adenoid cystic carcinoma (ACC) is a slowly growing malignant neoplasm with a propensity for perineural invasion. Microscopic invasion of ACC often prevents its detection on computed tomography (CT) or magnetic resonance imaging (MRI). We herein report a rare case of sublingual ACC presenting as a “skip lesion” that rapidly infiltrated the mandible after tumor resection. A 64-year-old man presented to Okayama University Hospital with an 18-month history of swelling in the right floor of the mouth. Clinical examination displayed an ulcerated swollen mass in that region. An enhanced mass was detected in the right sublingual space on CT and MRI. Bone surface erosion was observed at the inferior border of the mandible, but continuity with the sublingual mass or mass around that lesion was not detected by imaging. Sublingual tumor resection and selective neck dissection were performed by the pull-through method. Histopathologically, the surgical margins were free of cancer cells, and the tumor was diagnosed as ACC. Continuity with the sublingual mass and mandibular bone was not detected intraoperatively. However, marked bone resorption was detected in the anterior mandible 3 months after the operation. Biopsy was performed, and the findings indicated the same histological type of sublingual ACC. This case suggests that a malignant tumor close to the jaw bone requires the clinician to consider the possibility of bone invasion and to observe a wide region surrounding the tumor using imaging examination.

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  • Involvement of miR-140-3p in Wnt3a and TGFβ3 signaling pathways during osteoblast differentiation in MC3T3-E1 cells Reviewed International journal

    Shigeko Fushimi, Tsutomu Nohno, Hitoshi Nagatsuka, Hironobu Katsuyama

    Genes to Cells   23 ( 7 )   517 - 527   2018.7

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    The Wnt/β-catenin signaling and TGFβ signaling pathways play a key role in osteoblast differentiation. The miRNAs play important roles in regulating gene expression at the post-transcriptional level through fine-tuning of protein-encoding gene expression. However, involvement of miRNAs is not established for Wnt3a and TGFβ signaling pathways in osteoblast differentiation. Here, we examined the role of miRNAs expressed differentially after Wnt3a expression during osteoblast differentiation. Over-expression of the Wnt3a gene increased ALP transcription, but decreased Col1, Runx2, and OCN transcription in osteoblastic MC3T3-E1 cells. Expression profiling and quantitative PCR for miRNAs showed that miR-140-3p decreased in Wnt3a-over-expressing osteoblastic cells. Wnt3a over-expression increased TGFβ3 expression, whereas transfection of the miR-140-3p mimic into MC3T3-E1 cells significantly inhibited TGFβ3 expression. Luciferase assay for the TGFβ3 transcript showed that TGFβ3 was a direct target of miR-140-3p. miR-140-3p mimic transfection resulted in significantly increased OCN transcription, but did not affect ALP, Col1, and Runx2 transcription in MC3T3-E1 cells. rTGFβ3 treatment decreased OCN transcription in MC3T3-E1 cells. These results suggest that the miR-140-3p is involved in osteoblast differentiation as a critical regulatory factor between Wnt3a and TGFβ3 signaling pathways.

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  • Cell supplying to the experimentally induced absorbable suture thread foreign body granuloma from the bone marrow tissues

    Y. Nakayasu, S. Aoki, M. Shoumura, N. Osuga, N. Okafuji, K. Nakano, H. Nagatsuka, H. Tsujigiwa, Toshiyuki Kawakami

    International Journal of Dentistry and Oral Science   5 ( 6 )   641 - 644   2018.6

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    Using the experimental system of GFP (Green florescence Protein) bone marrow transplanted rats, we implanted the Vicryl absorbable suture thread in subcutaneous tissue and examined the formation of foreign body granuloma histopathologically. We also compared the main cellular components, namely, the macrophage and foreign body giant cell immunohistochemically using GFP to confirm their origin. Histologically, the disintegrated suture thread was observed as a circular in void surrounded by the proliferation of macrophages and foreign body giant cells. Fibrous connective tissue including the fibroblasts was interposed among large masses. Even after 6 months, some clusters considered to be residues of macrophages that grew on the suture were still remained. Immunohistochemical examination of GFP showed that all proliferated macrophages and foreign body giant cells were GFP-positive. However, the relatively thin fibrous tissues formed on the outermost layer of the granulation tissue growth were mostly GFP-negative. Based on the results of the experiment, the macrophages and foreign body giant cells that are GFP-positive were derived from the mesenchymal tissue of transplanted bone marrow tissues.

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  • The role of bone marrow-derived cells during ectopic bone formation of mouse femoral muscle in GFP mouse bone marrow transplantation model Reviewed International journal

    Kiyofumi Takabatake, Hidetsugu Tsujigiwa, Yu Song, Hiroyuki Matsuda, Hotaka Kawai, Masae Fujii, Mei Hamada, Keisuke Nakano, Toshiyuki Kawakami, Hitoshi Nagatsuka

    International Journal of Medical Sciences   15 ( 8 )   748 - 757   2018.5

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    Multipotential ability of bone marrow-derived cells has been clarified, and their involvement in repair and maintenance of various tissues has been reported. However, the role of bone marrow-derived cells in osteogenesis remains unknown. In the present study, bone marrow-derived cells during ectopic bone formation of mouse femoral muscle were traced using a GFP bone marrow transplantation model. Bone marrow cells from C57BL/6-Tg (CAG-EGFP) mice were transplanted into C57BL/6 J wild type mice. After transplantation, insoluble bone matrix (IBM) was implanted into mouse muscle. Ectopic bone formation was histologically assessed at postoperative days 7, 14, and 28. Immunohistochemistry for GFP single staining and GFP-osteocalcin double staining was then performed. Bone marrow transplantation successfully replaced hematopoietic cells with GFP-positive donor cells. Immunohistochemical analyses revealed that osteoblasts and osteocytes involved in ectopic bone formation were GFP-negative, whereas osteoclasts and hematopoietic cells involved in bone formation were GFP-positive. These results indicate that bone marrow-derived cells might not differentiate into osteoblasts. Thus, the main role of bone marrow-derived cells in ectopic osteogenesis may not be to induce bone regeneration by differentiation into osteoblasts, but rather to contribute to microenvironment formation for bone formation by differentiating tissue stem cells into osteoblasts.

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  • The prognostic implications of bone invasion in gingival squamous cell Carcinoma Reviewed International journal

    Shoko Yoshida, Tsuyoshi Shimo, Yurika Murase, Kiyofumi Takabatake, Koji Kishimoto, Soichiro Ibaragi, Norie Yoshioka, Tatsuo Okui, Hitoshi Nagatsuka, Akira Sasaki

    Anticancer Research   38 ( 2 )   955 - 962   2018.2

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    Background/Aim: This study evaluated the associations between bone invasion of gingival squamous cell carcinoma (SCC) and clinicopathological manifestations, and aimed to determine whether bone invasion is an independent prognostic factor in gingival SCC. Patients and Methods: The study was a retrospective review of 78 patients with gingival SCC who underwent surgery with curative intent. The level of bone invasion was pathologically categorized as medullary, cortical or no bone invasion. Results: Cortical and medullary bone invasion was present in 29 and 22 patients, respectively. There was a significant association between medullary bone invasion and tumor size (p=0.017), pathological N classification (p0.001), differentiation (p=0.017) and lymphovascular invasion (p=0.007). Medullary bone invasion and lymphovascular invasion were independent predictors of reduced overall survival (p=0.015, 0.048); medullary bone invasion was also an independent predictor of reduced disease-specific survival (p=0.018). Conclusion: Pathologically-proven medullary bone invasion and lymphovascular invasion were found to be key prognostic factors in gingival SCC. The results suggest that it is necessary to consider adjuvant therapy in patients with medullary bone invasion.

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  • Characterization and potential roles of bone marrow-derived stromal cells in cancer development and metastasis Reviewed International journal

    Hotaka Kawai, Hidetsugu Tsujigiwa, Chong Huat Siar, Keisuke Nakano, Kiyofumi Takabatake, Masae Fujii, Mei Hamada, Ryo Tamamura, Hitoshi Nagatsuka

    International Journal of Medical Sciences   15 ( 12 )   1406 - 1414   2018

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    Background: The tumor microenvironment and its stromal cells play an important role in cancer development and metastasis. Bone marrow-derived cells (BMDCs), a rich source of hematopoietic and mesenchymal stem cells, putatively contribute to this tumoral stroma. However their characteristics and roles within the tumor microenvironment are unclear. In the present study, BMDCs in the tumor microenvironment were traced using the green fluorescent protein (GFP) bone marrow transplantation model. Methods: C57BL/6 mice were irradiated and rescued by bone marrow transplantation from GFP-transgenic mice. Lewis lung cancer cells were inoculated into the mice to generate subcutaneous allograft tumors or lung metastases. Confocal microscopy, immunohistochemistry for GFP, α-SMA, CD11b, CD31, CD34 and CD105, and double-fluorescent immunohistochemistry for GFP-CD11b, GFP-CD105 and GFP-CD31 were performed. Results: Round and dendritic-shaped GFP-positive mononuclear cells constituted a significant stromal subpopulation in primary tumor peripheral area (PA) and metastatic tumor area (MA) microenvironment, thus implicating an invasive and metastatic role for these cells. CD11b co-expression in GFP-positive cells suggests that round/dendritic cell subpopulations are possibly BM-derived macrophages. Identification of GFP-positive mononuclear infiltrates co-expressing CD31 suggests that these cells might be BM-derived angioblasts, whereas their non-reactivity for CD34, CD105 and α-SMA implies an altered vascular phenotype distinct from endothelial cells. Significant upregulation of GFP-positive, CD31-positive and GFP/CD31 double-positive cell densities positively correlated with PA and MA (P<0.05). Conclusion: Taken together, in vivo evidence of traceable GFP-positive BMDCs in primary and metastatic tumor microenvironment suggests that recruited BMDCs might partake in cancer invasion and metastasis, possess multilineage potency and promote angiogenesis.

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  • Osteogenic capacity of mixed-acid and heat-treated titanium mesh prepared by a selective laser melting technique

    Kayoko Yamamoto, Seiji Yamaguchi, Tomiharu Matsushita, Shigeo Mori, Azumi Hirata, Nahoko Kato-Kogoe, Hiroyuki Nakano, Yoichiro Nakajima, Yoshihiro Nishitani, Hitoshi Nagatsuka, Takaaki Ueno

    RSC Advances   8 ( 46 )   26069 - 26077   2018

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    The practical use of additive manufacturing to create artificial bone as a material for repairing complex bone defects is currently attracting attention. In this study, we compared the osteogenic capacity of materials composited by the method developed by Kokubo et al. of treating 3D-printed titanium (Ti) mesh with a mixture of H2SO4 and HCl and heating (mixed-acid and heat treatment) with that of materials subjected to conventional chemical treatment. Ti plates treated with this method have been found to promote highly active bone formation on their surface when inserted into rabbit tibial bone defects. No previous study has compared this method with other surface treatment methods. In this study, we used histological and other observations to compare the bone formation process in bone defects when Ti meshes prepared by the selective laser melting technique (SLM) and treated either with mixed acids and heat or with conventional chemical Ti surface treatments were implanted in a rat calvarial bone defect model. We found that both micro-computed tomography and observations of undecalcified ground sections showed that the best bone formation was observed in rats implanted with mesh treated with mixed acids and heat. Our results suggest that mixed-acid and heat-treated Ti mesh prepared by SLM may have a high osteogenic capacity in bone defects.

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  • In vitro efficacy of CaCO<inf>3</inf> content in CaTiO<inf>3</inf> - CaCO<inf>3</inf> composites for bone growth Reviewed

    Andrea Paola Rodríguez, María Alejandra Sánchez, Betiana Felice, Martín Lucas Zamora, Hidetsugu Tsujigiwa, Kiyofumi Takabatake, Hotaka Kawai, Keisuke Nakano, Hitoshi Nagatsuka

    Journal of Hard Tissue Biology   27 ( 3 )   250 - 256   2018

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    The effect of CaTiO3 compounded with different amounts of CaCO3 on osteoblastic KUSA/A1 cells was evaluated. CaTiO3-CaCO3 composites were obtained by alkoxide method, a simple, low-cost and reproducible technique used for large-scale production of material. The content of CaCO3 in our samples was controlled by varying the sintering time of the overall process. Composite morphology was assessed by scanning electron microscopy (SEM) showing particles with sizes ranging from100 to 500 nm. The presence of CaCO3 was revealed by XRD and thermogravimetric analyses, which suggested that samples treated at 650ºC for 30 min contained higher amounts of CaCO3 than samples treated for 2 and 10 h. Additionally, in vitro studies demonstrated that CaTiO3–CaCO3 composites sintered for 30 min induced augmented cell proliferation and mineralization in comparison to composites sintered for longer periods of time. Hence, our findings clearly suggest that the amount of CaCO3 within CaTiO3-CaCO3 composites exerts a critical effect on osteoblastic cells response. Enhanced bone regeneration could be achieved by increasing the content of CaCO3 within the composites, thus establishing CaTiO3-CaCO3 as a promising material for bone augmentation procedures in dental field.

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  • DKK3 overexpression increases the malignant properties of head and neck squamous cell carcinoma cells Reviewed International journal

    Naoki Katase, Shin Ichiro Nishimatsu, Akira Yamauchi, Masahiro Yamamura, Kumiko Terada, Masumi Itadani, Naoko Okada, Nur Mohammad Monsur Hassan, Hitoshi Nagatsuka, Tohru Ikeda, Tsutomu Nohno, Shuichi Fujita

    Oncology Research   26 ( 1 )   45 - 58   2018

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    DKK3, a member of the dickkopf Wnt signaling pathway inhibitor family, is believed to be a tumor suppressor because of its reduced expression in cancer cells. However, our previous studies have revealed that DKK3 expression is predominantly observed in head and neck/oral squamous cell carcinoma (HNSCC/OSCC). Interestingly, HNSCC/OSCC patients with DKK3 expression showed a high rate of metastasis and poorer survival, and siRNA-mediated knockdown of DKK3 in HNSCC-derived cancer cell lines resulted in reduced cellular migration and invasion. From these data, it was hypothesized that DKK3 might exert an oncogenic function specific to HNSCC. In the present research, the DKK3 overexpression model was established, and its influences were investigated, together with molecular mechanism studies. The DKK3 expression profile in cancer cell lines was investigated, including HNSCC/OSCC, esophageal, gastric, colorectal, pancreatic, prostatic, and lung cancers. DKK3 overexpression was performed in HNSCC-derived cells by transfection of expression plasmid. The effects of DKK3 overexpression were assessed on cellular proliferation, migration, invasion, and in vivo tumor growth. The molecular mechanism of DKK3 overexpression was investigated by Western blotting and microarray analysis. DKK3 overexpression significantly elevated cellular proliferation, migration, and invasion, as well as increased mRNA expression of cyclin D1 and c-myc. However, reporter assays did not show TCF/LEF activation, suggesting that the increased malignant property of cancer cells was not driven by the Wnt/β-catenin pathway. For the investigation of the pathways/molecules in DKK3-mediated signals, the Western blot analyses revealed that phosphorylation of Akt (S473) and c-Jun (Ser63) was elevated. The application of a PI3K kinase inhibitor, LY294002, on HSC-3 DKK3 cells significantly decreased tumor cell proliferation, migration, and invasion. From these results, we demonstrated that DKK3 might contribute to cellular proliferation, invasion, migration, and tumor cell survival in HNSCC cells through a mechanism other than the canonical Wnt signaling pathway, which might be attributed to PI3K-Akt signaling.

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  • Role of neurokinin 3 receptor signaling in oral squamous cell carcinoma International journal

    Kyoichi Obata, Tsuyoshi Shimo, Tatsuo Okui, Kenichi Matsumoto, Hiroyuki Takada, Kiyofumi Takabatake, Yuki Kunisada, Soichiro Ibaragi, Norie Yoshioka, Koji Kishimoto, Hitoshi Nagatsuka, Akira Sasaki

    Anticancer Research   37 ( 11 )   6119 - 6123   2017.11

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    Background/Aim: The neurokinin 3 receptor (NK-3R) is differentially expressed in the central nervous system including cases of human oral squamous cell carcinoma. However, the role of NK-3R signaling in oral squamous cell carcinoma is not well known. Materials and Methods: NK-3R expression in surgically resected oral squamous cell carcinoma was examined immunohistochemically and the strength of the expression was quantified. We evaluated the function of NK-3R signaling using NK-3R antagonist in human oral squamous cell carcinoma bone invasion mouse model. Results: NK-3R was significantly expressed in tumor cells that had invaded the bone matrix compared to the oral side tumor cells. SB222200, a selective antagonist of NK-3R, significantly suppressed the radiographic osteolytic lesion and tumorigenesis. Conclusion: NK-3R signaling is a potential target for the treatment of oral squamous cell carcinoma in cases of bone destruction.

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  • Tertiary lymphoid structures in ameloblastoma Reviewed

    C. H. Siar, Z. A. Bin Abdul Rahman, H. Tsujigiwa, H. Nagatsuka, K. H. Ng

    VIRCHOWS ARCHIV   471   S2 - S2   2017.9

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  • Semaphorin 4D promotes bone invasion in head and neck squamous cell carcinoma International journal

    Hiroyuki Takada, Soichiro Ibaragi, Takanori Eguchi, Tatsuo Okui, Kyoichi Obata, Masanori Masui, Ayaka Morisawa, Kiyofumi Takabatake, Hotaka Kawai, Norie Yoshioka, Nur Mohammad Monsur Hassan, Tsuyoshi Shimo, Guo Fu Hu, Hitoshi Nagatsuka, Akira Sasaki

    International Journal of Oncology   51 ( 2 )   625 - 632   2017.8

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    Head and neck squamous cell carcinomas (HNSCCs) frequently invade the bones of the facial skeleton. Semaphorin 4D (Sema4D) is an axon guidance molecule produced by oligodendrocytes. Sema4D was also identified in the bone microenvironment and many cancer tissues including HNSCC. To date, however, the role of Sema4D in cancer-associated bone disease is still unknown. This is the first study to demonstrate the role of Sema4D in bone invasion of cancer. In the clinical tissue samples of bone lesion of HNSCC, Sema4D was detected at high levels, and its expression was correlated with insulin-like growth factor-I (IGF-I) expression. In vitro experiments showed that IGF-I regulates Sema4D expression and Sema4D increased proliferation, migration and invasion in HNSCC cells. Sema4D also regulated the expression of receptor activator of nuclear factor κβ ligand (RANKL) in osteoblasts, and this stimulated osteoclastgenesis. Fur thermore, knockdown of Sema4D in HNSCC cells inhibited tumor growth and decreased the number of osteoclasts in a mouse xenograft model. Taken together, IGF-I-driven production of Sema4D in HNSCCs promotes osteoclastogenesis and bone invasion.

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  • MCSF orchestrates branching morphogenesis in developing submandibular gland tissue International journal

    Gulsan Ara Sathi, Mahmoud Farahat, Emilio Satoshi Hara, Hiroaki Taketa, Hitoshi Nagatsuka, Takuo Kuboki, Takuya Matsumoto

    Journal of Cell Science   130 ( 9 )   1559 - 1569   2017.5

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    The importance of macrophages in tissue development and regeneration has been strongly emphasized. However, the specific roles of macrophage colony-stimulating factor (MCSF), the key regulator of macrophage differentiation, in glandular tissue development have been unexplored. Here, we disclose new macrophage-independent roles of MCSF in tissue development. We initially found that MCSF is markedly upregulated at embryonic day (E)13.5, at a stage preceding the colonization of macrophages (at E15.5), in mouse submandibular gland (SMG) tissue. Surprisingly, MCSF-induced branching morphogenesis was based on a direct effect on epithelial cells, as well as indirectly, by modulating the expression of major growth factors of SMG growth, FGF7 and FGF10, via the phosphoinositide 3-kinase (PI3K) pathway. Additionally, given the importance of neurons in SMG organogenesis, we found that MCSF-induced SMG growth was associated with regulation of neurturin expression and neuronal network development during early SMG development in an in vitro organogenesis model as well as in vivo. These results indicate that MCSF plays pleiotropic roles and is an important regulator of early SMG morphogenesis.

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  • De novo myoepithelial carcinoma with multiple metastases arising from a submandibular salivary gland: A case report International journal

    Karina Cecília Panelli Santos, Hidenobu Matsuzaki, Teruhisa Unetsubo, Shimo Tsuyoshi, Hitoshi Nagatsuka, Jun Ichi Asaumi

    Oncology Letters   13 ( 4 )   2679 - 2683   2017.4

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    Salivary gland carcinomas are rare tumors, representing ~0.5% of all malignancies. Myoepithelioma is also representing ~1% of all salivary gland tumors. Myoepithelial carcinoma (MC) is even rarer, representing 0.2 to 0.6% of all salivary gland tumors. We herein report a case of MC with multiple metastases arising from a submandibular gland in a 71-year-old male patient and present the associated imaging findings. The patient was considered to have a de novo type of myoepithelial carcinoma, which is reportedly associated with higher malignancy than the transformation type of the disease (i.e., a malignant change from pleomorphic adenoma or myoepithelioma). This was reflected in the multiple lung and bone metastases sites and strong positivity for p53 and Ki-67.

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  • miRNA-mediated crosstalk between Wnt3a and TGFβ3 in osteoblast differentiation

    Fushimi S, Nohno T, Nishimatsu S, Katase N, Terada K, Katsuyama M, Demura M, Saijoh K, Nagatsuka H, Katsuyama H

    The FASEB Journal   31 ( 1Suppl )   757.3   2017.4

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  • Parenchyma–stromal interactions induce fibrosis by secreting CCN2 and promote osteoclastogenesis by stimulating RANKL and CD68 through activated TGF-β/BMP4 in ameloblastoma International journal

    Yuichiro Takebe, Hidetsugu Tsujigiwa, Naoki Katase, Chong Huat Siar, Kiyofumi Takabatake, Masae Fujii, Ryo Tamamura, Keisuke Nakano, Hitoshi Nagatsuka

    Journal of Oral Pathology and Medicine   46 ( 1 )   67 - 75   2017.1

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    Background: Tumor parenchyma–stromal interactions affect the properties of tumors and their dynamics. Our group previously showed that secreted frizzled related protein (sFRP)-2 impairs bone formation and promotes bone invasion in ameloblastoma. However, the effects of the secreted growth factors CCN2, TGF-β, and BMP4 on stromal tissues in ameloblastoma remain unclear. Materials and results: Thirty-five paraffin-embedded ameloblastoma cases, ameloblastoma-derived cell lines (AM-1), and primary cultures of ameloblastoma stromal fibroblasts (ASF) were used. Immunohistochemistry, MTT assay, Western blotting, and RT-PCR were performed on these samples. Parenchyma–stromal CCN2 overexpression correlated significantly with fibrous-type stroma, but not with myxoid-type stroma, suggesting a role of CCN2 in fibrosis (P < 0.05). Recombinant CCN2 induction of enhanced ASF proliferation in AM-1 medium supports this view. Conversely, BMP4 and TGF-β were expressed in myxoid-type fibroblasts, but little expression was found in parenchyma. RANKL-positive and CD68-positive stromal cell populations were significantly greater in myxoid-type tumor areas than in fibrous-type tumor areas, while a higher Ki-67 labeling index was recorded in ameloblastoma with fibrous-type stroma. These data suggest that stromal properties influence bone resorption-related activities and growth rates, respectively. Conclusions: These results suggest that the effects of secreted growth factors are governed by ameloblastoma parenchyma–stromal interactions. CCN2 promotes fibrogenesis independent of TGF-β signaling. Absence of CCN2 expression is associated with a phenotypic switch to a myxoid-type microenvironment that is conducive for TGF-β/BMP4 signaling to promote osteoclastogenesis.

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  • Cytoplasmic ABCG2 and podoplanin expression in oral squamous cell carcinoma correlates with lymph node metastasis

    Han Liu, Shilin Xia, Lei Zhu, Nan Li, Qian Yang, Yan Dong, Keisuke Nakano, Hitoshi Nagatsuka, Jing Xiao

    Journal of Hard Tissue Biology   26 ( 3 )   268 - 273   2017

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    The cervical lymph node metastasis of Oral Squamous Cell Carcinoma (OSCC) has been considered to be the main causes of death. The aim of our study was to clarify the expression pattern of ABCG2 and podoplanin in OSCC tissues and corresponding cervical lymph node, and evaluate the diagnostic value of ABCG2 and podoplanin in OSCC for tumorigenesis, histological stage and clinical prognosis. ABCG2 showed a mixed membranous and cytoplasmic pattern of staining in specific regions of stratum corneum and the center of well differentiated cancer nest, while only expressed in cytoplasm of poorly differentiated tumor nests. Podoplanin showed strong staining in LV endothelia, the periphery of well differentiated cancer nests, and tumor stromal fibroblasts surrounding tumor nests. The expression of ABCG2, especially cytoplasmic ABCG2, and podoplanin protein showed significantly higher tendency to lymph node metastasis (P<0.05). Meanwhile, podoplanin positive rate increased with the decreasing degree of histological differentiation (P<0.05). ABCG2 and podoplanin expression pattern is correlated with lymph node metastasis of OSCC. This result suggested that cytoplasmic ABCG2 with podoplanin have clinical potential in reliable molecule diagonsis for OSCC.

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  • Oral Squamous Cell Carcinoma-derived Sonic Hedgehog Promotes Angiogenesis International journal

    Hiromasa Kuroda, Naito Kurio, Tsuyoshi Shimo, Kenichi Matsumoto, Masanori Masui, Kiyofumi Takabatake, Tatsuo Okui, Soichiro Ibaragi, Yuki Kunisada, Kyoichi Obata, Norie Yoshioka, Koji Kishimoto, Hitoshi Nagatsuka, Akira Sasaki

    Anticancer Research   37 ( 12 )   6731 - 6737   2017

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    Background: Sonic hedgehog (SHH) signaling is related to the pathogenesis of oral squamous cell carcinoma (OSCC), but its role in OSCC is not yet well understood. In this study, we analyzed the role of SHH signaling in OSCC. Materials and Methods: We examined the expression pattern of SHH and its signal proteins in clinically resected OSCC samples by immunohistochemistry. We also evaluated the function of SHH signaling using the hedgehog signaling inhibitor cyclopamine in vivo and in vitro by proliferation, migration and angiogenesis analyses. Results: We found that SHH was highly expressed in human tongue OSCC, whereas patched (PTCH1), glioma-associated oncogene 1 (GLI1) and GLI2 proteins were expressed in the microvascular cells in the tumor invasive front. Administration of cyclopamine to mice suppressed the growth and angiogenesis of OSCC xenografts in vivo. Moreover, cyclopamine inhibited endothelial cell proliferation and migration, and reduced aorta vascular length in the rat. Conclusion: These findings suggest that OSCC-derived SHH stimulates angiogenesis at the tumor invasive front.

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  • Antibacterial activity and biocompability of zinc oxide and graphite particles as endodontic materials

    Silvia Noemí Kozuszko, María Alejandra Sánchez, María Inés Gutiérrez de Ferro, Ana María Sfer, Ana Paula Moreno Madrid, Kiyofumi Takabatake, Keisuke Nakano, Hitoshi Nagatsuka, Andrea Paola Rodríguez

    Journal of Hard Tissue Biology   26 ( 4 )   311 - 318   2017

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    The aim of this work is to evaluate the antibacterial effect and biocompatibility of zinc oxide (ZnO) nanopaticles and graphite-type carbon (Gt) microparticles commercial powders. SEM analysis was performed to assess particles morphology. The antibacterial behavior was studied against Staphylococcus aureus (Staph. Aureus) (bacterial strain ATCC 29213) and TEM analysis of bacteria was performed to determine ultrastructural alterations; in addition, biocompatibility was evaluated in subcutaneous tissue of Wistar rats at 3, 7 and 28 d. ZnO and Gt powders exhibited antibacterial activity while TEM images of Staph. aureus showed membrane disruption followed by the release of internal content. Also, an electron-light region within the cytoplasm was observed for microorganisms treated with ZnO. Regarding biocompatibility, Gt samples induced a foreign body reaction response with presence of giant cells whereas ZnO samples showed fibroblastic connective tissue with chronic inflammatory cells and new small vessels. Also, collagen fibers and lack of capsule was observed by Trichome Masson stain. Thus, ZnO improved wound healing by enhancing tissue regeneration in contrast with calcium hydroxide control sample response which showed a fibrous tissue scar. Hence, ZnO nano-powder seems to be a potential material in the regenerative endodontic field.

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  • Tachykinin receptor 3 distribution in human oral squamous cell carcinoma International journal

    Kyoichi Obata, Tsuyoshi Shimo, Tatsuo Okui, Kenichi Matsumoto, Hiroyuki Takada, Kiyofumi Takabatake, Yuki Kunisada, Soichiro Ibaragi, Hitoshi Nagatsuka, Akira Sasaki

    Anticancer Research   36 ( 12 )   6335 - 6341   2016.12

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    Background: Tachykinin 3 (TAC3) and its preferred tachykinin receptor 3 (TACR3) that are prominently detected in the central nervous system, play significant roles in physiological development and specifically in the human reproductive system. The roles of TAC3/TACR3 in oral squamous cell carcinoma are unknown. Materials and Methods: We examined the expression pattern of TAC3/TACR3 in clinically-resected oral squamous cell carcinoma samples using immunohistochemistry and immunofluorescence analysis. Results: We found that even though the expression level of TACR3 was negative in the normal epithelium, it was highly elevated in tumor cells. A more intense signal was observed in the invasive front of tumor cells that had migrated into the mandible bone matrix. TAC3 was not detected in tumor cells, but was expressed in PGP-9.5-positive sensory nerves in the mandible. Conclusion: Our results suggest that peripheral sensory nerve-derived TAC3 may affect gingival oral squamous cell carcinoma cells through TACR3 in the bone matrix.

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  • Invadopodia proteins, cortactin, N-WASP and WIP differentially promote local invasiveness in ameloblastoma International journal

    Chong Huat Siar, Zainal Ariff Bin Abdul Rahman, Hidetsugu Tsujigiwa, Kamila Mohamed Om Alblazi, Hitoshi Nagatsuka, Kok Han Ng

    Journal of Oral Pathology and Medicine   45 ( 8 )   591 - 598   2016.9

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    Background: Cell migration and invasion through interstitial tissues are dependent upon several specialized characteristics of the migratory cell notably generation of proteolytic membranous protrusions or invadopodia. Ameloblastoma is a benign odontogenic epithelial neoplasm with a locally infiltrative behaviour. Cortactin and MMT1-MMP are two invadopodia proteins implicated in its local invasiveness. Other invadopodia regulators, namely N-WASP, WIP and Src kinase remain unclarified. This study addresses their roles in ameloblastoma. Materials and method: Eighty-seven paraffin-embedded ameloblastoma cases (20 unicystic, 47 solid/multicystic, 3 desmoplastic and 17 recurrent) were subjected to immunohistochemistry for expression of cortactin, N-WASP, WIP, Src kinase and F-actin, and findings correlated with clinicopathological parameters. Results: Invadopodia proteins (except Src kinase) and F-actin were widely detected in ameloblastoma (cortactin: n = 73/87, 83.9%; N-WASP: n = 59/87; 67.8%; WIP: n = 77/87; 88.5%; and F-actin: n = 87/87, 100%). Protein localization was mainly cytoplasmic and/or membranous, and occasionally nuclear for F-actin. Cortactin, which functions as an actin-scaffolding protein, demonstrated significantly higher expression levels within ameloblastoma tumoral epithelium than in stroma (P < 0.05). N-WASP, which coordinates actin polymerization and invadopodia-mediated extracellular matrix degradation, was overexpressed in the solid/multicystic subtype (P < 0.05). WIP, an upstream regulator of N-WASP, and F-actin were significantly upregulated along the tumour invasive front compared to tumour centres (P < 0.05). Except for males with cortactin overexpression, other clinical parameters (age, ethnicity and anatomical site) showed no significant correlations. Conclusions: Present results suggest that local invasiveness of ameloblastoma is dependent upon the migratory potential of its tumour cells as defined by their distribution of cortactin, N-WASP and WIP in correlation with F-actin cytoskeletal dynamics.

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  • A case of a calcifying cystic odontogenic tumor with odontoma in a 5-year-old boy

    Norifumi Moritani, Naoki Nakata, Eiki Yamachika, Tatsushi Matsumura, Hitoshi Nagatsuka, Seiji Iida

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   28 ( 5 )   421 - 425   2016.9

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    We report a case of calcifying cystic odontogenic tumor (CCOT) with odontoma developing in the deciduous dentition period, and present previously reported cases in Japan. A 5-year-old boy visited a dental clinic because of swelling on his left mandibular buccal alveolar region, and was referred to our department. Clinical examination revealed a 20-mm (in diameter), bone-like, hard mass on the left mandibular buccal gingiva at the first deciduous molar region. A panoramic radiograph showed a 25 mm × 20 mm, unilocular, cystic radiolucent area from the left mandibular second deciduous molar to the first molar region. There were radiopaque tiny flecks at the upper side of the lesion. The clinical diagnosis was a benign tumor of the left mandible. Consequently, tumor enucleation was performed under general anesthesia. Histopathological diagnosis confirmed a CCOT associated with odontoma. Five years after surgery, the left mandibular region has healed well, with no evidence of recurrence.

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  • Efficacy of honeycomb TCP-induced microenvironment on bone tissue regeneration in craniofacial area International journal

    Satoko Watanabe, Kiyofumi Takabatake, Hidetsugu Tsujigiwa, Toshiyuki Watanabe, Eijiro Tokuyama, Satoshi Ito, Hitoshi Nagatsuka, Yoshihiro Kimata

    International Journal of Medical Sciences   13 ( 6 )   466 - 476   2016.6

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    Artificial bone materials that exhibit high biocompatibility have been developed and are being widely used for bone tissue regeneration. However, there are no biomaterials that are minimally invasive and safe. In a previous study, we succeeded in developing honeycomb β-tricalcium phosphate (β-TCP) which has through-and-through holes and is able to mimic the bone microenvironment for bone tissue regeneration. In the present study, we investigated how the difference in hole-diameter of honeycomb β-TCP (hole-diameter: 75, 300, 500, and 1600 μm) influences bone tissue regeneration histologically. Its osteoconductivity was also evaluated by implantation into zygomatic bone defects in rats. The results showed that the maximum bone formation was observed on the β-TCP with hole-diameter 300μm, included bone marrow-like tissue and the pattern of bone tissue formation similar to host bone. Therefore, the results indicated that we could control bone tissue formation by creating a bone microenvironment provided by β-TCP. Also, in zygomatic bone defect model with honeycomb β-TCP, the result showed there was osseous union and the continuity was reproduced between the both edges of resected bone and β-TCP, which indicated the zygomatic bone reproduction fully succeeded. It is thus thought that honeycomb β-TCP may serve as an excellent biomaterial for bone tissue regeneration in the head, neck and face regions, expected in clinical applications.

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  • In Vivo evaluation of adipogenic induction in fibrous and honeycomb-structured atelocollagen scaffolds International journal

    Andrea P. Rodríguez, Betiana Felice, María A. Sánchez, Hidetsugu Tsujigiwa, Carmelo J. Felice, Hitoshi Nagatsuka

    Materials Science and Engineering C   63   125 - 130   2016.6

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    Nowadays, soft tissue restoration techniques are mainly focused on volume regeneration instead of function recovering. So far, autologous fat transplant has been the most popular method although its multiple reported problems like volume and function loss. Adipose tissue engineering therefore emerges as a solution for development of biological substitutes for soft tissue which promotes not only volume regeneration but also function restoration with minimal consequences. Here we tested fibrous-structured atelocollagen (FSA) scaffolds and honeycomb atelocollagen (HCA) scaffolds for their ability to induce adipogenesis in vivo. Implants were subjected to histological and immunohistochemical assessment after 1, 2, and 4 weeks of implantation. Our studies showed that FSA scaffolds induced in vivo a markedly adipogenic response, whereas an acute inflammatory process was observed at HCA scaffolds without tissue regeneration detected within them. Our histological findings concerning FSA scaffolds clearly showed the presence of adipose-like tissue surprisingly composed by a mixture of brown-like and white-like adipocytes at week 2 whereas only white-like adipocytes at week 4. Subsequent positive Pax7 immunostaining at weeks 1 and 2 suggested the existence of a common myogenic progenitor shared by brown-like and white-like adipocytes observed. Then, in this work we present FSA scaffolds as a promising structure for brown and white adipose tissue engineering.

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  • Novel midkine inhibitor iMDK inhibits tumor growth and angiogenesis in oral squamous cell carcinoma International journal

    Masanori Masui, Tatsuo Okui, Tsuyoshi Shimo, Kiyofumi Takabatake, Takuya Fukazawa, Kenichi Matsumoto, Naito Kurio, Soichiro Ibaragi, Yoshio Naomoto, Hitoshi Nagatsuka, Akira Sasaki

    Anticancer Research   36 ( 6 )   2775 - 2781   2016.6

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    Midkine is a heparin-binding growth factor highly expressed in various human malignant tumors. However, its role in the growth of oral squamous cell carcinoma is not well understood. In this study, we analyzed the antitumor effect of a novel midkine inhibitor (iMDK) against oral squamous cell carcinoma. Administration of iMDK induced a robust antitumor response and suppressed cluster of differentiation 31 (CD31) expression in oral squamous cell carcinoma HSC-2 cells and SAS cells xenograft models. iMDK inhibited the proliferation of these cells dose-dependently, as well as the expression of midkine and phospho-extracellular signal-regulated kinase in HSC-2 and SAS cells. Moreover, iMDK significantly inhibited vascular endothelial growth factor and induced tube growth of human umbilical vein endothelial cells in a dose-dependent fashion. These findings suggest that midkine is critically involved in oral squamous cell carcinoma and iMDK can be effectively used for the treatment of oral squamous cell carcinoma.

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  • The role of sonic hedgehog signaling in osteoclastogenesis and jaw bone destruction International journal

    Tsuyoshi Shimo, Kenichi Matsumoto, Kiyofumi Takabatake, Eriko Aoyama, Yuichiro Takebe, Soichiro Ibaragi, Tatsuo Okui, Naito Kurio, Hiroyuki Takada, Kyoichi Obata, Pai Pang, Masahiro Iwamoto, Hitoshi Nagatsuka, Akira Sasaki

    PLoS ONE   11 ( 3 )   e0151731   2016.3

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    Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of its expression appear to correlate with disease progression and metastasis. However, the role of SHH in bone destruction associated with oral squamous cell carcinomas is still unclear. In this study we analyzed SHH expression and the role played by SHH signaling in gingival carcinoma-induced jawbone destruction. From an analysis of surgically resected lower gingival squamous cell carcinoma mandible samples, we found that SHH was highly expressed in tumor cells that had invaded the bone matrix. On the other hand, the hedgehog receptor Patched and the signaling molecule Gli-2 were highly expressed in the osteoclasts and the progenitor cells. SHH stimulated osteoclast formation and pit formation in the presence of the receptor activator for nuclear factor-κB ligand (RANKL) in CD11b+ mouse bone marrow cells. SHH upregulated phosphorylation of ERK1/2 and p38 MAPK, NFATc1, tartrate-resistant acid phosphatase (TRAP), and Cathepsin K expression in RAW264.7 cells. Our results suggest that tumor-derived SHH stimulated the osteoclast formation and bone resorption in the tumor jawbone microenvironment.

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  • Anti-osteoporosis effects of 1,4-dihydroxy-2-naphthoic acid in ovariectomized mice with increasing of bone density

    Kenichiro Kita, Eiki Yamachika, Masakazu Matsubara, Hidetsugu Tsujigiwa, Nobuhisa Ishida, Norifumi Moritani, Tatsushi Matsumura, Masahide Mizutani, Yuki Fujita, Kiyofumi Takabatake, Kenichiro Ejima, Hitoshi Nagatsuka, Yoshinori Yamaguchi, Seiji Iida

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   28 ( 1 )   66 - 72   2016.1

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    Objective: 1,4-Dihydroxy-2-naphthoic acid (DHNA) is the main component of the metabolic products after fermentation by Propionibacterium freudenreichii ET-3. In this study, DHNA, vitamin K2 (VK2), and risedronate (Ris) were administered to ovariectomized (OVX) mice to ascertain their suppressive effects on bone mass reduction. Methods: Fifty mice were divided into five groups: Sham, OVX, DHNA, VK2, and Ris groups. The drugs were administered daily for 8 weeks. Subsequently, blood was collected from the orbital venous plexus. The bilateral femurs and L5 lumbar vertebra were excised. To determine the effects of the drugs, we performed histomorphometric analyses of the left femur and L5 by micro-CT, biochemical analyses of serum samples, and histological analyses of the right femur. Results: The results for the total bone mineral density, bone volume density, trabecular thickness, trabecular number, trabecular separation, and histological analyses showed that bone resorption was improved in the DHNA and Ris groups compared with the OVX group. Furthermore, the biochemical analyses revealed that the production of inflammatory cytokines was suppressed in the DHNA and Ris groups. Conclusions: The present findings show that DHNA suppresses the bone mass reduction in OVX mice, suggesting that it could be an alternative treatment for postmenopausal osteoporosis.

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  • Surgical treatment and dental implant rehabilitation after the resection of an osseous dysplasia

    Shintaro Sukegawa, Takahiro Kanno, Hotaka Kawai, Akane Shibata, Kenichi Matsumoto, Yuka Sukegawa-Takahashi, Kyosuke Sakaida, Hitoshi Nagatsuka, Yoshihiko Furuki

    Journal of Hard Tissue Biology   25 ( 4 )   437 - 441   2016

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    Osseous dysplasia (OD), which is subdivided into four subtypes (focal cement-osseous dysplasia, florid osseous dysplasia, periapical cemental dysplasia, and familial gigantiform cementoma), is an idiopathic process located in the periapical region of the tooth-bearing jaw areas, characterized by a replacement of normal bone by fibrous tissue and metaplastic bone. Unless accompanied by bulging or secondary infection of the jawbone, treatment is not necessary. However, treatment for extirpation is required when a secondary infection is present. Consequently, occlusion reconstruction becomes difficult because of large bone defect. Herein, we report the surgical technique to maintain the alveolar ridge form after resecting the lesion and for the case of an infected alveolar bone in a patient with OD. The loss of the buccal cortical bone was inevitable after removal of the infected area. For postoperative occlusal reconstruction, we performed a bone graft to maintain the alveolar ridge form at the same time as the tumor extirpation. Deficient buccal cortical bone was rebuilt with bone taken from the mandibular ramus and a bioactive resorbable plate. We describe the management of OD and the surgical technique for alveolar ridge form management by resecting the lesion and infected alveolar bone.

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  • A clinical retrospective study of surgical treatment for medication-related osteonecrosis of the jaw

    Shintaro Sukegawa, Takahiro Kanno, Hotaka Kawai, Satoko Nakamura, Akane Shibata, Yuka Sukegawa-Takahashi, Hitoshi Nagatsuka, Yoshihiko Furuki

    Journal of Hard Tissue Biology   25 ( 4 )   447 - 454   2016

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    In 2014, the American Association of Oral and Maxillofacial Surgery recommended surgical treatment for medication-related osteonecrosis of the jaw (MRONJ) patients classified as stage 3 or those with mobile segments of bony sequestrum. However, there is limited information regarding the healing mechanism in MRONJ surgical treatments. This study aimed to retrospectively elucidate clinical outcomes of the surgical treatment of MRONJ patients. This study included 26 patients (7 men, 19 women; age: 42–92 years; mean ± standard deviation, 75.3 ± 11.7 years) who were classified as stage 3 or had mobile segments of bony sequestrum, and intake of the offending drug was ceased. The sequestrum was removed with surrounding vital bone, and segmental resection was performed in one patient with a pathological mandibular fracture. The outcome was classified into one of the following three categories: “Healing,” “Improvement,” “Unchanged.” and “Exacerbation.” The mean postoperative follow-up period was 16.6 months (3.0 –57.9 months), and complete healing was observed in 21 patients (80.8%), improvement of the lesion was observed in four patients (15.4%), and the outcome of one patient was unchanged (3.8%). The procedure described here may be recommended with relatively high clinical success rate for the patients with MRONJ requiring surgical treatment.

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  • Nasopalatine duct cyst associated with dental implant treatment: A case report Reviewed

    Shintaro Sukegawa, Takahiro Kanno, Hotaka Kawai, Yuichiro Takebe, Akane Shibata, Yuka Takahashi, Hitoshi Nagatsuka, Yoshihiko Furuki

    Oral and Maxillofacial Surgery Cases   1 ( 3 )   38 - 41   2015.9

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    Maxillary anterior implants are associated with the risk of nasopalatine canal damage. Here we present the case of a 37-year-old man who developed a nasopalatine duct cyst after maxillary implant placement. The patient received an implant 3 months after the extraction of a fractured maxillary right central incisor. At a maintenance visit 9 years after the procedure, he complained of swelling and mild pain in the palatal region of the implant. A panoramic radiograph and computed tomography (CT) scan revealed a large, well-circumscribed, periapical radiolucency surrounding the apical portion of the implant and extending to the nasopalatine duct. We removed the entire lesion without removing the implant. Histopathologic examination of the resected specimen revealed a nasopalatine duct cyst. Accidental contact with the nasopalatine canal during implant surgery may have led to the development of the nasopalatine duct cyst. Careful planning using a preoperative CT scan prior to implant placement may prevent such complications.

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  • Correlations between actin-binding protein expressions and clinico-pathologic variables in ameloblastoma Reviewed

    Siar C. H, Rahman Z. A. bin Abdul, Alblazi K, Mohamed Om, Tsujigiwa H, Nagatsuka H

    VIRCHOWS ARCHIV   467   S74   2015.9

  • Histological evaluation of periodontal ligament in response to orthodontic mechanical stress in mice Reviewed International journal

    Keiko Kaneko, Saeka Matsuda, Rina Muraoka, Keisuke Nakano, Takami Iwasaki, Mihoko Tomida, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Toshiyuki Kawakami

    International Journal of Medical Sciences   12 ( 9 )   689 - 694   2015.8

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    The purpose of the study was to determine the cell dynamics in periodontal ligament in response to mechanical stress during orthodontic movement. Following Waldo’s method, a square sheet of rubber dam was inserted in between the first and second maxillary molars in 10 ddY mice leaving the stress load for 3 hours. After 3 days and at 1 week, cell count on pressure and tension sides of the periodontal ligament was determined. Furthermore, the type of cell present after mechanical stress was identified using GFP bone marrow transplantation mouse model. Immunohistochemistry was carried out at 0 min (immediately after mechanical stress), 24 hours, 1 week, 2 weeks and 6 months. Temporal changes in the expression of GFP-positive bone marrow derived cells were examined. Moreover, double immunofluorescent staining was performed to determine the type of cell in the periodontal ligament. Cell count on the tension side tremendously increased 3 days after mechanical stress. At 1 week, spindle and round cell count increased compared to the control group. These changes were observed on both tension and pressure sides. Cell count on pressure side at 3 days (22.11+/-13.98) and at 1 week (33.23+/-11.39) was higher compared to the control group (15.26+/-8.29). On the tension side, there was a significantly increased at 3 days (35.46+/-11.85), but decreased at 1 week (29.23+/-13.89) although it is still higher compared to the control group (AD+/-SD: 10.37+/-8.69). Using GFP bone marrow transplantation mouse model, GFP positive cell count increased gradually over time in 6 months. GFP positive cells were also positive to CD31, CD68 and Runx2 suggesting that fibroblasts differentiated into osteoclasts and tissue macrophages. In conclusion, mechanical stress during orthodontic movement promoted the increase in the number of cells in the periodontal ligament on both tension and pressure sides. The increase in the number of cells in the periodontal ligament is believed to be due to the migration and cell division of undifferentiated mesenchymal cells.

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  • Early Initiation of Endochondral Ossification of Mouse Femur Cultured in Hydrogel with Different Mechanical Stiffness International journal

    Gulsan Ara Sathi, Kodai Kenmizaki, Satoshi Yamaguchi, Hitoshi Nagatsuka, Yasuhiro Yoshida, Aira Matsugaki, Takuya Ishimoto, Satoshi Imazato, Takayoshi Nakano, Takuya Matsumoto

    Tissue Engineering - Part C: Methods   21 ( 6 )   567 - 575   2015.6

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    Mineralization is one of the most important processes in normal bone tissue development and in disease condition. Developing a novel and standardized in vitro model system that can readily monitor both cellular dynamics and mineralization is crucial for better understanding the bone tissue development and growth. Recent studies indicated that the mechanical environment is a critical condition in mineralization. We hypothesized that hydrogel with different mechanical stiffness can provide a biomimetic mechanical environment that can modulate bone tissue growth and mineralization. A femur of mouse embryo (embryonic day 16) was embedded in agarose hydrogel (2-60 kPa) and cultured in an osteogenic medium for a week. Microcomputed tomography (μCT) results revealed enhanced mineralization was detected in the femur head cultured in the gel condition, whereas no mineralization in the femur head cultured in the control (floating culture) condition. The mineralized region was corresponding to the region of secondary ossification center. Both histological and quantitative analyses indicated that the mineralized region of femur head cultured in 10 kPa gel condition was the highest and the mineralized area was significantly larger than that cultured in 2, 40, and 60 kPa gel condition. Immunofluorescence results indicated the enhanced mineralization caused by the higher chondrogenic differentiation at that region. This enhancement mainly relating to the mechanical forces and not to the oxygen tension was also confirmed. Since this system enhances and shortens the mineralization procedure compared with the conventional two-dimensional or three-dimensional cell culture system, this hydrogel system would be one of the unique models for better understanding the mineralized tissue development.

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  • Long-term bioresorption of bone fixation devices made from composites of unsintered hydroxyapatite particles and poly-L-lactide Reviewed

    Shintaro Sukegawa, Takahiro Kanno, Hotaka Kawai, Akane Shibata, Yuka Takahashi, Hitoshi Nagatsuka, Yoshihiko Furuki

    Journal of Hard Tissue Biology   24 ( 2 )   219 - 224   2015.4

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    Osteosynthetic bone fixation devices made from composites of uncalcined and unsintered hydroxyapatite (u-HA) particles and poly-L-lactide (PLLA) are widely adopted for clinical use because of their bioresorbability and osteoconductive properties. However, how the plate systems constituting these devices change during long-term use in vivo is unknown. In this study, we present cases of two patients fitted with u- HA/PLLA devices for >5 years after surgery and evaluate the resorption process on the basis of the residual versus the resorbed material. In both cases, the majority of the degraded plates and screws had been replaced by bone. In post-operative three-dimensional (3D) CT imaging, plate and screws were maintained until two years after surgery, and then they were degraded and replaced to bone in 4-6 years after surgery. Examination of the aggregation of hydroxyapatite and decrease in molecular weight suggested that the residual material was in the final stages of resorption. The plate system examined demonstrated stable degradation without foreign body reactions in vivo. Although complete resorption is a lengthy process, it is possible to follow its progress using CT.

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  • RANK, RANKL, and OPG in recurrent solid/multicystic ameloblastoma: Their distribution patterns and biologic significance International journal

    Chong Huat Siar, Hidetsugu Tsujigiwa, Ismadi Ishak, Nurmawarnis Mat Hussin, Hitoshi Nagatsuka, Kok Han Ng

    Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology   119 ( 1 )   83 - 91   2015.1

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    Objectives To determine the distribution patterns of bone resorption regulators, receptor activator of nuclear factor κ-B (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) in recurrent ameloblastoma (RAs) and to clarify their impact on the biologic behavior of these neoplasms.

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  • A case of adenoid cystic carcinoma associated with IgG4-related disease Reviewed International journal

    Tsuyoshi Shimo, Mayumi Yao, Yuichiro Takebe, Yuko Ono, Kyoichi Obata, Naito Kurio, Soichiro Ibaragi, Norie Yoshioka, Koji Kishimoto, Yoshinobu Yanagi, Hitoshi Nagatsuka, Akira Sasaki

    International Journal of Surgery Case Reports   10   12 - 16   2015

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    Introduction Immunoglobulin G4-related disease (IgG4-RD) is an inflammatory condition associated with elevated serum IgG4 levels and tissue infiltration by IgG4-expressing plasma cells. We present a case of adenoid cystic carcinoma (ACC) of the submandibular gland with possible involvement of IgG4-RD. Presentation of case The patient was a 59-year-old man presenting with a swollen right submandibular gland. Laboratory tests revealed IgG4 levels of 176 mg/dl (reference range: 4.8-105). An initial open biopsy for histological diagnosis showed chronic sialadenitis. The region was monitored on an outpatient basis, and finally the right submandibular was totally resected because malignant tumor could not be excluded. Histological examination of the submandibular gland showed an ACC with lymphocytic infiltration containing many IgG4-positive plasma cells in the tumor stroma. Discussion We have described a case that indicated a possible involvement of ACC with IgG4-RD. This allows us to speculate that longstanding IgG4-RD may progress to malignancy or infiltration of IgG4-positive plasma cells through the signals of tumor stimuli. Further investigations are required to determine the potential pathogenic mechanism underlying this unique tumor. Conclusion This case underscores that caution is needed in the diagnosis of masses with high serum IgG4 levels, as the differential diagnosis includes malignancy.

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  • Effect of sintering time of CaTiO<inf>3</inf>–CaCO<inf>3</inf> in osteoblastic response of KUSA/A1 cells Reviewed

    Andrea P. Rodríguez, María A. Sánchez, Miho Inoue, Betiana Felice, Hitoshi Nagatsuka, Rossana E. Madrid, Carmelo Felice, Hidetsugu Tsujigiwa

    IFMBE Proceedings   49   159 - 162   2015

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    In recent years, calcium titanate (CaTiO3) and carbon-containing materials have gained much attention in a number of biomedical material researches. To maximize the advantages of both materials, we developed a novel alkoxide method to get ‘‘calcium titanate with calcium carbonate’’ (CaTiO3–CaCO3). Thus, our previous result indicated that calcium carbonate could play a key role in the cell response of CaTiO3 material. In the present study we evaluated the effect of sintering time of CaTiO3–CaCO3 in osteoblastic response of KUSA/A1 cells. We examined the material characterization as well as cellular proliferation and mineralization of KUSA/A1 cells cultured with the materials. The results showed that Ca-TiO3–CaCO3 material sintered during 30 min, has better influ-ence on the bone marrow stromal cells for their proliferation and mineralization compared to CaTiO3-CaCO3 sintered at 2 and 10 h. These results suggest that sintering time could be directly related to the amount of carbon within CaCO3 being crucial in cell response. In conclusion, our preliminary find-ings indicate that CaTiO3–CaCO3 could play a more dominant and favorable effect on cell response when sintered for 30 minutes.

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  • Does HMGB1 predict occult neck lymph node metastasis in early tongue carcinoma? A case-control study of 26 patients

    H. Hanakawa, Y. Orita, Y. Sato, M. Takeuchi, S. Takao, K. Ohno, T. Kohno, N. Iwaki, H. Marunaka, R. Tamamura, M. Nishibori, H. Nagatsuka, K. Nishizaki, T. Yoshino

    Journal of Laryngology and Otology   128 ( 10 )   926 - 931   2014.10

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    Objective: This study examined whether the occurrence of late neck metastasis in early tongue squamous cell carcinoma can be predicted by evaluating HMGB1 (high mobility group box 1) expression in the primary lesion. Methods: A case-control study was conducted. The cases comprised 10 patients with late neck metastasis. The controls consisted of 16 patients without recurrence. All were examined immunohistochemically for HMGB1 protein expression. The odds ratio for late neck metastasis in relation to HMGB1 was estimated. Results: Results for HMGB1 were dichotomised into positive staining scores (score, 5-7) and negative scores (0-4). Six cases (60 per cent) and four controls (25 per cent) were HMGB1-positive. Although no significant result was seen, compared with HMGB1-negative patients the odds ratio for late neck metastasis in HMGB1-positive patients was 3.8 (95 per cent confidence interval, 0.6-26.5) after adjusting for other factors. Conclusion: In the present study, immunohistochemical study of HMGB1 in early tongue squamous cell carcinoma did not appear to be very useful for predicting occult neck metastasis. Further study is necessary to clarify the relationship between HMGB1 expression and late neck metastasis in early tongue squamous cell carcinoma.

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  • DKK3 expression and its function in head and neck squamous cell carcinoma Reviewed

    Naoki Katase, Mehmet Gunduz, Hidetsugu Tsujigiwa, Satoshi Ito, Masae Fujii, Hitoshi Nagatsuka, Akira Sasaki, Tsutomu Nohno

    CANCER RESEARCH   74 ( 19 )   2014.10

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  • Effect of geometry and microstructure of honeycomb TCP scaffolds on bone regeneration International journal

    Kiyofumi Takabatake, Eiki Yamachika, Hidetsugu Tsujigiwa, Yasushi Takeda, Mariko Kimura, Shin Takagi, Hitoshi Nagatsuka, Seiji Iida

    Journal of Biomedical Materials Research - Part A   102 ( 9 )   2952 - 2960   2014.9

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    In recent years, artificial biological materials have been commonly used for the treatment of bone tissue defects caused by trauma, tumors, or surgical stress. Although tricalcium phosphate (TCP) is a promising absorbent bone tissue reconstruction biomaterial, it has been reported that its biocompatibility and osteoconductivity depend on its preparation method and sintering temperature. In addition, although it is thought that the microenvironment produced by the extracellular matrix plays an important role in cell growth and differentiation, there have been few studies on how the geometric structure of artificial biological materials affects cells. In the present study, a new honeycomb TCP scaffold containing through-holes with diameters of 300 μm has been developed. The influence of the sintering temperature on the crystal structure and material properties of the honeycomb TCP scaffold was investigated using scanning electron microscopy and X-ray diffraction. Its biocompatibility and osteoconductivity were also evaluated by implantation into experimental animals. It was found that a β-TCP scaffold sintered at 1200°C exhibited high biocompatibility and osteoconductivity, and when it was loaded with BMP-2, it exhibited both osteoconductivity and osteoinductivity, promoting rapid bone formation in both ectopic and orthotopic areas. It is thus a highly promising bone reconstruction material that is expected to find clinical applications. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2952-2960, 2014. © 2013 Wiley Periodicals, Inc.

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  • Regulatory T-cell infiltration in tongue squamous cell carcinoma Reviewed International journal

    Hiroyuki Hanakawa, Yorihisa Orita, Yasuharu Sato, Mai Takeuchi, Kyotaro Ohno, Yuka Gion, Kiyoaki Tsukahara, Ryo Tamamura, Toshihiro Ito, Hitoshi Nagatsuka, Kazunori Nishizaki, Tadashi Yoshino

    Acta Oto-Laryngologica   134 ( 8 )   859 - 864   2014.8

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    Conclusion: In tongue squamous cell carcinoma (SCC), high levels of regulatory T-cell (Treg) infiltration in tumor nests are observed in the cases with poor prognosis. Objectives: The role of Tregs in head and neck cancers remains unclear. The aim of this study was to observe the distribution of Tregs in different stages of tongue SCC and estimate the effects on prognosis. Methods: Thirty-four cases with tongue SCC were examined immunohistochemically for CD4, CD8, and Forkhead box P3 (Foxp3). Immunoreactive cells were counted in cancer stroma and nest regions, and relationships between cell numbers and disease-free survival rates were analyzed. Results: In the 34 cases, univariate analysis for disease-free survival indicated high-level infiltration of Tregs (CD4+Foxp3+) into both cancer nests and stroma and presence of helper T (CD4+Foxp3-) cells in cancer stroma as potential predictors of significantly worse prognosis. In early-stage cases (stage I/II), high-level infiltration of Tregs in cancer nests correlated significantly with poor disease-free survival rate. Multivariate analysis for disease-free survival found no independent variables. © Informa Healthcare.

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  • 口腔癌細胞株担癌マウスに対するBCG生菌と5-FU併用療法による延命効果の検討

    村上 純, 大原 直也, 中山 真彰, 辻極 秀次, 長塚 仁, 此内 浩信, 柳 文修, 苔口 進, 久富 美紀, 藤田 麻里子, 畦坪 輝寿, 浅海 淳一

    日本癌治療学会誌   49 ( 3 )   1533 - 1533   2014.6

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  • Locally injected dexmedetomidine inhibits carrageenin-induced inflammatory responses in the injected region International journal

    Shintaro Sukegawa, Hitoshi Higuchi, Miho Inoue, Hitoshi Nagatsuka, Shigeru Maeda, Takuya Miyawaki

    Anesthesia and Analgesia   118 ( 2 )   473 - 480   2014.2

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    BACKGROUND:: Dexmedetomidine, a highly selective agonist of α2-adrenoceptors, is a commonly used sedative; however, a potent anti-inflammatory effect has also been found. In the present study we evaluated the inhibitory effect of locally injected dexmedetomidine on inflammatory responses in the injected region. METHODS:: Local inflammation was induced in the hindpaws of male mice (aged 6-8 weeks) by intraplantar injection of lambda-carrageenin. To offset the central effect of tested agents, different agents were blindly injected into the left and right paws in the pairs of comparison. The effect of dexmedetomidine on edema (increase in paw volume), the accumulation of leukocytes, and production of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) were evaluated after carrageenin injection, using water displacement plethysmometry, histological imaging, immunohistochemistry, and Western blotting analysis. Furthermore, we also evaluated the effect of yohimbine, a full antagonist of α2-adrenoceptors, and phenylephrine, an agonist of the α1-adrenoceptor, on dexmedetomidine's action on inflammatory responses. RESULTS:: Paw volume and amount of leukocytes in the injected region significantly increased after the injection of carrageenin. Similarly, TNF-α and COX-2 production was found in the subcutaneous region injected with carrageenin, 4 hours after injection. Dexmedetomidine significantly inhibited all increases in paw volume, leukocytes, and production of TNF-α and COX-2. Furthermore, yohimbine significantly antagonized the anti-inflammatory effects of dexmedetomidine, whereas phenylephrine did not significantly alter them. CONCLUSIONS:: The findings suggest that locally injected dexmedetomidine exhibits an anti-inflammatory effect against local acute inflammatory responses, mediated by α2-adrenoceptors. © 2013 International Anesthesia Research Society.

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  • Expression and role of sonic hedgehog in oral squamous cell carcinoma induced jaw bone destruction. Reviewed

    Tsuyoshi Shimo, Naito Kurio, Masahiro Iwamoto, Tatsuo Okui, Hiromasa Kuroda, Kenichi Matsumoto, Soichiro Ibaragi, Norie Yoshioka, Yuichirou Takebe, Hitoshi Nagatsuka, Akira Sasaki

    JOURNAL OF BONE AND MINERAL RESEARCH   29   S372 - S372   2014.2

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  • Expression and roles of CCN2 in dental mesenchymal cells in primary culture-With findings in a case of odontogenic myxofibroma Reviewed

    Tsuyoshi Shimo, Eiki Koyama, Yuu Horikiri, Tatsuo Okui, Naito Kurio, Naoki Katase, Shoko Yoshida, Yuichiro Takebe, Koji Kishimoto, Norie Yoshioka, Hitoshi Nagatsuka, Akira Sasaki

    Oral Science International   11 ( 1 )   8 - 14   2014.1

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    Purpose of the research: Tooth germ development involves multiple events, including cell proliferation and cell differentiation. Connective tissue growth factor (CTGF/CCN2) is a signaling protein involved in tooth germ development, and we investigated how it is expressed and what roles it may have in primary cultures of mesenchymal cells derived from the developing tooth germ. We also examined the expression of CCN2 in a human odontogenic myxofibroma, a benign tumor of odontogenic mesenchymal origin, and considered the possible roles of CCN2 in the development of myxofibromas. Materials and methods: Mesenchymal cells of early bell-stage tooth germs were isolated from Day-90 bovine embryos and placed in primary culture. A resected specimen from a patient with odontogenic myxofibroma was prepared for immunohistochemical studies. Principal results: The CCN2 expression level in proliferating odontogenic mesenchymal cells freshly isolated from the early bell stage of developing bovine tooth germs and placed in primary culture was 3 times higher than that in the confluent non-proliferating cells. Recombinant CCN2 significantly increased the proliferation and type I collagen expression in odontogenic mesenchymal cells in primary culture. Immunohistochemical analysis on myxofibroma case revealed that CCN2 was detectable in MIB-1, a cellular marker of proliferation-positive odontogenic mesenchymal cells adjacent to capillary blood vessels and in the endothelial cells of the vessels in the tumor. Major conclusion: CCN2 signaling would influence the proliferation of and extracellular matrix production by dental mesenchymal cells. Our results suggest that the same mechanisms of CCN2 action toward dental mesenchymal cells would also be operative in the odontogenic myxofibroma microenvironment. © 2013 Japanese Stomatological Society.

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  • Fibrous dysplasia of the maxilla: A case report together with its conventional imaging and dynamic magnetic resonance imaging findings Reviewed

    Marina Hara, Hidenobu Matsuzaki, Naoki Katase, Teruhisa Unetsubo, Yoshinobu Yanagi, Hitoshi Nagatsuka, Jun Ichi Asaumi

    Oral Radiology   30 ( 1 )   105 - 110   2014.1

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    We previously reported that dynamic contrastenhanced MRI parameters and time-signal intensity curves (TICs; also known as contrast index curves) are useful for the differential diagnosis of jawbone lesions. In particular, odontogenic fibroma and ossifying fibroma, which possess similar histopathological features (i.e., a mixture of hard and soft tissue components), display unique TIC patterns, and we consider that the TIC patterns of these lesions reflect their hard and soft tissue components. Therefore, fibrous dysplasia, which contains fibrous tissue and immature isolated trabeculae composed of woven bone, is expected to display an interesting TIC. The purpose of this study was to assess the utility of TICs for differentiating between the abovementioned lesions, which have similar histopathological components. © Japanese Society for Oral and Maxillofacial Radiology and Springer Japan 2013.

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  • Freeze dried bone matrix on rat critical size defect regeneration

    María V. Jammal, Liliana R. Missana, Kiyofumi Takabatake, Shin Takagi, Hitoshi Nagatsuka

    Journal of Hard Tissue Biology   23 ( 2 )   233 - 237   2014

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    Bone allografts are commonly used for bone regeneration. The aim of this study was evaluate the efficacy of a freeze dried bone matrix (FDBM) in critical size defect (CZD) rat calvaria. Eighteen Wistar female rats (body weight 150 ± 50 g) with CZD (5mm) were divided in two groups: group 1, using freeze dried bone matrix; and group 2, only with coagulum. All samples were evaluated on the 1st, 3rd and 6th weeks post-surgery by soft X-ray, histological and histometric studies. Soft X-ray results showed a radiolucent image with many irregular radiopaque areas. Histologically, bone regeneration was initiated from the 3rd week, when a thin layer of new woven bone could be seen adjacent to the matrix. At the 6th week, lamellar bone covered over half (61.8%) of the defect area. The lack of FDBM resorption allowed its incorporation to the new regenerated bone. This behavior is important in circumstances where it is necessary not only to stimulate bone regeneration but also increase the volume in affected areas, such as during the placement of dental implants. The results obtained in this research are encouraging for the use of freeze dried bone matrix as a bone graft material. © 2014 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved.

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  • Expressions of ABCG2, CD133, and podoplanin in salivary adenoid cystic carcinoma Reviewed International journal

    Wuwei Li, Ryo Tamamura, Bo Wang, Qigui Liu, Han Liu, Tingjiao Liu, Naoki Katase, Jing Xiao, Hitoshi Nagatsuka

    BioMed Research International   2014   132349 - 132349   2014

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    Adenoid cystic carcinoma (ACC) is one of the most common salivary gland malignant tumors with a high risk of recurrence and metastasis. Current studies on cancer stem cells (CSCs) have verified that CSCs are the driving force behind tumor initiation and progression, suggesting that new cancer therapies may be established by effectively targeting and killing the CSCs. The primary goal of this study is to investigate the expression patterns of ABCG2, CD133, and podoplanin in ACC of minor salivary glands by immunohistochemistry analysis. We found that ABCG2 was weakly expressed in normal looking salivary gland tissues. A significant upregulation of ABCG2 expression in ACC was observed with a similar expression pattern of Ki-67. CD133 was detected in apical membrane of epithelial cells and podoplanin was expressed positively in myoepithelial cells of both normal looking tissue and ACC. However, no significant difference was found of the expression pattern of CD133 and podoplanin between normal looking tissues and ACC. Our observations suggest that CSCs may exist in quiescent cells with ABCG2 positive staining, which are surrounded by cells with positive expression of ABCG2 and Ki-67 in ACC, and costaining with ABCG2 and Ki-67 may help predict the location of CSCs. © 2014 Wuwei Li et al.

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  • Establishment of odontoblastic cells, which indicate odontoblast features both in vivo and in vitro International journal

    Hidetsugu Tsujigiwa, Naoki Katase, Mathieu Lefeuvre, Eiki Yamachika, Ryo Tamamura, Satoshi Ito, Yuichiro Takebe, Hiroyuki Matsuda, Hitoshi Nagatsuka

    Journal of Oral Pathology and Medicine   42 ( 10 )   799 - 806   2013.11

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    Tooth tissue engineering offers very attractive perspectives for elaboration of regenerative treatments, which enables to cure tooth loss and restore quality of life of the patients. To elaborate such treatment, isolation and culture of dental pulp cell must be achieved as a key element. In this article, we report the establishment of a stable cell line from GFP transgenic rat dental pulp, named TGC (Tooth Matrix-forming, GFP Rat-derived Cell). TGCs have exhibited odontoblastic feature both in vitro and in vivo. In vitro, TGC exposed to osteogenic medium demonstrated collagen fiber synthesis with matrix vesicle and mineralization and formed a sheet-like substrate on the cell culture dish. Increased ALP activity and elevated transcription level of various genes involved in calcification and dentin formation were also observed. In vivo, transplanted TGC in SCID mice with β-TCP particles formed dentin-like and pulp-like structure with lining odontoblast. Notably, even after up to 80 passages, TGCs retain their morphological features and differentiation ability. To our knowledge, this is the first report of a dental pulp-derived cell with such stable odontoblastic characteristics. TGC could be a very useful model for further study on dental pulp cell. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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  • Nestin is a wide-spectrum abluminal cell marker of salivary gland tumors International journal

    Hiroyuki Yanai, Yasuharu Sato, Hitoshi Nagatsuka, Tadashi Yoshino

    Pathology International   63 ( 10 )   496 - 501   2013.10

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    Nestin is an intermediate filament that was first identified in neural progenitor cells. It is expressed in various cell types in the nervous system as well as in other systems. In the present study, we investigated nestin expression in non-neoplastic salivary gland tissue and in salivary gland tumors. In non-neoplastic salivary glands, nestin expression was observed in only a few abluminal cells. In contrast, diffuse nestin staining was observed in the abluminal cells of pleomorphic adenoma (11 of 11 cases), basal cell adenoma (7 of 7 cases), and epithelial-myoepithelial carcinoma (2 of 2 cases). The stromal cells in basal cell adenoma also expressed nestin. In adenoid cystic carcinoma (6 of 7 cases) and polymorphous low-grade adenocarcinoma (3 of 3 cases), nestin positive cells were observed focally. Nestin was not detected in Warthin tumor (6 cases), classical acinic cell carcinoma (2 cases), mucoepidermoid carcinoma (5 cases), or salivary duct carcinoma (4 cases). Because the nestin expression pattern in each histological salivary gland tumor type is unique, nestin could be a very useful abluminal cell marker for the diagnosis of salivary gland tumors. © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

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  • 口腔癌に対するBCG生菌療法による抗腫瘍、延命効果の検討

    村上 純, 大原 直也, 中山 真彰, 辻極 秀次, 長塚 仁, 此内 浩信, 柳 文修, 畦坪 輝寿, 浅海 淳一

    Journal of Oral Biosciences Supplement   2013   222 - 222   2013.9

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  • カラゲニン誘発局所炎症反応に対するデクスメデトミジンの抑制作用

    助川 信太郎, 長塚 仁, 宮脇 卓也

    Journal of Oral Biosciences Supplement   2013   212 - 212   2013.9

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  • 角化嚢胞性歯原性腫瘍の再発に関する臨床的検討

    助川 信太郎, 高畑 和路, 片瀬 直樹, 管野 貴浩, 万代 とし子, 高橋 由佳, 篠原 丈裕, 長塚 仁, 古木 良彦

    Hospital Dentistry & Oral-Maxillofacial Surgery   25 ( 1 )   27 - 31   2013.6

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    角化嚢胞性歯原性腫瘍の再発に関する臨床的検討を行った。病理組織学的に歯原性角化嚢胞および角化嚢胞性歯原性腫瘍と診断され、病理標本上病変の性状を正確に評価でき、かつ加療後に6ヵ月以上の経過観察が行えた27例を対象とした。発生部位は上顎5例、下顎22例で、上顎は全て臼歯部であった。X線所見において、単房性透過像は23例、多房性透過像は4例であった。腫瘍径は平均39.9mmで、5cm来満のものが17例、5cm以上のものが10例であった。娘細胞は8例にみられ、19例には見られなかった。腫瘍に接する歯の処置は、根治的処理を行ったものが16例、保存的処置を行ったものが11例であった。5例で再発を認め、再発率は18.5%であった。腫瘍径が5cm以上の群で、有意に再発率が高かった。腫瘍に接する歯を根治的に処置した群で優位に再発率が低かった。

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  • Diagnostic value of MRI for odontogenic tumours

    M. Fujita, H. Matsuzaki, Y. Yanagi, M. Hara, N. Katase, M. Hisatomi, T. Unetsubo, H. Konouchi, H. Nagatsuka, J. I. Asaumi

    Dentomaxillofacial Radiology   42 ( 5 )   2013.5

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    Objectives: To evaluate the diagnostic value of MRI for odontogenic tumours. Materials and methods: 51 patients with odontogenic tumours were subjected to preoperative MRI examinations. For tumours with liquid components, i.e. ameloblastomas and keratocystic odontogenic tumours (KCOTs), the signal intensity (SI) uniformity of their cystic components (US) was calculated and then their US values were compared. For tumours with solid components that had been examined using dynamic contrast-enhanced MRI (DCEMRI), their CI max (maximum contrast index), Tmax (the time when CImax occurred), CIpeak (CImax×0.90), Tpeak (the time when CIpeak occurred) and CI300 (i.e. the CI observed at 300 s after contrast medium injection) values were determined from CI curves. We then classified the odontogenic tumours according to their DCE-MRI parameters. Results: Significant differences between the US values of the ameloblastomas and KCOT were observed on T1 weighted images, T2 weighted images and short TI inversion recovery images. Depending on their DCE-MRI parameters, we classified the odontogenic tumours into the following five types: Type A, CIpeak > 2.0 and Tpeak < 200 s; Type B, CIpeak < 2.0 and Tpeak < 200 s; Type C, CI 300 > 2.0 and Tmax < 600 s; Type D, CI300 > 2.0 and Tmax > 600 s; Type E, CI300 < 2.0 and Tmax > 600 s. Conclusion: Cystic component SI uniformity was found to be useful for differentiating between ameloblastomas and KCOT. However, the DCE-MRI parameters of odontogenic tumours, except for odontogenic fibromas and odontogenic myxomas, contributed little to their differential diagnosis. © 2013 The British Institute of Radiology.

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  • Knockdown of Dkk-3 decreases cancer cell migration and invasion independently of the Wnt pathways in oral squamous cell carcinoma‑derived cells. International journal

    Naoki Katase, Mathieu Lefeuvre, Hidetsugu Tsujigiwa, Masae Fujii, Satoshi Ito, Ryo Tamamura, Rosario Rivera Buery, Mehmet Gunduz, Hitoshi Nagatsuka

    Oncology reports   29 ( 4 )   1349 - 55   2013.4

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    Oral squamous cell carcinoma (OSCC) is thought to arise as the result of cumulative genetic or epigenetic alterations in cancer-associated genes. We focused on the Dickkopf-3 (Dkk-3) gene as a candidate tumor suppressor in OSCC. Dkk-3 is a potential tumor suppressor, and its downregulation has been reported in various types of malignancies. However, our previous data demonstrated that the Dkk-3 protein was dominantly expressed in OSCC tissue, and its expression was correlated with a high incidence of metastasis and with poor prognosis. In order to explain this paradox, we performed functional analyses of the Dkk-3 gene in cancer cell lines. RT-PCR revealed that Dkk-3 mRNA expression was observed in OSCC-derived cell lines but not in gastrointestinal or colorectal adenocarcinoma‑derived cell lines. The siRNA for Dkk-3 was transfected into Dkk-3-expressing cells, and the changes in cell proliferation, invasion and migration were assessed. The knockdown of Dkk-3 mRNA by siRNA transfection did not affect cell proliferation, but it significantly decreased cell migration and invasion. To further investigate the precise mechanism that contributes to the potential oncogenic function of Dkk-3, the Wnt canonical pathway and non-canonical pathways were assessed. Western blotting demonstrated that the effect of Dkk-3 knockdown on cell migration or invasion was not caused by activation of the Wnt pathways. These data demonstrated that Dkk-3 expression in OSCC was different than that in adenocarcinomas. Dkk-3 may possess an oncogenic function that is independent of Wnt signaling.

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  • The role of bone marrow-derived cells during the bone healing process in the GFP mouse bone marrow transplantation model International journal

    Hidetsugu Tsujigiwa, Yasuhisa Hirata, Naoki Katase, Rosario Rivera Buery, Ryo Tamamura, Satoshi Ito, Shin Takagi, Seiji Iida, Hitoshi Nagatsuka

    Calcified Tissue International   92 ( 3 )   296 - 306   2013.3

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    Bone healing is a complex and multistep process in which the origin of the cells participating in bone repair is still unknown. The involvement of bone marrow-derived cells in tissue repair has been the subject of recent studies. In the present study, bone marrow-derived cells in bone healing were traced using the GFP bone marrow transplantation model. Bone marrow cells from C57BL/6-Tg (CAG-EGFP) were transplanted into C57BL/6 J wild mice. After transplantation, bone injury was created using a 1.0-mm drill. Bone healing was histologically assessed at 3, 7, 14, and 28 postoperative days. Immunohistochemistry for GFP; double-fluorescent immunohistochemistry for GFP-F4/80, GFP-CD34, and GFP-osteocalcin; and double-staining for GFP and tartrate-resistant acid phosphatase were performed. Bone marrow transplantation successfully replaced the hematopoietic cells into GFP-positive donor cells. Immunohistochemical analyses revealed that osteoblasts or osteocytes in the repair stage were GFP-negative, whereas osteoclasts in the repair and remodeling stages and hematopoietic cells were GFP-positive. The results indicated that bone marrow-derived cells might not differentiate into osteoblasts. The role of bone marrow-derived cells might be limited to adjustment of the microenvironment by differentiating into inflammatory cells, osteoclasts, or endothelial cells in immature blood vessels. © 2012 Springer Science+Business Media New York.

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  • Comparative analysis of basal lamina type IV collagen α chains, matrix metalloproteinases-2 and -9 expressions in oral dysplasia and invasive carcinoma. International journal

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

    Acta histochemica   115 ( 2 )   113 - 9   2013.3

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    The aim of this study was to compare the expressions of basal lamina (BL) collagen IV α chains and matrix metalloproteinases (MMP)-2 and MMP-9 in oral dysplasia (OED) and invasive carcinoma. Ten cases each of OEDs, carcinomas-in situ and oral squamous cell carcinomas (OSCCs) were examined by immunohistochemistry. Another 5 cases, each of normal and hyperplastic oral mucosa, served as controls. Results showed that α1(IV)/α2(IV) and α5(IV)/α6(IV) chains were intact in BLs of control and OEDs. In BLs of carcinoma-in situ, α1(IV)/α2(IV) chains preceded α5(IV)/α6(IV) chains in showing incipient signs of disruption. OSCCs exhibited varying degrees of collagen α(IV) chain degradation. MMP-2 and MMP-9 were absent in controls and OED, but weakly detectable in carcinoma-in situ. In OSCC, these proteolytic enzymes were expressed in areas corresponding to collagen α(IV) chain loss. Enzymatic activity was enhanced in higher grade OSCC, and along the tumor advancing front. Overall the present findings suggest that loss of BL collagen α(IV) chains coincided with gain of expression for MMP-2 and MMP-9, and that these protein alterations are crucial events during progression from OED to OSCC.

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  • Conditions inhibiting eruption of permanent first molars

    Hidenobu Matsuzaki, Yoshinobu Yanagi, Naoki Katase, Hitoshi Nagatsuka, Marina Hara, Masakazu Ashida, Teruhisa Unetsubo, Akiko Sato, Mariko Fujita, Toshihiko Takenobu, Jun Ichi Asaumi

    Pediatric Dentistry   35 ( 1 )   67 - 70   2013.1

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    Purpose: The purpose of this study was to evaluate the radiological and histopathological findings of 11 patients with unerupted first molars to verify the factors obstructing spontaneous eruption. Methods: The patients' clinical, radiological, and histopathological data were evaluated retrospectively to determine histopathological diagnosis, radiographic findings, methods of surgical management, and postoperative course. Results: This study involved 4 male and 7 female patients (mean age=9.5 years old). Nine cases involved the mandible. The patients' histopathological diagnoses included 3 odontogenic tumors, 2 odontogenic cysts, and 6 hyperplastic dental follicles. Radiographically, 10 cases showed characterless enlargement of the follicular space, while only 1 displayed radiopaque bodies. One patient with a tumor underwent enucleation, and 1 with a cyst underwent cystectomy and tooth extraction. The others underwent wide excision or partial excision of the surrounding tissue at the top of the impacted tooth. Tumor relapse was observed in 3 cases. Conclusion: Surgeons should perform aggressive treatment for patients with unerupted teeth because spontaneous eruption is rare in cases involving non-neoplastic lesions such as hyperplastic dental follicles.

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  • Epithelium-poor type central odontogenic fibroma: An immunohistological study and review of the literature Reviewed

    Takashi Kimura, Seigo Ohba, Hitoshi Yoshimura, Naoki Katase, Yoshiaki Imamura, Takaaki Ueno, Hitoshi Nagatsuka, Kazuo Sano

    Journal of Hard Tissue Biology   22 ( 2 )   273 - 278   2013

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    The object of this study was to determine the characteristics of central odontogenic fibroma (COF) in order to help achieve a correct diagnosis. Central odontogenic fibroma, which tends to be epithelium-poor, is an extremely rare type of odontogenic fibroma. The lack of data concerning COF, due to its low incidence, can make this entity difficult to diagnose. We herein report an epithelium-poor type of COF of the mandible, which we examined immunohistologically. We also provide a review of the previous English literature to expand the knowledge about this disease. Positive reactions for vimentin and negative reactions for desmin andα-smooth muscle actin (α-SMA) in COFs were common findings in the previous reports. We also noted similar immunohistological findings. Our data (vimentin positive,α-SMA and desmin negative) should contribute to correctly diagnosing epithelium-poor type COF. © 2013 The Hard Tissue Biology Network Association.

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  • Improvement of the efcacy of 5-aminolevulinic acid-mediated photodynamic treatment in human oral squamous cell carcinoma hsc-4

    Masanao Yamamotoarf, Hirofumi Fujitaa, Naoki Katase, Keiji Inouec, Hitoshi Nagatsuka, Kozo Utsumi, Junzo Sasaki, Hideyo Ohuchi

    Acta Medica Okayama   67 ( 3 )   153 - 164   2013

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    Ever since protoporphyrin IX (PpIX) was discovered to accumulate preferentially in cancer cells after 5-aminolevulinic acid (ALA) treatment, photodynamic treatment or therapy (PDT) has been developed as an exciting new treatment option for cancer patients. However, the level of PpIX accumulation in oral cancer is fairly low and insufficient for PDT. Ferrochelatase (FECH) and ATP-binding cassette transporter G2 (ABCG2) are known to regulate PpIX accumulation In addition, serum enhances PpIX export by ABCG2. We investigated here whether and how inhibitors of FECH and ABCG2 and their combination could improve PpIX accumulation and PDT efficacy in an oral cancer cell fine in serum-containing medium. ABCG2 inhibitor and the combination of ABCG2 and FECH inhibitors increased PpIX in the presence of fetal bovine serum (FBS) in an oral cancer cell fine. Analysis of ABCG2 gene silencing also revealed the involvement of ABCG2 in the regulation of PpIX accumulation. Inhibitors of FECH and ABCG2, and their combination increased the efficiency of ALA-PDT even in the pres¬ence of FBS. ALA-PDT-induced cell death was accompanied by apoptotic events and lipid peroxida-tion. These results suggest that accumulation of PpIX is determined by the activities of ABCG2 and FECH and that treatment with a combination of their inhibitors improves the efficacy of PDT for oral cancer, especially in the presence of serum © 2013 by Okayama University Medical School.

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  • The ability of transplanted bone marrow-derived cells to differentiate into parenchymal cells of salivary glands

    Yao Wei Yuan, Ryo Tamamura, Lei Lei, Naoki Katase, Gulsan Ara Sathi, Satoshi Ito, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka

    Journal of Hard Tissue Biology   22 ( 4 )   433 - 438   2013

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    Salivary glands are important exocrine glands for oral health and initial digestion. Salivary gland dysfunction resulting from irreversible glandular damage usually leads to poor life quality in patients. Recent investigations showed that bone marrow-derived cells (BMDCs) could be grafted into non-hematopoietic cells in multiple tissues. In this study, BMDCs from green fluorescent protein (GFP) mice were transplanted into irradiated C57BL/6 mice to assess the ability of BMDCs to differentiate into parenchymal cells of salivary glands by immunohistochemistry and double fluorescent staining. The data revealed that a population of GFP positive cells showed the characteristics of acinar cells, ductal cells and myoepithelial cells in parotid and submandibular glands, and that some of BMDCs presented amylase expression. These results showed that BMDCs have the ability to differentiate into parenchymal cells of salivary glands with certain glandular cell functions. Such plasticity of BMDCs can be the first step for salivary gland regeneration by stem cells and tissue engineering therapy. © 2013 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved.

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  • Promotion of transplanted bone marrow-derived cell migration into the periodontal tissues due to orthodontic mechanical stress International journal

    Mihoko Tomida, Hidetsugu Tsujigiwa, Keisuke Nakano, Rina Muraoka, Takami Nakamura, Norimasa Okafuji, Hitoshi Nagatsuka, Toshiyuki Kawakami

    International Journal of Medical Sciences   10 ( 10 )   1321 - 1326   2013

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    Background: Bone marrow-derived cells (BMCs) have abilities of cell migration and differentiation into tissues/organs in the body and related with the differentiation of teeth or periodontal tissue including fibroblasts. Then, we examined the effect of orthodontic mechanical stress to the transplanted BMC migration into periodontal tissues using BMC transplantation model. Material and Method: BMC from green fluorescence protein (GFP) transgenic mice were transplanted into 8-week-old female C57BL/6 immunocompromised recipient mice, which had undergone 10 Gy of lethal whole-body-irradiation. Five mice as experimental group were received orthodontic mechanical stress using separator between first molar (M1) and second molar (M2) 1 time per week for 5 weeks and 5 mice as control group were not received mechanical stress. The maxilla with M1 and M2 was removed and was immunohistochemically analyzed using a Dako Envision + Kit-K4006 and a primary anti-GFP-polyclonal rabbit antibody. Immunohistochemically stained was defined as positive area and the pixel number of positive area in the periodontal tissue was compared with the previously calculated total pixel number of the periodontal tissue. Results: The immunohistochemistry revealed that GFP positive cells were detected in the periodontal tissues, both in the experimental and control specimens. The ratio of pixel number in the examination group showed 5.77 ± 3.24 % (mean ± SD); and that in the control group, 0.71±0.45 % (mean ± SD). The examination group was significantly greater than that of control group (Mann-Whitney U test: p<0.001). Conclusion: These results suggest that orthodontic mechanical stress accelerates transplanted BMC migration into periodontal tissues. © Ivyspring International Publisher.

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  • Osteogenic genes related to the canonic WNT pathway are down-regulated in ameloblastoma International journal

    Gulsan A. Sathi, Hidetsugu Tsujigiwa, Satoshi Ito, Chong Huat Siar, Naoki Katase, Ryo Tamamura, Hidemitsu Harada, Hitoshi Nagatsuka

    Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology   114 ( 6 )   771 - 777   2012.12

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    Objective: The aim of this study was to determine the expression of essential osteogenic genes related to the canonic WNT pathway, i.e., WDR5, sFRP-2, and their downstream genes, in ameloblastoma and to clarify their biologic impact on this neoplasm. Study Design: Forty-six paraffin-embedded ameloblastoma samples and ameloblastic (AM-1) and preosteoblastic (KUSA/A1) cell lines were used. Immunohistochemistry, Western blot, reverse-transcription polymerase chain reaction, and alkaline phosphatase (ALP) activity assay were performed. Results: WDR5, essential for osteoblast differentiation and canonic WNT pathway activation, was negative in most ameloblastoma cases and weakly expressed in AM-1 cells. Conversely, sFRP-2s was overexpressed. RUNX2 and C-MYC, downstream inductions of canonic WNT pathway activation, demonstrated weak mRNA expressions in ameloblastoma, suggesting WNT pathway impairment and WDR5 functional inactivity. Recombinant WDR5 weakly induced ALP activity of KUSA/A1 cells cultured in AM-1 conditioned medium. Conclusions: These findings suggest that WNT-related bone-forming genes are down-regulated in ameloblastoma. Concurrent sFRP-2 overexpression suggests that both bone-forming and bone-inhibiting genes equally contributed to reduced bone formation in this neoplasm. © 2012 Elsevier Inc.

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  • Transplanted Bone Marrow-Derived Cell Migration Into Periodontal Tissues Induced by Orthodontic Mechanical Stress Reviewed

    Tomida M, Tsujigiwa H, Nakano K, Muraoka R, Nagatsuka H, Kawakami T

    TRANSPLANTATION   94 ( 10 )   555   2012.11

  • Diagnostic value of dynamic contrast-enhanced MRI for submucosal palatal tumors International journal

    Hidenobu Matsuzaki, Yoshinobu Yanagi, Marina Hara, Naoki Katase, Miki Hisatomi, Teruhisa Unetsubo, Hironobu Konouchi, Toshihiko Takenobu, Hitoshi Nagatsuka, Jun Ichi Asaumi

    European Journal of Radiology   81 ( 11 )   3306 - 3312   2012.11

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    Objectives: To evaluate the diagnostic value of dynamic contrast-enhanced MRI (DCE-MRI) for differentiating between benign and malignant tumors in the palate. Materials and methods: 26 patients with submucosal palatal tumors were preoperatively examined using DCE-MRI. Their maximum contrast index (CImax), time of CImax (Tmax), and washout ratios (WR300 and WR600) were determined from contrast index curves. The submucosal palatal tumors were divided into two groups according to their Tmax values: the early enhancement group (Tmax < 300 s) consisted of 9 malignant tumors and 6 benign tumors, while the late enhancement group (Tmax ≥ 300 s) included one malignant tumor and 10 benign tumors. We compared the following DCE-MRI parameters between the benign and malignant tumors: CImax and Tmax in all cases and CImax, Tmax, and the washout ratios in the early enhancement group. In addition, we performed a regression analysis of the relationships between tumor size and DCE-MRI parameters; i.e., CImax, Tmax, and washout ratios, among the malignant salivary gland tumors and pleomorphic adenomas. Results: In all cases and the early enhancement group, significant differences in Tmax were detected between the benign and malignant tumors (P < 0.001 and P < 0.05, respectively), and the optimal Tmax cutoff value for differentiating between them was found to be 165 s. None of the other parameters displayed significant differences between the benign and malignant tumors. Only the WR600 of the pleomorphic adenomas was significantly correlated with tumor size (R2 = 0.92, P < 0.001). Conclusions: Tmax is a useful parameter for distinguishing between benign and malignant submucosal palatal tumors. © 2012 Elsevier Ireland Ltd. All rights reserved.

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  • Solid-type primary intraosseous squamous cell carcinoma of the mandible: A case report with histopathological and imaging features International journal

    Hidenobu Matsuzaki, Naoki Katase, Tatsushi Matsumura, Marina Hara, Yoshinobu Yanagi, Hitoshi Nagatsuka, Seiji Iida, Jun Ichi Asaumi

    Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology   114 ( 5 )   e71-7 - E77   2012.11

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    Primary intraosseous squamous cell carcinoma (PIOSCC) is a rare malignant odontogenic tumor arising from odontogenic epithelial remnants within the jawbones. PIOSCC is histopathologically divided into 3 types: solid-type carcinoma, carcinoma derived from a keratocystic odontogenic tumor, and carcinoma derived from an odontogenic cyst. In this article, we report a case of solid-type PIOSCC involving reactive bone formation in the mandible in a 60-year-old female patient together with its histopathological and imaging findings. © 2012 Elsevier Inc. All rights reserved.

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  • Ossifying fibroma of the maxilla: A case report including its imaging features and dynamic magnetic resonance imaging findings International journal

    Marina Hara, Hidenobu Matsuzaki, Naoki Katase, Yoshinobu Yanagi, Teruhisa Unetsubo, Jun Ichi Asaumi, Hitoshi Nagatsuka

    Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology   114 ( 4 )   e139-46 - E146   2012.10

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    Ossifying fibroma (OF), a rare nonodontogenic tumor, is defined as a bone-related jawbone lesion. The main histopathological feature of OF is the replacement of bone by benign connective tissue. Ossifying fibroma usually occurs in the second to fourth decades of life and shows a predilection for females. Ossifying fibroma most commonly occurs in the mandible, and OF arising from the anterior part of the maxilla is rare. Ossifying fibromas display various radiographic findings, including varying degrees of radiolucency and radiopacity, depending on the proportions of their soft and hard tissue components. Depending on their components, it can be difficult to distinguish OF from other fibroosseous lesions and some odontogenic tumors by using conventional radiographs, computed tomography, and magnetic resonance imaging (MRI). We report a case of OF in the anterior maxilla in a 56-year-old man, together with its histopathological and imaging findings including the dynamic MRI findings. © 2012 Elsevier Inc. All rights reserved.

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  • Heparanase and cyclooxygenase-2 gene and protein expressions during progression of oral epithelial dysplasia to carcinoma International journal

    Hitoshi Nagatsuka, Chong Huat Siar, Hidetsugu Tsujigiwa, Yoshio Naomoto, Phuu Pwint Han, Mehmet Gunduz, Toshio Sugahara, Akira Sasaki, Motowo Nakajima

    Annals of Diagnostic Pathology   16 ( 5 )   354 - 361   2012.10

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    Heparanase and cyclooxygenase-2 (COX-2) are 2 key enzymes that modulate diverse physiological processes during embryonic development and in adult life. Their deregulations have been implicated in the growth and progression of many cancer types. To date, comparatively little is known about the roles of these molecules during oral carcinogenesis. The aim of this study was to investigate the expression patterns of heparanase and COX-2 during progression of oral epithelial dysplasia (OED) to carcinoma. In situ hybridization and immunohistochemistry were performed on 5 cases of normal mucosa, 15 cases of OED, 5 cases of carcinoma in situ and/or microinvasive carcinoma, and 40 cases of oral squamous cell carcinoma (OSCC). Results demonstrated that heparanase and COX-2 messenger RNA and protein were absent in normal oral mucosa but were coexpressed in increasing intensity as OED progressed to OSCC. Concomitant heparanase- and COX-2-positive staining in the stromal cells suggests that OED/OSCC progression may be modulated by stromal-cancer cell interactions. Diffuse intense staining of poorly differentiated OSCC compared with staining localized to tumor nest periphery in well- and moderately differentiated OSCC suggests that heparanase and COX-2 overexpressions correlated with tumor grade. Strong expression of these enzymes in tumor cells at the advancing front suggests a role in local tumor spread. These results, taken together, suggest that heparanase and COX-2 might play complementary roles in the stepwise progression of OED to carcinoma. © 2012 Elsevier Inc.

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  • Minor salivary gland tumors in the oral cavity: Diagnostic value of dynamic contrast-enhanced MRI International journal

    Hidenobu Matsuzaki, Yoshinobu Yanagi, Marina Hara, Naoki Katase, Jun Ichi Asaumi, Miki Hisatomi, Teruhisa Unetsubo, Hironobu Konouchi, Toshihiko Takenobu, Hitoshi Nagatsuka

    European Journal of Radiology   81 ( 10 )   2684 - 2691   2012.10

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    Objective: To evaluate the diagnostic value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for minor salivary gland tumors in the oral cavity. Materials and methods: Thirty-two patients with minor salivary gland tumors were examined preoperatively using DCE-MRI. Their maximum contrast index (CImax), time of CImax (Tmax), Tpeak; i.e., the time that corresponded to the CImax × 0.90, and washout ratios (WR300 and WR600) were determined from contrast index (CI) curves. We compared these parameters between benign and malignant tumors and among the different histopathological types of minor salivary gland tumors. Then, we categorized the patients' CI curves into four patterns (gradual increase, rapid increase with high washout ratio, rapid increase with low washout, and flat). Results: Statistically significant differences in Tmax (P = 0.004) and Tpeak (P = 0.002) were observed between the benign and malignant tumors. Regarding each histopathological tumor type, significant differences in Tmax (P < 0.001), Tpeak (P < 0.001), and WR600 (P = 0.026) were observed between the pleomorphic adenomas and mucoepidermoid carcinomas. It was difficult to distinguish between benign and malignant tumors using our CI curve classification because that two-thirds of the cases were classified into the same type (gradual increase). Conclusion: The DCE-MRI parameters of minor salivary gland tumors contributed little to their differential diagnosis compared with those for major salivary gland tumors. During the diagnosis of minor salivary gland tumors, Tmax is useful for distinguishing between benign and malignant tumors. © 2011 Elsevier Ireland Ltd.

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  • Unusual MRI appearance of a lymphoepithelial cyst in the parotid gland Reviewed

    Hidenobu Matsuzaki, Naoki Katase, Yoshinobu Yanagi, Marina Hara, Mariko Fujita, Teruhisa Unetsubo, Hitoshi Nagatsuka, Jun Ichi Asaumi

    Oral Radiology   28 ( 2 )   133 - 139   2012.9

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    Lymphoepithelial cysts, which are also known as branchial cleft cysts, commonly occur in the lateral cervical region. Lymphoepithelial cysts arising in the parotid gland are rare and must be distinguished from parotid gland tumors. Magnetic resonance imaging (MRI) is useful for diagnosing parotid gland lesions, and MR images of lymphoepithelial cysts typically display a cystic mass that appears homogeneously hypointense on T1-weighted images and homogeneously hyperintense on T2-weighted images. However, some parotid gland tumors that retain fluid in their inner sections show similar MRI findings to lymphoepithelial cysts. Furthermore, lymphoepithelial cysts are sometimes modified by inflammation, and these cases are hard to diagnose. We report the case of a 59-yearold female with a lymphoepithelial cyst that arose in the parotid gland. The cyst had been affected by inflammation and displayed atypical imaging findings, i.e., heterogeneous signal intensity of the liquid component and the presence of a well-enhanced capsule-like structure surrounding the liquid component. In addition, we compare the MRI findings of this case with those of two other cervical lymphoepithelial cysts. © Japanese Society for Oral and Maxillofacial Radiology and Springer 2012.

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  • Imaging features of adenoid cystic carcinoma of the tongue with dedifferentiated components: A case report Reviewed

    Yoshinobu Yanagi, Hidenobu Matsuzaki, Naoki Katase, Tomoo Onoda, Marina Hara, Teruhisa Unetsubo, Hitoshi Nagatsuka, Jun Ichi Asaumi

    Oral Radiology   28 ( 2 )   157 - 165   2012.9

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    Adenoid cystic carcinoma (ACC) of the head and neck region is an uncommon epithelial tumor of the major and minor salivary glands. In the oral region, although ACC arising from the minor salivary glands is the second most commonly found tumor in the tongue base, its occurrence in the anterior part of the tongue is rare. Histopathologically, ACC is categorized into three growth patterns (tubular, cribriform, and solid types) and three histologic grades (I-III) that are based on the proportions of these patterns. According to this classification, tubularand cribriform-type ACCs are considered to be lower grade lesions, while solid-type ACCs are considered to be higher grade lesions. A fourth histopathological type has recently been reported by some authors, namely, dedifferentiation or high-grade transformation of ACC. However, very few studies have focused on the imaging features of these ACCs. We report here the case of a 63-year-old female patient with ACC of the tongue with dedifferentiated components, together with the radiological images and pathological features of this ACC. © Japanese Society for Oral and Maxillofacial Radiology and Springer 2012.

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  • CCN2 production of ameloblastoma is to define the nature of the tumor stroma

    Takebe Y, Katase N, Tsujigiwa H, Ito S, Fujii M, Sathi GSA, Harada H, Sasaki A, Nagatsuka H

    Journal of Hard Tissue Biology   22 ( 1 )   155   2012.8

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  • α2アドレナリン受容体作用薬デクスメデトミジンの抗炎症効果

    井上 美穂, 助川 信太郎, 長塚 仁, 宮脇 卓也

    日本歯科医師会雑誌   65 ( 5 )   688 - 688   2012.8

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  • 病理組織学的にエナメル上皮線維腫との鑑別が困難であったimmature odontomaの1例 Reviewed

    柴田 茜, 志茂 剛, 片瀬 直樹, 中妻 可奈子, 堀切 優, 岸本 晃治, 西山 明慶, 目瀬 浩, 長塚 仁, 佐々木 朗

    岡山歯学会雑誌   31 ( 1 )   15 - 20   2012.6

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  • Central odontogenic fibroma of the jawbone: 2 case reports describing its imaging features and an analysis of its DCE-MRI findings International journal

    Marina Hara, Hidenobu Matsuzaki, Naoki Katase, Yoshinobu Yanagi, Teruhisa Unetsubo, Jun Ichi Asaumi, Hitoshi Nagatsuka

    Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology   113 ( 6 )   e51-8 - E58   2012.6

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    Odontogenic fibroma (OF) is a rare nonepithelial benign tumor arising from the odontogenic mesenchymal tissue in the jawbone. OFs are topographically categorized into 2 types, the central type and peripheral type, and are histopathologically divided into the epithelium-poor type and epithelium-rich type. The radiological findings of central OF commonly include a uni- or multilocular radiolucent area with a well-defined margin, which are similar to those of cysts and other benign tumors of the jawbone. Therefore, it is difficult to distinguish OF from these jawbone lesions on radiographs because of their noncharacteristic radiological findings. In this article, we report the cases of 2 patients with central OF who underwent magnetic resonance (MR) examinations and describe the usefulness of dynamic contrast-enhanced MR imaging for diagnosing OF. © 2012 Elsevier Inc. All rights reserved.

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  • Differential expression of canonical and non-canonical Wnt ligands in ameloblastoma International journal

    Chong Huat Siar, Hitoshi Nagatsuka, Phuu Pwint Han, Rosario Rivera Buery, Hidetsugu Tsujigiwa, Keisuke Nakano, Kok Han Ng, Toshiyuki Kawakami

    Journal of Oral Pathology and Medicine   41 ( 4 )   332 - 339   2012.4

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    Background: Canonical and non-canonical Wnt signaling pathways modulate diverse cellular processes during embryogenesis and post-natally. Their deregulations have been implicated in cancer development and progression. Wnt signaling is essential for odontogenesis. The ameloblastoma is an odontogenic epithelial neoplasm of enamel organ origin. Altered expressions of Wnts-1, -2, -5a, and -10a are detected in this tumor. The activity of other Wnt members remains unclarified. Materials and Methods: Canonical (Wnts-1, -2, -3, -8a, -8b, -10a, and -10b), non-canonical (Wnts-4, -5a, -5b, -6, 7a, -7b, and -11), and indeterminate groups (Wnts-2b and -9b) were examined immunohistochemically in 72 cases of ameloblastoma (19 unicystic [UA], 35 solid/multicystic [SMA], eight desmoplastic [DA], and 10 recurrent [RA]). Results: Canonical Wnt proteins (except Wnt-10b) were heterogeneously expressed in ameloblastoma. Their distribution patterns were distinctive with some overlap. Protein localization was mainly membranous and/or cytoplasmic. Overexpression of Wnt-1 in most subsets (UA=19/19; SMA=35/35; DA=5/8; RA= 7/10) (P<0.05), Wnt-3 in granular cell variant (n=3/3), and Wnt-8b in DA (n=8/8) was key observations. Wnts-8a and -10a demonstrated enhanced expression in tumoral buddings and acanthomatous areas. Non-canonical and indeterminate Wnts were absent except for limited Wnt-7b immunoreactivity in UA (n=1/19) and SMA (n=1/35). Stromal components expressed variable Wnt positivity. Conclusion: Differential expression of Wnt ligands in different ameloblastoma subtypes suggests that the canonical and non-canonical Wnt pathways are selectively activated or repressed depending on the tumor cell differentiation status. Canonical Wnt pathway is most likely the main transduction pathway while Wnt-1 might be the key signaling molecule involved in ameloblastoma tumorigenesis. © 2011 John Wiley & Sons A/S.

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  • Basic fibroblast growth factor supports expansion of mouse compact bone-derived mesenchymal stem cells (MSCs) and regeneration of bone from MSC in vivo International journal

    Eiki Yamachika, Hidetsugu Tsujigiwa, Masakazu Matsubara, Yasuhisa Hirata, Kenichiro Kita, Kiyofumi Takabatake, Nobuyoshi Mizukawa, Yoshihiro Kaneda, Hitoshi Nagatsuka, Seiji Iida

    Journal of Molecular Histology   43 ( 2 )   223 - 233   2012.4

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    Some progress has been made in development of methods to regenerate bone from cultured cells, however no method is put to practical use. Here, we developed methods to isolate, purify, and expand mesenchymal stem cells (MSCs) from mouse compact bone that may be used to regenerate boneinvivo. These cells were maintainedinlong-term culture and were capable of differentiating along multiple lineages, including chondrocyte, osteocyte, and adipocyte trajectories. We used standard cell isolation and culture methods to establish cell cultures from mouse compact bone and bone marrow. Cultures were grown in four distinct media to determine the optimal composition of culture medium for bone-derived MSCs. Putative MSCs were subjected to flow cytometry, alkaline phosphatase assays, immunohistochemical staining, and several differentiation assays to assess cell identity, protein expression, and developmental potential. Finally, we used an in vivo bone formation assay to determine whether putative MSCs were capable of regenerating bone. We found that compact bone of mice was a better source of MCSs than the bone marrow, that growth in plastic flasks served to purify MSCs from hematopoietic cells, and that MSCs grown in basic fibroblast growth factor (bFGF)-conditioned medium were, based on multiple criteria, superior to those grown in leukemia inhibitory factor-conditioned medium. Moreover, we found that the MSCs isolated from compact bone and grown in bFGF-conditioned medium were capable of supporting bone formation in vivo. The methods and results described here haveimplicationsfor understanding MSC biology and for clinical purpose.. © Springer Science+Business Media B.V. 2012.

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  • Analysis of immunoexpression of common cancer stem cell markers in ameloblastoma International journal

    Gulsan Ara Sathi, Ryo Tamamura, Hidetsugu Tsujigiwa, Naoki Katase, Mathieu Lefeuvre, Chong Huat Siar, Hiroyuki Matsuda, Hitoshi Nagatsuka

    Experimental and Therapeutic Medicine   3 ( 3 )   397 - 402   2012.3

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    Recent studies have established that, in benign tumors, a large number of cancer stem cells are present, which have great implications in tumor development. However, in ameloblastoma, a highly aggressive, locally invasive tumor with a high recurrence rate, whether or not cancer stem-like cells are present remains undetermined. Therefore, in this study we analyzed the protein expression of three candidate stem cell markers in ameloblastoma. Immunohistochemical staining for cancer stem cell (CSC) markers (CD133, CD44 and ABCG2) and for the proliferation marker Ki-67 was performed using 23ameloblastoma cases. In all 23 samples, CD133, CD44 and ABCG2 were expressed. Nine (39.13%) cases showed high expression and 14cases (60.87%) showed low expression for CD133. Twelve of the 23cases (52.17%) showed high expression and 11cases (47.83%) showed low expression for both CD44 and ABCG2, respectively. Ki-67 was mainly expressed in peripheral ameloblast-like cells, suggesting that these cells have a higher degree of differentiation and, therefore, are less likely to contain cancer stem-like cells. On the other hand, cells positive for CSC markers situated at the close proximity to peripheral cells were devoid of Ki-67 and may have the potential to be cancer stem-like cells. After analyzing the correlation between expression of three CSC markers with clinicopathological factors and Ki-67 expression, only CD44 expression was correlated with tumor recurrence (P=0.0391). In conclusion, this study showed various expression patterns of different types of cancer stem cell markers and the presence of candidate CSC-like cells in ameloblastoma, which are possibly involved in cell proliferation, tumor progression and recurrence.

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  • Absence of Dickkopf (Dkk)-3 protein expression is correlated with longer disease-free survival and lower incidence of metastasis in head and neck squamous cell carcinoma International journal

    Naoki Katase, Mathieu Lefeuvre, Mehmet Gunduz, Esra Gunduz, Levent Bekir Beder, Reidar Grenman, Masae Fujii, Ryo Tamamura, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka

    Oncology Letters   3 ( 2 )   273 - 280   2012.2

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    Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently occurring types of cancer worldwide. We focused on the fact that the aberrant function of Wnt/β-catenin signaling is a frequent event in malignancies. Dickkopf (Dkk)-3 is a major negative regulator of Wnt/β catenin signaling, which is a known tumor suppressor and is down regulated in various types of cancer. However, the expression profile of the Dkk-3 protein in HNSCC has not yet been reported. The present study was conducted to investigate Dkk-3 protein expression in 90 cases of HNSCC tissue samples and HNSCC-derived cell lines. In contrast to findings available on other types of cancer, the Western blot analysis revealed that HNSCC cell lines expressed the Dkk-3 protein. In immunohistochemistry, 76 cases (84.4%) out of 90 tissue samples were Dkk-3-positive, whereas only 14 cases (15.6%) were negative. Notably, survival analysis showed that the Dkk-3 (-) group exhibited significantly longer disease-free survival (p=0.038), metastasis-free survival (p=0.013) and longer overall survival (p=0.155). The results showed that the Dkk-3 protein was dominantly expressed and may be involved in carcinogenesis and metastasis in HNSCC. Moreover, the findings suggest that the function of Dkk-3 differs depending on the tissue of origin, and that it may exert an oncogenic function in HNSCC.

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  • Magnetic resonance imaging (MRI) and dynamic MRI evaluation of extranodal non-Hodgkin lymphoma in oral and maxillofacial regions International journal

    Hidenobu Matsuzaki, Marina Hara, Yoshinobu Yanagi, Jun Ichi Asaumi, Naoki Katase, Teruhisa Unetsubo, Miki Hisatomi, Hironobu Konouchi, Toshihiko Takenobu, Hitoshi Nagatsuka

    Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology   113 ( 1 )   126 - 133   2012.1

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    Objective. The purpose of this study was to evaluate the diagnostic value of magnetic resonance imaging (MRI), especially dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), in extranodal non-Hodgkin lymphoma (NHL) of oral and maxillofacial regions. Study design. Thirteen cases with extranodal NHL were examined using MRI. T1-weighted images (T1WI) and T2-weighted images (T2WI) or short TI inversion recovery (STIR) images were obtained in all cases. Contrast-enhanced images and DCEMRI were acquired in 10 and 7 cases, respectively. On DCE-MRIs, we analyzed the parameters as follows: contrast index at maximal contrast enhancement (CImax), maximum contrast index (CI) gain/CImax ratio, and washout ratios (WR300, WR600, and WR900) at 300, 600, and 900 seconds after contrast medium injection. Results. The signal intensity of all lesions was hypointense to isointense on T1WIs and showed variable contrast enhancement patterns. On T2WIs and STIR images, the signal intensity was isointense to hyperintense in almost all cases. Analysis of DCEMRI parameters in extranodal NHLs resulted in the identification of 4 types of CI curves according to CImax and WR: (1) CImax greater than 2.0 and WR900 greater than 40%, (2) CImax greater than 2.0 and WR900 less than 40%, (3) CImax less than 1.5 and WR900 greater than 40%, and (4) CImax less than 1.5 and WR900 greater than 40%. Conclusions. The signal intensities on MRI were not specific to extranodal NHL and resembled those of other tumor types. When CImax was less than 1.5 or WR900 was less than 40%, these parameters contributed to diagnosis in extranodal NHLs. © 2012 Elsevier Inc. All rights reserved.

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  • 幼児の上顎歯肉粘液腫の1例

    伊原木 聰一郎, 西山 明慶, 吉岡 徳枝, 兒玉 真一, 長塚 仁, 目瀬 浩, 佐々木 朗

    日本口腔科学会雑誌   61 ( 1 )   182 - 182   2012.1

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  • Application of multiplanar computed tomography and the osirix imaging software for precise analysis of dens invaginatus in the maxillary third molar

    Hiroko Kondo, Takayoshi Tobita, Takaaki Ueno, Hitoshi Yoshimura, Naoki Katase, Seigo Ohba, Hitoshi Nagatsuka, Kazuo Sano

    Journal of Hard Tissue Biology   21 ( 3 )   337 - 340   2012

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    Dens invaginatus is a deep surface invagination of the dentin that is lined by enamel and is easily affected by dental caries, thus resulting in pulpitis and apical periodontitis. This report presents an image analysis of rare dens invaginatus of the maxillary third molar in a 23-year-old man. A radiographic examination showed a radiopaque structure in the dilated roots and a radiolucent area around the root. Tooth extraction and cystectomy were performed. The histological findings showed the tooth to have type III dens invaginatus. This report discusses the application of multiplanar computed tomography (CT) imaging and the free image analysis software (OsiriX) to achieve a more precise evaluation of dens invaginatus. © 2012 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved.

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  • Bone-healing pattern on critical-sized defects treated by rhPTH

    María V. Jammal, Nina F. Pastorino, Carlos M. Abate, Shin Takagi, Hitoshi Nagatsuka, Liliana R. Missana

    Journal of Hard Tissue Biology   21 ( 4 )   443 - 450   2012

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    Intermittent Recombinant Human Parathyroid Hormone (rhPTH 1-34) is an effective treatment for improving bone mass in patients with osteoporosis; however, its effects on bone regeneration are still unclear. The objective of this study was to evaluate the potential toxicity systemic rhPTH, as well as its ability to regenerate critical-sized defects (CZD) in bone. We used 43 female Wistar rats (body weight, 150 ± 50 g). Critical-sized bone defects in rat calvaria received vehicle alone (Control Group, CG) or daily rhPTH (20 ng/ Kg/day) by subcutaneous injection (Experimental Group, EG). We evaluated bone healing obtained at the 1st, 3rd, and 6th wks post-surgery by biochemical, soft x-ray, histological, and morphometric studies. In the EG, at the 1st and 3rd wks, many areas of focal osteoblast hyperplasia were found on parietal bone. At the 3rd wk, woven and/or lamellar bone, in an organized interconnected trabecular network, showed disrupted mineralization. At the 6th wk, looped bone was found to have formed patterns on parietal bone. New bone formed in the EG showed significant statistical differences (p = 0.023) at the 6th wk. Systemic rhPTH at the dose of 20 ng/Kg/ day was able to stimulate bone formation on rat CZD. Also, pre-existing and new bone showed non-proliferative forms of bone hyperostosis (increased non-neoplastic bone). © 2012 The Hard Tissue Biology Network Association.

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  • Dickkopf (Dkk)-3 and β-catenin expressions increased in the transition from normal oral mucosal to oral squamous cell carcinoma International journal

    Masae Fujii, Naoki Katase, Mathieu Lefeuvre, Mehmet Gunduz, Rosario Rivera Buery, Ryo Tamamura, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka

    Journal of Molecular Histology   42 ( 6 )   499 - 504   2011.12

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    Dickkopf (Dkk)-3, an inhibitor of the Wnt/β-catenin pathway, is reported as a potential tumor suppressor gene in many cancers. To gain a better comprehension of the mechanisms involved in the carcinogenesis of oral squamous epithelium, protein expression and localization of Dkk-3 and β-catenin was investigated in normal epithelium, dysplasias and squamous cell carcinoma (SCC). An increase in β-catenin and Ki-67 expressions was observed from dysplasias to poorly differentiated SCC. Interestingly, an increase in Dkk-3 positive cells was also noted, which was correlated to the cancer progression step. A change in Dkk-3 localization during the transformation of normal oral epithelium to SCC was clearly observed. Dkk-3 was localized in the cell membrane in normal oral epithelium and in dysplasias, whereas that was localized in both cell membrane and cytoplasm in SCC. These results suggest that Dkk-3 is involved in the carcinogenesis of SCC with a distinct function from those in other cancers. © 2011 Springer Science+Business Media B.V.

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  • Notch signaling and ghost cell fate in the calcifying cystic odontogenic tumor

    C. H. Siar, Toshiyuki Kawakami, R. R. Buery, K. Nakano, M. Tomida, H. Tsujigiwa, P. P. Han, H. Nagatsuka, K. H. Ng

    European Journal of Medical Research   16 ( 11 )   501 - 506   2011.11

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    Notch signaling is an evolutionarily conserved mechanism that enables adjacent cells to adopt different fates. Ghost cells (GCs) are anucleate cells with homogeneous pale eosinophilic cytoplasm and very pale to clear central areas (previous nucleus sites). Although GCs are present in a variety of odontogenic lesions notably the calcifying cystic odontogenic tumor (CCOT), their nature and process of formation remains elusive. The aim of this study was to investigate the role of Notch signaling in the cell fate specification of GCs in CCOT. Immunohistochemical staining for four Notch receptors (Notch1, Notch2, Notch3 and Notch4) and three ligands (Jagged1, Jagged2 and Delta1) was performed on archival tissues of five CCOT cases. Level of positivity was quantified as negative (0), mild (+), moderate (2+) and strong (3+). Results revealed that GCs demonstrated overexpression for Notch1 and Jagged1 suggesting that Notch1-Jagged1 signaling might serve as the main transduction mechanism in cell fate decision for GCs in CCOT. Protein localizations were largely membranous and/or cytoplasmic. Mineralized GCs also stained positive implicating that the calcification process might be associated with upregulation of these molecules. The other Notch receptors and ligands were weak to absent in GCs and tumoral epithelium. Stromal endothelium and fibroblasts were stained variably positive. © I. Holzapfel Publishers 2011.

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  • NRAS and BRAF mutation frequency in primary oral mucosal melanoma International journal

    Rosario Rivera Buery, Chong Huat Siar, Naoki Katase, Mehmet Gunduz, Mathieu Lefeuvre, Masae Fujii, Masahisa Inoue, Kojun Setsu, Hitoshi Nagatsuka

    Oncology Reports   26 ( 4 )   783 - 787   2011.10

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    Oral mucosal melanoma (OMM) is a fatal sarcoma of unknown etiology. Histological morphology and genetic events are distinct from those of its cutaneous counterpart. Mutation and up-regulation of c-kit has been identified in OMM which may activate downstream molecules such as RAS and RAF. These molecules are involved in the mitogen-activated protein kinase (MAPK) pathway leading to tremendous cell proliferation and survival. NRAS and BRAF mutation and protein expression have been studied in other melanoma subtypes. The purpose of this study was to determine RAS protein expression and NRAS and BRAF mutation in 18 primary OMM cases using immunohistochemistry and mutation analysis. Results showed that RAS is intensely expressed in both in situ and invasive OMMs. However, NRAS mutation was only observed in 2/15 polymerase chain reaction (PCR) amplified cases both of which were silent mutations. On the other hand, BRAF missense mutations were observed only in 1/15 cases with PCR amplification. NRAS and BRAF mutations were independent from previously reported c-kit mutations. The classical V600E BRAF mutation was not found; instead a novel V600L was observed suggesting that the oncogenic event in OMM is different from that in skin melanoma. The low frequency of NRAS and BRAF mutations indicate that these genes are not common, but probable events in OMM pathogenesis, most likely independent of c-kit mutation.

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  • Localization and characterization of lymphatic vessels in oral and cervical squamous cell carcinoma International journal

    Masahisa Inoue, Cheng Hsiung Roan, Tomomi Abe, Rosario R. Buery, Hitoshi Nagatsuka, Naoki Katase, Noriyuki Nagai, Kojun Setsu

    Experimental and Therapeutic Medicine   2 ( 5 )   793 - 797   2011.9

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    Lymph node metastasis is considered a factor in determining the prognosis of squamous cell carcinoma (SCC). Both oral and cervical SCC tumor cells prefer lymph vessels as the route of metastasis. D2-40 is a specific marker of lymphatic endothelial cells. This study clarifies the distribution and characteristics of lymphatic vessels in oral and cervical SCCs. Immunohistochemistry was performed in 20 oral and 20 cervical SCCs (10 non-metastatic and 10 metastatic to lymph nodes) using D2-40, CD31, CD34, CD105 and double staining with D2-40 and keratin. Lymphatic vessel density (LVD) was also determined morphologically. Results showed that lymphatic vessels in both types of SCCs were distributed mainly at the superficial region beneath the epithelium. The LVD in each tumor was significantly higher compared to the corresponding normal mucosa. Moreover, the LVD in lymph node metastasis in each tumor was significantly higher compared to their non-metastatic counterparts. Cancer cell invasion was observed in the lymphatic vessels suggesting the existence of lymph node involvement during metastasis. The new lymphatic vessels that proliferated around the cancer nests in both SCCs have endothelial cell characteristics inferred to be associated with early lymphatic development and initial dissemination of cancer cells.

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  • Primary extranodal lymphoma of the maxilla: A case report with imaging features and dynamic data analysis of magnetic resonance imaging International journal

    Hidenobu Matsuzaki, Naoki Katase, Marina Hara, Jun Ichi Asaumi, Yoshinobu Yanagi, Teruhisa Unetsubo, Miki Hisatomi, Hironobu Konouchi, Toshihiko Takenobu, Hitoshi Nagatsuka

    Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology   112 ( 3 )   e59-69 - E69   2011.9

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    Malignant lymphoma is the second-most common malignancy in the head and neck region. Waldeyer's ring is the most common site of extranodal Hodgkin's lymphoma (NHL) in that region, and a small percentage of primary extranodal NHL occurs in the oral cavity. The most common sites of extranodal NHL in the oral region are the palate and maxilla, and nearly half of extranodal NHL cases arise from bone. It is difficult to diagnose extranodal NHL because of the variety of its radiological features. We report a case of primary extranodal NHL of the maxilla in a 68-year-old female patient with atypical imaging findings, along with the results of analysis of dynamic magnetic resonance imaging (MRI). © 2011 Mosby, Inc.

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  • Dkk-3 protein and mRNA expression in head and neck squamous cell carcinoma and its correlation with the prognosis

    片瀬 直樹, グンデゥズ・メーメット, 辻極 秀次, ルフェーブル・マシュー, シャティ・グルサンアラ, 藤井 昌江, 長塚 仁

    日本癌学会総会記事   70回   171 - 171   2011.9

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  • CCN2 expression in ameloblastoma

    Takebe Y, Katase N, Tsujigiwa H, Lefeuvre M, Sathi GSA, Tamamura R, Sasaki A, Nagatsuka H

    Journal of Hard Tissue Biology   20 ( 3 )   267   2011.8

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  • Strawberry gingivitis as the first presenting sign of Wegener's granulomatosis: Report of a case

    C. H. Siar, K. B. Yeo, K. Nakano, H. Nagatsuka, H. Tsujigiwa, M. Tomida, K. H. Ng, Toshiyuki Kawakami

    European Journal of Medical Research   16 ( 7 )   331 - 334   2011.7

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    Wegener's granulomatosis is a rare multi-system disease characterized by the classic triad of necrotizing granulomas affecting the upper and lower respiratory tracts, disseminated vasculitis and glomerulonephritis. Oral lesions as a presenting feature are only encountered in 2% of these cases. Hyperplastic gingival lesions or strawberry gingivitis, is a characteristic sign of Wegener's granulomatosis. The latter consists of reddish-purple exophytic gingival swellings with petechial haemorrhages thus resembling strawberries. Recognition of this feature is of utmost importance for timely diagnosis and definitive management of this potentially fatal disease. A case of strawberry gingivitis as the first presenting sign of Wegener's granulomatosis affecting a 50-year-old Malay male is reported here. The differential diagnosis of red lesions that may present in the gingiva is discussed. © I. Holzapfel Publishers 2011.

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  • Ameloblastic carcinoma: A case report with radiological features of computed tomography and magnetic resonance imaging and positron emission tomography International journal

    Hidenobu Matsuzaki, Naoki Katase, Marina Hara, Jun Ichi Asaumi, Yoshinobu Yanagi, Teruhisa Unetsubo, Miki Hisatomi, Hironobu Konouchi, Hitoshi Nagatsuka

    Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology   112 ( 1 )   e40-7 - E47   2011.7

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    Ameloblastic carcinoma is a rare malignant odontogenic carcinoma that has metastatic potential, and because of its rare incidence, there are few reports focusing on its radiologic imaging. If it shows aggressive appearances, it can be diagnosed as malignant tumor. But in case of negative appearance, it is difficult to distinguish ameloblastic carcinoma from ameloblastoma. We report a case of ameloblastic carcinoma of the maxilla in a 76-year-old female patient with radiologic images and pathologic features. © 2011 Mosby, Inc. All rights reserved.

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  • Immunoexpression of different type stem cell marker in ameloblastoma

    G. A. Sathi, R. Tamamura, T. Hidetsugu, N. Katase, M. Lefeuvre, H. Nagatsuka

    ORAL ONCOLOGY   47   S54 - S54   2011.7

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  • Effect of fluoride-substituted apatite on in vivo bone formation International journal

    Miho Inoue, Andrea P. Rodriguez, Noriyuki Nagai, Hitoshi Nagatsuka, Racquel Z. Legeros, Hidetsugu Tsujigiwa, Masahisa Inoue, Etsuo Kishimoto, Shin Takagi

    Journal of Biomaterials Applications   25 ( 8 )   811 - 824   2011.5

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    Biological apatites are characterized by the presence of minor constituents such as magnesium (Mg), chloride (Cl), or fluoride (F) ions. These ions affect cell proliferation and osteoblastic differentiation during bone tissue formation. F-substituted apatites are being explored as potential bonegraft materials. The aim of the present study is to investigate the mechanism of bone formation induced by fluoride-substituted apatite (FAp) by analyzing the effect of FAp on the process of in vivo bone formation. FAps containing different F concentrations (l-FAp: 0.48wt%, m-FAp: 0.91wt%, h-FAp: 2.23wt%) and calcium-deficient apatite (CDA), as positive control, were implanted in rat tibia and bone formation was evaluated by histological examination, immuhistochemistry, in situ hybridization and tartrate-resistant acid phosphatase examinations. The results showed that l-FAp, m-FAp, h-FAp, and CDA biomaterials allowed migration of macrophages, attachment, proliferation, and phenotypic expression of bone cells leading to new bone formation in direct apposition to the particles. However, the l-FAp preparation allowed faster bone conduction compared to the other experimental materials. These results suggest that FAp with low F concentration may be an efficient bonegraft material for dental and medical application. © 2010 The Author(s).

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  • Tumor suppressor gene detection in oral tumors for new therapeutic strategy

    Naoki Katase, Mathieu Lefeuvre, Mehmet Gunduz, Hidetsugu Tsujigiwa, Silvia Susana Borkosky, Gul San Ara Sathi, Ryo Tamamura, Masae Fujii, Kenji Shimizu, Hitoshi Nagatsuka

    Oral Cancer: Causes, Diagnosis and Treatment   169 - 188   2011.4

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    In head and neck, oral and maxillofacial region, there are many kinds of neoplasms, which may originate from squamous epithelium, salivary glands and tooth germ etc. Generally, neoplasm development is considered to arise due to the cumulative abnorm alities of tumor-associated genes, i.e. oncogenes and tumor suppressor genes (TSGs). As for the neoplasms in head and neck, oral and maxillofacial regions, the responsible genes specifically associated with tumorigenesis and/or invasiveness have not been well understood. Therefore the biological characteristics of these neoplasms are yet to be determined. In order to establish a new approach for the better understanding, early diagnosis and advanced therapeutic strategies, we considered application of loss of heterozygosity (LOH) analysis for detection of TSGs.LOH analysis is a highly sensitive and specific method to detect allelic deletion of specific chromosomal locations. Briefly, paired samples of genomic DNA extracted from normal and tumor tissues of the same patients are used for the study. Certain sequences on the chromosomal loci are amplified by PCR using microsatellite markers. The PCR products are loaded into polyacrylamide gel electrophoresis and visualized with various methods including silver staining and SYBR green. Then the bands from normal and tumor DNA PCR products are compared. If the band form tumor DNA are weakened or disappeared as compared to normal counterpart after normalization with a band of housekeeping gene for each of normal and tumor DNA, LOH (+) is scored. Loci with frequent LOH might harbor TSGs.Based on the idea, we have reported several candidate TSGs as a carcinogenic as well as therapeutic target, including inhibition of growth (ING) and Dickkopf (Dkk) family of genes. LOH could be observed not only in malignant tumors but also in benign tumors. In this chapter, we will show the general data of LOH analysis in head and neck squamous cell carcinoma (HNSCC) and ameloblastoma as the actual examples.HNSCC is the 6th or 7th most occurring cancer worldwide. Despite improvement in surgery, radiation and chemotherapy, often HNSCC is difficult to be controlled in the cases with lymph nodal and/or distant metastasis. Therefore, its total survival rate is yet to be improved during decades. On the other hand, ameloblastoma is the most common odontogenic tumor, which possesses strong local invasiveness, although it is a benign tumor. Ameloblastoma generally occurs in the young population, and sometimes aggressive bone resection is needed, which might result in the impaired quality of life. Therefore, establishment of new and less aggressive therapeutic approaches are needed. Application of LOH analysis and combination with statistical analysis might be a powerful tool for detection of the role of candidate TSGs as prognostic factor. © 2011 by Nova Science Publishers, Inc. All rights reserved.

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  • Inhibition of mammalian target of rapamycin (mTOR) signaling by Temsirolimus as a potential therapeutic strategy for esophageal cancer treatment

    Munenori Takaoka, Toshio Nishikawa, Toshiaki Ohara, Yasuko Tomono, Yasuhiro Fujiwara, Yasuhiro Shirakawa, Hitoshi Nagatsuka, Takuya Fukazawa, Tomoki Yamatsuji, Xiaohong Bao, Huifang Hao, Kaori Shigemitsu, Ichiro Morita, Toshiyoshi Fujiwara, Yoshio Naomoto

    CANCER RESEARCH   71   2011.4

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  • Glutamine depletion induces murine neonatal melena with increased apoptosis of the intestinal epithelium International journal

    Takayuki Motoki, Yoshio Naomoto, Junji Hoshiba, Yasuhiro Shirakawa, Tomoki Yamatsuji, Junji Matsuoka, Munenori Takaoka, Yasuko Tomono, Yasuhiro Fujiwara, Hiroshi Tsuchita, Mehmet Gunduz, Hitoshi Nagatsuka, Noriaki Tanaka, Toshiyoshi Fujiwara

    World Journal of Gastroenterology   17 ( 6 )   717 - 726   2011.2

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    AIM: To investigate the possible biological outcome and effect of glutamine depletion in neonatal mice and rodent intestinal epithelial cells. METHODS: We developed three kinds of artificial milk with different amounts of glutamine; Complete amino acid milk (CAM), which is based on maternal mouse milk, glutamine-depleted milk (GDM), and glutaminerich milk (GRM). GRM contains three-fold more glutamine than CAM. Eighty-seven newborn mice were divided into three groups and were fed with either of CAM, GDM, or GRM via a recently improved nipple- bottle system for seven days. After the feeding period, the mice were subjected to macroscopic and microscopic observations by immunohistochemistry for 5-bromo-2'- deoxyuridine (BrdU) and Ki-67 as markers of cell proliferation, and for cleaved-caspase-3 as a marker of apoptosis. Moreover, IEC6 rat intestinal epithelial cells were cultured in different concentrations of glutamine and were subject to a 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)- 2H-5-tetrazolio]-1,3-benzene disulfonate cell proliferation assay, flow cytometry, and western blotting to examine the biological effect of glutamine on cell growth and apoptosis. RESULTS: During the feeding period, we found colonic hemorrhage in six of 28 GDM-fed mice (21.4%), but not in the GRM-fed mice, with no differences in body weight gain between each group. Microscopic examination showed destruction of microvilli and the disappearance of glycocalyx of the intestinal wall in the colon epithelial tissues taken from GDM-fed mice. Intake of GDM reduced BrdU incorporation (the average percentage of BrdU-positive staining; GRM: 13.8%, CAM: 10.7%, GDM: 1.14%, GRM vs GDM: P < 0.001, CAM vs GDM: P < 0.001) and Ki-67 labeling index (the average percentage of Ki- 67-positive staining; GRM: 24.5%, CAM: 22.4% GDM: 19.4%, GRM vs GDM: P = 0.001, CAM vs GDM: P = 0.049), suggesting that glutamine depletion inhibited cell proliferation of intestinal epithelial cells. Glutamine deprivation further caused the deformation of the nuclear membrane and the plasma membrane, accompanied by chromatin degeneration and an absence of fat droplets from the colonic epithelia, indicating that the cells underwent apoptosis. Moreover, immunohistochemical analysis revealed the appearance of cleaved caspase-3 in colonic epithelial cells of GDM-fed mice. Finally, when IEC6 rat intestinal epithelial cells were cultured without glutamine, cell proliferation was significantly suppressed after 24 h (relative cell growth; 4 mmol/L: 100.0% ± 36.1%, 0 mmol/L: 25.3% ± 25.0%, P < 0.05), with severe cellular damage. The cells underwent apoptosis, accompanied by increased cell population in sub-G0 phase (4 mmol/L: 1.68%, 0.4 mmol/L: 1.35%, 0 mmol/L: 5.21%), where dying cells are supposed to accumulate. CONCLUSION: Glutamine is an important alimentary component for the maintenance of intestinal mucosa. Glutamine deprivation can cause instability of the intestinal epithelial alignment by increased apoptosis. © 2011 Baishideng. All rights reserved.

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  • Transplanted bone marrow-derived cell migration into periodontal tissues and cell differentiation

    Rina Muraoka, Hidetsugu Tsujigiwa, Keisuke Nakano, Naoki Katase, Ryo Tamamura, Mihoko Tomida, Norimasa Okafuji, Hitoshi Nagatsuka, Toshiyuki Kawakami

    Journal of Hard Tissue Biology   20 ( 4 )   301 - 306   2011

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    We examined the transplanted bone marrow-derived cell migration into periodontal tissues. Bone marrow cells from green fluorescent protein (GFP) transgenic mice were transplanted. The immunohistochemistry (IHC) revealed that GFP-positive cells were detected in the periodontal tissues. The GFP-positive cells histopathologically differentiated into some cell types. The fluorescence IHC and TRAP staining techniques demonstrated these cells were detected as osteoclasts and macrophages. Furthermore, GFP-positive cells gathered adjacent blood vessels. The data suggest that GFP-positive bone marrow-derived cell migrate into periodontal tissues and differentiate periodontal tissue component-cells. © 2011 The Hard Tissue Biology Network Association.

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  • Co-expression of BMP-2 and -7 in the tumoral epithelium of CEOT with selective BMP-7 expression in amyloid materials

    Chong H. Siar, Keisuke Nakano, Phuu P. Han, Mihoko Tomida, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Kok H. Ng, Toshiyuki Kawakami

    Journal of Hard Tissue Biology   20 ( 2 )   125 - 132   2011

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    The calcifying epithelial odontogenic tumor (CEOT) is a benign but locally-invasive odontogenic neoplasm believed to take origin from the stratum intermedium of the developing tooth germ. Bone morphogenetic proteins (BMPs) are multifunctional signaling molecules that regulate diverse cellular processes including epithelial-mesenchymal interactions during odontogenesis. Aberrant BMP activity has been enumerated in the ameloblastoma but information about its distribution in the CEOT remains limited. The aim here was to investigate BMP expression in CEOT and to speculate on its significance. Immunolabelling for BMP-2 and BMP-7 was performed on archival tissues of six CEOT cases and the level of expression was quantified as negative (0), mild (+), moderate (2+) and strong (3+). Results disclosed that CEOT epithelium demonstrated co-expression of BMP-2 and -7 suggesting upregulation of these proteins at sites of tumor differentiation. Distribution patterns were distinct with some overlap. Their localizations were largely membranous and/or cytoplasmic. Amyloid-like materials strongly expressed BMP-7 but were nonreactive for BMP-2, implicating that these signaling proteins play differential roles in the formation of these extracellular products. Mineralized substances including Liesegang rings were mostly negative for both BMPs suggesting that calcification process is associated with repression of these molecules. Stromal endothelium and fibroblasts were stained variably positive. BMP was heterogeneously detected in the CEOT epithelium at the tumor advancing front suggesting their upregulation at active sites and downregulation in quiescent areas. Present findings suggest that BMP-2 and BMP-7 most likely play differential roles in the cellular differentiation and progression of CEOT. BMP-7 accumulation within amyloid-like protein is a novel finding. © 2011 The Hard Tissue Biology Network Association.

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  • Transplanted bone marrow derived cells differentiated totooth, bone and connective tissues in mice

    Hidetsugu Tsujigiwa, Naoki Katase, Gulsan A. Sathi, Rosario R. Buery, Yasuhisa Hirata, Midori Kubota, Keisuke Nakano, Toshiyuki Kawakami, Hitoshi Nagatsuka

    Journal of Hard Tissue Biology   20 ( 2 )   147 - 152   2011

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    Teeth are important structures for masticatory and phonetic purposes. Loss of teeth decreases these functions leading to impaired quality of life. Missing teeth replaced by tooth regeneration may be possible with emerging advances in stem cell biology and tissue engineering. Recent investigations have demonstrated that bone marrow derived cells (BMDC) can differentiate into cells other than blood cells. In the present study, the ability of BMDC to differentiate into tooth forming tissues was investigated using bone marrow transplantation model. BMDC from green fluorescent protein (GFP) transgenic mice were transplanted into 8-week old, C57BL/6 immunocompromised mice, which underwent 10-Gy whole body lethal irradiation. Immunohistochemical analysis revealed that bone marrow cells are positive to GFP, confirming successful bone marrow transplantation. Diffusedly GFP-positive cells were observed within the dental pulp of mouse incisor. GFP-positive cells in the dental pulp have arborescent processes resembling dendritic cell-like cells. Some odontoblast-like cells were also positive to GFP. Cells positive to GFP were observed in the cervical loop region and periodontal ligament. Langerhans cells in the oral epithelium, stromal fibroblasts, blood vessels and osteoclasts were also positive to GFP. These results indicate that BMDC have the ability to differentiate into tooth, bone and connective tissues. © 2011 The Hard Tissue Biology Network Association.

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  • Molecular screening of anti-quorum sensing capability of Salvadora persica on Enterococcus faecalis

    Afsaneh Rezaei, Glenn G. Oyong, Virgilio B. Borja, Masahisa Inoue, Tomomi Abe, Ryo Tamamura, Hitoshi Nagatsuka, Kojun Setsu, Rosario R. Buery

    Journal of Hard Tissue Biology   20 ( 2 )   115 - 124   2011

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    Quorum sensing (QS) refers to the phenomenon characterized by the accumulation of signaling molecules enabling a cell to sense a bacterial population triggering a coordinated response. Enterococcus faecalis is a resistant microorganism commonly found in oral infections. Salvadora persica has been traditionally used in Middle East countries to clean the teeth due to its antimicrobial activity. The study investigated the anti-quorum sensing (AQS) ability of S. persica extracts on E. faecalis. Extracts from the bark, leaves, root and shoots were tested against Chromobacterium violaceum. AQS ability was determined using differential scanning fluorimetry (DSF) and elastolytic assay to detect the level of protease and quantitative polymerase chain reaction (QPCR) to detect cytolysin (cylR1) and gelatinase (gelE) virulence factors. Preliminary disk diffusion assays revealed AQS activity by inhibiting violacein pigment production in C. violaceum without affecting its growth. Furthermore, only negligible amount of proteases was detected in DSF and elastolytic assays. CylR1 and gelE gene expression revealed no detectable signals even from the lowest possible threshold. The results indicate that S. persica has AQS ability against E. faecalis. S. persica extract can be used as alternative or in combination with other anti-microbial agents against infections caused by E. faecalis. © 2010 The Hard Tissue Biology Network Association.

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  • Increased expression of the PRL-3 gene in human oral squamous cell carcinoma and dysplasia tissues International journal

    Nur Mohammad Monsur Hassan, Jun Ichi Hamada, Takeshi Kameyama, Mitsuhiro Tada, Koji Nakagawa, Shoko Yoshida, Haruhiko Kashiwazaki, Yutaka Yamazaki, Yukiko Suzuki, Akira Sasaki, Hitoshi Nagatsuka, Nobuo Inoue, Tetsuya Moriuchi

    Asian Pacific Journal of Cancer Prevention   12 ( 4 )   947 - 951   2011

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    Phosphatase of regenerating liver (PRL) belongs to a class of the protein tyrosine phosphatase family, which is known so far to consist of 3 members, PRL-1, PRL-2, and PRL-3. The aim of this study was to uncover the role of PRL genes in development of oral malignancy. We analyzed expression levels of the 3 PRL genes in 50 human oral squamous cell carcinomas (OSCCs), 11 dysplasia and 12 normal mucosa tissues by a real-time RTPCR method. PRL-3 but not PRL-1 or PRL-2 expressions were significantly higher in OSCC and dysplasia than in normal mucosa tissues. Additionally, PRL-3 expressions were significantly higher in OSCC tissues harboring dominant-negative p53 or recessive p53 mutation than in those harboring wild-type p53. These results suggest that PRL-3 plays a role in oral cancer development and can be useful as a marker of pre-malignant and malignant lesion of oral mucosa.

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  • The utility of three-dimensional dynamic contrast-enhanced magnetic resonance imaging in delineating vessel-rich regions: A case report of an aneurysmal bone cyst of the mandible Reviewed

    Yoshinobu Yanagi, Mariko Fujita, Miki Hisatomi, Hidenobu Matsuzaki, Hironobu Konouchi, Naoki Katase, Hitoshi Nagatsuka, Jun Ichi Asaumi

    Oral Radiology   26 ( 2 )   110 - 115   2010.12

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    Aneurysmal bone cysts (ABCs) are classified as bone-related lesions based on the 2005 World Health Organization histological classification of odontogenic tumors. Most ABCs are diagnosed using a combination of conventional radiography, computed tomography, magnetic resonance imaging (MRI), and digital subtraction angiography. ABCs should be differentiated from true cysts or other pseudocysts because their treatment is different. Additionally, unlike other cysts, ABCs pose a hemorrhagic risk in surgery; thus, preoperative evaluation of intralesional blood flow is required. Here we report a case of a mandibular ABC in a 39-year-old woman and focus on its dynamic contrast-enhanced MRI (DCE-MRI) features. On DCE-MRI, the lesion was divided into two areas according to the enhancement pattern: the bloodpooling and blood-flow areas. The series of DCE-MR images of the blood-pooling area showed marked enhancement of the margin, but no enhancement in the inner part of the cavity. Additionally, the time-signal intensity curve (TIC) demonstrated no change in the signal intensity (SI) until approximately 15 min after gadoliniumdiethylenetriamine penta-acetic acid (Gd-DTPA) administration. In contrast, the series of DCE-MR images of the blood-flow area exhibited marked enhancement in the cyst cavity in the early phase. The TIC showed a rapid increase in SI in the early phase, followed by a rapid decrease until 150 s, and finally a gradual decrease until approximately 15 min after Gd-DTPA administration. Thus, in the current patient, preoperative DCE-MRI clearly delineated the vessel-rich area within the lesion. © Japanese Society for Oral and Maxillofacial Radiology and Springer 2010.

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  • Screening for DNA copy number aberrations in mucinous adenocarcinoma arising from the minor salivary gland: Two case reports International journal

    Kenichiro Uchida, Atsunori Oga, Takamitsu Mano, Hitoshi Nagatsuka, Yoshiya Ueyama, Kohsuke Sasaki

    Cancer Genetics and Cytogenetics   203 ( 2 )   324 - 327   2010.12

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    Mucinous adenocarcinoma (MAC) is a rare malignancy in the minor salivary gland. To our knowledge, genomic alterations in this tumor have not been reported previously. To identify DNA copy number aberrations, we applied comparative genomic hybridization (CGH) to four samples of MAC in minor salivary gland derived from two patients: a primary tumor and two cervical metastatic lymph nodes from one patient, and a primary tumor from the other patient. Copy number increases were commonly detected in 1q21∼q31 and 20q13, and these may play an important role in MAC carcinogenesis. Copy number increases in 1q, 12p, 12q, and 20q were commonly detected in all three samples derived from patient 1, and gain of 7p and loss of chromosome 4 were additionally detected in the two samples derived from metastatic lymph nodes. Amplifications were also detected in the chromosomal regions 8q22∼qter, 12p11∼p12, 12q11∼q21, and 20q13. Amplification of MDM2 (12q15) and of AURKA (20q13) was detected with fluorescence in situ hybridization. The DNA copy number aberrations detected in MAC in minor salivary glands were different from those reported for colorectal MAC. The present findings are novel in identifying genomic alterations of MAC arising from the minor salivary gland. © 2010 Elsevier Inc.

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  • Tumor-specific mutation and downregulation of ING5 detected in oral squamous cell carcinoma International journal

    Beyhan Cengiz, Esra Gunduz, Mehmet Gunduz, Levent Bekir Beder, Ryo Tamamura, Cahit Bagci, Noboru Yamanaka, Kenji Shimizu, Hitoshi Nagatsuka

    International Journal of Cancer   127 ( 9 )   2088 - 2094   2010.11

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    Our previous study showed high frequency of allelic loss at chromosome 2q37 region in oral cancer. This location contains several candidate tumor suppressor genes such as PPP1R7, ILKAP, DTYMK and ING5. We previously showed 3 members of inhibitor of growth (ING) family, ING1, ING3 and ING4 as tumor suppressor gene in head and neck cancer. As ING5 shows high homology with other members of ING genes including highly conserved carboxy-terminal plant homeodomain and nuclear localization signal, we first picked up ING5 and examined it as a possible tumor suppressor in oral cancer. For this aim, mutation and mRNA expression status of ING5 in paired normal and oral squamous cell carcinoma samples were examined by reverse transcription polymerase chain reaction (RT-PCR) and sequencing. Three missense mutations located within leucine zipper like (LZL) finger and novel conserved region (NCR) domains in ING5 protein were detected, probably abrogating its normal function. We also found 5 different alternative splicing variants of ING5. Then, we examined mRNA level of ING5 by quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) analysis, which demonstrated decreased expression of ING5 mRNA in 61% of the primary tumors as compared to the matched normal samples. In conclusion, tumor-specific mutation and downregulation of ING5 mRNA suggested it as a tumor suppressor gene in oral squamous cell carcinoma. © 2010 UICC.

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  • Inhibitory mechanism of bone formation in ameloblastoma.

    Nagatsuka H, Sathi GSA, Katase N, Tamamura R, Tsujigiwa H

    Journal of Hard Tissue Biology   20 ( 1 )   67 - 68   2010.11

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  • Immunolocalization of notch signaling protein molecules in a maxillary chondrosarcoma and its recurrent tumor

    C. H. Siar, K. O. Ha, L. O. Aung, K. Nakano, H. Tsujigiwa, H. Nagatsuka, K. H. Ng, Toshiyuki Kawakami

    European Journal of Medical Research   15 ( 10 )   456 - 460   2010.10

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    Background: Notch receptors are critical determinants of cell fate in a variety of organisms. Notch signaling is involved in the chondrogenic specification of neural crest cells. Aberrant Notch activity has been implicated in numerous human diseases including cancers; however its role in chondrogenic tumors has not been clarified. Method: Tissue samples from a case of primary chondrosarcoma of the maxilla and its recurrent tumor were examined immunohistochemically for Notch 1-4 and their ligands (Jagged1, Jagged2 and Delta1) expression. Results: Both primary and recurrent tumors were histopathologically diagnosed as conventional hyaline chondrosarcoma (WHO Grade I). Hypercellular tumor areas strongly expressed Notch3 and Jagged1 in spindle and pleomorphic cells suggesting up-regulation of these protein molecules at sites of tumor proliferation. Expression patterns were distinct with some overlap. Differentiated malignant and atypical chondrocytes demonstrated variable expression levels of Jagged1, and weak to absent staining for Notch1, 4 and Delta1. Protein immunolocalization was largely membranous and cytoplasmic, sometimes outlining the lacunae of malignant chondrocytes. Hyaline cartilage demonstrated a diffuse or granular precipitation of Jagged1 suggesting presence of soluble Jagged1 activity at sites of abnormal chondrogenesis. No immunoreactivity for the other Notch members was observed. Calcified cartilage was consistently Notch-negative indicating down-regulation of Notch with cartilage maturation. Stromal components namely endothelial cells and fibroblasts variably expressed Notch1, 3 and Jagged1 but were mildly or non-reactive for the other members. Conclusions: Results indicate that Notch signaling pathway may participate in cellular differentiation and proliferation in chondrosarcoma. Findings implicate Notch3 and Jagged1 as key molecules that influence the differentiation and maturation of cells of chondrogenic lineage. © I. Holzapfel Publishers 2010.

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  • Usefulness of MRI and dynamic contrast-enhanced MRI for differential diagnosis of simple bone cysts from true cysts in the jaw International journal

    Yoshinobu Yanagi, Jun Ichi Asaumi, Teruhisa Unetsubo, Masakazu Ashida, Toshihiko Takenobu, Miki Hisatomi, Hidenobu Matsuzaki, Hironobu Konouchi, Naoki Katase, Hitoshi Nagatsuka

    Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology   110 ( 3 )   364 - 369   2010.9

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    Introduction. It can be difficult to differentiate simple bone cysts (SBCs) from true cysts in the jaw when these lesions appear unilocular. The present study reports the MR imaging of subjects with SBCs and describes the diagnostic value of the MRI findings. Materials and methods. Ten subjects with SBCs in the jaw were examined using MRI. T1- and T2-weighted images (T1W1, T2WI) were obtained, and contrast-enhanced images and dynamic contrast-enhanced MRI (DCE-MRI) were acquired. Results. In all cases, the contrast-enhanced TIWI acquired approximately 6 minutes after the administration of GdDTPA showed marked enhancement of the margin and slight enhancement of the inner part of the cyst cavity. In all cases, the time-signal intensity (SI) curves show a gradual increase in the SI until approximately 15 minutes after the administration of Gd-DTPA. These findings might not be observed on the DCE-MRIs of the other true cysts with epithelial lining that show no enhancement in a cavity. MRI, especially DCE-MRI, can provide useful information for distinguishing SBCs from other cysts. © 2010 Published by Mosby, Inc.

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  • 口腔扁平上皮癌における1p36領域のLOH解析(LOH analysis of 1p36 region in oral squamous cell carcinoma)

    Lefeuvre Mathieu, 片瀬 直樹, 玉村 亮, 辻極 秀次, 長塚 仁

    Journal of Oral Biosciences   52 ( Suppl )   141 - 141   2010.9

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  • Immunohistochemical analysis of Dkk-3 expression in head and neck squamous cell carcinoma

    Fujii M, Katase N, Lefeuvre M, Tsujigiwa H, Kubota M, Sathi GSA, Matsuda H, Nagatsuka H

    Journal of Hard Tissue Biology   19 ( 3 )   208   2010.9

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  • Immunohistochemical Expression of Notch Signaling in Calcifying Cystic Odontogenic Tumor Reviewed

    Kawakami T, Siar C. H, Nakano K, Tomida M, Matsuura S, Tsujigiwa H, Nagatsuka H

    ORAL DISEASES   16 ( 6 )   517 - 518   2010.9

  • Differential expression of Notch receptors and their ligands in desmoplastic ameloblastoma International journal

    Chong Huat Siar, Keisuke Nakano, Phuu Pwint Han, Hitoshi Nagatsuka, Kok Han Ng, Toshiyuki Kawakami

    Journal of Oral Pathology and Medicine   39 ( 7 )   552 - 558   2010.8

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    Background: In mammals, the Notch gene family encodes four receptors (Notch1-4), and all of them are important for cell fate decisions. Notch signaling pathway plays an essential role in tooth development. The ameloblastoma, a benign odontogenic epithelial neoplasm, histologically recapitulates the enamel organ at bell stage. Notch has been detected in the plexiform and follicular ameloblastoma. Its activity in the desmoplastic ameloblastoma is unknown. Method: Notch1-4 and their ligands (Jagged1, Jagged2 and Delta1) were examined immunohistochemically in 10 cases of desmoplastic ameloblastoma. Results: Ameloblastoma tumor epithelium demonstrated positive expression for Notch1 (n = 5/10), Notch3 (n = 8/10), Notch4 (n = 10/10), Jagged1 (n = 6/10) and Delta1 (n = 5/10), but no reactivity for Notch2 (n = 10/10) and Jagged2 (10/10). Expression patterns were distinct with some overlap. Positive activity was detected largely in the cell membrane and cytoplasm of peripheral and central neoplastic epithelial cells, and sometimes in the nucleus. Staining score was highest for Notch4. Stromal components namely endothelial cells and fibroblasts showed overexpression for Notch4 but were mildly or non-reactive for the other Notch members and their ligands. Conclusions: These findings suggest that Notch receptors and their ligands may play differing roles during the development of the desmoplastic ameloblastoma with Notch4 probably playing a greater role in the acquisition of tissue-specific cellular characteristics in the desmoplastic ameloblastoma. © 2010 John Wiley & Sons A/S All rights reserved.

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  • Preferential up-regulation of heparanase and cyclooxygenase-2 in carcinogenesis of Barrett's oesophagus and intestinal-type gastric carcinoma International journal

    Ryotaro Sonoda, Yoshio Naomoto, Yasuhiro Shirakawa, Yasuhiro Fujiwara, Tomoki Yamatsuji, Kazuhiro Noma, Shunsuke Tanabe, Munenori Takaoka, Mehmet Gunduz, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Nobuya Ohara, Tadashi Yoshino, Kaiyo Takubo, Michael Vieth, Noriaki Tanaka

    Histopathology   57 ( 1 )   90 - 100   2010.7

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    Aims: Metaplastic changes secondary to chronic inflammation at the gastro-oesophageal junction and at the pyloric antrum are recognized as the premalignant conditions of Barrett's oesophageal adenocarcinoma and intestinal-type gastric carcinoma (GC), respectively. Heparanase (HPSE) and cyclooxygenase (COX)-2 have been proved to play critical roles in inflammation as well as in cancer. The aim was to examine the meaning of their expression in inflammation-related carcinogenesis. Methods and results: First, expression of HPSE and COX-2 in 78 clinical tissues of Barrett's oesophagus was examined by immunohistochemistry and in situ hybridization. Their expression was increased during the metaplasia-dysplasia sequence with increased neovascularization. Successively, their expression in Barrett's dysplasia was compared with that of GC (22 cases of diffuse-type and 10 of intestinal-type). Interestingly, the expression pattern in Barrett's dysplasia was similar to that in intestinal-type GC, which mainly arises from chronic inflammation. Furthermore, cultured cell lines isolated from differentiated GC tissues, which are often found to be of intestinal-type, revealed up-regulated mRNA expression of HPSE and COX-2. Conclusions: HPSE and COX-2 are preferentially up-regulated in Barrett's oesophagus and intestinal-type GC. These molecules may play an important role during the development of inflammation-related adenocarcinoma of the upper gastrointestinal tract. © 2010 Blackwell Publishing Limited.

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  • Expression and mutation analysis of her2 in head and neck squamous cell carcinoma International journal

    Mahmoud Al Sheikh Ali, Mehmet Gunduz, Esra Gunduz, Ryo Tamamura, Levent Bekir Beder, Naoki Katase, Omer Faruk Hatipoglu, Kunihiro Fukushima, Noboru Yamanaka, Kenji Shimizu, Hitoshi Nagatsuka

    Cancer Investigation   28 ( 5 )   495 - 500   2010.5

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    We analyzed mutation and expression status of human epidermal growth factor receptor 2 (Her2) in head and neck squamous cell carcinoma (HNSCC) using single strand conformation polymorphism (SSCP) mutation analysis and immunohistochemistry (IHC). Mutations were absent in all 85 cases. Out of 57 cases available for IHC, Her2 protein expression was negative (0) in 40 tumors (70). Seventeen tumors (29.8) expressed Her2, among these 13 tumors (22.8%) showed a weak (+1) expression and 4 (7%) showed a moderate expression (+2), none showed a strong (+3) expression. There was not a significant association between expression and any of the patients' clinical variables or prognosis. Our results suggest that Her2 may not be useful as a molecular target in HNSCC. Copyright © 2010 Informa Healthcare USA, Inc.

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  • Effect of CaTiO<inf>3</inf>-CaCO<inf>3</inf> prepared by alkoxide method on cell response International journal

    Andrea P. Rodriguez, Miho Inoue, Toshiyuki Tanaka, Michihiro Miyake, Ana M. Sfer, Etsuo Kishimoto, Hidetsugu Tsujigiwa, Rosario S. Rivera, Hitoshi Nagatsuka

    Journal of Biomedical Materials Research - Part A   93 ( 1 )   297 - 303   2010.4

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    In recent years, calcium titanate (CaTiO3) and carbon-containing materials have gained much attention in a number of biomedical material researches. To maximize the advantages of both materials, we developed a novel alkoxide method to get "calcium titanate with calcium carbonate" (CaTiO3-CaCO3). The objective was to evaluate the crystallinity and elemental composition of CaTiO3-CaCO3 prepared by alkoxide method, CaTiO3-aC elaborated by modified thermal decomposition method, commercially-prepared CaTiO3, and the effect of these materials on the bone marrow stromal cell. Hydroxyapatite was used as positive control material. We examined the cellular proliferation, osteoblastic differentiation, and mineralization of KUSA/A1 cells cultured with the materials. The results showed that CaTiO3-CaCO3 and CaTiO3-aC contained evidence of calcium carbonate enhancing cell proliferation, osteoblastic differentiation, and mineralization. On the contrary, the commercially-prepared CaTiO3 revealed absence of calcium carbonate with lower cell response than the other groups. The results indicated that calcium carbonate could play a key role in the cell response of CaTiO3 material. In conclusion, our findings suggest that CaTiO 3-CaCO3 could be considered an important candidate as a biomaterial for medical and dental applications. © 2009 Wiley Periodicals, Inc.

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  • Squamous odontogenic tumor of the mandible: A case report demonstrating immunoexpression of Notch1, 3, 4, Jagged1 and Delta1

    C. H. Siar, Keisuke Nakano, K. H. Ng, M. Tomida, H. Nagatsuka, T. Kawakami

    European Journal of Medical Research   15 ( 4 )   180 - 184   2010.4

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    Background: Squamous odontogenic tumor (SOT) is a rare benign odontogenic epithelial neoplasm. A slow-growing painless expansive swelling is the common presenting symptom. Histopathologically, SOT can be easily misdiagnosed as an acanthomatous ameloblastoma. Although Notch receptors and ligands have been shown to play a role in cell fate decisions in ameloblastomas, the role of these cell signaling molecules in SOT is unknown. Case report: This paper describes a case of SOT affecting the anterior mandible of a 10-year-old Indian female. The patient was treated by local surgical excision and there has been no follow-up clinical record of recurrence 5 years after primary treatment. Histopathological examination revealed a solid, locally-infiltrative neoplasm composed of bland-looking squamatoid islands scattered in a mature fibrous connective tissue stroma and the diagnosis was SOT. Immunohistochemical evaluation showed positive reactivity of varying intensity in the neoplastic epithelial cells for Notch1, Notch3, Notch4, and their ligands Jagged1 and Delta1. Expression patterns showed considerable overlap. No immunoreactivity was detected for Notch2 and Jagged2. Conclusions: Present findings suggest that Notch receptors and their ligands play differential roles in the cytodifferentiation of SOT. © I. Holzapfel Pubishers 2010.

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  • An unsuspected ameloblastoma in the subpontic region of the mandible with consideration of pathogenesis from the radiographic course

    C. H. Siar, Keisuke Nakano, P. I. Chelvanayagam, K. H. Ng, H. Nagatsuka, T. Kawakami

    European Journal of Medical Research   15 ( 3 )   135 - 138   2010.3

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    The purpose of this report is to document a case of unsuspected ameloblastoma involving the right mandibular subpontic region in a 38-year-old Cambodian female patient. This lesion was purportedly preceded by multiple radiolucencies which were diagnosed as radicular cysts and treated a few times in the past years by enucleation followed by endodontic therapy of the affected teeth. Bridgework restoration of the partially edentulous area was performed. This case report demonstrates radiographic changes that occurred in the periods before and after the diagnosis of ameloblastoma. The case may represent an example of radicular cysts and ameloblastoma occurring as a collision phenomenon, or the ameloblastoma may have arisen as a result of neoplastic transformation of the lining epithelium in an inflammatory odontogenic epithelial cyst. © I. Holzapfel Publishers 2010.

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  • Effect of a new titanium coating material (CaTiO<inf>3</inf>-aC) prepared by thermal decomposition method on osteoblastic cell response International journal

    Miho Inoue, Andrea P. Rodriguez, Tohru Takagi, Naoki Katase, Midori Kubota, Noriyuki Nagai, Hitoshi Nagatsuka, Masahisa Inoue, Noriyuki Nagaoka, Shin Takagi, Kazuomi Suzuki

    Journal of Biomaterials Applications   24 ( 7 )   657 - 672   2010.3

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    Titanium and hydroxyapatite (HA) are widely used as biomaterials for dental and medical applications. HA-coated titanium implants have excellent biocompatibility and mechanical properties. However, the adherence of HA film formed on titanium substrate is weak because of the lack of chemical interaction between HA and titanium. A solution to this problem is to form an intermediate film on titanium substrate, which provide excellent adherence to both titanium substrate and HA. We developed a novel biomaterial called calcium titanate-amorphous carbon (CaTiO3-aC) coating prepared by modified thermal decomposition method. The purpose of this study was to evaluate the effect of CaTiO3-aC and HA coating (positive control), and Ti (negative control) on osteoblastic (MT3T3-E1) cell responses. An increased cellular proliferation was observed in CaTiO3-aC coating compared to HA coating. The maximum expressions of ALP activity, Col I and ALP mRNA were higher and achieved in shorter period of time in CaTiO3-aC coating compared to others. These results demonstrated that CaTiO3-aC promoted better cell attachment, cellular proliferation, and osteoblastic differentiation compared with HA. In conclusion, we suggested that CaTiO 3-aC could be considered as an important candidate as a coating material.

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  • A case of malignant fibrous histiocytoma of the maxillary sinus International journal

    Yoshinobu Yanagi, Jun Murakami, Miki Hisatomi, Naoki Katase, Hitoshi Nagatsuka, Jun ichi Asaumi

    Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology   109 ( 3 )   E99 - E104   2010.3

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    Malignant fibrous histiocytoma (MFH) is recognized as one of the most common soft tissue sarcomas arising in late adulthood. Most MFHs arise from the extremities and the retroperitoneum, thus the incidence of head and neck MFH is relatively low. Because of its rare incidence, there are very few reports focusing on the imaging features of MFH arising in the maxillary sinus. A case of MFH of the maxillary sinus in a 67-year-old male patient is reported including imaging and pathological features. © 2010 Mosby, Inc. All rights reserved.

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  • Central Adenoid Cystic Carcinoma of the Mandible With Multiple Bone Metastases: Case Report International journal

    Takamitsu Mano, Noriko Wada, Kenichiro Uchida, Yukoh Muraki, Hitoshi Nagatsuka, Yoshiya Ueyama

    Journal of Oral and Maxillofacial Surgery   68 ( 2 )   446 - 451   2010.2

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  • Frequent allelic loss of Dkk-1 locus (10q11.2) is related with low distant metastasis and better prognosis in head and neck squamous cell carcinomas International journal

    Naoki Katase, Mehmet Gunduz, Levent Bekir Beder, Esra Gunduz, Mahmoud Al Sheikh Ali, Ryo Tamamura, Kursat Oguz Yaykasli, Noboru Yamanaka, Kenji Shimizu, Hitoshi Nagatsuka

    Cancer Investigation   28 ( 1 )   103 - 110   2010

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    Head and neck squamous cell carcinoma (HNSCC) is a frequently occurring cancer worldwide. Dickkopf (Dkk)-1 gene is suggested to function as tumor suppressor gene (TSG) in several kinds of malignancies. In this study, we performed loss of heterozygosity (LOH) analysis of Dkk-1 and examined the correlation between LOH status and clinicopathological parameters for the first time. A pretty high LOH ratio (50) was detected. Interestingly, in the cases with Dkk-1 retention group showed less distant metastasis and a tendency of longer disease free survival. These results indicate that Dkk-1 can play a role in HNSCC carcinogenesis and it may also be related to distant metastasis.

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  • Allelic loss of the ING gene family loci is a frequent event in ameloblastoma International journal

    Silvia S. Borkosky, Mehmet Gunduz, Levent Beder, Hidetsugu Tsujigiwa, Ryo Tamamura, Esra Gunduz, Naoki Katase, Andrea P. Rodriguez, Akira Sasaki, Noriyuki Nagai, Hitoshi Nagatsuka

    Oncology Research   18 ( 10 )   509 - 518   2010

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    Ameloblastoma is the most frequently encountered odontogenic tumor, characterized by a locally invasive behavior, frequent recurrences, and, although rare, metastatic capacity. Loss or inactivation of tumor suppressor genes (TSGs) allows cells to acquire neoplastic growth. The ING family proteins are tumor suppressors that physically and functionally interact with p53 to perform important roles in apoptosis, DNA repair, cell cycle regulation, and senescence. TP53 genetic alterations were reported to infrequently occur in ameloblastoma. Considering that other TSGs related to TP53 could be altered in this tumor, we focused our study on the ING family genes. We analyzed the loss of heterozygosity (LOH) status of the ING family (ING1-ING5) chromosomal loci in a group of ameloblastomas by microsatellite analysis, and correlated the ING LOH status with clinicopathological characteristics. By using specific microsatellite markers, high frequency of LOH was found at the loci of each ING gene family member (33.3-72.2%). A significant relationship was shown between LOH of D2S140 (ING5 locus) and solid tumor type (p = 0.02). LOH of ING3MS (ING3 locus) was also high in solid type tumors, showing a near significant association. In addition, a notable tendency toward higher LOH for half of the markers was observed in recurrent cases. LOH of ING family genes appears as a common genetic alteration in solid ameloblastoma. The current study provides interesting novel information regarding the potential prognostic significance of the allelic loss of the ING gene family loci in ameloblastoma tumorigenesis. Copyright © 2010 Cognizant Comm. Corp. All rights reserved.

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  • Immunohistochemical study of notch signaling proteins in the calcifying epithelial odontogenic tumor (Pindborg tumor)

    Chong Huat Siar, Kee Seng Chuah, Keisuke Nakano, Rosario Santos Rivera, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Kok Han Ng, Toshiyuki Kawakami

    Journal of Hard Tissue Biology   19 ( 3 )   167 - 174   2010

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    Notch signaling pathway mediates diverse biological processes including cell fate decisions during odontogenesis. Dysregulation of Notch has been implicated in the tumorigenesis of some odontogenic neoplasms but its role in the calcifying epithelial odontogenic tumor (CEOT) remains unclarified. The aim here was to investigate Notch expression in CEOT and to speculate on its significance. Receptors Notch1-4 and their ligands (Jagged1, Jagged2 and Delta1) were examined immunohistochemically in six CEOT cases. Expression levels were quantified according to the percentage of positive tumor cells, amyloid-like proteins and calcifications: (-), negative staining; (+), mild and focal positivity <25%; (++), moderate positivity in significant areas 25-50%; (+++), strong positivity in predominant areas >50%. CEOT epithelium demonstrated variable expression levels for Notch1, 3, 4, Jagged1 and Delta1 suggesting upregulation of these molecules at sites of tumor differentiation. Distribution patterns were distinct with some overlap. Their localizations were largely membranous and/or cytoplasmic. Notch2 and Jagged2 were absent. Amyloid-like materials strongly expressed Jagged1 but variably Notch1, 3 and Delta1 implicating that these signaling proteins maybe competitive substrates with CEOT amyloid-like proteins for proteolysis. Notch2, 4 and Jagged2 were absent. Mineralized substances including Liesegang rings were negative for Notch receptors and ligands suggesting that calcification process is associated with downregulation of these molecules. Stromal endothelium and fibroblasts were stained variably positive. Taken together, current data suggest that Notch receptors and their ligands may play differing roles in the acquisition of cell fates in CEOT. Notch accumulations within amyloid-like protein suggest impaired proteolysis. © 2010 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved.

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  • Immunohistochemical observation of notch signaling in a case of calcifying cystic odontogenic tumor

    Keisuke Nakano, Chong Huat Siar, Mihoko Tomida, Sachiko Matsuura, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Toshiyuki Kawakami

    Journal of Hard Tissue Biology   19 ( 3 )   147 - 152   2010

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    Odontogenesis is a complex biological process both with epithelial and mesenchymal tissues, and this process directly reflects the development of odontogenic neoplasms. Therefore, we have examined Notch signaling in a case of calcifying cystic odontogenic tumor, with ameloblastic fibroma and odontogenic myxoma cases as controls. In these specimens, Notch-positive-products were present both in the epithelial and ectomesenchymal components in the calcifying cystic odontogenic tumor and the ameloblastic fibroma case, but negative in the odontogenic myxoma case, having no odontogenic epithelial islands to IHC and ISH examinations. Therefore, the examination results suggest that Notch signaling plays some important roles in cytological differentiation or acquisition of tissue-specific characteristics between odontogenic epithelium and odontogenic ectomesenchymal tissues. © 2010 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved.

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  • The effect of calcium hydroxide removal and the influence on the sealing ability of root canals

    Ying Li, Mengyu Zhou, Mathieu Lefeuvre, Hitoshi Nagatsuka, Weidong Niu

    Journal of Hard Tissue Biology   19 ( 3 )   161 - 166   2010

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    The aims of this study are to evaluate the effectiveness of calcium hydroxide removal by using different irrigation regimens and the effect of the canal seals influenced by debris in root canal. 200 human premolar teeth were prepared, and divided randomly into two groups. Group A was filled with chemical calcium hydroxide and group B was filled with finished product calcium hydroxide. Each group was divided into 6 subsets and the calcium hydroxide in the root canal was removed in different ways: Group A1 and B1 by injection syringe and distilled water Ggroup A2 and B2 by injection syringe and 2.5% sodium hypochlorite; group A3 and B3 by injection syringe, 2.5% sodium hypochlorite and 17% EDTA; group A4 and B4 by ultrasonic and distilled water; group A5 and B5 by ultrasonic and 2.5% sodium hypochlorite; group A6 and B6 by ultrasonic, 2.5% sodium hypochlorite and 17% EDTA. Then, 8 teeth were randomly selected from each subset group and observed by scanning electron microscope. The other specimens were obturated by lateral condensation of cold gutta-percha, stained by Indian ink and then made into transparent teeth models. The results showed that in the same irrigation regimen, there was no significant difference between group A and group B; the result of groups associated with ultrasonic was better than that with injection syringe, which was of significant difference. The rinse solution of EDTA was the best, while distilled water was the worse. The length of dye staining had no significant difference among all groups. The conclusions are that ultrasonic is better than injection syringe; association of sodium hypochlorite and EDTA is the best rinse solution to remove the calcium hydroxide. However, none of these methods or rinse solutions can remove all the calcium hydroxide. The calcium hydroxide remains exert no remarkable influence on the root canal sealer. © 2010 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved.

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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

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    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.

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  • Notch4 overexpression in ameloblastoma correlates with the solid/multicystic phenotype International journal

    Chong Huat Siar, Hitoshi Nagatsuka, Kee Seng Chuah, Rosario Santos Rivera, Keisuke Nakano, Kok Han Ng, Toshiyuki Kawakami

    Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology   110 ( 2 )   224 - 233   2010

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    Objective: Notch signaling has been implicated in cell fate decisions during odontogenesis and tumorigenesis of some odontogenic neoplasms; however, its role in solid/multicystic (SA), unicystic (UA), and recurrent (RA) ameloblastoma remains unclear. The aim of this study was to determine Notch receptor and ligand expressions in these subtypes and to speculate on their significance. Methods: Notch receptors (Notch1, 2, 3, 4) and ligands (Jagged1, 2, and Delta1) were examined immunohistochemically in SA (n = 23), UA (n = 22), and RA (n = 19). Results: Notch4 overexpression in SA (n = 19/23; 82.6%) compared with UA (n = 1/22; 4.5%) or RA (n = 10/19; 52.6%) (P < .05) suggests positive correlation between Notch4 signaling and ameloblastomas with a solid/multicystic phenotype. Ligand (Jagged1 and Delta1) underexpression compared with their receptors (Notch1, 3, 4) (P < .05) and nonreactivity for Notch2 and Jagged2 in all 3 subsets suggests that ameloblastoma epithelium belongs to an earlier stage of differentiation (equivalent to inner enamel epithelium of developing tooth germ) before lineage commitment. Conclusion: Present findings suggest that Notch signaling molecules may play differing roles in the acquisition of different ameloblastoma phenotypes. © 2010 Mosby, Inc.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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  • 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

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • Prognostic Significance of p27Kip1, 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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  • 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

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  • Expression and characterization of PGD<inf>2</inf> receptors in chronic rhinosinusitis: Modulation of DP and CRTH2 by PGD<inf>2</inf> International journal

    Miki Yamamoto, Mitsuhiro Okano, Tazuko Fujiwara, Shin Kariya, Takaya Higaki, Hitoshi Nagatsuka, Hidetsugu Tsujigiwa, Masao Yamada, Tadashi Yoshino, Yoshihiro Urade, Kazunori Nishizaki

    International Archives of Allergy and Immunology   148 ( 2 )   127 - 136   2009.1

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    Background: Prostaglandin D2 (PGD2) participates in airway inflammation. We reported that levels of hematopoietic-type PGD 2 synthase (h-PGDS) in sinonasal tissues may play an important role in the pathophysiology of chronic rhinosinusitis (CRS). Two PGD2 receptors have been isolated, DP and CRTH2, but whether they participate in CRS remains unclear. We sought to determine the expression and characterization of DP and CRTH2 in CRS. Methods: Expression of DP and CRTH2 in nasal polyps (NP) and uncinate process mucosae (UPM) was examined by in situ hybridization and immunohistochemistry and evaluated by real-time quantitative PCR. h-PGDS, IL-5, eotaxin and RANTES expression was also determined. In addition, the effect of PGD2 on the expression of both receptors in UPM was assessed. Results: DP was widely expressed, not only in infiltrating inflammatory cells but also in constitutive cells such as vascular endothelial cells and ciliated columnar epithelia. CRTH2 was selectively expressed in inflammatory cells and some glands. Significantly greater levels of DP mRNA and conversely decreased levels of CRTH2 mRNA were observed in NP compared with UPM. DP and CRTH2 mRNA levels were not only positively and inversely correlated with levels of h-PGDS but also with eotaxin, respectively. Furthermore, addition of PGD2 significantly increased DP expression and conversely reduced CRTH2 expression in UPM. Conclusions: These results suggest that distinct expression of DP and CRTH2 is associated with the pathophysiology of CRS, including NP formation, and the expression of these receptors may be regulated by h-PGDS and PGD 2. Copyright © 2008 S. Karger AG.

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  • 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

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    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.

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  • 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

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    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.

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  • Patients with localized primary non-tonsillar oral diffuse large B-cell lymphoma exhibit favorable prognosis despite a non-germinal center B-cell-like phenotype International journal

    Yasuharu Sato, Naoko Onishi, Toshiaki Morito, Katsuyoshi Takata, Kohichi Mizobuchi, Hitoshi Nagatsuka, Kouichi Ichimura, Takehiro Tanaka, Maiko Tamura, Tadashi Yoshino

    Cancer Science   100 ( 1 )   42 - 46   2009

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    Diffuse large B-cell lymphomas are detected frequently in the oral cavity. Although tonsillar lymphomas have been rather well characterized, lymphomas originating from non-tonsillar regions, such as the gingiva, palate, and tongue, have not been well studied. We examined the pathology of clinical samples obtained from 21 patients with localized primary non-tonsillar oral diffuse large B-cell lymphoma. Immunohistological examination of CD10, Bcl-6, and MUM1 determined that 17 of 21 (81%) samples exhibited non-germinal center B-cell type, an increased proportion of non-germinal center B-cell type compared with previous reports in samples of tonsillar origin (P < 0.05). The four remaining samples exhibited germinal center B-cell type, although one sample expressed MUM1. Follow-up clinical survival data were obtained from the 17 patients over a range from 4 to 173 months (mean 52 months). All patients were treated with chemotherapies, irradiation, or surgical resection. Sixteen patients achieved complete remission and two patients relapsed, but no patient has died of disease. Extranodal diffuse large B-cell lymphomas of non-germinal center B-cell type are generally characterized by poor prognosis, regardless of localized disease. Interestingly, our results indicate that, unlike similar lymphomas of tonsillar origin, localized primary non-tonsillar oral diffuse large B-cell lymphomas exhibit favorable prognosis, suggesting that these lymphomas may be clinicopathologically distinct. © 2009 Japanese Cancer Association.

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  • hTERT in cancer chemotherapy: A novel target of histone deacetylase inhibitors

    Jun Murakami, Jun ichi Asaumi, Hidetsugu Tsujigiwa, Masao Yamada, Susumu Kokeguchi, Hitoshi Nagatsuka, Tatsuo Yamamoto, You Jin Lee

    Bacterial DNA, DNA Polymerase and DNA Helicases   187 - 224   2009

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    Chromatin structure plays an important role in the regulation of gene transcription. Chromatin structure can be modified by various post-translational modifications, including histone acetylation, phosphorylation, methylation and ribosylation. Among those modifications, histone acetylation/deacetylation is the most important mechanism for regulating transcription and is regulated by a group of enzymes known as histone acetyltransferases/histone deacetylases (HDACs). Recently, HDAC inhibitors have been shown to be a novel and promising new class of anti-cancer agent that can regulate the transcription of genes by disrupting the balance of acetylation/deacetylation in particular regions of chromatin. A number of HDAC inhibitors are currently in phase I and II clinical trials against a variety of cancers. Although some promising candidates have been identified (e.g., p21WAF1 and c-Myc), the precise molecular targets remain uncertain. In this article, we focus on one of the DNA polymerases, telomerase, as a new candidate molecular target for HDAC inhibitors. Telomerase is composed primarily of the catalytic subunit (hTERT) and the RNA template (hTERC), and its activity correlates with levels of hTERT mRNA. hTERT expression is apparently governed by complicated regulatory pathways. Based on recent studies, the hTERT gene is likely to be targeted by histone acetylation/deacetylation. © 2010 by Nova Science Publishers, Inc. All rights reserved.

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  • Heparanase and its related molecules in odontogenic tumors.

    Nagatsuka H, Katase N, Han PP, Tsujigiwa H, Siar CH, Nakajima M, Naomoto Y, Tamamura R, Kawakami T, Gunduz M

    Oral Med Pathol   2009

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  • Potential usage of ING family members in cancer diagnostics and molecular therapy International journal

    Mehmet Gunduz, Kadir Demircan, Esra Gunduz, Naoki Katase, Ryo Tamamura, Hitoshi Nagatsuka

    Current Drug Targets   10 ( 5 )   465 - 476   2009

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    The Inhibitor of Growth (ING) gene family is an emerging putative type II tumor suppressor gene (TSG). Proteins of INGs (ING1-5), critical modulator of the histone code via PHD fingers, are able to suppress cell growth and proliferation, induce apoptosis, and modulate cell cycle progression. ING proteins are involved in transcriptional regulation of genes, such as the p53-inducible gene p21. ING proteins also serve as shuttling proteins between nucleus and cytoplasm, and dysregulation of this nucleocytoplasmic traffic has been shown in some cancer cells. In cancer cells, ING mRNA levels are often lost or suppressed but the genes are rarely mutated. Recently the potential roles of ING proteins as prognostic biomarkers, detection of aggressive behavior of the tumor as well as prediction of chemo-radiotherapy response have also emerged. In this review, we summarize the up-to-date knowledge on functions of the ING proteins, the protein status in human tumors and discuss as a potential target in the molecular diagnostics and therapy of cancer. © 2009 Bentham Science Publishers Ltd.

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  • Wingless-type protein-1 (Wnt-1) expression in primary conventional and unicystic ameloblastomas and their recurrent tumors

    Kee Seng Chuah, Chong Huat Siar, Keisuke Nakano, Hitoshi Nagatsuka, Suan Phaik Khoo, Kok Han Ng, Toshiyuki Kawakami

    Journal of Hard Tissue Biology   18 ( 2 )   63 - 70   2009

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    Wingless-type protein (Wnt) is a family of 19 secreted glycoproteins that function as signaling transducers for cell-cell interaction, cell growth and differentiation. Wnt-1, a highly transforming member, has been implicated in tumorigenesis. The aim of this study was to elucidate the role of this cell signaling molecule in the development and progression of primary ameloblastoma and their recurrent tumors. Wnt-1 expression patterns were examined immunohistochemically in 22 primary and 14 recurrent ameloblastomas. These collectively consisted of the following subtypes: conventional (CA) (n=22), desmoplastic (DA) (n=2) and unicystic (UA) (n=12) ameloblastoma. Results demonstrated that CA (n=20/22; 90.9%), DA (n =2/2; 100%) and UA (11/12; 91.7%) showed high Wnt-1 expression percentages. Strong staining intensity for Wnt-1 was observed more frequently in primary CA (n =10/13; 76.9%) than in their recurrent counterparts (n= 2/9; 22.2%) (p<0.05). Conversely, in UA, recurrent tumors (n=3/5; 60.0%) tend to stain strongly for Wnt-1 more frequently than their primary lesions (n=3/7; 42.9%) (p>0.05). Keratinizing cells in areas of squamous metaplasia also expressed Wnt-1 more intensely compared to their surrounding polyhedral stellate reticulum-like cells. Tumor islands containing granular cells were also Wnt-1 positive. Present findings confirmed that the Wnt signaling pathway is activated in ameloblastoma. Strong Wnt-1 expression in primary conventional and recurrent unicystic ameloblastoma suggests that Wnt-1 plays a more critical role in these subtypes. Positive expression of Wnt-1 in keratinizing ameloblastomatous tumor epithelium and granular cells complies with the anti-apoptotic properties of Wnt-1. Negative reactivity for Wnt-1 in 3 cases of ameloblastoma suggests that the development and progression of ameloblastoma may occur independent of this cell signaling molecule. © The Hard Tissue Biology Network Association.

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  • Immunohistochemical detection of erythropoietin, platelet-derived growth factor and their receptors in ameloblastomas

    Xiaodong Yin, Jiankai Xu, Jinna Shi, Kewen Lv, Eryang Zhao, Tenglong Hu, Ryo Tamamura, Hitoshi Nagatsuka, Xiaohui Jiao

    Journal of Hard Tissue Biology   18 ( 1 )   19 - 26   2009

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    Ameloblastoma (AB) is the most common odontogenic epithelium-derived tumor, but has unclear etiology. Various ligand/receptor systems are implicated in ameloblastoma development. In this study, we explored the expression of erythropoietin (EPO), platelet-derived growth factor (PDGF) and their receptors (EPOR, PDGFR) in ABs, and the potential origins of ABs from keratocystic odontogenic tumors (KCOTs) and tooth germs in control groups. Immunostaining was performed using antibodies for EPO, EPOR, PDGF-A and PDGFR-ct. Statistical analysis was performed based on immunoreactivity. We found that EPOR expression was significantly higher in ABs than in KCOTs (P<0.05), but was similar to that of tooth germs. EPOR expression was also significantly different between the AB subtypes (P<0.05). Nevertheless, EPO expression was only significantly different between tooth germs and KCOTs (P<0.05). Immunoreactivity for PDGFR-α and PDGF-A was stronger in ABs than in KCOTs and tooth germs. However, significant differences were only found between individual groups or among types or subtypes of ABs (P<0.05 or P<0.01). In addition, the expression of both EPOR and PDGFR-α in the recrudescent ABs was significantly greater than in primary ABs (P<0.01). We conclude that EPO, EPOR, PDGF-A and PDGFR-α are essential for the growth of human teeth as well as for oncogenesis, development, cell differentiation and biological behavior of odontogenic neoplasm. © 2009 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved.

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  • P53 tumor baskilayici genin 72. kodon polimorfizminin bas-boyun kanserlerindeki prognostic rolu.

    Gunduz E, Gunduz M, Beder L, Yamanaka N, Shimizu K, Nagatsuka H

    Yeni Tip Dergisi   2009

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  • Establishment of a lymph node metastasis model from subcutaneous tumors of gastrointestinal stromal tumor model cells International journal

    Kazufumi Sakurama, Yoshio Naomoto, Toshiaki Ohara, Nobuyuki Watanabe, Munenori Takaoka, Hitoshi Nagatsuka, Yasuko Tomono, Toru Tanida, Kazuhiro Noma, Shunsuke Tanabe, Yasuhiro Fujiwara, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Seiichi Hirota, Takahiro Taguchi, Noriaki Tanaka

    Oncology Reports   21 ( 2 )   407 - 411   2009

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    There is currently no suitable animal model of metastasis using cultured human gastrointestinal stromal tumor cells even though the molecular mechanisms of c-KIT-mediated progression and metastasis should be clarified. Ba/F3 murine lymphocyte cells transduced with mutant c-KIT have been utilized to analyze some molecular mechanisms related to a constitutively activated c-KIT signaling and to assess the efficacy of molecular-targeted inhibitors. Using this cellular system, we coincidentally discovered the development of axillary and inguinal lymph node swelling three weeks after subcutaneous injection of Ba/F3 cells with c-KIT mutation into nude mice. Mutation-specific PCR detected c-KIT mutation in the swollen lymph nodes but not in unmetastasized normal lymph nodes, indicating that the lymph nodes contain tumor cells which should come from a primary subcutaneous tumor. Microscopic observation revealed tumor cells infiltrating through lymphatic follicles with Ki-67-positive staining to distinguish them from lymphocytes. The significance of this model is helpful to understand the molecular mechanisms of c-KIT-mediated metastasis and is useful for assessments of molecular therapeutics and in vivo imaging.

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  • Prolactin may stimulate proliferation in the olfactory epithelium of the female mouse

    Saeko Orita, Junko Yoshinobu, Yorihisa Orita, Hidetsugu Tsujigiwa, Masashi Kakiuchi, Hitoshi Nagatsuka, Shigenobu Nomiya, Noriyuki Nagai, Kazunori Nishizaki

    American Journal of Rhinology and Allergy   23 ( 2 )   135 - 138   2009

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    Background: Although it is well known that olfactory receptor neurons differentiated from stem cells have an unusual lifelong ability to continue neurogenesis, effective treatment of patients with sensorineural olfactory loss is still lacking. The purpose of this study was to determine whether intranasal prolactin (PRL) is an effective inducer of proliferation in the olfactory epithelium (OE). Methods: The OE of mice treated with PRL for 6 consecutive days and of pregnant mice on gestation day (GD) 7 was investigated by immunohistochemical study using antibodies to bromodeoxyuridine. Results: The number of bromodeoxyuridine -labeled cells in the OE increased significantly in PRL-treated female mice and GD 7 mice (but not PRL-treated male mice) compared with controls. Conclusion: Pregnancy may induce proliferation in the OE, and administration of intranasal PRL may have almost the same effect as pregnancy on the OE of female mice. Copyright © 2009, OceanSide Publications, Inc., U.S.A..

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  • Histopathological and immunohistochemical background of orthodontic treatment.

    Kawakami T, Nakano K, Shimizu T, Kimura A, Okafuji N, Tsujigiwa H, Hasegawa H, Nagatsuka H

    Int J Med Biol Front   2009

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  • Influence of the microenvironment on gene and protein expression of odontogenic-like and osteogenic-like cells International journal

    Andrea P. Rodriguez, Hidetsugu Tsujigiwa, Mehmet Gunduz, Beyhan Cengiz, Noriyuki Nagai, Ryo Tamamura, Silvia S. Borkosky, Tohru Takagi, Miho Inoue, Hitoshi Nagatsuka

    Biocell   33 ( 1 )   39 - 47   2009

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    Progenitor cells play an important biological role in tooth and bone formation, and previous analyses during bone and dentine induction have indicated that they may be a good alternative for tissue engineering. Thus, to clarify the influence of the microenvironment on protein and gene expression, MDPC-23 cells (mouse dental papilla cell line) and KUSA/Al cells (bone marrow stromal cell line) were used, both in vitro cell culture and in intra-abdominal diffusion chambers implanted in 4-week-old male immunodefficient mice (SCID mice). Our results indicate that KUSA/Al cells differentiated into osteoblast-like cells and induced bone tissue inside the chamber, whereas, MDPC-23 showed odontoblast-like characteristics but with a low ability to induce dentin formation. This study shows that MDPC-23 cells are especial cells, which possess morphological and functional characteristics of odontoblast-like cells expressing dentin sialophosphoprotein in vivo. In contrast, dentin sialophosphoprotein gene and protein expression was not detected in both cell lines in vitro. The intra-abdominal diffusion chamber appears as an interesting experimental model for studying phenotypic expression of dental pulp cells in vivo.

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  • Loss of heterozygosity at chromosome 14q is associated with poor prognosis in head and neck squamous cell carcinomas International journal

    Davut Pehlivan, Esra Gunduz, Mehmet Gunduz, Hitoshi Nagatsuka, Levent Bekir Beder, Beyhan Cengiz, Rosario S. Rivera, Kunihiro Fukushima, Sukru Palanduz, Sukru Ozturk, Noboru Yamanaka, Kenji Shimizu

    Journal of Cancer Research and Clinical Oncology   134 ( 12 )   1267 - 1276   2008.12

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    Purpose and methods: Loss of heterozygosity (LOH) in a chromosomal location indicates the presence of an inactivated tumor suppressor gene (TSG). Inactivation of TSG has a functional role in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC). Based on the recent evidences of a putative TSG on chromosome 14, we examined LOH on chromosome 14q using eight polymorphic microsatellite markers in 50 cases of HNSCCs. Results: Three regions were detected to have a high LOH rate which included 14q21.2-22.3 (42.5%), 14q31 (55%), and 14q32.1 (37%). The correlation between LOH and clinicopathological findings was investigated through statistical analyses. A strong correlation was observed between the highest LOH marker and the overall and disease-free survival. Conclusions: The results suggest that the distal part of chromosome 14 may host a TSG that may lead to the development and/or progression of HNSCCs. Several genes such as CHES1, BMP4, SAV, and PNN have arisen as candidate tumor suppressors in the region. © 2008 Springer-Verlag.

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  • Notch signaling in benign and malignant ameloblastic neoplasms

    Keisuke Nakano, C. H. Siar, H. Tsujigiwa, H. Nagatsuka, N. Nagai, T. Kawakami

    European Journal of Medical Research   13 ( 10 )   476 - 480   2008.10

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    Background: In general, Notch is a representative signal which controls morphosis and differentiation of cells, but its role in human odontogenic neoplasms, especially in ameloblastoma and its malignant counter-part, ameloblastic carcinoma, is not known. Methods: We examined Notch1 peptide and its gene (mRNA) in an ameloblastoma (case 1: 27-year-old female, right mandibular tumor) and an ameloblastic carcinoma (case 2: 93-year-old female, right mandibular tumor), using immunohistochemistry (IHC) and in situ hybridization (ISH) techniques. Results: Notch1 intracellular domain (NICD) positive products were observed in the cells at the peripheral layer of most proliferating epithelial tumor nests in case 1. In case 2, positive products were similarly detected. In particular, small numbers of mitoses were identified in the nuclear region with intense NICD positive reaction. Conclusions: Notch signaling plays some role in cytological differentiation or acquisition of tissue specific characteristics in neoplastic cells of odontogenic neoplasms, including ameloblastoma and ameloblastic carcinoma. Notch1 may also contribute to cell cycle arrest induced by Notch1 activation in ameloblastic carcinoma. © I. Holzapfel Publishers 2008.

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  • Expression of human β-defensin -1, -2, and -3 in non-inflamed pseudocyst, mucoceles

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

    Oral Diseases   14 ( 7 )   652 - 657   2008.10

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    Objectives and design: The expressions of human beta defensin-1 (HBD-1), -2 (HBD-2) and -3 (HBD-3) in non-inflamed pseudocysts such as mucoceles were investigated immunohistochemically in this study. Materials and methods: Mucocele specimens were obtained from 21 patients. The expression of HBDs was studied immunohistochemically by using antibodies directed against HBD-1, -2, and -3. Statistical analyses were carried out on serial sections stained with antibodies. Results: Cells expressing HBDs were found in mucoceles. The expression of HBD-2 was observed in floating cells in all the specimens, whereas HBD-1 and HBD-3-expressing cells were detected in 93% and 73% of the mucoceles, respectively. The HBD-2 signal was the most intense and the HBD-3 signal intensity was weaker than that of HBD-1. HBDs were expressed in neutrophils and in other floating cells. Interestingly, the signal intensity and the population of positive cells located close to the centers of cysts were higher than those located in the peripheral areas of cysts. Conclusion: The expression of HBDs was found even in non-inflamed pseudocysts such as mucoceles. These results suggest that an unknown mechanism not involved in biophylaxis for the expression of HBDs may exist. © 2008 The Authors.

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  • Stromal cells promote bone invasion by suppressing bone formation in ameloblastoma

    G. S.A. Sathi, H. Nagatsuka, R. Tamamura, M. Fujii, M. Gunduz, M. Inoue, R. S. Rivera, N. Nagai

    Histopathology   53 ( 4 )   458 - 467   2008.10

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    Aims: To study the stromal variation and role of stromal-tumour cell interaction in impaired bone formation as well as enhanced bone resorption in ameloblastoma. Methods and results: Four types of stroma were observed histologically; fibrous, desmoplastic, myxoid and myxoid with hyalinization. Osteoblast and osteoclast were counted using haematoxylin and eosin sections and immunohistochemistry with CD68. After histomorphometric analysis, only fibrous and myxoid types of stroma were distinctly identified. Secreted frizzled-related peptide (sFRP)-2, transforming growth factor-beta 1 and receptor activator of nuclear factor-κB ligand (RANKL) revealed strong expression in myxoid type compared with the normal stroma. Bone morphogenetic protein (BMP)-2 was negative in myxoid type, but positive in normal stroma. Fibrous-type stroma showed weak expression of all antigens except RANKL compared with myxoid type. Conclusions: The results suggest that stroma does not act only in bone resorption, but also in the suppression of new bone formation. sFRP-2 is the main factor for impaired bone formation. The expression of markers related to osteoclastogenesis and suppression of osteoblast formation is higher in myxoid-type than in fibrous-type stroma. Tumour cells create a favourable environment for impaired bone formation by secreting sFRP-2 as well as bone resorption by secreting RANKL and interleukin-6. © 2008 The Authors.

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  • Dual tyrosine kinase inhibitor for focal adhesion kinase and insulin-like growth factor-I receptor exhibits anticancer effect in esophageal adenocarcinoma in vitro and in vivo International journal

    Nobuyuki Watanabe, Munenori Takaoka, Kazufumi Sakurama, Yasuko Tomono, Shinji Hatakeyama, Osamu Ohmori, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Minoru Haisa, Junji Matsuoka, David G. Beer, Hitoshi Nagatsuka, Noriaki Tanaka, Yoshio Naomoto

    Clinical Cancer Research   14 ( 14 )   4631 - 4639   2008.7

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    Purpose: Focal adhesion kinase (FAK) regulates integrin and growth factor - mediated signaling pathways to enhance cell migration, proliferation, and survival, and its up-regulation correlates malignant grade and poor outcome in several types of cancer. In this study, we aimed to raise a potential therapeutic strategy using a FAK inhibitor for Barrett's esophageal adenocarcinoma. Experimental Design: The expression status of FAK in clinical Barrett's esophageal adenocarcinoma tissues was determined by immunohistochemistry. Cultured esophageal adenocarcinoma cells were treated with TAE226, a specific FAK inhibitor with an additional effect of inhibiting insulin-like growth factor-I receptor (IGF-IR), to assess its anticancer effect in vitro. Western blot was carried out to explore a participating signaling pathway for TAE226-induced cell death. Furthermore, TAE226 was orally administered to s.c. xenograft animals to investigate its anticancer effect in vivo. Results: Strong expression of FAK was found in 94.0% of Barrett's esophageal adenocarcinoma compared with 17.9% of Barrett's epithelia, suggesting that FAK might play a critical role in the progression of Barrett's esophageal adenocarcinoma. When esophageal adenocarcinoma cells were treated with TAE226, cell proliferation and migration were greatly inhibited with an apparent structural change of actin fiber and a loss of cell adhesion. The activities of FAK, IGF-IR, and AKT were suppressed by TAE226 and subsequent dephosphorylation of BAD at Ser136 occurred, resulting in caspase-mediated apoptosis. In vivo tumor volume was significantly reduced by oral administration of TAE226. Conclusions: These results suggest that TAE226, a dual tyrosine kinase inhibitor for FAK and IGF-IR, could become a new remedy for Barrett's esophageal adenocarcinoma. © 2008 American Association for Cancer Research.

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  • The inhibitor of growth (ING) gene family: Potential role in cancer therapy International journal

    Mehmet Gunduz, Esra Gunduz, Rosario S. Rivera, Hitoshi Nagatsuka

    Current Cancer Drug Targets   8 ( 4 )   275 - 284   2008.6

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    The discovery of ING1 gene paved the way to the identification of other ING members (ING2-5) and their isoforms associated with cell cycle, apoptosis and senescence. The ING family has been an emerging putative tumor suppressor gene (TSG) in which the major mechanism is through interaction with the determinants of chromatin function and gene-specific transcription factors. The regulatory mechanism highly involves the conserved plant homeodomain (PHD), which binds to histones in a methylation-sensitive manner, suggesting that ING proteins may contribute to the maintenance of the epigenetic code. Furthermore, ING family members contain nuclear localization signals and N-terminal sequences important in the interaction with histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) that regulate gene promoter activity within chromatin. Although ING proteins have the same PHD motif, the variation in the N-terminal dictates the differences in tumor the suppressive ability of ING in various tumors. Inactivation of the normal function is achieved through allelic loss of genomic regions containing the ING gene, alteration in the ING promoter region, variation of mRNA splicing efficacy or reduced mRNA stability. It is most probably the apparent combination of these aberrant mechanisms that resulted in reduced availability of functional ING protein. In cancer cells, ING transcript levels are often suppressed but the genes are rarely mutated. The mechanism of suppression of ING expression may have to do with the abnormally high methylation levels of the ING gene promoter, which have been correlated with low transcript levels. Emerging evidence on the function of ING and related regulatory mechanisms strongly points to ING as a candidate TSG and therefore a potential target in the molecular therapy of some types of tumor. © 2008 Bentham Science Publishers Ltd.

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  • Involvement of EphA2 in head and neck squamous cell carcinoma: mRNA expression, loss of heterozygosity and immunohistochemical studies International journal

    Rosario S. Rivera, Mehmet Gunduz, Hitoshi Nagatsuka, Esra Gunduz, Beyhan Cengiz, Kunihiro Fukushima, Levent Bekir Beder, Davut Pehlivan, Noboru Yamanaka, Kenji Shimizu, Noriyuki Nagai

    Oncology Reports   19 ( 5 )   1079 - 1084   2008.5

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    EphA2 is a 130-kDa transmembrane protein primarily found in adult human epithelial cells and is a member of one of the largest receptor tyrosine kinases. It is located on 1p36.1, a genetic hot spot in cancer. EphA2 over-expression has been observed in aggressive solid tumors and its potential role in tumorigenesis, which includes cell growth, survival, migration and angiogenesis have been reported. However, the role of EphA2 remains unknown in head and neck cancer. In this study, we investigated the genetic profile of EphA2 in primary head and neck squamous cell carcinoma (HNSCC) by determining mRNA level, status of loss of heterozygosity and protein expression. mRNA expression was also correlated with clinicopathological data. Infrequent loss of heterozygosity (20%) was observed, though a 10-fold increase of mRNA expression in tumors compared to normal tissues was noted. A significant number of samples with normal to high mRNA expression was observed among patients with regional metastasis, with T3-T4 tumor size and with moderate to poor differentiation. However, statistical studies did not show any correlation between mRNA expression and any of the clinicopathological parameters. Tumor cells expressed EphA2 protein, but only weakly. These results suggest thate EphA2 might be involved in the early development of HNSCC although not directly responsible for its progression.

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  • Heparanase and vascular endothelial growth factor expression in the progression of oral mucosal melanoma International journal

    Rosario S. Rivera, Hitoshi Nagatsuka, Chong Huat Siar, Mehmet Gunduz, Hidetsugu Tsujigiwa, Phuu Pwint Han, Naoki Katase, Ryo Tamamura, Kok Han Ng, Yoshio Naomoto, Motowo Nakajima, Noriyuki Nagai

    Oncology Reports   19 ( 3 )   657 - 661   2008.3

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    Oral mucosal melanoma is an aggressive neoplasm with poor prognosis. Heparanase is an endo-β-d-glucuronidase, which cleaves heparan sulphate chains. The vascular endothelial growth factor (VEGF) is the most potent angiogenic mitogen and interaction with its receptor (VEGFR) has been associated with angiogenesis. We investigated the expression of these molecules in the progression of oral mucosal melanoma. Immunohistochemistry was carried out in 15 oral melanotic macules and 19 oral melanomas using heparanase, VEGF, VEGFR-2, CD34 and Ki-67. Microvessel density was determined and subjected to statistical analysis. Heparanase and VEGFR-2 were not expressed in the oral melanotic macule. Atypical melanocytes and melanoma cells expressed heparanase, VEGF and VEGFR-2. An intense expression was noted in the early invasive phase, which marks the crucial transition from in situ to the invasive phase. In the invasive component, heparanase was intense but selective in the invasive fronts and at the periphery of nests unlike the extensive expression of VEGF and VEGFR-2. However, hot spots were only observed at the periphery of the nests. In conclusion, melanoma cells expressed heparanase, VEGF and VEGFR-2. The coexpression of these molecules in atypical melanocytes and melanoma cells suggests their function in cell migration and invasion. Moreover, the intense expression in the crucial transition from in situ to the invasive phase suggests their role in the progression of the tumor. The role of VEGF and VEGFR-2 in angiogenesis was evident only at the periphery of the nests in the invasive components.

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  • Downregulation of ING3 mRNA expression predicts poor prognosis in head and neck cancer International journal

    Mehmet Gunduz, Levent Bekir Beder, Esra Gunduz, Hitoshi Nagatsuka, Kunihiro Fukushima, Davut Pehlivan, Eren Cetin, Noboru Yamanaka, Kazunori Nishizaki, Kenji Shimizu, Noriyuki Nagai

    Cancer Science   99 ( 3 )   531 - 538   2008.2

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    Although many clinical and pathological prognostic factors such as tumor stage and lymph-node involvement have been described, to date no reliable or clinically applicable marker or tumor aggressiveness has been identified for head and neck cancer. In an attempt to identify such a molecular prognostic marker, we analyzed the mRNA expression status of ING3 by quantitative reverse transcription-polymerase chain reaction. We also examined p53 mutation status and investigated its relationship with ING3, as well its clinicopathological characteristics. About half of the 71 tumor samples demonstrated downregulation of ING3 compared to their matched normal counterparts. Although most clinicopathological variables were not significantly related to ING3 downregulation or p53 mutation status, a significant relationship was detected in terms of overall survival between the cases with low and normal to high ING3 expression. At 5 years follow up, approximately 60% of the patients with normal to high ING3 expression survived, whereas this was 35% in the patients with low ING3 expression. Multivariate analysis also showed downregulation of ING3 as an independent prognostic factor for poor overall survival. These results reveal that ING3 would function as a potential tumor suppressor molecule and that low levels of ING3 may indicate an aggressive nature of head and neck cancer. © 2007 Japanese Cancer Association.

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  • Gene expression of Jagged2 in mandibular condylar cartilage development

    T. Shimizu, H. Tsujigiwa, H. Nagatsuka, K. Nakano, N. Okafuji, S. Kurihara, N. Nagai, Toshiyuki Kawakami

    European Journal of Medical Research   13 ( 1 )   1 - 3   2008.1

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    Expression pattern of Jagged2 gene in mandibular condylar cartilage was examined by means of in situ hybridization (ISH) technique. At E14, Jagged2 mRNA signals appeared in cytoplasm of proliferating chondrocytes. From E15 to E19, Jagged2 mRNA was detected throughout almost all cytoplasm in all layers. However, the distribution pattern was not uniform. These results suggest that Jagged2 plays an essential role for mandibular condylar cartilage morphogenesis and development. © I. Holzapfel Publishers 2008.

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  • Cell differentiation of neoplastic cells originating in the oral and craniofacial regions

    Toshiyuki Kawakami, Hitoshi Nagatsuka, Keisuke Nakano, Takako Shimizu, Hidetsugu Tsujigiwa, Hiromasa Hasegawa, Noriyuki Nagai

    Cell Differentiation of Research Developments   1 - 30   2008.1

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    Development of the oral and craniofacial region is a complex and fascinating set of processes which require a sequential integration of numerous biological steps. For medical and dental doctors, interest is particularly high in this region, because it is composed of three blastoderms - ectoderm, mesoderm, and endoderm - as well as neural crest cells. There are many different types of neoplasms in this region. In general, proliferation, development and cytological differentiation of the neoplastic cells reflect the normal physiological development of the outbreak mother cells and/or tissues. Collected human neoplasm cases, such as osteosarcoma appearing in the oral and craniofacial region, are examined regarding the immunohistochemical expression of some morphogenesis regulation factors. Furthermore, examination of Notch signaling is also conducted for some odontogenic neoplasms. This chapter mainly describes the examination results of some morphogenesis regulation factors, such as Notch signaling, in the neoplastic cells originating in the oral and craniofacial region, especially in the odontogenic neoplasms, in both well-differentiated and poorly-differentiated neoplasms of tooth germ enamel organ-derived neoplasm. In general, these morphogenesis regulation factors are responsible for cytological regulation of cell fate, morphogenesis and/or development. The results suggest that these factors play some role in cytological differentiation or acquisition of tissue specific characteristics in neoplastic cells. Furthermore, there would appear to be a relationship between the cytological differentiation in the oral and craniofacial neoplastic cells and the physiological development and differentiation of their originating mother cells and tissues of the oral and craniofacial region. © 2007 by Nova Science Publishers, Inc. All rights reserved.

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  • C-kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma International journal

    Rosario S. Rivera, Hitoshi Nagatsuka, Mehmet Gunduz, Beyhan Cengiz, Esra Gunduz, Chong Huat Siar, Hidetsugu Tsujigiwa, Ryo Tamamura, Kok Ng Han, Noriyuki Nagai

    Virchows Archiv   452 ( 1 )   27 - 32   2008.1

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    C-kit is a trans-membrane receptor tyrosine kinase (RTK) encoded by the proto-oncogene KIT located at 4q11-12. Gain-of-function mutations arising to c-kit activation independent of its ligand were observed in various tumors related to germ cells, mast cells, and interstitial cells of Cajal. C-kit also participates in melanocyte development; hence, its involvement in oral mucosal melanoma (OMM) tumorigenesis was investigated. Immunohistochemistry and mutation analysis were performed using 18 cases of human primary OMM. Results revealed 16 cases positive to c-kit protein. Atypical melanocytes expressed c-kit. All in situ components expressed c-kit, but only four cases exhibited intense expression in the invasive component. Missense mutations were observed in four cases, and two of those correlated with increased protein expression. C-kit expression in atypical melanocytes suggests the role of c-kit in the early stage of OMM tumorigenesis. C-kit protein expression correlated with activating mutations indicating the pertinent role of the proto-oncogene KIT in the tumorigenesis of OMM. © 2007 Springer-Verlag.

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  • Deletion mapping of chromosome 4q22-35 and identification of four frequently deleted regions in head and neck cancers

    E. Cetin, B. Cengiz, E. Gunduz, M. Gunduz, H. Nagatsuka, L. Bekir Beder, K. Fukushima, D. Pehlivan, M. Ozaslan, N. Yamanaka, K. Nishizaki, K. Shimizu, N. Nagai

    Neoplasma   55 ( 4 )   299 - 304   2008

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    Head and neck squamous cell carcinoma (HNSCC) is a diverse group of cancers that are frequently aggressive in their biologic behavior. Inactivation of tumor suppressor gene (TSG) is one of the most critical steps leading to HNSCC. Loss of heterozygosity analysis is very sensitive method for the detection of frequent allelic loss in a chromosomal locus. This method has been considered as an important evidence for the localization of TSGs. We analyzed loss of heterozygosity (LOH) at chromosome 4q22-35 region by using 14 polymorphic microsatellite markers in 83 matched normal and HNSCC tissues. LOH was detected at least in one location in 71 of 83 (86%) tumor tissues. Frequent deletions were detected at the location of microsatellite markers, D4S2909 (46%), D4S2623 (51%), D4S406 (48%), D4S1644 (45%) and D4S2979 (40%). Four different frequently deleted regions at 4q22, 4q25, 4q31 and 4q34-35 were observed. These regions include several putative TSGs such as Caspase-6, SMARCAD1, SMARCA5, SAP30 and ING2. Further molecular analysis of each gene should be performed to clarify their roles in head and neck squamous cell carcinogenesis.

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  • Deletion at Dickkopf (Dkk)-3 locus (11p15.2) is related with lower lymph node metastasis and better prognosis in head and neck squamous cell carcinomas International journal

    Naoki Katase, Mehmet Gunduz, Levent Beder, Esra Gunduz, Mathieu Lefeuvre, Omer Faruk Hatipoglu, Silvia Susana Borkosky, Ryo Tamamura, Susumu Tominaga, Noboru Yamanaka, Kenji Shimizu, Noriyuki Nagai, Hitoshi Nagatsuka

    Oncology Research   17 ( 6 )   273 - 282   2008

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    Head and neck squamous cell carcinoma (HNSCC) is a frequently occurring cancer, and despite improvement of its treatment methods, including chemotherapy, radiotherapy, and surgery, the improvement of survival remains poor. Recent advances in molecular biology of human cancer indicated various molecular abnormalities in HNSCC, including activation of oncogenes and inactivation of tumor suppressor genes (TSGs). Dickkopf (Dkk)-3 gene is known as a negative regulator of Wnt signaling and is suggested to function as TSG in several kinds of malignancies. We hypothesized that Dkk-3 might play an important role in HNSCC, too. Thus, in the current study, we analyzed allelic alteration of Dkk-3 locus (chromosome 11p15.2) by means of loss of heterozygosity (LOH) analysis. The study population consisted of 50 patients with HNSCC (mean age of 65 years old). Furthermore, we also examined the correlation between LOH findings of Dkk-3 locus with clinicopathological parameters to investigate its use as a biomarker in HNSCC. A remarkable LOH ratio (57%) was detected in the cases studied, implying that Dkk-3 is likely to be involved in HNSCC carcinogenesis. However, interestingly and in contrast to the expectations, we found that the group with LOH of Dkk-3 locus had less lymph node metastasis, and showed a favorable overall survival compared to the patients with retention of Dkk-3 area in survival analysis. These results indicate that Dkk-3 can play a role in HNSCC carcinogenesis with unknown mechanism. Moreover, allelic loss at Dkk-3 locus may also be used as a novel prognostic biomarker in HNSCC. © 2008 Cognizant Comm. Corp. All rights reserved.

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  • Lack of B-RAF mutations in head and neck squamous cell carcinoma

    M. Al Sheikh Ali, Mehmet Gunduz, E. Gunduz, R. Tamamura, L. Beder, S. Tominaga, T. Onoda, N. Yamanaka, R. Grenman, K. Shimizu, N. Nagai, H. Nagatsuka

    Folia Biologica   54 ( 5 )   157 - 161   2008

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    B-RAF is one of the most commonly mutated oncogenes in human cancer. However, the mutation status of B-RAF has not been established completely in HNSCC. We have analysed the mutation status of the kinase domain of the B-RAF gene (exons 11 and 15) in 91 Japanese HNSCC patients as well as 12 HNSCC cell lines. DNA was extracted and amplified by PCR. Mutations were then analysed by SSCP mutation detection method. Since V600EB-RAF constitutes 90% of the mutations identified in B-RAF in human cancers, we also used MASA analysis to specifically detect this mutation in exon 15 of B-RAF. Using both methods, no mutation was found in both exon 11 and 15 in all patients and cell lines. Mutations are absent or rare in the kinase domain of B-RAF in Japanese HNSCC. However, more studies are still needed to determine its usefulness as a target for molecular therapy in these patients.

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  • Expression and mutation analysis of epidermal growth factor receptor in head and neck squamous cell carcinoma International journal

    Mahmoud A.L. Sheikh Ali, Mehmet Gunduz, Hitoshi Nagatsuka, Esra Gunduz, Beyhan Cengiz, Kunihiro Fukushima, Levent Bekir Beder, Kadir Demircan, Masae Fujii, Noboru Yamanaka, Kenji Shimizu, Reidar Grenman, Noriyuki Nagai

    Cancer Science   99 ( 8 )   1589 - 1594   2008

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    The epidermal growth factor receptor (EGFR)-RAS-RAF-mitogen-activated protein kinase signaling cascade is an important pathway in cancer development and recent reports show that EGFR and its downstream signaling molecules are mutated in a number of cancers. We have analyzed 91 Japanese head and neck squamous cell carcinomas (HNSCC) and 12 HNSCC cell lines for mutations in EGFR, ErbB2, and K-ras. Exons encoding the hot-spot regions in the tyrosine kinase domain of both EGFR (exons 18, 19, and 21) and ErbB2 (exons 18-23), as well as exons 1 and 2 of K-ras were amplified by polymerase chain reaction and sequenced directly. EGFR expression was also analyzed in 65 HNSCC patients using immunohistochemistry. Only one silent mutation, C836T, was found in exon 21 of EGFR in the UT-SCC-16A cell line and its corresponding metastasic cell line UT-SCC-16B. No other mutation was found in EGFR, ErbB2, or K-ras. All tumors showed EGFR expression. In 21 (32%) tumors, EGFR was expressed weakly (+1). In 27 (42%) tumors it was expressed (+2) moderately, and in 17 (26%) tumors high expression (+3) was detected. Overexpression (+2, +3) was found in 44 tumors (68%). A worse tumor differentiation and a positive nodal stage were significantly associated with EGFR overexpression (P = 0.02, P = 0.032, respectively). Similar to patients from western ethnicity, mutations are absent or rare in Japanese HNSCC. Protein overexpression rather than mutation might be responsible for activation of the EGFR pathway in HNSCC. © 2008 Japanese Cancer Association.

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  • A spindle cell carcinoma presenting with osseous metaplasia in the gingiva: A case report with immunohistochemical analysis International journal

    Naoki Katase, Ryo Tamamura, Mehmet Gunduz, Jun Murakami, Jun Ichi Asaumi, Goichi Tsukamoto, Akira Sasaki, Hitoshi Nagatsuka

    Head and Face Medicine   4 ( 1 )   28 - 28   2008

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    Background. Spindle cell carcinoma (SpCC) is a rare, high malignant variant of squamous cell carcinoma (SCC), which shows biphasic proliferation of conventional SCC component and malignant spindle shape cells with sarcomatous appearance. Methods. A case of Spindle cell carcinoma with bone-like calcified materials, occurring at the mandibular molar region of 71-years-old Japanese male patient was presented with gross finding, histological findings and MRI image. To identify the characteristics of the bone-like materials, immunohistochemistry were performed. Results. Histologically, the cancer cells were composed of spindle cells and epithelial cells which form nests with prominent keratinization. Histological findings showed typical histology of the SpCC, however, as an uncommon finding, spatters of calcified, bone-like materials were observed in between the cancer cells. Immunohistochemistry revealed that cancer cells were positive for cytokeratins and vimentin to a varying degree and negative for Desmin, S-100, Osteopontin, BMP-2 or BMP-4. These findings implied that the calcified materials were formed by metaplasia of the stromal cells. Discussion. Bone-like materials formation by osseous and/or cartilaginous metaplasia of the stroma in the carcinoma has been reported. However, the detailed mechanism of these metaplasia and affection on the clinical feature, prognosis and therapies are not well established. In summary, we presented an unique case of SpCC, which has not been described in the literature. © 2008 Katase et al; licensee BioMed Central Ltd.

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  • Immunohistochemical characteristics of odontogenic neoplasms and their physiological counterparts

    Keisuke Nakano, Hitoshi Nagatsuka, Hidetsugu Tsujigiwa, Mehmet Gunduz, Naoki Katase, Chong Huat Siar, Toshiyuki Kawakami

    Journal of Hard Tissue Biology   17 ( 3 )   79 - 90   2008

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    Development of the tooth is a complex and fascinating set of processes which require a sequential integration of numerous biological steps. For dental doctors, interest is particularly high, because the tooth is mainly composed of surface ectodermal epithelium and neural crest derived neuroectodermal mesenchyma, and formed by epithelial-mesenchymal interactions. There are many different types of odontogenic neoplasms. In general, proliferation, development and cytological differentiation of the neoplastic cells reflect the normal physiological development of the outbreak mother cells and/or tissues. There would appear to be a relationship between the cytological differentiation of odontogenic neoplastic cells and the physiological development and differentiation of tooth germ. We describe some morphogenesis regulation factors, such as Notch signaling, in the odontogenic neoplastic cells, in both well-differentiated and poorly-differentiated neoplasms. Our results suggest that these factors play some role in cytological differentiation or acquisition of tissue-specific characteristics in neoplastic cells. © 2008 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved.

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  • Chemical analysis of a novel coating material, CaTiO3-aC

    Mika Okauchi-Yabuuchi, Ryo Tamamura, Noriyuki Nagaoka, Shin Takagi, Etsuo Kishimoto, Tohru Takagi, Andrea Rodriguez, Miho Inoue, Hitoshi Nagatsuka, Masaru Akao, Noriyuki Nagai

    Journal of Hard Tissue Biology   17 ( 3 )   115 - 120   2008

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    In the current study, we compared the recently developed CaTiO 3-amorphous carbon (CaTiO 3-aC) as a bone inducing coating material with HA from aspects of surface electric charge and solubility. CaTiO 3,-aC had negative surface electric charge similar to HA. Thus similar tissue reaction and bone inducing ability were considered to obtain. On the other hand solubility of CaTiO 3-aC coating was lower than HA. Moreover though CaTiO 3-aC itself showed low solubility, CaCO 3 was found to be included in it, and long-term slow Ca 2+ release occurred. Thus the sample was suggested to be used as an ion exchange material. When the implant using Ti/CaTiO 3-aC/HA double layer coating was developed, first bioactive state of the implant will continue due to HA character. Then even early resorption of HA occurs, bioactive state will continue due to CaTiO 3-aC layer. Therefore Ti base will not expose. This result is supposed to contribute long term success of the implant. © 2008 The Hard Tissue Biology Network Association Printed in Japan, All rights reserved.

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  • A study of recurrent giant odontogenic myxoma of the mandible with immunohistochemical examination of Notch.

    Nakano N, Chelvanayagam P, Born K, Siar CH, Ng KH, Nagatsuka H, Kawakami T

    Oral Medicine & Pathology   12 ( 2 )   53 - 56   2008

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    Noriyuki Nagai, Mika Okauchi, Andrea Rodriguez, Mehmet Gunduz, Hailong Hu, Midori Kubota, Noriyuki Nagaoka, Miho Inoue, Hitoshi Nagatsuka, Tohru Takagi, Masaru Akao

    Journal of Hard Tissue Biology   17 ( 2 )   47 - 54   2008

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    We dveloped a novel method for titanium coating material using modified thermal decomposition technique, specifically focusing on presence of CaTiO 3 and carbon C. Two layers of thin film coating composed of CaTiO3-amorphous carbon compound (CaTiOa-aC) and hydroxyapatite (HA) were generated on titanium surface. In this method, ratios of Ca/P as well as Ca/Ti, sintering temperature and sintering velocity were carefully planned. Within crystal structure of CaTiO3 granules, 4 atomic % of carbon in amorphous state was included. By our method, inclusion of carbon in HA suggested formation of carbonate apatite. Regarding with attachment-detachment experiment at titanium surface, adhesion strength was 2.5 times stronger in CaTiO 3aC/HA coating substrate as compared to HA only coating material. Results of the novel developed modified thermal decomposition method suggested that the 2 layers biomaterial composed of CaTiO3-aC (0.6 μm) and carbonate apatite-included HA (2.4 μm) can be used as a coating material on titanium surface. © 2008 The Hard Tissue Biology Network.

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  • Juxta-epithelial hyalinization inhibits tumor growth and invasion in ameloblastoma

    Gul San Ara Sathi, Masae Fujii, Silvia Susana Borkosky Ryo Tamamura, Naoki Katase, Toshiyuki Kawakami, Hitoshi Nagatsuka, Noriyuki Nagai

    Journal of Hard Tissue Biology   17 ( 2 )   63 - 68   2008

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    In histological examination of ameloblastoma, marked juxta-epithelial hyalinization of the connective tissue adjacent to the epithelium was observed in many cases. However, the physicochemical mechanism of these changes and its role in ameloblastoma is still not understood. To analyze the expression pattern of the different types of basement membrane related molecules, apoptosis-related factors and their possible role in juxta-epithelial hyalinization, six cases of ameloblastoma were examined. Immunohistochemical staining was done using cell surface type heparan sulfate (HS), 10E4, basement membrane type HS, JM403, Heparanase, Caspase-6, BCL-2 and CD34 antibodies. Hyalinized area in all sections, were strongly positive to 10E4, but negative to heparanase. There was no CD34 positive endothelial cells within the hyalinization area. Tumor cells adjacent to this area were positive to 10E4, heparanase and caspase-6. This result suggests that hyalinization have an effect on tumor growth and stop stromal-tumor cell interaction by the help of HSPGs, resulting in the inhibition of the function of heparanase and angiogenesis. Finally, tumor cells adjacent to the hyalinization undergoes program cell death. © 2008 The Society for Hard Tissue Regenerative Biology.

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  • Inhibitor of growth (ING) family: An emerging molecular target for cancer therapy

    Esra Gunduz, Mehmet Gunduz, Levent Bekir Beder, Ryo Tamamura, Hitoshi Nagatsuka, Noriyuki Nagai

    Journal of Hard Tissue Biology   17 ( 1 )   1 - 10   2008

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    ING1 gene, the founding member of the ING tumor suppressor family, was originally identified through subtractive hybridization between normal mammary epithelial cells and breast cancer cell lines, and subsequent in vivo selection of genetic suppressor element that displayed oncogenic features. Soon after identification of ING1, four additional members of the ING family (ING2-5) were cloned and all the gene products contain a highly conserved plant homeodomain (PHD) finger motif in the carboxy (C)-terminal end, that plays important role for their function. Furthermore, ING family members contain nuclear localization signals and N-terminal sequences important in the interaction with historie acetyltransferase (HAT) and histone deacetyltransferase (HDAC) that regulate gene promoter activity within chromatin. Although exact functions of ING family genes have not been clarified, the gene products are involved in transcriptional regulation, apoptosis, cell cyle, angiogenesis and DNA repair through p53-dependent and -independent pathways. Chromosomal deletion and decreased expression of each ING family member gene in various cancer types strongly suggested products of these genes as tumor suppressor factors. Rare mutation but frequent allelic loss and epigenetic changes have been shown in ING family genes, suggesting them as a class II tumor suppressor gene. This review summarizes the known biological functions of the ING tumor suppressors and signaling related pathways. © 2008 The Hard Tunis Biology Network Printed in. Japan, All rights reserved.

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  • Localization of oxytalan fiber, type iii collagen and bmp family in conventional and desmoplastic ameloblastoma

    Masahisa Inoue, Hitoshi Nagatsuka, Ryo Tamamura, Chong Uuat Siar, Hidetsugu Tsujigiwa, Silvia Borkosky, M. Fujii, Noriyuki Nagai, Kojun Setsu

    Journal of Hard Tissue Biology   17 ( 1 )   23 - 30   2008

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    The histologic hallmark distinguishing desmoplastic ameloblastoma (DA) from conventional ameloblastoma (CA) is its pronounced stromal desmoplasia, and this formed the basis of this investigation. To elucidate the stromal characteristics, localization patterns of oxytalan fibers, type III collagen and BMP family in DA (n=8) was compared with CA (n=24), and periodontal ligament (PL) («= 8). Oxytalan fibers formed apico-occlusal bundles in PL, thick radial bundles around tumor nests in DA, and as scanty fibers in CA. Type III collagen was identified in PL, strongly expressed in DA stroma, but weakly in CA. BMP-2, -3, 4 and -7 expression patterns in tumor epithelium and stroma were more pronounced in DA (including sites of bone formation), than CA. No immunoreactivity for BMP-5 and -6 were detected. Current findings suggest that the stroma in DA is neoplastic and derived from odontogenic ectomesenchyme, and recommends its reclassification as an odontogenic epithelial-ectomcsenchymal neoplasm. © 2008 The Hard Tissue Biology Network Printed in. Japan, All rights reserved.

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  • Immunolocalization of cell signaling molecules in the granular cell ameloblastoma

    Gul San Ara Sathi, Phuu Pwint Han, Ryo Tamamura, Hitoshi Nagatsuka, Hailong Hu, Naoki Katase, Noriyuki Nagai

    Journal of Oral Pathology and Medicine   36 ( 10 )   609 - 614   2007.11

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    Background: Bone morphogenic protein (BMP) and Wnt signaling pathway molecules play important roles in cytodifferentiation and cell proliferation. We attempted to localize these signaling molecules in the granular cell ameloblastoma. Materials and methods: Four samples of paraffin-embedded ameloblastoma with granular cells were studied. Immunohistochemistry was performed to detect basement membrane type heparan sulfate (HS) (JM403), cell surface type HS (10E4), heparanase, Wnt-5a, Wnt-2, β-catenin, and BMP-4. Results: In all four samples, strong expression of β-catenin and Wnt-5a was detected within the granular cells, while BMP-4 expression was weak and Wnt-2 was negative. Immunoreactivities of basement membrane type HS, cell surface type HS, and heparanase were variable within granular cells in ameloblastoma. Conclusion: Granular cells in ameloblastoma exhibit abnormal biological behaviors, particularly synthesis and secretion of protein. Synthesis of signaling molecules is upregulated, but secretion is arrested in some cases, while both are lost in other cases. © 2007 The Authors.

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  • Notch signaling in mandibular condylar cartilage developmemt

    Takako Shimizu, K. Nakano, H. Tsujigiwa, H. Nagatsuka, T. Watanabe, N. Okafuji, S. Kurihara, H. Hasegawa, N. Nagai, T. Kawakami

    European Journal of Medical Research   12 ( 10 )   515 - 519   2007.10

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    Objective: The purpose of this study was to investigate the expression pattern of Notch signaling in mandibular condylar cartilage, as a type of secondary cartilage. Methods: Mandibular condyle of ddY mice were fixed from embryonic day 14 (E14) through just after birth (equivalent to E19). Samples were cut into 4 μ serial sections through the central area of the mandibular condyle at the sagittal plane. Serial sections were examined using histological, immunohistochemical (IHC) and in situ hybridization (ISH) techniques. Results: At E14, there were no developmental features of mandibular condyle. At the distal upper portion of developmental mandibular bone, mesenchymal cell proliferation and condensation without metacholomatic reaction to toluidine blue (TB) were seen. At E15, mandibular condylar cartilage was clearly evident, as TB metacholomasia. In IHC specimens at E14, expression of Notchl intracellular domain (NICD) was observed in the nuclei of coagulating mesenchymal cells. After E15, NICD appeared in the nuclei and the cytoplasms of cells. In ISH examination at E14, expressions of Notch1 mRNA appeared in cytoplasm of proliferating chondrocytes. From E15 to E19, Notch1 mRNA was detected throughout almost all cytoplasm in all layers. Conclusion: These IHC and ISH results suggest that Notch signaling plays an essential role for mandibular condylar cartilage morphogenesis and development. © I. Holzapfel Publishers 2007.

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  • Analysis of the neoplastic nature and biological potential of sporadic and nevoid basal cell carcinoma syndrome-associated keratocystic odontogenic tumor

    Naoki Katase, Hitoshi Nagatsuka, Hidetsugu Tsujigiwa, Mehmet Gunduz, Ryo Tamamura, Han Phuu Pwint, Rosario Santos Rivera, Motowo Nakajima, Yoshio Naomoto, Noriyuki Nagai

    Journal of Oral Pathology and Medicine   36 ( 9 )   550 - 554   2007.10

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    Background: Keratocystic odontogenic tumor (KCOT), also known as odontogenic keratocyst, is a benign cystic neoplasm, which may be associated with nevoid basal cell carcinoma syndrome (NBCCS) and if it does, will occur as multiple cystic lesions. KCOT is locally destructive despite its bland histological features. However, the neoplastic nature of KCOT is not well established. Heparanase is an endo-d-glucuronidase enzyme that specifically cleaves heparan sulfate (HS) and the increase of its level in tumors promotes invasion, angiogenesis, and metastasis. Methods: To investigate the neoplastic character of KCOT, we studied the localization patterns of heparanase in KCOT, focusing on the differences between sporadic and NBCCS-associated KCOTs, by immunohistochemistry and in situ hybridization. To compare the expression pattern of these cysts with non-tumorous odontogenic developmental cyst, dentigerous cyst was included. Results: All the odontogenic cysts showed positive immunoreaction for heparanase protein in various intensities. The expression pattern of heparanase gene corresponded to that of protein expression. Interestingly, intense gene and protein expressions were observed in KCOT associated with NBCCS compared with sporadic ones and dentigerous cyst. Conclusions: The results implied that heparanase expression may be correlated with the neoplastic properties of KCOT, particularly in NBCCS-associated cases. © 2007 The Authors.

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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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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  • The study of palatal cell proliferation and apoptosis in retinoic acid induced mouse cleft palate varied with different developmental stage.

    Xiao J, Cong W, Wang R, Wang B, Wang F, Zhu EX, Hu H, Katase N, Nagatsuka H

    J Hard Tissue Biology   16 ( 3 )   125 - 130   2007

  • Role of heparanase in the release of heparan sulphate binding growth factors in odontogenic tumors.

    Han PP, Nagatsuka H, Tamamura R, Katase N, Lefeuvre MB, Hu H, Takagi S, Ishida N, Nakano K, Kawakami K, Gunduz M

    J Hard Tissue Biology   16 ( 1 )   23 - 30   2007

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  • Characterization and gene expression profiling of human mesenchymal stem cells.

    Mori H, Itano Y, Kobayashi N, Kosaka Y, Tanaka N, Nagatsuka H, Inoue M, Setsu K, Nakanishi T

    J Hard Tissue Biology   16 ( 1 )   36 - 41   2007

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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

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    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.

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  • 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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  • Macrognathia secondary to dialysis-related renal osteodystrophy treated successfully by parathyroidectomy

    Tsuyoshi Hata, I. Irei, K. Tanaka, H. Nagatsuka, M. Hosoda

    International Journal of Oral and Maxillofacial Surgery   35 ( 4 )   378 - 382   2006.4

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    Renal osteodystrophy (ROD) is one of the most common complications affecting patients with chronic renal failure both before and after the initiation of maintenance dialysis, but macrognathia secondary to ROD is rare. Usually, enlarged jaws due to ROD do not return to their normal contours after the treatment of hyperparathyroidism. To the authors' knowledge, this article describes the second case of macrognathia secondary to dialysis-related ROD treated successfully by parathyroidectomy. Immunohistochemical study of the maxilla confirmed that parathyroidectomy could stop maladaptive parathyroid hormone stimulation, which leads not only to the formation of osteoblastic progenitors that become fibroblast-like cells but also to osteoclast formation. © 2005 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

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  • Comparison of ready-made and self-setting alginate membranes used as a barrier membrane for guided bone regeneration International journal

    Yoshiya Ueyama, Takahiro Koyama, Kunio Ishikawa, Takamitsu Mano, Yukio Ogawa, Hitoshi Nagatsuka, Kazuomi Suzuki

    Journal of Materials Science: Materials in Medicine   17 ( 3 )   281 - 288   2006.3

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    In order to understand the requirements of guided bone regeneration (GBR) involving alginate base self-setting barrier membranes, GBR was performed in the case of bicortical bone defects formed at the tibiae of experimental animals employing self-setting and ready-made alginate membranes. Connective tissue ingress into the bone defects at the skin side of the tibia was observed when GBR was generated utilizing ready-made alginate membrane. In contrast, bone defects were reconstructed with bone tissue when GBR was generated with self-setting alginate membrane formed from aqueous 3% sodium alginate and 3% CaCl2 solutions. The unreacted aqueous sodium alginate solution inherent to self-setting alginate membrane did not inhibit bone tissue regeneration. Rather, callus bone was formed using sodium alginate as the nucleus. However, when GBR was effected with self-setting alginate membrane formed from aqueous 10% CaCl2 solution, membrane was too thick and thus regeneration of bone tissue in the bone cavity was prevented. Therefore, we concluded that self-setting alginate membrane is very useful as a barrier membrane for GBR upon appropriate adjustment of conditions with respect to preparation of alginate membrane. © 2006 Springer Science + Business Media, Inc.

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  • Three cases of adenocarcinoma arising in extremely long-segment Barrett's esophagus International journal

    Toshiya Fujiwara, Yoshio Naomoto, Tomoki Yamatsuji, Yasuhiro Shirakawa, Hirofumi Noguchi, Toshiyoshi Fujiwara, Nobuya Oohara, Mehmet Gunduz, Hitoshi Nagatsuka, Manabu Nishie, Hirokazu Uetsuka, Shuji Hamazaki, Noriaki Tanaka

    Digestive Diseases and Sciences   51 ( 3 )   533 - 538   2006.3

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  • Cyclooxygenase 2 expression in otitis media with effusion

    Masashi Kakiuchi, Hidetsugu Tsujigiwa, Yorihisa Orita, Hitoshi Nagatsuka, Junko Yoshinobu, Shin Kariya, Shin Ichi Haginomori, Saeko Orita, Kunihiro Fukushima, Mitsuhiro Okano, Noriyuki Nagai, Kazunori Nishizaki

    American Journal of Otolaryngology - Head and Neck Medicine and Surgery   27 ( 2 )   81 - 85   2006.3

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    Objectives: To study whether cyclooxygenase 2 (COX-2) plays a role in the development of otitis media with effusion (OME). Study design/methods: An experimental model of endotoxin-induced OME was used in healthy BALB/c mice. Solutions of Salmonella typhimurium endotoxin were injected into the middle ears of the mice, and COX-2 expression in the middle ears was studied using reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization (ISH). Results: Analysis by RT-PCR showed that COX-2 expression in the middle ear increased in a dose-dependent fashion after injection of endotoxin. ISH demonstrated that COX-2 had distinct expression patterns in the epithelium of middle ears with endotoxin-induced OME. Conclusions: COX-2 expression, however, was not detected in normal middle ears. COX-2 expression may be one factor contributing to the development of OME. © 2006 Elsevier Inc. All rights reserved.

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  • COX-2 induction by heparanase in the progression of breast cancer International journal

    Takako Imada, Junji Matsuoka, Tetsuji Nobuhisa, Takaomi Okawa, Toshihiro Murata, Yoko Tabuchi, Yasuhiro Shirakawa, Nobuya Ohara, Mehmet Gunduz, Hitoshi Nagatsuka, Tatsuo Umeoka, Yasuhisa Yamamoto, Motowo Nakajima, Noriaki Tanaka, Yoshio Naomoto

    International Journal of Molecular Medicine   17 ( 2 )   221 - 228   2006.2

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    Breast cancer confined within the lactiferous duct or lobule, without invading the stroma, is called ductal carcinoma in situ (DCIS), whereas breast cancer that has invaded the stroma through the basal membrane is called invasive cancer. Heparanase, an endo-β-D-glucuronidase that specifically degrades heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM), plays an important role when breast cancer cells breach the basal membrane. Recently, we have reported that heparanase is involved in angiogenesis through direct induction of cyclo-oxygenase-2 (COX-2). COX-2 induces vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and is thus involved in neovascularization. The present study was undertaken to analyze surgically resected breast cancer specimens for heparanase and COX-2 expression, using specimens from 59 patients with invasive cancer and 85 patients with DCIS (including 41 cases of DCIS adjacent to invasive cancer). This study yielded the following results: a) the distribution of heparanase within tumor tissue was identical to that of COX-2; b) heparanase expression was more frequent in invasive cancer than in non-invasive cancer; c) a close positive correlation was noted between heparanase and COX-2 expression (this correlation was particularly strong in cases of invasive cancer); and d) COX-2 expression was always seen in cases positive for heparanase expression. Our results indicate that heparanase expression increases during the progression of breast cancer into invasive cancer, and that this change is accompanied by increased COX-2 expression. They also suggest that heparanase may play a novel role for COX-2 mediated tumor angiogenesis in breast-cancer progression.

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  • Identification of a candidate tumor suppressor gene RHOBTB1 located at a novel allelic loss region 10q21 in head and neck cancer International journal

    Levent B. Beder, Mehmet Gunduz, Mamoru Ouchida, Esra Gunduz, Akiko Sakai, Kunihiro Fukushima, Hitoshi Nagatsuka, Sachio Ito, Noriyasu Honjo, Kazunori Nishizaki, Kenji Shimizu

    Journal of Cancer Research and Clinical Oncology   132 ( 1 )   19 - 27   2006.1

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    Purpose: Aims of the study are to narrow-down the hotspot region on 10q21 defined by previous genome-wide loss of heterozygosity (LOH) analysis in head and neck squamous cell carcinomas (HNSCC) and to define candidate tumor suppressor genes (TSG) concerned with 10q21. Materials and methods: LOH analysis was carried out with ten polymorphic microsatellite markers. Expression analysis was performed by semi-quantitative RT-PCR, and mutation analysis by PCR and direct sequencing. Results: LOH analysis on 10q21 in 52 HNSCC indicated distinctive and frequent allelic loss at D10S589 (42%). Among flanking genes, we found the RHOBTB1 gene as a candidate TSG, since an intragenic marker demonstrated the highest LOH (44%). Expression analysis revealed down-regulation of RHOBTB1 mRNA in 37% of tumors. Interestingly, all the five tumors that showed decreased expression of RHOBTB1 were accompanied with LOH, supporting the haploinsufficiency and class 2 TSG characteristics of RHOBTB1. No pathogenic mutation of RHOBTB1 was found. Furthermore, another gene within the region, EGR2, was also taken under scope. LOH frequencies around the EGR2 gene were relatively low (23 and 33%). Albeit semi-quantitative expression analysis of EGR2 demonstrated downregulation in 45% of tumor samples, no relation was found between the expression levels and LOH status. Conclusion: Frequent allelic loss and decreased expression of RHOBTB1 suggested that this gene has a role in tumorigenesis of a subset of HNSCC. © Springer-Verlag 2005.

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  • 転移リンパ節が鰓性癌に類似した組織像を呈した舌癌の1症例

    諸富 彰彦, 伊田 正道, 内田 堅一郎, 福田 てる代, 真野 隆充, 上山 吉哉, 長塚 仁

    日本口腔外科学会雑誌   52 ( 1 )   34 - 34   2006.1

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  • A case report of ameloblastoma of the mandible with examination of Notch signaling.

    Siar CH, Han NG, Ariff Z, Muraki E, Shimizu T, Tsujigiwa H, Nagatsuka H, Nagai N, Kawakami T

    Oral Med Pathol   2006

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  • Transforming growth factor beta (TGFb) gene family members in developing and neoplastic odontogenic tissues.

    Heikinheimo K, Mori K, Nagatsuka H, Happonen RP

    J Hard Tissue Biology   15,1,1-5?   2006

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  • Epigenetic alterations of BRG1 leads to cancer development through its nuclear-cytoplasmic shuttling abnormalities International journal

    Esra Gunduz, Mehmet Gunduz, Hitoshi Nagatsuka, Levent Beder, Kadir Demircan, Ryo Tamamura, Omer Faruk Hatipoglu, Naila Mahmut, Naoki Katase, Yoshio Naomoto, Noriyuki Nagai

    Medical Hypotheses   67 ( 6 )   1313 - 1316   2006

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    SWI/SNF is a multiprotein chromatin remodeling complex important for gene regulation. BRG1 and its close relative BRM, have ATPase activity necessary for transcriptional regulation by conformational change of nucleosomes. Due to this role on gene expression, several members of SWI/SNF complex including BRG1 and BRM function as a tumor suppressor or negative regulator of cellular proliferation. On the other hand, the shuttling of proteins between nucleus and cytoplasm is strongly involved in the regulation of cell cycle and proliferation. Many of tumor suppressor gene (TSG)s including p53, BRCA1, ING1 play some of their functions through nucleocytoplasmic shuttling. Abnormalities related with this process abrogate the subcellular localization of the TSGs and lead to cancer development. We recently demonstrated BRG1 as a TSG in oral cancer. Our analysis also revealed an interesting finding that one of the splicing forms of BRG1 is selectively lost in cancer tissue as compared to normal counterparts. Our further analysis revealed a putative nuclear retention signal domain for this splicing form. In this article, we speculate the possible mechanism for the inactivation of BRG1 gene in oral cancer through an abnormality in its subcellular localization. © 2006 Elsevier Ltd. All rights reserved.

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  • Microcystic adnexal carcinoma in the mental region

    Nobuyoshi Mizukawa, Toshio Sugahara, Shin Takagi, Takaaki Ueno, Joji Fukunaga, Hitoshi Nagatsuka

    Asian Journal of Oral and Maxillofacial Surgery   18 ( 3 )   215 - 218   2006

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    Microcystic adnexal carcinoma is a rare tumour, first described in 1982. Prior to the recognition of microcystic adnexal carcinoma, instances of unusual basal cell carcinoma, sweat gland carcinoma, and trichofolliculoma had been reported. Microcystic adnexal carcinomas are slow growing and demonstrate aggressive local behaviour and a high recurrence rate. The mainstay of treatment is surgical excision using frozen sections to check the peripheral and deep margins. This report is of a microcystic adnexal carcinoma in the mental region of a 69-year-old woman. © 2006 Asian Association of Oral and Maxillofacial Surgeons.

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  • Frequent deletion of BRG1 locus at 19p13 predicts recurrence and previous cancer history in oral squamous cell carcinomas.

    Gunduz E, Gunduz M, Nagatsuka H, Beder LB, Tamamura R, Katase N, Mahmut N, Cengiz B, Fukushima K, Nishizaki K, Nagai N

    J Hard Tissue Biology   2006

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  • Differential distribution of type IV collagen alpha1 to alpha6 chains suggests distinct molecular interaction between the epithelial and mesenchymal components of benign odontogenic tumors.

    Han PP, Tamamura R, Katase N, Fujii E, Okauchi M, Jin T, Xiao J, Siar CH, Nagatsuka H

    J Hard Tissue Biology   2006

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  • Immunodetection of heparan sulphate and heparanase molecules in benign and malignant odontogenic tumors.

    Han PP, Nagatsuka H, Siar CH, Tsujigiwa H, Gunduz M, Tamamura R, Katase N, Nakajima M, Naomoto Y, Nagai N

    Oral Med Pathol   2006

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  • Fluoride supplement affects bone mineralization in young rats.

    Inoue M, LeGeroos RZ, Inoue M, Rivera RS, Gulsan AS, Tsujigiwa H, Nagatsuka H, Akita M, Setsu K

    J Hard Tissue Biology   2006

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  • Expression of WISP-1 (ccn4), WISP-2 (ccn5) and WISP-3 (ccn6) in rheumatoid arthritic synovium evaluated by DNA microarrays.

    Mori H, Nishida K, Ozaki T, Inoue H, Setsu K, Tsujigiwa H, Nagatsuka H, Gunduz M, Nakanishi T

    J Hard Tissue Biology   2006

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  • Immunohistochemical examination of cytological differentiation in osteosarcomas

    Toshiyuki Kawakami, T. Shimizu, A. Kimura, H. Hasegawa, C. H. Siar, K. H. Ng, H. Nagatsuka, N. Nagai, H. Kanda

    European Journal of Medical Research   10 ( 11 )   475 - 479   2005.11

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    In this immunohistochemical examination, the expression of Runx2, Notch1, Delta and Osteopontin peptides were detected in neoplastic cells in 10 Japanese cases of osteosarcoma. Immunohistochemically, Runx2 peptide expression appeared in the cytoplasm of almost all neoplastic cells of the 10 cases examined. However, Notch1 peptide expression appeared in the cytoplasm of neoplastic cells in the localized and comparatively well-differentiated area of osteosarcoma, which osteoblastic and chondroblastic containing osteoid and/or chondroid tissues. No expression of Notch1 peptide was detected in the fibroblastic and poorly differentiated areas. Delta peptide appearance was nearly the same pattern of Notch1 peptide. Expression of Osteopontin peptide appeared in almost all cells and the strength expression was shown in the area of comparatively well-differentiated tissues. Therefore, these results suggest that Runx2, Notch1, and Delta peptides are closely related to cytological differentiation or acquisition of tissue specific characteristics in neoplastic cells in osteosarcoma. © I. Holzapfel Publishers 2005.

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  • Role of O6-methylguanine-DNA methyltransferase and effect of O6-benzylguanine on the anti-tumor activity of cis- diaminedichloroplatinum(II) in oral cancer cell lines International journal

    Yu Maki, Jun Murakami, Jun Ichi Asaumi, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Susumu Kokeguchi, Kazuhiro Fukui, Noriko Kawai, Yoshinobu Yanagi, Masahiro Kuroda, Noriaki Tanaka, Nagahide Matsubara, Kanji Kishi

    Oral Oncology   41 ( 10 )   984 - 993   2005.11

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    The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) modulates the effectiveness of alkylating agents. However, the relationship between MGMT and the sensitivities to other agents has not been explored. In the present study, the association between MGMT expression and the cellular sensitivity to the platinum agent, CDDP was examined in four human oral cancer cell lines. CDDP depleted MGMT protein and mRNA levels in all four cell lines. Two cell lines with low MGMT expression were sensitive to an alkylating agent, N-methyl-N′-nitro-N-nitrosoguanidine and CDDP, whereas two other cell lines with high MGMT expression were resistant to both agents. Furthermore, the addition of the MGMT inhibitor, O6-benzylguanine (O 6-BG), invariably enhanced CDDP sensitivity. CDDP depleted MGMT expression, and CDDP sensitivity was enhanced by O6-BG. These results provide valuable information about the relationship between MGMT expression and CDDP sensitivity in oral cancer chemotherapy. © 2005 Elsevier Ltd. All rights reserved.

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  • Expression of Notch1 and Math1 in mandibular condyle cartilage in neonatal mice International journal

    Takako Shimizu, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Norimasa Okafuji, Saburo Kurihara, Noriyuki Nagai, Toshiyuki Kawakami

    Angle Orthodontist   75 ( 6 )   993 - 995   2005.11

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    On the basis of the cellular morphological changes in the cartilaginous area, the mandibular condylar cartilage is histopathologically composed of four different cell layers - fibrous, proliferative, maturative, and hypertrophic. Reaction for Notch1 was present in the hypertrophic cells only. However, Math1 was locally distributed in the hypertrophic layer and partially in the proliferative layer. The expression patterns of Notch1 and Math1 were slightly different. These results suggest that the morphogenesis regulation factors of Notch1 and Math1 may play some role in mandibular condylar cartilage. Positive reactions to osteopontin, as a control, were detected in the cytoplasm of all layers, although they varied from published data. © 2005 by The EH Angle Education and Research Foundation, Inc.

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  • Effects of immobilized recombinant human bone morphogenetic protein-2/succinylated type I atelocollagen on cellular activity of ST2 cells Reviewed

    Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Mehmet Gunduz, Andrea Rodriguez, Rosario S. Rivera, Racquel Z. Legeros, Miho Inoue, Noriyuki Nagai

    Journal of Biomedical Materials Research - Part A   75 ( 1 )   210 - 215   2005.10

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    The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) to induce ectopic bone formation requires a carrier. Type I atelocollagen, a biomaterial with a porous structure, excellent operational features, and biocompatibility, is an effective carrier for rhBMP-2. However, the conventionally used lyophilized rhBMP-2/collagen mixture does not necessarily give adequate bone-induction effect. In the present study, we examined the effect of immobilizing rhBMP-2 to type I atelocollagen on the cellular activity of ST2 cells. The following results were obtained: (1) rhBMP-2 was effectively immobilized to succinylated type I atelocollagen, indicating the usefulness of succinylated type I atelocollagen in immobilization; (2) studies of alkaline phosphatase activity confirmed the effectiveness of rhBMP-2 immobilized on succinylated atelocollagen in augmenting cellular activity. © 2005 Wiley Periodicals, Inc.

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  • Immunolocalization and distribution patterns of type IV collagen alpha chains in oral mucosal melanoma International journal

    Hitoshi Nagatsuka, Rosario Santos Rivera, Mehmet Gunduz, You Jin Lee, Ryo Tamamura, Esra Gunduz, Ichiro Naito, Yoshikazu Sado, Noriyuki Nagai

    Virchows Archiv   447 ( 4 )   710 - 716   2005.10

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    The basement membrane (BM) is mainly composed of type IV collagen, which is composed of triple combinations of six distinct alpha (α) chains in a tissue-specific manner. The six collagen chain-specific antibodies (α1-α6) were used to examine the BMs of the oral epithelium (OE) and tumor clusters in oral mucosal melanoma (OMM). Eight OMM cases were examined. Results showed that the α1 and α2 chains were constantly detected at the BM of the normal OE as well as at the OE with atypical melanocytic proliferation and in invasive melanoma with nodular nests. The α1 and α2 chains were intermittently detected in in situ OMM, early invasive OMM and advanced invasive OMM with sheet-like nests. Gradual loss of α5 and α6 from the OE with atypical melanocyte through in situ OMM and early invasive OMM was observed. These findings suggest that changes in the immunolocalization and distribution patterns of type IV collagen α chains are associated with the progression of OMM. The distribution pattern of type IV collagen α chain varies depending on the architecture of the nest. © Springer-Verlag 2005.

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  • In vivo effect of fluoride-substituted apatite on rat bone

    Miho Inoue, Hitoshi Nagatsuka, Hidetsugu Tsujigiwa, Masahisa Inoue, Racquel Z. LeGeros, Toshio Yamamoto, Noriyuki Nagai

    Dental Materials Journal   24 ( 3 )   398 - 402   2005.9

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    Different types of calcium phosphate compounds are commercially available for medical and dental applications as bone substitute materials. Biological apatites contain several kinds of minor elements such as carbonate (CO 3), magnesium (Mg), and fluoride (F) in enamel, dentin, and bone. It has been shown that F ion and F-substituted apatite promoted osteoblast proliferation and inhibited osteoclast cell activity. The purpose of this study was to investigate the in vivo rat tibia activity on F-substituted apatite (FAp). Apatites of unsintered calcium deficient apatite (CDA), and FAps, with low, medium, and high F concentrations, were implanted in rat tibia for 1 and 2 weeks. Implanted tissues were embedded in paraffin blocks, stained with hematoxylin-eosin and histomorphometrically observed. Results showed that low F concentration induced better and faster new bone formation in vivo compared to CDA. Therefore the results suggested that F as a minor element in bone rendered a suitable effect on bone formation in vivo.

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  • A case of squamous cell carcinoma ex pleomorphic adenoma in the palate: Immunohistochemical analysis and chromosomal alteration by comparative genomic hybridization

    Masamichi Ita, Kenichiro Utida, Hitoshi Nagatsuka, Toshikazu Gondo, Kohsuke Sasaki, Yoshiya Ueyama

    Oral Oncology Extra   41 ( 8 )   170 - 173   2005.9

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    Carcinoma ex pleomorphic adenoma (CXPA) is an uncommon tumor of salivary gland; moreover, histologically, squamous cell carcinoma (SCC) is exceedingly rare. This report documents a case of CXPA arising in the hard palate, which showed transformation from pleomorphic adenoma (PA) to SCC reacted to Ki-67 immunostaining. Other immunohistochemical stains also demonstrated different immunoreactivities between PA cells and SCC cells. Comparative genomic hybridization identified a chromosomal imbalance. Gain regions of the PA were 8q11-22 and 8q24 and the loss region was 13q32-34 in PA; additionally, in SCC, regions characterized by increased DNA copy number were 8p, 8q and 12q12-15. © 2005 Elsevier Ltd. All rights reserved.

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  • Analysis of amelogenin gene (AMGX, AMGY) expression in ameloblastoma International journal

    Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Pwint Han Phuu, Mehmet Gunduz, Huat Siar Chong, Shinichiro Oida, Noriyuki Nagai

    Oral Oncology   41 ( 8 )   843 - 850   2005.9

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    Although the amelogenin gene is expressed in ameloblastoma, the precise expression pattern of X and Y amelogenin genes (AMGX, AMGY) in this tumor has not yet identified. In this study, we analyzed amelogenin gene expression in 19 samples (9 male, 10 female) of oral ameloblastomas by RT-PCR and detect the chromosomal origin of amelogenin mRNA by restriction enzyme digestion of the RT-PCR product. All tumor samples expressed amelogenin mRNA. We could detect increased level of AMGY expression in all male samples, higher than that of AMEX. It is an interesting finding as in normal male tooth development, the expression of AMGY is very much lower than that of AMGX. We postulate that epigenetic change of sex chromosomes may have some correlations with tumorigenesis of ameloblastoma. We also discuss the other possible mechanisms and points for future studies on this change in expression pattern. © 2005 Elsevier Ltd. All rights reserved.

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  • Frequent deletion and down-regulation of ING4, a candidate tumor suppressor gene at 12p13, in head and neck squamous cell carcinomas International journal

    Mehmet Gunduz, Hitoshi Nagatsuka, Kadir Demircan, Esra Gunduz, Beyhan Cengiz, Mamoru Ouchida, Hidetsugu Tsujigiwa, Eiki Yamachika, Kunihiro Fukushima, Levent Beder, Satoshi Hirohata, Yoshifumi Ninomiya, Kazunori Nishizaki, Kenji Shimizu, Noriyuki Nagai

    Gene   356 ( 1-2 )   109 - 117   2005.8

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    We previously showed two members of the ING family, ING1 and ING3 as a tumor suppressor gene in head and neck cancer. Progress in human genome sequencing provided additional information of the new members of the ING family genes. ING4 is localized to chromosome 12p13.31 region and harbors the PHD domain highly homologous among ING family proteins. We analyzed loss of heterozygosity at 12p12-13 region in 50 head and neck squamous cell carcinomas by using six highly polymorphic microsatellite markers and found allelic loss in 66% (33/50) of the informative cases. To clarify the role of ING4 in head and neck carcinogenesis, we first checked mutation status in tumor samples. As mutation of the ING4 gene was not found in head and neck cancers, we examined the mRNA expression level. Quantitative real-time RT-PCR analysis demonstrated decreased expression of ING4 mRNA in 76% of primary tumors as compared with that of matched normal samples. Since p53 dependent pathways of other ING family members have been shown, we examined p53 mutation status and compared with ING4 mRNA expression in tumor samples. However, no such direct relationship has been detected. In conclusion, frequent deletion and decreased mRNA expression of ING4 suggested it as a class two tumor suppressor gene and may play an important role in head and neck cancer. © 2005 Elsevier B.V. All rights reserved.

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  • The engraftment of transplanted bone marrow-derived cells into the olfactory epithelium International journal

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

    Brain Research   1052 ( 1 )   10 - 15   2005.8

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    To investigate whether bone marrow cells migrate and are engrafted into the olfactory epithelium and differentiate into olfactory neurons, bone marrow cells of green fluorescence protein (GFP) mice were transplanted into lethally irradiated recipient mice. Immunohistochemical staining was performed to evaluate the engraftment of donor bone marrow cells into the olfactory epithelium. Immunostaining for GFP was found initially in the olfactory epithelium 2 weeks after bone marrow reconstruction. The percentage of GFP positive cells increased up to 12 months after bone marrow reconstruction. Double staining for GFP and olfactory marker protein showed that a population of the GFP-positive cells had characteristics of olfactory neurons. These results demonstrate that bone marrow cells can be engrafted in the olfactory epithelium and then differentiate into olfactory neuron cells. © 2005 Elsevier B.V. All rights reserved.

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  • Erdheim-Chester disease in a child presenting with multiple jaw lesions International journal

    Hitoshi Nagatsuka, Phuu Pwint Han, Koji Taguchi, Hidetsugu Tsujigiwa, Mehmet Gunduz, Joji Fukunaga, Toshio Sugahara, Junichi Asaumi, Noriyuki Nagai

    Journal of Oral Pathology and Medicine   34 ( 7 )   420 - 422   2005.8

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    BACKGROUND: Erdheim-Chester disease is a rare histiocytic disease entity related to juvenile xanthogranuloma. It is a systemic condition, usually occurs in adult, characterized by infiltration of foamy histiocytes within the bone and soft tissues. METHODS AND RESULTS: We report a case of 13-year-old female patient who first presented with multiple osteolytic lesions of the jaws followed by bilateral symmetrical bone lesions affecting the lower extremities, as well as brain and abdominal involvement. Histological findings of the jaw lesions showed lipid-storing CD68 (+), CDIa (-) histiocytes with Touton type giant cells. CONCLUSION: To the best of our knowledge, this is the first case of Erdheim-Chester disease with jaw bone lesions occurring as initial presenting symptom. © Blackwell Munksgaard 2005 · All rights reserved.

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  • Expression of Wnt5a gene in mouse embryonic orofacial development.

    J Xiao, EX Zhu, N Nagai, H Nagatsuka, CG Li

    DEVELOPMENTAL BIOLOGY   283 ( 2 )   612 - 612   2005.7

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  • Effects of histone deacetylase inhibitor FR901228 on the expression level of telomerase reverse transcriptase in oral cancer International journal

    Jun Murakami, Jun Ichi Asaumi, Noriko Kawai, Hidetsugu Tsujigiwa, Yoshinobu Yanagi, Hitoshi Nagatsuka, Tetsuyoshi Inoue, Susumu Kokeguchi, Shoji Kawasaki, Masahiro Kuroda, Noriaki Tanaka, Nagahide Matsubara, Kanji Kishi

    Cancer Chemotherapy and Pharmacology   56 ( 1 )   22 - 28   2005.7

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    We speculated whether or not the expression level of telomerase reverse transcriptase (hTERT) would be modulated by agents targeting epigenetics in oral cancer cell lines. Although hTERT is known to be targeted by epigenetic changes, it remains unclear how chemoagents targeting epigenetics work on hTERT transcription. In the present study, the epigenetic effects of the histone deacetylase (HDAC) inhibitor FR901228 on hTERT transcription in oral cancer cell lines were analyzed by RT-PCR. The mRNA expression of hTERT was upregulated after exposure to FR901228 in hTERT-negative Hep2 cells, and even SAS and KB cells expressed high levels of hTERT. Moreover, cotreatment of protein synthesis inhibitor cycloheximide (CHX) resulted in the induction of hTERT transcription by FR901228. This suggests that the induction of hTERT by FR901228 requires de novo protein synthesis to some extent and is more likely a direct than an indirect effect on epigenetic changes such as histone acetylation/deacetylation. We further examined the effect of FR901228 on c-myc protein, which is one of the main hTERT transcription activators. FR901228 repressed c-myc protein only in the absence of CHX, and depended on the enhancement of de novo protein synthesis. Our results indicate that c-myc protein is repressed indirectly by FR901228 but may not contribute to FR901228-induced hTERT transcription. The present study showed that the HDAC inhibitor FR901228 induced the hTERT gene by a complex mechanism that involved transcription factors other than c-myc, in addition to inhibition of histone deacetylation. © Springer-Verlag 2005.

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  • Fine deletional mapping of chromosome 4q22-35 region in oral cancer. International journal

    Yasuo Shinno, Esra Gunduz, Mehmet Gunduz, Hitoshi Nagatsuka, Hidetsugu Tsujigiwa, Beyhan Cengiz, You Jin Lee, Ryo Tamamura, Mamoru Ouchida, Kunihiro Fukushima, Kenji Shimizu, Noriyuki Nagai

    International journal of molecular medicine   16 ( 1 )   93 - 98   2005.7

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    We analyzed the loss of heterozygosity of the long arm of chromosome 4 in 40 oral cancers, using 16 microsatellite markers based on data from the human genome sequence, and defined the deletional mapping of the region with putative tumor suppressor genes. Our data revealed two distinct commonly deleted regions around the markers, D4S2623 and D4S1644, with an allelic deletion of 44 and 39%, respectively. Additional mapping and use of the markers near one of these hot spots narrowed down the minimally deleted region about 1.5 Mbp around the marker, D4S2623. Caspase 6 is localized 280 kb from the marker, D4S2623. Fine mapping of this region with possible tumor suppressor gene suggests caspase 6 as a putative tumor suppressor gene. Further molecular analysis of caspase 6 should be performed to clarify its role in oral carcinogenesis.

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  • Emergence of nuclear heparanase induces differentiation of human mammary cancer cells International journal

    Tetsuji Nobuhisa, Yoshio Naomoto, Munenori Takaoka, Yoko Tabuchi, Keizou Ookawa, Dai Kitamoto, Esra Gunduz, Mehmet Gunduz, Hitoshi Nagatsuka, Minoru Haisa, Junji Matsuoka, Motowo Nakajima, Noriaki Tanaka

    Biochemical and Biophysical Research Communications   331 ( 1 )   175 - 180   2005.5

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    The study of epithelial differentiation touches upon many modern aspects of biology. The epithelium is in constant dialogue with the underlying mesenchyme to control stem cell activity, proliferation in transit-amplifying compartments, lineage commitment, terminal differentiation and, ultimately, cell death. There are spatially distinct compartments dedicated to each of these events. Recently we reported that heparanase is expressed in nucleus as well as in the cytoplasm and that nuclear heparanase seems to be related to cell differentiation. In this study, we investigated the role of nuclear heparanase in differentiation by transducing human mammary epithelial cancer cells with heparanase which was delivered specifically into nucleus. We observed that expression of nuclear heparanase allowed the cells to differentiate with the appearance of lipid droplets. This finding supports the idea that heparanase plays a novel role in epithelial cell differentiation apart from its known enzymatic function. © 2005 Elsevier Inc. All rights reserved.

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  • Regeneration of rat auditory ossicles using recombinant human BMP-2/collagen composites International journal

    Yasushi Takeda, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Noriyuki Nagai, Junko Yoshinobu, Mitsuhiro Okano, Kunihiro Fukushima, Ayako Takeuchi, Tadashi Yoshino, Kazunori Nishizaki

    Journal of Biomedical Materials Research - Part A   73 ( 2 )   133 - 141   2005.5

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    Tympanoplasty operations to improve hearing impairment require a wide middle ear cavity and reconstruction of columellar formations. There is no specific material for use in the reconstruction of columellar formations. Tissue response to BMP has been employed as regenerative material. To our knowledge, however, there are no reports of the reconstruction of columellar formations using recombinant human bone morphogenetic protein-2/bovine collagen composites in the middle ear. The purpose of this study is to investigate whether recombinant human bone morphogenetic protein-2/bovine collagen composites (rhBMP-2 composites) are appropriate for use as regenerative material for tympanoplasty. In the form of pellets, rhBMP-2 composites were implanted as columellae into the tympanic cavity. At 2,4,6,8, and 12 weeks after surgery, the middle ear of the animals (n = 4 at each week) was stained with hematoxylineosin for light microscopic observation. All composites were in the process of ossification or had ossified according to their developmental stages and were covered with a single layer of squamous or cuboidal epithelium. The new bone formed in these composites was persistently stable and displayed some columellar conditions assessed by histological examination. This study led to the conclusion that rhBMP-2 composites make excellent regenerative material for auditory ossicles. © 2005 Wiley Periodicals, Inc.

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  • Regeneration of rat auditory ossicles using recombinant human BMP-2/collagen