Faculty Profiles - NAKANO Keisuke

Papers - NAKANO Keisuke

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SOD3 Expression in Tumor Stroma Provides the Tumor Vessel Maturity in Oral Squamous Cell Carcinoma. Reviewed International journal

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 ) 2022.10

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

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

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Deep learning model for analyzing the relationship between mandibular third molar and inferior alveolar nerve in panoramic radiography. Reviewed International journal

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 2022.10

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

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

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Lip pleomorphic adenomas: case series and literature review Reviewed

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 2022.10

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

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 2022.10

Effective deep learning for oral exfoliative cytology classification. Reviewed International journal

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 2022.8

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

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

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The Effectiveness of Pre-Operative Screening Tests in Determining Viral Infections in Patients Undergoing Oral and Maxillofacial Surgery. Reviewed International journal

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 ) 2022.7

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

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

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Incidence and Risk of Anti-Resorptive Agent-Related Osteonecrosis of the Jaw after Tooth Extraction: A Retrospective Study. Reviewed International journal

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 ) 2022.7

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

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

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口腔扁平上皮癌と前駆病変の診断と評価 Invited Reviewed

中野敬介, 長塚仁

診断病理 39 ( 3 ) 173 - 182 2022.7

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 Reviewed

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 2022.7

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 Reviewed

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 2022.6

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 Reviewed

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 2022.6

Crosstalk between cancer and different cancer stroma subtypes promotes the infiltration of tumor‑associated macrophages into the tumor microenvironment of oral squamous cell carcinoma. Reviewed International journal

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

International journal of oncology 60 ( 6 ) 2022.6

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

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

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Prognostic Factors in Endodontic Surgery Using an Endoscope: A 1 Year Retrospective Cohort Study. Reviewed International journal

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 ) 2022.5

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

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

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Identification of osteoporosis using ensemble deep learning model with panoramic radiographs and clinical covariates. Reviewed International journal

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 2022.4

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

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

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Significance of cancer stroma for bone destruction in oral squamous cell carcinoma using different cancer stroma subtypes. Reviewed International journal

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

Oncology reports 47 ( 4 ) 2022.4

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

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

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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 Reviewed

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 2022.3

口腔癌におけるCX3CL1の影響 Reviewed

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 2022.3

口腔癌と腫瘍間質 Invited Reviewed

中野敬介, 長塚仁

病理と臨床 40 ( 2 ) 183 - 185 2022.2

Heat Shock Protein Overexpression-Mediated Periodontal Ligament Regeneration: A Fundamental Approach to Generate a Potential Biomaterial. Reviewed International journal

Rina Muraoka, Keisuke Nakano, Toshiyuki Kawakami

Materials (Basel, Switzerland) 15 ( 3 ) 2022.1

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

The periodontal ligament (PDL) is a cell-rich fibrous connective tissue supporting the tooth roots. The tissue helps to maintain homeostasis and exhibits regenerative and repairing ability, which is mediated by the heat shock protein (HSP). Here, we experimentally created PDL tissue with notable ability to regenerate hard tissue and evaluated it as a potential biomaterial. We immunohistochemically examined the mechanical load-induced HSP overexpression in mouse PDL. Following mechanical load application and release, HSP70 localization in the PDL was altered immediately, suggesting that the HSP70 function may differ with the timing of its expression in PDL. HSP70 expressed in the cytoplasm and nucleus of fibroblasts in PDL on the tension side not only participated in periodontium repair, but also functioned as a molecular chaperone during protein expression involved in osteogenesis to restructure injured tissue. This study highlights the potential of artificially created highly functional PDL tissues as biomaterials.

DOI： 10.3390/ma15030809

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Evaluation of multi-task learning in deep learning-based positioning classification of mandibular third molars. Reviewed International journal

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 2022.1

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

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

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Papers - NAKANO Keisuke