研究者詳細 - 河合　穂高

論文 - 河合　穂高

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Efficacy of Cisplatin–CXCR4 Antagonist Combination Therapy in Oral Cancer 査読

Saori Yoshida, Hotaka Kawai, Yamin Soe, Htoo Shwe Eain, Sho Sanou, Kiyofumi Takabatake, Yohei Takeshita, Miki Hisatomi, Hitoshi Nagatsuka, Junichi Asaumi, Yoshinobu Yanagi

Cancers 16 ( 13 ) 2326 - 2326 2024年6月

担当区分：責任著者掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Cisplatin is a platinum-based compound that is widely used for treating inoperable oral squamous cell carcinoma (OSCC) in Japan; however, resistance to cisplatin presents a challenge and innovative approaches are required. We aimed to investigate the therapeutic potential of targeting the chemokine receptor CXCR4, which is involved in angiogenesis and tumor progression, using the CXCR4 inhibitor AMD3100, in combination with cisplatin. AMD3100 induced necrosis and bleeding in OSCC xenografts by inhibiting angiogenesis. We investigated the combined ability of AMD3100 plus cisplatin to enhance the antitumor effect in cisplatin-resistant OSCC. An MTS assay identified HSC-2 cells as cisplatin-resistant cells in vitro. Mice treated with the cisplatin-AMD combination exhibited the most significant reduction in tumor volume, accompanied by extensive hemorrhage and necrosis. Histological examination indicated thin and short tumor vessels in the AMD and cisplatin–AMD groups. These results indicated that cisplatin and AMD3100 had synergistic antitumor effects, highlighting their potential for vascular therapy of refractory OSCC. Antitumor vascular therapy using cisplatin combined with a CXCR4 inhibitor provides a novel strategy for addressing cisplatin-resistant OSCC.

DOI： 10.3390/cancers16132326

Double-faced CX3CL1 enhances lymphangiogenesis-dependent metastasis in an aggressive subclone of oral squamous cell carcinoma. 査読国際誌

Htoo Shwe Eain, Hotaka Kawai, Masaaki Nakayama, May Wathone Oo, Toshiaki Ohara, Yoko Fukuhara, Kiyofumi Takabatake, Quisheng Shan, Yamin Soe, Kisho Ono, Keisuke Nakano, Nobuyoshi Mizukawa, Seiji Iida, Hitoshi Nagatsuka

JCI insight 9 ( 10 ) 2024年5月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Because cancer cells have a genetically unstable nature, they give rise to genetically different variant subclones inside a single tumor. Understanding cancer heterogeneity and subclone characteristics is crucial for developing more efficacious therapies. Oral squamous cell carcinoma (OSCC) is characterized by high heterogeneity and plasticity. On the other hand, CX3C motif ligand 1 (CX3CL1) is a double-faced chemokine with anti- and pro-tumor functions. Our study reported that CX3CL1 functioned differently in tumors with different cancer phenotypes, both in vivo and in vitro. Mouse OSCC 1 (MOC1) and MOC2 cells responded similarly to CX3CL1 in vitro. However, in vivo, CX3CL1 increased keratinization in indolent MOC1 cancer, while CX3CL1 promoted cervical lymphatic metastasis in aggressive MOC2 cancer. These outcomes were due to double-faced CX3CL1 effects on different immune microenvironments indolent and aggressive cancer created. Furthermore, we established that CX3CL1 promoted cancer metastasis via the lymphatic pathway by stimulating lymphangiogenesis and transendothelial migration of lymph-circulating tumor cells. CX3CL1 enrichment in lymphatic metastasis tissues was observed in aggressive murine and human cell lines. OSCC patient samples with CX3CL1 enrichment exhibited a strong correlation with lower overall survival rates and higher recurrence and distant metastasis rates. In conclusion, CX3CL1 is a pivotal factor that stimulates the metastasis of aggressive cancer subclones within the heterogeneous tumors to metastasize, and our study demonstrates the prognostic value of CX3CL1 enrichment in long-term monitoring in OSCC.

DOI： 10.1172/jci.insight.174618

Enzyme-Cleaved Bone Marrow Transplantation Improves the Engraftment of Bone Marrow Mesenchymal Stem Cells. 査読国際誌

Hotaka Kawai, May Wathone Oo, Kiyofumi Takabatake, Ikue Tosa, Yamin Soe, Htoo Shwe Eain, Sho Sanou, Shigeko Fushimi, Shintaro Sukegawa, Keisuke Nakano, Takarada Takeshi, Hitoshi Nagatsuka

JBMR plus 7 ( 3 ) e10722 2023年3月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Mesenchymal stem cell (MSC) therapy is a promising approach to curing bone diseases and disorders. In treating genetic bone disorders, MSC therapy is local or systemic transplantation of isolated and in vitro proliferated MSC rather than bone marrow transplantation. Recent evidence showed that bone marrow MSC engraftment to bone regeneration has been controversial in animal and human studies. Here, our modified bone marrow transplantation (BMT) method solved this problem. Like routine BMT, our modified method involves three steps: (i) isolation of bone marrow cells from the donor, (ii) whole-body lethal irradiation to the recipient, and (iii) injection of isolated bone marrow cells into irradiated recipient mice via the tail vein. The significant modification is imported at the bone marrow isolation step. While the bone marrow cells are flushed out from the bone marrow with the medium in routine BMT, we applied the enzymes' (collagenase type 4 and dispase) integrated medium to wash out the bone marrow cells. Then, cells were incubated in enzyme integrated solution at 37°C for 10 minutes. This modification designated BMT as collagenase-integrated BMT (c-BMT). Notably, successful engraftment of bone marrow MSC to the new bone formation, such as osteoblasts and chondrocytes, occurs in c-BMT mice, whereas routine BMT mice do not recruit bone marrow MSC. Indeed, flow cytometry data showed that c-BMT includes a higher proportion of LepR+, CD51+, or RUNX2+ non-hematopoietic cells than BMT. These findings suggested that c-BMT is a time-efficient and more reliable technique that ensures the disaggregation and collection of bone marrow stem cells and engraftment of bone marrow MSC to the recipient. Hence, we proposed that c-BMT might be a promising approach to curing genetic bone disorders. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

DOI： 10.1002/jbm4.10722

SOD3 Expression in Tumor Stroma Provides the Tumor Vessel Maturity in Oral Squamous Cell Carcinoma. 査読国際誌

May Wathone Oo, Hotaka Kawai, Htoo Shwe Eain, Yamin Soe, Kiyofumi Takabatake, Sho Sanou, Qiusheng Shan, Yasunori Inada, Masae Fujii, Yoko Fukuhara, Ziyi Wang, Shintaro Sukegawa, Mitsuaki Ono, Keisuke Nakano, Hitoshi Nagatsuka

Biomedicines 10 ( 11 ) 2022年10月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Tumor angiogenesis is one of the hallmarks of solid tumor development. The progressive tumor cells produce the angiogenic factors and promote tumor angiogenesis. However, how the tumor stromal cells influence tumor vascularization is still unclear. In the present study, we evaluated the effects of oral squamous cell carcinoma (OSCC) stromal cells on tumor vascularization. The tumor stromal cells were isolated from two OSCC patients with different subtypes: low invasive verrucous squamous carcinoma (VSCC) and highly invasive squamous cell carcinoma (SCC) and co-xenografted with the human OSCC cell line (HSC-2) on nude mice. In comparison, the CD34+ vessels in HSC-2+VSCC were larger than in HSC-2+SCC. Interestingly, the vessels in the HSC-2+VSCC expressed vascular endothelial cadherin (VE-cadherin), indicating well-formed vascularization. Our microarray data revealed that the expression of extracellular superoxide dismutase, SOD3 mRNA is higher in VSCC stromal cells than in SCC stromal cells. Moreover, we observed that SOD3 colocalized with VE-cadherin on endothelial cells of low invasive stroma xenograft. These data suggested that SOD3 expression in stromal cells may potentially regulate tumor vascularization in OSCC. Thus, our study suggests the potential interest in SOD3-related vascular integrity for a better OSCC therapeutic strategy.

DOI： 10.3390/biomedicines10112729

Cancer-Associated Stromal Cells Promote the Contribution of MMP2-Positive Bone Marrow-Derived Cells to Oral Squamous Cell Carcinoma Invasion. 査読国際誌

May Wathone Oo, Hotaka Kawai, Kiyofumi Takabatake, Qiusheng Shan, Htoo Shwe Eain, Shintaro Sukegawa, Keisuke Nakano, Hitoshi Nagatsuka

Cancers 14 ( 1 ) 2021年12月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Tumor stromal components contribute to tumor development and invasion. However, the role of stromal cells in the contribution of bone marrow-derived cells (BMDCs) in oral squamous cell carcinoma (OSCC) invasion is unclear. In the present study, we created two different invasive OSCC patient-derived stroma xenografts (PDSXs) and analyzed and compared the effects of stromal cells on the relation of BMDCs and tumor invasion. We isolated stromal cells from two OSCC patients: less invasive verrucous OSCC (VSCC) and highly invasive conventional OSCC (SCC) and co-xenografted with the OSCC cell line (HSC-2) on green fluorescent protein (GFP)-positive bone marrow (BM) cells transplanted mice. We traced the GFP-positive BM cells by immunohistochemistry (IHC) and detected matrix metalloproteinase 2 (MMP2) expression on BM cells by double fluorescent IHC. The results indicated that the SCC-PDSX promotes MMP2-positive BMDCs recruitment to the invasive front line of the tumor. Furthermore, microarray analysis revealed that the expressions of interleukin 6; IL-6 mRNA and interleukin 1 beta; IL1B mRNA were higher in SCC stromal cells than in VSCC stromal cells. Thus, our study first reports that IL-6 and IL1B might be the potential stromal factors promoting the contribution of MMP2-positive BMDCs to OSCC invasion.

DOI： 10.3390/cancers14010137

Resident stroma-secreted chemokine CCL2 governs myeloid-derived suppressor cells in the tumor microenvironment 査読国際誌

May Wathone Oo, Hotaka Kawai, Kiyofumi Takabatake, Shuta Tomida, Takanori Eguchi, Kisho Ono, Qiusheng Shan, Toshiaki Ohara, Saori Yoshida, Haruka Omori, Shintaro Sukegawa, Keisuke Nakano, Kuniaki Okamoto, Akira Sasaki, Hitoshi Nagatsuka

JCI Insight 7 ( 1 ) 2021年12月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：American Society for Clinical Investigation

Accumulating evidence has shown that cancer stroma and BM-derived cells (BMDCs) in the tumor microenvironment (TME) play vital roles in tumor progression. However, the mechanism by which oral cancer stroma recruits any particular subset of BMDCs remains largely unknown. Here, we sought to identify the subset of BMDCs that is recruited by cancer stroma. We established a sequential transplantation model in BALB/c nude mice, including (a) BM transplantation of GFP-expressing cells and (b) coxenografting of patient-derived stroma (PDS; 2 cases, designated PDS1 and PDS2) with oral cancer cells (HSC-2). As controls, xenografting was performed with HSC-2 alone or in combination with normal human dermal fibroblasts (HDF). PDS1, PDS2, and HDF all promoted BMDC migration in vitro and recruitment in vivo. Multicolor immunofluorescence revealed that the PDS coxenografts recruited Arginase-1+CD11b+GR1+GFP+ cells, which are myeloid-derived suppressor cells (MDSCs), to the TME, whereas the HDF coxenograft did not. Screening using microarrays revealed that PDS1 and PDS2 expressed CCL2 mRNA (encoding C-C motif chemokine ligand 2) at higher levels than did HDF. Indeed, PDS xenografts contained significantly higher proportions of CCL2+ stromal cells and CCR2+Arginase-1+CD11b+GR1+ MDSCs (as receiver cells) than the HDF coxenograft. Consistently, a CCL2 synthesis inhibitor and a CCR2 antagonist significantly inhibited the PDS-driven migration of BM cells in vitro. Furthermore, i.p. injection of the CCR2 antagonist to the PDS xenograft models significantly reduced the CCR2+Arginase-1+CD11b+GR1+ MDSC infiltration to the TME. In conclusion, oral cancer stroma-secreted CCL2 is a key signal for recruiting CCR2+ MDSCs from BM to the TME.

DOI： 10.1172/jci.insight.148960

Biological Effects of Bioresorbable Materials in Alveolar Ridge Augmentation: Comparison of Early and Slow Resorbing Osteosynthesis Materials. 査読国際誌

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

Materials (Basel, Switzerland) 14 ( 12 ) 2021年6月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/ma14123286

Potential role of myeloid-derived suppressor cells in transition from reaction to repair phase of bone healing process. 査読国際誌

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

International journal of medical sciences 18 ( 8 ) 1824 - 1830 2021年

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.7150/ijms.51946

Impact of the Stroma on the Biological Characteristics of the Parenchyma in Oral Squamous Cell Carcinoma. 査読国際誌

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

International journal of molecular sciences 21 ( 20 ) 2020年10月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/ijms21207714

Triple knockdown of CDC37, HSP90-alpha and HSP90-beta diminishes extracellular vesicles-driven malignancy events and macrophage M2 polarization in oral cancer. 査読国際誌

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

Journal of extracellular vesicles 9 ( 1 ) 1769373 - 1769373 2020年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1080/20013078.2020.1769373

Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) in Oral Cancer. 査読国際誌

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

Cells 8 ( 7 ) 2019年7月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/cells8070761

Characterization and potential roles of bone marrow-derived stromal cells in cancer development and metastasis. 査読国際誌

Kawai Hotaka, Tsujigiwa H, Siar CH, Nakano K, Takabatake K, Fujii M, Hamada M, Tamamura R, Nagatsuka H

International journal of medical sciences 15 ( 12 ) 1406 - 1414 2018年

Risk factors for post-extraction infection of mandibular third molar: A retrospective clinical study. 国際誌

Yumika Mukainaka, Shintaro Sukegawa, Hotaka Kawai, Tetsuya Nishida, Minoru Miyake, Hitoshi Nagatsuka

Journal of stomatology, oral and maxillofacial surgery 125 ( 4S ) 101841 - 101841 2024年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Post-extraction infection is one of the most concerning complications of mandibular third molar extraction, which is the most common procedure in oral and maxillofacial surgery. We investigated risk factors for post-extraction infection by retrospectively analyzing 2,513 teeth/cases of mandibular third molar extraction (1,040 males, 1,473 females) performed at a single medical facility in Kobe, Japan from January 2014 to May 2022. The predictive variables were categorized as patient attributes, health status, and anatomic, pathological, and operative variables that may be associated with post-extraction infection. The outcome variable was the post-extraction infection rate. The post-extraction infection rate was 5.73 % (144 of the 2,513 teeth), and the mean age of the patients with a post-extraction infection was 41.76 ± 16.8 years. Our analyses also revealed that the postoperative infection rate was significantly increased in patients aged ≥36 years. A multivariate logistic regression analysis showed that the following variables were significantly associated with post-extraction infection: preoperative antibiotic administration (odds ratio [OR] 4.68, p < 0.001), postoperative paresthesia of the inferior alveolar nerve (OR 4.34, p < 0.001), intraoperative hemostatic procedure (OR 1. 74, p = 0.008), position of Pell and Gregory classifications (OR 1. 70, p < 0.001), Winter's classification (OR 1.28, p < 0.03), and age (OR 1.03, p < 0.001). Oral and maxillofacial surgeons should be aware of these risk factors.

DOI： 10.1016/j.jormas.2024.101841

Effect of Scaffold Geometrical Structure on Macrophage Polarization during Bone Regeneration Using Honeycomb Tricalcium Phosphate. 国際誌

Kiyofumi Takabatake, Hidetsugu Tsujigiwa, Keisuke Nakano, Anqi Chang, Tianyan Piao, Yasunori Inada, Takuma Arashima, Ayumi Morimatsu, Ayumi Tanaka, Hotaka Kawai, Hitoshi Nagatsuka

Materials (Basel, Switzerland) 17 ( 16 ) 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

The polarization balance of M1/M2 macrophages with different functions is important in osteogenesis and bone repair processes. In a previous study, we succeeded in developing honeycomb tricalcium phosphate (TCP), which is a cylindrical scaffold with a honeycomb arrangement of straight pores, and we demonstrated that TCP with 300 and 500 μm pore diameters (300TCP and 500TCP) induced bone formation within the pores. However, the details of the influence of macrophage polarization on bone formation using engineered biomaterials, especially with respect to the geometric structure of the artificial biomaterials, are unknown. In this study, we examined whether differences in bone tissue formation due to differences in TCP geometry were due to the polarity of the assembling macrophages. Immunohistochemistry for IBA-1, iNOS, and CD163 single staining was performed. The 300TCP showed a marked infiltration of iNOS-positive cells, which are thought to be M1 macrophages, during the osteogenesis process, while no involvement of CD163-positive cells, which are thought to be M2 macrophages, was observed in the TCP pores. In addition, 500TCP showed a clustering of iNOS-positive cells and CD163-positive cells at 2 weeks, suggesting the involvement of M2 macrophages in the formation of bone tissue in the TCP pores. In conclusion, we demonstrated for the first time that the geometrical structure of the artificial biomaterial, i.e., the pore size of honeycomb TCP, affects the polarization of M1/2 macrophages and bone tissue formation in TCP pores.

DOI： 10.3390/ma17164108

BIOLOGY TOPICS セツキシマブ抵抗性口腔癌への基礎研究戦略

小野喜章, 河合穂高, 長塚仁, 伊原木聰一郎

BIO Clinica 39 ( 8 ) 670 - 675 2024年7月

記述言語：日本語出版者・発行元：(株)北隆館

上皮成長因子受容体(EGFR)標的抗体薬セツキシマブは,口腔癌治療に用いる分子標的薬であるが,奏功率の低さや耐性の出現など治療抵抗性が課題である。口腔癌進展におけるEGFRやセツキシマブの分子機序について理解し,基礎的研究による問題解決が必要である。細胞外小胞(EV)は癌治療抵抗性を制御する重要な因子として注目されており,EVベースの治療・診断など,臨床応用に向けた研究開発が進んでいる。本稿では,著者らのこれまでの研究をもとに,セツキシマブ抵抗性口腔癌の新規的分子機序やEVとの関わりについて概説する。(著者抄録)

口腔扁平上皮癌に対する骨髄由来間葉系幹細胞の役割

佐能彰, 河合穂高, 高畠清文, 中野啓介, 長塚仁, 伊原木聰一郎

頭頸部癌 50 ( 2 ) 217 - 217 2024年5月

口腔扁平上皮癌に対する骨髄由来間葉系幹細胞の役割

佐能彰, 河合穂高, 高畠清文, 中野啓介, 長塚仁, 伊原木聰一郎

頭頸部癌 50 ( 2 ) 217 - 217 2024年5月

口腔癌間質による腫瘍実質の生物学的性格制御について

高畠清文, チャン・アンチ, ピャオ・ティンヤン, リー・ズウシャオ, 河合穂高, 中野敬介, 長塚仁

日本病理学会会誌 113 ( 1 ) 353 - 353 2024年2月

Novel mechanism of cisplatin resistance in head and neck squamous cell carcinoma involving extracellular vesicles and a copper transporter system. 国際誌

Tatsuo Ogawa, Kisho Ono, Shoji Ryumon, Hotaka Kawai, Tomoya Nakamura, Koki Umemori, Kunihiro Yoshida, Hideka Kanemoto, Kyoichi Obata, Norie Yoshioka, Tatsuo Okui, Kuniaki Okamoto, Hitoshi Nagatsuka, Soichiro Ibaragi

Head & neck 2024年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Cisplatin (CDDP) plays a central role in chemotherapy for head and neck squamous cell carcinoma (HNSCC), but drug resistance in HNSCC chemotherapy remains a problem, and the mechanism of CDDP resistance is unclear. We investigated CDDP-resistance mechanisms mediated by extracellular vesicles (EVs) and ATPase copper transporting beta (ATP7B) in HNSCC. METHODS: We established CDDP-resistant sublines of HNSCC cells and verified their ATP7B expression. We used an EV secretion inhibitor (GW4869) and ATP7B short hairpin (sh)RNA transfection to examine the correlation between EV secretion and ATP7B expression. RESULTS: The CDDP-resistant HNSCC sublines showed decreased CDDP sensitivity and increased ATP7B expression. GW4869 suppressed ATP7B expression, and ATP7B shRNA transfection suppressed EV secretion. The suppressions of EV secretion and ATP7B expression both enhanced CDDP's cell-killing effect. CONCLUSIONS: EVs were involved in the ATP7B-mediated mechanism underlying CDDP resistance. Further clarification of the EV-induced CDDP-resistance mechanism may lead to novel therapeutic strategies for HNSCC.

DOI： 10.1002/hed.27620

A histological study of the adult ligamentum arteriosum: Novel findings with application to a patent ductus arteriosus. 国際誌

Joe Iwanaga, Humza Chaudhry, Aaron Yu, Katsuhisa Matsuo, Hotaka Kawai, Aya Han, Yoko Tabira, Tsuyoshi Saga, Koichi Watanabe, Marios Loukas, R Shane Tubbs

Clinical anatomy (New York, N.Y.) 37 ( 1 ) 140 - 146 2024年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

The ligamentum arteriosum (LA) is the vestigial fibrous remnant of the ductus arteriosus (DA), a fetal vessel arising from the left dorsal segment of the sixth aortic arch that connects the left pulmonary artery to the aortic arch. Incomplete obliteration of the DA results in a patent ductus arteriosus (PDA), causing the shunting of oxygen-rich blood to recirculate to the lungs, which can lead to pulmonary hypertension. The current study aims to further elucidate the structural characteristics of the LA via histological analysis with data gathered from adult cadaveric specimens. The LA was harvested and histologically observed with Hematoxylin and Eosin, van Gieson, and Masson's trichrome staining. Fibrous and muscle tissues were observed in all 25 specimens. The LA was categorized into three types based on the morphological features of the LA. Type I (vessel-like structure), type II (fibrotic tissue with duct-like structure), and type III (no duct-like structure) were found in 4.0%, 80.0%, and 16.0%, respectively. Finally, the remnant of a valve in the LA was also observed at the junction between the AA and LA. We suggest that this valve be called the "pulmonary-aortic valve." In the majority of the adult LAs, a duct-like structure was still present. These data could better elucidate our understanding of the pathology and etiology of a PDA.

DOI： 10.1002/ca.24122

A Rare Case of Multiple Myeloma Identified Following the Diagnosis of Amyloidosis of the Tongue. 国際誌

Hideka Kanemoto, Kyoichi Obata, Koichi Kadoya, Kisho Ono, Hotaka Kawai, Yuki Kunisada, Mayumi Yao, Soichiro Ibaragi

Case reports in dentistry 2024 8836103 - 8836103 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Amyloidosis is a disease in which amyloid protein is deposited in organs and tissues, resulting in functional impairment. Amyloidosis occurs in 12%-30% of patients with multiple myeloma, but in rare cases, amyloidosis may precede the diagnosis of multiple myeloma. Our patient was a 76-year-old Japanese male on dialysis. Multiple nodules accompanied by ulcers were observed on his tongue. He had no subjective symptoms or clinical findings associated with multiple myeloma. The histopathological findings suggested amyloidosis. We suspected both systemic and localized amyloidosis and performed a comprehensive systemic examination. Since the patient had been on dialysis for only a short period of time (~3 months), dialysis-related amyloidosis was ruled out. After blood and urine tests, a diagnosis of multiple myeloma was made. Chemotherapy treatment was started, but the patient's multiple myeloma could not be suppressed and the tongue amyloidosis worsened, leading to his death 2 years and 2 months after the initial diagnosis.

DOI： 10.1155/2024/8836103

Transcutaneous carbon dioxide suppresses skeletal muscle atrophy in a mouse model of oral squamous cell carcinoma. 国際誌

Aki Sasaki, Daisuke Takeda, Hotaka Kawai, Yoshiaki Tadokoro, Aki Murakami, Nanae Yatagai, Satomi Arimoto, Hitoshi Nagatsuka, Masaya Akashi, Takumi Hasegawa

PloS one 19 ( 4 ) e0302194 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Cancer cachexia causes skeletal muscle atrophy, impacting the treatment and prognosis of patients with advanced cancer, but no treatment has yet been established to control cancer cachexia. We demonstrated that transcutaneous application of carbon dioxide (CO2) could improve local blood flow and reduce skeletal muscle atrophy in a fracture model. However, the effects of transcutaneous application of CO2 in cancer-bearing conditions are not yet known. In this study, we calculated fat-free body mass (FFM), defined as the skeletal muscle mass, and evaluated the expression of muscle atrophy markers and uncoupling protein markers as well as the cross-sectional area (CSA) to investigate whether transcutaneous application of CO2 to skeletal muscle could suppress skeletal muscle atrophy in cancer-bearing mice. Human oral squamous cell carcinoma was transplanted subcutaneously into the upper dorsal region of nude mice, and 1 week later, CO2 gas was applied to the legs twice a week for 4 weeks and FFM was calculated by bioimpedance spectroscopy. After the experiment concluded, the quadriceps were extracted, and muscle atrophy markers (muscle atrophy F-box protein (MAFbx), muscle RING-finger protein 1 (MuRF-1)) and uncoupling protein markers (uncoupling protein 2 (UCP2) and uncoupling protein 3 (UCP3)) were evaluated by real-time polymerase chain reaction and immunohistochemical staining, and CSA by hematoxylin and eosin staining. The CO2-treated group exhibited significant mRNA and protein expression inhibition of the four markers. Furthermore, immunohistochemical staining showed decreased MAFbx, MuRF-1, UCP2, and UCP3 in the CO2-treated group. In fact, the CSA in hematoxylin and eosin staining and the FFM revealed significant suppression of skeletal muscle atrophy in the CO2-treated group. We suggest that transcutaneous application of CO2 to skeletal muscle suppresses skeletal muscle atrophy in a mouse model of oral squamous cell carcinoma.

DOI： 10.1371/journal.pone.0302194

Rab11 suppresses head and neck carcinoma by regulating EGFR and EpCAM exosome secretion. 国際誌

Kunihiro Yoshida, Kaung Htike, Takanori Eguchi, Hotaka Kawai, Htoo Shwe Eain, Manh Tien Tran, Chiharu Sogawa, Koki Umemori, Tatsuo Ogawa, Hideka Kanemoto, Kisho Ono, Hitoshi Nagatsuka, Akira Sasaki, Soichiro Ibaragi, Kuniaki Okamoto

Journal of oral biosciences 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Rab11(Rab11a and Rab11b) localizes primarily along recycling endosomes in cells and is involved in various intracellular trafficking processes, including membrane receptor recycling and secretion of exosomes or small extracellular vesicles (EVs). Although Rab11 is closely associated with the progression and metastasis of various cancer types, little is known about Rab11' role in head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the roles of Rab11a and Rab11b in HNSCC. METHODS: The clinical significance of Rab11 expression in HNSCC was investigated using a public database and tissue microarray analysis. Stable cell lines with loss and gain of Rab11a or Rab11b were originally established to investigate their roles in the proliferative, migratory, and invasive capabilities of HNSCC cells. RESULTS: Database analysis revealed a significant association between Rab11b mRNA expression and a favorable patient survival rate in HNSCC. Tissue microarray analysis revealed that Rab11b expression was the highest in normal tissues and gradually decreased across the stages of HNSCC progression. Overexpression of Rab11a or Rab11b resulted in a decrease in epidermal growth factor receptor (EGFR), Epithelial cell adhesion molecule (EpCAM) exosome secretion, and the migratory and invasive potential of HNSCC cells. The knockdown of Rab11a or Rab11b increased EpCAM/CD9 exosome secretion in addition to the migratory and invasive potential of HNSCC cells. CONCLUSIONS: Rab11 suppresses HNSCC by regulating EGFR recycling and EpCAM exosome secretion in HNSCC cells. Our results indicate that Rab11b is a superior prognostic indicator of HNSCC and holds promise for developing novel therapeutic strategies.

DOI： 10.1016/j.job.2023.11.007

口腔扁平上皮癌腫瘍間質が腫瘍関連マクロファージの集簇・分化に与える影響について

Piao Tianyan, 高畠清文, Chan Anqi, 河合穂高, 中野敬介, 長塚仁

岡山歯学会雑誌 42 ( 2 ) 70 - 71 2023年12月

口腔癌におけるCX3CL1とリンパ節転移の関係(Relationship between CX3CL1 and lymph node metastasis in oral cancer)

河合穂高, トゥ・シュエイン, 中山真彰, 大原利章, 長塚仁

日本癌学会総会記事 82回 1421 - 1421 2023年9月

口腔癌におけるCX3CL1とリンパ節転移の関係(Relationship between CX3CL1 and lymph node metastasis in oral cancer)

河合穂高, トゥ・シュエイン, 中山真彰, 大原利章, 長塚仁

日本癌学会総会記事 82回 1421 - 1421 2023年9月

Effectiveness of deep learning classifiers in histopathological diagnosis of oral squamous cell carcinoma by pathologists. 国際誌

Shintaro Sukegawa, Sawako Ono, Futa Tanaka, Yuta Inoue, Takeshi Hara, Kazumasa Yoshii, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Shimada Katsumitsu, Fumi Nakai, Yasuhiro Nakai, Ryo Miyazaki, Satoshi Murakami, Hitoshi Nagatsuka, Minoru Miyake

Scientific reports 13 ( 1 ) 11676 - 11676 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

The study aims to identify histological classifiers from histopathological images of oral squamous cell carcinoma using convolutional neural network (CNN) deep learning models and shows how the results can improve diagnosis. Histopathological samples of oral squamous cell carcinoma were prepared by oral pathologists. Images were divided into tiles on a virtual slide, and labels (squamous cell carcinoma, normal, and others) were applied. VGG16 and ResNet50 with the optimizers stochastic gradient descent with momentum and spectral angle mapper (SAM) were used, with and without a learning rate scheduler. The conditions for achieving good CNN performances were identified by examining performance metrics. We used ROCAUC to statistically evaluate diagnostic performance improvement of six oral pathologists using the results from the selected CNN model for assisted diagnosis. VGG16 with SAM showed the best performance, with accuracy = 0.8622 and AUC = 0.9602. The diagnostic performances of the oral pathologists statistically significantly improved when the diagnostic results of the deep learning model were used as supplementary diagnoses (p-value = 0.031). By considering the learning results of deep learning model classifiers, the diagnostic accuracy of pathologists can be improved. This study contributes to the application of highly reliable deep learning models for oral pathological diagnosis.

DOI： 10.1038/s41598-023-38343-y

口腔扁平上皮癌の病理組織学的診断におけるAI深層学習補助診断の効果検討

助川信太郎, 中野敬介, 小野佐和子, 嶋田勝光, 高畠清文, 河合穂高, 村上聡, 長塚仁, 三宅実

日本口腔科学会雑誌 72 ( 2 ) 131 - 132 2023年7月

骨髄由来間葉系幹細胞の新規採取技術および骨髄由来間葉系幹細胞移植法の確立

河合穂高, メイワトゥ, 高畠清文, 佐能彰, 中野敬介, 宝田剛, 長塚仁

日本口腔科学会雑誌 72 ( 2 ) 134 - 134 2023年7月

口腔癌の細胞外小胞と銅輸送経路に着目したシスプラチン耐性機構の解明と克服のための挑戦的研究

小野喜章, 竜門省二, 小畑協一, 河合穂高, 奥井達雄, 伊原木聰一郎

日本口腔科学会雑誌 72 ( 2 ) 131 - 131 2023年7月

EpEX, the soluble extracellular domain of EpCAM, resists cetuximab treatment of EGFR-high head and neck squamous cell carcinoma. 国際誌

Koki Umemori, Kisho Ono, Takanori Eguchi, Hotaka Kawai, Tomoya Nakamura, Tatsuo Ogawa, Kunihiro Yoshida, Hideka Kanemoto, Kohei Sato, Kyoichi Obata, Shoji Ryumon, Hirokazu Yutori, Naoki Katase, Tatsuo Okui, Hitoshi Nagatsuka, Soichiro Ibaragi

Oral oncology 142 106433 - 106433 2023年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: Cetuximab (Cmab) is a molecularly targeted monoclonal antibody drug for head and neck squamous cell carcinoma (HNSC), although cetuximab resistance is a serious challenge. Epithelial cell adhesion molecule (EpCAM) is an established marker for many epithelial tumors, while the soluble EpCAM extracellular domain (EpEX) functions as a ligand for epidermal growth factor receptor (EGFR). We investigated the expression of EpCAM in HNSC, its involvement in Cmab action, and the mechanism by which soluble EpEX activated EGFR and played key roles in Cmab resistance. MATERIALS AND METHODS: We first examined EPCAM expression in HNSCs and its clinical significance by searching gene expression array databases. We then examined the effects of soluble EpEX and Cmab on intracellular signaling and Cmab efficacy in HNSC cell lines (HSC-3 and SAS). RESULTS: EPCAM expression was found to be enhanced in HNSC tumor tissues compared to normal tissues, and the enhancement was correlated with stage progression and prognosis. Soluble EpEX activated the EGFR-ERK signaling pathway and nuclear translocation of EpCAM intracellular domains (EpICDs) in HNSC cells. EpEX resisted the antitumor effect of Cmab in an EGFR expression-dependent manner. CONCLUSION: Soluble EpEX activates EGFR to increase Cmab resistance in HNSC cells. The EpEX-activated Cmab resistance in HNSC is potentially mediated by the EGFR-ERK signaling pathway and the EpCAM cleavage-induced nuclear translocation of EpICD. High expression and cleavage of EpCAM are potential biomarkers for predicting the clinical efficacy and resistance to Cmab.

DOI： 10.1016/j.oraloncology.2023.106433

分化度が異なるOSCCにおけるCXCR4阻害剤の有用性

吉田沙織, 河合穂高, 竹下洋平, 岡田俊輔, 藤倉満美子, 久富美紀, 河津俊幸, 長塚仁, 浅海淳一, 柳文修

日本病理学会会誌 112 ( 1 ) 290 - 290 2023年3月

CX3CL1の口腔癌リンパ節転移における役割の検討

河合穂高, トゥシュ・エイン, 高畠清文, 中野敬介, 長塚仁

日本病理学会会誌 112 ( 1 ) 263 - 263 2023年3月

Novel Artificial Scaffold for Bone Marrow Regeneration: Honeycomb Tricalcium Phosphate. 国際誌

Yasunori Inada, Kiyofumi Takabatake, Hidetsugu Tsujigiwa, Keisuke Nakano, Qiusheng Shan, Tianyan Piao, Anqi Chang, Hotaka Kawai, Hitoshi Nagatsuka

Materials (Basel, Switzerland) 16 ( 4 ) 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Bone marrow is complex structure containing heterogenetic cells, making it difficult to regenerate using artificial scaffolds. In a previous study, we succeeded in developing honeycomb tricalcium phosphate (TCP), which is a cylindrical scaffold with a honeycomb arrangement of straight pores, and we demonstrated that TCP with 300 and 500 μm pore diameters (300TCP and 500TCP) induced bone marrow structure within the pores. In this study, we examined the optimal scaffold structure for bone marrow with homeostatic bone metabolism using honeycomb TCP. 300TCP and 500TCP were transplanted into rat muscle, and bone marrow formation was histologically assessed. Immunohistochemistry for CD45, CD34, Runt-related transcription factor 2 (Runx2), c-kit single staining, Runx2/N-cadherin, and c-kit/Tie-2 double staining was performed. The area of bone marrow structure, which includes CD45(+) round-shaped hematopoietic cells and CD34(+) sinusoidal vessels, was larger in 300TCP than in 500TCP. Additionally, Runx2(+) osteoblasts and c-kit(+) hematopoietic stem cells were observed on the surface of bone tissue formed within TCP. Among Runx2(+) osteoblasts, spindle-shaped N-cadherin(+) cells existed in association with c-kit(+)Tie-2(+) hematopoietic stem cells on the bone tissue formed within TCP, which formed a hematopoietic stem cell niche similar to as in vivo. Therefore, honeycomb TCP with 300 μm pore diameters may be an artificial scaffold with an optimal geometric structure as a scaffold for bone marrow formation.

DOI： 10.3390/ma16041393

腫瘍微小環境における間質細胞は口腔扁平上皮癌の進行を促進する(Stromal cells in the tumor microenvironment promote the progression of oral squamous cell carcinoma)

Shan Qiusheng, 高畠清文, 河合穂高, Oo May Wathone, 稲田靖則, 中野敬介, 長塚仁

日本口腔診断学会雑誌 36 ( 1 ) 79 - 79 2023年2月

分化度の異なる口腔扁平上皮癌におけるシスプラチンとCXCR4阻害剤併用の効果

吉田沙織, 河合穂高, 竹下洋平, 岡田俊輔, 藤倉満美子, 久富美紀, 河津俊幸, 長塚仁, 浅海淳一, 柳文修

日本口腔診断学会雑誌 36 ( 1 ) 82 - 82 2023年2月

腫瘍微小環境における間質細胞は口腔扁平上皮癌の進行を促進する(Stromal cells in the tumor microenvironment promote the progression of oral squamous cell carcinoma)

Shan Qiusheng, 高畠清文, 河合穂高, Oo May Wathone, 稲田靖則, 中野敬介, 長塚仁

日本口腔診断学会雑誌 36 ( 1 ) 79 - 79 2023年2月

EGFR活性化経路としてのEpCAMに着目した口腔扁平上皮癌のセツキシマブ耐性機構の解明

梅森洸樹, 小野喜章, 小畑協一, 竜門省二, 中村友哉, 金本栄華, 吉田国弘, 河合穂高, 伊原木聰一郎

口腔組織培養学会誌 32 ( 1 ) 11 - 12 2023年2月

Multiplex Immunostaining Method to Distinguish HSP Isoforms in Cancer Tissue Specimens. 国際誌

Hotaka Kawai, Kisho Ono, Takanori Eguchi

Methods in molecular biology (Clifton, N.J.) 2693 281 - 291 2023年

記述言語：英語掲載種別：研究論文（学術雑誌）

Heat shock proteins (HSPs) are often expressed in all nucleated cells, but their expression profiles differ. In particular, HSP90α and HSP90β have high sequence identity and have not been fully examined for their individual and compensatory functions as molecular chaperones, differences in client proteins, and extracellular distributions with exosomes. Immunohistochemical staining is a technique to visualize the presence and localization of target antigens using specific antibodies, of which the multiplex immunostaining method can reveal differences in protein expression in the same tumor tissue and the localization of proteins of interest within tumor tissue or single cells. The common multiplex immunostaining method uses multiple secondary antibodies of different reacting animal species to identify and detect different antigens, thus requiring different animals to be immunized with each primary antibody. Furthermore, the fluorescent-antibody method is the predominant multiplex staining method but has the critical disadvantage that permanent specimens cannot be prepared. Here, we outline a multiplex staining method for HSP90α and HSP90β based on the enzyme-antibody method that allows permanent specimens to be prepared without the restriction of immunized animal species.

DOI： 10.1007/978-1-0716-3342-7_21

SCAND1 Reverses Epithelial-to-Mesenchymal Transition (EMT) and Suppresses Prostate Cancer Growth and Migration. 査読国際誌

Takanori Eguchi, Eva Csizmadia, Hotaka Kawai, Mona Sheta, Kunihiro Yoshida, Thomas L Prince, Barbara Wegiel, Stuart K Calderwood

Cells 11 ( 24 ) 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Epithelial-mesenchymal transition (EMT) is a reversible cellular program that transiently places epithelial (E) cells into pseudo-mesenchymal (M) cell states. The malignant progression and resistance of many carcinomas depend on EMT activation, partial EMT, or hybrid E/M status in neoplastic cells. EMT is activated by tumor microenvironmental TGFβ signal and EMT-inducing transcription factors, such as ZEB1/2, in tumor cells. However, reverse EMT factors are less studied. We demonstrate that prostate epithelial transcription factor SCAND1 can reverse the cancer cell mesenchymal and hybrid E/M phenotypes to a more epithelial, less invasive status and inhibit their proliferation and migration in DU-145 prostate cancer cells. SCAND1 is a SCAN domain-containing protein and hetero-oligomerizes with SCAN-zinc finger transcription factors, such as MZF1, for accessing DNA and the transcriptional co-repression of target genes. We found that SCAND1 expression correlated with maintaining epithelial features, whereas the loss of SCAND1 was associated with mesenchymal phenotypes of tumor cells. SCAND1 and MZF1 were mutually inducible and coordinately included in chromatin with hetero-chromatin protein HP1γ. The overexpression of SCAND1 reversed hybrid E/M status into an epithelial phenotype with E-cadherin and β-catenin relocation. Consistently, the co-expression analysis in TCGA PanCancer Atlas revealed that SCAND1 and MZF1 expression was negatively correlated with EMT driver genes, including CTNNB1, ZEB1, ZEB2 and TGFBRs, in prostate adenocarcinoma specimens. In addition, SCAND1 overexpression suppressed tumor cell proliferation by reducing the MAP3K-MEK-ERK signaling pathway. Of note, in a mouse tumor xenograft model, SCAND1 overexpression significantly reduced Ki-67(+) and Vimentin(+) tumor cells and inhibited migration and lymph node metastasis of prostate cancer. Kaplan-Meier analysis showed high expression of SCAND1 and MZF1 to correlate with better prognoses in pancreatic cancer and head and neck cancers, although with poorer prognosis in kidney cancer. Overall, these data suggest that SCAND1 induces expression and coordinated heterochromatin-binding of MZF1 to reverse the hybrid E/M status into an epithelial phenotype and, inhibits tumor cell proliferation, migration, and metastasis, potentially by repressing the gene expression of EMT drivers and the MAP3K-MEK-ERK signaling pathway.

DOI： 10.3390/cells11243993

分化度の異なる口腔扁平上皮癌におけるシスプラチンとCXCR4阻害剤併用の効果

吉田沙織, 河合穂高, 竹下洋平, 岡田俊輔, 藤倉満美子, 久富美紀, 河津俊幸, 長塚仁, 浅海淳一, 柳文修

日本口腔内科学会雑誌 28 ( 2 ) 106 - 106 2022年12月

Investigation of bone invasion and underlying mechanisms of oral cancer using a cell line-derived xenograft model. 査読国際誌

Qiusheng Shan, Kiyofumi Takabatake, Haruka Omori, Hotaka Kawai, May Wathone Oo, Shintaro Sukegawa, Masae Fujii, Yasunori Inada, Sho Sano, Keisuke Nakano, Hitoshi Nagatsuka

Oncology letters 24 ( 5 ) 382 - 382 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

The cancer stroma regulates bone invasion in oral squamous cell carcinoma (OSCC). However, data on normal stroma are limited. In the present study, the effects of gingival and periodontal ligament tissue-derived stromal cells (G-SCs and P-SCs, respectively) and human dermal fibroblasts (HDFs) on bone resorption and osteoclast activation were assessed using hematoxylin and eosin and tartrate-resistant acid phosphatase staining in a cell line-derived xenograft model. The results demonstrated that G-SCs promoted bone invasion and osteoclast activation and inhibited osteoclast proliferation following crosstalk with the human OSCC HSC-3 cell line, whereas P-SCs inhibited bone resorption and promoted osteoclast proliferation in vitro but had a minimal effect on osteoclast activation both in vitro and in vivo following crosstalk with HSC-3 cells. Furthermore, the effects of G-SCs, P-SCs and HDFs on protein expression levels of matrix metalloproteinase (MMP)-9, membrane type 1 MMP (MT1-MMP), Snail, parathyroid hormone-related peptide (PTHrP) and receptor activator of NF-κB ligand (RANKL) in HSC-3 cells in OSCC bone invasion regions were assessed using immunohistochemistry. The results demonstrated that G-SCs had a more prominent effect on the expression of MMP-9, MT1-MMP, Snail, PTHrP, and RANKL, whereas P-SCs only promoted RANKL and PTHrP expression and exerted a minimal effect on MMP-9, MT1-MMP and Snail expression. The potential genes underlying the differential effects of G-SCs and P-SCs on bone invasion in OSCC were evaluated using a microarray, which indicated that cyclin-dependent kinase 1, insulin, aurora kinase A, cyclin B1 and DNA topoisomerase II alpha underlaid these differential effects. Therefore, these results demonstrated that G-SCs promoted bone invasion in OSCC by activating osteoclasts on the bone surface, whereas P-SCs exerted an inhibitory effect. These findings could indicate a potential regulatory mechanism for bone invasion in OSCC.

DOI： 10.3892/ol.2022.13502

Deep learning model for analyzing the relationship between mandibular third molar and inferior alveolar nerve in panoramic radiography. 査読国際誌

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

Scientific reports 12 ( 1 ) 16925 - 16925 2022年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

In this study, the accuracy of the positional relationship of the contact between the inferior alveolar canal and mandibular third molar was evaluated using deep learning. In contact analysis, we investigated the diagnostic performance of the presence or absence of contact between the mandibular third molar and inferior alveolar canal. We also evaluated the diagnostic performance of bone continuity diagnosed based on computed tomography as a continuity analysis. A dataset of 1279 images of mandibular third molars from digital radiographs taken at the Department of Oral and Maxillofacial Surgery at a general hospital (2014-2021) was used for the validation. The deep learning models were ResNet50 and ResNet50v2, with stochastic gradient descent and sharpness-aware minimization (SAM) as optimizers. The performance metrics were accuracy, precision, recall, specificity, F1 score, and area under the receiver operating characteristic curve (AUC). The results indicated that ResNet50v2 using SAM performed excellently in the contact and continuity analyses. The accuracy and AUC were 0.860 and 0.890 for the contact analyses and 0.766 and 0.843 for the continuity analyses. In the contact analysis, SAM and the deep learning model performed effectively. However, in the continuity analysis, none of the deep learning models demonstrated significant classification performance.

DOI： 10.1038/s41598-022-21408-9

Lip pleomorphic adenomas: case series and literature review 査読

Koki Umemori, Kisho Ono, Hideka Kanemoto, Kyoichi Obata, Hotaka Kawai, Tomoya Nakamura, Keisuke Nakano, Soichiro Ibaragi, Hitoshi Nagatsuka, Akira Sasaki

Gland Surgery 11 ( 10 ) 1730 - 1740 2022年10月

Elucidation of ameloblastoma fenestration mechanism via HIF-1α(和訳中) 査読

Inada Yasunori, Takabatake Kiyofumi, Fujii Masae, Tianyan Piao, Angi Chang, Kawai Hotaka, Nakano Keisuke, Nagatsuka Hitoshi

Journal of Hard Tissue Biology 31 ( 4 ) 272 - 272 2022年10月

Clinicopathological and histological analysis of secondary malignant giant cell tumors of bone without radiotherapy. 査読国際誌

Eiji Nakata, Hotaka Kawai, Tomohiro Fujiwara, Toshiyuki Kunisada, Hirofumi Inoue, Mashu Futagawa, Haruyoshi Katayama, Takuto Itano, Toshifumi Ozaki

Oncology letters 24 ( 3 ) 319 - 319 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Giant cell tumor of bone (GCTB) is an intermediate bone tumor that rarely undergoes malignant transformation. Secondary malignant GCTB (SMGCTB) is defined as a lesion in which high-grade sarcoma occurs at the site of previously treated GCTB. The present study retrospectively reviewed the medical records of patients with GCTB treated at Okayama University Hospital between April 1986 and April 2020. The clinicopathological and histological features of patients with SMGCTB without prior radiotherapy were investigated. A total of three patients (4%) with SMGCTB were detected, and the tumor sites were the distal ulna, distal femur and sacrum. Two of the patients had been treated with curettage and bone graft, and one had been treated with denosumab. In all cases, the lesions were made up of two components, the conventional GCTB component and the malignant component. The Ki67 labeling index was higher in the malignant components of SMGCTB and metastatic lesions compared with that in primary and recurrent conventional GCTB, or the conventional GCTB component of SMGCTB. Moreover, p53 expression was higher in these same components in patients who underwent curettage and bone grafting; however, there was no difference in the patient that received denosumab treatment. In this patient, clinical cancer genomic profiling revealed loss of CDKN2A, CDKN2B and MTAP expression. All three patients developed distant metastasis. The patients with SMGCTB in the ulna and femur died 13 and 54 months after detection of malignant transformation, respectively. The patient with SMGCTB in the sacrum received carbon-ion radiotherapy to the sacrum and pazopanib; the treatment was effective and the patient was alive at the last follow-up 3 years later. In conclusion, p53 may be associated with malignant transformation in GCTB. Future studies should investigate the association of between denosumab treatment and malignant transformation, as well as molecular targeted therapy to improve the clinical outcomes of SMGCTB.

DOI： 10.3892/ol.2022.13439

細胞外小胞に搭載されたムーンライティングMMPによるマトリックス制御と転移促進(Metalloproteinase on extracellular vesicles regulates ECM in tumor microenvironment and promotes invasion and metastasis)

奥舎有加, タハ・エマン, 陸彦因, シータ・モナ, 河合穂高, 十川千春, 岡元邦彰, 江口傑徳

日本癌学会総会記事 81回 P - 1118 2022年9月

Effective deep learning for oral exfoliative cytology classification. 査読国際誌

Shintaro Sukegawa, Futa Tanaka, Keisuke Nakano, Takeshi Hara, Kazumasa Yoshii, Katsusuke Yamashita, Sawako Ono, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

Scientific reports 12 ( 1 ) 13281 - 13281 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

The use of sharpness aware minimization (SAM) as an optimizer that achieves high performance for convolutional neural networks (CNNs) is attracting attention in various fields of deep learning. We used deep learning to perform classification diagnosis in oral exfoliative cytology and to analyze performance, using SAM as an optimization algorithm to improve classification accuracy. The whole image of the oral exfoliation cytology slide was cut into tiles and labeled by an oral pathologist. CNN was VGG16, and stochastic gradient descent (SGD) and SAM were used as optimizers. Each was analyzed with and without a learning rate scheduler in 300 epochs. The performance metrics used were accuracy, precision, recall, specificity, F1 score, AUC, and statistical and effect size. All optimizers performed better with the rate scheduler. In particular, the SAM effect size had high accuracy (11.2) and AUC (11.0). SAM had the best performance of all models with a learning rate scheduler. (AUC = 0.9328) SAM tended to suppress overfitting compared to SGD. In oral exfoliation cytology classification, CNNs using SAM rate scheduler showed the highest classification performance. These results suggest that SAM can play an important role in primary screening of the oral cytological diagnostic environment.

DOI： 10.1038/s41598-022-17602-4

The Effectiveness of Pre-Operative Screening Tests in Determining Viral Infections in Patients Undergoing Oral and Maxillofacial Surgery. 査読国際誌

Shintaro Sukegawa, Yuka Sukegawa, Kazuaki Hasegawa, Sawako Ono, Tomoya Nakamura, Ai Fujimura, Ayaka Fujisawa, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Yumika Mukainaka, Hitoshi Nagatsuka, Yoshihiko Furuki

Healthcare (Basel, Switzerland) 10 ( 7 ) 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

We analyzed the rate of patients with hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection diagnosed by pre-operative screening and estimated its cost. We retrospectively analyzed patients who underwent elective surgery at our maxillofacial surgery department between April 2014 and March 2022. We compared the number of patients with each infection identified by pre-operative screening and a pre-operative questionnaire. We also compared the prevalence of infections with varying age, sex, and oral diseases, and calculated the cost of screening per positive result. The prevalence of HBV, HCV, and HIV was 0.39% (62/15,842), 0.76% (153/15,839), and 0.07% (10/12,745), respectively. The self-reported rates were as follows: HBV, 63.4% (26/41); HCV, 50.4% (62/123); HIV, 87.5% (7/8). Differences in sex were statistically significant for all infectious diseases; age significantly affected HBV and HCV rates. There was no association between the odds ratio of oral disease and viral infections. The cost per positive result was $1873.8, $905.8, and $11,895.3 for HBV, HCV, and HIV, respectively. Although self-assessment using questionnaires is partially effective, it has inadequate screening accuracy. Formulating an auxiliary diagnosis of infectious diseases with oral diseases was challenging. The cost determined was useful for hepatitis, but not HIV.

DOI： 10.3390/healthcare10071348

Incidence and Risk of Anti-Resorptive Agent-Related Osteonecrosis of the Jaw after Tooth Extraction: A Retrospective Study. 査読国際誌

Rieko Shimizu, Shintaro Sukegawa, Yuka Sukegawa, Kazuaki Hasegawa, Sawako Ono, Tomoya Nakamura, Ai Fujimura, Ayaka Fujisawa, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

Healthcare (Basel, Switzerland) 10 ( 7 ) 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

Bone-modifying agents (BMA) such as bisphosphonates and denosumab are frequently used for the treatment of bone metastases, osteoporosis, and multiple myeloma. BMA may lead to anti-resorptive agent-related osteonecrosis of the jaw (ARONJ). This study aimed to clarify the risk factors for and probabilities of developing ARONJ after tooth extraction in patients undergoing BMA therapy. In this study, the records of 505 target sites of 302 patients undergoing BMA who presented with mandibular fractures at the Department of Oral and Maxillofacial Surgery, Kagawa Prefectural Central Hospital, from March 2014 to January 2022, were retrospectively analyzed for the onset of ARONJ after tooth extraction. The following variables were investigated as attributes: anatomy, health status, and dental treatment. The correlation coefficient was calculated for the success or failure of endodontic surgery for each variable, the odds ratio was calculated for the upper variable, and the factors related to the onset of ARONJ were identified. The incidence rate of ARONJ was found to be 3.2%. Hypoparathyroidism was an important factor associated with ARONJ development. Thus, systemic factors are more strongly related to the onset of ARONJ after tooth extraction than local factors.

DOI： 10.3390/healthcare10071332

正常間質組織による口腔扁平上皮癌の生物学的性格制御の可能性

高畠清文, 大森悠加, Shan Qiusheng, 河合穂高, Oo May Wathone, 稲田靖則, 中野敬介, 長塚仁

日本口腔科学会雑誌 71 ( 2 ) 105 - 105 2022年7月

Crosstalk between cancer and different cancer stroma subtypes promotes the infiltration of tumor‑associated macrophages into the tumor microenvironment of oral squamous cell carcinoma. 査読国際誌

Qiusheng Shan, Kiyofumi Takabatake, Hotaka Kawai, May Wathone Oo, Shintaro Sukegawa, Masae Fujii, Keisuke Nakano, Hitoshi Nagatsuka

International journal of oncology 60 ( 6 ) 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Tumor‑associated macrophages (TAMs) are linked to the progression of numerous types of cancer. However, the effects of the tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC), particularly the cancer stroma on TAMs, remains to be elucidated. In the present study, the effects of verrucous SCC‑associated stromal cells (VSCC‑SCs), SCC‑associated stromal cells (SCC‑SCs) and human dermal fibroblasts (HDFs) on the differentiation, proliferation and migration of macrophages in vitro was assayed using Giemsa staining, and immunofluorescence, MTS and Transwell (migration) assays, respectively. The combined results suggested that both VSCC‑SCs and SCC‑SCs promoted the differentiation of macrophages into M2 type TAMs, as well as the proliferation and migration of macrophages following crosstalk with HSC‑3 cells in vitro. Moreover, the SCC‑SCs exerted a more prominent effect on TAMs than the VSCC‑SCs. Immunohistochemical staining was used to examine the expression of CD34, CD45, CD11b and CD163 to assay the effects of VSCC‑SCs, SCC‑SCs and HDFs on microvessel density (MVD) and the infiltration of CD45(+) monocytes, CD11b(+) TAMs and CD163(+) M2 type macrophages. The results suggested that both VSCC‑SCs and SCC‑SCs promoted MVD and the infiltration of CD45(+) monocytes, CD11b(+) TAMs and CD163(+) M2 type TAMs into the TME of OSCC following crosstalk with HSC‑3 cells in vivo. The SCC‑SCs exerted a more prominent promoting effect than the VSCC‑SCs. Finally, the potential genes underlying the differential effects of VSCC‑SCs and SCC‑SCs on the infiltration of TAMs were investigated using microarray analysis. The results revealed that interleukin 1β, bone morphogenetic protein 4, interleukin 6 and C‑X‑C motif chemokine ligand 12 had great potential to mediate the differential effects of VSCC‑SCs and SCC‑SCs on TAM infiltration. On the whole, the findings presented herein, demonstrate that both VSCC‑SCs and SCC‑SCs promote the infiltration of TAMs into the TME of OSCC following crosstalk with HSC‑3 cells; the SCC‑SCs were found to exert a more prominent promoting effect. This may represent a potential regulatory mechanism for the infiltration of TAMs into the TME of OSCC.

DOI： 10.3892/ijo.2022.5368

口腔癌間質由来のCCL2はCCR2陽性骨髄由来免疫抑制細胞の腫瘍間質への動員に関与する

河合穂高, メイ・ワトウ, 高畠清文, 冨田秀太, 小野喜章, 江口傑徳, 大原利章, 中野敬介, 長塚仁

日本がん免疫学会総会プログラム・抄録集 26回 91 - 91 2022年6月

口腔癌間質由来のCCL2はCCR2陽性骨髄由来免疫抑制細胞の腫瘍間質への動員に関与する

河合穂高, メイ・ワトウ, 高畠清文, 冨田秀太, 小野喜章, 江口傑徳, 大原利章, 中野敬介, 長塚仁

日本がん免疫学会総会プログラム・抄録集 26回 91 - 91 2022年6月

Prognostic Factors in Endodontic Surgery Using an Endoscope: A 1 Year Retrospective Cohort Study. 査読国際誌

Shintaro Sukegawa, Rieko Shimizu, Yuka Sukegawa, Kazuaki Hasegawa, Sawako Ono, Ai Fujimura, Izumi Yamamoto, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

Materials (Basel, Switzerland) 15 ( 9 ) 2022年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

This retrospective study clarified the success rate of endoscopic endodontic surgeries and identified predictors accounting for successful surgeries. In this retrospective study, 242 patients (90 males, 152 females) who underwent endoscopic endodontic surgery at a single general hospital and were diagnosed through follow-up one year later were included. Risk factors were categorized into attributes, general health, anatomy, and surgery. Then, the correlation coefficient was calculated for the success or failure of endodontic surgery for each variable, the odds ratio was calculated for the upper variable, and factors related to the surgical prognosis factor were identified. The success rate of endodontic surgery was 95.3%, showing that it was a highly predictable treatment. The top three correlation coefficients were post, age, and perilesional sclerotic signs. Among them, the presence of posts was the highest, compared with the odds ratio, which was 9.592. This retrospective study revealed the success rate and risk factors accounting for endoscopic endodontic surgeries. Among the selected clinical variables, the presence of posts was the most decisive risk factor determining the success of endodontic surgeries.

DOI： 10.3390/ma15093353

Identification of osteoporosis using ensemble deep learning model with panoramic radiographs and clinical covariates. 査読国際誌

Shintaro Sukegawa, Ai Fujimura, Akira Taguchi, Norio Yamamoto, Akira Kitamura, Ryosuke Goto, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

Scientific reports 12 ( 1 ) 6088 - 6088 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Osteoporosis is becoming a global health issue due to increased life expectancy. However, it is difficult to detect in its early stages owing to a lack of discernible symptoms. Hence, screening for osteoporosis with widely used dental panoramic radiographs would be very cost-effective and useful. In this study, we investigate the use of deep learning to classify osteoporosis from dental panoramic radiographs. In addition, the effect of adding clinical covariate data to the radiographic images on the identification performance was assessed. For objective labeling, a dataset containing 778 images was collected from patients who underwent both skeletal-bone-mineral density measurement and dental panoramic radiography at a single general hospital between 2014 and 2020. Osteoporosis was assessed from the dental panoramic radiographs using convolutional neural network (CNN) models, including EfficientNet-b0, -b3, and -b7 and ResNet-18, -50, and -152. An ensemble model was also constructed with clinical covariates added to each CNN. The ensemble model exhibited improved performance on all metrics for all CNNs, especially accuracy and AUC. The results show that deep learning using CNN can accurately classify osteoporosis from dental panoramic radiographs. Furthermore, it was shown that the accuracy can be improved using an ensemble model with patient covariates.

DOI： 10.1038/s41598-022-10150-x

Significance of cancer stroma for bone destruction in oral squamous cell carcinoma using different cancer stroma subtypes. 査読国際誌

Qiusheng Shan, Kiyofumi Takabatake, Hotaka Kawai, May Wathone Oo, Yasunori Inada, Shintaro Sukegawa, Shigeko Fushimi, Keisuke Nakano, Hitoshi Nagatsuka

Oncology reports 47 ( 4 ) 2022年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Stromal cells in the tumor microenvironment (TME) can regulate the progression of numerous types of cancer; however, the bone invasion of oral squamous cell carcinoma (OSCC) has been poorly investigated. In the present study, the effect of verrucous SCC‑associated stromal cells (VSCC‑SCs), SCC‑associated stromal cells (SCC‑SCs) and human dermal fibroblasts on bone resorption and the activation of HSC‑3 osteoclasts in vivo were examined by hematoxylin and eosin, AE1/3 (pan‑cytokeratin) and tartrate‑resistant acid phosphatase staining. In addition, the expression levels of matrix metalloproteinase (MMP)9, membrane‑type 1 MMP (MT1‑MMP), Snail, receptor activator of NF‑κB ligand (RANKL) and parathyroid hormone‑related peptide (PTHrP) in the bone invasion regions of HSC‑3 cells were examined by immunohistochemistry. The results suggested that both SCC‑SCs and VSCC‑SCs promoted bone resorption, the activation of osteoclasts, and the expression levels of MMP9, MT1‑MMP, Snail, RANKL and PTHrP. However, SCC‑SCs had a more prominent effect compared with VSCC‑SCs. Finally, microarray data were used to predict potential genes underlying the differential effects of VSCC‑SCs and SCC‑SCs on bone invasion in OSCC. The results revealed that IL1B, ICAM1, FOS, CXCL12, INS and NGF may underlie these differential effects. In conclusion, both VSCC‑SCs and SCC‑SCs may promote bone invasion in OSCC by enhancing the expression levels of RANKL in cancer and stromal cells mediated by PTHrP; however, SCC‑SCs had a more prominent effect. These findings may represent a potential regulatory mechanism underlying the bone invasion of OSCC.

DOI： 10.3892/or.2022.8292

口腔癌間質由来のCCL2はCCR2陽性骨髄由来免疫抑制細胞の遊走に関与する

メイ・ワトウ, 河合穂高, 高畠清文, 藤井昌江, 稲田靖則, 大森悠加, 中野敬介, 長塚仁

日本病理学会会誌 111 ( 1 ) 277 - 277 2022年3月

口腔癌におけるCX3CL1の影響

トゥ・シュ・エイン, 河合穂高, 中山真彰, メイ・ワトウ, 伏見滋子, 中野敬介, 飯田征二, 長塚仁

日本病理学会会誌 111 ( 1 ) 278 - 278 2022年3月

Evaluation of multi-task learning in deep learning-based positioning classification of mandibular third molars. 査読国際誌

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

Scientific reports 12 ( 1 ) 684 - 684 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pell and Gregory, and Winter's classifications are frequently implemented to classify the mandibular third molars and are crucial for safe tooth extraction. This study aimed to evaluate the classification accuracy of convolutional neural network (CNN) deep learning models using cropped panoramic radiographs based on these classifications. We compared the diagnostic accuracy of single-task and multi-task learning after labeling 1330 images of mandibular third molars from digital radiographs taken at the Department of Oral and Maxillofacial Surgery at a general hospital (2014-2021). The mandibular third molar classifications were analyzed using a VGG 16 model of a CNN. We statistically evaluated performance metrics [accuracy, precision, recall, F1 score, and area under the curve (AUC)] for each prediction. We found that single-task learning was superior to multi-task learning (all p < 0.05) for all metrics, with large effect sizes and low p-values. Recall and F1 scores for position classification showed medium effect sizes in single and multi-task learning. To our knowledge, this is the first deep learning study to examine single-task and multi-task learning for the classification of mandibular third molars. Our results demonstrated the efficacy of implementing Pell and Gregory, and Winter's classifications for specific respective tasks.

DOI： 10.1038/s41598-021-04603-y

Is attention branch network effective in classifying dental implants from panoramic radiograph images by deep learning? 査読国際誌

Shintaro Sukegawa, Kazumasa Yoshii, Takeshi Hara, Futa Tanaka, Katsusuke Yamashita, Tutaro Kagaya, Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Hitoshi Nagatsuka, Yoshihiko Furuki

PloS one 17 ( 7 ) e0269016 2022年

記述言語：英語掲載種別：研究論文（学術雑誌）

Attention mechanism, which is a means of determining which part of the forced data is emphasized, has attracted attention in various fields of deep learning in recent years. The purpose of this study was to evaluate the performance of the attention branch network (ABN) for implant classification using convolutional neural networks (CNNs). The data consisted of 10191 dental implant images from 13 implant brands that cropped the site, including dental implants as pretreatment, from digital panoramic radiographs of patients who underwent surgery at Kagawa Prefectural Central Hospital between 2005 and 2021. ResNet 18, 50, and 152 were evaluated as CNN models that were compared with and without the ABN. We used accuracy, precision, recall, specificity, F1 score, and area under the receiver operating characteristics curve as performance metrics. We also performed statistical and effect size evaluations of the 30-time performance metrics of the simple CNNs and the ABN model. ResNet18 with ABN significantly improved the dental implant classification performance for all the performance metrics. Effect sizes were equivalent to "Huge" for all performance metrics. In contrast, the classification performance of ResNet50 and 152 deteriorated by adding the attention mechanism. ResNet18 showed considerably high compatibility with the ABN model in dental implant classification (AUC = 0.9993) despite the small number of parameters. The limitation of this study is that only ResNet was verified as a CNN; further studies are required for other CNN models.

DOI： 10.1371/journal.pone.0269016

Reproduction of the Antitumor Effect of Cisplatin and Cetuximab Using a Three-dimensional Spheroid Model in Oral Cancer. 査読国際誌

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年

記述言語：英語掲載種別：研究論文（学術雑誌）

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

新規生体材料の幾何学的構造制御による象牙質再生

稲田靖則, 高畠清文, 辻極秀次, 河合穂高, 中野敬介, 長塚仁

岡山歯学会雑誌 40 ( 2 ) 36 - 37 2021年12月

A Pilot Study of Seamless Regeneration of Bone and Cartilage in Knee Joint Regeneration Using Honeycomb TCP. 査読国際誌

Kiyofumi Takabatake, Hidetsugu Tsujigiwa, Aki Yoshida, Takayuki Furumatsu, Hotaka Kawai, May Wathone Oo, Keisuke Nakano, Hitoshi Nagatsuka

Materials (Basel, Switzerland) 14 ( 23 ) 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

The knee joint is a continuous structure of bone and cartilage tissue, making it difficult to regenerate using artificial biomaterials. In a previous study, we succeeded in developing honeycomb tricalcium phosphate (TCP), which has through-and-through holes and is able to provide the optimum microenvironment for hard tissue regeneration. We demonstrated that TCP with 300 μm pore diameters (300TCP) induced vigorous bone formation, and that TCP with 75 μm pore diameters (75TCP) induced cartilage formation. In the present study, we regenerated a knee joint defect using honeycomb TCP. 75TCP and 300TCP were loaded with transforming growth factor (TGF)-β alone or bone morphogenic protein (BMP)-2+TGF-β with or without Matrigel and transplanted into knee joint defect model rabbits. 75TCP showed no bone or cartilage tissue formation in any of the groups with TGF-β alone and BMP-2+TGF-β with/without Matrigel. However, for 300TCP and BMP-2+TGF-β with or without Matrigel, vigorous bone tissue formation was observed in the TCP holes, and cartilage tissue formation in the TCP surface layer was continuous with the existing cartilage. The cartilage area in the TCP surface was larger in the group without Matrigel (with BMP-2+TGF-β) than in the group with Matrigel (with BMP-2+TGF-β). Therefore, honeycomb TCP can induce the seamless regeneration of bone and cartilage in a knee joint.

DOI： 10.3390/ma14237225

Extracellular vesicles of P. gingivalis-infected macrophages induce lung injury. 査読国際誌

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

Biochimica et biophysica acta. Molecular basis of disease 1867 ( 11 ) 166236 - 166236 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1016/j.bbadis.2021.166236

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

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

ONCOLOGY LETTERS 22 ( 5 ) 2021年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPANDIDOS PUBL LTD

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

DOI： 10.3892/ol.2021.13039

Porphyromonas gingivalisはマクロファージの細胞外小胞を介して胎盤・胎児の成長発育を阻害する(Porphyromonas gingivalis impairs placental and fetal development through macrophage-derived extracellular vesicles)

棚井あいり, 福原瑶子, 江口傑徳, 河合穂高, 池亀美華, 岡村裕彦, 植田幸嗣

Journal of Oral Biosciences Supplement 2021 205 - 205 2021年10月

歯髄由来細胞の分化を制御するためのハニカムTCPの幾何構造(Geometrical structure of honeycomb TCP to control dental pulp-derived cell differentiation)

Inada Yasunori, Takabatake Kiyofumi, Tsujigiwa Hidetsugu, Kawai Hotaka, Nakano Keisuke, Nagatsuka Hitoshi

Journal of Hard Tissue Biology 30 ( 4 ) 401 - 401 2021年10月

口腔扁平上皮癌における腫瘍実質の生物学的特性に対する腫瘍間質の影響(Effect of the stroma on the biological characteristics of the parenchyma in oral squamous cell carcinoma)

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

Journal of Hard Tissue Biology 30 ( 4 ) 401 - 401 2021年10月

Stromal cells in the tumor microenvironment promote the progression of oral squamous cell carcinoma. 査読国際誌

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

International journal of oncology 59 ( 3 ) 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3892/ijo.2021.5252

Effect of Patient Clinical Variables in Osteoporosis Classification Using Hip X-rays in Deep Learning Analysis. 査読国際誌

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

Medicina (Kaunas, Lithuania) 57 ( 8 ) 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/medicina57080846

Lymphoepithelial Carcinoma in the Lateral Tongue: The Case Report

Sawako Ono, Hidenori Marunaka, Hiroyuki Yanai, Hotaka Kawai, Kiyofumi Takabatake, Kenji Nishida, Tomohiro Toji, Keisuke Nakano, Hitoshi Nagatsuka, Tadashi Yoshino

Reports 4 ( 3 ) 24 - 24 2021年8月

掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Lymphoepithelial carcinoma (LEC) of the tongue is a rare subtype of squamous cell carcinoma. Histologically, it is an undifferentiated carcinoma with rich lymphocyte and plasma cell infiltration. The most common location for LEC in the head and neck is the salivary glands, and LEC of the oral cavity is extremely rare. The second case report of LEC in the lateral tongue is presented. In addition, a review of the literature was performed, and the relationship between LEC and Epstein–Barr virus infection was considered.

DOI： 10.3390/reports4030024

The Origin of Stroma Influences the Biological Characteristics of Oral Squamous Cell Carcinoma. 査読国際誌

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

Cancers 13 ( 14 ) 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/cancers13143491

ハニカムTCPを用いた細胞外微小環境制御による象牙質再生

高畠清文, 辻極秀次, 吉田沙織, 稲田靖則, 河合穂高, 中野敬介, 長塚仁

日本口腔科学会雑誌 70 ( 2 ) 127 - 127 2021年7月

Preparation of Absorption-Resistant Hard Tissue Using Dental Pulp-Derived Cells and Honeycomb Tricalcium Phosphate. 査読国際誌

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

Materials (Basel, Switzerland) 14 ( 12 ) 2021年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/ma14123409

Multi-Task Deep Learning Model for Classification of Dental Implant Brand and Treatment Stage Using Dental Panoramic Radiograph Images. 査読国際誌

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

Biomolecules 11 ( 6 ) 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/biom11060815

Factors of Successful Treatment Using the Bone Lid Technique in Maxillofacial Surgery: A Pilot Study(和訳中) 査読

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

Journal of Hard Tissue Biology 30 ( 2 ) 193 - 198 2021年4月

顎顔面手術においてbone lid法を用いた治療法成功の要因予備研究(Factors of Successful Treatment Using the Bone Lid Technique in Maxillofacial Surgery: A Pilot Study)

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

Journal of Hard Tissue Biology 30 ( 2 ) 193 - 198 2021年4月

記述言語：英語出版者・発行元：硬組織再生生物学会

bone lid(BL)法による顎顔面手術を2014年1月〜2019年12月に受けた患者30名(男19名、女11名)を対象として、顎顔面におけるBL法の成功要因を後向きコホート研究で検討した。予測変数は臨床因子で構成し、属性(年齢、性別)、健康状態(喫煙、飲酒)、解剖学(上顎/下顎側、左/右側、皮質骨幅)、病巣(病巣サイズ、位置、病理診断)、治療状態(吸収性骨接合材料の差)に分類した。結果変数は術後のBL壊死とし、術後BL壊死に対する危険因子について統計的に検討した。その結果、術後BL壊死は3名(10.0%)に認められたが、その属性、解剖学、治療状態に有意差は認められなかった。健康状態変数である喫煙と飲酒に有意差を認め、病巣変数における歯槽頂からの病巣距離にも有意差を認めた。以上より、喫煙と飲酒はBL壊死の危険因子であり、歯槽頂への近接も病巣発達の危険因子であると考えられた。

その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J04713&link_issn=&doc_id=20210427250013&doc_link_id=%2Fdq4hdtib%2F2021%2F003002%2F013%2F0193-0198%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdq4hdtib%2F2021%2F003002%2F013%2F0193-0198%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

A Case Report of Spindle Cell Carcinoma with Osteoid and Cartilage Formation in the Tongue

Sawako Ono, Takuma Makino, Hiroyuki Yanai, Hotaka Kawai, Kiyofumi Takabatake, Keisuke Nakano, Kenji Nishida, Kohei Taniguchi, Tomohiro Toji, Hitoshi Nagatsuka, Tadashi Yoshino

Reports 4 ( 1 ) 5 - 5 2021年2月

掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Spindle cell carcinoma (SCSCC) with osteoid and/or cartilage formation in the head and neck is rare; only one case was reported in the tongue. Herein, we report an SCSCC with osteoid and cartilage formation of the tongue developed in an 85-year-old man, and then review the report.

DOI： 10.3390/reports4010005

A Case Report of Primordial Odontogenic Tumor That Required Distinction from a Dentigerous Cyst

Sawako Ono, Hotaka Kawai, Shintaro Sukegawa, Kiyofumi Takabatake, Keisuke Nakano, Hitoshi Nagatsuka, Tadashi Yoshino

Reports 4 ( 1 ) 4 - 4 2021年2月

掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

Primordial odontogenic tumor (POT) is a rare odontogenic tumor characterized by a variably cellular loose fibrous tissue with areas similar to the dental papilla and covered by cuboidal to columnar epithelium. We herein report a case of POT in a 14-year-old boy. Computed tomography (CT) exhibited a round cavity with a defined cortical border circumscribing the tooth of the second molar. However, the gross finding was a solid mass, not a cyst. Histologically, the tumor consisted of dental papillalike myxoid connective tissue covered by columnar epithelium. Therefore, although the clinical diagnosis was dentigerous cyst (DC), we diagnosed POT based on histologic findings. Clinical findings of POT resemble DC, but the clinical behavior of POT is different to DC, such as cortical expansion and root resorption of teeth. Therefore, histological differentiation of POT from DC is critical for accurate diagnosis.

DOI： 10.3390/reports4010004

A case of oral cancer with delayed occipital lymph node metastasis: Case report. 査読国際誌

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年12月

Geometrical Structure of Honeycomb TCP to Control Dental Pulp-Derived Cell Differentiation. 査読国際誌

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

Materials (Basel, Switzerland) 13 ( 22 ) 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/ma13225155

Deep Learning for Osteoporosis Classification Using Hip Radiographs and Patient Clinical Covariates. 査読国際誌

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

Biomolecules 10 ( 11 ) 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/biom10111534

Clinical retrospective study of dental implant removal: do patients who require implant removal desire implant prosthesis again? 査読

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

MEDICINA ORAL PATOLOGIA ORAL Y CIRUGIA BUCAL 25 ( 6 ) E784 - E790 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MEDICINA ORAL S L

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

DOI： 10.4317/medoral.23789

High-mobility group box 1 induces bone destruction associated with advanced oral squamous cancer via RAGE and TLR4. 査読国際誌

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年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Clinical study on primary screening of oral cancer and precancerous lesions by oral cytology. 査読国際誌

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

Diagnostic pathology 15 ( 1 ) 107 - 107 2020年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1186/s13000-020-01027-6

ニコチンが口腔癌細胞に与える影響の検討査読

伊原木聰一郎, 清水理恵子, 奥井達雄, 高畠清文, 河合穂高, 小野喜章, 長塚仁, 佐々木朗

日本口腔科学会雑誌 69 ( 3 ) 235 - 235 2020年9月

ニコチンが口腔癌細胞に与える影響の検討査読

伊原木聰一郎, 清水理恵子, 奥井達雄, 高畠清文, 河合穂高, 小野喜章, 長塚仁, 佐々木朗

日本口腔科学会雑誌 69 ( 3 ) 235 - 235 2020年9月

Biomechanical Loading Comparison between Titanium and Bioactive Resorbable Screw Systems for Fixation of Intracapsular Condylar Head Fractures. 査読国際誌

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

Materials (Basel, Switzerland) 13 ( 14 ) 2020年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/ma13143153

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

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

The Journal of craniofacial surgery 31 ( 5 ) 1338 - 1342 2020年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

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

DOI： 10.1097/SCS.0000000000006352

口腔扁平上皮癌の腫瘍微小環境における骨髄由来細胞の分化と役割

高畠清文, 河合穂高, Oo May Wathone, 吉田沙織, 大森悠加, 中野敬介, 辻極秀次, 長塚仁

日本口腔科学会雑誌 69 ( 2 ) 132 - 132 2020年7月

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

高畠清文, 河合穂高, 大森悠加, Oo May Wathone, 吉田沙織, 中野敬介, 長塚仁

日本口腔科学会雑誌 69 ( 2 ) 132 - 133 2020年7月

口腔扁平上皮癌の腫瘍微小環境における骨髄由来細胞の分化と役割

高畠清文, 河合穂高, Oo May Wathone, 吉田沙織, 大森悠加, 中野敬介, 辻極秀次, 長塚仁

日本口腔科学会雑誌 69 ( 2 ) 132 - 132 2020年7月

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

高畠清文, 河合穂高, 大森悠加, Oo May Wathone, 吉田沙織, 中野敬介, 長塚仁

日本口腔科学会雑誌 69 ( 2 ) 132 - 133 2020年7月

Outer membrane vesicles of Porphyromonas gingivalis attenuate insulin sensitivity by delivering gingipains to the liver. 査読国際誌

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

Biochimica et biophysica acta. Molecular basis of disease 1866 ( 6 ) 165731 - 165731 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.1016/j.bbadis.2020.165731

Knockout of MMP3 Weakens Solid Tumor Organoids and Cancer Extracellular Vesicles. 査読国際誌

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

Cancers 12 ( 5 ) 2020年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/cancers12051260

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

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

Reports — Medical Cases, Images, and Videos 3 ( 2 ) 6 - 6 2020年3月

掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI AG

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

DOI： 10.3390/reports3020006

口腔癌間質細胞が骨髄由来細胞の動員に与える影響

河合穂高, メイワト・ウ, 辻極秀次, 高畠清文, 大森悠加, 藤井昌江, 中野敬介, 長塚仁

日本病理学会会誌 109 ( 1 ) 315 - 315 2020年3月

エナメル上皮腫開窓術の適応に関する組織学的検討

大森悠加, 高畠清文, 河合穂高, 吉田沙織, メイワト・ウ, 浜田芽衣, 中野敬介, 長塚仁

日本病理学会会誌 109 ( 1 ) 316 - 316 2020年3月

Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3. 査読国際誌

Chiharu Sogawa, Takanori Eguchi, Manh Tien Tran, Masayuki Ishige, Kilian Trin, Yuka Okusha, Eman Ahmed Taha, Yanyin Lu, Hotaka Kawai, Norio Sogawa, Masaharu Takigawa, Stuart K Calderwood, Kuniaki Okamoto, Ken-Ichi Kozaki

Cancers 12 ( 2 ) 2020年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. The properties of three-dimensional (3D) tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a 3D tumoroid-based screening system. We screened six pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with a matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-κB, and β-catenin, and the properties of cancer stem cells/cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited the tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors.

DOI： 10.3390/cancers12020523

口腔扁平上皮癌が作り出す腫瘍微小環境における骨髄由来細胞の役割

高畠清文, 吉田沙織, Oo May Wathone, 大森悠加, 河合穂高, 中野敬介, 長塚仁

日本口腔診断学会雑誌 33 ( 1 ) 114 - 114 2020年2月

腫瘍組織に動員される骨髄由来細胞へ腫瘍間質が及ぼす影響の検討

Oo May Wathone, 河合穂高, 吉田沙織, 高畠清文, 中野敬介, 長塚仁

日本口腔診断学会雑誌 33 ( 1 ) 116 - 116 2020年2月

Morphological characteristics of radicular cysts using computed tomography. 査読

Shintaro Sukegawa, Hidenobu Matsuzaki, Naoki Katase, Hotaka Kawai, Takahiro Kanno, Jun-Ichi Asaumi, Yoshihiko Furuki

Odontology 108 ( 1 ) 74 - 83 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

The purpose of this study was to evaluate computed tomography (CT) findings of radicular cysts with a focus on location, size, and condition of the surrounding bone. Subjects comprised 60 men and 86 women (mean age 47.2 years) with histopathologically confirmed radicular cysts who underwent CT examination between 2012 and 2014. Mesiodistal and buccolingual diameters were measured at the location where the lesion appeared to be largest on CT axial images. Of the 146 cases, 103 lesions were in the maxilla and 43 were in the mandible. Mesiodistal diameter of the maxillary lesions was significantly larger than that of the mandibular lesions. However, the ratio of mesiodistal diameter to buccolingual diameter in the mandible was significantly larger than that in the maxilla. Bone expansion was more significant in the maxilla than in the mandible. Mesiodistal and buccolingual diameters in only the maxilla and perilesional sclerotic radiolucency in images of both jaws were significantly associated with the severity of clinical symptoms. The findings suggest that radicular cysts in the maxilla are accompanied by bone expansion in the mesiodistal and buccolingual directions and those in the mandible progress in the mesiodistal direction without bone expansion. Clinical acute symptoms (pain and swelling) are correlated with lesion size in the maxilla; such a correlation is not clear for mandibular lesions, and discovery of mandibular lesions may, therefore, be delayed.

DOI： 10.1007/s10266-019-00443-5

Differentiation and roles of bone marrow-derived cells on the tumor microenvironment of oral squamous cell carcinoma. 査読国際誌

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

Oncology letters 18 ( 6 ) 6628 - 6638 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3892/ol.2019.11045

ハニカムTCPの硬組織形成制御機構解明と臨床応用

大森悠加, 高畠清文, 辻極秀次, 河合穂高, 吉田沙織, Oo May Wathone, 中野敬介, 長塚仁

岡山歯学会雑誌 38 ( 2 ) 86 - 87 2019年12月

口腔扁平上皮癌が作り出す腫瘍微小環境における骨髄由来細胞の役割

高畠清文, 吉田沙織, Oo May Wathone, 大森悠加, 河合穂高, 中野敬介, 長塚仁

日本口腔内科学会雑誌 25 ( 2 ) 104 - 104 2019年12月

腫瘍組織に動員される骨髄由来細胞へ腫瘍間質が及ぼす影響の検討

Oo May Wathone, 河合穂高, 吉田沙織, 高畠清文, 中野敬介, 長塚仁

日本口腔内科学会雑誌 25 ( 2 ) 106 - 106 2019年12月

The Role of Sonic Hedgehog Signaling in the Tumor Microenvironment of Oral Squamous Cell Carcinoma. 査読国際誌

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

International journal of molecular sciences 20 ( 22 ) 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/ijms20225779

Advantage of Alveolar Ridge Augmentation with Bioactive/Bioresorbable Screws Made of Composites of Unsintered Hydroxyapatite and Poly-L-lactide. 査読国際誌

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

Materials (Basel, Switzerland) 12 ( 22 ) 2019年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.3390/ma12223681

高転移臓器における転移促進的微小環境の性質の検討

河合穂高, 信長ひかり, Oo May Wathone, 吉田沙織, 大森悠加, 高畠清文, 中野敬介, 辻極秀次, 長塚仁

Journal of Oral Biosciences Supplement 2019 261 - 261 2019年10月

骨・軟骨形成に対するハニカムTCPの幾何学的構造の影響の解析と臨床応用(Analysis of the geometrical structure effect of honeycomb TCP on bone and cartilage formation and clinical application)

Takabatake Kiyofumi, Tsujigiwa Hidetsugu, Kawai Hotaka, Yoshida Saori, Omori Haruka, Nakano Keisuke, Kawakami Toshiyuki, Nagatsuka Hitoshi

Journal of Hard Tissue Biology 28 ( 4 ) 395 - 395 2019年10月

コレステリン肉芽腫の骨髄由来免疫抑制細胞(MDSC)の免疫組織化学的検討(Immunohistohemical examination of Myeloid-derived suppressor cells(MDSC) of cholesterol granuloma)

Nakano Keisuke, Kawai Hotaka, Takabatake Kiyofumi, Yoshida Saori, Omori Haruka, Nagatsuka Hitoshi, Kawakami Toshiyuki

Journal of Hard Tissue Biology 28 ( 4 ) 395 - 395 2019年10月

Oropharyngeal adenoid cystic carcinoma invading the mandibular bone through the mandibular foramen 査読

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

ORAL RADIOLOGY 35 ( 3 ) 335 - 340 2019年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

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

DOI： 10.1007/s11282-018-0359-3

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

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年7月

Biomechanical Loading Comparison between Titanium and Unsintered Hydroxyapatite/Poly-L-Lactide Plate System for Fixation of Mandibular Subcondylar Fractures. 査読国際誌

Sukegawa S, Kanno T, Yamamoto N, Nakano K, Takabatake K, Kawai Hotaka, Nagatsuka H, Furuki Y

Materials (Basel, Switzerland) 12 ( 9 ) 2019年5月

Notch Signaling Affects Oral Neoplasm Cell Differentiation and Acquisition of Tumor-Specific Characteristics. 査読国際誌

Nakano K, Takabatake K, Kawai Hotaka, Yoshida S, Maeda H, Kawakami T, Nagatsuka H

International journal of molecular sciences 20 ( 8 ) 2019年4月

Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma. 査読国際誌

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年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Immunohistochemistry of YAP and dNp63 and survival analysis of patients bearing precancerous lesion and oral squamous cell carcinoma. 査読国際誌

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

International journal of medical sciences 16 ( 5 ) 766 - 773 2019年

記述言語：英語掲載種別：研究論文（学術雑誌）

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

DOI： 10.7150/ijms.29995

Locally injected ivabradine inhibits carrageenan-induced pain and inflammatory responses via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. 査読国際誌

Miyake S, Higuchi H, Honda-Wakasugi Y, Fujimoto M, Kawai Hotaka, Nagatsuka H, Maeda S, Miyawaki T

PloS one 14 ( 5 ) e0217209 2019年

Feasible Advantage of Bioactive/Bioresorbable Devices Made of Forged Composites of Hydroxyapatite Particles and Poly-L-lactide in Alveolar Bone Augmentation: A Preliminary Study. 査読国際誌

Sukegawa S, Kawai Hotaka, Nakano K, Kanno T, Takabatake K, Nagatsuka H, Furuki Y

International journal of medical sciences 16 ( 2 ) 311 - 317 2019年

Solitary Fibrous Tumor Arising in the Buccal Space. 査読国際誌

Tatsuo Okui, Soichiro Ibaragi, Hotaka Kawai, Akira Sasaki

Case reports in medicine 2019 9459837 - 9459837 2019年

記述言語：英語

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

Do the Presence of Mandibular Third Molar and the Occlusal Support Affect the Occurrence and the Mode of Mandibular Condylar Fractures? 査読

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

JOURNAL OF HARD TISSUE BIOLOGY 28 ( 4 ) 377 - 382 2019年

脂質・コレステロール排出ポンプABCG1標的による腫瘍内エクソソーム蓄積および腫瘍縮小

江口傑徳, 十川千春, 難波友里, 奥舎有加, 河合穂高, 小野喜章, 板垣まみ, 村上純, 大山和美, 浅海淳一, 岡元邦彰

日本薬理学会年会要旨集 92 2-YIA-26 2019年

記述言語：日本語出版者・発行元：公益社団法人日本薬理学会

The ATP-binding cassette transporter G1 (ABCG1) is a cholesterol lipid efflux pump whose role in tumor growth has been largely unknown. Our transcriptomics revealed that ABCG1 was powerfully expressed in rapidly metastatic, aggregative colon cancer cells, in all the ABC transporter family members. Coincidently, genetic amplification of ABCG1 is found in 10% to 35% of clinical samples of metastatic cancer cases. Expression of ABCG1 was further elevated in three-dimensional tumoroids (tumor organoids) within stemness-enhancing tumor milieu, whereas depletion of ABCG1 lowered cellular aggregation and tumoroid growth in vitro as well as hypoxia-inducible factor 1α in cancer cells around the central necrotic areas in tumors in vivo. Notably, depletion of ABCG1 triggered the intracellular accumulation of extracellular vesicles (EVs) and regression of tumoroids. Collectively, these data suggest that ABCG1 plays a crucial role in tumorigenesis in metastatic cancer and that depletion of ABCG1 triggers tumor regression with the accumulation of EVs, their derivatives and cargos, implicating a novel ABCG1-targeting therapeutic strategy by which redundant and toxic substances may be accumulated in tumors leading to their regression.

DOI： 10.1254/jpssuppl.92.0_2-yia-26

Lactate Transporter Monocarboxylate Transporter 4 Induces Bone Pain in Head and Neck Squamous Cell Carcinoma. 査読国際誌

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年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.3390/ijms19113317

口腔扁平上皮癌における腫瘍間質による腫瘍生物学特性の制御(Control of tumor biological character by tumor stroma in oral squamous cell carcinoma)

Takabatake Kiyofumi, Kawai Hotaka, Yoshida Saori, Matsuda Hiroyuki, Fujii Masae, Nakano Keisuke, Nagatsuka Hitoshi

Journal of Hard Tissue Biology 27 ( 4 ) 365 - 366 2018年10月

ハニカムTCP構造の幾何学構造が骨・軟骨形成および血管新生に及ぼす影響(Effects of the geometrical structure of a honeycomb TCP structure on bone and cartilage formation and angiogenesis)

Matsuda Hiroyuki, Takabatake Kiyofumi, Tsujigiwa Hidetsugu, Kawai Hotaka, Yoshida Saori, Nakano Keisuke, Nagatsuka Hitoshi

Journal of Hard Tissue Biology 27 ( 4 ) 367 - 367 2018年10月

Effects of the Geometrical Structure of a Honeycomb TCP on Relationship between Bone / Cartilage Formation and Angiogenesis. 査読国際誌

Matsuda H, Takabatake K, Tsujigiwa H, Watanabe S, Ito S, Kawai Hotaka, Hamada M, Yoshida S, Nakano K, Nagatsuka H

International journal of medical sciences 15 ( 14 ) 1582 - 1590 2018年

Depletion of Lipid Efflux Pump ABCG1 Triggers the Intracellular Accumulation of Extracellular Vesicles and Reduces Aggregation and Tumorigenesis of Metastatic Cancer Cells. 査読国際誌

Namba Y, Sogawa C, Okusha Y, Kawai Hotaka, Itagaki M, Ono K, Murakami J, Aoyama E, Ohyama K, Asaumi JI, Takigawa M, Okamoto K, Calderwood SK, Kozaki KI, Eguchi T

Frontiers in oncology 8 376 - 376 2018年

The Role of Bone Marrow-Derived Cells during Ectopic Bone Formation of Mouse Femoral Muscle in GFP Mouse Bone Marrow Transplantation Model. 査読国際誌

Takabatake K, Tsujigiwa H, Song Y, Matsuda H, Kawai Hotaka, Fujii M, Hamada M, Nakano K, Kawakami T, Nagatsuka H

International journal of medical sciences 15 ( 8 ) 748 - 757 2018年

In Vitro Efficacy of CaCO3 Content in CaTiO3-CaCO3 Composites for Bone Growth 査読

Rodriguez Andrea Paola, Sanchez Maria Alejandra, Felice Betiana, Zamora Martin Lucas, Tsujigiwa Hidetsugu, Takabatake Kiyofumi, Kawai Hotaka, Nakano Keisuke, Nagatsuka Hitoshi

JOURNAL OF HARD TISSUE BIOLOGY 27 ( 3 ) 250 - 256 2018年

Pathological and Clinical Study of Japanese Ameloblastic Fibro-Odontomas 査読

Shintaro Sukegawa, Keisuke Nakano, Takahiro Kanno, Hotaka Kawai, Kenichi Matsumoto, Yuka Sukegawa-Takahashi, Masanori Masui, Yoshihiko Furuki

JOURNAL OF HARD TISSUE BIOLOGY 26 ( 4 ) 425 - 430 2017年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JOURNAL HARD TISSUE BIOLOGY

Ameloblastic fibro-odontoma (AFO) is defined as a tumor with general characteristics of an ameloblastic fibroma along with the presence of enamel and dentine. AFO is a well-encapsulated, painless, slow-growing, and expanding tumor in young patients. Histologically, it has been classified as an ameloblastic fibroma or odontoma. In the 2017 new WHO classification of odontogenic tumor, AFO is described that they in most cases represent developmental stages of either complex or compound odontoma and that retaining them as separate entities would therefore be illogical. However, there is still considerable confusion concerning the nature and histology of AFO and the surgical therapy for this lesion. Here we present a case of maxillary AFO and review the relevant literature regarding the clinical and surgical features of this lesion.

DOI： 10.2485/jhtb.26.425

腫瘍移植マウスを用いた、遠隔臓器に含まれる骨髄由来細胞の局在同定(Localization of bone marrow-derived cells of distant organs using tumor transplanted mouse)

Kawai Hotaka, Tsujigiwa Hidetsugu, Nobunaga Hikari, Takabatake Kiyofumi, Nakano Keisuke, Matsuda Hiroyuki, Fushimi Shigeko, Nagatsuka Hitoshi

Journal of Hard Tissue Biology 26 ( 4 ) 438 - 438 2017年10月

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

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年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPANDIDOS PUBL LTD

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.

DOI： 10.3892/ijo.2017.4050

A Clinical Retrospective Study of Surgical Treatment for Medication-Related Osteonecrosis of the Jaw 査読

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

JOURNAL OF HARD TISSUE BIOLOGY 25 ( 4 ) 447 - 454 2016年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JOURNAL HARD TISSUE BIOLOGY

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

DOI： 10.2485/jhtb.25.447

Surgical Treatment and Dental Implant Rehabilitation after the Resection of an Osseous Dysplasia 査読

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

JOURNAL OF HARD TISSUE BIOLOGY 25 ( 4 ) 437 - 441 2016年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JOURNAL HARD TISSUE BIOLOGY

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

DOI： 10.2485/jhtb.25.437

GFPマウス骨髄移植モデルの異所性骨形成における骨髄由来細胞の役割(The role of bone marrow-derived cells in ectopic bone regeneration in the GFP mouse bone marrow transplantation model)

Yu Song, Takabatake Kiyofumi, Tsujigiwa Hidetsugu, Matsuda Hiroyuki, Kawai Hotaka, Yoshida Saori, Nakano Keisuke, Nagatsuka Hitoshi

Journal of Hard Tissue Biology 25 ( 4 ) 458 - 458 2016年10月

Postoperative Infection Caused by a Resorbable Plate Used to Treat a Zygomatic Fracture 査読

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

Clinics in Surgery 1 ( 1 ) 2016年

Spontaneous regression of plasmablastic lymphoma in an elderly human immunodeficiency virus (HIV)-negative patient 査読

Takuro Igawa, Yasuharu Sato, Hotaka Kawai, Eisei Kondo, Mai Takeuchi, Tomoko Miyata-Takata, Katsuyoshi Takata, Tadashi Yoshino

DIAGNOSTIC PATHOLOGY 10 183 2015年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BIOMED CENTRAL LTD

Plasmablastic lymphoma (PBL) is an aggressive lymphoma commonly associated with human immunodeficiency virus (HIV) infection. Herein we describe a rare case of PBL that spontaneously regressed. An 80-year-old man was referred to our hospital owing to an exophytic gingival tumor in the right maxillary second molar region. He had no significant past medical history, and a screening test for HIV was negative. Imaging showed that the tumor measured 26 x 23 x 16 mm and was confined in the alveolar bone. The tumor was histologically comprised of highly proliferative immunoblastic cells positive for CD138 and Epstein-Barr virus (EBV)-encoded RNA. Monoclonal IgH chain gene rearrangement was detected via polymerase chain reaction. After biopsy and diagnosis of PBL, the tumor began to decrease in size and had apparently disappeared at the time of surgery. There was no histological evidence of a residual lesion in the surgical specimen. In conclusion, a minority of immunosenescence-associated PBLs in the elderly should be recognized as a unique clinicopathological entity distinct from common aggressive PBL.

DOI： 10.1186/s13000-015-0421-y

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

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

Oral and Maxillofacial Surgery Cases 1 ( 3 ) 38 - 41 2015年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier Inc

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

DOI： 10.1016/j.omsc.2015.06.003

Long-Term Bioresorption of Bone Fixation Devices Made from Composites of Unsintered Hydroxyapatite Particles and Poly-L-Lactide 査読

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

JOURNAL OF HARD TISSUE BIOLOGY 24 ( 2 ) 219 - 224 2015年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JOURNAL HARD TISSUE BIOLOGY

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

DOI： 10.2485/jhtb.24.219

エナメル上皮腫細胞による腫瘍間質の多様性の解析(Analyze of variation of the tumor stroma by ameloblastoma cells)

Takebe Yuichiro, Kawai Hotaka, Takabatake Kiyofumi, Song Yu, Ito Satoshi, Huji Masae, Tsujigiwa Hidetsugu, Nagatsuka Hitoshi

Journal of Hard Tissue Biology 23 ( 4 ) 470 - 471 2014年10月

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