Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Carcinogenesis is a multistep process wherein cells accumulate multiple genetic alterations and progress to a more malignant phenotype. It has been proposed that sequential accumulation of gene abnormalities in specific genes drives the transition from non-tumorous epithelia through a preneoplastic lesion/benign tumor to cancer. Histologically, oral squamous cell carcinoma (OSCC) progresses in multiple ordered steps that begin with mucosal epithelial cell hyperplasia, which is followed by dysplasia, carcinoma in situ and invasive carcinoma. It is therefore hypothesized that genetic alteration-mediated multistep carcinogenesis would be involved in the development of OSCC; however, the detailed molecular mechanisms are unknown. We clarified the comprehensive gene expression patterns and carried out an enrichment analysis using DNA microarray data from a pathological specimen of OSCC (including a non-tumor region, carcinoma in situ lesion and invasive carcinoma lesion). The expression of numerous genes and signal activation were altered in the development of OSCC. Among these, the p63 expression was increased and the MEK/ERK-MAPK pathway was activated in carcinoma in situ lesion and in invasive carcinoma lesion. Immunohistochemical analyses revealed that p63 was initially upregulated in carcinoma in situ and ERK was sequentially activated in invasive carcinoma lesions in OSCC specimens. ADP-ribosylation factor (ARF)-like 4c (ARL4C), the expression of which is reportedly induced by p63 and/or the MEK/ERK-MAPK pathway in OSCC cells, has been shown to promote tumorigenesis. Immunohistochemically, in OSCC specimens, ARL4C was more frequently detected in tumor lesions, especially in invasive carcinoma lesions, than in carcinoma in situ lesions. Additionally, ARL4C and phosphorylated ERK were frequently merged in invasive carcinoma lesions. Loss-of-function experiments using inhibitors and siRNAs revealed that p63 and MEK/ERK-MAPK cooperatively induce the expression of ARL4C and cell growth in OSCC cells. These results suggest that the stepwise activation of p63 and MEK/ERK-MAPK contributes to OSCC tumor cell growth through regulation of ARL4C expression.

DOI： 10.1016/j.prp.2023.154493.

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Various types of tumors, including malignant and benign ones, occur in the oral cavity. These arise from the mucosal epithelium, odontogenic epithelium, and salivary gland. To date, few major driver events in oral tumors have been identified. Accordingly, molecular targets in anti-tumor therapy for oral tumors are lacking. We focused on elucidating the function of aberrantly activated signal transduction related to oral tumor formation, especially in oral squamous cell carcinoma, ameloblastoma, and adenoid cystic carcinoma, which are raised as common oral tumors. Wnt/β-catenin-dependent pathway is involved in the developmental process, organ homeostasis and disease pathogenesis through regulating various cellular functions by enhancing transcriptional activity. Recently, we identified ADP-ribosylation factor (ARF)-like 4c (ARL4C) and Semaphorin 3A (Sema3A), the expression of which is regulated by Wnt/β-catenin-dependent pathway, and characterized their functions in the developmental process and tumor formation. This review highlights the recent advances in understanding the roles of Wnt/β-catenin-dependent pathway, ARL4C and Sema3A, as determined by pathological and experimental studies.

DOI： 10.1111/pin.13325.

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

Mixed tumor of the skin (MTS) is a rare neoplasm derived from the sweat glands with a reported frequency of 0.01‑0.098% among all primary skin tumors. MTS often occurs in the head and neck region and is characterized by a mixture of epithelial, myoepithelial and stromal components. MTS also shows various morphological patterns, thus the presence of variants with rare components and its rarity make the clinical diagnosis even more difficult. A 47‑year‑old man was referred due to a painless, slowly growing, exophytic swelling intracutaneous mass of the upper lip. Magnetic resonance imaging revealed that the mass was a solid tumor with a fatty component in the proximal portion, while the distal portion was cystic and possibly contained highly viscous fluid. The mass was located between the skin and the orbicularis oris muscle in the upper lip. Excisional biopsy was performed and the lesion showed two intriguing features: A tumor with extensive lipomatous stroma and some large cysts. It was histopathologically diagnosed as lipomatous MTS with cystic formation in the upper lip. No evident signs of recurrence were observed during follow‑up. The present report describes this case and includes a brief literature review of reported cases in the lip, since MTS can be confused with various skin lesions in clinical settings due to this rarity. Recognition by clinicians of different variants of MTSs, including the present case, is important for preventing erroneous diagnosis and treatment.

DOI： 10.3892/etm.2022.11600

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CiNii Research

Other Link： https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9477013/

Repository Public URL： https://hdl.handle.net/2324/7173430

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Biochemical and Biophysical Research Communications  

Tooth germ development involves continuous and sequential steps with reciprocal interactions between odontogenic epithelium and the adjacent mesenchyme. Several growth factors, including Wnt, are essential for tooth germ development. Molecular mechanisms underlying Wnt/β-catenin-regulated tooth germ development are poorly understood. In tooth germ rudiments culture, we recently demonstrated that Semaphorin 3A (Sema3A), an axonal guidance factor, stimulation reversed Wnt/β-catenin signaling-dependent decreased cell proliferation but did not completely rescue the morphological anomalies of tooth germ, suggesting that an uncharacterized signaling pathway may be essential in Wnt/β-catenin signaling-dependent tooth germ development. Herein, an enrichment analysis using DNA microarray data, which was obtained in our previous research, revealed that Wnt/β-catenin signaling negatively regulates YAP1 and/or TGF-β signalings. In odontogenic epithelial cells and tooth germ rudiments, Wnt/β-catenin signaling activation reduced YAP1 expression, thereby suppressing YAP1 and TGF-β signalings sequentially. Additionally, YAP1 signaling induced TGF-β2 expression to promote TGF-β signaling in the cells. Finally, Wnt/β-catenin signaling-dependent disorganized tooth germ development, in which YAP1 signaling was suppressed, was reversed by TGF-β stimulation. These results suggest that Wnt/β-catenin signaling contributes to the tooth germ development through YAP1-TGF-β signaling.

DOI： 10.1016/j.bbrc.2022.09.012

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PubMed

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pathology Research and Practice  

We recently demonstrated that Semaphorin 3 A (Sema3A), the expression of which is negatively regulated by Wnt/β-catenin signaling, promotes odontogenic epithelial cell proliferation, suggesting the involvement of Sema3A in tooth germ development. Salivary glands have a similar developmental process to tooth germ development, in which reciprocal interactions between the oral epithelium and adjacent mesenchyme proceeds via stimulation with several growth factors; however, the role of Sema3A in the development of salivary glands is unknown. There may thus be a common mechanism between epithelial morphogenesis and pathogenesis; however, the role of Sema3A in salivary gland tumors is also unclear. The current study investigated the involvement of Sema3A in submandibular gland (SMG) development and its expression in adenoid cystic carcinoma (ACC) specimens. Quantitative RT-PCR and immunohistochemical analyses revealed that Sema3A was expressed both in epithelium and in mesenchyme in the initial developmental stages of SMG and their expressions were decreased during the developmental processes. Loss-of-function experiments using an inhibitor revealed that Sema3A was required for AKT activation-mediated cellular growth and formation of cleft and bud in SMG rudiment culture. In addition, Wnt/β-catenin signaling decreased the Sema3A expression in the rudiment culture. ACC arising from salivary glands frequently exhibits malignant potential. Immunohistochemical analyses of tissue specimens obtained from 10 ACC patients showed that Sema3A was hardly observed in non-tumor regions but was strongly expressed in tumor lesions, especially in myoepithelial neoplastic cells, at high frequencies where phosphorylated AKT expression was frequently detected. These results suggest that the Sema3A-AKT axis promotes cell growth, thereby contributing to morphogenesis and pathogenesis, at least in ACC, of salivary glands.

DOI： 10.1016/j.prp.2022.153991

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PubMed

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pathology Research and Practice  

Clear cell squamous cell carcinoma (CCSCC), where cells show abundant clear cytoplasm, is a variant of squamous cell carcinoma (SCC) and a rare entity in the oral cavity. The characteristics of CCSCC, especially in immunohistochemical features, remain unclear. We characterized a case of CCSCC arising from the oral mucosal epithelium of tongue, where the clear cell lesion accounted for a predominant portion of the tumor. This CCSCC, which was partially surrounded by conventional SCC, exhibited cellular atypia immunohistopathologically and histopathologically with a high Ki-67 index, increased number of mitotic figures and enlarged nuclei. Intravascular invasion of the carcinoma cells was also observed. Furthermore, the CCSCC recurred and metastasized to the cervical lymph nodes and both lungs three months after resection. Immunohistochemical analyses demonstrated decreased expression of p40 (an isoform of SCC marker p63), ADP-ribosylation factor (ARF)-like 4c (ARL4C), yes-associated protein (YAP) and 5-methylcytosine (5mC) in the CCSCC lesion compared with the surrounding SCC lesion, where the expression of ARL4C was upregulated compared with non-tumor region and YAP showed nuclear translocation. In addition, siRNA loss-of-function experiments revealed that p63 expression was required for ARL4C expression and DNA methylation was induced by p63 and YAP/transcriptional co-activator with PDZ-binding motif (TAZ) signaling in oral SCC cell lines. These results suggest that CCSCC, in which several markers of SCC-associated intracellular signaling pathways are downregulated, together with evidence of altered epigenetic regulation, is characterized as an undifferentiated SCC variant.

DOI： 10.1016/j.prp.2022.153909

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PubMed

Other Link： https://www.sciencedirect.com/science/article/pii/S0344033822001534?via%3Dihub

Repository Public URL： https://hdl.handle.net/2324/7178626

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Pathology  

Ameloblastoma is an odontogenic neoplasm characterized by slow intraosseous growth with progressive jaw resorption. Recent reports have revealed that ameloblastoma harbours an oncogenic BRAF V600E mutation with mitogen-activated protein kinase (MAPK) pathway activation and described cases of ameloblastoma harbouring a BRAF V600E mutation in which patients were successfully treated with a BRAF inhibitor. Therefore, the MAPK pathway may be involved in the development of ameloblastoma; however, the precise mechanism by which it induces ameloblastoma is unclear. The expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C), induced by a combination of the EGF-MAPK pathway and Wnt/β-catenin signalling, has been shown to induce epithelial morphogenesis. It was also reported that the overexpression of ARL4C, due to alterations in the EGF/RAS-MAPK pathway and Wnt/β-catenin signalling, promotes tumorigenesis. However, the roles of ARL4C in ameloblastoma are unknown. We investigated the involvement of ARL4C in the development of ameloblastoma. In immunohistochemical analyses of tissue specimens obtained from 38 ameloblastoma patients, ARL4C was hardly detected in non-tumour regions but tumours frequently showed strong expression of ARL4C, along with the expression of both BRAF V600E and RAF1 (also known as C-RAF). Loss-of-function experiments using inhibitors or siRNAs revealed that ARL4C elevation depended on the RAF1-MEK/ERK pathway in ameloblastoma cells. It was also shown that the RAF1-ARL4C and BRAF V600E-MEK/ERK pathways promoted cell proliferation independently. ARL4C-depleted tumour cells (generated by knockdown or knockout) exhibited decreased proliferation and migration capabilities. Finally, when ameloblastoma cells were co-cultured with mouse bone marrow cells and primary osteoblasts, ameloblastoma cells induced osteoclast formation. ARL4C elevation in ameloblastoma further promoted its formation capabilities through the increased RANKL expression of mouse bone marrow cells and/or primary osteoblasts. These results suggest that the RAF1-MEK/ERK-ARL4C axis, which may function in cooperation with the BRAF V600E-MEK/ERK pathway, promotes ameloblastoma development.

DOI： 10.1002/path.5814

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Most cancer cells are exposed to altered extracellular environments, such as an increase in extracellular matrix (ECM) stiffness and soluble signals consisting of growth factors and cytokines. It is therefore conceivable that changes in tumor extracellular environments affect tumor cell behavior. The Hippo pathway reportedly responds to the extracellular environment and regulates the nuclear localization of the transcription co-activator, yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ). Inactivation of the Hippo pathway with nuclear translocation of YAP/TAZ stimulates cell proliferation. Its pathway also regulates gene expression, but the precise molecule(s) meditating the cell-proliferating effect of YAP signaling on oral squamous cell carcinoma (OSCC) is unclear. First, we examined the effects of YAP signaling on OSCC tumorigenesis. Loss-of-function experiments using siRNA or an inhibitor, and immunohistochemical analyses of tissue specimens obtained from OSCC patients demonstrated that YAP signaling was involved in OSCC cell proliferation. Second, we identified Piezo-type mechanosensitive ion channel component 1 (PIEZO1), a Ca2+ channel, as a transcriptional target of YAP signaling and showed that elevated PIEZO1 was required for PIEZO1 agonist-dependent Ca2+ entry and cell proliferation in OSCC cells. Experiments using three-dimensional and suspension culture revealed that PIEZO1 was involved in OSCC cellular growth. Finally, YAP overexpression in the nucleus and/or cytoplasm was immunohistochemically detected in tumor lesions with frequent expression of both PIEZO1 and Ki-67, but not in non-tumor regions of OSCC specimens. These results suggest that the YAP/PIEZO1 axis promotes OSCC cell growth.

DOI： 10.1002/path.5553

Repository Public URL： http://hdl.handle.net/2324/4481560

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Most human malignant tumor cells arise from epithelial tissues, which show distinctive characteristics, such as polarization, cell-to-cell contact between neighboring cells, and anchoring to a basement membrane. When tumor cells invaginate into the stroma, the cells are exposed to extracellular environments, including the extracellular matrix (ECM). Increased ECM stiffness has been reported to promote cellular biological activities, such as excessive cellular growth and enhanced migration capability. Therefore, tumorous ECM stiffness is not only an important clinical tumor feature but also plays a pivotal role in tumor cell behavior. Transient receptor potential vanilloid 4 (TRPV4), a Ca2+-permeable nonselective cation channel, has been reported to be mechano-sensitive and to regulate tumorigenesis, but the underlying molecular mechanism in tumorigenesis remains unclear. The function of TRPV4 in oral squamous cell carcinoma (OSCC) is also unknown. The current study was conducted to investigate whether or not TRPV4 might be involved in OSCC tumorigenesis. TRPV4 mRNA levels were elevated in OSCC cell lines compared with normal oral epithelial cells, and its expression was required for TRPV4 agonist-dependent Ca2+ entry. TRPV4-depleted tumor cells exhibited decreased proliferation capabilities in three-dimensional culture but not in a low-attachment plastic dish. A xenograft tumor model demonstrated that TRPV4 expression was involved in cancer cell proliferation in vivo. Furthermore, loss-of-function experiments using siRNA or an inhibitor revealed that the TRPV4 expression was required for CaMKII-mediated AKT activation. Immunohistochemical analyses of tissue specimens obtained from 36 OSCC patients showed that TRPV4 was weakly observed in non-tumor regions but was strongly expressed in tumor lesions at high frequencies where phosphorylated AKT expression was frequently detected. These results suggest that the TRPV4/CaMKII/AKT axis, which might be activated by extracellular environments, promotes OSCC tumor cell growth.

DOI： 10.1038/s41374-019-0357-z.

Repository Public URL： https://hdl.handle.net/2324/4123614

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

Odontomas, developmental anomalies of tooth germ, frequently occur in familial adenomatous polyposis patients with activated Wnt/β-catenin signaling. However, roles of Wnt/β-catenin signaling in odontomas or odontogenic cells are unclear. Herein, we investigated β-catenin expression in odontomas and functions of Wnt/β-catenin signaling in tooth germ development. β-catenin frequently accumulated in nucleus and/or cellular cytoplasm of odontogenic epithelial cells in human odontoma specimens, immunohistochemically. Wnt/β-catenin signaling inhibited odontogenic epithelial cell proliferation in both cell line and tooth germ development, while inducing immature epithelial bud formation. We identified Semaphorin 3A (Sema3A) as a downstream molecule of Wnt/β-catenin signaling and showed that Wnt/β-catenin signaling-dependent reduction of Sema3A expression resulted in suppressed odontogenic epithelial cell proliferation. Sema3A expression is required in appropriate epithelial budding morphogenesis. These results suggest that Wnt/β-catenin signaling negatively regulates odontogenic epithelial cell proliferation and tooth germ development through decreased-Sema3A expression, and aberrant activation of Wnt/β-catenin signaling may associate with odontoma formation.

DOI： 10.1038/s41598-019-39686-1

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Low-grade myofibroblastic sarcoma (LGMS) is a rare intermediate tumor, which rarely metastasizes and has myofibroblastic differentiation in various sites. It is particularly associated with the tongue in the head and neck region. The lack of any pathological features means it is difficult to make a conclusive diagnosis of LGMS. The immunohistochemical features and genomic rearrangements, including SS18-SSXs and MYH9-USP6s and the genetic mutations of cancer-associated genes, including APC, CTNNB1, EGFR, KRAS, PIK3CA and p53 were examined in a case of LGMS arising in the tip of the tongue. Immunohistochemically, the tumor cells were positive for alpha-smooth muscle actin and vimentin, as in previous reports. They demonstrated neither genomic rearrangements nor point mutations of cancer-associated genes. Although several tumor cells demonstrated intravascular invasion, the MIB-l labeling index of the cells was the same as the original lesion. To the best of our knowledge, this is the first case report of LGMS arising in the tip of the tongue with intravascular invasion.

DOI： 10.3892/ol.2018.9115

Repository Public URL： https://hdl.handle.net/2324/7178628

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE:Keratin 17 (KRT17) has been suggested as a potential diagnostic marker of squamous cell carcinoma including oral squamous cell carcinoma (OSCC). The current study was conducted to clarify the function of KRT17 and its expression mechanism in OSCC.METHODS:Immunohistochemical analyses were carried out to examine the expression of KRT17, GLI family zinc finger (GLI)-1, GLI-2, or cleaved caspase-3 in OSCCs. The expression of KRT17, GLI-1, or GLI-2 was investigated among OSCC cell lines, and the effects of loss-of-function of KRT17 or GLI, using siRNA or inhibitor, on the cell growth of the OSCC cell line HSC-2 particularly with respect to apoptosis were examined.RESULTS:Immunohistochemical analyses of tissue specimens obtained from 78 OSCC patients revealed that KRT17 was not observed in non-tumor regions but was strongly expressed at high frequencies in tumor regions. Knockdown of KRT17 increased the number of cleaved caspase-3-positive cells, leading to the reduction of cell number. Loss-of-function of GLI-1 or GLI-2 also increased the cell numbers of apoptotic cells positive for staining of Annexin-V and propidium iodide (PI) and the terminal deoxynucleotidyl transferase dUTP-biotin nick-end labeling (TUNEL) method, and induced DNA fragmentation. This inhibitory effect on cell growth was partially rescued by exogenous KRT17 expression. In the KRT17-positive regions in OSCCs, GLI-1 or GLI-2 was frequently detected, and the number of cells with cleaved caspase-3 positive was decreased.CONCLUSIONS:KRT17 promotes tumor cell growth, at least partially, through its anti-apoptotic effect as a result of the KRT17 overexpression by GLIs in OSCC.

DOI： 10.1007/s00432-017-2398-2

Other Link： https://link.springer.com/article/10.1007/s00432-017-2398-2

Repository Public URL： https://hdl.handle.net/2324/7178627

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10735-016-9680-5

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/ijmm.2015.2118.

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

DOI： doi: 10.1371/journal.pone.0103928.

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DOI： doi: 10.1016/j.scr.2013.11.006.

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DOI： 10.1387/ijdb.120240hs.

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DOI： 10.1371/journal.pone.0080998

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DOI： doi: 10.3892/ijo.2012.1594.

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

DOI： 10.1007/s00418-012-1033-1

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/ijmm.2012.1102.

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

DOI： 10.3892/ijo.2012.1594.

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DOI： 10.1186/1471-213X-10-115.

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DOI： 10.1159/000086949

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DOI： 10.1007/s00418-005-0040-x

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

In situ expression of RANKL, RANK, osteoprotegerin and cytokines in osteoclasts of rat periodontal tissue.

DOI： 10.1111/j.1600-0765.2004.00699.x

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

An L1 element disrupts human bone sialoprotein promoter: lack of tissue-specific regulation by distalless5 (Dlx5) and runt homeodomain protein2 (Runx2)/core binding factor a1 (Cbfa1) elements.

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

Immunohistochemical expression of CA19-9 and CA125 in mucoepidermoid and adenoid cystic carcinomas of the salivary gland.

DOI： 10.1016/S1368-8375(01)00049-5

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

In situ expression of heat shock proteins, Hsc73, Hsj2 and Hsp86 in the developing tooth germ of mouse lower first molar.

DOI： 10.1023/A:1020930228303

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

Expression of Set-alpha during morphogenesis of mouse lower first molar

DOI： 10.1023/A:1014491111628

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

Expression of p53 tumor suppressor gene in adenoid cystic and mucoepidermoid carcinomas of the salivary glands

DOI： 10.1016/S1368-8375(00)00083-X

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

Localization of activated caspase-3-positive and apoptotic cells in the developing tooth germ of the mouse lower first molar

DOI： 10.1023/A:1017900305661

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

Detection of differentially expressed genes in the early developmental stage of the mouse mandible

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

Incidence of human papillomavirus 16 and 18 infection and p53 mutation in patients with oral squamous cell carcinoma in Japan

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

Epithelial-myoepithelial carcinoma arising in pleomorphic adenoma of the palate.

DOI： 10.1067/moe.2000.108099

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

Age-dependent changes in the distribution of BrdU- and TUNEL-positive cells in the murine gingival tissue.

DOI： 10.1902/jop.1999.70.9.973

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

Prevalence of Epstein-Barr virus in oral squamous cell carcinoma.

DOI： 10.1002/(SICI)1096-9896(199909)189:1<34::AID-PATH391>3.0.CO;2-4

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

The distribution of BrdU- and TUNEL-positive cells during odontogenesis in mouse lower first molars.

DOI： 10.1023/A:1003796023992

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

Immunohistochemical and ultrastructural study of a papillary cystadenocarcinoma arising from the sublingual gland.

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

Immunohistochemical localization of laminin, collagen type IV and heparan sulfate proteoglycan in human colorectal adenocarcinoma: correlation with local invasive pattern and lymph node metastasis

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

Salivary Duct Carcinoma with Sebaceous Cell Differentiation arising from Parotid Gland: Histological, Immunohistochemical and Ultrastructural Analyses of a Case.

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

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Oral and Maxillofacial Surgery Medicine and Pathology  

Objective: To evaluate useful parameters for differentiating metastatic lymph nodes in oral squamous cell carcinoma using dual-energy computed tomography (DECT) in the venous phase. Methods: A total of 117 lymph nodes without visually obvious necrosis (83 non-metastatic and 34 metastatic) from 40 patients were retrospectively analyzed. The region of interest was defined at the area with the maximum short diameter. Nine parameters were calculated and correlated with the pathology images: CT values of virtual monochromatic X-ray images at 40, 70, and 100 keV (HU<inf>40 keV</inf>, HU<inf>70 keV</inf>, HU<inf>100 keV</inf>), iodine concentration (IC), CT value variation at 40–70 keV (λ<inf>40–70</inf> <inf>HU</inf>), 40–100 keV (λ<inf>40–100</inf> <inf>HU</inf>), lymph node long diameter, short diameter, and long-short diameter ratio. Results: Metastatic lymph nodes had lower CT and IC values than non-metastatic nodes. However, the short diameter had the highest the area under the receiver operating characteristic curve (AUC) with 0.846 (95 % confidence interval: 0.741–0.914), and the respective sensitivity and specificity were 82.4 % and 84.3 % at a cutoff of 7.54 mm. For parameters using CT values and IC, HU<inf>100 keV</inf> had the highest AUC (0.737), followed by HU<inf>70 keV</inf> (0.717), HU<inf>40 keV</inf> (0.686), IC (0.660), λ<inf>40–100</inf> <inf>HU</inf> (0.659), and λ<inf>40–70</inf> <inf>HU</inf> (0.659). Six DECT-derived parameters showed the significant negative correlation to the short axis length. Conclusion: In the venous phase, although the significant differences were found in the DECT-derived parameters, the maximal short diameter was found to be the most useful parameter for the differentiation of metastatic lymph nodes.

DOI： 10.1016/j.ajoms.2025.01.012

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

Primary intraosseous carcinoma not otherwise specified (PIOC NOS) is a rare tumor assumed to arise from the epithelium, such as odontogenic cysts or benign tumors. Its clinical and imaging diagnoses are often challenging, especially in the early stages, as it mimics jaw cysts and benign tumors, and no specific findings have been identified. This report presents the case of a 66-year-old male patient with mandibular PIOC, highlighting the imaging findings over time. Magnetic resonance imaging (MRI) before symptom onset showed a cystic lesion in the right mandible with a soft tissue component. Both the fluid component and soft tissue exhibited low apparent diffusion coefficient values (1.0 × 10^–3 mm²/s and 1.3 × 10^–3 mm²/s, respectively). Subsequent MRI approximately 5 months later during symptom onset showed a slight increase in the soft tissue component. Based on the clinical and imaging findings, ameloblastoma was suspected, prompting a biopsy for confirmation. However, the histopathological findings showed squamous cell carcinoma (SCC). MRI performed approximately 1 month later exhibited significant tumor growth and extension beyond the jawbone, consistent with a malignant tumor. Histopathological examination identified areas with a basal layer in a palisading arrangement, indicating a pre-existing odontogenic cyst, and showed a transition from epithelial dysplasia to SCC. In addition, carcinoma cell invasion and proliferation into the cyst were observed. Based on these findings, PIOC of the right mandible was determined to be the definitive diagnosis.

DOI： 10.1007/s11282-024-00788-w

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Language：English   Publisher：Oral Radiology  

Objective: To summarize the ultrasonography (US) and magnetic resonance imaging (MRI) findings of lymphoepithelial cysts (LECs) and dermoid cysts (DCs) and to discuss the hyperinternal echo in LECs based on histopathological findings. Methods: Patients who underwent US and MRI before resection and whose lesions were pathologically diagnosed as LECs or DCs were included (January 2010 to December 2023). Internal echo, convective flow, and Doppler signals were evaluated on US, while on MRI, we measured the apparent diffusion coefficient (ADC). Results: Surprisingly, all lesions (4 LECs and 7 DCs) had hyperinternal echoes. Convective flow and Doppler signals were observed in 2 of the 4 cases of LEC, and the ADC was high in these cases (2.4 × 10^–3 and 2.0 × 10^–3 mm²/s). In the two cases where they were not, the ADC was low (1.4 × 10^–3 and 0.81 × 10^–3 mm²/s). Various cells, such as lymphocyte cells, foam cells, erythroid cells, and keratin, have been found in the cystic cavity, which are thought to be the cause of hyperecho. Considering the ADC, the presence or absence of convection and Doppler signals is thought to reflect the ease of movement of the contents. In the DCs, neither internal convection nor obvious Doppler signals were observed. ADCs were quite low for cysts, which was a characteristic finding (1.1 ± 0.13^–3 mm²/s). Conclusion: It is well known that DCs appear hyperechoic on US owing to the presence of keratin; however, it is necessary to recognize that some LECs are depicted as hyperechoic masses and have convective flow and Doppler signals depending on the content.

DOI： 10.1007/s11282-025-00818-1

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

Oral lichen planus (OLP) is a chronic inflammatory disorder with autoimmune features and malignant transformation risk, lacking a definitive treatment, with CD4⁺ T cells being pivotal in its pathogenesis. Dysbiosis, an imbalance in the microbiome, is linked to various autoimmune and inflammatory diseases, where CD4⁺ T cells play a significant role. Given these insights, the development of OLP might be influenced by dysbiosis. This study investigates the association between dysbiosis and CD4⁺ T cells in OLP. We collected stool and saliva samples from OLP patients, conducting 16S rRNA gene analysis and mass spectrometry, and assessed CD4⁺ T cell characteristics in lesions through multiplex immunofluorescence and single-cell RNA sequencing. Peripheral blood samples were subjected to flow cytometry and cell culture assays. Results showed extensive gut dysbiosis in OLP patients, notably a reduction in short-chain fatty acid (SCFA)-producing bacteria essential for regulatory T cell (Treg) differentiation. While various CD4⁺ T cell subsets, including Tregs, were present in tissues, these Tregs as unresponsive to specific antigens, showing reduced immunosuppressive molecule expression. The decline in SCFA-producing bacteria correlated with fewer activated Tregs in tissues and blood. These findings suggest that gut dysbiosis may contribute to OLP by impairing Treg regulation, influencing disease pathogenesis.

DOI： 10.1016/j.mucimm.2025.05.009

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PubMed

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

Nuclear factor-κB (NF-κB) is a transcription factor that regulates the expression of various genes involved in inflammatory diseases and immune responses. Recently, a novel transcriptional regulatory mechanism of NF-κB involving the phosphorylation of serine 536 (534 in mice; S534) of its p65 subunit was reported; however, further research is required to elucidate the physiological role of S534 phosphorylation. Therefore, we generated S534A knock-in (KI) mice, in which the S534 of p65 was substituted with alanine. Similar to the wild-type (WT) mice, S534A KI mice developed normally. After stimulation with tumor necrosis factor α (TNFα), mouse embryonic fibroblasts (MEFs) derived from S534A KI mice exhibited increased target gene expression compared with that in the WT MEFs, which was induced by long-term binding of p65 to DNA. According to comprehensive gene expression analysis after stimulation with TNFα, the expression of genes p65ted to inflammatory and immune responses was increased, and the expression of genes p65ted to lipolysis was decreased in S534A KI MEFs. Analyses of a periodontal disease model established using WT and S534A KI mice revealed that alveolar bone resorption was enhanced in S534A KI mice owing to an increase in the number of osteoclasts, which was not attributed to the differentiation of osteoclast precursor cells but to an increased expression of interleukin-1β and receptor activator of NF-κB ligand in the periodontal tissue. Hence, phosphorylation of S536 negatively regulates inflammatory responses in vitro and in vivo.

DOI： 10.1007/s10753-024-02140-0

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Biochemical and Biophysical Research Communications  

Nuclear factor (NF)-κB signaling is not only important for the immune and inflammatory responses but also for the normal development of epithelial cells, such as those in the skin and tooth. Here, we generated epithelial cell-specific p65-deficient (p65Δepi−/−) mice to analyze the roles of NF-κB signaling in epithelial cell developent. Notably, p65Δepi−/− mice exhibited no abnormalities in their appearance compared to the control (p65flox/flox) littermates. Furthermore, no major changes were observed in the skin, hair growth, and shape and color of the incisors and molars. However, 65 % of p65Δepi−/− mice exhibited corneal thickening after 8 weeks of age, and 30 % of p65Δepi−/− mice exhibited hair growth from the mandibular incisors around 24 weeks of age. No hair growth was observed at 36 and 42 weeks of age. However, micro-computed tomography images revealed a large cavity below the mandibular incisors extending to the root of the incisor. Histological analysis revealed that the cavity was occupied by a connective tissue containing hair-like structures with many dark brown granules that disappeared after melanin bleaching, confirming the presence of hair. Although inflammatory cells were also observed near the eruption site of the incisor teeth of p65Δepi−/− mice, no major disturbance was observed in the arrangement of enamel epithelial cells. Overall, these results highlight the role of p65 in the maintenance of epithelial cell homeostasis during aging.

DOI： 10.1016/j.bbrc.2024.150143

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Allergy and Clinical Immunology  

Background: IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound healing. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified. Objective: We sought to perform single-cell RNA sequencing and T-cell receptor and B-cell receptor sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T and B cells. Methods: We performed unbiased single-cell RNA-sequencing analysis for the transcriptome and T-cell receptor sequencing and B-cell receptor sequencing on sorted CD3⁺ T or CD19⁺ B cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3⁺ T-cell and CD19⁺ B-cell subsets in 68 patients with IgG4-RD and 30 patients with Sjögren syndrome. Results: Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4⁺ cytotoxic T cells or GZMK⁺CD8⁺ T cells. These GZMK-expressing cytotoxic T cells also expressed amphiregulin and TGF-β but did not express immune checkpoints, and the tissue-infiltrating CD8⁺ T cells were phenotypically heterogeneous. MKI67⁺ B cells and IgD⁻CD27⁻CD11c⁻CXCR5⁻ double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK⁺CD4⁺ cytotoxic T cells colocalized with MKI67⁺ B cells in the extrafollicular area from affected tissue sites. Conclusions: The above-mentioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4⁺ and CD8⁺ T cells expressing GZMK, amphiregulin, and TGF-β in the pathogenesis of inflammatory fibrotic disorders.

DOI： 10.1016/j.jaci.2023.11.916

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PubMed

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

Background / Diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) are widely used in the orofacial region. Furthermore, quantitative analyses have proven useful. However, a few reports have described the correlation between DWI-derived parameters and DCE-MRI-derived parameters, and the results have been controversial. / Purpose / To evaluate the correlation among parameters obtained by DWI and DCE-MRI and to compare them between benign and malignant lesions. / Material and Methods / Fifty orofacial lesions were analysed. The apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudodiffusion coefficient (D*) and perfusion fraction (f) were estimated by DWI. For DCE-MRI, TK model analysis was performed to estimate physiological parameters, for example, the influx forward volume transfer constant into the extracellular-extravascular space (EES) (Ktrans) and fractional volumes of EES and plasma components (ve and vp). / Results / Both ADC and D showed a moderate positive correlation with ve (ρ = 0.640 and 0.645, respectively). Ktrans showed a marginally weak correlation with f (ρ = 0.296), while vp was not correlated with f or D*; therefore, IVIM perfusion-related parameters and TK model perfusion-related parameters were not straightforward. Both D and ve yielded high diagnostic power between benign lesions and malignant tumours with areas under the curve (AUCs) of 0.830 and 0.782, respectively. / Conclusion / Both D and ve were reliable parameters that were useful for the differential diagnosis. In addition, the true diffusion coefficient (D) was affected by the fractional volume of EES.

CiNii Research

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Endodontic Journal  

Aim: Cyst formation of the jaws is frequently accompanied by the proliferation of odontogenic epithelial cells located in the periodontal ligament (PDL), which consists of heterozygous cells and includes the most fibroblasts. The lining epithelium of radicular cyst, an odontogenic cyst of inflammatory origin, is derived from the proliferation of the remnants of the Hertwig epithelial root sheath (odontogenic epithelial cell rests of Malassez; ERMs) in the PDL. ERMs are maintained at a lower proliferative state under physiological conditions, but the regulatory mechanisms underlying the inflammation-dependent enhanced-proliferative capabilities of ERMs are not fully understood. The aim of this study was to evaluate the effects of cytokine pathway association between TGF-β signalling and IL-1β signalling on the regulation of odontogenic epithelial cell proliferation using radicular cyst pathological specimens and odontogenic epithelial cell lines. Methodology: Immunofluorescence analyses were performed to clarify the expression levels of Smad2/3 and Ki-67 in ERMs of 8-week-old mouse molar specimens. In radicular cyst (n = 52) and dentigerous cysts (n = 6) specimens from human patients, the expression of p65 (a main subunit of NF-κB), Smad2/3 and Ki-67 were investigated using immunohistochemical analyses. Odontogenic epithelial cells and PDL fibroblastic cells were co-cultured with or without an inhibitor or siRNAs. Odontogenic epithelial cells were cultured with or without TGF-β1 and IL-1β. The proliferative capabilities and Smad2 phosphorylation levels of odontogenic epithelial cells were examined. Results: Immunohistochemically, Smad2/3-positivity was increased, and p65-positivity and Ki-67-positivity were decreased both in ERMs and in the epithelial cells in dentigerous cysts, a non-inflammatory developmental cyst. In contrast, p65-positive cells, along with the expression of Ki-67, were increased and Smad2/3-positive cells were decreased in the lining epithelia of radicular cysts. Co-culture experiments with odontogenic epithelial cells and PDL fibroblastic cells revealed that PDL cells-derived TGF-β1/2 and their downstream signalling suppressed odontogenic epithelial cell proliferation. Moreover, TGF-β1 stimulation induced Smad2 phosphorylation and suppressed odontogenic epithelial cell proliferation, while IL-1β stimulation reversed these phenotypes through p65 transactivation. Conclusions: These results suggest that IL-1β-p65 signalling promotes odontogenic epithelial cell proliferation through suppressing TGF-β-Smad2 signalling, which would be involved in the pathogenesis of radicular cysts.

DOI： 10.1111/iej.14016

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Allergy and Clinical Immunology  

Background: Germinal center (GC) responses controlled by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells are crucial for the generation of high-affinity antibodies. Acquired immune responses to tissue-released antigens might be mainly induced in tertiary lymphoid organs (TLOs) with GCs in affected tissues. IgG4-related disease (IgG4-RD) demonstrates polarized isotype switching and TLOs in affected tissues. We performed single-cell transcriptomics of tissue-infiltrating T cells from these TLOs to obtain a comprehensive, unbiased view of tissue-infiltrating GC-Tfh cells. Objective: To identify GC-Tfh-cell subsets in TLOs in patients with IgG4-RD using single-cell transcriptomics. Methods: Single-cell RNA sequencing of sorted CD3⁺ T cells and multicolor immunofluorescence analysis were used to investigate CD4⁺CXCR5⁺Bcl6⁺ GC-Tfh cells in affected lesions from patients with IgG4-RD. Results: Infiltrating CD4⁺CXCR5⁺Bcl6⁺ Tfh cells were divided into 5 main clusters. We detected HLA⁺ granzyme K⁺ (GZMK⁺) Tfh cells with cytotoxicity-associated features in patients with IgG4-RD. We also observed abundant infiltrating Tfr cells with suppressor-associated features in patients with IgG4-RD. These GZMK⁺ Tfh cells and Tfr cells clustered together in affected tissues from patients with IgG4-RD. Conclusions: This single-cell data set revealed a novel subset of HLA⁺GZMK⁺ cytotoxic Tfh cells infiltrating affected organs in patients with IgG4-RD, suggesting that infiltrating Tfr cells might suppress cytotoxic Tfh cells.

DOI： 10.1016/j.jaci.2023.08.019

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PubMed

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

Background: IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound healing. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified.

Objective: We performed single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) and B-cell receptor (BCR) sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T- and B-cells.

Methods: We performed unbiased scRNA-seq analysis for the transcriptome and TCR-seq and BCR-seq on sorted CD3+ T- or CD19+ B-cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3+ T and CD19+ B subsets in 68 IgG4-RD and 30 Sjögren's syndrome (SjS) patients.

Results: Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4+ cytotoxic T cells (CTLs) or GZMK+CD8+ T cells. These GZMK-expressing CTLs also expressed amphiregulin and TGFβ but did not express immune-checkpoints, and the tissue-infiltrating CD8+ T cells were phenotypically heterogeneous. MKI67+ B cells and IgD-CD27-CD11c-CXCR5- double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK+CD4+ CTLs co-localized with MKI67+ B cells in the extrafollicular area from affected tissue sites.

Conclusion: The abovementioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4+ and CD8+ T cells expressing GZMK, amphiregulin, and TGFβ in the pathogenesis of inflammatory fibrotic disorders.

DOI： 10.1016/j.jaci.2023.11.916.

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

Background: Cancer immunotherapy targeting CD8+ T cells has made remarkable progress, even for oral squamous cell carcinoma (OSCC), a heterogeneous epithelial tumor without a substantial increase in the overall survival rate over the past decade. However, the therapeutic effects remain limited due to therapy resistance. Thus, a more comprehensive understanding of the roles of CD4+ T cells and B cells is crucial for more robust development of cancer immunotherapy. Methods: In this study, we examined immune responses and effector functions of CD4+ T cells, CD8+ T cells and B cells infiltrating in OSCC lesions using single-cell RNA sequencing analysis, T cell receptor (TCR) and B cell receptor (BCR) repertoire sequencing analysis, and multi-color immunofluorescence staining. Finally, two Kaplan-Meier curves and several Cox proportional hazards models were constructed for the survival analysis. Results: We observed expansion of CD4+ cytotoxic T lymphocytes (CTLs) expressing granzymes, which are reported to induce cell apoptosis, with a unique gene expression patterns. CD4+ CTLs also expressed CXCL13, which is a B cell chemoattractant. Cell–cell communication analysis and multi-color immunofluorescence staining demonstrated potential interactions between CD4+ CTLs and B cells, particularly IgD- CD27- double negative (DN) B cells. Expansion of CD4+ CTLs, DN B cells, and their contacts has been reported in T and B cell-activated diseases, including IgG4-related disease and COVID-19. Notably, we observed upregulation of several inhibitory receptor genes including CTLA-4 in CD4+ CTLs, which possibly dampened T and B cell activity. We next demonstrated comprehensive delineation of the potential for CD8+ T cell differentiation towards dysfunctional states. Furthermore, prognostic analysis revealed unfavorable outcomes of patients with a high proportion of CD4+ CTLs in OSCC lesions. Conclusion: Our study provides a dynamic landscape of lymphocytes and demonstrates a systemic investigation of CD4+ CTL effects infiltrating into OSCC lesions, which may share some pathogenesis reported in severe T and B cell-activated diseases such as autoimmune and infectious diseases.

DOI： 10.3389/fimmu.2023.1305783

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PubMed

Language：English   Publisher：Scientific Reports  

Oral lichen planus (OLP) is a chronic inflammatory disease associated with T cell infiltration. The crosstalk between oral epithelium and mucosal T cells was considered to be crucial in the pathogenesis of OLP. Here, we selectively extracted the normal epithelium (NE) and lesional epithelium (LE) of buccal mucosa specimens from three patients with OLP by laser capture microdissection due to identify the pathogenic factors. Cathepsin K (CTSK) was identified as one of common upregulated genes in the LE by DNA microarray. Immunohistochemically, CTSK was distinctly detected in and around the LE, while it was rarely seen in the NE. Recent studies showed that CTSK enhanced Toll-like receptor 9 (TLR9) signaling in antigen-presenting cells, leading to Th17 cell differentiation. TLR9 expression mainly co-localized with CD123⁺ plasmacytoid dendritic cells (pDCs). The number of RORγt-positive cells correlated with that of CTSK-positive cells in OLP tissues. CD123⁺ pDCs induced the production of Th17-related cytokines (IL-6, IL-23, and TGF-β) upon stimulation with TLR9 agonist CpG DNA. Moreover, single cell RNA-sequencing analysis revealed that TLR9-positive pDCs enhanced in genes associated with Th17 cell differentiation in comparison with TLR9-negative pDCs. CTSK could induce Th17-related production of CD123⁺ pDCs via TLR9 signaling to promote the pathogenesis of OLP.

DOI： 10.1038/s41598-023-46090-3

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PubMed

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

Background: Cancer immunotherapy targeting CD8+ T cells has made remarkable progress, even for oral squamous cell carcinoma (OSCC), a heterogeneous epithelial tumor without a substantial increase in the overall survival rate over the past decade. However, the therapeutic effects remain limited due to therapy resistance. Thus, a more comprehensive understanding of the roles of CD4+ T cells and B cells is crucial for more robust development of cancer immunotherapy.

Methods: In this study, we examined immune responses and effector functions of CD4+ T cells, CD8+ T cells and B cells infiltrating in OSCC lesions using single-cell RNA sequencing analysis, T cell receptor (TCR) and B cell receptor (BCR) repertoire sequencing analysis, and multi-color immunofluorescence staining. Finally, two Kaplan-Meier curves and several Cox proportional hazards models were constructed for the survival analysis.

Results: We observed expansion of CD4+ cytotoxic T lymphocytes (CTLs) expressing granzymes, which are reported to induce cell apoptosis, with a unique gene expression patterns. CD4+ CTLs also expressed CXCL13, which is a B cell chemoattractant. Cell-cell communication analysis and multi-color immunofluorescence staining demonstrated potential interactions between CD4+ CTLs and B cells, particularly IgD- CD27- double negative (DN) B cells. Expansion of CD4+ CTLs, DN B cells, and their contacts has been reported in T and B cell-activated diseases, including IgG4-related disease and COVID-19. Notably, we observed upregulation of several inhibitory receptor genes including CTLA-4 in CD4+ CTLs, which possibly dampened T and B cell activity. We next demonstrated comprehensive delineation of the potential for CD8+ T cell differentiation towards dysfunctional states. Furthermore, prognostic analysis revealed unfavorable outcomes of patients with a high proportion of CD4+ CTLs in OSCC lesions.

Conclusion: Our study provides a dynamic landscape of lymphocytes and demonstrates a systemic investigation of CD4+ CTL effects infiltrating into OSCC lesions, which may share some pathogenesis reported in severe T and B cell-activated diseases such as autoimmune and infectious diseases.

DOI： 10.3389/fimmu.2023.1305783.

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

Oral lichen planus (OLP) is a chronic inflammatory disease associated with T cell infiltration. The crosstalk between oral epithelium and mucosal T cells was considered to be crucial in the pathogenesis of OLP. Here, we selectively extracted the normal epithelium (NE) and lesional epithelium (LE) of buccal mucosa specimens from three patients with OLP by laser capture microdissection due to identify the pathogenic factors. Cathepsin K (CTSK) was identified as one of common upregulated genes in the LE by DNA microarray. Immunohistochemically, CTSK was distinctly detected in and around the LE, while it was rarely seen in the NE. Recent studies showed that CTSK enhanced Toll-like receptor 9 (TLR9) signaling in antigen-presenting cells, leading to Th17 cell differentiation. TLR9 expression mainly co-localized with CD123+ plasmacytoid dendritic cells (pDCs). The number of RORγt-positive cells correlated with that of CTSK-positive cells in OLP tissues. CD123+ pDCs induced the production of Th17-related cytokines (IL-6, IL-23, and TGF-β) upon stimulation with TLR9 agonist CpG DNA. Moreover, single cell RNA-sequencing analysis revealed that TLR9-positive pDCs enhanced in genes associated with Th17 cell differentiation in comparison with TLR9-negative pDCs. CTSK could induce Th17-rel

DOI： 10.1038/s41598-023-46090-3.

Language：English   Publisher：Biochemical and Biophysical Research Communications  

Murine tooth germ development proceeds in continuous sequential steps with reciprocal interactions between the odontogenic epithelium and the adjacent mesenchyme, and several growth factor signaling pathways and their activation are required for tooth germ development. The expression of ADP-ribosylation factor (Arf)-like 4c (Arl4c) has been shown to induce cell proliferation, and is thereby involved in epithelial morphogenesis and tumorigenesis. In contrast, the other functions of Arl4c (in addition to cellular growth) are largely unknown. Although we recently demonstrated the involvement of the upregulated expression of Arl4c in the proliferation of ameloblastomas, which have the same origin as odontogenic epithelium, its effect on tooth germ development remains unclear. In the present study, single-cell RNA sequencing (scRNA-seq) analysis revealed that the expression of Arl4c, among 17 members of the Arf-family, was specifically detected in odontogenic epithelial cells, such as those of the stratum intermedium, stellate reticulum and outer enamel epithelium, of postnatal day 1 (P1) mouse molars. scRNA-seq analysis also demonstrated the higher expression of Arl4c in non-ameloblast and inner enamel epithelium, which include immature cells, of P7 mouse incisors. In the mouse tooth germ rudiment culture, treatment with SecinH3 (an inhibitor of the ARNO/Arf6 pathway) reduced the size, width and cusp height of the tooth germ and the thickness of the eosinophilic layer, which would involve the synthesis of dentin and enamel matrix organization. In addition, loss-of-function experiments using siRNAs and shRNA revealed that the expression of Arl4c was involved in cell proliferation and osteoblastic cytodifferentiation in odontogenic epithelial cells. Finally, RNA-seq analysis with a gene set enrichment analysis (GSEA) and Gene Ontology (GO) analysis showed that osteoblastic differentiation-related gene sets and/or GO terms were downregulated in shArl4c-expressing odontogenic epithelial cells. These results suggest that the Arl4c-ARNO/Arf6 pathway axis contributes to tooth germ development through osteoblastic/ameloblastic differentiation.

DOI： 10.1016/j.bbrc.2023.09.014

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PubMed

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

Background: Germinal center (GC) responses controlled by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells are crucial for the generation of high-affinity antibodies. Acquired immune responses to tissue-released antigens might be mainly induced in tertiary lymphoid organs (TLOs) with GCs in affected tissues. IgG4-related disease (IgG4-RD) demonstrates polarized isotype switching and TLOs in affected tissues. We performed single-cell transcriptomics of tissue-infiltrating T cells from these TLOs to obtain a comprehensive, unbiased view of tissue-infiltrating GC-Tfh cells.

Objective: To identify GC-Tfh-cell subsets in TLOs in patients with IgG4-RD using single-cell transcriptomics.

Methods: Single-cell RNA sequencing of sorted CD3+ T cells and multicolor immunofluorescence analysis were used to investigate CD4+CXCR5+Bcl6+ GC-Tfh cells in affected lesions from patients with IgG4-RD.

Results: Infiltrating CD4+CXCR5+Bcl6+ Tfh cells were divided into 5 main clusters. We detected HLA+ granzyme K+ (GZMK+) Tfh cells with cytotoxicity-associated features in patients with IgG4-RD. We also observed abundant infiltrating Tfr cells with suppressor-associated features in patients with IgG4-RD. These GZMK+ Tfh cells and Tfr cells clustered together in affected tissues from patients with IgG4-RD.

Conclusions: This single-cell data set revealed a novel subset of HLA+GZMK+ cytotoxic Tfh cells infiltrating affected organs in patients with IgG4-RD, suggesting that infiltrating Tfr cells might suppress cytotoxic Tfh cells.

DOI： 10.1016/j.jaci.2023.08.019.

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology  

Metastatic tumors in the oral cavity are rare, accounting for only 1% of all oral malignancies. The most common site of metastatic tumors in the oral cavity is the mandibular molar region. The primary sites differ between the sexes. Among men, the primary sites are the lung, kidney, liver, and prostate in the order of frequency. Moreover, 11% of jawbone metastases among men originate from the prostate gland. Symptoms differ according to the location of the metastasis; besides, metastases-related imaging findings are nonspecific, making it difficult to reach an accurate diagnosis. Metastatic oral cancer has a poor prognosis; therefore, early diagnosis and treatment are important to improve the survival-rate and quality of life. A 76-year-old male patient was referred to our hospital with complaint of right-sided mandibular swelling and past medical history of adenocarcinoma of the prostate gland. Intraoral examination revealed a hard hemispherical mass on the right mandibular first molar region. Computed tomography showed a well-marginated radiopaque hemisphere mass with a typical sunburst periosteal reaction. Based on the imaging findings, we suspected primary osteosarcoma or metastatic prostate cancer. Histopathological examination of the mandible revealed a glandular structure with atypia similar to that of the primary prostate cancer cells. After prostate specific antigen monitoring therapy, the metastatic cancer did not grow. Metastatic cancers from other organs should be considered in the differential diagnosis of jawbone malignancies because the metastatic cancer might present similarities to the primary cancer in imaging findings, as in the present case that clinically mimicked osteosarcoma.

DOI： 10.1016/j.ajoms.2023.01.009

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

Synovial sarcoma (SS) is a malignant soft tissue tumor that usually arises in the para-articular regions of the extremities. Only nine cases of SS in the mandible have been reported to date. The present study described a case of SS arising from the left mandible. A 54-year-old woman was referred to Kyushu University Hospital (Fukuoka, Japan) with a complaint of numbness in the left mental nerve area. Computed tomography revealed replacement of the left mandibular bone marrow with soft tissue and destruction of the mandibular canal. Magnetic resonance imaging revealed an isointense mass on T1-weighted images and hyperintensity on T2-weighted images. The tumor showed homogeneous enhancement. A biopsy was performed, and monophasic SS was diagnosed based on immunohistochemical staining features and genetic analysis. Hemimandible dissection and supraomophyoid neck resection were performed with fibular osteocutaneous flap reconstruction, followed by adjuvant chemotherapy. There was no evidence of recurrence or distant metastases. The present study also reviewed the clinical, imaging, histological, and immunohistochemical features of the SS in the mandible.

DOI： doi: 10.3892/ol.2023.13904.

Language：English   Publisher：Spandidos Publications  

Synovial sarcoma (SS) is a malignant soft tissue tumor that usually arises in the para‑articular regions of the extremities. Only nine cases of SS in the mandible have been reported to date. The present study described a case of SS arising from the left mandible. A 54‑year‑old woman was referred to Kyushu University Hospital (Fukuoka, Japan) with a complaint of numbness in the left mental nerve area. Computed tomography revealed replacement of the left mandibular bone marrow with soft tissue and destruction of the mandibular canal. Magnetic resonance imaging revealed an isointense mass on T1‑weighted images and hyperintensity on T2‑weighted images. The tumor showed homogeneous enhancement. A biopsy was performed, and monophasic SS was diagnosed based on immunohistochemical staining features and genetic analysis. Hemimandible dissection and supraomophyoid neck resection were performed with fibular osteocutaneous flap reconstruction, followed by adjuvant chemotherapy. There was no evidence of recurrence or distant metastases. The present study also reviewed the clinical, imaging, histological, and immunohistochemical features of the SS in the mandible.

DOI： 10.3892/ol.2023.13904

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CiNii Research

Language：English   Publisher：Pathology International  

Various types of tumors, including malignant and benign ones, occur in the oral cavity. These arise from the mucosal epithelium, odontogenic epithelium, and salivary gland. To date, few major driver events in oral tumors have been identified. Accordingly, molecular targets in anti-tumor therapy for oral tumors are lacking. We focused on elucidating the function of aberrantly activated signal transduction related to oral tumor formation, especially in oral squamous cell carcinoma, ameloblastoma, and adenoid cystic carcinoma, which are raised as common oral tumors. Wnt/β-catenin-dependent pathway is involved in the developmental process, organ homeostasis and disease pathogenesis through regulating various cellular functions by enhancing transcriptional activity. Recently, we identified ADP-ribosylation factor (ARF)-like 4c (ARL4C) and Semaphorin 3A (Sema3A), the expression of which is regulated by Wnt/β-catenin-dependent pathway, and characterized their functions in the developmental process and tumor formation. This review highlights the recent advances in understanding the roles of Wnt/β-catenin-dependent pathway, ARL4C and Sema3A, as determined by pathological and experimental studies.

DOI： 10.1111/pin.13325

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Oral and Maxillofacial Surgery  

The aim of this study was to clarify the correlation between imaging findings obtained using intraoral ultrasonography (US) and pathological findings of tongue cancers, and to examine the predictive value of intraoral US findings with respect to occult nodal metastasis. This was a retrospective study based on the medical records of 123 patients with T1-2N0 tongue cancer. The depth of invasion (DOI) on intraoral US was positively correlated with the pathological invasion depth (PID) (ρ = 0.7080, P < 0.0001). Receiver operating characteristic analyses revealed an optimal DOI cut-off value of 4.1 mm and optimal PID cut-off value of 3.9 mm to detect nodal metastasis. Regarding the margin shape of the primary tumour on intraoral US, the incidence of nodal metastasis was significantly higher for the permeated type than for the pressure type (P < 0.001) and wedge-shaped type (P = 0.002). Furthermore, tumours with peritumoural vascularity assessed by power Doppler US had a significantly higher incidence of nodal metastasis than tumours without (P = 0.003). The sensitivity, specificity, and accuracy of the permeated type to predict nodal metastasis was 53.6%, 95.8%, and 86.2%, respectively. These results suggest that intraoral US findings closely reflect pathological findings and could be useful to predict occult nodal metastasis in patients with early-stage tongue cancer.

DOI： 10.1016/j.ijom.2022.08.021

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PubMed

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

Salivary glands develop through epithelial-mesenchymal interactions and are formed through repeated branching. The Crk-associated substrate protein (p130Cas) serves as an adapter that forms a complex with various proteins via integrin and growth factor signaling, with important regulatory roles in several essential cellular processes. We found that p130Cas is expressed in ductal epithelial cells of the submandibular gland (SMG). We generated epithelial tissue-specific p130Cas-deficient (p130CasΔepi-) mice and aimed to investigate the physiological role of p130Cas in the postnatal development of salivary glands. Histological analysis showed immature development of granular convoluted tubules (GCT) of the SMG in male p130CasΔepi- mice. Immunofluorescence staining showed that nuclear-localized androgen receptors (AR) were specifically decreased in GCT cells in p130CasΔepi- mice. Furthermore, epidermal growth factor-positive secretory granules contained in GCT cells were significantly reduced in p130CasΔepi- mice with downregulated AR signaling. GCTs lacking p130Cas showed reduced numbers and size of secretory granules, disrupted subcellular localization of the cis-Golgi matrix protein GM130, and sparse endoplasmic reticulum membranes in GCT cells. These results suggest that p130Cas plays a crucial role in androgen-dependent GCT development accompanied with ER-Golgi network formation in SMG by regulating the AR signaling.

DOI： 10.1038/s41598-023-32390-1.

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

Objectives: To compare the delineation of mandibular cancer by 3D T1 turbo field echo with compressed SENSE (CS-3D-T1TFE) images and MDCT images, and to compare both sets of images with histopathological findings, as the gold standard, to validate the accuracy and clinical usefulness of CS-3D-T1TFE reconstruction.

Methods: Twenty-four patients with mandibular squamous cell carcinoma (SCC) who underwent MRI including CS-3D-T1TFE and MDCT examinations before surgery were retrospectively included. For both examinations, 0.5-mm-thick coronal plane images and 0.5-mm-thick plane images perpendicular and parallel to the dentition were constructed. Two radiologists rated bone invasion in three categories indexed by cortical bone, cancellous bone, and mandibular canal (MC), and inter-rater agreement was assessed by weighted kappa statistics. In 20 of the 24 patients who underwent surgery, the correlation of bone invasion with the histopathological evaluation by pathologists was assessed using Pearson's correlation coefficient. Soft-tissue invasion was assessed by diagnosing the presence of invasion into the mylohyoid muscle, gingivobuccal fold, and masticator space, and inter-rater agreement was assessed by kappa statistics.

Results: The interobserver agreement for bone invasion assessment was almost perfect with CS-3D-T1TFE and substantial with MDCT. The image evaluations by both observers agreed with the pathological evaluations in 15 of the 20 cases, showing high correlation (r > 0.8). CS-3D-T1TFE also showed higher inter-rater agreement than MDCT for all measures of soft-tissue invasion.

Conclusions: CS-3D-T1TFE reconstructed images were clinically useful in accurately depicting the extent of mandibular cancer invasion and potentially solving the problem of lesion overestimation associated with conventional MRI.

DOI： 10.1007/s00330-022-09075-w

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology  

Kaposi's sarcoma (KS) is one of the most common malignancies in patients with acquired immunodeficiency syndrome (AIDS). KS is frequently detected in the skin, gastrointestinal tract and oral cavity, but rarely occurs in multiple systemic lymph nodes. Here, we report a case of AIDS-associated KS that occurred in both the oral region and multiple systemic lymph nodes. A 27-year-old man was referred to our department because of a mass in the oral cavity. The main clinical findings included multiple dark red masses in the oral cavity and generalized lymphadenopathy. Blood tests revealed infection with human immunodeficiency virus and human herpes virus 8. The histopathological diagnosis of both the oral masses and cervical lymph nodes was KS. After initiating antiretroviral therapy and chemotherapy with pegylated liposomal doxorubicin the lesions went into partial remission, and there was no sign of relapse 1 year later.

DOI： 10.1016/j.ajoms.2021.11.009

Web of Science

Scopus

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Allergy and Clinical Immunology  

Background: How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T cell-dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs (SLOs and TLOs) in patients with elevated tissue expression levels of IgE (Kimura's disease, KD) and those of IgG4 (IgG4-related disease, IgG4-RD) can provide important insights regarding cytokine expression by Tfh cells.

Objective: To identify disease-specific Tfh cell subsets in SLOs and TLOs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in two distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes).

Methods: Single-cell RNA-sequencing, in situ sequencing, and multi-color immunofluorescence analysis was used to investigate B cells, Tfh cells and infiltrating type 2 cells in lesion tissues from patients with KD or IgG4-RD.

Results: Infiltrating Tfh cells in TLOs from IgG4-RD were divided into six main clusters. We encountered abundant infiltrating IL-10-expressing LAG3+ Tfh cells in patients with IgG4-RD. Furthermore, we found that infiltrating AID+CD19+B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG4 expression. In contrast, we found that infiltrating IL-13-expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13-expressing Tfh cells in tissues from patients with IgG4-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG4-RD, and in contrast Type 2 immune cells were abundant in KD.

Conclusions: This single-cell dataset revealed a novel subset of IL10+LAG3+Tfh cells infiltrating the affected organs of IgG4-RD patients. In contrast, IL13+Tfh cells and type 2 immune cells infiltrated those of KD patients.

DOI： 10.1016/j.jaci.2022.03.034

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology  

According to the fourth revised edition of the world health organization classification of hematopoietic tumors, methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD), an atypical pathological condition, is categorized under other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs). An 80-year-old woman presented with OIIA-LPDs that simultaneously occurred in the gingiva and intestinal mucosa, causing intestinal perforation requiring emergency surgery. She was referred to our hospital because of poor wound healing after maxillary right first molar extraction. She had been prescribed MTX and prednisolone for rheumatoid arthritis and bisphosphonate for osteoporosis. We diagnosed her with medication-related osteonecrosis of the jaw, as the lesion showed bone exposure with mild redness and swelling of the surrounding gingiva and a cytological result of Class II. However, 9 months later, following the exfoliation of a partial sequestrum of the maxillary right first molar, a rapidly growing mass with gingival necrosis appeared, necessitating a biopsy. Simultaneously, abdominal pain worsened, and computed tomography revealed intestinal perforation; an emergency laparotomy was performed to remove the perforation and the surrounding ulcer-prone area. Histopathological examination of both lesions revealed diffuse large B-cell lymphomas. The final diagnosis was of MTX-LPD, as the mass, gingival necrosis, and residual small intestinal ulcer disappeared 2 months after MTX discontinuation. The exposed bone completely disappeared after 24 months, and no recurrence was noted after 60 months following MTX discontinuation. Although intestinal perforation due to MTX-LPD is extremely rare, patients with RA are immunosuppressed. Therefore, MTX-LPD must be recognized as a dangerous condition that requires careful general monitoring in such patients.

DOI： 10.1016/j.ajoms.2021.08.012

Web of Science

Scopus

Language：English   Publisher：Bone  

Amelogenesis consists of secretory, transition, maturation, and post-maturation stages, and the morphological changes of ameloblasts at each stage are closely related to their function. p130 Crk-associated substrate (Cas) is a scaffold protein that modulates essential cellular processes, including cell adhesion, cytoskeletal changes, and polarization. The expression of p130Cas was observed from the secretory stage to the maturation stage in ameloblasts. Epithelial cell-specific p130Cas-deficient (p130Cas^Δepi-) mice exhibited enamel hypomineralization with chalk-like white mandibular incisors in young mice and attrition in aged mouse molars. A micro-computed tomography analysis and Vickers micro-hardness testing showed thinner enamel, lower enamel mineral density and hardness in p130Cas^Δepi- mice in comparison to p130Cas^flox/flox mice. Scanning electron microscopy, and an energy dispersive X-ray spectroscopy analysis indicated the disturbance of the enamel rod structure and lower Ca and P contents in p130Cas^Δepi- mice, respectively. The disorganized arrangement of ameloblasts, especially in the maturation stage, was observed in p130Cas^Δepi- mice. Furthermore, expression levels of enamel matrix proteins, such as amelogenin and ameloblastin in the secretory stage, and functional markers, such as alkaline phosphatase and iron accumulation, and Na⁺/Ca²⁺+K⁺-exchanger in the maturation stage were reduced in p130Cas^Δepi- mice. These findings suggest that p130Cas plays important roles in amelogenesis (197 words).

DOI： 10.1016/j.bone.2021.116210

Web of Science

Scopus

PubMed

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

Amelogenesis consists of secretory, transition, maturation, and post-maturation stages, and the morphological changes of ameloblasts at each stage are closely related to their function. p130 Crk-associated substrate (Cas) is a scaffold protein that modulates essential cellular processes, including cell adhesion, cytoskeletal changes, and polarization. The expression of p130Cas was observed from the secretory stage to the maturation stage in ameloblasts. Epithelial cell-specific p130Cas-deficient (p130Casepi-) mice exhibited enamel hypomineralization with chalk-like white mandibular incisors in young mice and attrition in aged mouse molars. A micro-computed tomography analysis and Vickers micro-hardness testing showed thinner enamel, lower enamel mineral density and hardness in p130Casepi- mice in comparison to p130Casflox/flox mice. Scanning electron microscopy, and an energy dispersive X-ray spectroscopy analysis indicated the disturbance of the enamel rod structure and lower Ca and P contents in p130Casepi- mice, respectively. The disorganized arrangement of ameloblasts, especially in the maturation stage, was observed in p130Casepi- mice. Furthermore, expression levels of enamel matrix proteins, such as amelogenin and ameloblastin in the secretory stage, and functional markers, such as alkaline phosphatase and iron accumulation, and Na+/Ca2++K+-exchanger in the maturation stage were reduced in p130Casepi- mice. These findings suggest that p130Cas plays important roles in amelogenesis.

DOI： 10.1016/j.bone.2021.116210.

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

Oral malignant melanoma, which frequently invades the hard palate or maxillary bone, is extremely rare and has a poor prognosis. Bone morphogenetic protein (BMP) is abundantly expressed in bone matrix and is highly expressed in malignant melanoma, inducing an aggressive phenotype. We examined the role of BMP signaling in the acquisition of an aggressive phenotype in melanoma cells in vitro and in vivo. In five cases, immunohistochemistry indicated the phosphorylation of Smad1/5 (p-Smad1/5) in the nuclei of melanoma cells. In the B16 mouse and A2058 human melanoma cell lines, BMP2, BMP4, or BMP7 induces morphological changes accompanied by the downregulation of E-cadherin, and the upregulation of N-cadherin and Snail, markers of epithelial–mesenchymal transition (EMT). BMP2 also stimulates cell invasion by increasing matrix metalloproteinase activity in B16 cells. These effects were canceled by the addition of LDN193189, a specific inhibitor of Smad1/5 signaling. In vivo, the injection of B16 cells expressing constitutively activated ALK3 enhanced zygoma destruction in comparison to empty B16 cells by increasing osteoclast numbers. These results suggest that the activation of BMP signaling induces EMT, thus driving the acquisition of an aggressive phenotype in malignant melanoma.

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

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (0IIA-LPDs), which are uncontrolled lymphoid proliferation or lymphoma induced by immunosuppressive medication, arise mainly in patients with rheumatoid arthritis (RA). The vast majority of OIIA-LPDs are caused by methotrexate (MTX), and the reported incidence rates in the oral and maxillofacial regions are similar to those in other organs. In addition, tofacitinib (TFC), which is a Janus kinase inhibitor, has been clinically applied for the immunosuppressive treatment of RA in recent years. Herein, we present a case of OIIA-LPD of the oral floor in a patient with RA who had been treated with TFC and MTX. Clinical and pathological findings suggested that inflammatory stomatitis and/or infective response by oral bacteria promoted lymphoid activation in the oral mucosa, which could potentially become malignant. This case report indicates that OIIA-LPD might result from the combined usage of MTX and TFC, and a synergistic influence between MTX and TFC on immunosuppression may lead to diversification of OIIA-LPDs. The findings suggest the difficulty in controlling complications of RA and the importance of understanding the mechanisms of immunosuppressive treatments.

DOI： 10.1016/j.ajoms.2020.12.002

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

Protease-activated receptor 1 (PAR1) is known as a thrombin receptor. Recent studies have reported PAR1 expression in various malignancies; however, its role in oral squamous cell carcinoma (OSCC) requires clarification. A previous study showed that down-regulation of ΔNp63, a homolog of p53, augments PAR1 expression in OSCC. In the present study, the association of PAR1 expression with clinicopathological findings in OSCC was examined retrospectively. Expression of PAR1, thrombin, and ΔNp63 was examined immunohistochemically in OSCC specimens. Patients were divided into three groups based on the expression pattern of PAR1 at the invasive front: group A, PAR1-negative in both cancer and stromal cells; group B, positive in stromal cells but negative in cancer cells; group C, positive in both cancer and stromal cells. Histologically high-grade tumours were significantly more common in group C. Patients in group C had the highest incidence rate of nodal metastasis (P<0.001) and a lower survival rate (P=0.085) than those in the other groups. At the invasive front, in group C, thrombin was expressed but ΔNp63 expression was weak. These results indicate that increased PAR1 expression in both cancer and stromal cells could be a useful predictive marker of nodal metastasis and that ΔNp63 is involved in regulating PAR1 expression.

DOI： 10.1016/j.ijom.2020.04.021.

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

Bone invasion is a critical factor in determining the prognosis of oral squamous cell carcinoma (OSCC) patients. Transforming growth factor β (TGF-β) is abundantly expressed in the bone matrix and is involved in the acquisition of aggressiveness by tumors. TGF-β) is also important to cytoskeletal changes during tumor progression. In this study, we examined the relationship between TGF-β signaling and cytoskeletal changes during bone invasion by OSCC. Immunohistochemical staining of OSCC samples from 5 patients showed the expression of p130Cas (Crk-associated substrate) in the cytoplasm and phosphorylated Smad3 expression in the nucleus in OSCC cells. TGF-β1 induced the phosphorylation of Smad3 and p130Cas as well as epithelial-mesenchymal transition (EMT) accompanied by the downregulation of the expression of E-cadherin, a marker of epithelial cells, and the upregulation of the expression of N-cadherin, or Snail, a marker of mesenchymal cells, in human HSC-2 cells and mouse SCCVII cells. SB431542, a specific inhibitor of Smad2/3 signaling, abrogated the TGF-β1-induced phosphorylation of p130Cas and morphological changes. Silencing p130Cas using an shRNA or siRNA in SCCVII cells suppressed TGF-β1-induced cell migration, invasion, EMT, and matrix metalloproteinase-9 (MMP-9) production. Compared with control SCCVII cells, SCCVII cells with silenced p130Cas strongly suppressed zygomatic and mandibular destruction in vivo by reducing the number of osteoclasts, cell proliferation and MMP-9 production. Taken together, these results showed the expression of TGF-β/p130Cas might be a new target for the treatment of OSCC bone invasion.

DOI： 10.1093/carcin/bgaa007.

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

Periodontal ligament (PDL) stem cells (PDLSCs) have been reported as a useful cell source for periodontal tissue regeneration. However, one of the issues is the difficulty of obtaining a sufficient number of PDLSCs for clinical application because very few PDLSCs can be isolated from PDL tissue of donors. Therefore, we aimed to identify a specific factor that converts human PDL cells into stem-like cells. In this study, microarray analysis comparing the gene profiles of human PDLSC lines (2-14 and 2-23) with those of a cell line with a low differentiation potential (2-52) identified the imprinted gene mesoderm-specific transcript (MEST). MEST was expressed in the cytoplasm of 2-23 cells. Knockdown of MEST by siRNA in 2-23 cells inhibited the expression of stem cell markers, such as CD105, CD146, p75NTR, N-cadherin, and NANOG; the proliferative potential; and multidifferentiation capacity for osteoblasts, adipocytes, and chondrocytes. On the other hand, overexpression of MEST in 2-52 cells enhanced the expression of stem cell markers and PDL-related markers and the multidifferentiation capacity. In addition, MEST-overexpressing 2-52 cells exhibited a change in morphology from a spindle shape to a stem cell-like round shape that was similar to 2-14 and 2-23 cell morphologies. These results suggest that MEST plays a critical role in the maintenance of stemness in PDLSCs and converts PDL cells into PDLSC-like cells. Therefore, this study indicates that MEST may be a therapeutic factor for periodontal tissue regeneration by inducing PDLSCs.

DOI： 10.1155/2020/9672673

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

Objectives: In this study, we investigated the diagnostic utility of submandibular gland (SMG) sonography and labial salivary gland (LSG) biopsy as a less invasive procedure for diagnosing IgG4-related dacryoadenitis and sialadenitis (IgG4-DS)Methods: Sixty-eight patients with suspected IgG4-DS by presenting swelling of elevated serum IgG (>1747 mg/dl) and/or swelling glands underwent SMG sonography, LSG biopsy and measurement for serum IgG4. SMG sonographic diagnosis was determined by the following characteristic changes; 'hypoechoic areas of a nodal pattern with high vascularity' and/or 'hypoechoic areas of a reticular pattern in the superficial part'.Results: Thirty-one patients were diagnosed with IgG4-DS, 5 with IgG4-RD unaccompanied by lacrimal and salivary gland lesions, 28 with Sjögren's syndrome, and 4 with malignant lymphoma. The sensitivity, specificity, and accuracy of SMG sonography and LSG biopsy were 100%, 83.8%, 91.2% and 64.5%, 73.8%, 75.0%, respectively. Moreover, those of SMG sonography and LSG biopsy combined with serum IgG4 concentration (>135 mg/dl) were 100%, 94.6%, 97.1% and 64.5%, 91.9%, 79.4%, respectively.Conclusion: LSG biopsy needs to be extremely careful to diagnose IgG4-DS because of its low sensitivity. SMG sonography is sufficient for the diagnosis of IgG4-DS, especially when combined with serologic analysis. Thus, SMG sonography could adapt to the diagnostic criteria of IgG4-DS as a non-invasive method.

DOI： 10.1080/14397595.2019.1576271

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

Objective
Cytokeratin (CK) 19 is a member of the acidic type I CK family. Recently, CK19 expression has been found in various tumor tissues; however, the significance of this remains unknown. The purpose of this study is to clarify the roles of CK19 in the progression of oral squamous cell carcinoma (OSCC).

Methods
A total of 100 patients who had been diagnosed with OSCC at our department between January 2011 and December 2016 was included. The patients were divided into three groups based on an optimal cut-off points (5% and 77%) of the labeling index (LI) as follows: group A; LI < 5%, group B; 5%≤ LI < 77%, group C; LI ≥ 77%. Then, clinicopathological features and survival rates were compared among the groups.

Results
Histologically high-grade tumors were significantly more common in group C than in groups A and B. Furthermore, the incidence of nodal metastasis was significantly higher in group C than in other groups. Intense CK19 immunoreactivity was detected in metastatic lymph nodes of groups B and C, but not from group A. Moreover, patients with advanced pN stage and extranodal extension were more common in groups B and C than group A. Disease-specific survival curves revealed poorer prognoses in group C.

Conclusions
These results suggest that CK19 is involved in OSCC invasion and metastasis and could be a novel biomarker of highly invasive OSCC with metastatic potential.

DOI： 10.1016/j.ajoms.2019.10.007

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

OBJECTIVE: IgG4-related disease (IgG4-RD) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll-like receptor (TLR) pathway. This study was undertaken to examine the expression of TLRs in salivary glands (SGs) from patients with IgG4-RD.
METHODS: SGs from 15 patients with IgG4-RD, 15 patients with Sjögren's syndrome (SS), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically. TLR family gene expression (TLR-1 through TLR-10) was analyzed by DNA microarray in the submandibular glands (SMGs). Up-regulation of TLRs was confirmed in SGs from patients with IgG4-RD. Finally, the phenotype of human TLR-7 (huTLR-7)-transgenic C57BL/6 mice was assessed before and after stimulation with TLR agonist.
RESULTS: In patients with IgG4-RD, TLR-4, TLR-7, TLR-8, and TLR-9 were overexpressed. Polymerase chain reaction validated the up-regulation of TLR-7 in IgG4-RD compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of TLR-7-positive cells in the SGs of patients with IgG4-RD. Double immunohistochemical staining showed that TLR-7 expression colocalized with CD163+ M2 macrophages. After in vitro stimulation with a TLR-7 agonist, CD163+ M2 macrophages produced higher levels of interleukin-33 (IL-33), which is a Th2-activating cytokine. In huTLR-7-transgenic mice, the focus and fibrosis scores in SMGs, pancreas, and lungs were significantly higher than those in wild-type mice (P < 0.05). Moreover, the concentration of serum IgG, IgG1, and IL-33 in huTLR-7-transgenic mice was distinctly increased upon stimulation with a TLR-7 agonist (P < 0.05).

DOI： 10.1002/art.41052

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

RATIONALE: Kimura disease (KD) is a rare, chronic inflammatory disorder characterized by subcutaneous granuloma in the head and neck region, as well as increased eosinophil counts and high serum immunoglobulin E (IgE) levels. Kimura disease is suspected to be an IgE-mediated disease, associated with an allergic response, in which antigen-specific B cells are stimulated to undergo specific IgE class switching with disease-specific CD4+ T (Th) cells help. Thus, exploration of the Th cells in affected tissues with KD is a highly promising field of the investigation. However, there have been no reports with direct evidence to implicate Th cells in affected lesions with KD. Here we quantitatively demonstrate that CD4+ GATA3+ T cells and interleukin (IL)-4+ IgE+ c-kit+ mast cells prominently infiltrate in affected lesion with KD.
PATIENT CONCERNS: A 56-year-old Japanese man who exhibited painless swelling in the left parotid region.
DIAGNOSES: Diagnosis of KD was made based on characteristic histopathologic findings, in conjunction with peripheral eosinophilia and elevated serum IgE levels.
INTERVENTIONS: The patient underwent corticosteroid therapy and had been followed for 2 years.
OUTCOMES: We report a rare case of KD of the parotid region in a 56-year-old man, followed by corticosteroid therapy for 2 years. The mass decreased in size and skin itchiness decreased after therapy. He was discharged without any complications. Furthermore, we quantitatively demonstrate the dominance of CD4+ GATA3+ T cells in affected tissues of KD and detect IL-4+ IgE+ c-kit+ mast cells in lesions by multicolor staining approaches.
LESSONS: The findings from this case suggest that peripheral blood eosinophilia might serve as a marker of recurrent disease, long-term follow-up is necessary due to the possibility of recurrent. Interactions among expanded IgE+ B cells, CD4+ GATA3+ T cells, eosinophils, and activated mast cells might play a critical role in the pathogenesis of KD.

DOI： 10.1097/MD.0000000000018300.

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

Periodontitis is one of the most common chronic oral inflammatory conditions worldwide and is associated with a risk of developing oral squamous cell carcinoma (OSCC). Porphyromonas gingivalis is a major pathogen in periodontitis, and its lipopolysaccharide (LPS) promotes the expression of cyclooxygenase-2 (COX-2) in OSCC both in vivo and in vitro. Celecoxib is a selective COX-2 inhibitor; however, its antitumor effects on P. gingivalis LPS-stimulated OSCC and the underlying molecular mechanism remain unclear. To elucidate the association between periodontitis and OSCC, the effect of P. gingivalis-derived LPS on OSCC cell proliferation was examined both in vitro and in vivo in the present study. The expression levels of COX-2 and p53 in OSCC cells with/without celecoxib treatment were determined via western blotting. The therapeutic potential of celecoxib in LPS-stimulated OSCC was evaluated by staining for Ki-67 and p21, as well as with terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling staining. LPS treatment significantly increased OSCC cell proliferation in vitro, and celecoxib significantly inhibited cell proliferation with/without LPS treatment. Celecoxib treatment of OSCC cells downregulated the protein expression levels of COX-2 compared with untreated cells, but there was little change in p53 expression. In the mouse xenograft model, oral administration of celecoxib significantly suppressed tumor growth, reduced the expression of Ki-67, increased the apoptosis index and induced p21 expression with/without LPS treatment. The results from the present study demonstrate that P. gingivalis' LPS can stimulate tumor growth by interacting with OSCC cells. In conclusion, these results suggest that celecoxib could be used for the effective prevention and treatment of LPS-stimulated OSCC.

DOI： 10.3892/ol.2019.10975.

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

Odontomas, developmental anomalies of tooth germ, frequently occur in familial adenomatous polyposis patients with activated Wnt/β-catenin signaling. However, roles of Wnt/β-catenin signaling in odontomas or odontogenic cells are unclear. Herein, we investigated β-catenin expression in odontomas and functions of Wnt/β-catenin signaling in tooth germ development. β-catenin frequently accumulated in nucleus and/or cellular cytoplasm of odontogenic epithelial cells in human odontoma specimens, immunohistochemically. Wnt/β-catenin signaling inhibited odontogenic epithelial cell proliferation in both cell line and tooth germ development, while inducing immature epithelial bud formation. We identified Semaphorin 3A (Sema3A) as a downstream molecule of Wnt/β-catenin signaling and showed that Wnt/β-catenin signaling-dependent reduction of Sema3A expression resulted in suppressed odontogenic epithelial cell proliferation. Sema3A expression is required in appropriate epithelial budding morphogenesis. These results suggest that Wnt/β-catenin signaling negatively regulates odontogenic epithelial cell proliferation and tooth germ development through decreased-Sema3A expression, and aberrant activation of Wnt/β-catenin signaling may associate with odontoma formation.

DOI： 10.1038/s41598-019-51149-1

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

Osteoid osteoma is a benign bone-forming tumor and characterized by its limited growth potential, not exceeding 2 cm. The radiological hallmark of this tumor is a nidus, which is a small round area of relative radiolucency. Osteoid osteoma can involve any bone but is most commonly found in long bones and is extremely rare in the head and neck region. This disease characteristically presents with dull pain, worse at night, and sometimes relieved with NSAIDs. A 24-year-old Japanese woman presented with spontaneous pain and tenderness on the lingual side of her mandibular second molar on the right side. The patient reported that her pain had gradually increased, becoming more continuous and severe and no longer responding to NSAIDs. An initial panoramic radiograph revealed an oval, internally non-uniform, somewhat obscure boundaries in the right mandible. Computed tomography (CT) scan revealed a sclerotic lesion with a delineated central calcified nidus surrounded by a radiolucent band. The interior of the nidus was a non-uniform, irregularly shaped area of high absorption. The nidus was removed with intralesional curettage under general anesthesia. The histopathology of the specimen consisted of actively proliferating osteoblasts mixed with an interlacing network of immature bone and osteoid trabeculae. Immunohistochemistry revealed that hardly detected osteoblasts or fibrous stromal cells with intense nuclear immunoreactivity for p16 and/or murine double minute 2 (mdm2). We thus distinguished the tumor from Low-grade central osteosarcoma (LGCO) with immunohistochemical findings. The histopathological diagnosis was thus osteoid osteoma.

DOI： 10.1016/j.ajoms.2019.04.002

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

RATIONALE: Ossifying fibroma is benign fibro-osseous neoplasm. The authors report a case of ossifying fibroma in the mandibular angle suspected as metastasis of clear cell renal cell carcinoma.
PATIENT CONCERNS: A 74-year-old man presented to the primary hospital complaining of frequent urination. A tumor in the left kidney was detected via an abdominal computed tomography scan. The patient then visited the Department of Urology at our hospital.
DIAGNOSES: According to whole-body imaging examinations, the patient was suspected of having renal cancer with mandibular metastasis. Also, a cystic lesion of the maxilla was revealed.
INTERVENTIONS: Left nephrectomy was performed by urologists, and the patient was diagnosed with clear cell renal cell carcinoma of the left kidney. Approximately 1 month later, resection with a safety margin of the mandibular lesion and removal of the maxillary lesion were performed by oral and maxillofacial surgeons.
OUTCOMES: The patient was diagnosed with ossifying fibroma of the mandible and an odontogenic keratocyst of the maxilla via a histopathological examination. Eighteen months have passed since the operation without clinical and imaging findings associated with recurrence.
LESSONS: Ossifying fibroma in the mandibular angle of elderly patients is extremely rare. Surgeons should consider the possibility of metastasis when osteolytic lesions of the jaw are found in patients with cancer.

DOI： 10.1097/MD.0000000000016595.

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

Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors in the oral region. Despite current therapeutic strategies, the survival rate has not been improved for several decades. Thus, it is important to develop a novel approach for the treatment of OSCC. Epigallocatechin‑3‑gallate (EGCG) is a major constituent of green tea and has previously been demonstrated to inhibit the growth of several types of cancer cells. However, few studies have investigated the effect of EGCG on human OSCC cells, especially in experimental animal models. The aim of the present study was to evaluate the therapeutic potential of EGCG for targeting human OSCC in vitro and in vivo. In the in vitro experiments, EGCG suppressed HSC‑3 cell viability in a time‑ and dose‑dependent manner. Cell cycle analysis revealed that EGCG induced G1 phase arrest of the tumor cells. Apoptosis was examined by Annexin V and propidium iodide staining, assays of caspase‑3 and -7 activity and TdT‑mediated dUTP nick end labeling (TUNEL) staining. Treatment with EGCG significantly increased caspase‑3 and -7 activities, and the percentage of apoptotic cells when compared with control cells. In the in vivo xenograft experiment on mice, EGCG treatment resulted in a 45.2% reduction in tumor size as compared with the control group without weight loss. In vivo cell proliferation and apoptosis were assessed by immunohistochemical Ki‑67 staining and the TUNEL staining. There were significant differences in Ki‑67 expression between the EGCG treatment group and control group, and the percentage of apoptotic cells in the EGCG treatment group was significantly greater than that in the control group. These results indicated that EGCG significantly inhibited cell proliferation by affecting the cell cycle progression and apoptosis in vitro and in vivo. These findings suggest that EGCG may have clinical applications as a novel approach to oral‑cancer therapy.

DOI： 10.3892/mmr.2019.10331

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

Recurrent or chronic oral pain is a great burden for patients. Recently, the links between epithelial barrier loss and disease were extended to include initiation and propagation. To explore the effects of pathohistological changes in oral epithelia on pain, we utilized labial mucosa samples in diagnostic labial gland biopsies from patients with suspected Sjögren's syndrome (SS), because they frequently experience pain and discomfort. In most labial mucosa samples from patients diagnosed with SS, disseminated epithelial cellular edema was prevalent as ballooning degeneration. The disrupted epithelia contained larger numbers of infiltrating macrophages in patients with oral pain than in patients without pain. Immunohistochemistry revealed that edematous areas were distinct from normal areas, with disarranged cell-cell adhesion molecules (filamentous actin, E-cadherin, β-catenin). Furthermore, edematous areas were devoid of immunostaining for transient receptor potential channel vanilloid 4 (TRPV4), a key molecule in adherens junctions. In an investigation on whether impaired TRPV4 affect cell-cell adhesion, calcium stimulation induced intimate cell-cell contacts among oral epithelial cells from wild-type mice, while intercellular spaces were apparent in cells from TRPV4-knockout mice. The present findings highlight the relationship between macrophages and epithelia in oral pain processing, and identify TRPV4-mediated cell-cell contacts as a possible target for pain treatment.

DOI： 10.1369/0022155418812405

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

Fibro-osseous and osteochondromatous lesions are non-neoplastic lesions containing metaplastic bone and/or cementum. The World Health Organization classification (4th edition, 2017) has categorized these lesions into subgroups: ossifying fibroma, familial gigantiform cementoma, fibrous dysplasia, cemento-osseous dysplasia and osteochondroma. We report a highly unusual case of cemento-osseous dysplasia in a 32-year-old male complaining of discomfort of the left cheek. The radiographic examination revealed that a spherical radiopaque lesion, which involved a tooth, was located in the left maxillary sinus. A definitive diagnosis could not be made based only on the radiographic and clinical findings. An excisional biopsy was performed by opening the left maxillary sinus under the general anaesthesia. Histopathological examination revealed that the lesion consists of fibrous tissue, woven bone and masses of cementum-like material associated with a dislocated tooth. Together with the radiographic, clinical and histopathological findings, the lesion was diagnosed as cemento-osseous dysplasia. Differential diagnosis between fibro-osseous lesions and tumor is critical; the present case highlights the importance of correlating clinical, radiological and histopathological findings in order to correctly diagnose and manage oral and maxillofacial lesions.

DOI： 10.1016/j.ajoms.2018.08.002

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

We previously revealed that epithelial-to-mesenchymal transition (EMT) was mediated by ΔNp63β, a splicing variant of ΔNp63, in oral squamous cell carcinoma (OSCC). Recent studies have highlighted the involvement of microRNA (miRNA) in EMT of cancer cells, though the mechanism remains unclear. To identify miRNAs responsible for ΔNp63β-mediated EMT, miRNA microarray analyses were performed by ΔNp63β-overexpression in OSCC cells; SQUU-B, which lacks ΔNp63 expression and displays EMT phenotypes. miRNAs microarray analyses revealed miR-205 was the most up-regulated following ΔNp63β-overexpression. In OSCC cells, miR-205 expression was positively associated with ΔNp63 and negatively with zinc-finger E-box binding homeobox (ZEB) 1 and ZEB2, potential targets of miR-205. miR-205 overexpression by miR-205 mimic transfection into SQUU-B cells led to decreasing ZEB1, ZEB2, and mesenchymal markers, increasing epithelial markers, and reducing cell motilities, suggesting inhibition of EMT phenotype. Interestingly, the results opposite to this phenomenon were obtained by transfection of miR-205 inhibitor into OSCC cells, which express ΔNp63 and miR-205. Furthermore, target protector analyses revealed direct regulation by miR-205 of ZEB1 and ZEB2 expression. These results showed tumor-suppressive roles of ΔNp63β and miR-205 by inhibiting EMT thorough modulating ZEB1 and ZEB2 expression in OSCC.

DOI： 10.1002/jcp.26267

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

Programmed cell death ligand 1 (PD-L1) and its receptor PD-1 are immune checkpoint molecules that attenuate the immune response. Blockade of PD-L1 enhances the immune response in a variety of tumours and thus serves as an effective anti-cancer treatment. However, the biological and prognostic roles of PD-L1/PD-1 signalling in oral squamous cell carcinoma (OSCC) remain to be elucidated. The purpose of this study was to examine the correlation of PD-L1/PD-1 signalling with the prognosis of OSCC patients to assess its potential therapeutic relevance. The expression of PD-L1 and of PD-1 was determined immunohistochemically in 97 patients with OSCC and the association of this expression with clinicopathological characteristics was examined. Increased expression of PD-L1 was found in 64.9% of OSCC cases and increased expression of PD-1 was found in 61.9%. Univariate and multivariate analysis revealed that increased expression of PD-L1 and PD-1 positively correlated with cervical lymph node metastasis. The expression of CD25, an activated T-cell marker, was negatively correlated with the labelling index of PD-L1 and PD-1. Moreover, the patient group with PD-L1-positive and PD-1-positive expression showed a more unfavourable prognosis than the group with PD-L1-negative and PD-1-negative expression. These data suggest that increased PD-L1 and PD-1 expression is predictive of nodal metastasis and a poor prognosis and is possibly involved in cancer progression via attenuating the immune response.

DOI： 10.1016/j.ijom.2018.01.004

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

Angiogenesis serves a crucial role in tumor growth. Vascular endothelial growth factor (VEGF) is a potent regulator of tumor angiogenesis and is highly expressed in oral squamous cell carcinoma (OSCC). Bevacizumab, which binds to VEGF-A, inhibits the biological activity of VEGF and is clinically administered by intravenous injection. As intravenous chemotherapy intensifies the side effects experienced by OSCC patients, an alternative treatment option is desirable, particularly for older patients with OSCC who present with systemic disease complications. Generally, local injections of antitumor agents enhance tumoricidal activity and decrease side effects. However, the antitumor effects of peritumoral bevacizumab injections in OSCC are not fully understood. Therefore, the present study examined the effects of peritumoral bevacizumab injections in an experimental nude mouse model of OSCC through immunohistochemical staining for cluster of differentiation (CD)31 and α-smooth muscle actin (α‑SMA) and apoptosis assays. It was identified that peritumoral injections of bevacizumab significantly inhibited tumor growth in OSCC xenografts compared with peritumoral saline injections or no treatment (controls), and it was also revealed that treatment with bevacizumab significantly reduced CD31- and α-SMA-positive microvessel density (P<0.01) and increased level of tumor cell apoptosis (P<0.01) compared with the controls. In conclusion, these results collectively support the experimental basis for the clinical development of peritumoral bevacizumab injections for the treatment of OSCC.

DOI： 10.3892/ol.2018.8399

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

Distinct T follicular helper (TFH) subsets that influence specific class-switching events are assumed to exist, but the accumulation of isotype-specific TFH subsets in secondary lymphoid organs (SLOs) and tertiary lymphoid organs has not been hitherto demonstrated. IL-4-expressing TFH cells are surprisingly sparse in human SLOs. In contrast, in IgG4-related disease (IgG4-RD), a disorder characterized by polarized Ig class switching, most TFH cells in tertiary and SLOs make IL-4. Human IL-4+ TFH cells do not express GATA-3 but express nuclear BATF, and the transcriptomes of IL-4-secreting TFH cells differ from both PD1hi TFH cells that do not secrete IL-4 and IL-4-secreting non-TFH cells. Unlike IgG4-RD, IL-4+ TFH cells are rarely found in tertiary lymphoid organs in Sjögren's syndrome, a disorder in which IgG4 is not elevated. The proportion of CD4+IL-4+BATF+ T cells and CD4+IL-4+CXCR5+ T cells in IgG4-RD tissues correlates tightly with tissue IgG4 plasma cell numbers and plasma IgG4 levels in patients but not with the total plasma levels of other isotypes. These data describe a disease-related TFH subpopulation in human tertiary lymphoid organs and SLOs that is linked to IgG4 class switching.

DOI： 10.26508/lsa.201800050

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

Undifferentiated odontogenic epithelium and dental papilla cells differentiate into ameloblasts and odontoblasts, respectively, both of which are essential for tooth development. These differentiation processes involve dramatic functional and morphological changes of the cells. For these changes to occur, activation of mitochondrial functions, including ATP production, is extremely important. In addition, these changes are closely related to mitochondrial fission and fusion, known as mitochondrial dynamics. However, few studies have focused on the role of mitochondrial dynamics in tooth development. The purpose of this study was to clarify this role. We used mouse tooth germ organ cultures and a mouse dental papilla cell line with the ability to differentiate into odontoblasts, in combination with knockdown of the mitochondrial fission factor, dynamin related protein (DRP)1. In organ cultures of the mouse first molar, tooth germ developed to the early bell stage. The amount of dentin formed under DRP1 inhibition was significantly larger than that of the control. In experiments using a mouse dental papilla cell line, differentiation into odontoblasts was enhanced by inhibiting DRP1. This was associated with increased mitochondrial elongation and ATP production compared to the control. These results suggest that DRP1 inhibition accelerates dentin formation through mitochondrial elongation and activation. This raises the possibility that DRP1 might be a therapeutic target for developmental disorders of teeth.

DOI： 10.1016/j.bbrc.2017.12.026

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

Long-term methotrexate (MTX) treatment can cause MTX-related lymphoproliferative disorder (MTX-LPD). We experienced a case of MTX-LPD that was associated with severe osteonecrosis of the jaw mimicking medication-related osteonecrosis of the jaw. The patient was an 81-year-old woman with rheumatoid arthritis (RA) who was treated with MTX and bisphosphonate. After 7 years, she was referred to our department for the assessment of giant ulcer and exposure of the alveolar bone of the left maxilla. Histopathological and immunological analyses confirmed a diagnosis of MTX-LPD. At seven months after the cessation of MTX treatment, the ulcerative and necrotic lesions had markedly decreased in size. A 1-year follow-up examination showed no evidence of recurrence and good RA control.

DOI： 10.2169/internalmedicine.8946-17

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

Background/Aim: Adenoid cystic carcinoma (AdCC) is a rare cancer of the salivary gland with high risk of recurrence and metastasis. Wnt signalling is critical for determining tumor grade in AdCC, as it regulates invasion and migration. β-catenin dephosphorylation plays an important role in the Wnt pathway, but its underlying molecular mechanism remains unclear. Materials and Methods: Because the regulatory subunits of protein phosphatase 2A (PP2A) drive Wnt signalling via target molecules, including β-catenin, we used qRT-PCR and immunoblot analysis to investigate the expression of these subunits in an AdCC cell line (ACCS) and a more aggressive subline (ACCS-M). Results: PR55β was highly expressed in ACCS-M, suggesting its functional importance. In addition, PR55β expression was associated with tumor grade, with ACCS-M exhibiting higher PR55β levels. More importantly, knockdown of PR55β in ACCS-M cells significantly reduced invasiveness and metastatic ability. Furthermore, dephosphorylation and total levels of β-catenin were dependent on PR55β in ACCS-M. Finally, we confirmed a correlation between PR55β staining intensity and histopathological type in human AdCC tissues. Conclusion: Our study provides new insight into the interaction between PR55β and β-catenin and suggests that PR55β may be a target for the clinical treatment of AdCC.

DOI： 10.21873/cgp.20064

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

We previously reported that epithelial-to-mesenchymal transition (EMT) was mediated by ΔNp63β in oral squamous cell carcinoma (OSCC). In this study, DNA microarray analyses were performed using ΔNp63β-overexpressing OSCC cells to identify genes associated with ΔNp63β-mediated EMT. Thereby, we focused on kallikrein-related peptidase (KLK) 6, most up-regulated following ΔNp63β-overexpression, that activates protease-activated receptors (PARs). In RT-PCR analyses, ΔNp63 was positively associated with KLK6 and PAR2 and negatively with PAR1 in OSCC cells. By ΔNp63 knockdown, KLK6 and PAR2 expression was decreased and PAR1 was increased. Furthermore, KLK6 knockdown led to enhancing migration and invasion, and inhibiting proliferation, suggesting EMT-phenotypes. Although, in the KLK6 or PAR2 knockdown cells, phosphorylation of ERK was reduced, it was restored in the KLK6 knockdown OSCC cells treated with recombinant KLK6 proteins. Immunohistochemistry showed ΔNp63, KLK6, and PAR2 were more strongly expressed in the epithelial dysplasia and central region of OSCC than normal oral epithelium, whereas PAR1 expression was undetectable. Interestingly, at the invasive front of OSCC, ΔNp63, KLK6, and PAR2 were reduced, but PAR1 was elevated. In addition, the OSCC patients with decreasing KLK6 expression at the invasive front had more unfavourable prognosis. These results suggested differential roles of KLK6 in malignant transformation and EMT; high ΔNp63β expression up-regulates KLK6-PAR2 and down-regulates PAR1, inducing malignant transformation in oral epithelium with stimulating proliferation through ERK signal activation. Moreover, KLK6-PAR2 expression is down-regulated and PAR1 is up-regulated when ΔNp63β expression is decreased, leading to EMT with enhancing migration and invasion through ERK signal reduction at the invasive front.

DOI： 10.1016/j.oraloncology.2017.11.004

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

OBJECTIVES: We previously showed that ΔNp63β, a splicing variant of ΔNp63, mediated EMT and affected cell motility. DNA microarray was thus performed to elucidate the mechanism that ΔNp63β affects cell motility. As the results, Wnt5a was significantly down-regulated by ΔNp63β overexpression in tongue SCC cell line (SQUU-B) with EMT phenotype.
MATERIALS AND METHODS:
Seven OSCC cell lines were used. Expression of ΔNp63, Wnt5a, its receptor Ror2, and matrix metalloproteinases (MMPs) were analyzed by RT-PCR, real-time PCR, and western blotting, and gelatin zymography. Furthermore, we examined the effects of siRNA for Wnt5a or Ror2 and recombinant human Wnt5a (rhWnt5a) on motility of tongue SCC cells. Biopsy specimens from tongue SCC patients were used for immunohistochemical staining of Wnt5a and Ror2.
RESULTS:
Wnt5a and Ror2 were expressed only in SQUU-B cells without ΔNp63 expression, and negatively associated with ΔNp63 expression in other cells. ΔNp63β overexpression in SQUU-B cells decreased Wnt5a and Ror2 expression. By Wnt5a or Ror2 knockdown, cell motility was remarkably inhibited, but EMT markers expression was unaffected. MMP-2 expression and the activities inversely correlated with ΔNp63 expression, and were inhibited by Wnt5a or Ror2 knockdown. Cell motility and MMP-2 activities were recovered by adding rhWnt5a in the cells with Wnt5a knockdown, but not in those with Ror2 knockdown. Moreover, immunohistochemical analyses in tongue SCC specimens found that high expression of Wnt5a or Ror2 was associated with poorer prognosis.
CONCLUSION:
Wnt5a-Ror2 signaling enhanced tongue SCC cell aggressiveness and promoted production of MMP-2 following ΔNp63β-mediated EMT.

DOI： 10.1016/j.oraloncology.2017.03.019

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

Tumor-associated macrophages (TAMs) promote cancer cell proliferation, invasion, and metastasis by producing various mediators. Although preclinical studies demonstrated that TAMs preferentially express CD163 and CD204, the TAM subsets in oral squamous cell carcinoma (OSCC) remain unknown. In this study, we examined the expression and role of TAM subsets in OSCC. Forty-six patients with OSCC were analyzed for expression of TAMs in biopsy samples by immunohistochemistry. We examined TAM subsets and their production of immune suppressive molecules (IL-10 and PD-L1) in peripheral blood mononuclear cells from three OSCC patients by flow cytometry. CD163 was detected around the tumor or connective tissue, while CD204 was detected in/around the tumors. Flow cytometric analysis revealed that CD163+CD204+ TAMs strongly produced IL-10 and PD-L1 in comparison with CD163+CD204- and CD163-CD204+ TAMs. Furthermore, the number of activated CD3+ T cells after co-culture with CD163+CD204+ TAMs was significantly lower than that after co-culture with other TAM subsets. In clinical findings, the number of CD163+CD204+ TAMs was negatively correlated with that of CD25+ cells and 5-year progression-free survival. These results suggest that CD163+CD204+ TAMs possibly play a key role in the invasion and metastasis of OSCC by T-cell regulation via IL-10 and PD-L1 production.

DOI： 10.1038/s41598-017-01661-z

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

We report an extremely rare case of an impacted maxillary third molar inversely fused with a supernumerary tooth in a 51-year-old male. The panoramic and dental radiographs show a radiopaque and tooth-like mass of 20×15 mm located in the third maxillary region of the right maxilla. Computed tomography revealed that the tooth-like structure was a union of the impacted maxillary third molar with a inversed supernumerary tooth, creating a fused tooth with a common dental pulp. To our knowledge, only one case of inversely fusion of a maxillary third molar with a supernumerary tooth has been reported.

DOI： 10.5348/ijcri-201723-CR-10762

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

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

舌対称性脂肪腫症（SLT）は，成熟した脂肪組織が両側の舌筋内へ浸潤性増殖する疾患と定義される。今回われわれは，巨舌を呈したSLTの症例を経験したので，文献的考察を加えて報告する。
患者は，両側舌縁部に無痛性で弾性軟，多発性の腫瘤を認めた71歳の男性である。舌縁部の外向性腫瘤により，患者の舌幅は下顎の歯列弓幅よりも広く，いわゆる巨舌を呈していた。両側舌縁部の腫瘤は，MRIのT1および T2強調画像で高信号，T2脂肪抑制像で信号低下を示した。生検組織の病理組織学的診断は脂肪腫であった。病変が対称性はないものの，両側の舌縁部にあることから，SLTと診断した。慢性心房細動に対して抗凝固薬を内服しており，術後の出血および腫脹による気道閉塞が懸念されたため，左右2回に分けて全身麻酔下に腫瘍減量術を行った。切除物の病理組織検査では，成熟した脂肪組織が舌筋組織内へ浸潤性増殖している所見がみられ，病理組織学的診断はSLTであった。術後2年経過したが，増大所見は認めない。

DOI： http://doi.org/10.5843/jsot.28.293

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

Objective: For the definitive diagnosis of IgG4-related disease (IgG4-RD), biopsies of local lesions are recommended so as to exclude other diseases, including lymphoma and cancer. However, performing biopsies of underlying organs is technically difficult. In this study, we examined the diagnostic utility of labial salivary gland (LSG) biopsy as a less invasive procedure.
METHODS: Sixty-six patients with suspected IgG4-RD by clinical findings or high serum IgG4 underwent LSG biopsy. We examined the relationship between the number of IgG4-positive plasma cells in LSG and clinical findings.
RESULTS: The final diagnosis was 45 patients with IgG4-RD, 12 with Sjögren's syndrome, four with suspected Sjögren's syndrome, three with malignant lymphoma, one with systemic lupus erythematosus, and one with Warthin's tumor. The sensitivity, specificity, and accuracy of LSG biopsy were 55.6%, 100.0%, and 70.0%, respectively. Forty-five IgG4-RD patients were divided into two groups: 1) 25 with lesions of salivary glands (IgG4-RD S+) and 2) 20 without these lesions (IgG4-RD S-). Seventeen of 25 (68.0%) IgG4-RD S + and 8 of 20 (40.0%) IgG4-RD S - patients were positive for LSG biopsy. In the IgG4-RD S - patients, the mean number of affected organs and serum IgG4 in the positive cases for LSG biopsy were significantly higher than in the negative cases.
CONCLUSION: A solo LSG biopsy is insufficient for the diagnosis of IgG4-RD because of its low sensitivity. However, LSG biopsy combined with clinical findings, including serum IgG4 and number of affected organs, may contribute towards a diagnosis of IgG4-RD patients with affected underlying organs.

DOI： 10.3109/14397595.2016.1148225.

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

The administration of pre-operative chemotherapy with S-1 and concurrent radiotherapy at a total dose of 30 Gy was clinicopathologically evaluated as a treatment for locally advanced oral squamous cell carcinoma (OSCC) in the present study. The participants comprised 81 patients with OSCC, consisting of 29 patients with stage II disease, 12 patients with stage III disease and 40 patients with stage IV disease. All patients received a total radiation dose of 30 Gy in daily fractions of 2 Gy, 5 times a week, for 3 weeks, and the patients were concurrently administered S-1 at a dose of 80-120 mg, twice daily, over 4 consecutive weeks. Radical surgery was performed in all cases at 2-6 weeks subsequent to the end of pre-operative chemoradiotherapy. The most common adverse event was oropharyngeal mucositis, but this was transient in all patients. No severe hematological or non-hematological toxicities were observed. The clinical and histopathological response rates were 70.4 and 75.3%, respectively. Post-operatively, local failure developed in 6 patients (7.4%) and neck failure developed in 2 patients (2.5%). Distant metastases were found in 7 patients (8.6%). The overall survival rate, disease-specific survival rate and locoregional control rate at 5 years were 87.7, 89.9 and 90.6%, respectively. Locoregional recurrence occurred more frequently in patients that demonstrated a poor histopathological response compared with patients that demonstrated a good response (P<0.01). These results indicate that pre-operative S-1 chemotherapy with radiotherapy at a total dose of 30 Gy is feasible and effective for patients with locally advanced OSCC, and that little or no histopathological response may be a risk factor for locoregional recurrence in this treatment.

DOI： 10.3892/ol.2016.4411

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

Langerhans’-cell histiocytosis (LCH) is a relatively rare proliferative disorder of Langerhans’ cells with unknown etiology 1～3）. LCH can occur throughout the body, and cases have been reported in the skin, liver, spleen, lung, lymph nodes, and bone. We present a case of LCH in a 1-year-old boy who presented with fever and swelling of the right cheek. Radiographic examinations revealed expansion of the mandibular molar region with destruction of the cortex. Because such findings might mimic a malignant tumor, we made a clinical diagnosis of mandibular tumor. After confirming the pathological diagnosis, chemotherapy was performed according to the protocol of the Japan LCH study group. No recurrence was noted during a 3-year follow-up period. However, in infants, hypoplasia of the teeth can occur as a side effect of chemotherapy or a direct effect of the tumor itself. Long-term follow-up in cooperation with pediatricians and pedodontists is recommended for infants with LCH.

DOI： http://doi.org/10.5794/jjoms.62.238

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

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

Metastatic tumors to the jaws and oral cavity account for 1% to 2% of all oral cancers. We report the clinical characteristics of the tumors in 11 patients among a total of 697 cases of oral cancer treated in the Section of Oral and Maxillofacial Surgery, Kyushu University Hospital from 1985 through 2010. At the first visit, 9 of the 11 patients had a history of primary tumor, while the primary cancer sites were uncertain in the other 2 patients. Six of the 9 patients had recurrence or metastasis of their primary tumors, and in the other 3 patients tumor spread was controlled. The tumor was detected in mandibular and maxillary bones in 9 patients and 2 patients, respectively. Ten of the 11 patients had metastases in the molar region. Five of the 8 patients with mandibular molar metastasis had symptoms of hypoesthesia in the lower lips and chin. Seven of the 11 cases were adenocarcinoma. Regardless of treatment such as surgical resection, radiotherapy, or chemotherapy, alone or combined, all patients had poor outcomes, and the average survival time from the first visit was 3.2 months.

DOI： http://doi.org/10.5794/jjoms.62.199

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

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DOI： doi: 10.1097/MD.0000000000002853.

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DOI： 10.1002/hed.24036

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DOI： 10.1186/s12882-015-0164-8

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DOI： 10.1186/s12957-015-0697-0

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DOI： doi: 10.1186/s12957-015-0644-0.

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DOI： doi: 10.3892/or.2015.3838.

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DOI： doi: 10.1097/MD.0000000000000704.

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DOI： 10.1111/odi.12259.

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DOI： doi: 10.1186/s12957-015-0459-z.

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DOI： doi: 10.1016/j.ijom.2014.06.014.

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DOI： 10.1186/1477-7819-11-234

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DOI： doi.org/10.1016/j.ajoms.2013.01.004

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The role of macrophages in the absorption process of suture materials: A histological and immunohistochemical study.

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DOI： DOI: 10.1111/j.1600-0765.1997.tb00575.x

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DOI： 10.1016/s0003-9969(96)00067-2.

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DOI： DOI: 10.1016/0003-9969(95)00060-3

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Language：Japanese   Book type：Scholarly book

Event date： 2024.7 - 2024.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：新潟市   Country：Japan  

Event date： 2024.7 - 2024.8

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Venue：新潟市   Country：Japan  

Event date： 2024.2

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Venue：福岡（WEB併用ハイブリッド形式）   Country：Japan  

Event date： 2023.9

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Venue：東京都千代田区   Country：Japan  

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Venue：東京都千代田区   Country：Japan  

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Venue：Taipei City   Country：Taiwan, Province of China  

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Venue：Taipei City   Country：Taiwan, Province of China  

Event date： 2023.4

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Venue：下関   Country：Japan  

Event date： 2023.1 - 2023.2

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Venue：WEB開催   Country：Japan  

Event date： 2022.10

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Venue：福岡（WEB併用ハイブリッド形式）   Country：Japan  

Event date： 2022.10

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Venue：福岡（WEB併用ハイブリッド形式）   Country：Japan  

Event date： 2022.9

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Venue：北海道札幌市   Country：Japan  

Event date： 2022.9

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Venue：徳島県徳島市   Country：Japan  

Event date： 2022.9

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Venue：徳島県徳島市   Country：Japan  

Event date： 2022.9

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Venue：徳島県徳島市   Country：Japan  

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Venue：徳島県徳島市   Country：Japan  

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Venue：神戸   Country：Japan  

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Venue：神戸   Country：Japan  

Event date： 2021.11

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Venue：福岡（WEB併用ハイブリッド形式）   Country：Japan  

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Venue：神奈川（WEB開催）   Country：Japan  

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Venue：神奈川（WEB開催）   Country：Japan  

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Venue：神奈川（WEB開催）   Country：Japan  

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Venue：神奈川（WEB開催）   Country：Japan  

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Venue：神奈川（WEB開催）   Country：Japan  

Event date： 2021.6

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Venue：東京   Country：Japan  

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Venue：東京   Country：Japan  

Event date： 2020.9 - 2020.10

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Venue：鹿児島   Country：Japan  

Event date： 2020.9 - 2020.10

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Venue：鹿児島   Country：Japan  

Event date： 2020.9 - 2020.10

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Venue：鹿児島   Country：Japan  

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Venue：鹿児島   Country：Japan  

Event date： 2020.7

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Venue：福岡   Country：Japan  

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Venue：福岡   Country：Japan  

Event date： 2020.7

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Venue：福岡   Country：Japan  

Event date： 2020.7

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Venue：福岡   Country：Japan  

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Venue：福岡   Country：Japan  

Event date： 2019.8

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Country：Japan  

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Venue：福岡   Country：Japan  

Event date： 2019.7

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Venue：福岡   Country：Japan  

Event date： 2019.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2019.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2018.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2018.2

Language：English   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.1

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：新潟市   Country：Japan  

Event date： 2017.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2017.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：松本   Country：Japan  

Event date： 2017.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：川越   Country：Japan  

Event date： 2017.3

Language：English   Presentation type：Oral presentation (general)  

Venue：San Francisco, Calif   Country：United States  

Event date： 2016.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2016.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2016.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2016.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2016.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2016.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2016.8

Language：English   Presentation type：Oral presentation (general)  

Venue：Hiroshima   Country：Japan  

Event date： 2016.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜   Country：Japan  

Event date： 2016.6

Language：English   Presentation type：Oral presentation (general)  

Venue：Fukuoka   Country：Japan  

Event date： 2016.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2016.1

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜   Country：Japan  

Event date： 2015.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2015.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2015.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2015.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：名古屋   Country：Japan  

Event date： 2015.9

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡   Country：Japan  

Event date： 2015.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2015.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2014.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2014.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2014.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：広島   Country：Japan  

Event date： 2014.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：広島   Country：Japan  

Event date： 2014.3

Language：English  

Venue：San Diego, CA（San Diego Convention Center）   Country：United States  

Event date： 2014.2 - 2014.3

Language：English   Presentation type：Oral presentation (general)  

Venue：Fukuoka   Country：Japan  

Event date： 2014.1

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2013.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：岡山   Country：Japan  

Event date： 2013.9

Language：Japanese  

Venue：岡山   Country：Japan  

Event date： 2013.9

Language：Japanese  

Venue：岡山   Country：Japan  

Event date： 2013.8

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2013.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2012.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2012.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2012.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2011.9 - 2011.10

Presentation type：Oral presentation (general)  

Venue：岐阜   Country：Japan  

Event date： 2011.8

Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2011.4

Presentation type：Oral presentation (general)  

Venue：横浜   Country：Japan  

Event date： 2011.3

Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2011.3

Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2010.9

Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2010.9

Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2010.7

Venue：Barcelona (Spain)   Country：Spain  

Event date： 2010.4 - 2011.4

Presentation type：Oral presentation (general)  

Venue：横浜   Country：Japan  

Event date： 2010.4

Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2010.4

Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2010.2

Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2009.9

Presentation type：Oral presentation (general)  

Venue：新潟   Country：Japan  

Event date： 2009.8

Venue：長崎   Country：Japan  

Event date： 2009.7

Venue：札幌 (北海道)   Country：Japan  

Pathological study of biopsied minor salivary glands in IgG4-related sclerosing disease. -Report of a case-

Event date： 2009.5

Venue：京都   Country：Japan  

Event date： 2009.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：浜松   Country：Japan  

Event date： 2009.4

Presentation type：Oral presentation (general)  

Venue：Maiami   Country：United States  

Event date： 2008.7

Venue：Toronto (Canada)   Country：Canada  

Event date： 2008.5

Venue：石川県金沢   Country：Japan  

Event date： 2008.5

Venue：石川県金沢   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：Seoul   Country：Korea, Republic of  

Presentation type：Oral presentation (general)  

Venue：東京　新宿   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：Australia Brisbane   Country：Australia  

Transcriptional Regulation of S100A7 in Oral Squamous Cell Carcinoma

Presentation type：Oral presentation (invited, special)  

Venue：Kyushu University   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：札幌 (北海道)   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：札幌 (北海道)   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2025.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台市   Country：Japan  

Event date： 2025.2

Language：English   Presentation type：Oral presentation (general)  

Venue：福岡（WEB併用ハイブリッド形式）   Country：Japan  

Event date： 2025.2

Language：English   Presentation type：Oral presentation (general)  

Venue：福岡（WEB併用ハイブリッド形式）   Country：Japan  

Event date： 2024.11

Language：English   Presentation type：Poster presentation  

Venue：長崎市   Country：Japan  

Event date： 2024.11

Language：English   Presentation type：Poster presentation  

Venue：長崎市   Country：Japan  

Event date： 2024.11

Language：English   Presentation type：Poster presentation  

Venue：長崎市   Country：Japan  

Event date： 2024.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：長崎市   Country：Japan  

Event date： 2024.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：長崎市   Country：Japan  

Event date： 2024.7 - 2024.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：新潟市   Country：Japan  

Event date： 2024.2

Language：English   Presentation type：Oral presentation (general)  

Venue：福岡（WEB併用ハイブリッド形式）   Country：Japan  

Event date： 2024.2

Language：English   Presentation type：Oral presentation (general)  

Venue：福岡（WEB併用ハイブリッド形式）   Country：Japan  

Event date： 2023.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京都千代田区   Country：Japan  

Event date： 2022.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：徳島県徳島市   Country：Japan  

Event date： 2021.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神奈川（WEB開催）   Country：Japan  

Event date： 2021.9 - 2021.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台（WEB開催）   Country：Japan  

Event date： 2018.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2018.7

Language：English   Presentation type：Oral presentation (general)  

Venue：London   Country：United Kingdom  

Event date： 2018.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：青森市   Country：Japan  

Event date： 2018.5

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2017.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神戸   Country：Japan  

Event date： 2017.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：盛岡   Country：Japan  

Event date： 2017.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：松本   Country：Japan  

Event date： 2017.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：松本   Country：Japan  

Event date： 2017.5

Language：English   Presentation type：Oral presentation (general)  

Venue：Okinawa   Country：Japan  

Event date： 2017.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2017.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：松山市   Country：Japan  

Event date： 2016.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：金沢   Country：Japan  

Event date： 2016.1

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜   Country：Japan  

Event date： 2015.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2014.9

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：宇都宮市   Country：Japan  

Event date： 2012.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡市   Country：Japan  

Event date： 2009.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2009.10

Presentation type：Oral presentation (general)  

Venue：長崎   Country：Japan  

Event date： 2008.9

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2007.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神戸市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：Snowbird, Utah   Country：United States  

Action of PRIP, an Ins(1,4,5)P3 binding protein, in insulin secretion.

Presentation type：Oral presentation (general)  

Venue：Vancouver   Country：Canada  

Cell proliferation and cell death during odontogenesis in the mouse

Presentation type：Oral presentation (general)  

Venue：Chiba   Country：Japan  

Cell proliferation and cell death during odontogenesis in the mouse

Presentation type：Oral presentation (general)  

Venue：北海道　札幌市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：北海道　札幌市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：広島　広島市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：広島　広島市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：神奈川　横浜市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：宮城　仙台市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：宮城　仙台市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：大阪　大阪市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：大阪　大阪市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：大阪　大阪市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：福岡　福岡市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：福岡　福岡市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：東京　新宿   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：Australia Brisbane   Country：Australia  

Presentation type：Oral presentation (general)  

Venue：Hokkaido Sapporo   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：Hokkaido Sapporo   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：神奈川　横浜市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：神奈川　横浜市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：長崎   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：九州大学   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：九州大学   Country：Japan  

Language：Japanese