GTPases of immunity-associated protein 2 (GIMAP2) is a GTPase family member associated with T cell survival. However, its mechanisms of action in oral squamous cell carcinoma (OSCC) remain largely unknown. Therefore, the present study aimed to elucidate the possible role of GIMAP2 in OSCC development by investigating its expression levels and molecular mechanisms in OSCC. Reverse transcription quantitative PCR, immunoblotting and immunohistochemistry indicated that GIMAP2 expression was significantly upregulated (P<0.05) in OSCC-derived cell lines and primary OSCC specimens compared with that in their normal counterparts. GIMAP2-knockdown OSCC cells exhibited decreased cell growth, which was associated with cyclin-dependent kinase (CDK)4, CDK6 and phosphorylated Rb downregulation and p53 and p21 upregulation. In addition to cell cycle arrest, GIMAP2 affected anti-apoptotic functions in GIMAP2-knockdown cells by upregulating Bcl-2 and downregulating Bax and Bak. These findings indicated that GIMAP2 may significantly influence OSCC development and apoptosis inhibition and thus is a potential biomarker of OSCC.

The epithelial-stromal interaction 1 gene (EPSTI1) is known to play multiple roles in the malignant progression of breast cancer and also in some aspects of the immune responses to the tumor. However, the relevance of the gene in the onset/progression of oral squamous cell carcinoma (OSCC) and lung squamous cell carcinoma (LSCC) is not yet known. The present study was aimed at revealing the roles of EPSTI1 in conferring malignant characteristics to OSCC and LSCC, and the underlying mechanisms. Quantitative real-time polymerase chain reaction (PCR) and western blot analyses demonstrated significant upregulation of EPSTI1 in all four OSCC cell lines (HSC2, HSC3, HSC3-M3 and HSC4), and significant downregulation of EPST11 in all three LSCC cell lines (LK-2, EBC-1 and H226) used in the present study, as compared to the expression levels in the corresponding control cell lines. Both knockdown of EPST11 in OSCC and overexpression of the gene in LSCC suppressed cell proliferation, and induced cell-cycle arrest in the G1 phase, with upregulation of p21 and downregulation of CDK2 and cyclin D1. Furthermore, these alterations of EPST11 gene expression in the OSCC and LSCC cell lines suppressed the cell migration ability and reversed the EMT phenotype of the tumor cells. Collectively, while EPSTI1 appears to have oncogenic roles in OSCC, it appears to exert tumor-suppressive roles in LSCC. PCR array analyses revealed some genes whose expression levels were altered along with the modified EPSTI1 expression in both the OSCC and LSCC cell lines. These findings suggest that EPSTI1 may be a therapeutic target for both OSCC and LSCC.

We report a rare case of high-grade MEC developed in the palate. Myoepithelial carcinoma (MEC) is an uncommon malignant tumor, which is also known as malignant myoepithelioma. It generally occurs in major salivary glands. A 79-year-old female presented complaining a painless swelling on the left side palate which grew rapidly in 3 weeks. A soft and pendulous mass with approximately 42 x 30 mm in diameter with ulceration was observed in the palate.Radiological imaging analyses (e-CT, e-MRI and FDG-PETCT) showed an irregular mass of the left palate with bone invasion into the palatal bone and suggested potential metastases in submandibular lymph nodes. A biopsy was performed and diagnosed as MEC of the palate. Surgical tumor resection and radical neck dissection were performed under general anesthesia. Pathologic evaluation showed that the lesion was mainly consisted of atypical cells with abundant eosinophilic cytoplasm including a mixture of spindled or epithelioid cells. Immunohistochemically, the lesion included specifically and diffusely positive for S-100, CD10, calponin, GFAP, and p63. Cell proliferation activity assessed by the Ki67 labeling index was 55 %. From these findings, the lesion was finally diagnosed as MEC of the palate. The patient has been followed for 6years without a recurrence. (C) 2020 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.

Pneumatosis intestinalis (PI) is characterized by the presence of gas in the bowel wall and is associated with a wide range of clinical conditions, such as pulmonary, gastrointestinal, infectious, and autoimmune diseases, and an immunosuppressive state such as that resulting from cancer chemotherapy. It is not a distinct disease but rather a physical or radiographic finding and can be categorized into types: primary and secondary. Primary PI is idiopathic, while secondary PI occurs as a result of an underlying disease. Several theories were suggested for the etiology of this condition. Intestinal gas, mucosal integrity, intraluminal pressure, and bacterial flora play interactive roles in the development of PI; yet, the mechanisms involved remain unclear. PI can be seen in benign or life-threatening situations. Choosing an appropriate treatment owing to the various interpretations of the clinical significance of PI is difficult. An urgent surgical procedure is necessary for patients with signs of bowel perforation, peritonitis, or necrotizing enterocolitis. Potentially, these life-threatening conditions should be ruled out, based on the physical and radiographic findings of the patient. Herein, we report a rare case of PI in a 72-year-old woman who was administrated cisplatin and radiation as adjuvant chemoradiotherapy for oral cancer. During the therapy, free air was detected via chest radiography. Based on the physical and computed tomographic findings, the development of free air was considered as a non-life-threatening PI phenomenon caused by the cancer chemotherapy.

Supernumerary teeth (ST) are common clinical dental anomalies characterized by the presence of excessive teeth. It can cause diverse complications in the developing jaw and dentition, which could prevent the acquisition of normal oral functions. The presence of multiple ST is rare and commonly associated with genetic syndromes or developmental anomalies. In such cases, the related clinical problems should be considered along with the treatment of multiple ST. Then, it is important to pay attention to the craniofacial, skeletal, and other physical findings. Herein, we report a rare case of eight ST in a patient without any associated syndromes. Early diagnosis and successive radiographic evaluations are critical for preventing the complications caused by ST.

Hemorrhagic colitis due to antibiotics has increased with the widespread use of antibiotics for various diseases. The clinical features included sudden onset a few days after the administration of antibiotics, abdominal pain and bloody diarrhea.

S-1 is an anticancer agent that is comprised of tegafur, gimeracil, and oteracil potassium, and is widely used in various carcinomas including oral squamous cell carcinoma (OSCC). Although an established prediction tool is not available, we aimed to develop prediction models for the sensitivity of primary OSCC cases to the preoperative administration of S-1. We performed DNA microarray analysis of 95 cases with OSCC. Using global gene expression data and the clinical data, we developed two different prediction models, namely, model 1 that comprised the complete response (CR) + the partial response (PR) versus stable disease (SD) + progressive disease (PD), and model 2 that comprised responders versus non-responders. Twelve and 18 genes were designated as feature genes (FGs) in models 1 and 2, respectively, and, of these, six genes were common to both models. The sensitivity was 96.3%, the specificity was 91.2%, and the accuracy was 92.6% for model 1, and the sensitivity was 95.6%, the specificity was 85.2%, and the accuracy was 92.6% for model 2. These models were validated using receiver operating characteristic analysis, and the areas under the curves were 0.967 and 0.949 in models 1 and 2, respectively. The data led to the development of models that can reliably predict the sensitivity of patients with OSCC to the preoperative administration of S-1. The mechanism that regulates S-1 sensitivity remains unclear; however, the prediction models developed provide hope that further functional investigations into the FGs will lead to a greater understanding of drug resistance.

The main symptom of Kimura disease (KD), a rare, chronic inflammatory disorder of unknown etiology, is painless granulation preferentially developing in the head and neck region’s soft tissues, especially in the parotid and submandibular glands and neck lymph nodes. KD is characterized clinically by peripheral blood eosinophilia and elevated serum immunoglobulin E (IgE) levels and histopathologically by high capillary vascularization and lymphoid follicle formation with eosinophil infiltration in the connective tissues. Angiolymphoid hyperplasia with eosinophilia (ALHE), a rare benign tumor of unknown etiology, also occurs in the head and neck frequently as single/multiple angiomatous papules/nodules varying from light brown to pink. Histopathologically, accelerated endothelial cell proliferation and high lymphocyte and eosinophil infiltration are observed. Due to KD’s and ALHE’s similar clinical and pathological symptoms, differential diagnosis is challenging. Their manifestations include a painless head/neck subcutaneous swelling. Here, we have described a case involving a 44-year-old man who presented with an upper lip mass that increased in size for 1 year. Laboratory studies revealed leukocytosis and eosinophilia. Computed tomography and magnetic resonance imaging examinations revealed a submucosal lip mass. Suspect minor salivary gland malignancies and lymphomas were surgically excised. Histopathologically, we observed marked lymphoid follicle proliferation with inflammatory cell, including eosinophil infiltration, capillary proliferation, and a developed vessel not normally present in the lip. Because differentiating between KD and ALHE is difficult, clinical differentiation was our focus. The Asian male patient with lymphadenopathy, eosinophilia, and high IgE levels was finally diagnosed with KD that has not recurred in 1 year.

Introduction: Epithelial-stromal interaction 1 (EPSTI1) is a gene mapped to human chromosome 13q13.3. Recent studies have shown that EPSTI1 regulates many malignant features of cancers. However, the relevance of EPSTI1 to oral squamous cell carcinomas (OSCC) and lung squamous cell carcinoma (LSCC) are not known. The present study aimed to uncover the roles and the underlying mechanisms of EPSTI1 in OSCC and LSCC. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assay were used to evaluate the expression of EPSTI1 in four OSCC cell lines, HSC2, HSC3, HSC3M3 and HSC4, and three LSCC cell lines, LK-2, EBC-1 and H226. In vitro experiments were carried out in parental, their shRNA EPSTI1 knockdown and EPSTI1 overexpressing cells. Cell cycle was evaluated by flow cytometry, and epithelial-to-mesenchymal transition (EMT)-related proteins were evaluated by western blot assay. Changes in expression of EPSTI1-related genes in transfected cells were confirmed by using RT2 Profiler PCR Array Human Cancer Pathway Finder. Results: EPSTI1 was significantly up-regulated in OSCC cell lines, and significantly down-regulated in LSCC cell lines compared to their normal counterparts. Knockdown of EPSTI1 in OSCC cells and overexpression of the gene in LSCC cells suppressed cell proliferation accompanied by cell-cycle arrest in the G1 phase with up-regulation of p21 and down-regulation of CDK2 and cyclin D1. These indicate that EPSTI1 was significantly involved in tumor growth in OSCC and LSCC, but in an opposite direction. Furthermore, EPSTI1 was related to enhanced cell migration and EMT phenotype in OSCC, and it was related to suppressed cell migration and reversed EMT in LSCC. In PCR-array analyses in two OSCC and two LSCC cells, some common genes were regulated similarly in each OSCC and LSCC. Conclusion: EPSTI1 was up-regulated and its down-regulation suppressed the malignant phenotypes, indicating oncogenic roles of the gene in OSCC. In contrast the gene was down-regulated and its up-regulation suppressed the malignant phenotypes, indicating tumor suppressive roles of the gene in LSCC. These findings suggest that EPSTI1 might be a therapeutic target for OSCC and LSCC. Citation Format: Meng Meng Fan, Makoto Arai, Akinobu Tawada, Tetsuhiro Chiba, Reo Fukushima, Katsuhiro Uzawa, Masashi Shiiba, Naoya Kato, Hideki Tanzawa, Yuichi Takiguchi. Contrasting functions of EPSTI1 in human oral and lung squamous cell cancer cell lines - its tumor promoting roles in oral and tumor suppressing roles in lung squamous cell carcinomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2580.

Cyberknife (CK) is one of the treatment options for oral squamous cell carcinoma. However, there are few reports regarding treatment with CK in Japan, and standard criteria defining indications have not been established. We often perform radiation therapy with CK in patients who cannot undergo standard therapy because of extremely advanced disease, high-risk general conditions, refusal of surgery, or other reasons. We retrospectively assessed 32 patients treated from 2006 to 2017 and evaluated the clinical significance. Within 4 months after CK treatment, the response rate was 72%. The overall survival rates at 2 years and 5 years were 42% and 15%, respectively, and the median survival was 23 months. Clinical factors for CK treatment outcomes were explored. The results showed that primary tumor size (T classification), stage, irradiation timing, and planning target volume (PTV) were statistically significant factors. Tumors with a small diameter at the time of primary onset could be controlled similar to surgery in terms of the 3-year survival rate. This study suggested that CK treatment might be an effective treatment for tumor suppression in patients in whom no other treatment was indicated.

Langerhans cell histiocytosis (LCH? is a rare disease caused by excessive proliferation of Langerhans cells in various regions of the body. Previous studies have reported that 10% of LCH occurs in the oral and maxillofacial regions. In the oral and maxillofacial regions, swelling and pain are the typical symptoms, and jaw fracture and tooth loss are often seen in advanced cases. In this study, we present the results of a literature review of LCH that developed in the oral and maxillofacial regions. The history, pathological conditions, diagnosis, treatment, and progress of LCH are discussed.

Semaphorin family members (Semaphorins; SEMAs) consist of a large family that includes both secreted and membrane-associated proteins that are originally found to provide axon guidance in selected areas for neural development. The SEMAs have diverse biologic activities such as neuronal cellular migration, axon guidance, vasculogenesis, branching morphogenesis, and cardiac organogenesis. Recent studies have reported that SEMAs also play crucial roles in various carcinomas. However, the association and their role in oral squamous cell carcinoma (OSCC) are still poorly understood. In this study, we evaluated SEMAs mRNA expression in OSCC-derived cell lines using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis and revealed the altered gene expression profile of the SEMAs in OSCC cell lines compared with human normal oral keratinocytes. We found that tendency for up-regulation of SEMA3E, 4C, 5A, 6B, and 7A in OSCC-derived cell lines. Especially, SEMA3E and SEMA7A mRNA were significantly up-regulated in all OSCC-derived cell lines. On the other hands, SEMA3A, 3C, 3F, and 6A mRNA were significantly down-regulated in all OSCC-derived cell lines. The expression and role of SEMAs in OSCC depend on the forms and may provide novel insights and therapeutic target for OSCCs.

Drug resistance to anti-cancer agents is a major concern regarding the successful treatment of malignant tumors. Recent studies have suggested that acquired resistance to anti-epidermal growth factor receptor (EGFR) therapies such as cetuximab are in part caused by genetic alterations in patients with oral squamous cell carcinoma (OSCC). However, the molecular mechanisms employed by other complementary pathways that govern resistance remain unclear. In the current study, we performed gene expression profiling combined with extensive molecular validation to explore alternative mechanisms driving cetuximab-resistance in OSCC cells. Among the genes identified, we discovered that a urokinase-type plasminogen activator receptor (uPAR)/integrin β1/Src/FAK signal circuit converges to regulate ERK1/2 phosphorylation and this pathway drives cetuximab-resistance in the absence of EGFR overexpression or acquired EGFR activating mutations. Notably, the polyphenolic phytoalexin resveratrol, inhibited uPAR expression and consequently the signaling molecules ERK1/2 downstream of EGFR thus revealing additive effects on promoting OSCC cetuximab-sensitivity in vitro and in vivo. The current findings indicate that uPAR expression plays a critical role in acquired cetuximab resistance of OSCC and that combination therapy with resveratrol may provide an attractive means for treating these patients.

Laugier-Hunziker-Baran (LHB) syndrome is an acquired, macular hyperpigmentation of the lips, and oral mucosa, often associated with pigmentation of the nails, palms, and fingertips. LHB syndrome is considered to be a benign disease with no systemic manifestation or malignant potential. Normally, no treatment is required for this condition, unless for esthetic reason, mainly due to pigmentation on the lip mucosa. Here we present a case of LHB syndrome, 32-year-old male, whose pigmentations on his tongue, buccal mucosa, palate, and ventral surface of fingertip, diagnosed by clinical and dermoscopic findings.

Unc-93 homolog B1 (UNC93B1), a transmembrane protein, is correlated with immune diseases, such as influenza, herpes simplex encephalitis, and the pathogenesis of systemic lupus erythematosus; however, the role of UNC93B1 in cancers including human oral squamous cell carcinomas (OSCCs) remains unknown. In the current study, we investigated the UNC93B1expression level in OSCCs using quantitative reverse transcription-polymerase chain reaction, immunoblot analysis, and immunohistochemistry. Our data showed that UNC93B1 mRNA and protein expressions increased markedly (p < 0.05) in OSCCs compared with normal cells and tissues and that high expression of UNC93B1 in OSCCs was related closely to tumoral size. UNC93B1 knockdown (shUNC93B1) OSCC cells showed decreased cellular proliferation by cell-cycle arrest in the G1 phase with up-regulation of p21Cip1 and down-regulation of CDK4, CDK6, cyclin D1, and cyclin E. We also found that granulocyte macrophage colony-stimulating factor (GM-CSF) was down-regulated significantly (p < 0.05) in shUNC93B1 OSCC cells. Moreover, inactivation of GM-CSF using neutralization antibody led to cell-cycle arrest at the G1 phase similar to the phenotype of the shUNC93B1 cells. The current findings indicated that UNC93B1 might play a crucial role in OSCC by controlling the secretion level of GM-CSF involved in tumoral growth and could be a potential therapeutic target for OSCCs.

Collagens represent a large family of structurally related proteins containing a unique triple-helical structure. Among them, the fibril-forming collagens are the most abundant in vertebrates providing tissues with form and stability. One of the characteristics of the fibrillar collagens is its sequential posttranslational modifications of specific lysine residues that have major effects on molecular assembly and stability of the fibrils in the extracellular space. Hydroxylation of lysine residues is the first modification catalyzed by lysyl hydroxylases, and is critical for the following glycosylation and in determining the fate of covalent cross-linking. This chapter presents an overview of lysine hydroxylation and cross-linking of collagen, and the analytical methods we have developed.

Ameloblastic carcinoma (AC) is an odontogenic malignant tumor which combines the histological features of ameloblastoma and cytologic atypia. The key point of the diagnosis and clinical characteristics of AC have not been well defined, as it is a rare type of tumor. Hence, in this study, we present’ for better clarity the diagnostic flowchart for AC, ameloblastoma, and metastasizing ameloblastoma.

Synaptotagmin12 (SYT12) has been well characterized as the regulator of transmitter release in the nervous system, however the relevance and molecular mechanisms of SYT12 in oral squamous cell carcinoma (OSCC) are not understood. In the current study, we investigated the expression of SYT12 and its molecular biological functions in OSCC by quantitative reverse transcriptase polymerase chain reaction, immunoblot analysis, and immunohistochemistry. SYT12 were up-regulated significantly in OSCC-derived cell lines and primary OSCC tissue compared with the normal counterparts (P<0.05) and the SYT12 expression levels were correlated significantly with clinical indicators, such as the primary tumoral size, lymph node metastasis, and TNM stage (P<0.05). SYT12 knockdown OSCC cells showed depressed cellular proliferation, migration, and invasion with cell cycle arrest at G1 phase. Surprisingly, we found increased calcium/calmodulin-dependent protein kinase 2 (CAMK2) inhibitor 1 (CAMK2N1) and decreased CAMK2-phosphorylation in the knockdown cells. Furthermore, treatment with L-3, 4-dihydroxyphenylalanine (L-dopa), a drug approved for Parkinson's disease, led to down-regulation of SYT12 and similar phenotypes to SYT12 knockdown cells. Taken together, we concluded that SYT12 plays a significant role in OSCC progression via CAMK2N1 and CAMK2, and that L-dopa would be a new drug for OSCC treatment through the SYT12 expression.