Publications by authors named "Shuichi Kawashiri"

45 Publications

Metalloelastase-12 is involved in the temporomandibular joint inflammatory response as well as cartilage degradation by aggrecanases in STR/Ort mice.

Biomed Rep 2021 Jun 1;14(6):51. Epub 2021 Apr 1.

Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.

Temporomandibular joint dysfunction (TMJD) is characterised by clinical symptoms involving both the masticatory muscles and the temporomandibular joint (TMJ). Disc internal derangement and osteoarthritis (OA) are the most common forms of TMJD. Currently, the molecular process associated with degenerative changes in the TMJ is unclear. Our previous study showed that elastin-digested peptides act on human TMJ synovial cells and lead to upregulation of interleukin-6 (IL-6) and metalloelastase-12 (MMP-12; an elastin-degrading enzyme) . However, there is limited information regarding the involvement of elastin-degradation by MMP-12 in the processes of inflammatory responses and cartilage degradation . STR/Ort mice were used as a model of TMJ OA in the present study. Significant articular cartilage degeneration was observed starting at 20 weeks of age in the STR/Ort mice and this progressed gradually until 40 weeks, compared with the age-matched CBA mice. Immunostaining analysis showed that MMP-12 and IL-6 were expressed in the chondrocytes in the superficial zones of the cartilage. Immunostaining also showed that aggrecanases [a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5] were expressed in the chondrocytes in the superficial zones of the cartilage. These findings suggest that an inflammatory and degradative process was initiated in the TMJ. Harmful mechanical stimuli, particularly pressure, may cause damage to the elastin fibres in the most elastin-rich superficial layer of the articular cartilage. Elastin-digested peptides are then generated as endogenous warning signals and they initiate a pro-inflammatory cascade. This leads to upregulation of pro-inflammatory mediators, such as IL-6 and MMP-12, which further trigger tissue damage resulting in elevated levels of elastin-digested peptides. IL-6 increases expression of the aggrecanases ADAMTS-4 and ADAMTS-5, following cartilage degradation. This leads to the establishment of a positive feedback loop and may result in chronic inflammation and cartilage degradation of the TMJ .
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http://dx.doi.org/10.3892/br.2021.1427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042671PMC
June 2021

Comparison of Postoperative Stability Between BSSRO and Le Fort 1 Osteotomy with BSSRO in Skeletal Class III Malocclusion with Severe Open Bite.

J Maxillofac Oral Surg 2020 Dec 26;19(4):591-595. Epub 2019 Oct 26.

Oral and Maxillofacial Surgery, Department of Oral Patho-biological Science, Graduate School of Dental Medicine, Hokkaido University, Kita 13 Nishi 7 Kita-ku, Sapporo, Hokkaido 060-8586 Japan.

Introduction: We aimed to investigate postoperative stability after orthognathic surgery in patients with skeletal class III malocclusion with severe open bite by comparison between bilateral sagittal splitting osteotomy (BSSRO) and BSSRO with Le Fort 1 osteotomy.

Materials And Methods: Seventeen patients with skeletal class III malocclusion with severe open bite who were needed more than 6 degree counterclockwise rotation of distal segment by only BSSRO in preoperative cephalometric prediction. The subjects were divided into group A, where 9 patients were treated by BSSRO, and group B, where 8 patients were treated by BSSRO with Le Fort 1 osteotomy. Patient's characteristics of age, gender, preoperative over jet (OJ) and over bite (OB) were not found to be significantly different between the two groups. Counterclockwise rotation of distal segment in preoperative cephalometric prediction by only BSSRO was not found to be significantly different between group A of 7.6 (6-10.6) degree and group B of 9 (6-13) degree. The amount of rotation was reduced to 5.4 (3-10) degree by bimaxillary surgery using BSSRO and Le Fort 1 osteotomy in group B. OJ and OB were measured as occlusal stability factor. Distance between ANS-to-PNS plane and the edge of upper incisor (NF-U1Ed), and distance between Menton and edge of lower incisor (Me-L1Ed) were measured as skeletal stability factor using cephalometric analysis. These lengths were measured at pre-surgery (T0), 2 weeks after surgery (T1) and 1 year after surgery (T2), and these differences between the two groups were statistically analyzed.

Results: OJ and OB kept a good relation at any experimental periods. The change of Me-L1Ed was significantly larger in group A (1.21 mm at T0-T1, 1.02 mm at T0-T2) than in group B (0.14 mm at T0-T1, 0.16 mm at T0-T2). The change of NF-U1Ed was not significantly different between group A (1.07 mm at T0-T1, 0.57 mm at T0-T2) and group B (0.51 mm at T0-T1, - 0.05 mm at T0-T2).

Conclusion: In case with more than 6 degree counterclockwise rotation of distal segment, skeletal stability was better after bimaxillary surgery than only BSSRO; however, OJ and OB kept a good relation.
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http://dx.doi.org/10.1007/s12663-019-01300-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524990PMC
December 2020

Comparison of Maximum Mouth Opening Following Mandibular Bilateral Sagittal Splitting Ramus osteotomies in Class III Females Using Two Different Osteosynthesis Methods.

J Oral Rehabil 2020 Oct 2;47(10):1242-1246. Epub 2020 Aug 2.

Oral and Maxillofacial Surgery, Department of Oral Patho-biological Science, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.

Background: Limitation of mouth opening is a common complaint following orthognathic surgery.

Objectives: This investigation reports on the progress of maximum incisal opening following orthognathic surgery and compares the impact of two different osteosynthesis methods on mouth opening in female patients with Class III dentofacial deformities.

Methods: Forty cases of skeletal class III malocclusion were divided into twenty cases treated using the conventional single miniplate osteosynthesis method (P1) and twenty cases using the additional L-shaped miniplate osteosynthesis method (P2). No significant differences in pre-operative clinical status were detected between the P1 and P2 group, and all patients were managed with elastics in the post-operative period. Independent mouth opening exercises were initiated seven days after surgery, and inter-incisal distance was measured as maximum mouth opening (MMO) at 1 week, 2 weeks, and 1, 2, 3, 6 months. Statistical analysis was performed in order to analyse differences in MMO between the P1 and P2 groups (Prism 7 GraphPad software, San Diego, CA). Values of P < .05 were considered to be significant.

Results: MMO significantly increased from 2 weeks after surgery in both groups. The MMO of P2 was significantly larger than that of P1 in all experimental periods after surgery. MMO was statistically improved in P2 at 2 months after surgery, while MMO in P1 was significantly smaller than the pre-operative MMO, even at 6 months post-operative. A minimum MMO of 40 mm was achieved by all patients.

Conclusion: L-shaped miniplate osteosynthesis was more useful for early limitation of mandibular opening improvement than conventional single miniplate osteosynthesis.
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http://dx.doi.org/10.1111/joor.13059DOI Listing
October 2020

Relationship between pharyngeal airway depth and ventilation condition in mandibular setback surgery: A computational fluid dynamics study.

Orthod Craniofac Res 2020 Aug 4;23(3):313-322. Epub 2020 Mar 4.

Department of Pediatric Dentistry, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima-City, Japan.

Objectives: This study aimed to determine the anteroposterior depth (APD) of the pharyngeal airway (PA) where post-operative PA obstruction was predicted, using computer fluid dynamics (CFD), in order to prevent obstructive sleep apnoea after mandibular setback surgery.

Settings And Sample Population: Nineteen skeletal Class III patients (8 men; mean age, 26.7 years) who required mandibular setback surgery had computed tomography images taken before and 6 months after surgery.

Methods: The APD of each site of the four cross-sectional reference planes (retropalatal airway [RA], second cervical vertebral airway, oropharyngeal airway and third cervical vertebral airway) were measured. The Maximum negative pressure (Pmax) of the PA was measured at inspiration using CFD, based on a three-dimensional PA model. Intersite differences were determined using analysis of variance and the Friedman test with Bonferroni correction. The relationship between APD and Pmax was evaluated by Spearman correlation coefficients and non-linear regression analysis.

Results: The smallest PA site was the RA. Pmax was significantly correlated with the APD of the RA (r  = .628, P < .001). The relationship between Pmax and the APD-RA was fitted to a curve, which showed an inversely proportional relationship of Pmax to the square of the APD-RA. Pmax substantially increased even with a slight reduction of the APD-RA. In particular, when the APD-RA was 7 mm or less, Pmax increased greatly, suggesting that PA obstruction was more likely to occur.

Conclusions: The results of this study suggest that APD-RA is a useful predictor of good PA ventilation after surgery.
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http://dx.doi.org/10.1111/ocr.12371DOI Listing
August 2020

Caveolin-1 Expression at Metastatic Lymph Nodes Predicts Unfavorable Outcome in Patients with Oral Squamous Cell Carcinoma.

Pathol Oncol Res 2020 Oct 6;26(4):2105-2113. Epub 2020 Jan 6.

Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.

We evaluated the clinical and prognostic value of the protein expression of caveolin-1 (CAV1) and p16 at the primary site and metastatic lymph nodes of oral squamous cell carcinoma (OSCC). Primary site specimens from 80 OSCC cases were randomly selected and lymph node specimens from 15 preserved metastatic lymph nodes from among those patients were selected for examination. We evaluated the CAV1 and p16 expression at both the primary site and metastatic lymph nodes, and analyzed the patients' clinicopathological data in relation to CAV1 and p16 expression. Our analysis revealed significant positive correlations between CAV1 expression at the primary site and pathological metastasis, cell differentiation, and mode of invasion (p = 0.019, p = 0.002, p = 0.015, respectively), but p16 expression was not associated with any clinicopathological factors. Patients with high CAV1 expression at the primary sites showed significantly worse prognoses than those with low or negative CAV1 expression (p = 0.002), and multivariate analysis showed that the T classification and CAV1 expression were independent OSCC prognostic factors. CAV1 expression was also present in the metastatic lymph nodes of the OSCC cases with particularly poor differentiation and high invasive grade, and patients with CAV1-positive metastatic lymph nodes showed significantly worse prognoses than those with CAV1-negative metastatic lymph nodes (p = 0.018). CAV1 may activate metastaticity and the invasive capacity of OSCC cells. CAV1 expression, particularly at metastatic lymph nodes, predicts a worse outcome for OSCC, suggesting that CAV1 could be used as a prognostic marker for OSCC.
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http://dx.doi.org/10.1007/s12253-019-00791-1DOI Listing
October 2020

Factors related to patients' nutritional state after orthognathic surgery.

Oral Maxillofac Surg 2019 Dec 4;23(4):481-486. Epub 2019 Nov 4.

Oral and Maxillofacial Surgery, Department of Oral Patho-biological Science, Graduate School of Dental Medicine, Hokkaido University, Kita 13 Nishi 7 Kita-ku, Sapporo, Hokkaido, 060-8586, Japan.

Purpose: The purpose of this study was to evaluate patients' nutritional state after orthognathic surgery.

Methods: The subjects were 40 female patients with dentofacial deformity aged 17-33 years who were undergoing bilateral sagittal splitting ramus osteotomy. Twenty patients were treated with intermaxillary fixation, and 20 patients were treated without intermaxillary fixation. Age and body mass index (kg/m) were assessed as physical factors, operation time, blood loss, and amount of mandibular movement with or without intermaxillary fixation were assessed as operation stress factors, and the following laboratory data, total protein, serum albumin, total cholesterol, total lymphocytes, and cholinesterase were assessed as nutritional state factors at 1 and 2 weeks after surgery. Statistical analysis was performed for body weight loss and relationship between body weight loss and examination factors.

Results: Body weight significantly decreased 2.3% at 1 week and 3.9% at 2 weeks after surgery rather than preoperation. All laboratory data except total lymphocyte were decreased at 1 week after surgery and still remained significantly decreased at 2 weeks after surgery. There was a statistically significant relationship between body weight loss at 1 week after surgery and operation time.

Conclusions: These results indicate that long operation time caused body weight loss in orthognathic surgery.
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http://dx.doi.org/10.1007/s10006-019-00801-1DOI Listing
December 2019

Focal Adhesion Kinase (FAK) Overexpression and Phosphorylation in Oral Squamous Cell Carcinoma and their Clinicopathological Significance.

Pathol Oncol Res 2020 Jul 14;26(3):1659-1667. Epub 2019 Sep 14.

Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.

Focal adhesion kinase (FAK) is involved in progression of various cancers, and FAK overexpression has been associated with cancer invasion and metastasis. However, the involvement of FAK expression in the clinicopathological malignancy of oral squamous cell carcinoma (OSCC) remains unknown. In addition, there is no consensus regarding the role of p16 expression in OSCC. In this study, the immunohistochemically measured expression of FAK, phosphorylated FAK (FAKpY397) and p16 expressions and their associations with clinicopathological features and 5-year survival rates were examined in surgical samples from 70 patients with primary OSCC. FAK and FAKpY397 were expressed at high levels in 42 cases (60.0%) and 34 cases (48.6%), respectively, and 9 cases (12.9%) were positive for p16. FAK expression was significantly correlated with local recurrence, subsequent metastasis, and the mode of invasion. FAKpY397 expression was significantly correlated with both N classification and the mode of invasion. p16 expression was significantly correlated with clinical stage only. Patients having high expression of FAK, FAKpY397, or both showed significantly worse prognosis, but p16 expression showed no significant relation to prognosis. The results suggested that overexpression and phosphorylation of FAK in OSCC may affect cancer progression, such as local invasion and lymph node metastasis, and thereby contribute to life prognosis.
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http://dx.doi.org/10.1007/s12253-019-00732-yDOI Listing
July 2020

Selectively high efficacy of eribulin against high-grade invasive recurrent and/or metastatic squamous cell carcinoma of the head and neck.

Oncol Lett 2019 Jun 19;17(6):5064-5072. Epub 2019 Mar 19.

Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.

Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) have a poor prognosis. Over the past decade, a major development in the first-line treatment of R/M SCCHN was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy. Currently, a promising novel treatment option in R/M SCCHN has emerged, termed immune checkpoint inhibitors. However, only a few patients presenting with R/M SCCHN have exhibited meaningful tumor regression with these agents. Therefore, novel agents are required to order improve the overall survival of patients with R/M SCCHN. Recently, we demonstrated that R/M SCCHN cells are highly sensitive to eribulin. In the present study, the effects of eribulin, paclitaxel and vinblastine were investigated in R/M SCCHN (OLC-01 and OSC-19) and locally advanced SCCHN (OSC-20) cells. Tumour-inhibitory activities of eribulin against R/M SCCHN were evaluated in orthotopic xenograft models. The data revealed that eribulin has sub-nM growth inhibitory activities against OLC-01 cells, and that it is more potent than paclitaxel and vinblastine. The reduced expression of Tubulin Beta 3 Class III (TUBB3) following treatment was correlated with a high sensitivity to eribulin. Histological analysis of OLC-01 cells in NOD-SCID mice demonstrated that they had a higher invasiveness in the tissue around the alveolar cancer when compared with the histology of OSC-19 cells, which has been reported in our previous study. Treatment with eribulin revealed marked inhibitory activities at 0.125 mg/kg against OLC-01 cells orthotopic xenografts. In conclusion, the results highlight the existence of invasive-type heterogeneity in R/M SCCHN with respect to eribulin sensitivity. Eribulin is already an approved clinical agent; therefore, the continued investigation of its preclinical antitumor attributes may contribute significantly to the future process of identifying novel uses of eribulin against R/M SCCHN.
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http://dx.doi.org/10.3892/ol.2019.10165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507455PMC
June 2019

Detection of sentinel lymph node using contrast-enhanced agent, Sonazoid, and evaluation of its metastasis with superb microvascular imaging in oral and oropharyngeal cancers: a preliminary clinical study.

Acta Otolaryngol 2019 Jan 24;139(1):94-99. Epub 2019 Jan 24.

a Department of Otolaryngology, and Head & Neck Surgery , Kanazawa University , Kanazawa , Japan.

Background: In sentinel lymph node (SLN) biopsy for head and neck cancers, the radioisotope method has been the gold standard. However, this method has several problems, such as unavoidable radiation exposure and requirements of expensive equipment.

Aims/objectives: To overcome these problems, we evaluated the contrast-enhanced ultrasonography (CEUS)-guided SLN-detection method, and predicted the SLN metastatic status using novel ultrasound technology, superb microvascular imaging (SMI).

Methods: Ten patients (6 with oral and 4 with oropharyngeal cancers) without neck lymph node metastasis were enrolled in this study. Ultrasound contrast agent, Sonazoid, was infiltrated into the mucosa at the primary site to observe the lymphatic ducts and SLNs in the neck field. The detected SLNs were examined for blood flow using SMI to categorize the SLNs metastases-positive or negative.

Results: SLNs were successfully detected in 8 out of 10 cases. In 7 out of the 8 cases, in whom SLNs were successfully detected, the metastatic status of SLNs was correctly diagnosed with SMI.

Conclusions And Significance: Although more clinical data are needed based on a larger cohort, establishing the CEUS-guided SLN-detection and criteria for the accurate diagnosis of SLN-metastases using SMI would be valuable as an alternative to radioisotope method, in oral and oropharyngeal cancers.
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http://dx.doi.org/10.1080/00016489.2018.1535193DOI Listing
January 2019

Clinicopathological Significance of the ET Axis in Human Oral Squamous Cell Carcinoma.

Pathol Oncol Res 2019 Jul 31;25(3):1083-1089. Epub 2018 Oct 31.

Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.

The interaction between cancer cells and the surrounding microenvironment in malignant tumor tissue is known to be closely associated with cancer cell invasion and proliferation. Endothelin (ET) present in the microenvironment surrounding tumors has been reported to play a role in cancer cell invasion and proliferation by binding to receptors on the cell membrane of cancer cells. Here, we immunohistologically detected the expression of ET-1 and its receptor ETR in oral squamous cell carcinoma (OSCC) and evaluated the association between the expression of each as well as their co-expression (ET-axis expression) and clinicopathological factors. A significant difference was observed between the invasion pattern as a parameter of cancer cell malignancy and the expressions of ET-1 and ETR. The survival rates were significantly lower among the patients who were strongly positive for ET-1 and the ETR-positive patients compared to negative patients. There was also a significant difference between ET-axis expression and the degree of histological differentiation and mode of invasion, and the survival rate of the positive cases was significantly lower than that of the negative cases. Our findings suggested that ET-axis assessments are important for assessing the malignancy of cancer cells and predicting the prognoses of OSCC patients.
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http://dx.doi.org/10.1007/s12253-018-0514-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614151PMC
July 2019

Tooth loss-related dietary patterns and cognitive impairment in an elderly Japanese population: The Nakajima study.

PLoS One 2018 15;13(3):e0194504. Epub 2018 Mar 15.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.

Although several studies have demonstrated a potential correlation of dietary patterns with cognitive function, the relationship between tooth loss and dietary patterns and cognitive function have not been identified. In this cross-sectional study, we used a reduced rank regression (RRR) analysis, a technique used previously to observe dietary patterns based on the intakes of nutrients or levels of biomarkers associated with the condition of interest, to identify tooth loss-related dietary patterns and investigate the associations of such patterns with cognitive impairment in 334 community-dwelling Japanese subjects aged ≥ 60 years. According to Pearson correlation coefficients, the intakes of six nutrients (ash content, sodium, zinc, vitamin B1, α- and β-carotene) correlated significantly with the number of remaining teeth. Using RRR analysis, we extracted four dietary patterns in our subject population that explained 86.67% of the total variation in the intakes of these six nutrients. Particularly, dietary pattern 1 (DP1) accounted for 52.2% of the total variation. Food groups with factor loadings of ≥ 0.2 included pickled green leafy vegetables, lettuce/cabbage, green leaves vegetables, cabbage, carrots/squash; by contrast, rice had a factor loading of <-0.2. In a multivariate regression analysis, the adjusted odds ratios regarding the prevalence of cognitive impairment for the lowest, middle and highest tertiles of the DP1 score were 1.00 (reference), 1.224 (95% confidence interval [CI]: 0.611-2.453) and 0.427 (95% CI: 0.191-0.954), respectively. To our knowledge, this is the first report to show that tooth loss-related dietary patterns are associated with a high prevalence of cognitive impairment. These results may motivate changes in dental treatment and the dietary behaviours and thereby lower the risk of cognitive impairment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194504PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854423PMC
July 2018

MicroRNA-205-5p suppresses the invasiveness of oral squamous cell carcinoma by inhibiting TIMP‑2 expression.

Int J Oncol 2018 Mar 31;52(3):841-850. Epub 2018 Jan 31.

Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan.

MicroRNAs (miRNAs or miRs) play important roles in carcinogenesis. The miRNA, miR-205-5p, has been reported to suppress the growth of various types of tumor; however, its functional contribution to oral squamous cell carcinoma (OSCC) is not yet clear. Thus, this study was conducted to determine the miRNA expression signatures in OSCC and to investigate the functional role of miR‑205‑5p in OSCC cells. We measured miR‑205‑5p expression by RT-qPCR, and examined the function of miR‑205‑5p by transfecting a miR‑205‑5p mimic or inhibitor into OSCC cells and measuring cell proliferation, migration and invasiveness. Genes targeted by miR‑205‑5p were identified using the TargetScan database and verified by western blot analysis, luciferase reporter assay and ELISA. We found that miR‑205‑5p was significantly downregulated in OSCC cell lines and tissue specimens. Following transfection of miR‑205‑5p mimic or inhibitor into the cancer cell lines, miR‑205‑5p overexpression significantly suppressed cancer cell migration and invasion. We further demonstrated that miR‑205‑5p directly targeted and regulated the tissue inhibitor of metalloproteinases‑2 (TIMP‑2) gene. The silencing of TIMP‑2 suppressed cancer cell invasion and the activation of pro‑matrix metalloproteinase‑2 (pro‑MMP‑2). These results suggest that TIMP‑2 promotes tumor progression, and that miR‑205‑5p directly regulates TIMP‑2, thereby suppressing pro‑MMP‑2 activation and inhibiting OSCC cell invasiveness. Our data describing the pathways regulated by miR‑205‑5p provide new insight into the mechanisms responsible for OSCC development and metastasis.
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http://dx.doi.org/10.3892/ijo.2018.4260DOI Listing
March 2018

Regulation of programmed-death ligand in the human head and neck squamous cell carcinoma microenvironment is mediated through matrix metalloproteinase-mediated proteolytic cleavage.

Int J Oncol 2018 Feb 11;52(2):379-388. Epub 2017 Dec 11.

Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.

Recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. According to recent clinical studies, tumour growth can be effectively reduced and survival can be improved by blocking the programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD‑L1) pathway. PD-L1 expression has been proposed as a potential causative mechanism, as HNSCC is highly immunosuppressive. However, anti-PD-1 treatment is beneficial only for certain patients. Therefore, the mechanisms controlling PD-L1 expression warrant further investigation in order to provide a better understanding of the predicting efficacy of and optimising anti-PD-1 therapy, alone or in combination. In this study, PD-L1 protein extracted from the cell membrane was found to be downregulated in OSC-20 cells compared with OSC-19 cells, despite a higher PD-L1 expression in the total cell lysate of the OSC-20 compared with the OSC-19 cells. Several matrix metalloproteinases (MMPs) were found to be upregulated in HNSCC; in particular, MMP-7 and -13 were upregulated in the OSC-20 compared with the OSC-19 cells. Purified PD-L1 was degraded by recombinant MMP-13 and -7. The expression of PD-L1 was significantly restored by a specific inhibitor of MMP-13 (CL82198), which suggested the involvement of MMP-13 in the shedding/cleavage of PD-L1 in the OSC-20 cells. Among the anticancer drugs conventionally used in the treatment of patients with HNSCC, paclitaxel increased MMP-13 expression in R/M HNSCC cells (HOC313 cells) co-cultured without/with dendritic cells (DCs). These results suggest that the shedding/cleavage of PD-L1 by MMP-13 is one of the mechanisms behind the protective effect against invasion and metastasis. Thus, MMP-13 has potential value as a marker predictive of the decreased efficacy of anti-PD-1 therapy. In addition, paclitaxel is a particularly promising candidate for combination therapy in R/M HNSCC with anti-PD-1 therapy.
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http://dx.doi.org/10.3892/ijo.2017.4221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741372PMC
February 2018

Elastin‑derived peptides are involved in the processes of human temporomandibular disorder by inducing inflammatory responses in synovial cells.

Mol Med Rep 2017 Sep 15;16(3):3147-3154. Epub 2017 Jul 15.

Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920‑8640, Japan.

Temporomandibular joint dysfunction (TMD) is a collection of clinical symptoms that involve masticatory muscles and the temporomandibular joint (TMJ). Common symptoms include limited jaw motion and joint sound/pain, along with TMJ disc displacement. TMD is frequently associated with synovitis, a chronic inflammation of the synovium. Fibroblast‑like synovial cells have been identified to produce several inflammatory mediators and may have an important role in the progression of TMJ inflammation. Degradation of the extracellular matrix molecule elastin may lead to the release of bioactive peptides. The present study aimed to explore the role of elastin‑derived peptides (EDPs) in human temporomandibular disorders. Therefore, interleukin‑6 (IL‑6) expression in the synovial fluid obtained from patients with TMD correlated significantly with two clinical parameters, specifically TMJ locking and pain/jaw function on a visual analog scale (VAS). To the best of our knowledge, this is the first study to determine that the concentration of EDPs in synovial fluid from patients with TMD may also be significantly correlated with the duration of TMJ locking, the VAS score and IL‑6 expression. In vitro, EDPs act on human TMJ synovial cells to promote upregulation of IL‑6 and the elastin‑degrading enzyme matrix metalloproteinase‑12 (MMP‑12). The upregulation of IL‑6 and MMP‑12 expression by EDPs may be mediated through elastin‑binding proteins (EBP) and a protein kinase A signalling cascade. These findings suggest a model for inflammation in the TMJ where EDPs are generated by harmful mechanical stimuli, induce both a pro‑inflammatory cascade and increase expression of MMP‑12 through activation of the EBP signalling cascade. This may lead to further increases in EDP levels, establishing a positive feedback loop leading to chronic inflammation in the TMJ. Therefore, significantly elevated levels of EDPs and IL‑6 in the synovial fluid of the TMJ may be indicators of the pathological conditions of the joint.
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http://dx.doi.org/10.3892/mmr.2017.7012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548023PMC
September 2017

Bone scan index of the jaw: a new approach for evaluating early-stage anti-resorptive agents-related osteonecrosis.

Ann Nucl Med 2017 Apr 19;31(3):201-210. Epub 2016 Dec 19.

Department of Nuclear Medicine, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.

Objective: A computer-aided diagnosis of bone scintigraphy using a bone scan index (BSI) has not been applied to a diagnosis of anti-resorptive agents-related osteonecrosis of the jaw (ARONJ). The aim of this study was to validate a diagnostic ability of BSI for early-stage ARONJ.

Methods: A total of 44 cancer patients treated with anti-resorptive drugs were evaluated retrospectively. All patients underwent bone scintigraphy and the tracer uptakes were analyzed by BSI. The software BONENAVI (FUJIFILM RI Pharma; EXINIbone, EXINI Diagnostics) could automatically detect abnormal intensities and calculate each regional BSI (rBSI). Among the rBSIs, the largest one in the jaw was manually selected and defined as maximum BSI of the jaw (BSIJmax). Uptake ratio (UR) between the maximum jaw count-to-average forehead count was also calculated. Screening accuracy of ARONJ based on 2 parameters was compared. Receiver operating characteristic analysis and Fisher's exact test were performed.

Results: The BSIJmax was significantly higher in patients who developed ARONJ than in those who did not, 3 months before the diagnosis of stage 2 ARONJ (p < 0.0001 and p = 0.02 in the maxilla and mandible, respectively). Using the cutoff values of 0.09% in the maxilla and 0.06% in the mandible, BSIJmax for predicting stage 2 ARONJ showed sensitivity and specificity of 88 and 96%, respectively, in the maxilla and 64 and 89%, respectively, in the mandible at 3 months before the diagnosis. The BSIJmax >0.09% and BSIJmax >0.06% in the maxilla and mandible, respectively, were much more frequently observed in patients who subsequently developed stage 2 ARONJ 3 months after the bone scintigraphy than in those who did not (p < 0.0001 and odds ratio = 182 in the maxilla and p < 0.005 and odds ratio = 14 in the mandible). The UR showed comparable diagnostic ability.

Conclusion: The BSIJ provided a new index for evaluating ARONJ. For predicting occurrence of ARONJ, the thresholds of BSIJmax = 0.09 and 0.06% in the maxilla and mandible, respectively, may be used in patients treated with anti-resorptive drugs, and a differential diagnosis including ARONJ is recommended.
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http://dx.doi.org/10.1007/s12149-016-1145-0DOI Listing
April 2017

Regulation of PD-L1 expression in a high-grade invasive human oral squamous cell carcinoma microenvironment.

Int J Oncol 2017 Jan 2;50(1):41-48. Epub 2016 Dec 2.

Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Ishikawa 920-8640, Japan.

Blockade of the programmed-death 1 receptor (PD-1)/programmed-death ligand (PD-L1) pathway efficiently reduces tumour growth and improves survival. Durable tumour regression with blockade of the PD-1/PD-L1 checkpoint has been demonstrated in recent clinical studies. Oral squamous cell carcinoma (OSCC) is highly immunosuppressive, and PD-L1 expression has been proposed as a potential mechanism responsible for this phenotype. Despite the fact that anti-PD-1 treatment can produce durable responses, such therapy appears to benefit only a subset of patients. Thus, it is important to understand the mechanisms underlying regulation of PD-L1 expression in the OSCC microenvironment. In this study, we showed that PD-L1 expression in high-grade invasive OSCC cell lines was lower than that in a low-grade invasive OSCC line and found a close correlation between PD-L1 expression and the epithelial-mesenchymal transition (EMT). PD-L1 expression was upregulated in macrophages and dendritic cells (DCs) in high-grade invasive human OSCC tissues or co-cultured with mesenchymal-phenotype OSCC cells in vitro. TLR4-inhibitory peptide successfully suppressed PD-L1 upregulation on macrophages and DCs co-cultured with mesenchymal-phenotype OSCC cells, suggesting that some EMT-induced tumour antigen is critical for PD-L1 induction on tumour-associated macrophages and DCs. Further studies are necessary to explore the impact of EMT on the tumour immune microenvironment and to identify potential biomarkers for selecting patients who might preferentially benefit from PD-1/PD-L1 blockade or immunotherapies more broadly.
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http://dx.doi.org/10.3892/ijo.2016.3785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182007PMC
January 2017

Eribulin sensitizes oral squamous cell carcinoma cells to cetuximab via induction of mesenchymal-to-epithelial transition.

Oncol Rep 2016 Dec 21;36(6):3139-3144. Epub 2016 Oct 21.

Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.

Inhibition of epidermal growth factor receptor (EGFR) signalling has emerged as a new treatment strategy for oral squamous cell carcinoma (OSCC). Previously, we found that loss of EGFR expression in OSCC was associated with epithelial-mesenchymal transition (EMT), and may have functional implications with regard to resistance to cetuximab, a monoclonal anti-EGFR antibody. Eribulin (a microtubule inhibitor) reportedly renders breast cancer less aggressive, and less likely to metastasise, by triggering mesenchymal‑to‑epithelial (MET) transition. In the present study we evaluated whether eribulin-induced MET was associated with re-sensitization of resistant OSCC cell lines to cetuximab. In vitro antiproliferative activities were determined in three human OSCC lines (OSC-20, OSC-19 and HOC313) treated with eribulin. These three human OSCC represented different EMT/MET states. Interestingly, HOC313 cells (mesenchymal phenotype) were highly sensitive to eribulin in comparison with other cell lines, and significantly enhanced the anti-proliferative effect of cetuximab in response to the drug. Eribulin also underwent a MET-associated gene switch that resulted in morphological changes and high EGFR expression in HOC313 cells, and abrogated a TGF-β-induced EMT gene expression signature. Eribulin-dependent sensitization of OSCC to cetuximab is likely due to induction of MET. Combination therapies based on eribulin and cetuximab have potential as a novel treatment regimen in OSCC.
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http://dx.doi.org/10.3892/or.2016.5189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112623PMC
December 2016

A Case of Sublingual Ranula That Responded Successfully to Localized Injection Treatment with OK-432 after Healing from Drug Induced Hypersensitivity Syndrome.

Case Rep Dent 2016 6;2016:6939568. Epub 2016 Apr 6.

Department of Oral and Maxillofacial Surgery, Division of Medicine, Interdisciplinary Graduate School of Medical and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.

A ranula is a mucus retention cyst or pseudocyst caused by leakage of mucus from the sublingual gland and generally occurs in the oral floor. In addition, drug induced hypersensitivity syndrome (DIHS) is a rare but well-recognized serious adverse effect characterized by fever, skin rashes, generalized lymphadenopathy, hepatitis, and hepatosplenomegaly and oral stomatitis. This paper presents the first case of successfully treated sublingual ranula with localized injection of OK-432 after healing from drug induced hypersensitivity syndrome, which has previously been unreported in the literature. We present the case of a 38-year-old Japanese woman with sublingual ranula that responded successfully to localized injection treatment with OK-432 after healing from drug induced hypersensitivity syndrome. She was affected with cutaneous myositis and interstitial lung disease when she was 26 years old. At the age 34 years, she received additional oral treatment of diaminodiphenyl-sulfone due to deterioration of the cutaneous myositis, which resulted in drug induced hypersensitivity syndrome (DIHS) with severe oral stomatitis. Local injection of OK-432 to the ranula may be a very safe and useful treatment method even if the patient has a history of drug allergy and has connective tissue disease such as cutaneous myositis.
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http://dx.doi.org/10.1155/2016/6939568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837263PMC
May 2016

Loss of epidermal growth factor receptor expression in oral squamous cell carcinoma is associated with invasiveness and epithelial-mesenchymal transition.

Oncol Lett 2016 Jan 27;11(1):201-207. Epub 2015 Oct 27.

Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.

Inhibition of epidermal growth factor receptor (EGFR) signaling has emerged as a novel therapeutic strategy for the treatment of oral squamous cell carcinoma (OSCC). The EGFR-directed inhibitor cetuximab is currently the only approved targeted therapy for the treatment of OSCC. EGFR status may affect the patient response to cetuximab treatment. In the present study, via analysis of the immunomarker for EGFR, it was revealed that 58.3% of the total cases investigated stained positively for EGFR expression, and furthermore, that invasiveness was inversely correlated with EGFR expression. Expression levels of EGFR were quantified, and the correlation between EGFR expression and cetuximab sensitivity was investigated using three varying grades of invasive human OSCC line. EGFR expression in high-grade invasive cells was significantly downregulated compared with that of low-grade invasive cells. There was no significant antiproliferative effect in the high-grade invasive cells treated with various concentrations of cetuximab. The EMT-associated genes, N-cadherin, vimentin and Snail, were upregulated in the high-grade invasive cells. The low-grade invasive cells exhibited characteristics of typical epithelial cells, including the expression of E-cadherin and absence of the expression of N-cadherin, vimentin and Snail. Transforming growth factor-β induced low-grade invasive cells to undergo an epithelial-mesenchymal transition (EMT)-associated gene switch, which resulted in low levels of EGFR expression. The results of the present study suggested that loss of EGFR expression in OSCC was associated with EMT, and may have functional implications with regard to tumor invasiveness and the resistance to cetuximab treatment.
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http://dx.doi.org/10.3892/ol.2015.3833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727181PMC
January 2016

Krüppel-like factors 4 and 5 expression and their involvement in differentiation of oral carcinomas.

Int J Clin Exp Pathol 2015 1;8(4):3701-9. Epub 2015 Apr 1.

Department of Biochemistry, School of Life Dentistry at Tokyo, The Nippon Dental University Fujimi 1-9-20, Chiyoda-ku, Tokyo 102-8159, Japan.

Proliferation-differentiation balance of epithelial cells is regulated by Krüppel-like factors (KLF) 4 and 5, and the unbalanced expression relates to carcinoma progression. However, little is known about the expression and role in oral carcinomas. This study examined expression of KLF4 and KLF 5 in the carcinomas by immunohistochemistry (n = 67) and the involvement in proliferation and differentiation of carcinoma cells. KLF4 was detected in keratinizing carcinoma cells and KLF5 in non-keratinizing cells. KLF4 staining declined in the patient with lymph node metastasis (P < 0.05) and in parallel with the histological dedifferentiation (P = 0.09). Exogenous overexpression of KLF4 arranged cells in a cobble-like structure with desmosomes and KLF5 elongated cells like fibroblasts without desmosomes. KLF4 suppressed fibronectin expression, and KLF5 down-regulated and degraded E-cadherin. The proliferation was not affected by KLFs. Thus, down-regulation of KLF4 and up-regulation of KLF5 may stimulate oral carcinoma progression through the dedifferentiation of carcinoma cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466938PMC
March 2016

Membrane-type 1 matrix metalloproteinase regulates fibronectin assembly and N-cadherin adhesion.

Biochem Biophys Res Commun 2014 Jul 26;450(2):1016-20. Epub 2014 Jun 26.

Division of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address:

Fibronectin matrix formation requires the increased cytoskeletal tension generated by cadherin adhesions, and is suppressed by membrane-type 1 matrix metalloproteinase (MT1-MMP). In a co-culture of Rat1 fibroblasts and MT1-MMP-silenced HT1080 cells, fibronectin fibrils extended from Rat1 to cell-matrix adhesions in HT1080 cells, and N-cadherin adhesions were formed between Rat1 and HT1080 cells. In control HT1080 cells contacting with Rat1 fibroblasts, cell-matrix adhesions were formed in the side away from Rat1 fibroblasts, and fibronectin assembly and N-cadherin adhesions were not formed. The role of N-cadherin adhesions in fibronectin matrix formation was studied using MT1-MMP-silenced HT1080 cells. MT1-MMP knockdown promoted fibronectin matrix assembly and N-cadherin adhesions in HT1080 cells, which was abrogated by double knockdown with either integrin β1 or fibronectin. Conversely, inhibition of N-cadherin adhesions by its knockdown or treatment with its neutralizing antibody suppressed fibronectin matrix formation in MT1-MMP-silenced cells. These results demonstrate that fibronectin assembly initiated by MT1-MMP knockdown results in increase of N-cadherin adhesions, which are prerequisite for further fibronectin matrix formation.
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http://dx.doi.org/10.1016/j.bbrc.2014.06.100DOI Listing
July 2014

Concomitant loss of p120-catenin and β-catenin membrane expression and oral carcinoma progression with E-cadherin reduction.

PLoS One 2013 6;8(8):e69777. Epub 2013 Aug 6.

Department of Biochemistry, School of Life Dentistry at Tokyo, The Nippon Dental University, Tokyo, Japan.

The binding of p120-catenin and β-catenin to the cytoplasmic domain of E-cadherin establishes epithelial cell-cell adhesion. Reduction and loss of catenin expression degrades E-cadherin-mediated carcinoma cell-cell adhesion and causes carcinomas to progress into aggressive states. Since both catenins are differentially regulated and play distinct roles when they dissociate from E-cadherin, evaluation of their expression, subcellular localization and the correlation with E-cadherin expression are important subjects. However, the same analyses are not readily performed on squamous cell carcinomas in which E-cadherin expression determines the disease progression. In the present study, we examined expression and subcellular localization of p120-catenin and β-catenin in oral carcinomas (n = 67) and its implications in the carcinoma progression and E-cadherin expression using immunohitochemistry. At the invasive front, catenin-membrane-positive carcinoma cells were decreased in the dedifferentiated (p120-catenin, P < 0.05; β-catenin, P < 0.05) and invasive carcinomas (p120-catenin, P < 0.01; β-catenin, P < 0.05) and with the E-cadherin staining (p120-catenin, P < 0.01; β-catenin, P < 0.01). Carcinoma cells with β-catenin cytoplasmic and/or nuclear staining were increased at the invasive front compared to the center of tumors (P < 0.01). Although the p120-catenin isoform shift from three to one associates with carcinoma progression, it was not observed after TGF-β, EGF or TNF-α treatments. The total amount of p120-catenin expression was decreased upon co-treatment of TGF-β with EGF or TNF-α. The above data indicate that catenin membrane staining is a primary determinant for E-cadherin-mediated cell-cell adhesion and progression of oral carcinomas. Furthermore, it suggests that loss of p120-catenin expression and cytoplasmic localization of β-catenin fine-tune the carcinoma progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069777PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3735538PMC
April 2014

xCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma.

Cancer Res 2013 Mar 14;73(6):1855-66. Epub 2013 Jan 14.

Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, School of Medicine, Keio University, Shinjuku-ku, Japan.

The targeting of antioxidant systems that allow stem-like cancer cells to avoid the adverse consequences of oxidative stress might be expected to improve the efficacy of cancer treatment. Here, we show that head and neck squamous cell carcinoma (HNSCC) cells that express variant isoforms of CD44 (CD44v) rely on the activity of the cystine transporter subunit xCT for control of their redox status. xCT inhibition selectively induces apoptosis in CD44v-expressing tumor cells without affecting CD44v-negative differentiated cells in the same tumor. In contrast to CD44v-expressing undifferentiated cells, CD44v-negative differentiated cells manifest EGF receptor (EGFR) activation and rely on EGFR activity for their survival. Combined treatment with inhibitors of xCT-dependent cystine transport and of EGFR resulted in a synergistic reduction of EGFR-expressing HNSCC tumor growth. Thus, xCT-targeted therapy may deplete CD44v-expressing undifferentiated HNSCC cells and concurrently sensitize the remaining differentiating cells to available treatments including EGFR-targeted therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-3609-TDOI Listing
March 2013

Loss of claudin-7 is a negative prognostic factor for invasion and metastasis in oral squamous cell carcinoma.

Oncol Rep 2013 Feb 30;29(2):445-50. Epub 2012 Nov 30.

Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan.

Claudin-7 belongs to the claudin family, which consists of 24 subtypes of essential tight junction (TJ) integral membrane proteins with molecular weights of 20-27 kDa. We investigated the interrelationship between clinicopathological findings and claudin-7 expression in oral squamous cell carcinoma (OSCC). Using immunohistochemical techniques to examine the expression levels of claudin-7 in 67 cases of OSCC, claudin-7 expression was detected in 35 (52.2%) of the 67 cases. We also compared the clinicopathological features of the OSCC cases with claudin-7 expression levels. Moreover, six cell lines with various invasive properties were investigated in vitro to compare mRNA and protein levels of claudin-7 using reverse transcription-polymerase chain reaction (RT-PCR) and the western blotting method. Decreased claudin-7 expression correlated significantly with T-category (p<0.05), lymph node metastasis (p<0.01), and mode of invasion (p<0.001). Patients with positive claudin-7 expression had a significantly better prognosis (p<0.05). Claudin-7 protein and mRNA levels were lower in the HOC313 and TSU cells, which have higher invasive potentials compared with other cell lines. These results suggest that loss of claudin-7 expression is associated closely with invasion and lymph metastasis and is an unfavorable prognostic factor in patients with OSCC.
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http://dx.doi.org/10.3892/or.2012.2161DOI Listing
February 2013

Progression of oral squamous cell carcinoma accompanied with reduced E-cadherin expression but not cadherin switch.

PLoS One 2012 23;7(10):e47899. Epub 2012 Oct 23.

Department of Biochemistry, The Nippon Dental University, Tokyo, Japan.

The cadherin switch from E-cadherin to N-cadherin is considered as a hallmark of the epithelial-mesenchymal transition and progression of carcinomas. Although it enhances aggressive behaviors of adenocarcinoma cells, the significance and role of cadherin switch in squamous cell carcinomas (SCCs) are largely controversial. In the present study, we immunohistochemically examined expression of E-cadherin and N-cadherin in oral SCCs (n = 63) and its implications for the disease progression. The E-cadherin-positive carcinoma cells were rapidly decreased at the invasive front. The percentage of carcinoma cells stained E-cadherin at the cell membrane was reduced in parallel with tumor dedifferentiation (P<0.01) and enhanced invasion (P<0.01). In contrast, N-cadherin-positive cells were very limited and did not correlate with the clinicopathological parameters. Mouse tongue tumors xenotransplantated oral SCC cell lines expressing both cadherins in vitro reproduced the reduction of E-cadherin-positive carcinoma cells at the invasive front and the negligible expression of N-cadherin. These results demonstrate that the reduction of E-cadherin-mediated carcinoma cell-cell adhesion at the invasive front, but not the cadherin switch, is an important determinant for oral SCC progression, and suggest that the environments surrounding carcinoma cells largely affect the cadherin expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047899PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479144PMC
April 2013

A hypothesis on the desired postoperative position of the condyle in orthognathic surgery: a review.

Oral Surg Oral Med Oral Pathol Oral Radiol 2012 Nov 20;114(5):567-76. Epub 2012 Jul 20.

Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kanazawa University, Takaramachi, Kanazawa, Japan.

It is very important to clarify the relationship between a dentofacial structure and a temporomandibular joint (TMJ) structure in orthognathic surgery. Recently, it was reported that the skeletal and occlusal patterns were associated with the TMJ morphology, including the disk position. In orthognathic surgery, some surgeons state that alterations in the condylar position from surgery can lead to malocclusion associated with the risk of early relapse, and also favor the development of temporomandibular disorders. For these reasons, several positioning devices have been proposed and applied, but now there is no scientific evidence to support the use of condylar positioning devices. There are some reasons why scientific evidence cannot be obtained; however, it also includes the question of whether the preoperative position of the condyle is the desired postoperative position. The purpose of this study was to verify the desired condylar position in orthognathic surgery, based on literature on the postoperative condylar position in orthognathic surgery. From the studies reviewed, it was suggested that the preoperative position of the condyle was not the desired postoperative position in orthognathic surgery.
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http://dx.doi.org/10.1016/j.oooo.2011.12.026DOI Listing
November 2012

Assessment of bone healing and hypoesthesia in the upper lip after Le Fort I osteotomy with self-setting α-tricalcium phosphate and absorbable plates.

J Craniomaxillofac Surg 2013 Mar 20;41(2):129-34. Epub 2012 Jul 20.

Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8641, Japan.

Purpose: The purpose of this study was to evaluate hypoesthesia of the upper lip and bone formation using self-setting α-tricalcium phosphate (Biopex(®)) between the segments following Le Fort I osteotomy with bent absorbable plate fixation.

Subjects And Methods: The subjects were 47 patients (94 sides) who underwent Le Fort I osteotomy with and without mandibular osteotomy. They were divided into a Biopex(®) group (48 sides) and a control group (46 sides). The Biopex(®) was inserted into the anterior part of the gap between the segments in the Biopex(®) group. Trigeminal nerve hypoesthesia at the region of the upper lip was assessed bilaterally by the trigeminal somatosensory-evoked potential (TSEP) method. The area of the Biopex(®) at the anterior part in the maxilla was assessed immediately after surgery and 1 year postoperatively by computed tomography (CT).

Results: The mean measurable period and standard deviation were 13.2 ± 18.5 weeks in the control group, 14.5 ± 17.9 weeks in the Biopex(®) group, and there was no significant difference in TSEP. The area of the Biopex(®) after 1 year was significantly smaller than that immediately after surgery (right side: P = 0.0024, left side: P = 0.0001) and bone defects between the segments could not be found in the Biopex(®) group. In the control group, although the areas of bone defect after 1 year were significantly smaller than that immediately after surgery on the right side (P = 0.0133) and left side (P = 0.0469) in the frontal view, complete healing of the bone defects could be seen in 12 of 46 sides after 1 year.

Conclusion: This study suggested that inserting Biopex(®) in the gap between the maxillary segments was useful for new bone formation and it did not prevent the recovery of upper lip hypoesthesia after Le Fort I osteotomy with absorbable plate fixation.
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http://dx.doi.org/10.1016/j.jcms.2012.06.004DOI Listing
March 2013

Changes in temporomandibular joint and ramus after sagittal split ramus osteotomy in mandibular prognathism patients with and without asymmetry.

J Craniomaxillofac Surg 2012 Dec 14;40(8):821-7. Epub 2012 Apr 14.

Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8641, Japan.

The purpose of this study was to examine the changes in the temporomandibular joint (TMJ) and ramus after sagittal split ramus osteotomy (SSRO) with and without Le Fort I osteotomy. The subjects consisted of 87 Japanese patients diagnosed with mandibular prognathism with and without asymmetry. They were divided into 2 groups (42 symmetric patients and 45 asymmetric patients). The TMJ disc tissue was assessed by magnetic resonance imaging (MRI) and the TMJ space, condylar and ramus angle were assessed by computed tomography (CT) preoperatively and postoperatively. Medial joint space on the deviation side in the asymmetry group was significantly larger than that in the symmetry group (P = 0.0043), and coronal ramus angle on the non-deviation side in the asymmetry group was significantly larger than that in the symmetry group preoperatively (P = 0.0240). The horizontal condylar angle on the deviation side in the asymmetry group was significantly larger than that in the symmetry group (P = 0.0302), posterior joint space on the non-deviation side in the symmetry group was significantly larger than that in the asymmetry group postoperatively (P = 0.00391). The postoperative anterior joint space was significantly larger than the preoperative value on both sides in both groups (the deviation side in the symmetry group: P = 0.0016, the non-deviation side in the symmetry group: P < 0.0001, the deviation side in the asymmetry group: P = 0.0040, the non-deviation side in the asymmetry group: P = 0.0024). The preoperative disc position could was not changed in either group. These results suggest that significant expansion of anterior joint space could occur on the deviation side and non-deviation side in the asymmetry group as well as on both sides in the symmetry group, although disc position did not change in either group.
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http://dx.doi.org/10.1016/j.jcms.2012.03.003DOI Listing
December 2012

Expression of urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor and maspin in oral squamous cell carcinoma: Association with mode of invasion and clinicopathological factors.

Oncol Rep 2011 Dec 10;26(6):1555-60. Epub 2011 Aug 10.

Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.

It is well documented that the binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR), which has been implicated in cancer invasion and metastasis, is regulated by several inhibitors such as maspin. In this study, we investigated the interrelationship between clinicopathologic findings and expression of uPA, uPAR and maspin in oral squamous cell carcinoma (OSCC) to elucidate the participation of maspin in the uPA/uPAR system in the malignant behavior of OSCC. Using immunohistochemical techniques to examine the expression levels of uPA, uPAR and maspin in 54 cases of OSCC, we also compared the clinicopathologic features of OSCC with the expression levels of each. Moreover, we examined the expression of uPA, uPAR and maspin in six cell lines derived from OSCC using reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. uPA and uPAR showed a positive correlation with the mode of cancer invasion; conversely maspin showed a negative correlation with the mode of invasion. Multivariate analysis revealed that only two factors (N-category and uPA+/uPAR+/maspin- expression pattern) were significant and independent variables with relative risks of 3.84 and 2.52, respectively. In particular, tumors exhibiting an expression pattern of uPA+/uPAR+/maspin- were highly malignant and were associated with the worst survival rate (5-year overall survival rate, 29.4%), while tumors with an expression pattern, uPA-/uPAR-/Μaspin+, showed the most favorable survival rate (5-year overall survival rate, 77.8%). In vitro, lower expression of maspin was also noted in the cell lines derived from grade 4D OSCC, which exhibited a stronger invasive potential than the cells lines derived from the other grades of OSCC, while uPA and uPAR demonstrated an expression trend opposite to maspin. These results indicate that uPA, uPAR and maspin expression patterns may be useful markers for evaluating the clinical course or prognosis of OSCC patients.
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http://dx.doi.org/10.3892/or.2011.1419DOI Listing
December 2011

Expression form of p53 and PCNA at the invasive front in oral squamous cell carcinoma: correlation with clinicopathological features and prognosis.

J Oral Pathol Med 2011 Oct 18;40(9):693-8. Epub 2011 Apr 18.

Department of Oral and Maxillofacial Surgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background:  Abnormalities in cell-cycle-controlling genes are important in the malignant transformation and proliferation of tumors. Among these genes, the tumor suppressor gene p53 is the most notable, and its mutations provide an indicator of tumor progression and prognosis. Proliferating cell nuclear antigen (PCNA) is a highly conserved nuclear protein that is expressed during cell replication and DNA repair. This study examined the expression of p53 and PCNA at the invasive front of oral squamous cell carcinomas (OSCC) by immunohistochemical staining, and investigated the relationship of these proteins to clinicopathological findings and prognosis.

Methods:  Fifty-nine biopsy cases of OSCC were examined by immunohistochemical staining. Clinicopathological data were gathered and patient survival was analyzed.

Results:  The p53 labeling index (p53-LI) and PCNA labeling index (PCNA-LI) were examined at the invasive front of the tumors. A high p53-LI (p53+) was observed in 17 of the 59 cases (28.8%) and a high PCNA-LI (PCNA+) was observed in 28 of the 59 cases (47.5%). Among the modes of cancer invasion, many of the p53+/PCNA+ cases could be confirmed as highly invasive cancer (P < 0.05). In addition, the p53+/PCNA+ cases showed a high risk of tumor recurrence compared with the other expression forms, and patients with p53+/PCNA+ had a worse prognosis than those with the other expression forms. High labeling indices of p53 and PCNA are associated with poor prognosis in patients with OSCC.

Conclusion:  We suggest that it is important to investigate the expression of p53 and PCNA at the invasive front of OSCC.
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http://dx.doi.org/10.1111/j.1600-0714.2011.01032.xDOI Listing
October 2011