Search

A promising approach to improve the poor antibacterial properties of dental composite resins has been the addition of metal oxide nanoparticles into the resin matrix. This systematic review aimed to determine whether the addition of zinc oxide nanoparticles (ZnO-NPs) improves the antibacterial properties of direct dental composite resins. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered with the PROSPERO database: CRD42019131383. A systematic literature search was conducted using the following databases: Medline (Ovid), the Cochrane Library, SCOPUS, CINAHL, Web of Science, Trove, Google Scholar, World Cat, and OpenGrey. The initial search retrieved 3178 results, which were then screened against inclusion and exclusion criteria, resulting in a total of four studies that were eligible for qualitative synthesis within this review. All the included studies were in vitro non-randomized post-test design experimental studies. A lack of congruity in the results obtained from these studies that used different tests to evaluate antibacterial activity was evident. Although some studies demonstrated a significant improvement of antibacterial properties in composites containing at least 1% ZnO-NPs (wt %), they are unlikely to present any clear clinical advantage due to the short lifetime of observed antibacterial properties.

DKK3, a member of the dickkopf Wnt signaling pathway inhibitor family, is believed to be a tumor suppressor because of its reduced expression in cancer cells. However, our previous studies have revealed that DKK3 expression is predominantly observed in head and neck/oral squamous cell carcinoma (HNSCC/OSCC). Interestingly, HNSCC/OSCC patients with DKK3 expression showed a high rate of metastasis and poorer survival, and siRNA-mediated knockdown of DKK3 in HNSCC-derived cancer cell lines resulted in reduced cellular migration and invasion. From these data, it was hypothesized that DKK3 might exert an oncogenic function specific to HNSCC. In the present research, the DKK3 overexpression model was established, and its influences were investigated, together with molecular mechanism studies. The DKK3 expression profile in cancer cell lines was investigated, including HNSCC/OSCC, esophageal, gastric, colorectal, pancreatic, prostatic, and lung cancers. DKK3 overexpression was performed in HNSCC-derived cells by transfection of expression plasmid. The effects of DKK3 overexpression were assessed on cellular proliferation, migration, invasion, and in vivo tumor growth. The molecular mechanism of DKK3 overexpression was investigated by Western blotting and microarray analysis. DKK3 overexpression significantly elevated cellular proliferation, migration, and invasion, as well as increased mRNA expression of cyclin D1 and c-myc. However, reporter assays did not show TCF/LEF activation, suggesting that the increased malignant property of cancer cells was not driven by the Wnt/β-catenin pathway. For the investigation of the pathways/molecules in DKK3-mediated signals, the Western blot analyses revealed that phosphorylation of Akt (S473) and c-Jun (Ser63) was elevated. The application of a PI3K kinase inhibitor, LY294002, on HSC-3 DKK3 cells significantly decreased tumor cell proliferation, migration, and invasion. From these results, we demonstrated that DKK3 might contribute to cellular proliferation, invasion, migration, and tumor cell survival in HNSCC cells through a mechanism other than the canonical Wnt signaling pathway, which might be attributed to PI3K‐Akt signaling.

Head and neck squamous cell carcinomas (HNSCCs) frequently invade the bones of the facial skeleton. Semaphorin 4D (Sema4D) is an axon guidance molecule produced by oligodendrocytes. Sema4D was also identified in the bone microenvironment and many cancer tissues including HNSCC. To date, however, the role of Sema4D in cancer-associated bone disease is still unknown. This is the first study to demonstrate the role of Sema4D in bone invasion of cancer. In the clinical tissue samples of bone lesion of HNSCC, Sema4D was detected at high levels, and its expression was correlated with insulin-like growth factor-I (IGF-I) expression. In vitro experiments showed that IGF-I regulates Sema4D expression and Sema4D increased proliferation, migration and invasion in HNSCC cells. Sema4D also regulated the expression of receptor activator of nuclear factor κβ ligand (RANKL) in osteoblasts, and this stimulated osteoclastgenesis. Furthermore, knockdown of Sema4D in HNSCC cells inhibited tumor growth and decreased the number of osteoclasts in a mouse xenograft model. Taken together, IGF-I-driven production of Sema4D in HNSCCs promotes osteoclastogenesis and bone invasion.

The purpose of this paper is to review current evidence for a concomitant relationship between oral diseases and malnutrition in the elderly. A narrative overview of current literature was undertaken to combine the context for research with critical elaboration and commentary. Oral disease is one of the most common public health issues worldwide with significant socio-economic impacts, and yet it is frequently neglected in public health policy. Epidemiologic studies show that oral disease frequently causes malnutrition in the elderly. In particular, malnutrition is associated with poor quality of life and poor efficacy of oncologic therapy in oral cancer patients. As oral disease remains a major public health burden worldwide, it is of great importance to integrate oral health into the nutrition agenda via the Common Risk Factor Approach. As such the long-term sustainable strategy for global oral health should focus on health promotion and malnutrition prevention in the elderly.

The contemporary practice of lung auscultation as an essential part of physical examination can be traced back to the time of Hippocrates [1].

Background Children with complex neurodevelopmental disabilities such as cerebral palsy (CP), have a higher risk of dental disease related at least in part to greater difficulties in performing and maintaining effective oral hygiene and oral care practices. However, to date, there are very few studies that have considered the impact of dental disease on the Oral Health-Related Quality of Life (OHRQoL) of children and adolescents with cerebral palsy. This study aimed to investigate the association between dental caries experience and oral health related quality of life (OHRQoL) among children and adolescents with cerebral palsy in a low-resource setting (Bangladesh). Methods A total of 90 children and adolescents with CP, 2–17 years old (median age 10 years; 37.8% female and 62.2% male) were randomly selected from the Bangladesh Cerebral Palsy Register (BCPR) The decayed, missing and filled teeth (dmft/DMFT) index was used to measure caries experience. Child Perceptions Questionnaire (CPQ) and Family Impact Scale (FIS) were used to assess oral health–related quality of life (OHRQoL). Binary logistic regression was used to investigate factors that may contribute to dental caries experience. Results Dental caries were observed among 55.6% of the participants. After adjusting for age and gender, binary logistic regression analysis showed that dental caries experience was significantly associated with those who had teeth/mouth pain (rate ratio 7.3; P = 0.02), food caught between teeth (rate ratio: 6.4; P = 0.02), difficulty in eating and drinking (rate ratio 5.9; p = 0.02) and those who felt frequently upset (rate ratio: 54.7; P = 0.02). Conclusion In this study, we found that children and adolescents with CP in a low-resource setting had high dental caries experience and that dental caries had a negative impact on OHRQoL amongst these participants and their parents/caregivers. Health care professionals should be aware of the importance of dental health and oral hygiene in this population. These findings highlight the need for oral health promotion programs for children and adolescents with CP in these settings to reduce pain and to improve quality of life.

Cleidocranial dysplasia (CCD) is a congenital autosomal dominant syndrome characterised by dental and osseous dysplasia that leads to multiple dental and craniofacial anomalies. Two-thirds of CCD cases are associated with mutations of the runt-related transcription factor 2 (RUNX2) gene which codes for a transcription factor that is responsible for differentiation of osteoblasts and osteoclasts and skeletal development. Multiple mutations have been identified in the Runx2 gene, primarily clustered in the Runt domain. Other genes such as CCAAT/enhancer-binding protein beta (Cebpb) and T-box transcription factor TBX1 (Tbx1) are under investigation. There are multiple clinical and radiological signs of CCD, e.g. brachycephaly, frontal and parietal bossing, open sutures and fontanelles, delayed closure of fontanelles, kyphosis, narrow sloping shoulders, multiple wormian bones, and delayed mineralisation of the skull. Although the signs present themselves in varying degrees, certain signs such as supernumerary teeth, frontal bossing, hypoplastic maxilla, and prognathic mandible are characteristic. However, many of them may not appear before the growth spurt in all cases. Early identification of CCD, especially prenatal ultrasound diagnosis, has a better prognosis as early orthodontic intervention can be commenced. Apart from clinical and radiographic analysis, identification of a RUNX2 mutation can serve as a diagnostic aid in families with a history of CCD. However, it is important to understand that only two-thirds of the people with CCD have RUNX2 mutation, so genetic analysis will not be of use in people without the mutations.

Introduction Most Australian universities have abbreviated the anatomy curriculum and modified its mode of delivery. This study examines dental student perceptions of different methods of head and neck anatomy teaching with respect to the adequacy of allocated time and the relative meaningfulness of the teaching methods. Methods All second-year students in the School of Dentistry and Health Sciences at Charles Sturt University (CSU) were invited to complete a matrix-grid questionnaire. Participants were asked to score four methods of teaching (lectures, study of prosected materials, tutorials and quizzes) using a 5-point Likert scale. The questionnaire included questions about the time adequacy for anatomy lectures, tutorials and laboratory study, and the potential value of learning anatomy through the study of prosected materials. SPSS (Version 21.0) was used to analyse the data, and statistical significance was set at 0.05. Results Seventy-two students (79.5%) responded to the survey. Overall, learning anatomy through the study of prosected materials was the single highest scored method, followed by lectures, tutorials and quizzes. Graduate entrants felt that not enough time was devoted to learning anatomy through the study of prosected materials, compared with school leavers (89.4% and 10.6%, respectively), having one extra session of learning in the anatomy laboratory (71.4% and 28.6%, respectively) and adding dissection (75.0% and 25.0%, respectively) would be helpful. Conclusion This study demonstrates that dental students perceive the study of prosected materials in the wet laboratory as the most valuable method of learning anatomy, but an extended anatomy curriculum would be even more effective and appreciated.

Background and Aim: Heat shock protein 90 (HSP90) and mammalian target of rapamycin (mTOR) are involved in the molecular pathogenesis of advanced oral squamous cell carcinoma. HSP90 inhibitors are capable of effectively interfering with multiple signaling pathways, including the mTOR signaling pathway. However, the combined effects of HSP90 and mTOR inhibitors on oral squamous cell carcinoma are still unknown. In this study, we investigated the dual treatment of the novel HSP90 inhibitor NVP-AUY922 and temsirolimus against oral squamous cell carcinoma. Materials and Methods: The effect of the combination of NVP-AUY922 and temsirolimus on oral squamous cell carcinoma in vitro and in vivo was determined by MTS assay and mouse xenograft models. The effect of the combination on angiogenesis was determined by tube formation assay and angioreactor. Results: The combination treatment of NVP-AUY922 and temsirolimus significantly inhibited the proliferation of SAS oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. We have clearly shown that the combination treatment of NVP-AUY922 and temsirolimus inhibited vascular formation both in vitro and in vivo. Moreover, the combination treatment of NVP-AUY922 and temsirolimus prolonged the survival rate in mice xenografted with oral squamous cell carcinoma. Conclusions: Here, we showed the activity of a combination of mTOR and HSP90 inhibitors for the treatment of advanced oral squamous carcinoma.

Aim To describe the oral health status and investigate factors affecting dental caries experience among children with cerebral palsy (CP) in rural Bangladesh. Method A cross-sectional study was conducted among children with CP who are part of the Bangladesh Cerebral Palsy Register (BCPR) study. Caries experience was measured by identifying decayed, missing, and filled teeth for deciduous and permanent teeth (dmft/DMFT). Clinical periodontal index, body mass index, oral hygiene behaviour, masticatory ability, and dietary habits were recorded. CP motor types and severity of functional mobility (Gross Motor Function Classification System [GMFCS]) were assessed. Results Of 90 children with CP (mean age 9y 7mo, range 2–17y, 37.8% female and 62.2% male), 35% of 2 to 6 year olds, and 70% of 7 to 11 year olds (p=0.014) experienced caries (dmft+DMFT>0). The mean values (standard deviation [SD]) of dmft and DMFT were 2.46 (3.75) and 0.72 (1.79) respectively. After adjusting for age and sex, binary logistic regression analysis showed a significant relationship with dental caries for children who had quadriplegia (odds ratio [OR] 5.56, p=0.035), tooth cleaning less than one time/day (OR 0.08, p=0.016), using toothpowder or charcoal for cleaning (OR 7.63, p=0.015), and snacking between meals more than one time/day (OR 6.93, p=0.012). Interpretation Early oral health preventive care is required for children with CP because dental caries is highly prevalent in these children.

Summary Sonic hedgehog (Shh) and its signaling have been identified in several human cancers, and increased levels of its expression appear to correlate with disease progression and metastasis. However, the role of Shh in bone destruction associated with oral squamous cell carcinomas, which frequently invade the maxilla or the mandible, is still unclear. In this study we show that the use of siRNA for Shh to block SHH secreted by SAS oral squamous cell carcinoma cells suppressed the tumor growth and tumor angiogenesis of subcutaneous SAS xenografts in vivo . Moreover, blockade of Shh in SAS cells decreased tumor growth and osteoclast number in a tibial metaphysis mouse model. Significantly, we clearly show that SHH stimulated osteoclast formation in a co-culture system consisting of murine bone stromal ST2 cells and murine CD11b + bone marrow cells. These findings suggest that Shh signaling is a potential target for the treatment of oral squamous cell carcinoma associated with bone destruction.

Purpose of the research Ligneous gingivitis is a rare disease characterized by nodular gingival enlargement secondary to fibrin deposits induced by micro-injury in the gingiva, which disorder results from plasminogen (PLG) deficiency. Although none have investigated the association of wound healing factors with ligneous gingivitis. In this study, in addition to a histopathologic examination of ligneous gingivitis in a case of type I PLG deficiency, we further present data showing the effect of wound healing factors in association with fibrin in vitro to clarify the pathobiology of ligneous gingivitis in PLG-deficient patients. Principle results Immunohistochemical analysis revealed that transforming growth factor (TGF)-β1, connective tissue growth factor/CCN2 (CCN2), and endothelin-1 (ET-1) had accumulated in the extracellular matrix around the epithelial and fibroblastic cells near the fibrin deposition. Consistent with these results, fibrin and TGF-β1 synergistically up-regulated CCN2 and ET-1 gene expression in human dermal fibroblasts. Major conclusions Fibrin plays a vicious role in ligneous gingivitis pathobiology by up-regulating CCN2 and ET-1 expression through the TGF-β signaling pathway.

Focal adhesion kinase (FAK) is a 125-kDa non-receptor type tyrosine kinase that localizes to focal adhesions. FAK overexpression is frequently found in invasive and metastatic cancers of the breast, colon, thyroid, and prostate, but its role in osteolytic metastasis is not well understood. In this study, we have analyzed anti-tumor effects of the novel FAK Tyr(397) inhibitor TAE226 against bone metastasis in breast cancer by using TAE226. Oral administration of TAE226 in mice significantly decreased bone metastasis and osteoclasts involved which were induced by MDA-MB-231 breast cancer cells and increased the survival rate of the mouse models of bone metastasis. TAE226 also suppressed the growth of subcutaneous tumors in vivo and the proliferation and migration of MDA-MB-231 cells in vitro. Significantly, TAE226 inhibited the osteoclast formation in murine pre-osteoclastic RAW264.7 cells, and actin ring and pit formation in mature osteoclasts. Moreover, TAE226 inhibited the receptor activator for nuclear factor κ B Ligand (RANKL) gene expression induced by parathyroid hormone-related protein (PTHrP) in bone stromal ST2 cells and blood free calcium concentration induced by PTHrP administration in vivo. These findings suggest that FAK was critically involved in osteolytic metastasis and activated in tumors, pre-osteoclasts, mature osteoclasts, and bone stromal cells and TAE226 can be effectively used for the treatment of cancer induced bone metastasis and other bone diseases.

Head and neck squamous cell carcinoma (HNSCC) poses a significant challenge clinically, as it can invade facial bones and cause bone pain that is undertreated and poorly understood. Here we studied HNSCC bone pain (HNSCC-BP) in an intratibial mouse xenograft model that uses a human HNSCC cell line (SAS cells). These mice develop HNSCC-BP associated with an upregulation of phosphorylated ERK1/2 (pERK1/2), which is a molecular indicator of neuron excitation in the dorsal root ganglia (DRGs) of sensory nerve cell bodies. Our experiments demonstrated that the inhibition of monocarboxylate transporter 4 (MCT4) by short hairpin (shRNA) transduction suppressed the HNSCC-BP, the lactate level in bone marrow, and the pERK1/2 expression in DRG. The sensory nerves also expressed increased levels of the acid-sensing receptor TRPV1. DRG neurons co-cultured with SAS cells showed increased neurite outgrowth, and were inhibited by MCT4 silencing with shRNA. Collectively, our results show that HNSCC induced an acidic bone microenvironment that evokes HNSCC-BP via MCT4 expression.

More than half of all human cancers are associated with mutations of the TP53 gene. In regard to the functional interaction with the remaining wild-type (WT) p53 allele, p53 mutations are classified into two types, recessive and dominant-negative (DN) mutations. The latter mutant protein has a DN activity over the remaining WT allele. We previously showed that the DN p53 mutant was useful as a predictor of poor outcome or a risk factor for metastatic recurrence in patients with some types of cancers, regardless of the presence or absence of loss of heterozygosity (LOH) of WT p53, suggesting that the DN p53 had 'gain-of-function (GOF)' activity besides the transdominance function. In this study, we investigated GOF activity of two DN p53 mutants which had a point mutation at codon 248 (R248Q and R248W), one of the hot spots, by transfecting them respectively into H1299 cells which originally expressed no p53 protein. Growth activity of the transfectants with the two mutants was not different from that of parent or Mock transfectants. Meanwhile, in vitro invasions of Matrigel and type I collagen gel by R248Q-transfectants were significantly higher than those by R248W-transfectants or the control cells. However, there were no differences in cell motile activities, expressions of extracellular matrix-degradative enzymes such as matrix metalloproteinases, urokinase-type plasminogen activator and heparanase, and their inhibitors, between R248Q- and R248W-transfectants. These findings indicate that the p53 mutants have a different quality in GOF activities even if the mutations occurred at the same codon. And detailed information of the status of p53, including transdominancy and GOF activity, is expected to be useful for diagnosis and therapeutic strategy fitting the individual patients.

The purpose of this research was to identify biomarkers for predicting cervical lymph node metastasis in oral squamous cell carcinoma (OSCC). We surveyed the expressions of 1289 cancer-related genes in 41 cases of OSCC by cDNA array analysis. We extracted genes upregulated or downregulated in their expression in association with lymph node metastasis. Of 1289 cancer-related genes, we identified 39 genes differentially expressed in OSCC with or without lymph node metastasis. Expression levels of 9 genes were lower, and those of 30 genes were higher, in node-positive cases. The genes expressed at higher levels in node-positive cases included angiogenesis-related molecules, cell adhesion molecules, and proteolytic enzymes. We suggest that these characteristic genes could provide, if verifiable, useful information for predicting the risk of lymph node metastasis in OSCC.

The definitive version is available at www.blackwell-synergy.com, The prevalences of signs and symptoms of temporomandibular disorder (TMD) in Bangladeshi adolescents and their associations with intake of various hard food items were investigated. A group of 1,200 randomly selected high school students aged 12-17 years from three communities (rural, semi-urban and urban) completed a questionnaire on dietary habits and presence of TMD symptoms and were examined clinically. In bivariate analysis, no significant relationship was observed between TMD symptoms and eating of hard foods. However, in logistic regression analysis, clicking showed a significant correlation with consumption of hard vegetable and fruits more than 3 times per week (P

Oral squamous cell carcinoma (OSCC) is a worldwide malignancy and is ranked the sixth most common cancer. At current rates, approximately 45,000 cases in the United States and more than 650,000 cases worldwide will be diagnosed each year (Jemel et al., 2008). One promising strategy for the treatment of OSCC and other cancers, which has developed as a result of breakthroughs in the fields of molecular biology, cancer genetics, and cancer biology, is molecular targeted therapy. Patients with a head-and-neck squamous cell carcinoma (HNSCC) often develop multiple malignant lesions. The oral sites that give rise to the majority of HNSCCs undergo cornification and shed squames during terminal differentiation, a process that is impaired in malignancies. The lymph nodes of the head and neck region form the principle site of primary metastasis, and perineural invasion marks tumours with a poor prognosis. Genetic changes correlate with lymph node metastasis in SCC. It is frequently observed that genetic damage persists beyond the histological border of precancerous lesions and tumours often develop far from the precancerous site (Braakhuis et al., 2003).

Summary Objectives Focal adhesion kinase (FAK) overexpression is frequently found in invasive and metastatic cancers, but its role in oral squamous cell carcinoma is not yet well understood. In order to seek therapies targeting oral squamous cell carcinoma, we developed the novel FAK Tyr397 inhibitor TAE226 and investigated its anti-tumor effects and mechanisms. Materials and Methods Expression of phosphorylated FAK Tyr397 was examined by immunohistochemical and immunoblot analysis. The effect of TAE226 on in vitro and in vivo studies were confirmed by proliferation, cell cycle, apoptosis and angiogenesis analysis. Results We found that phosphorylated FAK was highly expressed in human tongue oral squamous cell carcinoma in patients. Importantly, TAE226 greatly suppressed the proliferation, migration and invasion of human oral squamous cell carcinoma SAS cells with an apparent structural change of actin fiber and a loss of cell adhesion. In addition, TAE226 inhibited the expression of phospho-FAK Tyr397 and phospho AKT Ser473, resulting in caspase-mediated apoptosis. Furthermore, oral administration of TAE226 in mice suppressed the growth and angiogenesis of oral squamous cell carcinoma xenografts in vivo. Conclusions Our results provide compelling evidence that FAK is critically involved in oral squamous cell carcinoma and that the FAK inhibitor TAE226 can potentially be effectively used for the treatment of oral squamous cell carcinoma.

Breast cancer cells frequently metastasize to the skeleton and produce and secrete proteinases, such as matrix metalloproteinase-13 (MMP-13), which promote destruction of the bone matrix. However, the mechanism of MMP-13 expression induced in areas of bone metastasis is unknown. Here, the interaction between tumors and type I collagen in bone metastasis was investigated.A mouse model of bone metastasis was prepared by inoculating mice with suspensions of cells of the human metastatic breast cancer cell line MDA-MB-231 via the left cardiac ventricle. MMP-13 expression was examined by immunohistochemical, Western blot, and real-time RT-PCR analyses.MMP-13 expression was highly up-regulated in MDA-MB-231 cells, and attachment of these cells to type I collagen and the induction of MMP-13 were down-regulated by treatment with integrin α1, α2 or β1 neutralizing antibodies. The attachment of MDA-MB-231 cells to type I collagen induced the activation of focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK). Inhibition of FAK and p38 MAPK down-regulated type I collagen-induced MMP-13 expression.Our study indicates that metastatic breast cancer cells in the bone microenvironment attached to type I collagen, which stimulated integrins α1β1 and α2β1, via FAK and p38 MAPK pathways, to induce MMP13 expression and further osteolysis.

Patients with an oral squamous cell carcinoma (OSCC) often develop multiple malignant lesions. This report examined whether individual tumours developed in a patient show the same genetic alteration, such as p53 mutations. This case study describes three SCCs and three leukoplakias which developed simultaneously in a single 67-year-old Japanese man. A p53 mutation was detected in two of the three SCCs and one of the three leukoplakias. One SCC had a missense mutation at codon 285 (GAGAAG, GluLys) and the other a nonsense mutation at codon 336, and the leukoplakia had a missense mutation at codon 273 (CGTCAT, ArgHis). This case showed that individual oral tumours may have different genetic changes even when they develop in a single patient. Therefore, this report provided strong evidence that in cases of multiple tumours it is necessary to design tailor-made therapies for each individual tumour rather than a single standardised therapy for all multiple tumours.

The mammalian target of rapamycin (mTOR) is engaged in the molecular pathogenesis of oral squamous cell carcinoma, which frequently invades the maxilla or the mandible. However, the effects of a mTOR inhibitor on bone destruction associated with oral squamous cell carcinoma are still unclear. In this study, we investigated the antitumor effect of temsirolimus-mediated mTOR inhibition against advanced oral squamous cell carcinoma. Temsirolimus inhibited the proliferation and migration of HSC-2 oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. Significantly, we clearly show that temsirolimus inhibited osteoclast formation both in vitro and in vivo. Reverse transcriptase-PCR analysis showed that temsirolimus decreased the mRNA expression of receptor activator for nuclear factor-κB ligand, known as an osteoclast differentiation factor in bone stromal ST2 cells. Moreover, temsirolimus normalized blood-free calcium concentration in mouse models for humoral hypercalcemia. These findings suggest that mTOR signaling is a potential target of oral squamous cell carcinoma associated with bone destruction, and hence we describe the efficacy of temsirolimus for the treatment of advanced oral squamous carcinoma. Mol Cancer Ther; 9(11); 2960–9. ©2010 AACR.

Gingival squamous cell carcinoma (SCC) cells frequently invade mandibular bone, and this destruction is associated with a worse prognosis. However, the relationship between bone destruction and associated factors is unclear. In this study, the role and diagnostic utility of transforming growth factor-beta (TGF-beta) type I receptor (TbetaRI) in bone destruction of the mandible was investigated.The expression of TbetaRI was explored by using an immunohistochemical method on paraffin-embedded tissues from 21 cases of mandibular SCC. An inhibitor of the kinase activity of the TbetaRI (TbetaRI-I) was used to assess the role of TbetaRI in bone destruction by a human oral SCC cell line (HSC-2) that highly expresses TbetaRI.TbetaRI-positive signals were closely associated with destructive invasion of the mandible by oral SCC cells. Consistent with these results, TbetaRI-I greatly reduced HSC-2 cell-induced bone destruction and osteoclast formation in vivo and in vitro. TbetaRI-I treatment reduced the expression of TNF-alpha, RANKL and connective tissue growth factor (CTGF/CCN2), all of which were up-regulated by TGF-beta in HSC-2 cells.These data demonstrated an important role for TGF-beta signalling in bone invasion by oral SCC cells, and suggest that the bone destruction is mediated by RANKL, TNF-alpha and CCN2.

To determine the association between temporomandibular disorders (TMD) and experiences of jaw injury, third molar removal, and orthodontic treatment, controlling for confounding factors such as age, sex, emotional stress, and oral parafunction.First-year university students (n = 2,374) were instructed to answer a questionnaire regarding symptoms of TMD, jaw injury, third molar removal, orthodontic treatment, stress, and parafunctional habits. All subjects were classified according to the level of TMD symptoms. Logistic regression was applied to assess the associations of experiences of jaw injury, third molar removal, and orthodontic treatment with presence of TMD symptoms after controlling for age, sex, stress, and parafunctional habits.Of the 2,374 students, 715 students were TMD symptom-positive. They were classified into 7 groups consisting of those with only clicking (group 1), only pain in the temporomandibular joint (group 2), only difficulty in mouth opening (group 3), clicking and pain (group 4), clicking and difficulty in mouth opening (group 5), difficulty in mouth opening and pain (group 6), and all 3 symptoms (group 7). TMD symptoms were significantly associated with jaw injury. Odds ratios were 2.25, 2.47, 3.38, and 2.01 for groups 2, 3, 6, and 7, respectively. Experience of third molar removal was significantly associated with TMD (odds ratio = 1.81 for group 1). No association was found between orthodontic experience and TMD.Experiences of jaw injury and third molar removal might be cumulative and precipitating events in TMD.

Genetic alteration of p53 is a significant determining factor in the carcinogenesis. The loss of function, mutant p53 can possess a dominant negative effect on wild-type p53 and may also exert gain-of-function activity. It is, however, not clear how p53 functional status due to various types of mutation results in outcome of patients with oral cancer. A total of 60 oral SCC samples were subjected to yeast functional assay that screens human p53 function in yeast, and sequencing for determination of p53 mutations. The detected mutants were further investigated for their dominant negative activity using a yeast-based transdominance assay that tests dominant negative activity of a mutant p53 over wild-type p53 by coexpressing the mutant and wild-type p53 in a yeast transcriptional reporter system. p53 mutation was found in 42 out of 60 of which 10 (24%) exhibited dominant negative activity and 32 (76%) without dominant activity (recessive mutation). The remaining 18 (30%) were considered to have wild-type p53. The patients with dominant negative mutation had significantly shorter disease-free survival than patients with no mutation (log-rank test, p < 0.001) and those with a recessive mutation (p < 0.016). There were slight significant differences in disease-free survival were found between the patients with tumours harbouring a recessive p53 mutation and those with tumours harbouring a wild-type p53 (p < 0.038). The presence and absence of a dominant negative p53 mutation may thus provide a predictor of early recurrence in oral SCC patients.

Human HOX genes consist of 39 genes and encode transcription factors that function as master developmental regulators. We hypothesized that the misexpression of HOX genes was associated with carcinogenesis and malignant progression. The expression levels of 39 HOX genes in 31 human oral squamous cell carcinoma (SCC), 11 dysplasia, and 10 normal mucosa tissues were quantified by the real-time RT-PCR method. The expression levels of 18 HOX genes in the SCC tissues were significantly higher than those in the normal mucosa tissues. The dysplasia tissues showed higher expression of HOXA2, A3, B3, and D10 than normal mucosa tissues whereas they showed lower expression of HOXA1, B7, B9, and C8 than SCC. The SCC with lymph node metastasis showed high expression of HOXC6 compared to the SCC without it. These results suggest that misexpressions of particular HOX genes are implicated in the development of oral dysplasia and SCC.

Aim: To determine the relationship between betel quid chewing additives and established periodontitis in Bangladeshi subjects. Material and Methods: A total of 864 subjects participated in this study. Among them, 140 pairs of sex- and age-matched case subjects and control subjects were selected. A case was defined as a person who had at least two sites with a clinical attachment level (CAL) ≥ 6 mm and at least one site with probing depth (PD) ≥ 5 mm. Subjects who did not fulfill these criteria were considered as controls. Information on sociodemographic variables, psychological stress, dental health behaviour, smoking and betel quid chewing habits was obtained. Results: Multiple logistic regression analysis showed that current betel quid chewers had greater probabilities of having established periodontal disease than did non-chewers (odds ratio = 3.97, p < 0.05). Mean PD, mean CAL, mean percentage of bleeding on probing and number of missing teeth were significantly higher in chewers of betel quid with tobacco and masala than in chewers of betel quid without such additives adjusting for age, sex, smoking habit, body mass index, dental visit pattern, stress and plaque index. Higher frequency and longer duration of betel quid chewing showed a significant relation to an increase in periodontal parameters. Conclusion: The results indicate that betel quid additives might significantly enhance periodontitis in the population studied.

Breast cancer (BC) cells often metastasize to bone where they express large amounts of parathyroid hormone-related protein (PTHrP). In this study, we investigated the possibility that PTHrP may have roles in breast cancer bone metastasis independently of, or in addition to, its roles in osteoclastic function.A mouse model of bone metastasis was prepared by inoculating mice with suspensions of the human BC cell line MDA-MB-231 tumor cells via the left cardiac ventricle. Matrix metalloproteinase-13 (MMP-13) expression in the bone microenvironment was examined by Western blot and Real-time RT-PCR (RT-PCR) analysis, as well as by confocal microscopy.The invading MDA-MB-231 cells contained conspicuous amounts of both PTHrP and MMP-13, an important matrix-degrading enzyme; and treatment of the cells in culture with exogenous PTHrP markedly stimulated MMP13 gene expression. Analysis of signaling mechanisms showed that PTHrP treatment led to rapid increases in the levels of phosphorylated protein kinase C (PKCα) and extracellular signal-regulated kinase (ERK1/2). Pharmacologic inhibition of ERK1/2 and PKC as well as of PKA activities counteracted the PTHrP-dependent stimulation of MMP13 expression. Indeed, pharmacologic activation of PKA or PKC was sufficient for stimulation of MMP13 expression.Consistent with these findings, the inhibition of PKC prevented PTHrP-induced activation of ERK1/2, whereas 12-O-tetradecanoylphorbol-13-acetate (TPA), a stimulator of PKC, up-regulated the PTHrP-induced activation of ERK1/2. Taken together, our data indicate that the MDA-MB-231 breast cancer cells may carry out bone destruction and favor their own metastatic behavior by producing MMP-13. Given that the cells expressed PTHrP and that this factor stimulated MMP-13 expression, metastatic bone destruction may result from a PTHrP autocrine loop involving a PKC-ERK1/2 signaling pathway.

Parathyroid hormone-related protein (PTHrP) is a key regulator of osteolytic metastasis of breast cancer (BC) cells, but its targets and mechanisms of action are not fully understood. This study investigated whether/how PTHrP (1-34) signaling regulates expression of vascular endothelial growth factor (VEGF) produced by BC cells.A mouse model of bone metastasis was prepared by inoculating mice with tumour cell suspensions of the human BC cell line MDA-MB-231 via the left cardiac ventricle. VEGF expression was examined by Western blot and real-time RT-PCR analysis, as well as by confocal microscopy in the bone microenvironment.PTHrP was expressed in cancer cells producing PTH/PTHrP receptor and VEGF that had invaded the bone marrow, and PTHrP was up-regulated VEGF in MDA-MB-231 in vitro. The culture medium conditioned by PTHrP-treated MDA-MB-231 cells stimulated angiogenesis and osteoclastogenesis compared with control medium, giving a response that was inhibited by VEGF-neutralizing antibody treatment. Inhibition of protein kinase C (PKC) prevented PTHrP-induced extracellular signal-regulated kinase (ERK1/2) and p38 activation, and PTHrP-induced VEGF expression.PTHrP plays an important role in modulating the angiogenic and bone osteolytic actions of VEGF through PKC-dependent activation of an ERK1/2 and p38 signaling pathway during bone metastasis by breast cancer cells.

Head and neck cancers are the fifth most common cancer type worldwide, affecting more than half a million patients annually. Development of effective therapeutic drugs is, therefore, required for this type of disease. This study assessed the effects of synthetic terrein on head and neck cancer.Synthetic terrein was prepared by using the modified Altenhach's procedure. The effect of synthetic terrein on cell proliferation of head and neck cancer cells and HUVECs was assessed. Angiogenin secretion and ribosome biogenesis were examined by ELISA and silver staining of the nucleolar organizer region. A mouse xenograft model was prepared by inoculating mice with suspensions of cells of the human head and neck cancer cell line OSC-19 subcutaneously into the dorsal region of each mouse. Ki-67, CD31 and angiogenin expression in xenografted tumors was examined by immunohistochemistry.Synthetic terrein inhibited the growth of various head and neck cancer cells. In addition, an in vivo experiment revealed that synthetic terrein inhibited a xenograft tumor growth in athymic mice. Immunohistochemical analysis revealed that expression of Ki-67, CD31 and ANG was down-regulated in synthetic terrein-treated tumors, compared to controls. Synthetic terrein suppressed the ANG secretion and ribosome biogenesis in cancer cells, and cell proliferation in vascular endothelial cells.The mechanism underlying the anti-tumor effects of synthetic terrein against head and neck cancer consists of the inhibition of both tumor cell proliferation and angiogenesis via the suppression of ANG production.

The aims of this study were first to identify the risk indicators for permanent tooth extraction in patients who were receiving free dental treatment, and second to determine whether or not the reasons for tooth extraction are related to socio-demographic factors.Bangladeshi adults who visited Dhaka Dental College Hospital participated in this study. For each extraction, the clinician recorded age, sex, educational status, type of tooth extracted, dietary habits, oral hygiene, history of smoking and betel quid chewing and reasons for tooth extraction. A series of bivariate analyses and logistic regression analyses were carried out to assess the effects of major variables.A total of 868 teeth were extracted from 582 patients. Among them, 586 (67.5%) of the teeth were extracted due to caries and its sequelae, 161 (18.5%) and 121 (13.9%) were extracted for periodontal and other reasons. Logistic regression analysis revealed that tooth extraction due to caries had significant associations with age (P = 0.0001), tooth type (P = 0.013), consumption of sweets, snacks and soft drinks (P = 0.0001 and P = 0.0001, respectively), frequency of teeth cleaning (P = 0.007) and dental attendance pattern (P = 0.004). For tooth extraction due to periodontal disease, associations with age (P = 0.001), educational level (P = 0.018), tooth type (P = 0.024), betel quid chewing (P = 0.0001), smoking habit (P = 0.032), method of teeth cleaning (P = 0.001) and the use of dentifrices (P = 0.024) were statistically significant.In this group of patients, caries and its sequelae were the most common reasons for extraction of teeth, followed by periodontal disease. Betel quid chewing, smoking and dietary and oral hygiene habits were also significant predictors of tooth loss.

Background To investigate the associations of aural symptoms, headache and depression with the presence of temporomandibular disorder (TMD) symptoms in a young adult population in Japan. Methods A personal interview survey was conducted on first-year university students (n = 1,930) regarding symptoms of TMD, aural problems, headache, shoulder pain and depression. Logistic regression was applied to assess the associations of these problems with the presence of TMD symptoms after controlling for age and gender. Results Among the 1,930 students, 543 students exhibited TMD symptoms and were classified into 7 groups: clicking only (Group I, n = 319), pain in the TMJ only (Group II, n = 21), difficulty in mouth opening only (Group III, n = 18), clicking and pain (Group IV, n = 29), clicking and difficulty in mouth opening (Group V, n = 48), difficulty in mouth opening and pain (Group VI, n = 11), and combination of three symptoms (Group VII, n = 97). The control group (n = 1,387) were subjects without any TMD symptoms. After adjusting for age and gender, a strong association was observed between TMD symptoms (Group II and IV) and tinnitus (OR = 12.1 and 13.2, respectively). TMD symptoms (Group I, II and III) were also associated with vertigo and headache. Otalgia and depression were significantly associated with the presence of clicking only. Conclusions TMD symptoms were significantly correlated to aural symptoms and headache. A functional evaluation of the stomatognathic system should be considered in subjects with unexplained aural symptoms and headache.

Heat-shock protein 90 (HSP90) is a major cellular chaperone protein. HSP90 supports the correct conformation, stabilization, activation, and localization of 'client' oncoproteins, many of which are involved in tumor progression. Therefore, the use of HSP90 inhibitors has become a new strategy in antitumor therapy. However, the effects of an HSP90 inhibitor on oral squamous cell carcinoma are still unclear. NVP-AUY922 (Novartis) is a novel 4,5-diaryloxazole adenosine triphosphate-binding site HSP90 inhibitor. In this study, we investigated the antitumor effect of novel HSP90 inhibitor NVP-AUY922 against oral squamous cell carcinoma. NVP-AUY922 inhibited the proliferation of oral squamous cell carcinoma cells in vitro. NVP-AUY922 caused degradation of client protein inducing ErbB2, p-Akt, p-S6, hypoxia-inducible factor 1-α (HIF1-α) and vascular endothelial growth factor (VEGF) and up-regulation of HSP70 in HSC-2 oral squamous cell carcinoma. NVP-AUY922 increased the expression of cleaved caspase-3 and induced apoptosis in HSC-2 cells. Treatment of NVP-AUY922 induced a robust antitumor response and suppressed p-Akt and VEGF expression in an HSC-2 xenograft model. In summary, NVP-AUY922 exhibits in vitro and in vivo efficiency against oral squamous cell carcinoma, representing a promising therapeutic approach for oral squamous cell carcinoma.

Phosphatase of regenerating liver (PRL) belongs to a class of the protein tyrosine phosphatase family, which is known so far to consist of 3 members, PRL-1, PRL-2, and PRL-3. The aim of this study was to uncover the role of PRL genes in development of oral malignancy. We analyzed expression levels of the 3 PRL genes in 50 human oral squamous cell carcinomas (OSCCs), 11 dysplasia and 12 normal mucosa tissues by a real-time RT-PCR method. PRL-3 but not PRL-1 or PRL-2 expressions were significantly higher in OSCC and dysplasia than in normal mucosa tissues. Additionally, PRL-3 expressions were significantly higher in OSCC tissues harboring dominant-negative p53 or recessive p53 mutation than in those harboring wild-type p53. These results suggest that PRL-3 plays a role in oral cancer development and can be useful as a marker of pre-malignant and malignant lesion of oral mucosa.