Toyoko Tajima, Maki Hosoki, Mayu Miyagi, Miho Inoue, Aya Ozawa, Mizuki Shinkai, Mio Naritani, Yoshiaki Kubo, Raman Lakshmi Swarna, Parimal Chavan, Kazuyuki Koike and Yoshizo Matsuka : Correlation between pierced earrings and metal allergy prevalence in Tokushima University hospital: A 15-year retrospective analysis, Scientific Reports, 15, 1, 10939, 2025.
(Summary)
In Japan, metal allergies are becoming increasingly prevalent, raising concerns for public health. This study examined metal allergy characteristics, patient histories, and clinical signs associated with patch test results over a 15-year period at the Dental Metal Allergy Clinic of Tokushima University Hospital. A retrospective analysis of 1085 patients revealed that 65.4% tested positive for at least one metal allergen, with palladium chloride, nickel sulfate, potassium dichromate, and cobalt chloride identified as the most common allergens. Female patients were disproportionately affected, accounting for 78.4% of the study population. Notably, there was a substantial increase in patients reporting inflammation due to pierced earrings, increasing from 5.0% in 2005 to 43.2% in 2020, particularly among females. Patients with a history of inflammation from earrings had an 81.3% prevalence of metal allergies, which was significantly higher than the 60.4% reported in those without such a history (chi-square test, p < 0.001). These findings suggest a strong link between earrings and metal allergies, underscoring the need for improved education, early detection, and preventive strategies to address the growing impact of metal allergies on public health.
Tetsu Shimane, Kazuyuki Koike, Shigeyuki Fujita, Hiroshi Kurita, Tanaka Emiko Isomura, Daichi Chikazu, Naomi Kanno, Keiichi Sasaki, Satoshi Hino, Hideharu Hibi, Takahiro Koyama, Seiji Nakamura, Takeshi Nomura, Yoshiyuki Mori, Itaru Tojyo, Toshiro Yamamoto, Iku Yamamori, Keiko Aota and Hideki Tanzawa : Positive impact of perioperative oral management on the risk of surgical site infections after abdominal surgery: Sixteen universities in Japan, Medicine, 102, 37, E35066, 2023.
(Summary)
Surgical site infections (SSI) are associated with increased morbidity and mortality rates. This study aimed to investigate the ability of perioperative oral management (POM) to reduce the risk of SSI in abdominal surgery Real-world data collected from 16 university hospitals in Japan were reviewed. The medical records of consecutive 2782 patients (1750 men and 1032 women) who underwent abdominal surgery under general anesthesia at 16 university hospitals were retrospectively reviewed. Detailed information about SSI was assessed and compared between patients with and without POM in univariate and multivariate analyses. SSI were observed in 275 patients (incidence rate:9.9%), and POM was administered to 778 patients (28.0%). Univariate analyses revealed that diabetes mellitus, Eastern Cooperative Oncology Group performance status, American Society of Anesthesiologists classification, surgical site, preoperative Prognostic Nutritional Index score, POM, extent of surgery, operation time, and intraoperative blood loss were significantly associated with postoperative SSI (Chi-square or Mann-Whitney U test, P < .01). Multivariate analysis revealed that POM had significant preventive effects against postoperative SSI (estimate: -0.245, standard error: 0.080, P < .01). Surgical site, American Society of Anesthesiologists classification, and operation time were also significant and independent clinical predictors of SSI. The analysis of real-world data from 16 university hospitals revealed that, regardless of the content and degree of the problem, the addition of POM has significant beneficial effects in reducing the risk of SSI in patients who undergo abdominal surgery. Medical records from each hospital and data from the Health Care Payment Fund were collected and analyzed retrospectively.
(Keyword)
general anesthesia / multicenter analysis / perioperative oral management / surgical site infections
Ichi Shin Yamada, Kazuyuki Koike, Tanaka Emiko Isomura, Daichi Chikazu, Kenji Yamagata, Masahiro Iikubo, Satoshi Hino, Hideharu Hibi, Kouji Katsura, Seiji Nakamura, Takeshi Nomura, Yoshiyuki Mori, Itaru Tojyo, Narisato Kanamura, Iku Yamamori, Keiko Aota, Shigeyuki Fujita, Hideki Tanzawa and Hiroshi Kurita : The effects of perioperative oral management on perioperative serum albumin levels in patients treated surgically under general anesthesia: A multicenter retrospective analysis in Japan, Medicine, 100, 10, E25119, 2021.
(Summary)
The purpose of the present study was to investigate the efficacy of perioperative oral managements (POMs) on perioperative nutritional conditions in patients undergoing surgery with general anesthesia. Medical records were retrospectively reviewed and the effects of POMs were investigated based on a large number of cases using a multicenter analysis. The profile of serum albumin levels was assessed and compared between patients with and without POMs using the multivariate analysis. Seventeen Eleven thousand and one hundred sixty patients (4,873 males and 6,287 females) were reviewed. Of these, 2710 patients (24.3%) had undergone POMs. The results of a multivariate analysis revealed the significant positive effect of POMs on perioperative serum albumin level (change between at admission and discharge, (Estimate: 0.022, standard error: 0.012, P < .0001). Patient gender, age, surgical site, performance status, the American Society of Anesthesiologists (ASA) physical status classification, operation time, amount of blood loss, and serum albumin level at admission were also significant predictors. Adjusted multivariate analysis of the effects of POMs on perioperative change of serum albumin level in all subjects reveled the significance of POMs intervention (estimate: 0.022, standard error: 0.012, P < .0001). These results suggest that POMs exerts significant positive effects on perioperative serum albumin levels in patients underwent surgery under general anesthesia.
(Keyword)
oral care / perioperative oral management / serum albumin / surgery
Issei Okunaga, Kohei Shikano, Hajime Kasai, Kazuyuki Koike, Takeshi Kawasaki, Ayaka Kuriyama, Shunichiro Iwasawa, Toshihiko Sugiura, Hideki Tanzawa and Koichiro Tatsumi : A case of intractable medication-associated osteonecrosis of the jaw complicated by cervical abscess and sepsis, Chiba Medical Journal, 97E, 49-56, 2021.
Kazuya Hiroshima, Masashi Shiiba, Noritoshi Oka, Fumihiko Hayashi, Sho Ishida, Reo Fukushima, Kazuyuki Koike, Manabu Iyoda, Dai Nakashima, Hideki Tanzawa and Katsuhiro Uzawa : Tspan15 plays a crucial role in metastasis in oral squamous cell carcinoma, Experimental Cell Research, 384, 2, 111622, 2019.
(Summary)
Tetraspanin 15 (Tspan15) is a member of the tetraspanin family, which is associated with various biological events and several diseases, however, its role in human oral squamous cell carcinoma (OSCC) remains unknown. The current study aimed to clarify the role of Tspan15 in OSCC. The mRNA and protein expression levels of Tspan15 were up-regulated in OSCC cases and OSCC-derived cell lines. Significant up-regulated Tspan15 expression was found in the advanced OSCC cases; primary tumoral size (P = 0.042), regional lymph node metastasis (P = 0.036) and TNM classification (P = 0.024). The decreased expression of Tspan15 did not significantly affect cellular proliferation, whereas tumoral invasion and migration activities were suppressed in Tspan15-down-regulated cells, suggesting that Tspan15 might activate metastasis-related signaling. Moreover, in the Tspan15-down-regulated cells, the expression of a disintegrin and metalloproteinase (ADAM) 10 was also down-regulated and the cells secreted less soluble N-cadherin compared with control cells. And weak immunoreactivity of β-catenin in the nucleus was detected in Tspan15-down-regulated cells compared with the control cells. These findings suggested that overexpression of Tspan15 positively regulates development of OSCC, and that ADAM10, N-cadherin, β-catenin might be involved in the Tspan15-mediated pathway. These unusual conditions of cell adhesion molecules may lead to high metastasis rate found in Tspan15-overexpressing cases.
Drug resistance to anti-cancer agents is a major concern regarding the successful treatment of malignant tumors. Recent studies have suggested that acquired resistance to anti-epidermal growth factor receptor (EGFR) therapies such as cetuximab are in part caused by genetic alterations in patients with oral squamous cell carcinoma (OSCC). However, the molecular mechanisms employed by other complementary pathways that govern resistance remain unclear. In the current study, we performed gene expression profiling combined with extensive molecular validation to explore alternative mechanisms driving cetuximab-resistance in OSCC cells. Among the genes identified, we discovered that a urokinase-type plasminogen activator receptor (uPAR)/integrin β1/Src/FAK signal circuit converges to regulate ERK1/2 phosphorylation and this pathway drives cetuximab-resistance in the absence of EGFR overexpression or acquired EGFR activating mutations. Notably, the polyphenolic phytoalexin resveratrol, inhibited uPAR expression and consequently the signaling molecules ERK1/2 downstream of EGFR thus revealing additive effects on promoting OSCC cetuximab-sensitivity in vitro and in vivo. The current findings indicate that uPAR expression plays a critical role in acquired cetuximab resistance of OSCC and that combination therapy with resveratrol may provide an attractive means for treating these patients.
Katsuhiro Uzawa, Atsushi Kasamatsu, Tomoaki Saito, Akihiro Kita, Yuki Sawai, Yuriko Toeda, Kazuyuki Koike, Dai Nakashima, Yosuke Endo, Masashi Shiiba, Yuichi Takiguchi and Hideki Tanzawa : Growth suppression of human oral cancer cells by candidate agents for cetuximab-side effects, Experimental Cell Research, 376, 2, 210-220, 2019.
(Summary)
Cetuximab, an inhibitor of the epidermal growth factor receptor that is used widely to treat human cancers including oral squamous cell carcinoma (OSCC), has characteristic side effects of skin rash and hypomagnesemia. However, the mechanisms of and therapeutic agents for skin rashes and hypomagnesemia are still poorly understood. Our gene expression profiling analyses showed that cetuximab activates the p38 MAPK pathways in human skin cells (human keratinocyte cell line [HaCaT]) and inhibits c-Fos-related signals in human embryonic kidney cells (HEK293). We found that while the p38 inhibitor SB203580 inhibited the expression of p38 MAPK targets in HaCaT cells, flavagline reactivated c-Fos-related factors in HEK293 cells. It is noteworthy that, in addition to not interfering with the effect of cetuximab by both compounds, flavagline has additive effect for OSCC growth inhibition in vivo. Collectively, our results indicate that combination of cetuximab and these potential therapeutic agents for cetuximab-related toxicities could be a promising therapeutic strategy for patients with OSCC.
Keitaro Eizuka, Dai Nakashima, Noritoshi Oka, Sho Wagai, Toshikazu Takahara, Tomoaki Saito, Kazuyuki Koike, Atsushi Kasamatsu, Masashi Shiiba, Hideki Tanzawa and Katsuhiro Uzawa : SYT12 plays a critical role in oral cancer and may be a novel therapeutic target, Journal of Cancer, 10, 20, 4913-4920, 2019.
Fumihiko Hayashi, Atsushi Kasamatsu, Yosuke Endo-Sakamoto, Keitaro Eizuka, Kazuya Hiroshima, Akihiro Kita, Tomoaki Saito, Kazuyuki Koike, Hideki Tanzawa and Katsuhiro Uzawa : Increased expression of tripartite motif (TRIM) like 2 promotes tumoral growth in human oral cancer, Biochemical and Biophysical Research Communications, 508, 4, 1133-1138, 2018.
(Summary)
Tripartite motif family-like 2 (TRIML2), a member of the TRIM proteins family, is closely related to Alzheimer's disease, however, no studies of TRIML2 have been published in the cancer research literature. In the current study, we investigated the expression level of TRIML2 and its molecular mechanisms in human oral squamous cell carcinoma (OSCC); reverse transcriptase-quantitative polymerase chain reaction, immunoblot analysis, and immunohistochemistry showed that TRIML2 is up-regulated significantly in OSCCs in vitro and in vivo. TRIML2 knockdown OSCC cells showed decreased cellular proliferation by cell-cycle arrest at G1 phase that resulted from down-regulation of CDK4, CDK6, and cyclin D1 and up-regulation of p21Cip1 and p27Kip1. Surprisingly, resveratrol, a polyphenol, led to not only down-regulation of TRIML2 but also cell-cycle arrest at G1 phase similar to TRIML2 knockdown experiments. Taken together, we concluded that TRIML2 might play a significant role in tumoral growth and that resveratrol may be a new drug for treating OSCC by interfering with TRIML2 function.
Yuriko Toeda, Atsushi Kasamatsu, Kazuyuki Koike, Yosuke Endo-Sakamoto, Kazuaki Fushimi, Hiroki Kasama, Yukio Yamano, Masashi Shiiba, Hideki Tanzawa and Katsuhiro Uzawa : FBLIM1 enhances oral cancer malignancy via modulation of the epidermal growth factor receptor pathway, Molecular Carcinogenesis, 57, 12, 1690-1697, 2018.
(Summary)
Filamin-binding LIM protein 1 (FBLIM1) is related to regulation of inflammatory responses, such as chronic recurrent multifocal osteomyelitis; however, the relevance of FBLIM1 in oral squamous cell carcinoma (OSCC) is unknown. The aim of the current study was to elucidate the possible role of FBLIM1 in the carcinogenesis of OSCC. We analyzed FBLIM1 expression using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunoblot analysis, and immunohistochemistry. The expression levels of FBLIM1 were up-regulated significantly (P < 0.05) in OSCC-derived cell lines and primary OSCCs specimens compared with normal counterparts. FBLIM1 expression also was correlated with the primary tumoral size (P < 0.05) and vascular invasion (P < 0.05). We then assessed tumoral progression after treatment with FBLIM1 siRNA and clopidogrel, an antiplatelet agent. Similar to the FBLIM1 knockdown effect, clopidogrel-treated cells had attenuated functions of proliferation, migration, and invasiveness. Interestingly, clopidogrel treatment led to down-regulation of epidermal growth factor receptor (EGFR) and FBLIM1. These findings identify FBLIM1 as a putative therapeutic target by using clopidogrel for inhibiting over activation of EGFR signaling to prevent OSCC malignancy.
Katsuhiro Uzawa, Atsushi Kasamatsu, Tomoaki Saito, Toshikazu Takahara, Yasuyuki Minakawa, Kazuyuki Koike, Masanobu Yamatoji, Dai Nakashima, Morihiro Higo, Yosuke Sakamoto, Masashi Shiiba and Hideki Tanzawa : Long-term culture of human odontoma-derived cells with a Rho kinase inhibitor, Experimental Cell Research, 347, 1, 232-240, 2016.
(Summary)
Because of cellular senescence/apoptosis, no effective culture systems are available to maintain replication of cells from odontogenic tumors especially for odontoma, and, thus, the ability to isolate human odontoma-derived cells (hODCs) for functional studies is needed. The current study was undertaken to develop an approach to isolate hODCs and fully characterize the cells in vitro. The hODCs were cultured successfully with a Rho-associated protein kinase inhibitor (Y-27632) for an extended period with stabilized lengths of the telomeres to sustain a similar phenotype/property as the primary tumoral cells. While the hODCs showed stable long-term expansion with expression of major dental epithelial markers including dentin sialophosphoprotein (DSPP) even in the three-dimensional microenvironment, they lack the specific markers for the characteristics of stem cells. Moreover, cells from dental pulp showed significant up-regulation of DSPP when co-cultured with the hODCs, while control fibroblasts with the hODCs did not. Taken together, we propose that the hODCs can be isolated and expanded over the long term with Y-27632 to investigate not only the development of the hODCs but also other types of benign human tumors.
Ayumi Yamamoto, Atsushi Kasamatsu, Shunsaku Ishige, Kazuyuki Koike, Kengo Saito, Yukinao Kouzu, Hirofumi Koike, Yosuke Sakamoto, Katsunori Ogawara, Masashi Shiiba, Hideki Tanzawa and Katsuhiro Uzawa : Exocyst complex component Sec8: A presumed component in the progression of human oral squamous-cell carcinoma by secretion of matrix metalloproteinases, Journal of Cancer Research and Clinical Oncology, 139, 4, 533-542, 2012.
(Summary)
Sec8, a component of the exocyst complex, has been implicated in tethering of secretory vesicles to specific regions on the plasma membrane. To investigate the involvement of Sec8 in oral squamous-cell carcinoma (OSCC), we evaluated the expression status and effect of Sec8 in OSCC cell lines. Sec8 mRNA and protein expressions in human OSCC cell lines were assessed by quantitative reverse transcriptase-polymerase chain reaction and immunoblotting. Functional analyses, proliferation assay, invasiveness assay, and gelatin zymography in Sec8 knockdown cells were performed. Also the correlation between Sec8 expression and the clinicopathological features in 98 primary OSCCs samples was evaluated by immunohistochemistry. Sec8 mRNA and protein expression were significantly up-regulated in all cell lines (p < 0.05). Sec8 knockdown cells were characterized by reduced cellular proliferation, invasiveness, and secretion of matrix metalloproteinases (MMPs) (MMP-2, proMMP-2, and proMMP-9). Sec8 protein expression in primary OSCCs also was significantly (p < 0.05) greater than in normal counterparts, and higher Sec8 expression was correlated with tumor size (p = 0.03). Our results suggested for the first time that Sec8 might play a specific role in OSCC progression by mediating MMP secretion.
Kazuyuki Koike, Atsushi Kasamatsu, Manabu Iyoda, Yasuhiro Saito, Yukinao Kouzu, Hirofumi Koike, Yosuke Sakamoto, Katsunori Ogawara, Hideki Tanzawa and Katsuhiro Uzawa : High prevalence of epigenetic inactivation of the human four and a half LIM domains 1 gene in human oral cancer, International Journal of Oncology, 42, 1, 141-150, 2012.
(Summary)
The four and a half LIM domains 1 (FHL1) gene has been related to carcinogenesis. However, the expression status of FHL1 in human oral squamous cell carcinoma (OSCC) remains unclear and the detailed mechanism of gene silencing is poorly understood. The aim of this study was to examine the FHL1 expression level and its regulatory mechanism in OSCCs. Quantitative reverse-transcriptase-polymerase chain reaction (PCR) and western blotting showed significant downregulation of FHL1 in all OSCC-derived cell lines (Sa3, HSC-2, HSC-3, HSC-4, HO-1-u-1, HO-1-N-1, KON and Ca9-22) compared to human normal oral keratinocytes. We also found that FHL1 mRNA expression was frequently downregulated (P<0.01) in 51 (86.4%) of 59 primary OSCCs compared with the corresponding normal oral tissues, while there was no significant difference between the status of the FHL1 protein expression in OSCCs and the clinicopathological features. Using methylation-specific PCR, we detected methylated FHL1 in all cell lines and treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine restored the FHL1 expression. However, no significant restoration of FHL1 expression was observed using sodium butyrate, an inhibitor of histone deacetylase and chromatin immunoprecipitation showed that histone H3 lysine 9 in the FHL1 promoter region was significantly acetylated. In addition, no mutation in the entire coding region of the FHL1 gene was found. Therefore, our data suggested that inactivation of the FHL1 gene is a frequent event during oral carcinogenesis and that the mechanism of FHL1 downregulation in OSCCs is through DNA methylation of the promoter region rather than histone deacetylation or mutation.
(Keyword)
5-aza-2'-deoxycytidine / Chromatin immunoprecipitation / Four and a half LIM domains 1 / Immunohistochemistry / Methylation specific PCR / Oral squamous cell carcinoma / Quantitative reverse-transcriptase-polymerase chain reaction / Sodium butyrate / Western blotting
Toshihiro Shimizu, Atsushi Kasamatsu, Ayumi Yamamoto, Kazuyuki Koike, Shunsaku Ishige, Hiroaki Takatori, Yosuke Sakamoto, Katsunori Ogawara, Masashi Shiiba, Hideki Tanzawa and Katsuhiro Uzawa : Annexin A10 in Human Oral Cancer: Biomarker for Tumoral Growth via G1/S Transition by Targeting MAPK Signaling Pathways, PLoS ONE, 7, 9, e45510, 2012.
(Summary)
Annexins are calcium and phospholipid binding proteins that form an evolutionary conserved multigene family. Considerable evidence indicates that annexin A10 (ANXA10) is involved in tumoral progression, although little is known about its role in human oral carcinogenesis. In this study, we investigated the involvement of ANXA10 in oral squamous cell carcinoma (OSCC). ANXA10 mRNA and protein expressions were assessed by quantitative reverse transcriptase polymerase chain reaction and immunoblotting, and we conducted a proliferation assay and cell-cycle analysis in ANXA10 knockdown cells in vitro. We evaluated the correlation between the ANXA10 expression status in 100 primary OSCCs and the clinicopathological features by immunohistochemistry. ANXA10 mRNA and protein expression levels were up-regulated in all cellular lines examined (n = 7, p<0.05). ANXA10 knockdown cells showed that cellular proliferation decreased by inactivation of extracellular regulated kinase (ERK) (p<0.05), and cell-cycle arrest at the G1 phase resulted from up-regulation of cyclin-dependent kinase inhibitors. ANXA10 protein expression in primary OSCCs was also significantly greater than in normal counterparts (p<0.05), and higher expression was correlated with tumoral size (p = 0.027). Our results proposed for the first time that ANXA10 is an indicator of cellular proliferation in OSCCs. Our results suggested that ANXA10 expression might indicate cellular proliferation and ANXA10 might be a potential therapeutic target for the development of new treatments for OSCCs.
笠井 玲緒, Yoshitaka Suzuki, 奥野 健太郎, Kazuo Okura, Kazuyuki Koike, Miho Inoue, 新開 瑞希, 柴垣 あかり, 谷脇 竜弥, 渡邊 亮友, 高橋 一也 and Yoshizo Matsuka : 徳島大学・大阪歯科大学歯学科生における睡眠歯科に対する関心の調査, The Journal of the Japan Prosthodontic Society, May 2025.
7.
Kazuyuki Koike : 「掌蹠膿疱症歯科診療の手引き」WG報告 金属アレルギーと掌蹠膿疱症, 第79回NPO法人日本口腔科学会学術集会, May 2025.
8.
Maki Hosoki, Kazuyuki Koike, Toyoko Tajima, Mayu Miyagi and Yoshizo Matsuka : パッチテスト陽性金属除去が有効だった掌蹠膿疱症性骨関節炎の1症例, The Journal of the Japan Prosthodontic Society, May 2025.
Elucidation of occurrence mechanism of common complications of various EGFR molecular target drugs and development of therapeutic drug for alleviation. (Project/Area Number: 18K17191 )
Development study of normal salivary gland cell function maintenance, long-term mass culture method and completely new autotransplantation method (Project/Area Number: 18K09805 )
Elucidation of the cancer progression through the a1b1 integrin pathway for establishment of a novel treatment for tumor growth (Project/Area Number: 16K20559 )