Faculty Profiles - NAGATSUKA Hitoshi

Papers - NAGATSUKA Hitoshi

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口腔扁平上皮癌が作り出す腫瘍微小環境における骨髄由来細胞の役割

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

日本口腔診断学会雑誌 33 ( 1 ) 114 - 114 2020.2

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

大森悠加, 吉田沙織, 藤井昌江, 浜田芽衣, 安田政実, 長塚仁

日本口腔診断学会雑誌 33 ( 1 ) 115 - 115 2020.2

CXCR4の阻害が口腔扁平上皮癌の腫瘍血管に与える影響 Reviewed

吉田沙織, 河合穂高, メイ・ワトン・ウ, 常安き, 浜田芽衣, 高畠清文, 中野敬介, 長塚仁

日本口腔診断学会雑誌 33 ( 1 ) 116 - 116 2020.2

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

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

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

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

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

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

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

Oncology Letters 19 ( 4 ) 2602 - 2608 2020

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

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

DOI： 10.3892/ol.2020.11358

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：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 prosthe-ses. Age, sex, diabetes, smoking, implant site distribution, reason for implant removal, and blade and root-form implants were categorized as predictive variables. The outcome variable was desire for re-implantation or use of other prosthetic methods after implant removal. A logistic regression model was created to identify patient factors that could predict the re-implantation of dental prostheses after implant removal. Results: A total of 215 dental implants were removed from 143 patients. The most common reason for implant removal was peri-implantitis that was identified in 165 implants. After implant removal, re-implantation was performed in 98 implants (45.6%). Bivariate analyses showed that age, diabetes, implant type, and reason for implant removal were associated with the desire for re-implanted prostheses. The multiple regression model revealed that age, implant type, and reason for implant removal were associated with an increased desire for re-implant prostheses after implant removal. Conclusions: Re-implantation of prostheses after the removal of dental implants was desired by patients who were younger, had implants placed in the root form, and had implants removed due to prosthetic-related complications.

DOI： 10.4317/medoral.23789

口腔扁平上皮癌が作り出す腫瘍微小環境における骨髄由来細胞の役割

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

日本口腔内科学会雑誌 25 ( 2 ) 104 - 104 2019.12

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

大森悠加, 吉田沙織, 藤井昌江, 浜田芽衣, 安田政実, 長塚仁

日本口腔内科学会雑誌 25 ( 2 ) 105 - 105 2019.12

腫瘍組織に動員される骨髄由来細胞へ腫瘍間質が及ぼす影響の検討

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

日本口腔内科学会雑誌 25 ( 2 ) 106 - 106 2019.12

ハニカムTCPの硬組織形成制御機構解明と臨床応用

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

岡山歯学会雑誌 38 ( 2 ) 86 - 87 2019.12

CXCR4の阻害が口腔扁平上皮癌の腫瘍血管に与える影響 Reviewed

吉田沙織, 河合穂高, ウ・メイ・ワトン, 常安き, 浜田芽衣, 高畠清文, 中野敬介, 長塚仁

日本口腔内科学会雑誌 25 ( 2 ) 106 - 106 2019.12

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

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

International Journal of Molecular Sciences 20 ( 22 ) 2019.11

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

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 Reviewed International journal

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

Materials 12 ( 22 ) 2019.11

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

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 2019.10

エナメル上皮腫における細胞診の有用性

藤井昌江, 高畠清文, 河合穂高, 吉田沙織, 大森悠加, 中野敬介, 長塚仁

日本臨床細胞学会雑誌 58 ( Suppl.2 ) 716 - 716 2019.10

SMARCA4-deficient thoracic sarcomaの一例 Reviewed

浜田芽衣, 加藤智美, 扇田智彦, 目黒葉子, 永田耕治, 佐藤次生, 佐藤奈帆子, 川崎朋範, 新井栄一, 長塚仁, 安田政実

日本臨床細胞学会雑誌 58 ( Suppl.2 ) 709 - 709 2019.10

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 2019.10

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 2019.10

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

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

Oral Radiology 35 ( 3 ) 335 - 340 2019.9

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

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

吉田祥子, 岸本晃治, 村瀬友里香, 伊原木聰一郎, 吉岡徳枝, 奥井達雄, 長塚仁, 佐々木朗

日本口腔腫瘍学会誌 31 ( 3 ) 151 - 156 2019.9

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

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

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Papers - NAGATSUKA Hitoshi