Updated on 2021/07/12

写真a

 
OKUI Tatsuo
 
Organization
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
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Research Interests

  • 骨代謝

  • がん骨転移

  • 知覚神経

Research Areas

  • Others / Others

Research History

  • 島根大学医学部歯科口腔外科学講座   准教授

    2020.12

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  • 岡山大学病院 口腔外科 病態系 助教

    2016.4 - 2020.11

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  • インディアナ大学 米国   博士研究員

    2014.4 - 2016.3

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  • 岡山大学病院 口腔外科 病態系 医員

    2011.4 - 2014.3

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  • Okayama University   Graduate School of Medicine , Dentistry and Pharmaceutical Sciences

    2007.4 - 2011.3

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  • 岡山大学病院 総合歯科(研修医)

    2006.4 - 2007.3

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Papers

  • The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone. International journal

    Tatsuo Okui, Masahiro Hiasa, Shoji Ryumon, Kisho Ono, Yuki Kunisada, Soichiro Ibaragi, Akira Sasaki, G David Roodman, Fletcher A White, Toshiyuki Yoneda

    Journal of bone oncology   26   100330 - 100330   2021.2

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    Bone pain is a common complication of breast cancer (BC) bone metastasis and is a major cause of increased morbidity and mortality. Although the mechanism of BC-associated bone pain (BCABP) remains poorly understood, involvement of BC products in the pathophysiology of BCABP has been proposed. Aggressive cancers secrete damage-associated molecular patterns (DAMPs) that bind to specific DAMP receptors and modulate cancer microenvironment. A prototypic DAMP, high mobility group box 1 (HMGB1), which acts as a ligand for the receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs), is increased in its expression in BC patients with poor outcomes. Here we show that 4T1 mouse BC cells colonizing bone up-regulate the expression of molecular pain markers, phosphorylated ERK1/2 (pERK) and pCREB, in the dorsal root ganglia (DRGs) innervating bone and induced BCABP as evaluated by hind-paw mechanical hypersensitivity. Importantly, silencing HMGB1 in 4T1 BC cells by shRNA reduced pERK and pCREB and BCABP with decreased HMGB1 levels in bone. Further, administration of a neutralizing antibody to HMGB1 or an antagonist for RAGE, FPS-ZM1, ameliorated pERK, pCREB and BCABP, while a TLR4 antagonist, TAK242, showed no effects. Consistent with these in vivo results, co-cultures of F11 sensory neuron-like cells with 4T1 BC cells in microfluidic culture platforms increased neurite outgrowth of F11 cells, which was blocked by HMGB1 antibody. Our results show that HMGB1 secreted by BC cells induces BCABP via binding to RAGE of sensory neurons and suggest that the HMGB1/RAGE axis may be a potential novel therapeutic target for BCABP.

    DOI: 10.1016/j.jbo.2020.100330

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  • Expression of SARS-CoV-2 entry factors in human oral tissue. International journal

    Yoshihiko Sawa, Soichiro Ibaragi, Tatsuo Okui, Junro Yamashita, Tetsuro Ikebe, Hiroyuki Harada

    Journal of anatomy   2021.1

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    The distribution of cells expressing SARS-CoV-2 entry factor angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) in human oral tissues were tested. The investigation was conducted with normal flesh tissue and paraffin-embedded specimens. The ACE2 and TMPRSS2 expression was detected with all subjects in the normal mucosa of the keratinized stratified squamous epithelia of the tongue and non-keratinized stratified squamous epithelia of the lip and cheek. It was found that ACE2 is expressed in the cytoplasm and on the cell membrane mainly in the stratum granulosum of the epithelia while the TMPRSS2 is strongly expressed on the cell membrane mainly in the stratum granulosum and stratum spinosum, but not in the stratum basale. Antibodies' reactions for ACE2 and TMPRSS2 were not observed in the nuclei or keratin layer. The expression of ACE2 and TMPRSS2 in the oral epithelia appears to be general, and the expression was also observed in the mucous and serous acini of the labial glands. The SARS-CoV-2 may transiently attach to the oral mucosa and the minor salivary glands which are present under all of the oral mucosa. The oral cavity can be considered an important organ for SARS-CoV-2 attachment and may provide a preventive medical avenue to guard against COVID-19 by preventing saliva from scattering.

    DOI: 10.1111/joa.13391

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  • Surgical resection of a giant peripheral ossifying fibroma in mouth floor managed with fiberscopic intubation. International journal

    Tatsuo Okui, Soichiro Ibaragi, Kisho Ono, Kazuaki Hasegawa, Akira Sasaki

    Clinical case reports   9 ( 1 )   180 - 184   2021.1

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    Tracheal intubation for general anesthesia can sometimes be difficult in patients with a large mass in the mouth floor. Preoperative evaluation of the patient's airway is most important when treating large oral disease.

    DOI: 10.1002/ccr3.3494

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  • Bone Regeneration Capacity of Newly Developed Uncalcined/Unsintered Hydroxyapatite and Poly-l-lactide-co-glycolide Sheet in Maxillofacial Surgery: An In Vivo Study. International journal

    Huy Xuan Ngo, Quang Ngoc Dong, Yunpeng Bai, Jingjing Sha, Shinji Ishizuka, Tatsuo Okui, Shintaro Sukegawa, Takahiro Kanno

    Nanomaterials (Basel, Switzerland)   11 ( 1 )   2020.12

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    Uncalcined/unsintered hydroxyapatite and poly-l-lactide-co-glycolide (u-HA/PLLA/PGA) is a new bioresorbable nanomaterial with superior characteristics compared with current bioresorbable materials, including appropriate mechanical properties, outstanding bioactive/osteoconductive features, and remarkably shorter resorption time. Nevertheless, the bone regeneration characteristics of this nanomaterial have not been evaluated in maxillofacial reconstructive surgery. In this study, we used a rat mandible model to assess the bone regeneration ability of u-HA/PLLA/PGA material, compared with uncalcined/unsintered hydroxyapatite and poly-l-lactide acid (u-HA/PLLA) material, which has demonstrated excellent bone regenerative ability. A 4-mm-diameter defect was created at the mandibular angle area in 28 Sprague Dawley male rats. The rats were divided into three groups: u-HA/PLLA/PGA (u-HA/PLLA/PGA graft + defect), u-HA/PLLA (u-HA/PLLA graft + defect), and sham control (defect alone). At 1, 3, 8, and 16 weeks after surgeries, the rats were sacrificed and assessed by micro-computed tomography, histological analysis with hematoxylin and eosin staining, and immunohistochemical analyses. The results confirmed that the accelerated bone bioactive/regenerative osteoconduction of u-HA/PLLA/PGA was comparable with that of u-HA/PLLA in the rat mandible model. Furthermore, this new regenerative nanomaterial was able to more rapidly induce bone formation in the early stage and had great potential for further clinical applications in maxillofacial reconstructive surgery.

    DOI: 10.3390/nano11010022

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  • High mobility group box 1 induces bone pain associated with bone invasion in a mouse model of advanced head and neck cancer. Reviewed International journal

    Tomoya Nakamura, Tatsuo Okui, Kazuaki Hasegawa, Shoji Ryumon, Soichiro Ibaragi, Kisho Ono, Yuki Kunisada, Kyoichi Obata, Masanori Masui, Tsuyoshi Shimo, Akira Sasaki

    Oncology reports   44 ( 6 )   2547 - 2558   2020.12

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

    Advanced head and neck cancer (HNC) can invade facial bone and cause bone pain, thus posing a significant challenge to the quality of life of patients presenting with advanced HNC. The present study was designed to investigate HNC bone pain (HNC‑BP) in an intratibial mouse xenograft model that utilized an HNC cell line (SAS cells). These mice develop HNC‑BP that is associated with an expression of phosphorylated ERK1/2 (pERK1/2), which is a molecular indicator of neuron excitation in dorsal root ganglia (DRG) sensory neurons. Our experiments demonstrated that the inhibition of high mobility group box 1 (HMGB1) by short hairpin (shRNA) transduction, HMGB1 neutralizing antibody, and HMGB1 receptor antagonist suppressed the HNC‑BP and the pERK1/2 expression in DRG. It was also observed that HNC‑derived HMGB1 increased the expression of the acid‑sensing nociceptor, transient receptor potential vanilloid 1 (TRPV1), which is a major cause of osteoclastic HNC‑BP in DRG. Collectively, our results demonstrated that HMGB1 originating in HNC evokes HNC‑BP via direct HMGB1 signaling and hypersensitization for the acid environment in sensory neurons.

    DOI: 10.3892/or.2020.7788

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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.

    DOI: 10.1002/ccr3.3086

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  • Rab11A Functions as a Negative Regulator of Osteoclastogenesis through Dictating Lysosome-Induced Proteolysis of c-fms and RANK Surface Receptors. International journal

    Yuka Okusha, Manh Tien Tran, Mami Itagaki, Chiharu Sogawa, Takanori Eguchi, Tatsuo Okui, Tomoko Kadowaki, Eiko Sakai, Takayuki Tsukuba, Kuniaki Okamoto

    Cells   9 ( 11 )   2020.10

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    Osteoclast differentiation and activity are controlled by two essential cytokines, macrophage colony-stimulating factor (M-CSF) and the receptor activator of nuclear factor-κB ligand (RANKL). Rab11A GTPase, belonging to Rab11 subfamily representing the largest branch of Ras superfamily of small GTPases, has been identified as one of the crucial regulators of cell surface receptor recycling. Nevertheless, the regulatory role of Rab11A in osteoclast differentiation has been completely unknown. In this study, we found that Rab11A was strongly upregulated at a late stage of osteoclast differentiation derived from bone marrow-derived macrophages (BMMs) or RAW-D murine osteoclast precursor cells. Rab11A silencing promoted osteoclast formation and significantly increased the surface levels of c-fms and receptor activator of nuclear factor-κB (RANK) while its overexpression attenuated osteoclast formation and the surface levels of c-fms and RANK. Using immunocytochemical staining for tracking Rab11A vesicular localization, we observed that Rab11A was localized in early and late endosomes, but not lysosomes. Intriguingly, Rab11A overexpression caused the enhancement of fluorescent intensity and size-based enlargement of early endosomes. Besides, Rab11A overexpression promoted lysosomal activity via elevating the endogenous levels of a specific lysosomal protein, LAMP1, and two key lysosomal enzymes, cathepsins B and D in osteoclasts. More importantly, inhibition of the lysosomal activity by chloroquine, we found that the endogenous levels of c-fms and RANK proteins were enhanced in osteoclasts. From these observations, we suggest a novel function of Rab11A as a negative regulator of osteoclastogenesis mainly through (i) abolishing the surface abundance of c-fms and RANK receptors, and (ii) upregulating lysosomal activity, subsequently augmenting the degradation of c-fms and RANK receptors, probably via the axis of early endosomes-late endosomes-lysosomes in osteoclasts.

    DOI: 10.3390/cells9112384

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  • High-mobility group box 1 induces bone destruction associated with advanced oral squamous cancer via RAGE and TLR4. Reviewed International journal

    Yumi Sakamoto, Tatsuo Okui, Toshiyuki Yoneda, Shoji Ryumon, Tomoya Nakamura, Hotaka Kawai, Yuki Kunisada, Soichiro Ibaragi, Masanori Masui, Kisho Ono, Kyoichi Obata, Tsuyoshi Shimo, Akira Sasaki

    Biochemical and biophysical research communications   531 ( 3 )   422 - 430   2020.10

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    Bone destruction of maxillary and mandibular bone by invasive oral squamous cell cancer (OSCC) raises various problems in the management of patients, resulting in poor outcomes and survival. However, the mechanism behind bone destruction by OSCC remains unclear. High-mobility group box 1 (HMGB1), a highly conserved ubiquitous nuclear non-histone DNA-binding protein, has been demonstrated to be secreted by aggressive cancers and regulate osteoclastogenesis, a central player during bone destruction. We therefore reasoned that HMGB1 secreted by OSCCs contributes to bone destruction. Our results showed that HMGB1 is produced by human cell lines of OSCC and promotes osteoclastogenesis via up-regulation of the expression of receptor activator of nuclear factor kappa-Β ligand in osteoblasts and osteocytes, and consequently osteoclastic bone destruction in mice. Further, we found that these actions of HMGB1 are mediated via the receptor for advanced glycation end products and toll-like receptors. These findings suggest that HMGB1 of OSCC and its down-stream signal pathways are potential targets for the treatment of bone destruction associated with advanced OSCC.

    DOI: 10.1016/j.bbrc.2020.07.120

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  • Revisiting major anatomical risk factors of maxillary sinus lift and soft tissue graft harvesting for dental implant surgeons. Reviewed International journal

    Joe Iwanaga, Tsuyoshi Tanaka, Soichiro Ibaragi, Tatsuo Okui, Junya Hamaguchi, Seiko Min, R Shane Tubbs

    Surgical and radiologic anatomy : SRA   42 ( 9 )   1025 - 1031   2020.9

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    The anatomical variations of the maxillary sinus septa, greater palatine artery, and posterior superior alveolar arteries might cause unexpected complications when they are damaged. Dentists who know these structures well might hope to learn more practical knowledge to avoid and assess injury preoperatively. Therefore, this review paper aimed to review the reported anatomy and variations of the maxillary sinus septa, greater palatine artery/nerve, and posterior superior alveolar artery, and to discuss what has to be assessed preoperatively to avoid iatrogenic injury. To assess the risk of injury of surgically significant anatomical structures in the maxillary sinus and hard palate, the operator should have preoperative three-dimensional images in their mind based on anatomical knowledge and palpation. Additionally, knowledge of the average measurement results from previous studies is important.

    DOI: 10.1007/s00276-020-02468-w

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  • Expression and Role of IL-1β Signaling in Chondrocytes Associated with Retinoid Signaling during Fracture Healing. Reviewed International journal

    Tsuyoshi Shimo, Hiroaki Takebe, Tatsuo Okui, Yuki Kunisada, Soichiro Ibaragi, Kyoichi Obata, Naito Kurio, Karnoon Shamsoon, Saki Fujii, Akihiro Hosoya, Kazuharu Irie, Akira Sasaki, Masahiro Iwamoto

    International journal of molecular sciences   21 ( 7 )   2020.3

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    The process of fracture healing consists of an inflammatory reaction and cartilage and bone tissue reconstruction. The inflammatory cytokine interleukin-1β (IL-1β) signal is an important major factor in fracture healing, whereas its relevance to retinoid receptor (an RAR inverse agonist, which promotes endochondral bone formation) remains unclear. Herein, we investigated the expressions of IL-1β and retinoic acid receptor gamma (RARγ) in a rat fracture model and the effects of IL-1β in the presence of one of several RAR inverse agonists on chondrocytes. An immunohistochemical analysis revealed that IL-1β and RARγ were expressed in chondrocytes at the fracture site in the rat ribs on day 7 post-fracture. In chondrogenic ATDC5 cells, IL-1β decreases the levels of aggrecan and type II collagen but significantly increased the metalloproteinase-13 (Mmp13) mRNA by real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. An RAR inverse agonist (AGN194310) inhibited IL-1β-stimulated Mmp13 and Ccn2 mRNA in a dose-dependent manner. Phosphorylated extracellular signal regulated-kinases (pERK1/2) and p-p38 mitogen-activated protein kinase (MAPK) were increased time-dependently by IL-1β treatment, and the IL-1β-induced p-p38 MAPK was inhibited by AGN194310. Experimental p38 inhibition led to a drop in the IL-1β-stimulated expressions of Mmp13 and Ccn2 mRNA. MMP13, CCN2, and p-p38 MAPK were expressed in hypertrophic chondrocytes near the invaded vascular endothelial cells. As a whole, these results point to role of the IL-1β via p38 MAPK as important signaling in the regulation of the endochondral bone formation in fracture healing, and to the actions of RAR inverse agonists as potentially relevant modulators of this process.

    DOI: 10.3390/ijms21072365

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  • Methotrexate-Associated Lymphoproliferative Disorder Developed Ectopically in the Maxillary Gingiva and Bilateral Lungs. Reviewed International journal

    Kyoichi Obata, Tatsuo Okui, Koji Kishimoto, Soichiro Ibaragi, Akira Sasaki

    Case reports in medicine   2020   4814519 - 4814519   2020

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    A 58-year-old Japanese woman complained of a painful right maxillary premolar gingiva and ulcer. The patient had RA and had been treated with several immunosuppressive drugs such as methotrexate. Head and neck CT indicated no obvious bone destruction with maxillary. However, chest CT indicated the presence of nodular mass of the bilateral lungs. FDG-PET/CT indicated the presence of increased uptake in both lesions. On immunohistochemistry, atypical large-sized lymphocytes were positive for CD20 and EBER-ISH and negative for CD3, CD5, and CD10; the Ki-67 labeling index was high, the histopathological diagnosis was EBV-positive DLBCL, and the clinical diagnosis was MTX-LPD. The patient's treatment with MTX was then discontinued; we removed the alveolar bone which necrosed after 5 weeks. The lesion and the nodular mass at the bilateral lungs had completely disappeared after 7 weeks.

    DOI: 10.1155/2020/4814519

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  • Ammonium tetrathiomolybdate enhances the antitumor effect of cisplatin via the suppression of ATPase copper transporting beta in head and neck squamous cell carcinoma. Reviewed International journal

    Shoji Ryumon, Tatsuo Okui, Yuki Kunisada, Koji Kishimoto, Tsuyoshi Shimo, Kazuaki Hasegawa, Soichiro Ibaragi, Kentaro Akiyama, Nguyen Thi Thu Ha, Nur Mohammad Monsur Hassan, Akira Sasaki

    Oncology reports   42 ( 6 )   2611 - 2621   2019.12

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    Platinum‑based antitumor agents have been widely used to treat head and neck squamous cell carcinoma (HNSCC) and numerous other malignancies. Cisplatin is the most frequently used platinum‑based antitumor agent, however drug resistance and numerous undesirable side effects limit its clinical efficacy for cancer patients. Cancer cells discharge cisplatin into the extracellular space via copper transporters such as ATPase copper transporting beta (ATP7B) in order to escape from cisplatin‑induced cell death. In the present study, it was demonstrated for the first time that the copper chelator ammonium tetrathiomolybdate (TM) has several promising effects on cisplatin and HNSCC. First, TM suppressed the ATP7B expression in HNSCC cell lines in vitro, thereby enhancing the accumulation and apoptotic effect of cisplatin in the cancer cells. Next, it was revealed that TM enhanced the antitumor effect of cisplatin in HNSCC cell tumor progression in a mouse model of bone invasion, which is important since HNSCC cells frequently invade to facial bone. Finally, it was demonstrated that TM was able to overcome the cisplatin resistance of a human cancer cell line, A431, via ATP7B depression in vitro.

    DOI: 10.3892/or.2019.7367

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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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    Language:Japanese   Publisher:(一社)日本口腔腫瘍学会  

    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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  • A case of intraoral plasmablastic lymphoma spontaneously regressed after biopsy in HIV-negative patient Reviewed

    Ono Kisho, Okui Tatsuo, Ibaragi Soichiro, Kawai Hotaka, Obata Kyoichi, Fujita Mariko, Sasaki Akira

    JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY MEDICINE AND PATHOLOGY   31 ( 4 )   280 - 283   2019.7

  • A Case of Pleomorphic Adenoma Originating from Accessory Parotid Gland. Reviewed

    Tatsuo Okui, Soichiro Ibaragi, Mariko Fujita, Akira Sasaki

    Journal of Maxillofacial and Oral Surgery   2019.5

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  • Emerging Evidence of Mast Cell Involvement in Oral Squamous Cell Carcinoma Reviewed

    Simon Basha, Nur Mohammad Monsur Hassan, Rahena Akhter, Soichiro Ibaragi, Tatsuo Okui, Stephen Cox, Akira Sasaki

    Biomedical Journal of Scientific & Technical Research   16 ( 2 )   1 - 6   2019.3

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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.

    DOI: 10.3892/ijo.2018.4631

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  • Retinoic Receptor Signaling Regulates Hypertrophic Chondrocyte-specific Gene Expression. Reviewed

    Shimo T, Koyama E, Okui T, Masui M, Kunisada Y, Ibaragi S, Yoshioka N, Kurio N, Yoshida S, Sasaki A, Iwamoto M

    In vivo (Athens, Greece)   33 ( 1 )   85 - 91   2019.1

  • Solitary Fibrous Tumor Arising in the Buccal Space. Reviewed International journal

    Tatsuo Okui, Soichiro Ibaragi, Hotaka Kawai, Akira Sasaki

    Case reports in medicine   2019   9459837 - 9459837   2019

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    A 39-year-old Japanese woman presented to the Department of Oral and Maxillofacial Surgery, Okayama University Hospital, with the complaint of a slowly growing buccal mass. The mass was well defined, had rounded margins, and was free from skin and muscles. A color Doppler echographic examination indicated high flow velocity of the blood surrounding the mass. Contrast-enhanced images on CT and contrast-enhanced T1-weighted images on MRI displayed a homogeneous enhanced mass with a well-defined margin. A fine-needle aspiration biopsy and histological examination were performed. On immunohistochemistry, spindle cells were strongly positive for CD34, STAT6, and vimentin and negative for EMA, S100, and α-SMA. The tumor was removed with extracapsular dissection. The tumor was composed of bland spindle cells proliferating in a patternless arrangement with a collagenous background. Most of the tumor mass consisted of hypocellular areas including ectatic blood vessels. A prominent branching vascular pattern was observed. Immunohistochemistry demonstrated that the tumor cells were positive for CD34, STAT6, vimentin, and Bcl-2, and negative for α-SMA, S100, and EMA. Three mitotic cells were observed per 10 high-power fields, and the Ki-67 index was 5.7%. The morphological and immunohistochemical features were consistent with a diagnosis of solitary fibrous tumor.

    DOI: 10.1155/2019/9459837

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  • Crosstalk Between Sensory Nerves and Cancer in Bone. Reviewed International journal

    Toshiyuki Yoneda, Masahiro Hiasa, Tatsuo Okui

    Current osteoporosis reports   16 ( 6 )   648 - 656   2018.12

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    PURPOSE OF REVIEW: Sensory nerves (SNs) richly innervate bone and are a component of bone microenvironment. Cancer metastasis in bone, which is under the control of the crosstalk with bone microenvironment, induces bone pain via excitation of SNs innervating bone. However, little is known whether excited SNs in turn affect bone metastasis. RECENT FINDINGS: Cancer cells colonizing bone promote neo-neurogenesis of SNs and excite SNs via activation of the acid-sensing nociceptors by creating pathological acidosis in bone, evoking bone pain. Denervation of SNs or inhibition of SN excitation decreases bone pain and cancer progression and increases survival in preclinical models. Importantly, patients with cancers with increased SN innervation complain of cancer pain and show poor outcome. SNs establish the crosstalk with cancer cells to contribute to bone pain and cancer progression in bone. Blockade of SN excitation may have not only analgesic effects on bone pain but also anti-cancer actions on bone metastases.

    DOI: 10.1007/s11914-018-0489-x

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  • Oral diverticulum. Reviewed

    Koichi Kadoya, Soichiro Ibaragi, Eri Tokunaga, Takayuki Kono, Tatsuo Okui, Akira Sasaki

    Journal of general and family medicine   19 ( 6 )   221 - 222   2018.11

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    Oral diverticulum .

    DOI: 10.1002/jgf2.205

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  • Lactate Transporter Monocarboxylate Transporter 4 Induces Bone Pain in Head and Neck Squamous Cell Carcinoma. Reviewed International journal

    Kazuaki Hasegawa, Tatsuo Okui, Tsuyoshi Shimo, Soichiro Ibaragi, Hotaka Kawai, Shoji Ryumon, Koji Kishimoto, Yuka Okusha, Nur Mohammad Monsur Hassan, Akira Sasaki

    International journal of molecular sciences   19 ( 11 )   2018.10

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    Head and neck squamous cell carcinoma (HNSCC) poses a significant challenge clinically, as it can invade facial bones and cause bone pain that is undertreated and poorly understood. Here we studied HNSCC bone pain (HNSCC-BP) in an intratibial mouse xenograft model that uses a human HNSCC cell line (SAS cells). These mice develop HNSCC-BP associated with an upregulation of phosphorylated ERK1/2 (pERK1/2), which is a molecular indicator of neuron excitation in the dorsal root ganglia (DRGs) of sensory nerve cell bodies. Our experiments demonstrated that the inhibition of monocarboxylate transporter 4 (MCT4) by short hairpin (shRNA) transduction suppressed the HNSCC-BP, the lactate level in bone marrow, and the pERK1/2 expression in DRG. The sensory nerves also expressed increased levels of the acid-sensing receptor TRPV1. DRG neurons co-cultured with SAS cells showed increased neurite outgrowth, and were inhibited by MCT4 silencing with shRNA. Collectively, our results show that HNSCC induced an acidic bone microenvironment that evokes HNSCC-BP via MCT4 expression.

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  • The intranuclear PEX domain of MMP involves proliferation, migration, and metastasis of aggressive adenocarcinoma cells. Reviewed International journal

    Yuka Okusha, Takanori Eguchi, Chiharu Sogawa, Tatsuo Okui, Keisuke Nakano, Kuniaki Okamoto, Ken-Ichi Kozaki

    Journal of cellular biochemistry   119 ( 9 )   7363 - 7376   2018.9

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    Members of matrix metalloproteinase (MMP) family promote cancer cell migration, invasion, and metastasis through alteration of the tumor milieu, intracellular signaling pathways, and transcription. We examined gene expression signatures of colon adenocarcinoma cell lines with different metastatic potentials and found that rapidly metastatic cells powerfully expressed genes encoding MMP3 and MMP9. The non-proteolytic PEX isoform and proteolytic isoforms of MMPs were significantly expressed in the metastatic cells in vitro. Knockdown of MMP3 attenuated cancer cell migration and invasion in vitro and lung metastasis in vivo. Profound nuclear localization of MMP3/PEX was found in tumor-stroma marginal area. In contrast, MMP9 was localized in central area of subcutaneous tumors. Overexpression of the PEX isoform of MMP3 promoted proliferation and migration of the rapidly metastatic cells in vitro. Taken together, the non-proteolytic PEX isoform of MMPs locating in cell nuclei involves proliferation, migration, and subsequent metastasis of aggressive adenocarcinoma cells.

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  • Ameloblastic fibro-odontoma in a nine-year-old boy Reviewed

    Tatsuo Okui, Soichiro Ibaragi, Tsuyoshi Shimo, Kiyofumi Takabatake, Mariko Fujita, Nur Mohammad Monsur Hassan, Akira Sasaki

    Stomatological Disease and Science   2 ( 7 )   1 - 5   2018.7

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  • Depletion of lipid efflux pump ABCG1 triggers the intracellular accumulation of extracellular vesicles and reduces aggregation and tumorigenesis of metastatic cancer cells Reviewed

    Matsumoto K, Shimo T, Kurio N, Okui T, Ibaragi S, Kunisada Y, Obata K, Masui M, Pai P, Horikiri Y, Yamanaka N, Takigawa M, Sasaki A

    Frontiers in Oncology   119 ( 6 )   4352 - 4360   2018.6

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  • Low-intensity pulsed ultrasound stimulation promotes osteoblast differentiation through hedgehog signaling. Reviewed International journal

    Kenichi Matsumoto, Tsuyoshi Shimo, Naito Kurio, Tatsuo Okui, Soichiro Ibaragi, Yuki Kunisada, Kyoichi Obata, Masanori Masui, Pang Pai, Yuu Horikiri, Nobuyuki Yamanaka, Masaharu Takigawa, Akira Sasaki

    Journal of cellular biochemistry   119 ( 6 )   4352 - 4360   2018.6

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    Low-intensity pulsed ultrasound (LIPUS) has been used as an adjunct to fracture healing therapies, but the mechanisms underlying its action are not known. We reported that sonic hedgehog (SHH) signaling was activated in osteoblasts at the dynamic remodeling site of a bone fracture. Mechanical stimulation is a crucial factor in bone remodeling, and it is related to the primary cilia as a sensor of hedgehog signaling. Here we observed that LIPUS promoted callus formation in accord with Gli2-positive cells after 14 days at the mouse femur fractured site compared with a control group. An immunofluorescence analysis showed that the numbers of primary cilia and cilia/osterix double-positive osteoblasts were increased at the fracture site by LIPUS. LIPUS stimulated not only the number and the length of primary cilia, but also the levels of ciliated protein, Ift88 mRNA, and SHH, Gli1, and Gli2 in MC3T3-E1 cells. Further experiments revealed that LIPUS stimulated osteogenic differentiation in the presence of smoothened agonist (SAG) treatment. These results indicate that LIPUS stimulates osteogenic differentiation and the maturation of osteoblasts by a primary cilium-mediated activation of hedgehog signaling.

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  • Basal cell adenoma arising in the minor salivary gland of the hard palate Reviewed

    Tatsuo Okui, Soichiro Ibaragi, Keisuke Nakano, Yukiko Fujii, Akira Sasaki

    Journal of Clinical and Diagnostic Research   12 ( 4 )   ZD04 - ZD05   2018.4

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    Basal Cell Adenoma (BCA) is an extremely rare benign salivary gland tumour that usually arises in the parotid gland. The incidence of BCA is 1%-3% of all salivary gland tumours. Here, we report an extremely rare case of BCA arising in the minor salivary gland of the hard palate of a young man.

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  • Ammonium tetrathiomolybdate enhances the antitumor effects of cetuximab via the suppression of osteoclastogenesis in head and neck squamous carcinoma. Reviewed International journal

    Ayaka Morisawa, Tatsuo Okui, Tsuyoshi Shimo, Soichiro Ibaragi, Yuka Okusha, Mitsuaki Ono, Thi Thu Ha Nguyen, Nur Mohammad Monsur Hassan, Akira Sasaki

    International journal of oncology   52 ( 3 )   989 - 999   2018.3

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    Head and neck squamous cell carcinoma (HNSCC) poses a significant challenge clinically where one of the mechanisms responsible for the invasion into facial bones occurs via the activation of osteoclasts. Copper has been demonstrated to play a key role in skeletal remodeling. However, the role of copper in cancer-associated bone destruction is thus far unknown. Lysyl oxidase (LOX) is a copper-dependent enzyme that promotes osteoclastogenesis. In the present study, we investigated the effects of copper on HNSCC with bone invasion by the copper chelator, ammonium tetrathiomolybdate (TM) in vitro and in vivo. We demonstrate that TM blocks the proliferation of HNSCC cells, inhibits LOX activation and decreases the expression of the receptor activator of nuclear factor-κB ligand (RANKL) in osteoblasts and osteocytes, subsequently suppressing bone destruction. These findings suggest that copper is a potential target for the treatment of HNSCCs associated with bone destruction.

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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 (p<0.001), 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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  • [Bone and calcium metabolism associated with malignancy. The interaction of bone pain and cancer progression.] Reviewed

    Okui T

    Clinical calcium   28 ( 11 )   1473 - 1478   2018

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  • Ameloblastic fibro-odontoma in a 9-year-old boy Reviewed

    Stomatological Disease and Science   2   7   2018

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  • Oral Squamous Cell Carcinoma-derived Sonic Hedgehog Promotes Angiogenesis Reviewed

    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   2017.12

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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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  • Maxillofacial Fractures in Elderly Patients Reviewed

    Hiroaki Takakura, Tsuyoshi Shimo, Norie Yoshioka, Mayumi Yao, Kyoichi Obata, Soichiro Ibaragi, Tatsuo Okui, Yuki Kunisada, Ayaka Morisawa, Akane Shibata, Shoko Yoshida, Yurika Murase, Koji Kishimoto, Akiyoshi Nishiyama, Hiroshi Mese, Akira Sasaki

    International Journal of Surgery & Surgical Procedures   2 ( 128 )   1 - 5   2017.11

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  • Role of Neurokinin 3 Receptor Signaling in Oral Squamous Cell Carcinoma Reviewed

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

    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 kappa beta ligand (RANKL) in osteoblasts, and this stimulated osteoclastgenesis. Furthermore, 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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  • Examination of Diseases Requiring Oral Surgery Treated via Medical-Dental Cooperation in the Department of Oral and Maxillofacial Surgery (Biopathology), Okayama University Hospital Reviewed

    Masanori Masui, Tsuyoshi Shimo, Norie Yoshioka, Soichiro Ibaragi, Tatsuo Okui, Yuki Kunisada, Mayumi Yao, Shoko Yoshida, Yurika Murase, Koji Kishimoto, Akiyoshi Nishiyama, Yoshihiko Soga, Akira Sasaki

    2 ( 115 )   1 - 7   2017.5

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  • Bone Pain Induced by Multiple Myeloma Is Reduced by Targeting V-ATPase and ASIC3 Reviewed

    Masahiro Hiasa, Tatsuo Okui, Yohance M. Allette, Matthew S. Ripsch, Ge-Hong Sun-Wada, Hiroki Wakabayashi, G. David Roodman, Fletcher A. White, Toshiyuki Yoneda

    CANCER RESEARCH   77 ( 6 )   1283 - 1295   2017.3

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    Multiple myeloma patients experience severe bone pain (MMBP) that is undertreated and poorly understood. In this study, we studied MMBP in an intratibial mouse xenograft model that employs JJN3 human multiple myeloma cells. In this model, mice develop MMBP associated in bone with increased sprouting of calcitonin gene-related peptide-positive (CGRP(+)) sensory nerves and in dorsal root ganglia (DRG) with upregulation of phosphorylated ERK1/2 (pERK1/2) and pCREB, two molecular indicators of neuron excitation. We found that JJN3 cells expressed a vacuolar proton pump (V-ATPase) that induced an acidic bone microenvironment. Inhibition of JJN3-colonized bone acidification by a single injection of the selective V-ATPase inhibitor, bafilomycin A1, decreased MMBP, CGRP(+) sensory neuron sprouting, and pERK1/2 and pCREB expression in DRG. CGRP(+) sensory nerves also expressed increased levels of the acid-sensing nociceptor ASIC3. Notably, a single injection of the selective ASIC3 antagonist APETx2 dramatically reduced MMBP in the model. Mechanistic investigations in primary DRG neurons cocultured with JJN3 cells showed increased neurite outgrowth and excitation inhibited by bafilomycin A1 or APETx2. Furthermore, combining APETx2 with bafilomycin A1 reduced MMBP to a greater extent than either agent alone. Finally, combining bafilomycin A1 with the osteoclast inhibitor zoledronic acid was sufficient to ameliorate MMBP, which was refractory to zoledronic acid. Overall, our results show that osteoclasts and multiple myeloma cooperate to induce an acidic bone microenvironment that evokes MMBP as a result of the excitation of ASIC3-activated sensory neurons. Furthermore, they present a mechanistic rationale for targeting ASIC3 on neurons along with the multiple myeloma-induced acidic bone microenvironment as a strategy to relieve MMBP in patients. (C)2017 AACR.

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  • Orthognathic surgery during breast cancer treatment-A case report. Reviewed International journal

    Tsuyoshi Shimo, Norie Yoshioka, Masahiro Nakamura, Soichiro Ibaragi, Tatsuo Okui, Yuki Kunisada, Masanori Masui, Mayumi Yao, Koji Kishimoto, Shoko Yoshida, Akiyoshi Nishiyama, Hiroshi Kamioka, Akira Sasaki

    International journal of surgery case reports   31   30 - 34   2017

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    INTRODUCTION: In recent years, patients with orthognathic surgery in middle-aged and elderly people have come to be a more frequent occurrence. Breast cancer is the most frequently diagnosed cancer in woman worldwide, and its prevalence rate is steadily increasing. PRESENTATION OF CASE: We report a case of a 47-year-old Japanese woman in whom left-side breast cancer (Stage 1) was unexpectedly found just before orthognathic surgery in April 2012. Breast-conserving surgery was performed (estrogen receptor+, progesterone receptor+, HER2 -, surgical margin+, sentinel lymph node +) that May. From June to August docetaxel (75mg/m2) and cyclophosphamide (600mg/m2) were administrated four times every 21days and thereafter radiotherapy (total 60Gy) was completed. The cancer surgeon declared the prognosis good and the patient had a strong desire to undergo orthognathic surgery, so in November we performed a bimaxillary osteotomy, and administration of tamoxifen began 6 weeks after the osteotomy. DISCUSSION: There are breast cancer cases in which the prognosis is sufficiently good for a planned orthognathic surgery to proceed. Good communication among surgeons and the patient is important. CONCLUSION: We experienced a case in which breast cancer was found just before the orthognathic surgery; we performed a bimaxillary osteotomy, including follow-up tamoxifen administration, during breast cancer treatment.

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  • Tachykinin Receptor 3 Distribution in Human Oral Squamous Cell Carcinoma Reviewed

    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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  • Novel Midkine Inhibitor iMDK Inhibits Tumor Growth and Angiogenesis in Oral Squamous Cell Carcinoma Reviewed

    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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  • Synthetic Terrein Inhibits Progression of Head and Neck Cancer by Suppressing Angiogenin Production Reviewed

    Akane Shibata, Soichiro Ibaragi, Hiroki Mandai, Toki Tsumura, Koji Kishimoto, Tatsuo Okui, Nur Mohammad Monsur Hassan, Tsuyoshi Shimo, Kazuhiro Omori, Guo-Fu Hu, Shogo Takashiba, Seiji Suga, Akira Sasaki

    ANTICANCER RESEARCH   36 ( 5 )   2161 - 2168   2016.5

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    Background/Aim: Head and neck cancers are the fifth most common cancer type worldwide, affecting more than half a million patients annually. Development of effective therapeutic drugs is, therefore, required for this type of disease. This study assessed the effects of synthetic terrein on head and neck cancer. Materials and Methods: Synthetic terrein was prepared by using the modified Altenhach's procedure. The effect of synthetic terrein on cell proliferation of head and neck cancer cells and HUVECs was assessed. Angiogenin secretion and ribosome biogenesis were examined by ELISA and silver staining of the nucleolar organizer region. A mouse xenograft model was prepared by inoculating mice with suspensions of cells of the human head and neck cancer cell line OSC-19 subcutaneously into the dorsal region of each mouse. Ki-67, CD31 and angiogenin expression in xenografted tumors was examined by immunohistochemistry. Results: Synthetic terrein inhibited the growth of various head and neck cancer cells. In addition, an in vivo experiment revealed that synthetic terrein inhibited a xenograft tumor growth in athymic mice. Immunohistochemical analysis revealed that expression of Ki-67, CD31 and ANG was down-regulated in synthetic terrein-treated tumors, compared to controls. Synthetic terrein suppressed the ANG secretion and ribosome biogenesis in cancer cells, and cell proliferation in vascular endothelial cells. Conclusion: The mechanism underlying the anti-tumor effects of synthetic terrein against head and neck cancer consists of the inhibition of both tumor cell proliferation and angiogenesis via the suppression of ANG production.

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  • Expression and Role of Sonic Hedgehog in the Process of Fracture Healing with Aging Reviewed

    Kenichi Matsumoto, Tsuyoshi Shimo, Naito Kurio, Tatsuo Okui, Kyoichi Obata, Masanori Masui, Pai Pang, Yuu Horikiri, Akira Sasaki

    IN VIVO   30 ( 2 )   99 - 105   2016.3

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    Aging is one of the risk factors for delayed fracture healing. Sonic hedgehog (SHH) protein, an inducer of embryonic development, has been demonstrated to be activated in osteoblasts at the dynamic remodeling site of a bone fracture. Herein, we compared and examined the distribution patterns of SHH and the functional effect of SHH signaling on osteogenesis and osteoclastogenesis between young (5-week-old) and aged (60-week-old) mice during fracture healing. We found that SHH was expressed in bone marrow cells from the fractured site of the rib of young mice on day 5, but was barely detectable in the corresponding cells from the rib of aged mice. SHH was also detected in osteoblasts and bone marrow cells at the callus remodeling stage on days 14 and 28 in both young and aged mice. The number of alkaline phosphatase (ALP)-positive osteoblasts was significantly higher in young mice on days 5 and 14, whereas the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts was significantly higher in aged mice. SHH stimulated significantly more osteoblast formation in the young compared to old mice. SHH stimulated the osteoclast formation directly in the aged mice and suppressed the formation indirectly through osteoprotegerin expression in the young mice. Results indicate that an aged-related delay of fracture healing may contribute to the unbalanced bone formation and resorption, regulated by hedgehog signaling.

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  • The Role of Sonic Hedgehog Signaling in Osteoclastogenesis and Jaw Bone Destruction Reviewed

    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-kappa B 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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  • SOX2 suppresses CDKN1A to sustain growth of lung squamous cell carcinoma Reviewed

    Takuya Fukazawa, Minzhe Guo, Naomasa Ishida, Tomoki Yamatsuji, Munenori Takaoka, Etsuko Yokota, Minoru Haisa, Noriko Miyake, Tomoko Ikeda, Tatsuo Okui, Nagio Takigawa, Yutaka Maeda, Yoshio Naomoto

    SCIENTIFIC REPORTS   6   20113   2016.2

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    Since the SOX2 amplification was identified in lung squamous cell carcinoma (lung SCC), SOX2 transcriptional downstream targets have been actively investigated; however, such targets are often cell line specific. Here, in order to identify highly consensus SOX2 downstream genes in lung SCC cells, we used RNA-seq data from 178 lung SCC specimens (containing tumor and tumor-associated cells) and analyzed the correlation between SOX2 and previously-reported SOX2-controlled genes in lung SCC. In addition, we used another RNA-seq dataset from 105 non-small cell lung cancer cell lines (NSCLC; including 4 lung SCC cell lines) and again analyzed the correlation between SOX2 and the reported SOX2-controlled genes in the NSCLC cell lines (no tumor-associated cells). We combined the two analyses and identified genes commonly correlated with SOX2 in both datasets. Among the 99 genes reported as SOX2 downstream and/or correlated genes, we found 4 negatively-correlated (e.g., CDKN1A) and 11 positively-correlated genes with SOX2. We used biological studies to demonstrate that CDKN1A was suppressed by SOX2 in lung SCC cells. G1 cell cycle arrest induced by SOX2 siRNA was rescued by CDKN1A siRNA. These results indicate that the tumorigenic effect of SOX2 in lung SCC cells is mediated in part by suppression of CDKN1A.

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  • Detection of sonic hedgehog in patients undergoing orthognathic surgery Reviewed

    Yuki Kunisada, Tsuyoshi Shimo, Masanori Masui, Norie Yoshioka, Soichiro Ibaragi, Kenichi Matsumoto, Tatsuo Okui, Naito Kurio, Shohei Domae, Koji Kishimoto, Akiyoshi Nishiyama, Akira Sasaki

    International Journal of Surgery Open   5   1 - 4   2016

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    Purpose Sonic Hedgehog (SHH) is a regulatory protein involved in bone fracture healing. Orthognathic surgery involves surgical osteotomy of the mandible or maxilla to restore the proper anatomic and functional position in patients with dentofacial deformity. The purpose of this study was to analyze SHH local blood serum concentrations after osteotomy to gain further understanding of the molecular regulation of the initial stage of osteotomy healing. Methods Serum samples (local drainage and peripheral venous) of 34 patients (24 females and 10 males, mean age was 23.4 (16–42) years) who underwent orthognathic surgery were isolated from patients at different time points during the perioperative period. The levels of SHH, soluble receptor activator of nuclear factor-κB ligand (sRANKL) and osteoprotegerin (OPG) were measured using ELISA. Results SHH was detected in the local drainage immediately after osteotomy (309.5 ± 58.2 pg/ml), and decreased for 2 days after the operation (197.5 ± 43.6 pg/ml). The sRANKL local serum concentrations were at the maximum level immediately after the operation (141.4 ± 22.6 pg/ml) and decreased for 2 days (110.1 ± 23.4 pg/ml). On the other hand, the OPG concentration in the local serum was at a minimum after osteotomy (59.4 ± 4.6 pg/ml) and reached its maximum (181.5 ± 17.8 pg/ml, P &lt
     0.01) at 2 days after osteotomy. SHH and OPG local serum levels on day 2 were associated with the amount of bleeding during the operation. The local drainage serum level of SHH of maxillary/mandibular osteotomy had a tendency to be higher than that of mandible-only osteotomy at 2 days after operation. Conclusions Elevated levels of SHH in local serum after osteotomy, especially during the initial stage of healing, indicates its importance in osteotomy healing.

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  • Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain. Reviewed

    Yoneda T, Hiasa M, Nagata Y, Okui T, White F

    Biochimica et biophysica acta   1848 ( 10 Pt B )   2677 - 2684   2015.10

  • Familial adenoid cystic carcinoma of sublingual salivary glands Reviewed

    Norie Yoshioka, Hiroshi Mese, Tatsuo Okui, Soichiro Ibaragi, Akira Sasaki

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   27 ( 3 )   353 - 356   2015.5

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    Tumors of the sublingual salivary gland are extremely rare. Most of the sublingual tumors are malignant, adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma being the most common histological types. Here we report the first case of a familial occurrence of ACC in a family in which the father and daughter were treated for ACC of the sublingual salivary gland. A 75-year-old man was referred with a swelling of the floor of the mouth on his right side and diagnosed as ACC of sublingual salivary gland synchronous with adenocarcinoma of the lung. One year later, his daughter presented, at the age of 46 years, with a swelling of the floor of the mouth on her right side, which was also diagnosed as ACC. This is the first case of familial recurring ACC of sublingual salivary gland worldwide.

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  • Expression and Roles of CCN2 in Dental Epithelial Cells Reviewed

    Tsuyoshi Shimo, Eiki Koyama, Naito Kurio, Kenichi Matsumoto, Tatsuo Okui, Soichiro Ibaragi, Norie Yoshioka, Akira Sasaki

    IN VIVO   29 ( 2 )   189 - 195   2015.3

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    Connective tissue growth factor (CCN2) regulates diverse cellular functions, including tooth development. In order to delineate the precise role of CCN2 in the epithelium during odontogenesis, we investigated how it is expressed and what roles it may have in primary cultures of epithelial cells derived from developing tooth germ of the bovine fetus. Ccn2 mRNA and protein were strongly expressed in the inner dental epithelium, which is consistent with the expression of transforming growth factor-beta 2 mRNA and proliferating cell nuclear antigen. Bone morphogenetic protein 4 (BMP4) and fibroblast growth factor 2 (FGF2) were also expressed in the inner dental epithelium, indicating that CCN2 functionally interacts with these factors in the epithelium. The stimulatory effects of FGF2 on cell proliferation and BMP4 on cell differentiation were additively up-regulated by CCN2 in a newly-established dental epithelium cell culture. Taken together, our data provide clear evidence that CCN2 is synthesized by inner dental epithelial cells, and appears to act as an autocrine factor, which regulates dental epithelial cell proliferation and differentiation in concert with growth factors.

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  • Acidic microenvironment and bone pain in cancer-colonized bone. Reviewed

    Yoneda T, Hiasa M, Nagata Y, Okui T, White FA

    BoneKEy reports   4   690   2015

  • 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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  • Sonic Hedgehog Regulates Osteoblast Function by Focal Adhesion Kinase Signaling in the Process of Fracture Healing Reviewed

    Yuu Horikiri, Tsuyoshi Shimo, Naito Kurio, Tatsuo Okui, Kenichi Matsumoto, Masahiro Iwamoto, Akira Sasaki

    PLOS ONE   8 ( 10 )   e76785   2013.10

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    Several biological studies have indicated that hedgehog signaling plays an important role in osteoblast proliferation and differentiation, and sonic hedgehog (SHH) expression is positively correlated with phosphorylated focal adhesion kinase (FAK) Tyr(397). However, the relationship between them and their role in the process of normal fracture repair has not been clarified yet. Immunohistochemical analysis revealed that SHH and pFAK Tyr(397) were expressed in bone marrow cells and that pFAK Tyr(397) was also detected in ALP-positive osteoblasts near the TRAP-positive osteoclasts in the fracture site in the ribs of mice on day 5 after fracture. SHH and pFAK Tyr(397) were detectable in osteoblasts near the hypertrophic chondrocytes on day 14. In vitro analysis showed that SHH up-regulated the expression of FAK mRNA and pFAK Tyr(397) time dependently in osteoblastic MC3T3-E1 cells. Functional analysis revealed that 5 lentivirus encoding short hairpin FAK RNAs (shFAK)-infected MC3T3-E1 cell groups displayed a round morphology and decreased proliferation, adhesion, migration, and differentiation. SHH stimulated the proliferation and differentiation of MC3T3-E1 cells, but had no effect on the shFAK-infected cells. SHH also stimulated osteoclast formation in a co-culture system containing MC3T3-E1 and murine CD11b(+) bone marrow cells, but did not affect the shFAK-infected MC3T3-E1 co-culture group. These data suggest that SHH signaling was activated in osteoblasts at the dynamic remodeling site of a bone fracture and regulated their proliferation and differentiation, as well as osteoclast formation, via FAK signaling.

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  • Inhibition of the Growth Factor MDK/Midkine by a Novel Small Molecule Compound to Treat Non-Small Cell Lung Cancer Reviewed

    Huifang Hao, Yutaka Maeda, Takuya Fukazawa, Tomoki Yamatsuji, Munenori Takaoka, Xiao-Hong Bao, Junji Matsuoka, Tatsuo Okui, Tsuyoshi Shimo, Nagio Takigawa, Yasuko Tomono, Motowo Nakajima, Iris M. Fink-Baldauf, Sandra Nelson, William Seibel, Ruben Papoian, Jeffrey A. Whitsett, Yoshio Naomoto

    PLOS ONE   8 ( 8 )   e71093   2013.8

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    Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, in turn enhancing the survival of tumors. Therefore, the inhibition of MDK is considered a potential strategy for cancer therapy. In the present study, we demonstrate a novel small molecule compound (iMDK) that targets MDK. iMDK inhibited the cell growth of MDK-positive H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells, both of which are types of untreatable lung cancer. However, iMDK did not reduce the cell viability of MDK-negative A549 lung adenocarcinoma cells or normal human lung fibroblast (NHLF) cells indicating its specificity. iMDK suppressed the endogenous expression of MDK but not that of other growth factors such as PTN or VEGF. iMDK suppressed the growth of H441 cells by inhibiting the PI3K pathway and inducing apoptosis. Systemic administration of iMDK significantly inhibited tumor growth in a xenograft mouse model in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of lung cancers that are driven by MDK.

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  • Novel HSP90 inhibitor NVP-AUY922 enhances the anti-tumor effect of temsirolimus against oral squamous cell carcinoma. Reviewed International journal

    Tatsuo Okui, Tsuyoshi Shimo, Takuya Fukazawa, Nur Mohammad Monsur Hassan, Tatsuki Honami, Soichiro Ibaragi, Munenori Takaoka, Yoshio Naomoto, Akira Sasaki

    Current cancer drug targets   13 ( 3 )   289 - 99   2013.3

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    BACKGROUND AND AIM: Heat shock protein 90 (HSP90) and mammalian target of rapamycin (mTOR) are involved in the molecular pathogenesis of advanced oral squamous cell carcinoma. HSP90 inhibitors are capable of effectively interfering with multiple signaling pathways, including the mTOR signaling pathway. However, the combined effects of HSP90 and mTOR inhibitors on oral squamous cell carcinoma are still unknown. In this study, we investigated the dual treatment of the novel HSP90 inhibitor NVP-AUY922 and temsirolimus against oral squamous cell carcinoma. MATERIALS AND METHODS: The effect of the combination of NVP-AUY922 and temsirolimus on oral squamous cell carcinoma in vitro and in vivo was determined by MTS assay and mouse xenograft models. The effect of the combination on angiogenesis was determined by tube formation assay and angioreactor. RESULTS: The combination treatment of NVP-AUY922 and temsirolimus significantly inhibited the proliferation of SAS oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. We have clearly shown that the combination treatment of NVP-AUY922 and temsirolimus inhibited vascular formation both in vitro and in vivo. Moreover, the combination treatment of NVP-AUY922 and temsirolimus prolonged the survival rate in mice xenografted with oral squamous cell carcinoma. CONCLUSIONS: Here, we showed the activity of a combination of mTOR and HSP90 inhibitors for the treatment of advanced oral squamous carcinoma.

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  • Hypoxia-induced up-regulation of angiogenin, besides VEGF, is related to progression of oral cancer Reviewed

    Koji Kishimoto, Shoko Yoshida, Soichiro Ibaragi, Norie Yoshioka, Tatsuo Okui, Guo-fu Hu, Akira Sasaki

    ORAL ONCOLOGY   48 ( 11 )   1120 - 1127   2012.11

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    Objectives: Angiogenin (ANG) is a prominent angiogenic factor that has been shown to have a dual effect on tumor progression by inducing both angiogenesis and cancer cell proliferation through stimulating ribosomal RNA transcription in both endothelial cells and cancer cells. In the present study, we investigated the expression profiles of ANG and vascular endothelial growth factor (VEGF) in oral cancer and their correlation with hypoxia and evaluated the possible value of ANG as a therapeutic target for oral cancer.
    Materials and Methods: Immunohistochemistry (IHC), ELISA, real-time RT-PCR and Western blotting were used to examine the expression of ANG, VEGF, and hypoxia-inducible factor 1 alpha (HIF-1 alpha) in oral squamous cell carcinoma (OSCC) specimens and human OSCC cell lines. In order to examine the role of ANG, we knocked down ANG expression in HSC-2 cells by means of plasmid-mediated RNA interference.
    Results: IHC showed that the expression of ANG was significantly correlated with that of HIF-1 alpha in 50 OSCC specimens (P = 0.031). However, no significant correlation between VEGF and HIF-1 alpha expression was found (P = 0.243). Consistently, ANG secretion increased under hypoxia in all of the 10 OSCC cell lines tested; and a significant increase was observed in 6 of them. In contrast, there was no noticeable increase in VEGF secretion under hypoxia in any of these cell lines. In HSC-2 and SAS OSCC cells, the increase in ANG mRNA expression correlated very well with that of HIF-1 alpha protein expression after hypoxia onset. However, no noticeable increase in VEGF mRNA expression was observed even after 12 h of hypoxia. Down-regulation of ANG expression in HSC-2 cells highly expressing and secreting VEGF inhibited ribosome biogenesis, cell proliferation, tumor angiogenesis, and xenograft growth in athymic mice.
    Conclusion: These results suggest that ANG is up-regulated in the hypoxic environment of oral cancers and that its inhibition can have a therapeutic implication. (C) 2012 Elsevier Ltd. All rights reserved.

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  • Anti-tumor effect of a novel FAK inhibitor TAE226 against human oral squamous cell carcinoma Reviewed

    Naito Kurio, Tsuyoshi Shimo, Takuya Fukazawa, Tatsuo Okui, Nur Mohammad Monsur Hassan, Tatsuki Honami, Yuu Horikiri, Shinji Hatakeyama, Munenori Takaoka, Yoshio Naomoto, Akira Sasaki

    ORAL ONCOLOGY   48 ( 11 )   1159 - 1170   2012.11

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    Objectives: Focal adhesion kinase (FAK) overexpression is frequently found in invasive and metastatic cancers, but its role in oral squamous cell carcinoma is not yet well understood. In order to seek therapies targeting oral squamous cell carcinoma, we developed the novel FAK Tyr(397) inhibitor TAE226 and investigated its anti-tumor effects and mechanisms.
    Materials and Methods: Expression of phosphorylated FAK Tyr(397) was examined by immunohistochemical and immunoblot analysis. The effect of TAE226 on in vitro and in vivo studies were confirmed by proliferation, cell cycle, apoptosis and angiogenesis analysis.
    Results: We found that phosphorylated FAK was highly expressed in human tongue oral squamous cell carcinoma in patients. Importantly, TAE226 greatly suppressed the proliferation, migration and invasion of human oral squamous cell carcinoma SAS cells with an apparent structural change of actin fiber and a loss of cell adhesion. In addition, TAE226 inhibited the expression of phospho-FAK Tyr(397) and phospho AKT Ser(473), resulting in caspase-mediated apoptosis. Furthermore, oral administration of TAE226 in mice suppressed the growth and angiogenesis of oral squamous cell carcinoma xenografts in vivo.
    Conclusions: Our results provide compelling evidence that FAK is critically involved in oral squamous cell carcinoma and that the FAK inhibitor TAE226 can potentially be effectively used for the treatment of oral squamous cell carcinoma. (C) 2012 Elsevier Ltd. All rights reserved.

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  • Sonic hedgehog signaling promotes growth of oral squamous cell carcinoma cells associated with bone destruction Reviewed

    Tatsuki Honami, Tsuyoshi Shimo, Tatsuo Okui, Naito Kurio, Nur Mohammad Monsur Hassan, Masahiro Iwamoto, Akira Sasaki

    ORAL ONCOLOGY   48 ( 1 )   49 - 55   2012.1

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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, which frequently invade the maxilla or the mandible, is still unclear. In this study we show that the use of siRNA for Shh to block SHH secreted by SAS oral squamous cell carcinoma cells suppressed the tumor growth and tumor angiogenesis of subcutaneous SAS xenografts in vivo. Moreover, blockade of Shh in SAS cells decreased tumor growth and osteoclast number in a tibial metaphysis mouse model. Significantly, we clearly show that SHH stimulated osteoclast formation in a co-culture system consisting of murine bone stromal ST2 cells and murine CD11b(+) bone marrow cells. These findings suggest that Shh signaling is a potential target for the treatment of oral squamous cell carcinoma associated with bone destruction. (C) 2011 Elsevier Ltd. All rights reserved.

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  • Novel pathogenic role of fibrin as revealed by a case study on ligneous gingivitis Reviewed

    Tsuyoshi Shimo, Akiyoshi Nishiyama, Satoshi Kubota, Naito Kurio, Tatsuo Okui, Naoki Katase, Nur Mohammad Monsur Hassan, Tatsuki Honami, Koji Kishimoto, Hiroshi Mese, Masaharu Takigawa, Akira Sasaki

    Oral Science International   8 ( 2 )   44 - 49   2011.11

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    Purpose of the research: Ligneous gingivitis is a rare disease characterized by nodular gingival enlargement secondary to fibrin deposits induced by micro-injury in the gingiva, which disorder results from plasminogen (PLG) deficiency. Although none have investigated the association of wound healing factors with ligneous gingivitis. In this study, in addition to a histopathologic examination of ligneous gingivitis in a case of type I PLG deficiency, we further present data showing the effect of wound healing factors in association with fibrin in vitro to clarify the pathobiology of ligneous gingivitis in PLG-deficient patients. Principle results: Immunohistochemical analysis revealed that transforming growth factor (TGF)-β1, connective tissue growth factor/CCN2 (CCN2), and endothelin-1 (ET-1) had accumulated in the extracellular matrix around the epithelial and fibroblastic cells near the fibrin deposition. Consistent with these results, fibrin and TGF-β1 synergistically up-regulated CCN2 and ET-1 gene expression in human dermal fibroblasts. Major conclusions: Fibrin plays a vicious role in ligneous gingivitis pathobiology by up-regulating CCN2 and ET-1 expression through the TGF-β signaling pathway. © 2011 Japanese Stomatological Society.

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  • Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAX and IGF-IR in vitro and in vivo Reviewed

    Naito Kurio, Tsuyoshi Shimo, Takuya Fukazawa, Munenori Takaoka, Tatsuo Okui, Nur Mohammad Monsur Hassan, Tatsuki Honami, Shinji Hatakeyama, Masahiko Ikeda, Yoshio Naomoto, Akira Sasaki

    EXPERIMENTAL CELL RESEARCH   317 ( 8 )   1134 - 1146   2011.5

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    Focal adhesion kinase (FAR) is a 125-kDa non-receptor type tyrosine kinase that localizes to focal adhesions. FAR overexpression is frequently found in invasive and metastatic cancers of the breast. colon, thyroid, and prostate, but its role in osteolytic metastasis is not well understood. In this study, we have analyzed anti-tumor effects of the novel FAR Tyr(397) inhibitor TAE226 against bone metastasis in breast cancer by using TAE226. Oral administration of TAE226 in mice significantly decreased bone metastasis and osteoclasts involved which were induced by MDA-MB-231 breast cancer cells and increased the survival rate of the mouse models of bone metastasis. TAE226 also suppressed the growth of subcutaneous tumors in vivo and the proliferation and migration of MDA-MB-231 cells in vitro. Significantly, TAE226 inhibited the osteoclast formation in murine pre-osteoclastic RAW264.7 cells, and actin ring and pit formation in mature osteoclasts. Moreover, TAE226 inhibited the receptor activator for nuclear factor kappa B Ligand (RANKL) gene expression induced by parathyroid hormone-related protein (PTHrP) in bone stromal ST2 cells and blood free calcium concentration induced by PTHrP administration in vivo. These findings suggest that FAR was critically involved in osteolytic metastasis and activated in tumors, pre-osteoclasts, mature osteoclasts, and bone stromal cells and TAE226 can be effectively used for the treatment of cancer induced bone metastasis and other bone diseases. (C) 2011 Elsevier Inc. All rights reserved.

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  • Antitumor Effect of Novel HSP90 Inhibitor NVP-AUY922 against Oral Squamous Cell Carcinoma Reviewed

    Tatsuo Okui, Tsuyoshi Shimo, Nur Mohammad Monsur Hassan, Takuya Fukazawa, Naito Kurio, Munenori Takaoka, Yoshio Naomoto, Akira Sasaki

    ANTICANCER RESEARCH   31 ( 4 )   1197 - 1204   2011.4

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    Heat-shock protein 90 (HSP90) is a major cellular chaperone protein. HSP90 supports the correct conformation, stabilization, activation, and localization of &apos;client&apos; oncoproteins, many of which are involved in tumor progression. Therefore, the use of HSP90 inhibitors has become a new strategy in antitumor therapy. However, the effects of an HSP90 inhibitor on oral squamous cell carcinoma are still unclear. NVP-AUY922 (Novartis) is a novel 4,5-diaryloxazole adenosine triphosphate-binding site HSP90 inhibitor. In this study, we investigated the antitumor effect of novel HSP90 inhibitor NVP-AUY922 against oral squamous cell carcinoma. NVP-AUY922 inhibited the proliferation of oral squamous cell carcinoma cells in vitro. NVP-AUY922 caused degradation of client protein inducing ErbB2, p-Akt, p-S6, hypoxia-inducible factor 1-alpha (HIF1-alpha) and vascular endothelial growth factor (VEGF) and up-regulation of HSP70 in HSC-2 oral squamous cell carcinoma. NVP-AUY922 increased the expression of cleaved caspase-3 and induced apoptosis in HSC-2 cells. Treatment of NVP-AUY922 induced a robust antitumor response and suppressed p-Akt and VEGF expression in an HSC-2 xenograft model. In summary, NVP-AUY922 exhibits in vitro and in vivo efficiency against oral squamous cell carcinoma, representing a promising therapeutic approach for oral squamous cell carcinoma.

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  • Antitumor Effect of Temsirolimus against Oral Squamous Cell Carcinoma Associated with Bone Destruction Reviewed

    Tatsuo Okui, Tsuyoshi Shimo, Takuya Fukazawa, Naito Kurio, Nur Mohammad Monsur Hassan, Tatsuki Honami, Munenori Takaoka, Yoshio Naomoto, Akira Sasaki

    MOLECULAR CANCER THERAPEUTICS   9 ( 11 )   2960 - 2969   2010.11

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    The mammalian target of rapamycin (mTOR) is engaged in the molecular pathogenesis of oral squamous cell carcinoma, which frequently invades the maxilla or the mandible. However, the effects of a mTOR inhibitor on bone destruction associated with oral squamous cell carcinoma are still unclear. In this study, we investigated the antitumor effect of temsirolimus-mediated mTOR inhibition against advanced oral squamous cell carcinoma. Temsirolimus inhibited the proliferation and migration of HSC-2 oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. Significantly, we clearly show that temsirolimus inhibited osteoclast formation both in vitro and in vivo. Reverse transcriptase-PCR analysis showed that temsirolimus decreased the mRNA expression of receptor activator for nuclear factor-kappa B ligand, known as an osteoclast differentiation factor in bone stromal ST2 cells. Moreover, temsirolimus normalized blood-free calcium concentration in mouse models for humoral hypercalcemia. These findings suggest that mTOR signaling is a potential target of oral squamous cell carcinoma associated with bone destruction, and hence we describe the efficacy of temsirolimus for the treatment of advanced oral squamous carcinoma. Mol Cancer Ther; 9(11); 2960-9. (C) 2010 AACR.

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  • PTHrP Regulates Angiogenesis and Bone Resorption via VEGF Expression Reviewed

    Sachiko Isowa, Tsuyoshi Shimo, Soichiro Ibaragi, Naito Kurio, Tatsuo Okui, Kiminori Matsubara, Nur Mohammad Monsur Hassan, Koji Kishimoto, Akira Sasaki

    ANTICANCER RESEARCH   30 ( 7 )   2755 - 2767   2010.7

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    Background: Parathyroid hormone-related protein (PTHrP) is a key regulator of osteolytic metastasis of breast cancer (BC) cells, but its targets and mechanisms of action are not fully understood. This study investigated whether/how PTHrP (1-34) signaling regulates expression of vascular endothelial growth factor (VEGF) produced by BC cells. Materials and Methods: A mouse model of bone metastasis was prepared by inoculating mice with tumour cell suspensions of the human BC cell line MDA-MB-231 via the left cardiac ventricle. VEGF expression was examined by Western blot and real-time RT-PCR analysis, as well as by confocal microscopy in the bone microenviromnent. Results: PTHrP was expressed in cancer cells producing PTH/PTHrP receptor and VEGF that had invaded the bone marrow, and PTHrP was up-regulated VEGF in MDA-MB-231 in vitro. The culture medium conditioned by PTHrP-treated MDA-MB-231 cells stimulated angiogenesi.s- and osteoclastogenesis compared with control medium, giving a response that was inhibited by VEGF-neutralizing antibody treatment. Inhibition of protein kinase C (PKC) prevented PTHrP-induced extracelhdar signal-regulated kinase (ERK1/2) and p38 activation, and PTHrP-induced VEGF expression. Conclusion: PTHrP plays an important role in modulating the angiogenic and bone osteolytic actions of VEGF through PKC-dependent activation of an ERK1/2 and p38 signaling pathway during bone metastasis by breast cancer cells.

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  • Bone Destruction by Invading Oral Squamous Carcinoma Cells Mediated by the Transforming Growth Factor-beta Signalling Pathway Reviewed

    Takeshi Goda, Tsuyoshi Shimo, Yasuto Yoshihama, Nur Mohammad Monsur Hassan, Soichiro Ibaragi, Naito Kurio, Tatsuo Okui, Tatsuki Honami, Koji Kishimoto, Akira Sasaki

    ANTICANCER RESEARCH   30 ( 7 )   2615 - 2623   2010.7

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    Background: Gingival squamous cell carcinoma (SCC) cells frequently invade mandibular bone, and this destruction is associated with a worse prognosis. However, the relationship between bone destruction and associated factors is unclear. In this study, the role and diagnostic utility of transforming growth factor-beta (TGF-beta) type I receptor (T beta RI) in bone destruction of the mandible was investigated. Patients and Methods: The expression of T beta RI was explored by using an immunohistochemical method on paraffin-embedded tissues from 21 cases of mandibular SCC. An inhibitor of the kinase activity of the T beta RI (T beta RI-I) was used to assess the role of T beta RI in bone destruction by a human oral SCC cell line (HSC-2) that highly expresses,T beta RI. Results: T beta RI-positive signals were closely associated with destructive invasion of the mandible by oral SCC cells. Consistent with these results, T beta RI-I greatly reduced HSC-2 cell-induced bone destruction and osteoclast formation in vivo and in vitro. T beta RI-I treatment reduced the expression of TNF-alpha, RANKL and connective tissue growth factor (CTGF/CCN2), all of which were up-regulated by TGF-beta in HSC-2 cells. Conclusion: These data demonstrated an important role for TGF-beta signalling in bone invasion by oral SCC cells, and suggest that the bone destruction is mediated by RANKL, TNF-alpha and CCN2.

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  • Sonic Hedgehog Positively Regulates Odontblast Differentiation by a BMP2/4 dependent mechanism

    Shimo T, Koyama E, kanyama M, Kurio N, Okui T, Yamamoto D, Hassan NMM, Sasaki A

    J Oral Tissue Engineering   7   26 - 37   2009

  • Possible Involvement of p38 MAP Kinase in Retinoidstimulated Expression of Indian Hedgehog in Prehypertrophic Chondrocytes Reviewed

    Tsuyoshi Shimo, Eiki Koyama, Soichiro Ibaragi, Naito Kurio, Daisuke Yamamoto, Tatsuo Okui, Koji Kishimoto, Hiroshi Mese, Akira Sasaki

    Oral Science International   5 ( 1 )   1 - 14   2008

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    The mandibular condyle formation during temporomandibular joint (TMJ) development exhibits endochondral bone formation, and the elongation process is dependent on the normal cartilage proliferation and differentiation. Retinoids are important for maturation of growth-plate chondrocytes, but the identity of their downstream effectors remains unclear. In this study, we carried out a series of studies at the cellular, biochemical, and molecular levels to determine whether, and if so how, retinoid signaling is related to the expression and function of Indian hedgehog (Ihh) in chondrocyte proliferation. First we analyzed the RA receptor (RAR) and Ihh expression pattern in E18 mandibular condyle. RAR α and RAR β mRNA were characterized in the per-ichondrium around the condyle, whereas RARy mRNA was expressed in the immature and prehypertrophic chondrocytes and the expression was overlapped with Ihh gene expression. Next we established a high-density culture model of chick cephalic chondrocytes in the prehypertrophic stage. We found that all-trans retinoic acid (RA) induced Ihh mRNA gene expression in this system. The RA pan-antagonist Ro 41-5253 inhibited both endogenous and RA-induced Ihh mRNA in a dose-dependent manner. The Ihh mRNA expression induced by RA required de novo protein synthesis, and was mediated by RARy. Immunoblots showed that the prehypertrophic chondrocytes contained sizable levels of phosphorylated p38 mitogen-activated protein (MAP) kinase that were time- and dose-dependently increased by the RA treatment. Experimental p38 inhibition led to a severe drop in baseline and RA-stimulated Ihh expression. Exogenous recombinant Ihh stimulated the proliferation of proliferating chondrocytes, whereas RA inhibited the proliferation of these chondrocytes through p38 MAPK. Retinoids appear to play a primary role in controlling both the expression and function of Ihh in prehypertrophic chondrocytes and do so via p38 MAP kinase. © 2008, Japanese Stomatological Society. All rights reserved.

    DOI: 10.11277/osi.5.1

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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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  • レチノイド受容体シグナルは肥大軟骨細胞特異的遺伝子制御に関わる

    志茂 剛, 奥井 達雄, 増井 正典, 國定 勇希, 伊原木 聰一郎, 吉岡 徳枝, 栗尾 奈愛, 吉田 祥子, 佐々木 朗, 小山 英樹, 岩本 容泰

    日本口腔科学会雑誌   68 ( 2 )   173 - 173   2019.7

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  • Ammonium Tetrathiomolybdateは骨芽細胞におけるRANKL発現抑制を介して口腔癌骨破壊病変を制御する

    奥井 達雄, 森澤 彩香, 長谷川 利聡, 竜門 省二, 伊原木 聰一郎, 佐々木 朗

    日本口腔科学会雑誌   68 ( 2 )   88 - 89   2019.7

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  • レチノイド受容体シグナルは肥大軟骨細胞特異的遺伝子制御に関わる

    志茂 剛, 奥井 達雄, 増井 正典, 國定 勇希, 伊原木 聰一郎, 吉岡 徳枝, 栗尾 奈愛, 吉田 祥子, 佐々木 朗, 小山 英樹, 岩本 容泰

    日本口腔科学会雑誌   68 ( 2 )   173 - 173   2019.7

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  • 顎矯正手術における、術者経験レベルによる手術時間と出血量の比較検討

    西山 明慶, 吉岡 徳枝, 岸本 晃治, 奥井 達雄, 伊原木 聰一朗, 佐々木 朗

    日本顎変形症学会雑誌   29 ( 2 )   169 - 169   2019.5

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  • 顎放射線菌症治療中に発症した急性出血性直腸潰瘍の1例

    長谷川 利聡, 奥井 達雄, 伊原木 聰一郎, 國定 勇希, 竜門 省二, 佐々木 朗

    日本口腔外科学会雑誌   65 ( 2 )   105 - 109   2019.2

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    85歳男性。下顎歯右7を抜歯後に右側顎関節部の腫脹と自発痛が出現し、右側関節突起の著明な骨吸収を示す右側下顎骨骨髄炎と診断された。急性冠症候群に対する経皮的肝動脈形成術の既往歴がある。入院し抗菌薬(セファゾリンナトリウム、クリンダマイシン)投与を行ったが、硬結や開口障害は改善せず、第7病日に右側顎関節部を切開排膿した。膿汁にActinomyces israelii菌塊を認めたため顎放線菌症と診断し、抗菌薬をベンジルペニシリン持続投与に変更した。症状は改善したが抗菌薬変更後に頻回の下痢症状、無痛性新鮮血下血が出現した。下部消化管内視鏡で直腸軟膜の潰瘍と同部からの出血を認め、クリッピング術を行った。各検査所見は抗菌薬起因性大腸炎は否定的で、動脈硬化を背景とし感染症を伴う消耗と低栄養状態から臥床状態となったことにより発症した急性出血性直腸潰瘍(AHUR)と診断した。

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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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  • 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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  • 硬性内視鏡下で摘出した上顎洞内異物の1症例

    奥井 達雄, 西山 明慶, 伊原木 聰一郎, 佐々木 朗

    岡山歯学会雑誌   37 ( 2 )   33 - 35   2018.12

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    症例は40歳代男性で、近医歯科にて左側上顎第二小臼歯歯根破折の診断のもと、抜歯を施行されるも、術中に歯科用切削バーが歯科用タービンヘッドから逸脱し上顎洞内に迷入した。抜歯を中断し、抜歯処置後6日目に当科を紹介され受診した。パノラマX線写真にて、左側上顎洞内に長径約20mmの迷入した歯科切削バーと思われる不透過像を認めた。患者は欠損に対するインプラント治療を希望していたため、口腔内からのアプローチで抜歯と異物除去を同時に行うこととした。洗浄を行い光源下で洞内を観察するため開洞孔より硬性内視鏡を用い上顎洞内を観察し、バーが自然孔付近の上顎洞粘膜内に一部埋伏していることを確認、同孔よりマイクロ鉗子を用いて内視鏡画像上でバーを把持、除去した。さらに、残存していた左側上顎第二小臼歯歯根を抜去し、創を縫合し手術を終了した。術後経過は良好であり、術後3日目に退院とした。

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  • 生体微量金属とがん

    奥井 達雄, 佐々木 朗

    口腔組織培養学会誌   27 ( 2 )   1 - 8   2018.11

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    近年、微量金属元素、金属酵素と癌の発生あるいは腫瘍の進展との関連が報告されており、新たな癌治療の標的として微量金属が注目されるようになってきた。癌、特に骨代謝に影響を与え、骨浸潤あるいは骨転移を示す癌との関係が示唆されている、鉄、亜鉛、銅について最近の知見を紹介した。微量金属の多くは骨内に貯蔵されるため、金属キレート剤等は骨転移などの骨内で増大する癌に著効する可能性を有していると考えられた。

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  • 【悪性腫瘍と骨・カルシウム代謝】骨痛とがんの相互作用

    奥井 達雄

    Clinical Calcium   28 ( 11 )   1473 - 1478   2018.10

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    <文献概要>がんは高頻度に骨に転移する。その詳細なメカニズムはいまだ不明であるが,がんは骨微小環境,特に破骨細胞や骨芽細胞と互助的に,いわゆる悪循環を成立させ骨恒常性を破綻しながら増殖することが示されている。知覚神経は骨に豊富に終末し,骨微小環境の一要素であることが見出されている。近年末梢神経系の活性が悪性腫瘍の増大,転移に促進的に働くことが示されている。これらの知見は,知覚神経興奮の抑制は鎮痛効果のみならず,従来とは異なる抗がん治療アプローチとしても有効であることを示唆している。がん性骨痛とがんの相互作用に対する新知見をreviewする。

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  • 核内およびエクソソーム中に存在するMMPs/PEXの癌進展における役割とその抑制

    奥舎 有加, 江口 傑徳, 十川 千春, 小野 喜章, 奥井 達雄, 中野 敬介, 岡元 邦彰

    Journal of Oral Biosciences Supplement   2018   150 - 150   2018.9

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  • 知覚神経の興奮は骨内での乳がん進展に寄与する

    奥井 達雄, 小野 喜章, 佐々木 朗

    Journal of Oral Biosciences Supplement   2018   201 - 201   2018.9

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  • 癌の治療抵抗性と転移におけるHSP90およびMMP3の役割

    江口 傑徳, 小野 喜章, 奥舎 有加, 十川 千春, 内部 健太, 中野 敬介, 奥井 達雄, 滝川 正春, 岡元 邦彰, カルダーウッド・スチュアート

    Journal of Oral Biosciences Supplement   2018   142 - 142   2018.9

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  • 骨代謝学と口腔外科学のクロスオーバーからクロスイノベーションへ 知覚神経興奮による骨痛とがんの増大、転移の制御

    奥井 達雄, 日浅 雅博, 米田 俊之

    日本骨代謝学会学術集会プログラム抄録集   36回   106 - 106   2018.7

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  • 当科における歯原性腫瘍症例の臨床的検討

    王 碩, 岸本 晃治, 國定 勇希, 西山 明慶, 吉岡 徳枝, 伊原木 聰一郎, 奥井 達雄, 佐々木 朗

    日本口腔科学会雑誌   67 ( 2 )   123 - 123   2018.7

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  • 骨代謝学と口腔外科学のクロスオーバーからクロスイノベーションへ 知覚神経興奮による骨痛とがんの増大、転移の制御

    奥井 達雄, 日浅 雅博, 米田 俊之

    日本骨代謝学会学術集会プログラム抄録集   36回   106 - 106   2018.7

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  • 当科における骨格性2級症例の臨床的検討

    西山 明慶, 吉岡 徳枝, 伊原木 聰一郎, 奥井 達雄, 岸本 晃治, 佐々木 朗

    日本顎変形症学会雑誌   28 ( 2 )   201 - 201   2018.5

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  • 逆行性超選択的動注化学放射線療法中に腫瘍栄養動脈が閉塞し吻合枝から急速動注した舌癌の1例

    伊原木 聰一郎, 吉岡 徳枝, 奥井 達雄, 國定 勇希, 志茂 剛, 光藤 健司, 藤内 祝, 佐々木 朗

    日本口腔腫瘍学会誌   30 ( 1 )   23 - 27   2018.3

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    今回われわれは、舌癌に対して逆行性超選択的動注化学放射線療法を施行中に腫瘍栄養動脈が閉塞したため、腫瘍栄養動脈の吻合枝から急速動注療法を施行した舌癌の1例を経験したので報告する。症例:43歳女性。2012年7月に当科を受診し、左側舌癌・両側頸部リンパ節転移(T4aN2cM0、扁平上皮癌)と診断した。原発巣は逆行性超選択的動注化学放射線療法を行い、頸部リンパ節転移に対しては照射後に頸部郭清術を施行する予定とした。2012年8月に患側は浅側頭動脈から舌動脈と顔面動脈の共通幹に、健側は浅側頭動脈から舌動脈に、それぞれカテーテルを留置した。定期的にインジゴカルミン染色でカテーテル脱落の有無を検査していたが、46Gy照射後から、患側の舌動脈と顔面動脈の共通幹の支配領域が染色されなくなった。Seldinger法で患側の外頸動脈にカテーテルを留置し外頸動脈分枝を造影すると、舌動脈と顔面動脈は造影されず、顎動脈分枝の頬動脈および下歯槽動脈から顔面動脈への吻合枝が描出された。下歯槽動脈をコイルで塞栓し頬動脈からシスプラチンを急速動注した。2012年10月に70Gy照射を終了した。2012年11月に両側頸部郭清術を行った。治療終了から現在までに約5年経過しているが再発および転移なく経過良好である。(著者抄録)

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  • 銅キレート剤Ammonium TetrathiomolybdateはLOX活性を介した口腔癌骨破壊病変を制御する

    奥井 達雄, 森澤 彩香, 志茂 剛, 佐々木 朗

    口腔組織培養学会誌   27 ( 1 )   25 - 25   2018.3

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  • 当科における重症歯性感染症の臨床統計的検討

    竜門 省二, 志茂 剛, 吉岡 徳枝, 矢尾 真弓, 柴田 茜, 伊原木 聰一郎, 奥井 達雄, 國定 勇希, 吉田 祥子, 岸本 晃治, 西山 明慶, 佐々木 朗

    日本口腔診断学会雑誌   31 ( 1 )   116 - 116   2018.2

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  • 岡山大学病院口腔外科(病態系)医科歯科連携におけるMRONJ患者の調査

    坂本 裕美, 志茂 剛, 國定 勇希, 増井 正典, 小畑 協一, 吉岡 徳枝, 矢尾 真弓, 柴田 茜, 伊原木 聰一郎, 奥井 達雄, 吉田 祥子, 村瀬 友里香, 岸本 晃治, 西山 明慶, 佐々木 朗

    日本口腔診断学会雑誌   31 ( 1 )   83 - 83   2018.2

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  • 岡山大学病院口腔外科(病態系)医科歯科連携におけるMRONJ患者の調査

    坂本 裕美, 志茂 剛, 國定 勇希, 増井 正典, 小畑 協一, 吉岡 徳枝, 矢尾 真弓, 柴田 茜, 伊原木 聰一郎, 奥井 達雄, 吉田 祥子, 村瀬 友里香, 岸本 晃治, 西山 明慶, 佐々木 朗

    日本口腔内科学会雑誌   23 ( 2 )   127 - 127   2017.12

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  • 当科における重症歯性感染症の臨床統計的検討

    竜門 省二, 志茂 剛, 吉岡 徳枝, 矢尾 真弓, 柴田 茜, 伊原木 聰一郎, 奥井 達雄, 國定 勇希, 吉田 祥子, 岸本 晃治, 西山 明慶, 佐々木 朗

    日本口腔内科学会雑誌   23 ( 2 )   160 - 160   2017.12

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  • V-ATPaseプロトンポンプおよび酸感受性イオンチャンネルASIC3阻害は多発性骨髄腫の骨痛を緩和する

    日浅 雅博, 奥井 達雄, 米田 俊之

    日本骨代謝学会学術集会プログラム抄録集   35回   205 - 205   2017.7

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  • 口腔扁平上皮癌におけるNeurokinin B/Neurokinin 3 receptorの発現とその役割の検討

    小畑 協一, 志茂 剛, 奥井 達雄, 伊原木 聰一郎, 國定 勇希, 松本 憲一, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   35回   205 - 205   2017.7

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  • 骨芽細胞におけるメカニカルストレスがヘッジホッグシグナルに与える影響

    松本 憲一, 志茂 剛, 奥井 達雄, 栗尾 奈愛, 伊原木 聡一郎, 國定 勇希, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   35回   160 - 160   2017.7

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  • TRPV1を通じて興奮した知覚神経はHGF産生により骨内でのがんの進展および骨からの二次転移を促進する

    奥井 達雄, 日浅 雅博, 志茂 剛, 佐々木 朗, 米田 俊之

    日本骨代謝学会学術集会プログラム抄録集   35回   205 - 205   2017.7

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  • 口腔扁平上皮癌におけるNeurokinin Bの役割の検討

    小畑 協一, 志茂 剛, 奥井 達雄, 高畠 清文, 伊原木 聰一郎, 長塚 仁, 佐々木 朗

    日本口腔科学会雑誌   66 ( 2 )   183 - 183   2017.7

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  • 口腔扁平上皮癌に対するMidkine阻害剤iMDKを用いた腫瘍抑制効果の検討

    増井 正典, 奥井 達雄, 志茂 剛, 伊原木 聰一郎, 佐々木 朗

    日本口腔科学会雑誌   66 ( 2 )   195 - 195   2017.7

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  • HMGB1を介した癌細胞と知覚神経の相互作用は癌性骨痛を増強する

    奥井 達雄, 日浅 雅博, White Fletcher, Roodman, G. David, 志茂 剛, 佐々木 朗, 米田 俊之

    日本口腔科学会雑誌   66 ( 2 )   173 - 173   2017.7

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  • HMGB1を介した癌細胞と知覚神経の相互作用は癌性骨痛を増強する

    奥井 達雄, 日浅 雅博, White Fletcher, Roodman, G. David, 志茂 剛, 佐々木 朗, 米田 俊之

    日本口腔科学会雑誌   66 ( 2 )   173 - 173   2017.7

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  • 岡山大学病院高度救命救急センターにおける頭部、顎顔面外傷患者の検討

    奥井 達雄, 伊原木 聰一郎, 志茂 剛, 森澤 綾香, 藤井 由紀子, 佐々木 朗

    岡山歯学会雑誌   36 ( 1 )   13 - 16   2017.6

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    当院高度救命救急センターにおける頭部、顎顔面外傷症例の実態を報告した。調査期間は2012年4月1日から2013年3月31日迄の12ヵ月で、搬送された患者ならびに救急外来受診患者の合計は2970人であった。そのうち外傷患者は425人であり、その中で頭部、顎顔面外傷患者は164人と全外傷患者の38.6%であった。頭部、顎顔面外傷患者164名の受傷原因は交通外傷74人(45%)、転倒41人(25%)、転落31人(19%)、スポーツ13人(8%)であった。受傷項目詳細は裂傷、擦過傷が最も多く71件であった。次いで頭蓋内損傷が57件、顔面打撲が25件であった。頭部、顎顔面外傷のみの受傷患者は100人(61%)であり、他部位の損傷を併発している患者は64人(39%)であった。多発外傷を呈した頭部、顎顔面外傷患者64名における頭部、顎顔面外傷以外の受傷項目について検討した。肋骨骨折は19件、上肢下肢骨折8件、骨盤骨折22件、肺損傷20件、腹部内臓損傷6件であった。

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  • 下顎後方移動に対する術式の選択基準に関する臨床的検討

    吉岡 徳枝, 西山 明慶, 伊原木 聰一郎, 奥井 達雄, 岸本 晃治, 志茂 剛, 佐々木 朗

    日本顎変形症学会雑誌   27 ( 2 )   103 - 103   2017.5

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  • 知覚神経はがん細胞の骨での増大と骨からの二次転移を促進する

    奥井 達雄, 米田 俊之, 日浅 雅博, 志茂 剛, White Fletcher A, Roodman G. David, 佐々木 朗

    口腔組織培養学会誌   26 ( 1 )   41 - 41   2017.3

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  • 岡山大学病院口腔外科(病態系)において医科歯科連携を行った症例の調査

    増井 正典, 志茂 剛, 吉岡 徳枝, 伊原木 聰一郎, 矢尾 真弓, 奥井 達雄, 岸本 晃治, 西山 明慶, 佐々木 朗

    日本口腔診断学会雑誌   30 ( 1 )   150 - 150   2017.2

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  • 下顎歯肉癌顎骨浸潤部におけるNeurokinin Bの発現とその役割の検討

    小畑協一, 志茂剛, 奥井達雄, 松本憲一, 高田紘行, 高畠清文, 伊原木聰一郎, 長塚仁, 佐々木朗

    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   35th   156   2017

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  • 岡山大学病院口腔外科(病態系)において医科歯科連携を行った症例の調査

    増井 正典, 志茂 剛, 吉岡 徳枝, 伊原木 聰一郎, 矢尾 真弓, 奥井 達雄, 岸本 晃治, 西山 明慶, 佐々木 朗

    日本口腔内科学会雑誌   22 ( 2 )   166 - 166   2016.12

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  • 骨細胞はコネキシン43を介して痛覚神経を興奮させ骨痛を増悪する

    日浅 雅博, 奥井 達雄, 米田 俊之

    日本骨代謝学会学術集会プログラム抄録集   34回   177 - 177   2016.7

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  • 知覚神経のHGFと乳がんのHMGB1との相互関連は乳がん進展と骨痛誘発を制御する

    奥井 達雄, 日浅 雅博, 米田 俊之

    日本骨代謝学会学術集会プログラム抄録集   34回   183 - 183   2016.7

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  • 機械的刺激が一次繊毛を介した骨折治癒に与える影響

    松本 憲一, 志茂 剛, 栗尾 奈愛, 奥井 達雄, 伊原木 聰一郎, 岸本 晃治, 佐々木 朗

    日本口腔科学会雑誌   65 ( 2 )   187 - 187   2016.7

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  • 口腔扁平上皮癌骨微小環境におけるヘッジホッグシグナルの関与

    志茂 剛, 松本 憲一, 青山 絵理子, 武部 祐一郎, 高畠 清文, 小畑 協一, 伊原木 聰一郎, 奥井 達雄, 栗尾 奈愛, 長塚 仁, 佐々木 朗

    口腔組織培養学会誌   25 ( 1 )   39 - 40   2016.1

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  • 多発性骨髄腫の酸性環境と骨痛

    日浅雅博, 日浅雅博, 奥井達雄, 奥井達雄, 米田俊之, 米田俊之

    癌と骨病変研究会抄録集   19th   21   2016

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  • Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain

    Toshiyuki Yoneda, Masahiro Hiasa, Yuki Nagata, Tatsuo Okui, Fletcher White

    BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES   1848 ( 10 )   2677 - 2684   2015.10

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    Solid and hematologic cancer colonized bone produces a number of pathologies. One of the most common complications is bone pain. Cancer-associated bone pain (CABP) is a major cause of increased morbidity and diminishes the quality of life and affects survival. Current treatments do not satisfactorily control CABP and can elicit adverse effects. Thus, new therapeutic interventions are needed to manage CABP. However, the mechanisms responsible for CABP are poorly understood. The observation that specific osteoclast inhibitors can reduce CABP in patients indicates a critical role of osteoclasts in the pathophysiology of CABP. Osteodasts create an acidic extracellular microenvironment by secretion of protons via vacuolar proton pumps during bone resorption. In addition, bone-colonized cancer cells also release protons and lactate via plasma membrane pH regulators to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Since acidosis is algogenic for sensory neurons and bone is densely innervated by sensory neurons that express acid-sensing nociceptors, the acidic bone microenvironments can evoke CABP. Understanding of the mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and the expression and function of the acid-sensing nodceptors are regulated should facilitate the development of novel approaches for management of CABP. Here, the contribution of the acidic microenvironment created in cancer-colonized bone to elicitation of CABP and potential therapeutic implications of blocking the development and recognition of acidic microenvironment will be described. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. (C) 2015 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.bbamem.2015.02.004

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  • メカニカルストレスが骨芽細胞におけるヘッジホッグシグナルに与える影響

    松本 憲一, 志茂 剛, 栗尾 奈愛, 奥井 達雄, 国定 勇希, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   33回   197 - 197   2015.7

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  • 口腔扁平上皮癌におけるヘッジホッグシグナル阻害剤の影響

    黒田 大雅, 志茂 剛, 栗尾 奈愛, 松本 憲一, 伊原木 聰一郎, 奥井 達雄, 佐々木 朗

    日本口腔科学会雑誌   64 ( 2 )   182 - 182   2015.7

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  • 骨芽細胞におけるメカニカルストレスがヘッジホッグシグナルに与える影響

    松本 憲一, 志茂 剛, 栗尾 愛奈, 奥井 達雄, 佐々木 朗

    日本口腔科学会雑誌   64 ( 2 )   201 - 201   2015.7

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  • 骨細胞は痛覚神経を刺激して骨痛を増悪する

    日浅 雅博, 奥井 達雄, 永田 友貴, 米田 俊之

    日本骨代謝学会学術集会プログラム抄録集   33回   166 - 166   2015.7

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  • 乳がん骨転移および骨からの二次転移における痛覚神経の関与

    奥井達雄, 日浅雅博, WHITE Fletcher A, ROODMAN G.David, 米田俊之

    癌と骨病変研究会抄録集   18th   35   2015

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  • ヘッジホッグと骨病変

    志茂剛, 松本憲一, 青山絵理子, 武部祐一郎, 高畠清文, 小畑協一, 伊原木聰一郎, 奥井達雄, 栗尾奈愛, 長塚仁, 佐々木朗

    癌と骨病変研究会抄録集   18th   37   2015

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  • 外科的矯正治療術後患者における骨代謝マーカーの検討

    國定 勇希, 志茂 剛, 増井 正典, 吉岡 徳枝, 伊原木 聰一郎, 銅前 昇平, 栗尾 奈愛, 奥井 達雄, 西山 明慶, 佐々木 朗

    日本口腔科学会雑誌   63 ( 4 )   442 - 442   2014.9

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  • 加齢に伴う骨折治癒過程におけるSonic hedgehogの発現とその役割

    松本 憲一, 志茂 剛, 堀切 優, 栗尾 奈愛, 奥井 達雄, 高田 紘行, 佐々木 朗

    日本口腔科学会雑誌   63 ( 4 )   439 - 439   2014.9

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  • 加齢に伴う骨折治癒過程におけるソニックヘッジホッグの関わり

    松本 憲一, 志茂 剛, 堀切 優, 栗尾 奈愛, 奥井 達雄, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   32回   256 - 256   2014.7

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  • 外科的矯正治療術後患者におけるソニックヘッジホッグの検出

    國定 勇希, 志茂 剛, 栗尾 奈愛, 増井 正典, 伊原木 聰一郎, 奥井 達雄, 西山 明慶, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   32回   315 - 315   2014.7

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  • 口腔癌顎骨浸潤におけるヘッジホッグシグナルの発現とその役割

    志茂 剛, 栗尾 奈愛, 奥井 達雄, 松本 憲一, 堀切 優, 伊原木 聰一郎, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   32回   316 - 316   2014.7

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  • 骨髄移植後の慢性GVHD患者に発生した多発性口腔扁平上皮癌の1例

    奥井 達雄, 目瀬 浩, 伊原木 聰一郎, 吉岡 徳枝, 志茂 剛, 佐々木 朗

    日本口腔外科学会雑誌   60 ( 3 )   151 - 155   2014.3

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    症例は42歳男性で、全身倦怠感を主訴に受診し、慢性骨髄性白血病と診断された。HLAが一致する弟をドナーとした骨髄移植を受け、移植直後に移植片対宿主病(GVHD)を発症し、慢性GVHDによる肝機能低下、GVHDに対するプレドニゾロン長期投与による軽度の腎機能低下を認めた。骨髄移植直後より口内炎を自覚していたが、右側頬粘膜に腫瘤を自覚するようになり、血液腫瘍内科より紹介受診した。体格中等度、栄養状態良好で、顔面、四肢皮膚に慢性GVHDによる色素逸脱を認めた。右側頬粘膜に22×16mmの弾性軟、周囲に硬結を触知する腫瘤を認めた。MR画像で右側頬粘膜に前後径20mm、厚み4mmの境界明瞭なSTIR高信号域を認め、左側下顎小臼歯部舌側歯肉に前後径10mmの境界明瞭なSTIR高信号域を認めた。骨髄移植によるGVHDを伴った二次性多発性口腔癌、白板症の疑いと臨床診断し、全身麻酔下に腫瘍切除術を施行した。左側下顎生検を行い、舌背中央部は軽度上皮異形成、左側下顎大臼歯歯肉頬移行部は高分化扁平上皮癌と病理組織学的に診断され、左側下顎歯肉癌に対し腫瘍切除術を施行した。術後12ヵ月再発を認めず、厳重な経過観察を行っている。

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  • The role of Insulin-like growth factor-I and Focal adhesion kinase in angiogenesis of tumor induced bone metastasis. Reviewed

    Naito Kurio, Tsuyoshi Shimo, Hiromasa Kuroda, Kenichi Matsumoto, Tatsuo Okui, Akira Sasaki

    JOURNAL OF BONE AND MINERAL RESEARCH   29   S230 - S230   2014.2

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  • Detection of sonic hedgehog in a patient with orthognathic surgery Reviewed

    Tsuyoshi Shimo, Yuki Kunisada, Naito Kurio, Masanori Masui, Norie Yoshioka, Soichiro Ibaragi, Tatsuo Okui, Akiyoshi Nishiyama, Akira Sasaki

    JOURNAL OF BONE AND MINERAL RESEARCH   29   S482 - S482   2014.2

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  • 長期経過観察し病理組織学的評価を行った下顎骨線維性異形成症の1例

    伊原木 聰一郎, 西山 明慶, 奥井 達雄, 栗尾 奈愛, 柴田 茜, 岸本 晃治, 志茂 剛, 佐々木 朗

    日本口腔診断学会雑誌   27 ( 1 )   27 - 31   2014.2

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    症例は2歳男児で、左側下顎部の腫脹を主訴とした。X線で左下D番の近心部から下顎枝までの楕円形の比較的境界明瞭な透過像を認め、内部に斑紋状の不規則な不透過像がみられた。同部の骨削除により組織生検を行い、病理所見は細胞成分に富む線維性組織の増殖からなり、線維骨の骨梁を伴っていた。線維性異形成症と診断し、1ヵ月後に掻爬術を追加し、生検部位から遠心に向かって菲薄化した頬側の骨を除去した。術後6ヵ月頃より患側下顎骨下縁に骨様硬の膨隆を認め、急速に増大して顔面の非対称が著明となったが、再手術は同意が得られず、定期的な経過観察を行った。下顎骨の成長や歯の萠出には問題がなく、18歳時には内部に骨梁構造を認めた。非対称改善のため口外法により左側下顎骨下縁切除術を施行し、病理所見で緻密な皮質骨内に疎な骨組織と線維性組織を認めたが、活動性の病変はなかった。術後6年経過し、下顎骨の形態に著変はない。

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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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  • Role of sonic hedgehog in the process of fracture healing with aging Reviewed

    Tsuyoshi Shimo, Kenichi Matsumoto, Naito Kurio, Tatsuo Okui, Yuu Horikiri, Akira Sasaki

    JOURNAL OF BONE AND MINERAL RESEARCH   29   S491 - S492   2014.2

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  • 骨折治癒過程におけるFocal adhesion kinaseを介したSonic hedgehogの役割

    堀切 優, 志茂 剛, 栗尾 奈愛, 奥井 達雄, 佐々木 朗

    日本口腔科学会雑誌   63 ( 1 )   168 - 168   2014.1

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  • ソニックヘッジホッグの腫瘍血管新生因子としての役割とメカニズム

    黒田 大雅, 志茂 剛, 栗尾 奈愛, 伊原木 聰一郎, 奥井 達雄, 堀切 優, 松本 憲一, 佐々木 朗

    日本口腔科学会雑誌   63 ( 1 )   120 - 120   2014.1

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  • 当科における顎矯正手術症例の臨床統計的観察 最近10年と以前との比較

    西山 明慶, 吉岡 徳枝, 伊原木 聰一郎, 栗尾 奈愛, 奥井 達雄, 銅前 昇平, 志茂 剛, 岸本 晃治, 目瀬 浩, 佐々木 朗

    日本口腔科学会雑誌   63 ( 1 )   199 - 199   2014.1

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  • 2型糖尿病治療薬メトホルミン塩酸塩の口腔扁平上皮癌に対する抗腫瘍効果

    栗尾 奈愛, 志茂 剛, 黒田 大雅, 堀切 優, 奥井 達雄, 松本 憲一, 佐々木 朗

    日本口腔科学会雑誌   63 ( 1 )   141 - 141   2014.1

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  • 自転車の傘差し運転に関するアンケート調査の検討

    吉岡 徳枝, 長谷川 利聡, 目 絵理子, 西岡 由紀子, 奥井 達雄, 佐々木 朗

    岡山歯学会雑誌   32 ( 2 )   89 - 89   2013.12

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  • 当科における口腔癌に対する逆行性超選択的動注化学放射線療法の治療経験

    伊原木 聰一郎, 吉岡 徳枝, 奥井 達雄, 國定 勇希, 岸本 晃治, 目瀬 浩, 志茂 剛, 佐々木 朗

    岡山歯学会雑誌   32 ( 2 )   88 - 88   2013.12

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  • 歯胚初代上皮細胞における結合組織増殖因子CCN2の発現とその役割

    志茂 剛, 栗尾 奈愛, 奥井 達雄, 黒田 大雅, 松本 憲一, 堀切 優, 伊原木 聰一郎, 吉岡 徳枝, 佐々木 朗

    Journal of Oral Biosciences Supplement   2013   190 - 190   2013.9

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  • 骨折治癒過程におけるソニックヘッジホッグの役割

    松本 憲一, 堀切 優, 志茂 剛, 栗尾 奈愛, 奥井 達雄, 黒田 大雅, 佐々木 朗

    Journal of Oral Biosciences Supplement   2013   204 - 204   2013.9

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  • 口腔扁平上皮癌におけるソニックヘッジホッグの血管新生因子としての役割

    黒田 大雅, 栗尾 奈愛, 志茂 剛, 伊原木 聰一郎, 奥井 達雄, 堀切 優, 松本 憲一, 佐々木 朗

    Journal of Oral Biosciences Supplement   2013   216 - 216   2013.9

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  • エナメル上皮腫摘出後に骨移植と骨延長により骨増量を行ったインプラント治療の1例

    伊原木 聰一郎, 目瀬 浩, 中山 周子, 兒玉 真一, 奥井 達雄, 吉岡 徳枝, 岸本 晃治, 中妻 可奈子, 志茂 剛, 佐々木 朗

    Japanese Journal of Maxillo Facial Implants   12 ( 2 )   53 - 57   2013.8

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    59歳女。右側頬部の腫脹を主訴に受診し、パノラマX線写真で右側下顎骨にX線透過像を認めた。CT写真では、腫瘍直下に下顎管が存在していた。局研麻酔下で生検を行い、エナメル上皮腫と診断した。全身麻酔下に腫瘍摘出術および抜歯を施行した。病理組織学的所見からエナメル上皮腫と診断した。腫瘍摘出術後3年3ヵ月後にインプラント治療に先立ち、下歯槽神経血管束移動術と右側下顎枝からの骨移植を行った。4ヵ月の治癒期間の後、骨延長を行った。頬側の骨量が不十分であったため、オトガイ部からの骨移植を再度行い、1年2ヵ月後にインプラント体を埋入した。現在、上部構造装着から4年が経過しているが、腫瘍の再発や、インプラント周囲粘膜組織の炎症徴候もなく、正常な咬合・咀嚼機能が維持されている。さらにパノラマX線写真においてもインプラント周囲の異常な骨吸収はなく、歯槽骨頂の骨レベルは維持され、経過は良好である。

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  • 岡山大学病院高度救命センターにおける頭頸部、顔面外傷の現状

    奥井 達雄, 伊原木 聰一郎, 吉岡 徳枝, 浦瀬 綾香, 藤井 由記子, 佐々木 朗

    口腔顎顔面外傷   12 ( 1 )   71 - 72   2013.6

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  • 自転車の傘差し運転に関するアンケート調査の検討

    吉岡 徳枝, 長谷川 利聡, 目 絵理子, 西岡 由紀子, 奥井 達雄, 佐々木 朗

    口腔顎顔面外傷   12 ( 1 )   70 - 70   2013.6

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  • 下顎枝垂直骨切り術と下顎枝垂直矢状分割術を併用した顔面非対称症例の術後安定性に関する検討

    吉岡 徳枝, 西山 明慶, 伊原木 聰一郎, 奥井 達雄, 志茂 剛, 岸本 晃治, 佐々木 朗

    日本顎変形症学会雑誌   23 ( 2 )   132 - 132   2013.5

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  • 前歯部空隙歯列を伴う骨格性下顎前突に対し下顎正中部骨削除と下顎枝矢状分割術を併用した外科的矯正治療例

    伊原木 聰一郎, 西山 明慶, 吉岡 徳枝, 奥井 達雄, 國定 勇希, 高木 雅人, 田井 規能, 佐々木 朗

    日本顎変形症学会雑誌   23 ( 2 )   125 - 125   2013.5

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  • 骨折早期におけるFocal adhesion kinaseの役割

    堀切 優, 志茂 剛, 栗尾 奈愛, 奥井 達雄, 佐々木 朗

    日本口腔科学会雑誌   62 ( 2 )   202 - 202   2013.3

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  • 骨髄移植後の口腔GVHD患者に発生した多発性口腔扁平上皮癌の1例

    奥井 達雄, 伊原木 聰一郎, 吉岡 徳枝, 目瀬 浩, 國定 勇希, 佐々木 朗

    日本口腔診断学会雑誌   26 ( 1 )   110 - 110   2013.2

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  • 歯性感染症が原因と疑われた脳膿瘍の1例

    桑島 大介, 吉岡 徳枝, 栗尾 奈愛, 奥井 達雄, 伊原木 聰一郎, 佐々木 朗

    日本口腔診断学会雑誌   26 ( 1 )   136 - 136   2013.2

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  • Angiogeninの核移行阻害剤neamineの口腔癌に対する抗腫瘍効果の検討

    岸本 晃治, 吉田 祥子, 奥井 達雄, 伊原木 聰一郎, 吉岡 徳枝, 兒玉 真一, 志茂 剛, 中妻 可奈子, 佐々木 朗

    日本口腔科学会雑誌   62 ( 1 )   93 - 94   2013.1

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  • 口腔扁平上皮癌の腫瘍血管新生におけるFAKの役割

    栗尾 奈愛, 志茂 剛, 奥井 達雄, 堀切 優, 佐々木 朗

    日本口腔科学会雑誌   62 ( 1 )   169 - 169   2013.1

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  • 歯原性粘液線維腫から明らかとなった新たなCCN2の役割

    志茂 剛, 堀切 優, 奥井 達雄, 栗尾 奈愛, 吉田 祥子, 武部 祐一郎, 中妻 可奈子, 岸本 晃治, 佐々木 朗

    日本口腔科学会雑誌   62 ( 1 )   129 - 129   2013.1

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  • 骨折早期におけるFAKの骨芽細胞に与える影響

    堀切 優, 志茂 剛, 栗尾 奈愛, 奥井 達雄, 佐々木 朗

    日本口腔科学会雑誌   62 ( 1 )   159 - 160   2013.1

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  • Inhibition of the growth factor MDK/midkine by a novel small molecule compound to treat non-small cell lung cancer. International journal

    Huifang Hao, Yutaka Maeda, Takuya Fukazawa, Tomoki Yamatsuji, Munenori Takaoka, Xiao-Hong Bao, Junji Matsuoka, Tatsuo Okui, Tsuyoshi Shimo, Nagio Takigawa, Yasuko Tomono, Motowo Nakajima, Iris M Fink-Baldauf, Sandra Nelson, William Seibel, Ruben Papoian, Jeffrey A Whitsett, Yoshio Naomoto

    PloS one   8 ( 8 )   e71093 - 199   2013

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    Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, in turn enhancing the survival of tumors. Therefore, the inhibition of MDK is considered a potential strategy for cancer therapy. In the present study, we demonstrate a novel small molecule compound (iMDK) that targets MDK. iMDK inhibited the cell growth of MDK-positive H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells, both of which are types of untreatable lung cancer. However, iMDK did not reduce the cell viability of MDK-negative A549 lung adenocarcinoma cells or normal human lung fibroblast (NHLF) cells indicating its specificity. iMDK suppressed the endogenous expression of MDK but not that of other growth factors such as PTN or VEGF. iMDK suppressed the growth of H441 cells by inhibiting the PI3K pathway and inducing apoptosis. Systemic administration of iMDK significantly inhibited tumor growth in a xenograft mouse model in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of lung cancers that are driven by MDK.

    DOI: 10.1371/journal.pone.0071093

    PubMed

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  • 歯性感染症が原因と疑われた脳膿瘍の1例

    桑島 大介, 吉岡 徳枝, 栗尾 奈愛, 奥井 達雄, 伊原木 聰一郎, 佐々木 朗

    日本口腔内科学会雑誌   18 ( 2 )   119 - 119   2012.12

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  • 歯原性粘液線維腫におけるCCN2の発現とその役割

    志茂 剛, 堀切 優, 奥井 達雄, 栗尾 奈愛, 吉田 祥子, 武部 祐一郎, 中妻 可奈子, 佐々木 朗

    日本再生歯科医学会誌   10 ( 1 )   60 - 60   2012.12

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  • 口腔癌骨破壊病変におけるmammalian target of rapamycin(mTOR)の役割と新規分子標的治療の探索

    奥井 達雄

    岡山歯学会雑誌   31 ( 2 )   86 - 87   2012.12

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  • 骨髄移植後の口腔GVHD患者に発生した多発性口腔扁平上皮癌の1例

    奥井 達雄, 伊原木 聰一郎, 吉岡 徳枝, 目瀬 浩, 國定 勇希, 佐々木 朗

    日本口腔内科学会雑誌   18 ( 2 )   93 - 93   2012.12

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  • Angiogeninの口腔癌治療に対する分子標的としての可能性

    岸本 晃治, 吉田 祥子, 奥井 達雄, 伊原木 聰一郎, 中妻 可奈子, 志茂 剛, 佐々木 朗

    日本癌治療学会誌   47 ( 3 )   2117 - 2117   2012.10

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  • Focal adhesion kinaseの骨折早期における骨芽細胞に与える影響

    堀切 優, 志茂 剛, 栗尾 奈愛, 奥井 達雄, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   30回   238 - 238   2012.7

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  • 下顎骨腫瘍摘出後の骨折および顔貌変形防止に対するプレートの応用

    岸本 晃治, 吉田 祥子, 銅前 昇平, 帆波 辰基, 伊原木 聰一郎, 奥井 達雄, 栗尾 奈愛, 中妻 可奈子, 佐々木 朗

    岡山歯学会雑誌   31 ( 1 )   15 - 19   2012.6

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    下顎エナメル上皮腫摘出後の骨折・顔貌変形を防止するために、口腔内から下顎骨に比較的大型のチタンプレート(ストライカー社製マンディブラルフラクチャープレート 14穴)を装着し、良好な結果が得られた症例(59歳男性例)を報告した。下顎骨腫瘍に対して摘出術や下顎骨辺縁切除術を施行後、残存骨が少なく顎骨骨折や顔貌変形が懸念される症例に対して本法は治療オプションの一つになりうると考えられた。

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  • Beckwith-Wiedemann症候群による巨舌に起因する著明な開咬に対して顎矯正手術を施行した1例

    吉岡 徳枝, 西山 明慶, 伊原木 聰一郎, 奥井 達雄, 高橋 巧, 佐々木 朗

    日本顎変形症学会雑誌   22 ( 2 )   112 - 112   2012.5

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  • 包括的な治療計画のもと上下顎骨切り術を行った著しいガミースマイルを伴う下顎後退位症例

    中村 政裕, 本城 正, 片岡 伴記, 上岡 寛, 吉岡 徳枝, 奥井 達雄, 西山 明慶, 佐々木 朗, 山城 隆

    日本顎変形症学会雑誌   22 ( 2 )   160 - 160   2012.5

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  • 口腔扁平上皮癌における血管新生に対するHSP90阻害薬の影響

    奥井 達雄, 志茂 剛, 帆波 辰基, 栗尾 奈愛, 吉岡 徳枝, 伊原木 聡一郎, 青木 香澄, 目瀬 浩, 佐々木 朗

    日本口腔科学会雑誌   61 ( 1 )   141 - 141   2012.1

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  • 口腔扁平上皮癌骨浸潤におけるソニックヘッジホッグの役割

    帆波 辰基, 志茂 剛, 奥井 達雄, 栗尾 奈愛, 青木 香澄, 堀切 優, 佐々木 朗

    日本口腔科学会雑誌   61 ( 1 )   140 - 140   2012.1

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  • Focal adhesion kinaseの口腔扁平上皮癌血管新生における役割

    栗尾 奈愛, 志茂 剛, 奥井 達雄, 帆波 辰基, 堀切 優, 佐々木 朗

    日本口腔科学会雑誌   61 ( 1 )   141 - 142   2012.1

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  • 癌軟骨破壊におけるInterleukin-1βの役割

    志茂 剛, 奥井 達雄, 伊原木 聰一郎, 栗尾 奈愛, 帆波 辰基, 堀切 優, 吉岡 徳枝, 岸本 晃治, 西山 明慶, 目瀬 浩, 佐々木 朗

    日本口腔科学会雑誌   61 ( 1 )   195 - 195   2012.1

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  • 凍結療法を併用したエナメル上皮腫摘出後の顎骨欠損部に腸骨移植と歯科インプラントにて咬合再建を行った1例

    吉田 祥子, 目瀬 浩, 西山 明慶, 岸本 晃治, 銅前 昇平, 中妻 可奈子, 伊原木 聰一郎, 奥井 達雄, 佐々木 朗

    Japanese Journal of Maxillo Facial Implants   10 ( 3 )   120 - 120   2011.11

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  • シスプラチン耐性扁平上皮癌細胞株におけるPim-1発現の役割

    山本 大介, 目瀬 浩, 奥井 達雄, 伊原木 聰一郎, 吉岡 徳枝, 佐々木 朗

    日本口腔外科学会雑誌   57 ( Suppl. )   240 - 240   2011.9

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  • 新規HSP90阻害薬NVP-AUY922はTemsirolimusの抗腫瘍効果を増強する

    奥井 達雄, 志茂 剛, 栗尾 奈愛, 吉岡 徳枝, 伊原木 聰一郎, 岸本 晃治, 帆波 辰基, 青木 香澄, 目瀬 浩, 佐々木 朗

    日本口腔外科学会雑誌   57 ( Suppl. )   308 - 308   2011.9

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  • ソニックヘッジホッグの口腔扁平上皮癌骨浸潤における役割

    帆波 辰基, 志茂 剛, 奥井 達雄, 栗尾 奈愛, 青木 香澄, 堀切 優, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   29回   227 - 227   2011.7

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  • 口腔扁平上皮癌に対する熱ショック蛋白質HSP-90阻害薬の効果の検討

    奥井 達雄, 志茂 剛, 栗尾 奈愛, Monsur Hassan, Nur Mohammed, 帆波 辰基, 青木 香澄, 堀切 優, 佐々木 朗

    日本口腔科学会雑誌   60 ( 1 )   160 - 160   2011.1

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  • メッケル軟骨基質改造におけるMMP-9、MMP-13、CCN2発現はレチノイド核内レセプターRARγを介して発現が制御される

    志茂 剛, 伊原木 聰一郎, 栗尾 奈愛, 奥井 達雄, Monsur Hassan, Nur Mohammad, 帆波 辰基, 岸本 晃治, 佐々木 朗

    日本口腔科学会雑誌   60 ( 1 )   123 - 123   2011.1

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  • メッケル軟骨成長過程におけるレチノイドシグナルの関わり

    志茂 剛, 岩本 容泰, 小山 英樹, 伊原木 聰一郎, 栗尾 奈愛, 奥井 達雄, Hassan Nur Mohammad Monsur, 帆波 辰基, 吉岡 徳枝, 岸本 晃治, 西山 明慶, 目瀬 浩, 佐々木 朗

    日本再生歯科医学会誌   8 ( 1 )   44 - 44   2010.12

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  • 下歯槽神経血管束移動術と歯槽骨延長および歯科インプラントにて咬合再建を行った1例

    伊原木 聰一郎, 目瀬 浩, 岸本 晃治, 奥井 達雄, 中妻 可奈子, 槙野 隆秀, 佐々木 朗

    Japanese Journal of Maxillo Facial Implants   9 ( 3 )   98 - 98   2010.11

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  • 口腔扁平上皮癌の骨破壊におけるソニックヘッジホッグの関与

    帆波 辰基, 志茂 剛, Hassan Nur Mohammad Monsur, 栗尾 奈愛, 奥井 達雄, 青木 香澄, 堀切 優, 佐々木 朗

    日本口腔外科学会雑誌   56 ( Suppl. )   253 - 253   2010.9

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  • プラスミノーゲンI型欠損症患者における木質様歯肉炎の病態解析

    志茂 剛, 西山 明慶, 栗尾 奈愛, 奥井 達雄, Hassan Nur Mohammad Monsur, 帆波 辰基, 岸本 晃治, 目瀬 浩, 佐々木 朗

    日本口腔外科学会雑誌   56 ( Suppl. )   288 - 288   2010.9

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  • 口腔扁平上皮癌に対するTAE226(FAK tyrosine kinase inhibitor)の抗腫瘍効果

    栗尾 奈愛, 志茂 剛, 奥井 達雄, Hassan Nur Mohammad Monsur, 帆波 辰基, 堀切 優, 佐々木 朗

    日本口腔外科学会雑誌   56 ( Suppl. )   260 - 260   2010.9

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  • 新規HSP-90阻害薬NVP-AUY922の口腔扁平上皮癌細胞に対する効果の検討

    奥井 達雄, 志茂 剛, 栗尾 奈愛, Hassan Nur Mohammad Monsur, 帆波 辰基, 堀切 優, 佐々木 朗

    日本口腔外科学会雑誌   56 ( Suppl. )   262 - 262   2010.9

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  • メッケル軟骨基質改造におけるMMP-9、MMP-13、CCN2発現とレチノイド核内レセプターRAR gammaの関わり

    志茂 剛, 岩本 容泰, 小山 英樹, 伊原木 聰一郎, 栗尾 奈愛, 奥井 達雄, 帆波 辰基, 吉岡 徳枝, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   28回   269 - 269   2010.7

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  • 当科における上顎洞挙上術後の移植骨吸収量に関する検討

    奥井 達雄, 目瀬 浩, 塚本 剛一, 中妻 可奈子, 佐々木 朗

    Japanese Journal of Maxillo Facial Implants   8 ( 2 )   97 - 97   2009.11

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  • Focal adhesion kinase(FAK)の破骨細胞性骨吸収における役割

    栗尾 奈愛, 志茂 剛, 奥井 達雄, 吉岡 徳枝, 佐々木 朗

    日本口腔科学会雑誌   58 ( 4 )   204 - 204   2009.9

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  • 低酸素環境下扁平上皮癌におけるシスプラチン耐性機序の検討

    梅原 亜矢子, 目瀬 浩, 矢尾 真弓, 奥井 達雄, 栗尾 奈愛, 岸本 晃治, 佐々木 朗

    日本口腔科学会雑誌   58 ( 4 )   267 - 267   2009.9

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  • 新規mTOR分子標的薬Temsirolimusの口腔扁平上皮癌骨浸潤に対する影響

    奥井 達雄, 志茂 剛, 栗尾 奈愛, 帆波 辰基, 吉岡 徳枝, 江藤 司, 青木 香澄, 目瀬 浩, 佐々木 朗

    日本口腔外科学会雑誌   55 ( Suppl. )   218 - 218   2009.9

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  • 口腔癌顎骨破壊誘導因子シグナルにおけるMammalian target of rapamycin(mTOR)の関与

    奥井 達雄, 志茂 剛, 栗尾 奈愛, 合田 健志, 吉岡 徳枝, 帆波 辰基, 目瀬 浩, 佐々木 朗

    日本口腔科学会雑誌   58 ( 4 )   203 - 204   2009.9

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  • 副甲状腺ホルモン関連タンパク質シグナルを分子標的とした癌骨破壊病変制御

    吉岡 徳枝, 山本 大介, 志茂 剛, 栗尾 奈愛, 奥井 達雄, 佐々木 朗

    日本口腔科学会雑誌   58 ( 4 )   204 - 204   2009.9

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  • ソニックヘッジホッグはBMPと相乗的に歯胚未分化間葉系細胞の象牙芽細胞分化誘導を促進する

    志茂 剛, 小山 英樹, 栗尾 奈愛, 奥井 達雄, 青木 香澄, 帆波 辰基, 江藤 司, 佐々木 朗

    日本口腔科学会雑誌   58 ( 4 )   278 - 278   2009.9

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  • mTOR阻害薬Temsirolimsは口腔扁平上皮癌による骨浸潤を抑制する(Temsirolims Suppresses Osteolysis Induced by Human Oral Squamous Cell Carcinoma)

    奥井 達雄, 志茂 剛, 栗尾 奈愛, 高岡 宗徳, 吉岡 徳枝, ムハンマド・ハッサン, 帆波 辰基, 猶本 良夫, 佐々木 朗

    日本癌学会総会記事   68回   487 - 487   2009.8

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  • 癌骨破壊におけるMammalian target of rapamycin(mTOR)シグナルの役割

    奥井 達雄, 志茂 剛, 栗尾 奈愛, 吉岡 徳枝, 帆波 辰基, Hassan Nur Mohammad Monsur, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   27回   188 - 188   2009.7

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  • 口腔扁平上皮癌における癌誘発の骨破壊に対するAngiogeninの役割

    吉岡 徳枝, 青木 香澄, 伊原木 聰一郎, 奥井 達雄, 栗尾 奈愛, 志茂 剛, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   27回   240 - 240   2009.7

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  • 癌骨転移、高カルシウム血症におけるFocal adhesion kinase(FAK)の役割

    栗尾 奈愛, 志茂 剛, 奥井 達雄, 吉岡 徳枝, Hassan Nur Mohammad Monsur, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   27回   240 - 240   2009.7

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  • Mammalian target of rapamycin(mTOR)シグナルの口腔癌骨破壊における関与

    奥井 達雄, 志茂 剛, 栗尾 奈愛, 小野 亜希子, 吉岡 徳枝, 山本 大介, 目瀬 浩, 佐々木 朗

    岡山歯学会雑誌   28 ( 1 )   94 - 95   2009.6

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  • 癌の骨浸潤・骨破壊におけるFocal adhesion kinase(FAK)の役割とシグナル制御

    栗尾 奈愛, 志茂 剛, 奥井 達雄, 吉岡 徳枝, 小野 亜希子, 山本 大介, 佐々木 朗

    岡山歯学会雑誌   28 ( 1 )   95 - 95   2009.6

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  • Parathyroid hormone 1(PTH1)レセプターアンタゴニストを用いた癌骨転移制御

    山本 大介, 吉岡 徳枝, 志茂 剛, 小野 亜希子, 栗尾 奈愛, 奥井 達雄, 佐々木 朗

    岡山歯学会雑誌   28 ( 1 )   97 - 98   2009.6

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  • 顎裂骨移植後の口腔前庭狭小に対して遊離歯肉移植を併用した口腔前庭拡張術を行った経験

    吉田 祥子, 岸本 晃治, 銅前 昇平, 奥井 達雄, 西山 明慶, 目瀬 浩, 佐々木 朗

    岡山歯学会雑誌   28 ( 1 )   92 - 92   2009.6

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  • 口腔癌の顎骨骨破壊におけるmTORシグナルの関与

    奥井 達雄, 志茂 剛, 栗尾 奈愛, 合田 健志, 小野 亜希子, 山本 大介, 吉岡 徳枝, 目瀬 浩, 佐々木 朗

    日本口腔科学会雑誌   58 ( 2 )   84 - 84   2009.3

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  • 顎裂骨移植後の口腔前庭狭小に対して遊離歯肉移植併用の口腔前庭拡張術を行った経験

    吉田祥子, 岸本晃治, 銅前昇平, 奥井達雄, 西山明慶, 目瀬 浩, 佐々木 朗

    岡山歯学会雑誌   28 ( 2 )   175 - 178   2009

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  • ソニックヘッジホッグによる歯胚未分化間葉系細胞の象牙芽細胞分化誘導

    志茂 剛, 小山 英樹, 栗尾 奈愛, 奥井 達雄, 山本 大介, 佐々木 朗

    日本再生歯科医学会誌   6 ( 1 )   65 - 65   2008.12

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  • Focal adhesion kinase(FAK)を分子標的とした癌骨転移制御

    栗尾 奈愛, 志茂 剛, 奥井 達雄, 吉岡 徳枝, 山本 大介, 佐々木 朗

    日本骨代謝学会学術集会プログラム抄録集   26回   189 - 189   2008.10

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  • 新規FAK分子標的治療薬TAE226の癌骨破壊病変に与える効果

    栗尾 奈愛, 志茂 剛, 奥井 達雄, 吉岡 徳枝, 山本 大介, 佐々木 朗

    日本口腔外科学会雑誌   54 ( Suppl. )   57 - 57   2008.9

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  • 口腔扁平上皮癌におけるTGF-βシグナルと癌の骨浸潤・骨破壊の治療への応用

    合田 健志, 志茂 剛, 吉濱 泰斗, 小野 亜希子, 栗尾 奈愛, 奥井 達雄, 山本 大介, 佐々木 朗

    日本口腔科学会雑誌   57 ( 4 )   545 - 545   2008.9

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  • 骨折修復過程におけるヘッジホッグシグナルの役割

    志茂 剛, 栗尾 奈愛, 奥井 達雄, 山本 大介, 佐々木 朗

    日本口腔外科学会雑誌   54 ( Suppl. )   121 - 121   2008.9

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  • 内軟骨性骨形成過程におけるRAシグナルのヘッジホッグ発現調節におよぼすメカニズムと役割の解明

    志茂 剛, 小山 英樹, 栗尾 奈愛, 奥井 達雄, 山本 大介, 岸本 晃治, 目瀬 浩, 佐々木 朗

    日本口腔科学会雑誌   57 ( 4 )   524 - 525   2008.9

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Awards

  • 生物学に関わる研究助成

    2020.9   両備てい園記念財団  

    奥井達雄

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  • 研究活動助成事業

    2019   ウエスコ学術振興財団  

    奥井達雄

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  • 学術研究費助成事業

    2018   川崎医学・医療福祉学振興会  

    奥井達雄

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  • 優秀演題賞

    2017   日本口腔科学会総会  

    奥井達雄

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  • EMW award

    2017   ヨーロッパ骨代謝学会  

    奥井達雄

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  • young investigated award

    2016.10   米国骨代謝学会  

    奥井達雄

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  • 優秀演題賞

    2016   日本口腔外科学会総会  

    奥井達雄

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  • 海外留学助成

    2014   上原記念財団  

    奥井達雄

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  • ゴールドリボン賞

    日本口腔外科学会総会  

    奥井達雄

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  • 科学研究助成

    両備てい園記念財団  

    奥井達雄

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  • 研究助成

    岡山県がん研究財団  

    奥井達雄

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  • 優秀論文賞

    岡山歯学会  

    奥井達雄

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Research Projects

  • 乳酸シャトルによる骨転移進展の制御

    Grant number:20H03859  2020.04 - 2024.03

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    米田 俊之, 奥井 達雄, 波多 賢二

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    Grant amount:\17680000 ( Direct expense: \13600000 、 Indirect expense:\4080000 )

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  • 口腔癌におけるangiogeninレセプターplexin-B2の発現と機能解析

    Grant number:20K10093  2020.04 - 2023.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    岸本 晃治, 奥井 達雄, 伊原木 聰一郎

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    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

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  • 癌の骨破壊病変に対する銅のキレートを応用した治療戦略の構築とその制御機構の解析

    Grant number:20H03889  2020.04 - 2023.03

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    佐々木 朗, 志茂 剛, 奥井 達雄, 吉岡 徳枝, 伊原木 聰一郎

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    Grant amount:\13260000 ( Direct expense: \10200000 、 Indirect expense:\3060000 )

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  • 癌骨破壊病変のHedgehogシグナルを起点とした癌代謝・癌免疫制御機構の解明

    Grant number:18H02999  2018.04 - 2022.03

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    志茂 剛, 佐々木 朗, 吉田 祥子, 青山 絵理子, 國定 勇希, 滝川 正春, 奥井 達雄, 長塚 仁, 高畠 清文, 久保田 聡

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    Grant amount:\17160000 ( Direct expense: \13200000 、 Indirect expense:\3960000 )

    腫瘍微小環境は,腫瘍実質と間質で構成されており,間質は,クロファージ,血管内皮細胞,癌関連線維芽細胞,免疫細胞など複数の異なる細胞で構成され,細胞外マトリックスから分泌されたサイトカイン,ケモカイン,成長因子,およびタンパク質を介して複雑な通信ネットワークを介して互いに相互作用するだけでなく,癌細胞とも相互作用する。
    本研究課題におけるSonic Hedgehogと口腔扁平上皮癌の腫瘍微小環境におけるその役割はまだ解明されておらず,我々は口腔癌切除標本を用いて検討した。
    浸潤能が強い癌細胞はそうでない癌細胞と比較して,Sonic Hedgehogとその受容体Patchedの両方をより強く発現し,一方でその間質は,CD31陽性の腫瘍血管内皮細胞,CD68陽性およびCD11b陽性のマクロファージ,α-smooth muscle actin陽性の癌関連線維芽細胞がPatchedを発現することが明らかになった。これらの結果は,Sonic Hedgehogのオートクライン効果が癌の浸潤を誘発し,一方でSonic Hedgehogパラクリン効果が口腔扁平上皮癌と間質相互作用を支配することが示唆された。

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  • 口腔癌の骨浸潤・骨転移において神経ペプチドCGRPが果たす役割と骨破壊制御機構

    Grant number:18K09811  2018.04 - 2021.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    吉岡 徳枝, 佐々木 朗, 奥井 達雄

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    今年度は知覚神経由来のCGRPが直接的あるいは間接的に口腔癌細胞の増殖に与える影響について検討した.最初に知覚神経細胞株F11細胞が初代培養知覚神経細胞DRGと同様にCGRPを発現することをウェスタンブロット法で確認した.F11細胞がDRGと同様にプロトンによる刺激により活性化されるかを検討するために,F11細胞をFura2蛍光色素でラベリングし,細胞興奮マーカーである細胞内カルシウム濃度を蛍光比で評価した.HCLを添加し細胞培養液注のpHを低下させると細胞内のCa2+濃度が上昇し,細胞興奮が惹起されることを確認した.このことからF11細胞は少なくともin vitroにおいて知覚神経としての細胞興奮性を有していることが明らかとなった.また血管内皮細胞HUVECの管腔形成におけるCGRPの影響についてTube formation assayを用いて検討した.F11培養上清を添加するとHUVECの管腔形成は誘導され,CGRP拮抗阻害薬(CGRP8-37)によりこの影響は阻害されたことから,知覚神経はCGRP産生を介してHUVECの管腔形成を促進する可能性が示唆された.各種口腔癌細胞株におけるCGRP受容体であるRAMP1の発現をウェスタンブロット法で確認し,CGRP添加によりこれら口腔癌細胞の細胞増殖は促進し,CGRP8-37添加により細胞増殖は阻害され,知覚神経由来のCGRPが直接的,間接的に口腔癌の増大を促進することが示唆された.さらにDRGに口腔癌細胞株の培養上製を添加し,培養すると軸索延長の促進が誘導された.これらの結果から,癌骨破壊病変において酸性環境は知覚神経を活性化させ,疼痛を惹起すると同時に知覚神経から放出されるCGRPが血管新生を介して間接的に癌細胞の増殖を誘導すること,あるいはCGRP受容体を介して間接的に癌細胞の増殖を促進する可能性があることが示唆された.

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  • HMGB1 induces bone pain associated with colonization of oral cancer in bone

    Grant number:18K17225  2018.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists  Grant-in-Aid for Early-Career Scientists

    Okui Tatsuo

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    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

    Oral cancer (OCa) invades to bone and causes bone pain. bone pain thus poses a significant challenge to the quality of life of patients presenting with OCa-BP. Here we studied OCa bone pain (OCa-BP) in an intratibial mouse xenograft model that uses a BCa cell line (SAS cells). These mice develop OCa-BP associated with an upregulation of phosphorylated ERK1/2 (pERK1/2), which is a molecular indicator of neuron excitation in the dorsal root ganglia (DRGs) of sensory nerve cell bodies. Our experiments demonstrated that inhibition of High mobility group box1(HMGB1) by short hairpin (shRNA) transduction, HMGB1 neutralizing antibody and HMGB1 receptor antagonist suppressed the OCa-BP and the pERK1/2 expression in DRG. Collectively, our results show that HMGB1 originating Bca evokes BCa-BP via direct HMGB1 signaling and hypersensitization for acid environment in SNs.

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  • The relationship between cancer-associted fibroblast and mast cell on the osteolysis of cancer induced bone disease

    Grant number:17H04405  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    Sasaki Akira

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    Grant amount:\16120000 ( Direct expense: \12400000 、 Indirect expense:\3720000 )

    Osteoclastic bone resorption plays an important role in bone invasion of cancer and bone destruction of bone metastases. Cancer-associated fibroblasts (B-CAF) present in the bone microenvironment of cancer bone-destructive lesion play an important role in the mechanism. On the other hand, mast cells, which are immune cells, are known to perform various functions such as angiogenesis of cancer, matrix degradation, and production of inflammatory substances related to pain. In this study, we investigated the mechanism of bone destruction by the interaction between B-CAF and mast cells. As a result, mast cells are induced in the cancer bone microenvironment, and their production factors not only directly promote osteoclastogenic bone resorption, but also induce bone resorption, matrix degradation, angiogenesis, etc. for B-CAF. It was suggested to be involved in bone destruction through facilitation and interaction.

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  • Development of molecular target therapy for oral cancer by an inhibitor of angiogenin activity, N65828

    Grant number:17K11873  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Kishimoto Koji

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    Grant amount:\4550000 ( Direct expense: \3500000 、 Indirect expense:\1050000 )

    An angiogenic protein, angiogenin (ANG) undergoes nuclear translocation and stimulates ribosomal RNA transcription in both endothelial and cancer cells. Consequently, ANG has a dual effect on cancer progression by inducing both angiogenesis and cancer cell proliferation. Our results revealed that N65828 [8-amino-5-(40-hydroxybiphenyl-4-ylazo)naphthalene-2-sulfonate], a small-molecule inhibitor of the ribonucleolytic activity of human ANG effectively inhibits oral cancer progression through inhibition of tumor angiogenesis. N65828 also directly inhibits proliferation of certain types of oral cancer cells. Therefore, N65828 has potential as a lead compound for oral cancer therapy.

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  • Midkine promotes oral cancer bone pain and progression

    Grant number:16H06992  2016.08 - 2018.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity Start-up  Grant-in-Aid for Research Activity Start-up

    Okui Tatsuo

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    Grant amount:\2990000 ( Direct expense: \2300000 、 Indirect expense:\690000 )

    we studied cancer bone pain in an intratibial mouse xenograft model that employs midkine positive human oral cancer cells.Mice intratibially injected with midkine positive oral cancer cells SAS developed characteristic osteolytic lesions on X-ray photograph.
    Midkine antagonist iMDK dramatically reduced cancer bone pain and progression of cancer cells in bone in mouse model. MIdkine antagonist iMDK dramatically suppressed osteoclast differentiation from bone marrow cells via vitamin D3 and MCSF stimulation.

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  • Role of cancer-associate fibroblasts on the regulation of angiognesis and bone resorption

    Grant number:26293429  2014.04 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    SASAKI AKIRA, OKUI Tatsuo, MORISAWA Ayaka, MASUI Masanori

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    Grant amount:\14820000 ( Direct expense: \11400000 、 Indirect expense:\3420000 )

    In the bone microenvironment of cancer induced bone destruction, the cancer-related fibroblasts play an important role on the regulation between angiogenesis and osteoclast formation and activity.
    As a result, exhaustive genetic analysis of cancer-related fibroblasts in bone, we showed that these cells highly express the RANKL and angiogenesis factor (VEGF, MMPs, IL-X, TNF,PGE, etc.).
    The copper ion regulator, ammonium tetrathiomolybdate (TM), which was candidates from screening of various angiogenesis inhibitors, inhibited the osteoclasts formation of the oral cancer bone destruction model and reinforced antitumor effect of Cetuximab in cancer bone destruction. In vitro study, TM inhibited osteoclasts formation through the suppression of angiogenesis and RANKL expression in osteoblast and osteocytes.

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  • Midkineを標的とした口腔扁平上皮癌に対する新規分子標的治療法の開拓

    Grant number:26861720  2014.04 - 2015.03

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    奥井 達雄

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    Grant amount:\3900000 ( Direct expense: \3000000 、 Indirect expense:\900000 )

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  • The role of mTOR and HSP90 against oral cancer induced angiogenesis

    Grant number:23890124  2011 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity Start-up  Grant-in-Aid for Research Activity Start-up

    OKUI Tatsuo

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    Grant amount:\3250000 ( Direct expense: \2500000 、 Indirect expense:\750000 )

    From surgically resected lower gingival squamous cell carcinoma samples, CD31 and VEGFR2 were highly expressed in vascular endothelial cells, and VEGF-A was expressed in tumor cells. The combination treatment of HSP90 inhibitor and mTOR inhibitor significantly inhibited VEGF induced cell proliferation, tube formation of human umbilical vein endothelial cells (HUVEC) more than the single treatment of them. Gelatin zymography showed that the combination treatment inhibited the activation of MMP-2 induced by VEGF in HUVEC more than the single treatment of them. Immunohistochemical analysis of mice xenografted with SAS oral squamous cell carcinoma cells showed a significant reduction in CD31-positive tumor vasculature in HSP90 inhibitor and mTOR inhibitor-administrated mouse tumor sections compared with the single treatment of them. Furthermore, the combination treatment of them suppressed both VEGFR2 and MMP-2 expression compared with both the control and the single treatments.

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  • Management of Systemic Diseases for Oral Surgery, blood disorder (2021academic year) Third semester  - 金1

  • Management of Systemic Diseases for Oral Surgery, blood disorder (2020academic year) Third semester  - 金1