Updated on 2024/02/24

写真a

 
KUNISADA Yuuki
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Assistant Professor
Position
Assistant Professor
Other name(s)
岡山大学
External link

Degree

  • 博士(歯学) ( 岡山大学 )

Research Interests

  • 腫瘍免疫

  • 制御性T細胞

  • DDS

Research Areas

  • Life Science / Oral pathobiological science

  • Life Science / Surgical dentistry

  • Life Science / Tumor diagnostics and therapeutics  / がん免疫学

  • Life Science / Immunology

Education

  • Okayama University   大学院医歯薬学総合研究科  

    2012.4 - 2016.3

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    Country: Japan

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  • Okayama University   歯学部   歯学科

    2004.4 - 2011.3

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    Country: Japan

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Research History

  • Okayama University   学術研究院 医歯薬学域 口腔顎顔面外科学   Assistant Professor

    2023.4

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    Country:Japan

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  • Columbia University   Surgery   Associate Research Scientist

    2021.7 - 2023.3

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    Country:United States

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

    2019.4 - 2021.7

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    Country:Japan

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

    2019.3

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  • Okayama University   Dental School

    2021.7 - 2023.3

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Professional Memberships

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Papers

  • Le Fort I型骨切り術と片側SSRO,分割オトガイ形成術で治療した第一第二鰓弓症候群による顔面非対称の1例

    西山 明慶, 小畑 協一, 國定 勇希, 竜門 省二, 小野 喜章, 吉岡 徳枝, 伊原木 聰一郎

    日本顎変形症学会雑誌   33 ( 2 )   180 - 180   2023.5

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    Language:Japanese   Publisher:(NPO)日本顎変形症学会  

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  • Craniomaxillofacial Fibrous Dysplasia Improved Cosmetic and Occlusal Problem by Comprehensive Treatment: A Case Report and Review of Current Treatments. International journal

    Kisho Ono, Norie Yoshioka, Yuki Kunisada, Tomoya Nakamura, Yuko Nakamura, Kyoichi Obata, Soichiro Ibaragi, Shogo Minagi, Akira Sasaki

    Diagnostics (Basel, Switzerland)   12 ( 9 )   2022.9

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    Fibrous dysplasia (FD) is a fibrous lesion of immature bone, with an incidence of 10-20% in the head and neck region. Most cases are monostotic, but when a lesion occurs on the maxillofacial region and spreads to the surrounding bone, it is classified as polyostotic, despite its localized occurrence. In some cases, surgical intervention is required to improve the cosmetic or functional disturbance of a FD in the maxillofacial region, but it is necessary to confirm symmetry of the maxillofacial region in real time, and a surgical support system is required to compensate. Furthermore, prosthetic intervention is considered when postoperative acquired defects occur or further cosmetic or occlusal function improvement is needed. A comprehensive approach by an oral surgeon and a maxillofacial prosthodontist is necessary for the successful treatment and rehabilitation of such patients. In this article, we describe the case of a craniomaxillofacial FD patient with facial asymmetry and denture incompatibility with improved quality of life measures by integrating surgical treatment using a navigation system and postoperative prosthetic rehabilitation. We also discuss recent diagnostic methods and treatment strategies for craniomaxillofacial FD in the literature.

    DOI: 10.3390/diagnostics12092146

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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

    西山 明慶, 吉岡 徳枝, 國定 勇希, 小畑 協一, 増井 正典, 小野 喜章, 竜門 省二, 伊原木 聰一郎, 佐々木 朗

    日本顎変形症学会雑誌   32 ( 2 )   222 - 222   2022.5

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  • 口腔癌の化学療法中に発症した肺血栓塞栓症の1例

    柴田 茜, 志茂 剛, 岸本 晃治, 國定 勇希, 目瀬 浩, 佐々木 朗

    日本口腔外科学会雑誌   68 ( 4 )   193 - 200   2022.4

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  • 歯科インプラント治療歴のある患者の治療後の問題に対する臨床的検討

    竜門 省二, 國定 勇希, 増井 正典, 坂本 裕美, 吉岡 徳枝, 西山 明慶, 伊原木 聰一郎, 佐々木 朗

    日本口腔診断学会雑誌   35 ( 1 )   115 - 116   2022.2

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  • Reproduction of the Antitumor Effect of Cisplatin and Cetuximab Using a Three-dimensional Spheroid Model in Oral Cancer. International journal

    Kisho Ono, Kohei Sato, Tomoya Nakamura, Yume Yoshida, Shogo Murata, Kunihiro Yoshida, Hideka Kanemoto, Koki Umemori, Hotaka Kawai, Kyoichi Obata, Shoji Ryumon, Kazuaki Hasegawa, Yuki Kunisada, Tatsuo Okui, Soichiro Ibaragi, Hitoshi Nagatsuka, Akira Sasaki

    International journal of medical sciences   19 ( 8 )   1320 - 1333   2022

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    Background/Aim: Cancer research has been conducted using cultured cells as part of drug discovery testing, but conventional two-dimensional culture methods are unable to reflect the complex tumor microenvironment. On the other hand, three-dimensional cultures have recently been attracting attention as in vitro models that more closely resemble the in vivo physiological environment. The purpose of this study was to establish a 3D culture method for oral cancer and to verify its practicality. Materials and Methods: Three-dimensional cultures were performed using several oral cancer cell lines. Western blotting was used for protein expression analysis of the collected cell masses (spheroids), and H-E staining was used for structural observation. The cultures were exposed to cisplatin and cetuximab and the morphological changes of spheroids over time and the expression changes of target proteins were compared. Results: Each cell line formed spheroidal cell aggregates and showed enhancement of cell adhesion molecules over time. H-E staining showed tumor tissue-like structures specific to each cell line. Cisplatin showed concentration-dependent antitumor effects due to loss of cell adhesion and spheroid disruption in each cell line, while cetuximab exhibited antitumor effects that correlated with EGFR expression in each cell line. Conclusion: Spheroids made from oral cancer cell lines appeared to have tumor-like characteristics that may reflect their clinical significance. In the future, it may become possible to produce tumor spheroids from tissue samples of oral cancer patients, and then apply them to drug screening and to develop individualized diagnostic and treatment methods.

    DOI: 10.7150/ijms.74109

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  • 歯科インプラント治療歴のある患者の治療後の問題に対する臨床的検討

    竜門 省二, 國定 勇希, 増井 正典, 坂本 裕美, 吉岡 徳枝, 西山 明慶, 伊原木 聰一郎, 佐々木 朗

    日本口腔内科学会雑誌   27 ( 2 )   115 - 116   2021.12

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  • Displacement of lower third molar into floor of mouth: a single institutional experience. International journal

    Masanori Masui, Soichiro Ibaragi, Yohei Takeshita, Joe Iwanaga, Yuki Kunisada, Akira Sasaki

    Oral and maxillofacial surgery   26 ( 3 )   447 - 453   2021.10

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    PURPOSE: The displacement of the tooth/tooth fragment into the floor of mouth sometimes happens during the lower third molar surgery and the patients are usually referred to oral and maxillofacial surgeons. To date, however, there is no consensus how to manage the displaced tooth due to the lack of available data. METHODS: In this study, we have retrospectively analyzed the management of the displaced lower third molar into the floor of mouth. Our institute experienced seven cases during 2010 to 2020. RESULTS: Incidence rate of the lingual nerve injury caused by displacement of the lower third molar was 1/7. Six patients out of seven underwent surgical removal of the displaced fragment. The direct approach was used when the fragment was palpable superficially and the fragment was horizontally located away from the lingual plate (2 cases), while when the fragment was not palpable, or was palpable and adjacent to the lingual plate, the lingual mucoperiosteal flap was selected (4 cases). CONCLUSION: We conclude that the palpation and preoperative diagnosis with computed tomographic images are significantly important to decide a better and most effective surgical approach.

    DOI: 10.1007/s10006-021-01012-3

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  • High mobility group box 1は口腔扁平上皮癌の骨破壊を誘発する

    坂本 裕美, 奥井 達雄, 竜門 省二, 中村 友哉, 國定 勇希, 増井 正典, 小野 喜章, 小畑 協一, 伊原木 聰一郎, 佐々木 朗

    日本口腔科学会雑誌   70 ( 2 )   115 - 115   2021.7

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  • Expression of Neurokinin B Receptor in the Gingival Squamous Cell Carcinoma Bone Microenvironment. International journal

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

    Diagnostics (Basel, Switzerland)   11 ( 6 )   2021.6

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

    DOI: 10.3390/diagnostics11061044

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  • A case of langerhans cell histiocytosis of the mandible that spontaneously regressed after biopsy in a child

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

    Clinical Case Reports   9 ( 6 )   2021.6

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    Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1002/ccr3.4321

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    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ccr3.4321

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

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

    International journal of surgery case reports   82   105883 - 105883   2021.5

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

    DOI: 10.1016/j.ijscr.2021.105883

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  • 上顎圧下時の頬骨下陵部の骨連続性維持のためのLe Fort I型骨切り術 軒先型骨切り術

    西山 明慶, 吉岡 徳枝, 小畑 協一, 國定 勇希, 小野 喜章, 村瀬 友理香, 竜門 省二, 岸本 晃治, 伊原木 聰一郎, 佐々木 朗

    日本顎変形症学会雑誌   31 ( 2 )   96 - 96   2021.5

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  • 切除後に再発を認めた舌のhobnail hemangiomaの1例

    國定 勇希, 槇野 隆秀, 伊原木 聰一郎, 熊谷 智代, 小野 喜章, 佐々木 朗

    日本口腔外科学会雑誌   67 ( 4 )   239 - 242   2021.4

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  • Comprehensive review of lower third molar management: A guide for improved informed consent. International journal

    Joe Iwanaga, Yuki Kunisada, Masanori Masui, Kyoichi Obata, Yohei Takeshita, Kotaro Sato, Shogo Kikuta, Yushi Abe, Yuki Matsushita, Jingo Kusukawa, R Shane Tubbs, Soichiro Ibaragi

    Clinical anatomy (New York, N.Y.)   34 ( 2 )   224 - 243   2021.3

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    Lower third molar removal is the most commonly performed dental surgical procedure. Nevertheless, it is difficult to ensure that all the informed consent forms given to patients are based on the best evidence as many newer publications could change the conclusions of previous research. Therefore, the goal of this review article is to cover existing meta-analyses, randomized control trials, and related articles in order to collect data for improved and more current informed consent.

    DOI: 10.1002/ca.23693

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  • 顎骨壊死を伴ったEBV陽性皮膚粘膜潰瘍(EBV-MCU)の2例

    竜門 省二, 岸本 晃治, 奥井 達雄, 吉岡 徳枝, 小畑 協一, 國定 勇希, 増井 正典, 小野 喜章, 伊原木 聰一郎, 佐々木 朗

    日本口腔診断学会雑誌   34 ( 1 )   71 - 71   2021.2

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  • 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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  • 顎骨壊死を伴ったEBV陽性皮膚粘膜潰瘍(EBV-MCU)の2例

    竜門 省二, 岸本 晃治, 奥井 達雄, 吉岡 徳枝, 小畑 協一, 國定 勇希, 増井 正典, 小野 喜章, 伊原木 聰一郎, 佐々木 朗

    日本口腔内科学会雑誌   26 ( 2 )   119 - 119   2020.12

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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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  • High-mobility group box 1 induces bone destruction associated with advanced oral squamous cancer via RAGE and TLR4. 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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  • High mobility group box 1 induces bone pain associated with bone invasion in a mouse model of advanced head and neck cancer

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

    Oncology Reports   2020.10

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

    DOI: 10.3892/or.2020.7788

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  • 骨折治癒過におけるIL-1βシグナルにレチノイド受容体アンタゴニストが与える影響

    藤井 彩貴, 奥井 達雄, 國定 勇希, 伊原木 聰一郎, 志茂 剛, 建部 廣明

    日本口腔科学会雑誌   69 ( 2 )   143 - 143   2020.7

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  • 顎矯正手術における偶発骨折の要因と対応について

    吉岡 徳枝, 西山 明慶, 奥井 達雄, 竜門 省二, 國定 勇希, 伊原木 聰一郎, 佐々木 朗

    日本顎変形症学会雑誌   30 ( 2 )   136 - 136   2020.5

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  • 最近10年間の顎矯正手術における合併症、偶発症に関する臨床的検討

    竜門 省二, 吉岡 徳枝, 國定 勇希, 岸本 晃治, 西山 明慶, 伊原木 聰一郎, 佐々木 朗

    日本顎変形症学会雑誌   30 ( 2 )   136 - 136   2020.5

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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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  • Surgical resection for advanced bisphosphonate-related osteonecrosis of the jaw associated with fibrous dysplasia: a case report. Reviewed International journal

    Yurika Murase, Koji Kishimoto, Shoko Yoshida, Yuki Kunisada, Koichi Kadoya, Soichiro Ibaragi, Akira Sasaki

    Journal of surgical case reports   2020 ( 3 )   rjaa061 - 3   2020.3

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    Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an adverse drug reaction represented by destruction and/or death of bone. Fibrous dysplasia (FD) is a rare bony disorder characterised by abnormal fibro-osseous tissue that has lowered resistance to infection. Effective treatments for BRONJ that follows FD are unclear. Here, we report that advanced BRONJ associated with FD was successfully treated by surgical resection. A 69-year-old woman, whose left maxillary bone showed a ground glass appearance on computed tomography (CT) images, was taking alendronate. At 1 year after teeth within the abnormal bone were extracted, exposed bone was observed in the extraction sites and CT images revealed separated sequestrums. Under the clinical diagnosis of Stage 2 BRONJ with FD, we performed not only sequestrectomy but also a partial resection of the FD. Thereafter, the healing was uneventful without recurrence. In conclusion, our case suggests that surgical resection is useful for advanced BRONJ associated with FD.

    DOI: 10.1093/jscr/rjaa061

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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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  • 当科における著名人のマスコミへの病名公表による受診率の影響について

    柴田 茜, 岸本 晃治, 小畑 協一, 國定 勇希, 吉岡 徳枝, 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   38 ( 2 )   92 - 92   2019.12

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  • 外科的矯正治療におけるオトガイ形成術の臨床的検討

    吉岡 徳枝, 西山 明慶, 國定 勇希, 伊原木 聰一郎, 佐々木 朗

    日本顎変形症学会雑誌   29 ( 2 )   150 - 150   2019.5

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  • Metformin induces CD11b+-cell-mediated growth inhibition of an osteosarcoma: implications for metabolic reprogramming of myeloid cells and anti-tumor effects. Reviewed

    Yuki Kunisada

    International immunology   2019.3

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    CD11b+ myeloid subpopulations, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), play crucial roles in the suppression of T-cell-mediated anti-tumor immunity. Regulation of these cell types is a primary goal for achieving efficient cancer immunotherapy. We found that metformin (Met) induces CD11b+-cell-mediated growth inhibition of a K7M2neo osteosarcoma independent of T cells, as growth inhibition of K7M2neo was still observed in wild-type (WT) mice depleted of T cells by antibodies and in SCID; this contrasted with the effect of Met on Meth A fibrosarcoma, which was entirely T-cell-dependent. Moreover, the inhibitory effect seen in SCID was abrogated by anti-CD11b antibody injection. PMN-MDSCs were significantly reduced in both spleens and tumors following Met treatment. In TAMs, production of IL-12 and TNF-α, but not IL-10, became apparent, and elevation of MHC class II with reduction of CD206 was observed, indicating a shift from an M2- to M1-like phenotype via Met administration. Metabolically, Met treatment decreased basal respiration and the oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio of CD11b+ cells in tumors, but not in the spleen. In addition, decreased reactive oxygen species (ROS) production and proton leakage in MDSCs and TAMs were consistently observed in tumors. Uptake of both 2-deoxy-2-d-glucose (2-NBDG) and BODIPY® decreased in MDSCs, but only BODIPY® incorporation was decreased in TAMs. Overall, our results suggest that Met redirects the metabolism of CD11b+ cells to lower oxidative phosphorylation (OXPHOS) while elevating glycolysis, thereby pushing the microenvironment to a state that inhibits the growth of certain tumors.

    DOI: 10.1093/intimm/dxy079

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  • メトホルミンは腫瘍内骨髄球系細胞の代謝を制御し骨肉腫増殖を抑制する

    上原 健敬, 榮川 伸吾, 國定 勇希, 長谷井 嬢, 中田 英二, 国定 俊之, 鵜殿 平一郎, 尾崎 敏文

    日本整形外科学会雑誌   93 ( 2 )   S53 - S53   2019.3

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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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  • 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.   33 ( 1 )   85 - 91   2019

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    Background/Aim: Retinoid signaling is important for the maturation of growth-plate chondrocytes. The effect of retinoid receptor gamma (RAR gamma) signaling on the expression of genes in hypertrophic chondrocytes is unclear. This study investigated the role of RAR gamma signaling in regulation of hypertrophic chondrocyte-specific genes. Materials and Methods: The gene expression in mouse E17.5 tibial cartilage was examined by in situ hybridization analysis. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunoblotting were used for analysis of mRNA and phosphorylated mitogen-activated protein kinase (MAPK). Results: mRNA expression of Rarg and connective tissue growth factor (Ccn2) was detected in maturing chondrocytes throughout the cartilaginous skeletal elements. In chondrogenic ATDC5 cells, an RAR gamma agonist induced the gene expression of type-X collagen (Col10A1), transglutaminase-2 (Tg2), matrix metalloproteinase-13 (Mmp13), and Ccn2 mRNA, whereas a retinoic acid pan-agonist suppressed RAR gamma agonist-stimulated gene expression. Phosphorylated extracellular signal regulated-kinases (pERK1/2), p-p38, and phosphorylated c-Jun N-terminal kinase (pJNK) MAPK were time-dependently increased by RAR gamma agonist treatment. Experimental p38 inhibition led to a severe drop in the RAR gamma agonist-stimulated expressions of Col10A1, Tg2, Mmp13, and Ccn2 mRNA. Conclusion: RARy signaling is required for the differentiation of hypertrophic chondrocytes, with differential cooperation with p38 MAPK.

    DOI: 10.21873/invivo.11443

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  • 腫瘍免疫の制御によるがん治療の展開 腫瘍微小環境の代謝改変は免疫を介して腫瘍増殖を抑制する(Regulation of tumor immunity and evolution of cancer treatments Metabolic reprogramming of tumor microenvironment leads to immune-mediated tumor growth inhibition)

    鵜殿 平一郎, 西田 充香子, 榮川 伸吾, 國定 勇希, 上原 健敬

    日本癌学会総会記事   77回   887 - 887   2018.9

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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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    DOI: 10.3389/fonc.2018.00376.

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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.

    DOI: 10.21873/anticanres.12132

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  • Attenuation of CD4(+) CD25(+) Regulatory T Cells in the Tumor Microenvironment by Metformin, a Type 2 Diabetes Drug Reviewed

    Yuki Kunisada, Shingo Eikawa, Nahoko Tomonobu, Shohei Domae, Takenori Uehara, Shohei Hori, Yukihiro Furusawa, Koji Hase, Akira Sasaki, Heiichiro Udono

    EBIOMEDICINE   25   154 - 164   2017.11

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    CD4(+) CD25(+) regulatory T cells (Treg), an essential subset for preventing autoimmune diseases, is implicated as a negative regulator in anti-tumor immunity. Wefound thatmetformin (Met) reduced tumor-infiltrating Treg (Ti-Treg), particularly the terminally-differentiated CD103(+) KLRG1(+) population, and also decreased effector molecules such as CTLA4 and IL-10. Met inhibits the differentiation of naive CD4(+) T cells into inducible Treg (iTreg) by reducing forkhead box P3 (Foxp3) protein, caused by mTORC1 activation that was determined by the elevation of phosphorylated S6 (pS6), a downstream molecule of mTORC1. Rapamycin and compound C, an inhibitor of AMP-activated protein kinase (AMPK) restored the iTreg generation, further indicating the involvement of mTORC1 and AMPK. The metabolic profile of iTreg, increased Glut1-expression, and reduced mitochondrial membrane-potential and ROS production of Ti-Treg aided in identifying enhanced glycolysis upon Met-treatment. The negative impact of Met on Ti-Treg may help generation of the sustained antitumor immunity. (C) 2017 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license

    DOI: 10.1016/j.ebiom.2017.10.009

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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.

    DOI: 10.21873/anticanres.12060

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  • 2型糖尿病薬メトホルミンによる腫瘍内制御性T細胞の機能抑制

    國定 勇希, 榮川 伸吾, 友信 奈保子, 銅前 昇平, 上原 健敬, 堀 昌平, 古澤 之裕, 長谷 耕二, 佐々木 朗, 鵜殿 平一郎

    日本癌学会総会記事   76回   J - 1090   2017.9

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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.

    DOI: 10.1016/j.ijscr.2016.12.014

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

    J Cell Biochem.   2017

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  • Maxillofacial Fractures in Elderly Patients. Reviewed

    Takakura H, Shimo T, Yoshioka N, Yao M, Obata K, Ibaragi S, Okui T, Kunisada Y, Morisawa A, Shibata A, Yoshida S, Murase Y, Kishimoto K, Nishiyama A, Mese H, Sasaki A

    Int J Surgical Proced.   2017

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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

    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

    International Journal of Surgery & Surgical Procedures   2 ( 1 )   1 - 7   2017

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    DOI: 10.15344/2456-4443/2017/115

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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.

    DOI: 10.21873/anticanres.11230

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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.

    DOI: 10.1016/j.ijso.2016.09.002

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  • 2型糖尿病薬メトホルミンの制御性T細胞抑制による抗腫瘍効果. Reviewed

    國定勇希

    岡山歯学会雑誌   35 ( 1 )   2016

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  • 腫瘍局所のmyeloid-derived suppressor cells(MDSCs)に与えるメトホルミン投与の効果

    上原 健敬, 榮川 伸吾, 國定 勇希, 渡邉 元嗣, 一柳 朋子, 山崎 千尋, 尾崎 敏文, 鵜殿 平一郎

    日本癌学会総会記事   74回   P - 2109   2015.10

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  • メトホルミンは腫瘍浸潤CD8T細胞においてエフェクターメモリー細胞を誘導し、多機能性を付与する(Metformin induced tumor infiltrating CD8 T-cells with effector memory phenotype and multi-functional reversion)

    榮川 伸吾, 根川 真実, 國定 勇希, 上原 健敬, 一柳 朋子, 山崎 千尋, 鵜殿 平一郎

    日本癌学会総会記事   73回   P - 1250   2014.9

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  • 咽頭弁により経鼻挿管困難であった唇顎口蓋裂患者に対し経口挿管で上下顎同時移動術を行った1例

    西山 明慶, 吉岡 徳枝, 伊原木 聰一郎, 國定 勇希, 福島 宏明, 村上 隆, 山城 隆, 佐々木 朗

    日本顎変形症学会雑誌   23 ( 2 )   108 - 108   2013.5

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  • 岡山大学病院腫瘍センターにおけるビスフォスフォネート使用患者に対する当科の取り組み

    吉岡 徳枝, 矢尾 真弓, 曽我 賢彦, 杉浦 裕子, 柴田 茜, 國定 勇希, 黒田 大雅, 伊原木 聰一郎, 目瀬 浩, 佐々木 朗

    日本口腔科学会雑誌   62 ( 1 )   57 - 57   2013.1

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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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  • 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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  • Karapandzic flapを応用して口角部を再建した頬粘膜癌の1例

    岸本 晃治, 吉岡 徳枝, 國定 勇希, 矢尾 真弓, 柴田 茜, 伊原木 聰一郎, 佐々木 朗

    頭頸部癌   45 ( 2 )   205 - 205   2019.5

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  • 長期経過の観察が可能であった小児遺伝性歯肉線維腫症の1例

    岸本 晃治, 矢尾 真弓, 國定 勇希, 角谷 宏一, 坂本 裕美, 佐々木 朗

    日本口腔診断学会雑誌   32 ( 1 )   81 - 81   2019.2

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  • 長期経過の観察が可能であった小児遺伝性歯肉線維腫症の1例

    岸本 晃治, 矢尾 真弓, 國定 勇希, 角谷 宏一, 坂本 裕美, 佐々木 朗

    日本口腔内科学会雑誌   24 ( 2 )   69 - 69   2018.12

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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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  • 代謝破綻と疾患 腫瘍微小環境の代謝改変とがん免疫治療への応用

    鵜殿 平一郎, 榮川 伸吾, 國定 勇希, 西田 充香子, 上原 健敬

    日本栄養・食糧学会大会講演要旨集   72回   174 - 174   2018.4

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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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  • 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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  • Metabolism of Tumor Infiltrating Immune Cells regulates anti-Tumor Immunity

    Heiichiro Udono, Shingo Eikawa, Yuki Kunisada, Takenori Uehara, Mototsugu Watanabe, Yuji Kimura, Akira Sasaki, Toshifumi Ozaki, Shinichi Toyooka, Toshiyoshi Fujiwara

    CANCER SCIENCE   109   535 - 535   2018.1

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  • Attenuation of CD4+CD25+regulatory T cells in the tumor microenvironment by metformin, a type 2 diabetes drug

    Yuki Kunisada, Shingo Eikawa, Nahoko Tomonobu, Shohei Domae, Takenori Uehara, Shohei Hori, Yukihiro Furusawa, Koji Hase, Akira Sasaki, Heiichiro Udono

    CANCER SCIENCE   109   106 - 106   2018.1

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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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  • 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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  • がん免疫療法の一段の進化へむけて 腫瘍浸潤免疫細胞の代謝は抗腫瘍免疫応答を制御する

    鵜殿 平一郎, 榮川 伸吾, 國定 勇希, 上原 健敬, 渡邉 元嗣, 木村 裕司, 佐々木 朗, 尾崎 敏文, 豊岡 伸一, 藤原 俊義

    日本癌学会総会記事   76回   S10 - 5   2017.9

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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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  • 骨肉腫における腫瘍浸潤骨髄球型細胞を介したメトホルミンの抗腫瘍効果

    上原 健敬, 榮川 伸吾, 國定 勇希, 渡邉 元嗣, 友信 奈保子, 吉田 晶, 藤原 智洋, 国定 俊之, 尾崎 敏文, 鵜殿 平一郎

    日本癌学会総会記事   75回   P - 3220   2016.10

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  • 癌患者由来末梢血CD8+T細胞における糖代謝の障害

    渡邉 元嗣, 榮川 伸吾, 友信 奈保子, 木村 裕司, 上原 健敬, 國定 勇希, 豊岡 伸一, 三好 新一郎, 鵜殿 平一郎

    日本癌学会総会記事   75回   P - 1161   2016.10

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  • 2型糖尿病薬メトホルミンはCD8T細胞のアミノ酸代謝および好気的解糖を促進し抗腫瘍作用を示す

    榮川 伸吾, 友信 奈保子, 山下 奈穂子, 渡邉 元嗣, 木村 裕司, 國定 勇希, 上原 健敬, 山崎 千尋, 福田 真嗣, 長谷 耕二, 鵜殿 平一郎

    日本癌学会総会記事   75回   J - 3066   2016.10

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  • メトホルミンは腫瘍局所で多機能性エフェクターT細胞を維持させるためにグルコースを必要とする

    友信 奈保子, 榮川 伸吾, 賀 芳, 山下 奈穂子, 渡邉 基嗣, 木村 裕司, 國定 勇希, 上原 健敬, 鵜殿 平一郎

    日本癌学会総会記事   75回   P - 1162   2016.10

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  • Metformin improves multiple cytokine producing ability of exhausted peripheral CD8+T cells of cancer patients

    Mototsugu Watanabe, Shingo Eikawa, Takenori Uehara, Yuki Kunisada, Shinichi Toyooka, Shinichiro Miyoshi, Heiichiro Udono

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-4865

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  • 2型糖尿病薬メトホルミンはCD8T細胞のアミノ酸代謝および好気的解糖を促進し抗腫瘍作用を示す

    榮川 伸吾, 友信 奈保子, 賀 芳, 山下 奈穂子, 渡邉 元嗣, 木村 裕司, 野島 一郎, 國定 勇希, 上原 健敬, 山崎 千尋, 長谷 耕二, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   20回   148 - 148   2016.6

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  • 2型糖尿病治療薬メトホルミンのヒト末梢血CD8T細胞への影響

    渡邉 元嗣, 榮川 伸吾, 友信 奈保子, 野島 一郎, 木村 裕司, 上原 健敬, 國定 勇希, 豊岡 伸一, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   20回   150 - 150   2016.6

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  • がんの細胞生物学とケミカルバイオロジー T細胞代謝制御によるがん免疫療法

    榮川 伸吾, 友信 奈保子, 賀 芳, 國定 勇希, 上原 健敬, 渡邉 元嗣, 野島 一郎, 木村 裕司, 鵜殿 平一郎

    日本細胞生物学会大会講演要旨集   68回   37 - 37   2016.5

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  • 口腔扁平上皮癌における術前化学療法に伴う腫瘍浸潤リンパ球の変化

    高倉 裕明, 銅前 昇平, 國定 勇希, 吉田 祥子, 小野 喜章, 岸本 晃治, 佐々木 朗

    頭頸部癌   42 ( 2 )   221 - 221   2016.5

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  • メトホルミンは腫瘍環境下においてCD8陽性エフェクターメモリー細胞の解糖系を亢進する

    榮川 伸吾, 庄 緋菲, 山下 奈穂子, 國定 勇希, 上原 健敬, 渡邉 元嗣, 小西 宏武, 近藤 智子, 西田 充香子, 一柳 朋子, 山崎 千尋, 鵜殿 平一郎

    日本癌学会総会記事   74回   J - 1165   2015.10

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  • 免疫疲弊T細胞に対するメトホルミンによる機能改善の検討

    渡邉 元嗣, 榮川 慎吾, Zhang Feifei, 野島 一郎, 國定 勇希, 上原 健敬, 豊岡 伸一, 鵜殿 平一郎

    日本癌学会総会記事   74回   P - 1257   2015.10

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  • メトホルミンは腫瘍局所における制御性T細胞の細胞死と抑制能を調節する

    國定 勇希, 榮川 伸吾, 銅前 昇平, 上原 健敬, 渡邉 元嗣, 山崎 千尋, 一柳 朋子, 佐々木 朗, 鵜殿 平一郎

    日本癌学会総会記事   74回   P - 2114   2015.10

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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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  • がん患者における疲弊CD8T細胞の多機能性解析(Monitoring multifunctionality of exhausted CD8 T-cells in cancer patients)

    根川 真実, 榮川 伸吾, 上原 健敬, 國定 勇希, 大植 祥弘, 黒瀬 浩史, 磯辺 みどり, 上中 明子, 垣見 和宏, 和田 尚, 岡 三喜男, 中山 睿一, 鵜殿 平一郎

    日本癌学会総会記事   73回   P - 1221   2014.9

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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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  • 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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  • 腫瘍浸潤CD8T細胞の免疫疲弊解除における活性化AMPKの役割

    榮川 伸吾, 根川 真実, 國定 勇希, 上原 健敬, 一柳 朋子, 山崎 千尋, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   18回   167 - 167   2014.6

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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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  • 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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  • 腫瘍局所における免疫疲弊CD8T細胞の機能回復を介したメトホルミンの抗腫瘍効果

    榮川 伸吾, 西田 充香子, 水上 修作, 山崎 千尋, 國定 勇希, 上原 健敬, 有吉 勇一, 鵜殿 平一郎

    日本がん免疫学会総会プログラム・抄録集   17回   114 - 114   2013.7

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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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  • 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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    Language:Japanese   Publisher:(一社)日本口腔内科学会  

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  • 下顎枝垂直骨切り術(IVRO)の術後における咬合の推移に関する研究

    江藤 司, 西山 明慶, 尾野 裕子, 國定 勇希, 吉岡 徳枝, 志茂 剛, 目瀬 浩, 佐々木 朗

    日本顎変形症学会雑誌   22 ( 2 )   147 - 147   2012.5

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Presentations

  • 2型糖尿病薬メトホルミンによる腫瘍局所の制御性T細胞抑制による抗腫瘍効果.

    國定勇希, 佐々木 朗

    第72回NPO法人日本口腔科学会学術集会  2018.5 

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  • Attenuation of CD4+CD25+ regulatory T cells in the tumor microenvironment by metformin, a type 2 diabetes drug.

    2017.9 

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  • 当科を受診したインプラント治療患者の問題に対する臨床的検討

    國定勇希, 岸本晃治, 清水理恵子, 坂本裕美, 吉田祥子, 奥井達雄, 伊原木聰一郎, 吉岡?枝, 西山明慶, 志茂 剛, 佐々木 朗

    第46回(公社)日本口腔外科学会 中国四国支部学術集会  2017.5 

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  • 糖尿病薬メトホルミンの腫瘍内制御性T細胞抑制による抗腫瘍効果

    國定勇希, 榮川伸吾, 銅前昇平, 上原健敬, 鵜殿平一郎, 佐々木朗

    第15回中国四国口腔癌研究会  2016.10 

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  • 2型糖尿病薬メトホルミンの腫瘍局所における制御性T細胞への作用

    國定勇希, 榮川伸吾, 銅前昇平, 上原健敬, 鵜殿平一郎

    第19回癌と免疫セミナー  2016.7 

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  • 2型糖尿病薬メトホルミンの制御性T細胞抑制による抗腫瘍効果

    國定勇希, 榮川伸吾, 銅前昇平, 上原健敬, 鵜殿平一郎

    第35回岡山免疫懇話会  2016.3 

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  • Metformin regulates survivals of Treg in tumor microenvironment

    2015.11 

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  • Metformin regulates cell survivals and suppressive function of Treg in tumor local site

    2015.10 

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  • Metformin regulates survivals of Treg in tumor microenvironment

    2015.7 

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  • Detection of sonic hedgehog in a patient with orthognathic surgery International conference

    Kunisada Y, Shimo T, Kurio N, Masui M, Yoshioka N, Ibaragi S, Okui T, Nishiyama A, Sasaki A

    ASBMR 2014 Annual Meeting  2014.9 

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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, 吉岡徳枝, 伊原木聰一郎, 奥井達雄, 西山明慶, 佐々木朗

    第32回 日本骨代謝学会学術集会  2014.7 

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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

    第68回日本口腔科学会学術集会  2014.5 

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Awards

  • 第72回NPO法人日本口腔科学会学術集会 優秀ポスター賞

    2018   NPO法人日本口腔科学会   2型糖尿病薬メトホルミンによる腫瘍局所の制御性T細胞抑制による抗腫瘍効果

    國定勇希

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Research Projects

  • 脂質代謝を標的とした新規免疫抑制解除型治療の基盤研究

    Grant number:19K16836  2019.04 - 2022.03

    日本学術振興会  科学研究費助成事業 若手研究  若手研究

    國定 勇希

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

    1. 蛍光免疫組織染色によるstage毎のがん細胞における脂肪酸合成と免疫細胞の相関関係の解析では口腔がん患者の組織切片で脂肪酸合成剤FASN(Fatty acid synthase)分子,Treg, CD8T細胞,CD4T細胞などの免疫細胞を多重蛍光免疫組織染色し,現在も症例数を増やして継続して解析中である.同実験では,腫瘍組織内に浸潤しているTregやCD8を可視化して,また同時に脂肪酸合成阻害剤との関連も検出出来ている.
    2. 脂肪酸合成阻害剤の直接的ながん細胞への作用の解析では脂肪酸合成阻害剤(スタチン)の存在下,非存在下で,ヒト口腔がん細胞株(SAS,HSC2,3)やマウスがん細胞株(SCC7)を培養し,脂肪酸合成阻害が直接的にが ん細胞の増殖能や浸潤能に影響するかどうかをin vitroの培養系で解析を行っている.がん細胞をシャーレで培養し,数の変化を経時的に観察し,増殖能の評価 を行い,transwell invasion assayを用いて浸潤能の評価を行っている.さらに,脂肪酸合成阻害剤(スタチン)の濃度を振り,マウスがん細胞株(SCC7)を培養し,フローサイトメーターを用いて細胞周期に変化があるかどうかの解析を行っている.
    3. マウス腫瘍移植モデルを用いた脂肪酸合成阻害剤による末梢あるいは腫瘍局所におけ るTregの数の変化,機能の変化の解析ではマウスがん細胞株をC57BL/6マウス背部皮内に移植し,脂肪酸合成阻害剤を使用して抗腫瘍効果があるか解析を試みた.

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  • The study of the regulatory mechanisms of cancer bone destruction metabolism and immunity in Hedgehog signaling

    Grant number:18H02999  2018.04 - 2022.03

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

    SHIMO Tsuyoshi

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

    Hedgehog downstream signaling molecules deployed from a comprehensive pathway analysis in the cancer bone destruction microenvironment (Shimo et al. PlosOne 2016) are associated with prognosis in gingival cancer patients with Stage IV jaw bone invasion (Yoshida, Shimo et al. Diagnostics (Basel) 2021).
    In addition, tumor vascular endothelial cells in patients with Stage II introverted tongue cancer showed significantly enhanced expression of Hedgehog signaling and a positive correlation with tumor-associated macrophage (TAM) accumulation (Takabatake, Shimo et al. Int J Mol Sci 2019). We also analyzed the histological and genetical effect of Gli-1 and Gli-2 dual inhibitor on the in vitro study and in vivo cancer bone destruction mouse model.

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  • Regulation of function and antitumor effect of regulatory T cells in the tumor microenvironment by metformine, a type 2 diabetes drug

    Grant number:17K15025  2017.04 - 2019.03

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

    Kunisada Yuki, UDONO Heiichiro, EIKAWA Shingo

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

    We have already demonstrated that the type 2 diabetes drug metformin has antitumor activity via immune cells. In this study, we analyzed the effect of metformin on immunoregulatory regulatory T cells (Tregs), which are said to contribute to tumor growth.
    In the mouse tumor transplantation model, we observed that administration of metformin induced Treg apoptosis and suppressed Treg function in only tumor local sites. In addition, we demonstrated that the metabolism of Treg, which metabolism is dominant in fatty acid oxidation, is predominantly changed from fatty acid oxidation to glycolytic metabolism at the time of differentiation / induction from non-Treg cells to Treg.

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  • Antitumor effect of anti-CCR4 antibody in head and neck cancer

    Grant number:26463042  2014.04 - 2017.03

    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)

    DOMAE Shohei, KUNISADA Yuki, TAKAKURA Hiroaki

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    Grant amount:\4810000 ( Direct expense: \3700000 、 Indirect expense:\1110000 )

    CCR4 expressing FoxP3+CD4 regulatory T cells (Treg) depletion using humanized anti-CCR4 monoclonal antibodies may enhance the host immune response against tumors. The current ongoing clinical trial investigates the use of humanized anti-human-CCR4 monoclonal antibody in the treatment of solid tumors. CCR4 expressing stroma infiltrating lymphocytes were detected in 32 of 42 (76.2%) head and neck cancer samples and were correlate with CCL22/MDC. CCR4 expressing tumor cells were detected in only 7 of 42 (16.7%) same samples. There was no markedly enhancement of antitumor effect by anti-CCR4 antibody in CCR4 expressing tumor cells.

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Class subject in charge

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