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Purpose Integrin αvβ3 is an essential molecule for tumor angiogenesis. This study aimed to investigate the anti-tumor effect of MK-0429, an integrin αvβ3 antagonist, on oral squamous cell carcinoma (OSCC) through its inhibitory effect on angiogenesis. Methods In this study, we investigated the effect of MK-0429 on cellular function and angiogenesis in vitro with the use of an immortalized human umbilical vein endothelial cell, HUEhT-1, which is immortalized by the electroporatic transfection of hTERT. The effect of MK-0429 on the integrin αvβ3 signaling pathway was examined by FAK, MEK1/2 and ERK 1/2 phosphorylation. The anti-angiogenic effect of MK-0429 was evaluated by in vitro tube formation assay. The anti-tumor effect on OSCC was assessed by administrating MK-0429 to mouse oral cancer xenografts. Results MK-0429 inhibited cell proliferation, migration, and adhesion of HUEhT-1 in a dose-dependent manner. FAK, MEK and ERK phosphorylation were significantly blocked by MK-0429 treatment. Tube formation was suppressed by MK-0429 in dose-dependent manner. Tumor progression was significantly suppressed by MK-0429 administration in mouse oral cancer xenografts. Histological study revealed that MK-0429 decreased tumor vascularization. Conclusion These results indicated integrin αvβ3 as a therapeutic target for OSCC and suggested that MK-0429 might be clinically applicable as an anti-tumor agent with potent anti-angiogenic activity.

Objective Canine impaction is a difficult condition to treat, and it usually necessitates a combination of surgical exposure and orthodontic traction or surgical extraction. An accurate assessment of the maxillary canine's position can help determine the severity of the impaction, the difficulty of therapy, and the treatment's prognosis. Materials and Methods A total of 55 impacted canines were studied and selected retrospectively. Difficulty indexes were used to measure the severity of impaction with pretreatment panoramic radiographs. Statistical Analysis Pearson correlation was used to test the validity of the difficulty index modification score. Regression statistical analysis was used to evaluate any correlation between total scoring from each index with surgical treatment. Results The validity test on the variable modification index score showed a valid value (p = 0.000). According to both treatment difficulty and modification index, odontectomy group showed higher mean of total scoring than surgical exposure group. Treatment difficulty and modification index showed a significant correlation with surgical treatment (p = 0.003 and p = 0.001). Conclusions The higher the severity of canine impaction, the greater is the possibility of odontectomy than surgical exposure. Both indexes can consider to be used in determining surgical treatment planning.

This report describes the treatment of severe skeletal Class II malocclusion in a young woman with a gummy smile and pronounced lower anterior facial height. Overjet and overbite were +12.0 mm and -1.0 mm, respectively. Cephalometric analysis revealed inferior positioning of the maxilla and severe mandibular retrusion with clockwise rotation. Both the upper and lower anterior teeth showed labial inclination. Based on a diagnosis of a skeletal Class II high angle with mandibular retrusion and a gummy smile, double-jaw orthognathic surgeries for upper and lower premolar extraction were chosen to gain ideal occlusion and an improvement in the esthetic facial profile. Le Fort I osteotomy was performed to move the anterior and posterior teeth upward by 4.0 mm and achieve mandibular counterclockwise rotation. Short lingual sagittal split ramus osteotomy was performed to move the mandible forward by 3.0 mm. As a result, normal overjet and overbite were achieved together with a straight profile and a good smile. After surgery, electromyographic evaluation of anterior temporal muscle activity showed an improvement in the percentage overlapping coefficient value (a symmetric index of bilateral muscle activity) from 28.1% to 63.2% compared to at pre-treatment. The pattern of jaw movement also showed an improvement. These results suggest that orthognathic surgery in skeletal Class II cases can improve not only malocclusion and the skeletal relationship of the jaws, but also masticatory function and jaw movement.

BACKGROUND Melatonin is a hormone that is primarily produced in the pineal gland and is involved in wide range of biological functions. However, the impact of melatonin on chemotherapy-induced cell death remains to be elucidated in oral squamous cell carcinoma (OSCC) cells. The objective of this study was to clarify the role of melatonin in cisplatin-induced cytotoxicity in CD44high OSCC cells. METHODS CD44high OSCC cells were cultured on fibronectin-coated hydrogel. A lactate dehydrogenase cytotoxicity assay was performed to evaluate cisplatin-induced cell death. The effect of melatonin on cisplatin-induced cell death and Derlin-1 (DERL1) endoplasmic reticulum membrane protein expression was investigated. RESULTS CD44high OSCC cells exhibited mesenchymal-like features when cultured on fibronectin-coated hydrogel. Mesenchymal-like CD44high OSCC cells demonstrated strong resistance to cisplatin-induced cell death compared with epithelial-like CD44high OSCC cells. DERL1 mRNA and DERL1 protein expression levels were significantly higher in mesenchymal-like CD44high cells compared with epithelial-like CD44high cells. Cisplatin-induced cell death was significantly enhanced after DERL1 siRNA knockdown, suggesting that DERL1 is involved in resistance to cisplatin-induced cell death. Melatonin significantly inhibited DERL1 expression and enhanced cisplatin-induced cell death in mesenchymal-like CD44high cells. miR-181c-5p expression was significantly upregulated in the presence of melatonin. Furthermore, melatonin-inhibited DERL1 expression was significantly recovered by miR-181c-5p inhibitor. In addition, melatoninenhanced cisplatin-induced cell death was attenuated by miR-181c-5p inhibitor. These results suggest that melatonin-induced miR-181c-5p enhances cisplatin-induced cell death through inhibition of DERL1 in mesenchymal-like CD44high cells. CONCLUSIONS Melatonin plays a vital role in promoting cisplatin-induced cytotoxicity in mesenchymal-like CD44high OSCC cells.

The purpose of this study was to evaluate the surface modification of calcium ions on roughened titanium as a surface treatment of dental implants for cell attachment, growth, and initial bacterial adhesion. When a surface-roughened, pure titanium disk was immersed in a calcium chloride solution (100 mM) containing 20 ppm ozone for 24 h at 25oC, calcium was detected on the surface by X-ray photoelectron spectroscopy. The calcium-modified, roughened titanium disk had a significantly greater concentration of the initially adhered cells as well as cells cultured over 7 days compared with titanium disks without surface modification. Furthermore, the initial bacterial adhesion on the calcium-ozone treated titanium disk was statistically less than on a pure titanium disk or titanium disk treated without ozone. Dissolved ozone was useful for modifying the surface of roughened titanium with calcium ions and the surface modification may be applicable for dental implants.

Giant cell granulomas are a type of giant cell lesions and classified as follows: central giant cell granulomas occurring in the mandible and peripheral giant cell granulomas occurring in the gingiva. Central giant cell granulomas are less frequent than peripheral giant cell granulomas, and it rarely occurs in the mandibular condyle. Mandibular condylectomy is a widely used treatment strategy for lesions in the mandibular condylar region. A commonly indicated treated for mandibular condylectomy is the preauricular approach or the Al-Kayat Bramley method; however, we used the high cervical transmasseteric anteroparotid (HC-TMAP) approach. In recent years, the use of this approach has been reported for open reduction and internal fixation for mandibular condylar fracture cases. In this case report, we describe a technique using the high cervical transmasseteric anteroparotid approach for resecting a mandibular condyle in which a central giant cell granuloma had developed.

Tooth ankylosis is a disorder characterized by the fusion of tooth and alveolar bone. This case report describes the treatment of a severe open bite due to tooth ankylosis. A 14-year-old female patient with a chief complaint of masticatory dysfunction was diagnosed with skeletal Class III severe anterior open bite and tooth ankylosis. She visited our university hospital with a chief complaint of an anterior open bite. After the surgical luxation of the ankylosed maxillary right central incisor, the tooth was orthodontically retracted using a nickel-titanium wire. The right mandibular lateral incisor and canine were luxated and retracted using intermaxillary elastics from a temporary anchorage device (TAD), which was inserted in the opposite jaw. During the treatment, skeletal Class III malocclusion deteriorated due to anterior growth of the mandible. Therefore, TADs were inserted into the retromolar pad on both sides of the mandible and retracted into the mandibular dental arch. Although the mandibular right canine was luxated several times, it could not be brought to the occlusal line, and was thus extracted; the extraction space was replaced with a prosthesis. Consequently, a normal overjet and overbite with a straight profile were achieved. Extrusion of ankylosed teeth by intermaxillary elastics from a TAD is a valid treatment option for patients with severe open bites.

Left ventricular noncompaction (LVNC) is a recently described rare type of congenital cardiomyopathy with a poor long-term prognosis. We performed dental extraction for a 6-year-old female patient with LVNC who had risk of endocarditis due to dental disease along with a history of being uncooperative with dental care. For this case, we utilized intranasal (IN) midazolam conscious sedation, which enables a rapid sedation onset and is considered appropriate for child patients with a high level of anxiety, as movement is effectively decreased, making dental surgery possible. In cases with a small number of teeth, IN midazolam conscious sedation provides a safe condition for high-risk or anxious children undergoing treatment.

Chronic obstructive pulmonary disease (COPD) is a risk factor for postoperative cardiovascular and respiratory complications. Thus, intravenous sedation can be a better option than general anesthesia for surgery in patients with severe COPD. Herein, we present 2 cases of analgesia-based sedation in patients with severe COPD who underwent oral surgery. The current study aimed to discuss these cases to provide knowledge about the appropriate sedation management in patients with this disease. In the current cases, the patients received sufficient analgesia and minimum sedation (analgesia-based sedation). Moreover, dexmedetomidine was used for maintaining sedation and fentanyl for analgesic effects. Furthermore, we focused on providing the maximum analgesic effect of local anesthesia. The patients' vital signs were stable. They did not have any psychological or physical complaints, such as anxiety and pain, during the procedure. Then, they were discharged from the hospital without any complications. Thus, analgesia-based sedation can be an alternative option for oral surgery in patients with COPD.

Tranexamic acid has been used to reduce intraoperative bleeding; however, its effect on anti-inflammation and the amount of drainage after orthognathic surgery is yet to be determined. Therefore, we aimed to examine the effect of tranexamic acid on intraoperative bleeding volume and operation time, amount of drainage, and anti-inflammation after orthognathic surgery. Forty healthy women who underwent bilateral sagittal split ramus osteotomy under general anesthesia participated in this study. The amount of intraoperative bleeding, the operation time, the amount of drainage, and the C-reactive protein level were compared between patients intravenously administered with tranexamic acid before surgery (before-surgery group) and those administered with the drug after surgery (after-surgery group). All data were analyzed using the Student t-test. Results were considered to be statistically significant when P 0.05. Although no significant difference was found in the amount of drainage between the groups (P 0.05), significant variations were detected in the amount of bleeding during surgery (before-surgery group: 161.7 ± 45.3 mL versus after-surgery group: 270.2 ± 24.0 mL; P = 0.0009), operation time (before-surgery group: 141.3 ± 16.8 min versus after-surgery group: 166.8 ± 24.9 min; P = 0.03), and postoperative C-reactive protein level (before-surgery group: 3.77 ± 0.40 mg/dL versus after-surgery group: 5.02 ± 0.75 mg/dL; P = 0.012) between the groups. In conclusion, administering tranexamic acid before surgery was found to significantly decrease bleeding, reduce operation time, and suppress postoperative inflammation.

PurposeIntegrin αvβ3 is an essential molecule for tumor angiogenesis. This study aimed to investigate the anti-tumor effect of MK-0429, an integrin αvβ3 antagonist, on oral squamous cell carcinoma (OSCC) through its inhibitory effect on angiogenesis.MethodsIn this study, we investigated the effect of MK-0429 on cellular function and angiogenesis in vitro with the use of an immortalized human umbilical vein endothelial cell, HUEhT-1, which is immortalized by the electroporatic transfection of hTERT. The effect of MK-0429 on the integrin αvβ3 signaling pathway was examined by FAK and ERK 1/2 phosphorylation. The anti-angiogenic effect of MK-0429 was evaluated by in vitro tube formation assay. The anti-tumor effect on OSCC was assessed by administrating MK-0429 to mouse oral cancer xenografts.ResultsMK-0429 inhibited cell proliferation, migration, and adhesion of HUEhT-1 in a dose-dependent manner. FAK and ERK phosphorylation were significantly blocked by MK-0429 treatment. Tube formation was suppressed by MK-0429 in dose-dependent manner. Tumor progression was significantly suppressed by MK-0429 administration in mouse oral cancer xenografts. Histological study revealed that MK-0429 decreased tumor vascularization.ConclusionThese results indicated integrin αvβ3 as a therapeutic target for OSCC and suggested that MK-0429 might be clinically applicable as an anti-tumor agent with potent antiangiogenic activity.

Integrin αvβIn this study, we investigated the effect of MK-0429 on cellular function and angiogenesis in vitro with the use of an immortalized human umbilical vein endothelial cell, HUEhT-1, which is immortalized by the electroporatic transfection of hTERT. The effect of MK-0429 on the integrin αvβMK-0429 inhibited cell proliferation, migration, and adhesion of HUEhT-1 in a dose-dependent manner. FAK, MEK and ERK phosphorylation were significantly blocked by MK-0429 treatment. Tube formation was suppressed by MK-0429 in dose-dependent manner. Tumor progression was significantly suppressed by MK-0429 administration in mouse oral cancer xenografts. Histological study revealed that MK-0429 decreased tumor vascularization.These results indicated integrin αvβ

We previously found that microRNAs play major roles in the maintenance of amoeboid-like oral squamous cell carcinoma (OSCC) cells with high expression of CD44 (CD44high ). However, the roles of microRNAs in chemotherapeutic resistance exhibited by CD44high amoeboid-like OSCC cells are unclear. Here, docetaxel-induced apoptosis was examined in CD44high OSCC cells (CD44high OM-1 cells) cultured on laminin-coated silicone gel. Amoeboid-like CD44high OSCC cells exhibited robust resistance to docetaxel-induced apoptosis and significant upregulation of miR-224-5p expression compared with epithelial-like CD44high OSCC cells and mesenchymal-like CD44high OSCC cells. The expression of pannexin-1 (PANX1), a channel-forming protein that regulates the release of ATP, was significantly upregulated following transfection of amoeboid-like CD44high OSCC cells with an miR-224-5p inhibitor. These results suggest that miR-224-5p inhibits PANX1 expression. Furthermore, miR-224-5p inhibitor-transfected amoeboid-like CD44high OSCC cells exhibited significant enhancement of the proportion of apoptotic cells; however, this effect was significantly inhibited by knockdown of PANX1 with PANX1 small interfering RNA. Additionally, the miR-224-5p inhibitor-enhanced extracellular ATP levels were significantly reduced by PANX1 knockdown. These findings imply that miR-224-5p plays a vital role in the resistance to docetaxel-induced apoptosis by attenuating PANX1-induced ATP discharge. Moreover, amoeboid-like CD44high OSCC cells may be involved in chemotherapeutic resistance of OSCC.

Cancer cells utilize epithelial to mesenchymal transition (EMT) during invasion and metastasis. This program has intermediate cell states with retained epithelial and gained mesenchymal features together, referred to as partial EMT. Histone demethylase LSD1 forms a complex with the EMT master transcription factor Snail to modify histone marks and regulate target gene expression. However, little is known about the formation of this complex during the Snail-dependent transition between partial EMT and EMT. Here we visualized the nuclear complex of Snail and LSD1 as foci signals using proximity ligation assay. We demonstrated that the nuclear foci numbers varied with the transition of exogenous Snail-dependent partial EMT to EMT. Furthermore, we found that long exposure to dexamethasone could revert exogenous Snail-dependent EMT to partial EMT. In this reversion, the nuclear foci numbers also returned to previous levels. Therefore, we concluded that Snail might select partial EMT or EMT by altering its association with LSD1.

Melatonin is a hormone that is primarily produced in the pineal gland and is involved in wide range of biological functions. However, the impact of melatonin on chemotherapy-induced cell death remains to be elucidated in oral squamous cell carcinoma (OSCC) cells. The objective of this study was to clarify the role of melatonin in cisplatin-induced cytotoxicity in CD44CD44CD44Melatonin plays a vital role in promoting cisplatin-induced cytotoxicity in mesenchymal-like CD44

We previously found that microRNAs play major roles in the maintenance of amoeboid-like oral squamous cell carcinoma (OSCC) cells with high expression of CD44 (CD44

Background In this study, we aimed to investigate the relationships between histopathological and intraoral ultrasonographic (IUS) findings in patients with tongue cancer. Methods IUS and histopathological findings in 46 patients with tongue cancer were considered for this study. We assessed the relationships between IUS findings regarding tumor thickness, margin type, border type, and internal echo intensity; internal/peripheral Doppler findings; and muscle invasion and histopathological findings regarding tumor thickness, differentiation, Yamamoto-Kohama (YK)-classification grade, blood vessel invasion, lymphatic invasion, perineural invasion, and muscle invasion. Results Statistical associations were found between the following findings: between thickness determined through IUS measurement and that determined through histopathological measurement, between the IUS findings regarding tumor margin and border types and the histopathologically determined YK-classifications grades, and between a Doppler image of the internal area of tongue lesions and lymphatic invasion. Conclusions IUS findings may be used to predict histopathological findings about tumor thickness and YK-classification grades.

The low-affinity nerve growth factor receptor p75 is a stratified epithelial stem/progenitor marker of human epithelia. We found OM-1, a human squamous cell carcinoma (SCC) cell line, showed distinct cells with p75 cluster, especially located at the center of a growing colony in a monolayer culture. A cell with p75 cluster was surrounded by cytokeratin 14- and cytokeratin 13-expressing cells that settled at the outer margin of the colony. OM-1 cells were also capable of forming tumor spheres in a cell suspension culture, an ability which was attenuated by the inhibition of p75-signaling. Intriguingly, we also found a p75-negative cell population from a growing culture of OM-1 that re-committed to become p75-clustering cells. These results indicated the possibility that SCC with epithelial multi-layering capacity can exploit the p75-dependent stratified epithelial progenitor property for the cancer stemness., Highlights • Squamous cell carcinoma cell line OM-1 maintained cell population with p75 cluster in the cell. • Single cell-derived OM-1 colonies with the cell at centre maintained hierarchical stratified epithelial linages. • OM-1 cells have p75-dependent epithelial progenitor and stemness properties.

Background Noninvasive management by closed reduction is a desirable treatment for temporomandibular joint dislocation. However, reduction of long-standing temporomandibular joint dislocation is often difficult. Various conservative treatments have been attempted, but these often render poor outcomes. This article reports the case of long-standing temporomandibular joint dislocation that was successfully closed using intraoral condylectomy. Case presentation A 69-year-old Japanese man who sustained an injury in a car collision was unable to close his mouth. Owing to the diagnosis of long-standing temporomandibular joint dislocation, intraoral condylectomy was performed. In the case of temporomandibular joint dislocation, it is convenient to reach the condyle from the oral cavity because sufficient opening is maintained. The condyle can be clearly visualized using an approach similar to sagittal split ramus osteotomy, and the operation using surgical instruments can be facilitated by resecting the coronoid process. By separating the surrounding soft tissue and pulling the cut condyle with sufficient visual field, the condyle can be resected while addressing the hemostasis. During the 12-month postoperative follow-up period, no temporomandibular joint dislocation recurred and the occlusion remained stable. Conclusions The limited intraoral incision of this surgical technique provides sufficient access for condylectomy. The results of this case report suggest that condylectomy by intraoral approach could become the treatment of choice for long-standing temporomandibular joint dislocation.

The purpose of this study was to evaluate the surface modification of calcium ions on roughened titanium as a surface treatment of dental implants for cell attachment, growth, and initial bacterial adhesion. When a surface-roughened, pure titanium disk was immersed in a calcium chloride solution (100 mM) containing 20 ppm ozone for 24 h at 25ºC, calcium was detected on the surface by X-ray photoelectron spectroscopy. The calcium-modified, roughened titanium disk had a significantly greater concentration of the initially adhered cells as well as cells cultured over 7 days compared with titanium disks without surface modification. Furthermore, the initial bacterial adhesion on the calcium-ozone treated titanium disk was statistically less than on a pure titanium disk or titanium disk treated without ozone. Dissolved ozone was useful for modifying the surface of roughened titanium with calcium ions and the surface modification may be applicable for dental implants.

Our previous study revealed that treatment with a combination of fibroblast growth factor‑2 and melatonin (MEL) synergistically augmented osteogenic activity and mineralization of MC3T3‑E1 mouse preosteoblast cells. Thus, the objective of the present study was to assess the effect of MEL on osteogenetic characteristics in human osteoblastic cells. Human jawbone‑derived osteoblastic (hOB) cells were isolated from mandibular bone fragments. RUNX family transcription factor 2 (Runx2) expression, alkaline phosphatase (ALP) enzyme activity and the mineralization ability of hOB cells in the presence of MEL were evaluated. Microarray analysis was also performed to assess the expression of MEL‑induced microRNAs (miRNAs/miRs) in hOB cells. Treatment with MEL significantly enhanced Runx2 expression, ALP activity and mineralization staining. However, this effect was significantly reduced following transforming growth factor‑β1 treatment. In total, 124 miRNAs were differentially expressed in MEL‑treated hOB cells, compared with untreated cells. Of the upregulated miRNAs, miR‑181c‑5p exhibited the largest fold change. Runx2 mRNA expression and mineralization staining in the presence of MEL were significantly reduced following transfection with a miR‑181c‑5p inhibitor. In addition, transfection with miR-181c-5p mimics significantly increased Runx2 expression and mineralization staining. These results suggested that MEL‑induced miR‑181c‑5p was involved in osteogenic differentiation and mineralization of hOB cells. Using TargetScan, a putative miR‑181c‑5p binding site was identified in the Notch2 gene. Moreover, Notch2 mRNA and protein expression levels in hOB cells were significantly reduced following transfection with miR‑181c‑5p mimics, confirming Notch2 as a target gene for miR‑181c‑5p. Notch2 siRNA knockdown significantly increased Runx2 expression and mineralization staining, which suggested that Notch2 may negatively regulate osteogenic differentiation of hOB cells by downregulating Runx2. In conclusion, MEL‑induced expression of miR‑181c‑5p enhanced osteogenic differentiation and calcification of hOB cells.

Tumor necrosis factor (TNF)‑α and interferon (IFN)‑γ, are inflammatory cytokines in the synovial fluid of patients with temporomandibular joint disorder (TMD). However, it remains unknown whether they participate in the regulation of various chemokine expression levels associated with TMD. The effects of TNF‑α and IFN‑γ on the expression of several different inflammatory chemokines, including interleukin (IL)‑8, C‑X‑C motif chemokine ligand (CXCL)1, C‑C motif chemokine ligand (CCL)20, CXCL9, CXCL10, and CXCL11 in synovial fibroblasts obtained from the temporomandibular joint (TMJ) were examined. The results demonstrated that TNF‑α increased the mRNA levels of all examined chemokines in synovial fibroblasts obtained from the TMJ. IFN‑γ treatment alone increased the mRNA expression levels of CXCR3 chemokines, including CXCL10, while they were significantly enhanced when administered in combination with TNF‑α compared with either treatment alone. However, the combination of IFN‑γ and TNF‑α resulted in lower mRNA expression levels of IL‑8 and CXCL1 as compared with those induced by TNF‑α alone. The nuclear factor‑κB inhibitor, Bay 11‑7082, decreased the TNF‑α‑mediated expression of IL‑8 and CXCL10 in the absence, and presence of IFN‑γ. In addition, the JAK2 inhibitor, AG490, decreased CXCL10 expression when administered with TNF‑α and IFN‑γ. Finally, the decrease in TNF‑α‑induced IL‑8 caused by IFN‑γ was recovered by AG490. The results of the present study suggest that TNF‑α and IFN‑γ function in a cooperative manner to regulate inflammatory chemokine expression in synovial fibroblasts, which may contribute to the pathological condition of the TMJ.

Cardiovascular disease (CVD) and renal disease are two major diseases which threaten human health. CVD with high prevalence have influences on many aspects of human body such as blood supply and oxygen supply. In the first part of this chapter, we elaborate the oral health status and periodontal condition in patients with CVD. Issues needed to be paid attention for CVD patients during preoperative, perioperative and postoperative periods are demonstrated in detail. The second part of Chap. 4 provides a thorough overview of precautions for performing dental implant treatment in patients with renal disease. Last two chapters focus on implant treatment among patients with thyroid disorders and hepatitis; although the further relationship between the prognosis of dental implants and these two diseases has not been largely reported, we summarize the key considerations for dental implant practitioners when facing these compromised patients.

Bisphosphonate-related osteonecrosis of the jaw (ONJ) is a major oral complication; however, its pathogenesis remains unclear. Impairment of osteoclast differentiation by bisphosphonates may be associated with the pathogenesis of ONJ. In our previous study, we reported that the expression of the gene encoding nuclear factor of activated T cells c1 (NFATc1), a known osteoclast differentiation marker, was significantly silenced by zoledronate, a bisphosphonate, in mouse osteoclast precursor cells (mOCPCs) using cDNA microarray. In the present study, the expression value of the NFATc1 gene was regarded as a cut-off and genes whose expression value was significantly decreased compared with that of the NFATc1 gene were extracted in mOCPCs. For validation, CD11b-positive (CD11b+) cells were used, which were purified from human peripheral blood mononuclear cells as human OCPCs. A total of 19 genes were identified; sequential expression analysis revealed that the gene encoding vascular endothelial growth factor receptor 2 (VEGFR2) was frequently silenced by zoledronate in CD11b+ cells. Furthermore, the number of tartrate-resistant acid phosphatase-positive multinucleated cells was decreased by VEGFR2 suppression using a VEGFR2 neutralizing antibody. Zoledronate inhibits human osteoclast differentiation via suppressing VEGFR2 expression. These results suggest that low expression of VEGFR2 in OCPCs may be involved in the pathogenesis of zoledronate-induced ONJ. The understanding of the role of VEGFR2 on bone remodeling is important to elucidate the pathogenesis of bisphosphonate-related ONJ.

The records of 70 patients with oral cancer who were treated at a single institution between 2008 and 2014 were reviewed. The body temperature, white blood cell count, and C-reactive protein (CRP) levels were compared between those who had received preoperative oral care (oral care group) and those who had not received any (non-oral care group). When the patients were divided into those who underwent minimally invasive surgery and those who underwent severely invasive surgery, the mean CRP level in the early postoperative period was lower in the oral care group as compared with the non-oral care group in those who underwent minimally invasive surgery as well as those who underwent severely invasive surgery. However, the mean CRP level was most evidently reduced in the severely invasive group on days 1 and 3–5. However, no significant differences were observed with regard to the percentage of postoperative infectious complications (for example, surgical site infection, anastomotic leak and pneumonia) between the oral care (13.6%) and non-oral care (20.8%) groups, though a reduced prevalence of postoperative complications following preoperative oral care was noted. The results of the present study suggest that preoperative oral care can decrease inflammation during the early postoperative stage in patients with oral cancer who undergo severely invasive surgery.

The present study reviewed the records of 58 patients who underwent orthognathic surgery [sagittal split ramus osteotomy (SSRO), Le Fort I osteotomy, genioplasty, anterior maxillary alveolar osteotomy] between 2010 and 2015. To investigate the influence of preoperative oral health care on postoperative inflammation, infection and length of hospital stay in those patients, white blood cell (WBC) count and C-reactive protein (CRP) levels were compared between patients who received and did not receive preoperative oral care. The mean CRP level throughout the postoperative term was lower in the oral care group as compared to the non-oral care group. By contrast, the oral care group had a lower occurrence of postoperative infectious complications (surgical site infection, anastomotic leak) (13.6 vs. 20.8%) and a shorter average length of hospital stay (16.2±3.8 vs. 21.2±7.4 days). These results suggest that preoperative professional oral health care decreases the duration of hospital stay following orthognathic surgery by inhibiting inflammation and infectious complications during the postoperative stage.

We found that high galectin-1 (Gal-1) mRNA levels were associated with invasive squamous cell carcinoma (SCC) cells that expressed Snail, an epithelial-to-mesenchymal transition (EMT) regulator. Both Gal-1 overexpression and soluble Gal-1 treatment accelerated invasion and collective cell migration, along with activation of cdc42 and Rac. Soluble Gal-1 activated c-Jun N-terminal kinase to increase expression levels of integrins α2 and β5, which were essential for Gal-1 dependent collective cell migration and invasiveness. Soluble Gal-1 also increased the incidence of EMT in Snail-expressing SCC cells; these were a minor population with an EMT phenotype under growing conditions. Our findings indicate that soluble Gal-1 promotes invasiveness through enhancing collective cell migration and increasing the incidence of EMT.

In this study, we found that wounding of a confluent monolayer of squamous cell carcinoma (SCC) cells induced epithelial-mesenchymal transition (EMT) specifically at the edge of the wound. This process required the combined stimulation of TGFβ, TNFα, and PDGF-D. Such a combined cytokine treatment of confluent monolayers of the cells upregulated the expression levels of Snail and Slug via PI3K. The PI3K downstream effector, AKT, was dispensable for the upregulation of Snail and Slug, but essential for enabling EMT in response to upregulation of Snail and Slug.

We found a linear correlation between the Prostaglandin E 2 (PGE 2 ) amount and the NR4A2 expression in oral squamous cell carcinoma (SCC) tissues through a statistical analysis among 41 clinical cases. In SCC cell lines, PGE 2 receptor (EP) ligation by exogenous PGE 2 promoted the NR4A2 expression in the cAMP/protein kinase A (PKA)-dependent manner. The process required a nature of SCC cell represented by constitutive activated epidermal growth factor receptor (EGFR) family. Targeted inactivation of the EGFRs interfered the PGE 2 -dependent NR4A2 expression. The PGE 2 -dependent NR4A2 induction is essential for the resistance to anti-cancer drug-induced apoptosis especially in SCC cells which showed constitutive EGFRs activity via autocrine epiregulin, a ligand for EGFRs. Conversely, SCC cells which lack epiregulin expression in their nature could gain the ability to promote the NR4A2 expression in response to PGE 2 and attain the resistance to anti-cancer drug-induced apoptosis under the existence of exogenous epiregulin. These findings suggest that susceptibility of SCC to anti-cancer drug could be compromised when PGE 2 was delivered in the microenvironment of SCC cells supported by constitutive EGFR family activities as their nature.

p63 is a member of the p53 family and DeltaNp63alpha is the dominant-expressing isoform of p63 in basal layer of normal stratified epithelium and human squamous cell carcinoma (SCC) cells. We have previously reported that down-regulation of p63 was accompanied with epithelial-to-mesenchymal transition (EMT) by Snail-expressing SCC cells, in which re-expression of DeltaNp63alpha diminished their invasiveness (Higashikawa K, Yoneda S, Tobiume K, Taki M, Shigeishi H, Kamata N. Snail-induced down-regulation of DeltaNp63alpha acquires invasive phenotype of human squamous cell carcinoma. Cancer Res 2007;67:9207-13). In this study, we found that DeltaNp63alpha positively regulated inhibitor of differentiation-3 (Id-3) expression. Id is a dominant negative regulator of E2A which is a transcriptional repressor of E-cadherin. Enforced expression of Id-3 was incapable of invoking E-cadherin expression in the SCC cells with EMT phenotype, whereas it significantly impaired their invasiveness with down-regulation of matrix-metalloproteinase-2 (MMP-2) expression. Reporter gene assay revealed that the Ets-1-induced MMP-2 promoter activity was suppressed by the Id-3, while the Id-3-dependent E-cadherin promoter activity was remarkably reduced in the presence of Snail. Furthermore, knockdown of p63 in SCC cells significantly decreased Id-3 expression, in which up-regulation of MMP-2 expression was concomitant with the acquired invasiveness. These findings propose a particular role of the off-signaling of the DeltaNp63alpha-Id-3 axis incident to Snail-mediated EMT for the MMP-2-dependent invasiveness in SCC cells.

There have been very few studies on the expression of Centromere proteins in human salivary gland carcinomas. The purpose of this study was to clarify the correlation between Centromere protein H (CENP-H) expression and clinicopathologic factors in salivary gland carcinomas. The expression of CENP-H mRNA was investigated in 28 human salivary gland tumors (7 pleomorphic adenomas, 3 Warthin tumors, 6 mucoepidermoid carcinomas, 6 adenoid cystic carcinomas, 5 acinic cell carcinomas and 1 malignant myoepithelioma) and 8 normal submandibular glands using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). The labeling index of PCNA and Ki-67 were also investigated immunohistochemically in 16 salivary gland carcinomas. The mean expression level of CENP-H mRNA was significantly higher in malignant tumors (0.55 ± 0.68) than normal submandibular glands (0.10 ± 0.029). A significant correlation between the PCNA labeling index and CENP-H mRNA expression was also found (Spearman's correlation coefficient by rank test, P=0.033). We also found a significant correlation between the Ki-67 labeling index and CENP-H mRNA expression in malignant tumors (Spearman's correlation coefficient by rank test, P=0.040). These results indicate that human CENP-H mRNA is closely linked to increased or abnormal cell proliferation in malignant salivary gland tumors.

Background CD44 and aldehyde dehydrogenase 1 (ALDH1) have been shown to be useful markers for identification of cancer stem cells (CSCs). We previously reported that glycogen synthase kinase 3β (GSK3β) is involved in regulation of the self-renewal ability of head and neck squamous cell carcinoma (HNSCC) CSCs. The purpose of the present study was to clarify the role of GSK3β in CD44(high) /ALDH1(high) HNSCC cells. Methods Cells with greater expression of CD44 and higher ALDH1 enzymatic activity were FACS sorted from the OM-1 HNSCC cell line. The self-renewal ability of CD44(high) /ALDH1(high) cells was then examined using a tumor sphere formation assay. mRNA expressions of the stem cell markers Sox2, Oct4, and Nanog, as well as GSK3β were evaluated by real-time RT-PCR. Results CD44(high) /ALDH1(high) cells exhibited higher tumor sphere forming ability and increased expression of stem cell markers as compared with CD44(high) /ALDH1(low) cells. Interestingly, spindle-shaped cells positive for vimentin were found in the CD44(high) /ALDH1(high) but not the CD44(high) /ALDH1(low) cell population. In addition, the ALDH1 activity and sphere forming ability of CD44(high) /ALDH1(high) cells was significantly inhibited by GSK3β knockdown. On the other hand, CD44(high) /ALDH1(low) cells exhibited high epidermal growth factor receptor (EGFR) expression and increased cell growth. Conclusions Our results show that GSK3β plays a major role in maintenance of stemness of CD44(high) /ALDH1(high) HNSCC cells. Additionally, they indicate a close relationship between CSC and mesenchymal characteristics in HNSCC.

Human butyrylcholinesterase (BChE) is an enzyme existing in plasma and liver that dissolves various choline-ester substrates. The serum cholinesterase level indicates the activity of BChE in serum. Low BChE activity is seen in patients with functional disorders of the liver, organic phosphorus exposure and hereditary serum BChE deficiency. In patients with low BChE activity, prolonged neuromuscular block is induced by the use of depolarizing muscle relaxants, such as succinylcholine for general anesthesia, or breathing trouble can be caused by the use of ester-form local anesthetics.We report a case of tongue fibroma in a 54-year-old man who had extremely low serum BChE activity. While monitoring the circulatory system, the tumor was resected with the use of an amino-form local anesthetic. Hypertension was seen before surgical treatment, possibly due to mental stress, and an antihypertensive was used. DNA sequencing analysis of the BChE gene in this patient revealed a homozygous missense mutation at nucleotide 1093, which resulted in GGA → CGA at Gly365Arg in exon 2.

Expression levels of CENP-F mRNA were investigated in 45 surgically resected oral squamous cell carcinomas (OSCC) and 10 samples of normal gingiva, using real time reverse-transcriptase polymerase chain reaction (RT PCR). The relations between CENP-F mRNA and clinicopathologic variables were studied. The mean expression level of CENP-F mRNA was higher in OSCC tissues than in normal gingiva. There was a significant correlation between the expression level of CENP-F mRNA and lymph node metastasis in the cases of OSCC (p=0.024). These results suggest that OSCC with a high expression level of CENP-F mRNA has high metastatic potential.

We established a pair of cell lines derived from the primary lesion (KK-p) and lymph node metastasis (KK-m) of a tongue carcinoma. We compared the profiles of genes expressed in KK-p and KK-m cells by microarray analysis. Seven genes were highly expressed and 26 were poorly expressed in KK-m cells as compared with KK-p cells. The expression ratios of 14 genes were confirmed by real time RT PCR, and the results were similar to those of the microarray analysis. These results suggested that some of the genes identified in this study may be new metastasis-related genes.

Objective. Our aim was to clarify the association of human papillomavirus (HPV) with oral carcinogenesis, especially its early stage. Study Design. Tissue specimens of normal mucosa, epithelial dysplasia, oral squamous cell carcinoma (OSCC), and OSCC cell lines were examined for the presence of HPV-16 and HPV-18 E6 DNA by means of the polymerase chain reaction test. Results. The detection rate of HPV-16 in epithelial dysplasia (31/51) was higher than that in normal mucosa (16/44) and in OSCC (30/86) and was statistically different from that in OSCC. The cases that progressed from epithelial dysplasia to carcinoma showed a significantly higher HPV-16 detection rate than the other cases in both epithelial dysplasia and OSCC. HPV-16 and HPV-18 were detected only at early passages of 2 of 10 OSCC cell lines. Conclusion. These results strongly suggest that HPV-16 may be involved in the early stages of the development of some oral carcinomas. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:594-600)

Malignant salivary gland tumors are rare and exhibit a broad spectrum of phenotypic heterogeneity. The objective of this study was to investigate prognostic factors in patients with salivary gland carcinomas and review the results in light of other reports. We retrospectively reviewed 40 patients with primary salivary gland carcinomas who were diagnosed and treated at our institution between 1991 and 2014. Of the 40 tumors, 19 (47.5%) were mucoepidermoid carcinomas, 11 (27.5%) were adenoid cystic carcinomas, 7 (17.5%) were acinic cell carcinomas, 2 (5.0%) were myoepithelial carcinomas and 1 (2.5%) was a squamous cell carcinoma. Clinically positive lymph nodes were present in 4 patients (10.0%). As regards clinical stage, 15 cases (37.5%) were stage I, 13 (32.5%) were stage II, 1 (2.5%) was stage III and 11 (27.5%) were stage IVA. The majority of the patients (97.5%) were treated with surgery, of whom 25 (62.5%) received surgery alone and 14 (35.0%) underwent surgery in combination with chemotherapy or chemotherapy and radiotherapy. The median follow-up time for all the patients was 48 months. The disease-specific survival rate at 5 years was 87.1%. We identified a significant correlation between poor survival rate and histological grade (intermediate/high), tumor size (T3/T4), lymph node metastasis (node-positive) and clinical stage (III/IV) using the Kaplan-Meier method (P

The effect of trichostatin A (TSA), histone deacetylase inhibitor, on cell growth and the mechanism of growth modulation was examined in 8 gastric and 3 oral carcinoma cell lines which included 9-cis-retinoic acid resistant (MKN-7 and Ho-1-N-1) and IFN-beta resistant cell lines (MKN-7, -28 and -45). TSA inhibited growth in all cell lines examined. Apoptotic cell death was confirmed by apoptotic ladder formation and induction of a cleaved form (85 kDa) of poly (ADP-ribose) polymerase (PARP) induction. TSA enhanced the protein expression of p21(WAF1), CREB-binding protein, cyclinE, cyclin A, Bak and Bax, while it reduced the expression of E2F-1, E2F-4, HDAC1, p53 and hyperphosphorylated form of Rb. Furthermore, TSA induced morphological changes, such as elongation of cytoplasm and cell-to-cell detachment, in gastric and oral carcinoma cell lines. These results suggest that TSA may inhibit cell growth and induce apoptosis of gastric and oral carcinoma cells through modulation of the expression of cell cycle regulators and apoptosis-regulating proteins.