Low-Permittivity and Low-Temperature Cofired BaSO4-BaF2 Microwave Dielectric Ceramics for High-Reliability Packaged Electronics.

In developing low-temperature cofired ceramic (LTCC) technology for high-density packaging or advanced packaged electronics, matching the coefficient of thermal expansion (CTE) among the packaged components is a critical challenge to improve reliability. The CTEs of solders and organic laminates are usually larger than 16.0 ppm of °C1-, while most low-permittivity (εr) dielectric ceramics have CTEs of less than 10.0 ppm °C1-. Therefore, a good CTE match between organic laminates and dielectric ceramics is required for further LTCC applications. In this paper, we propose a high-CTE BaSO4-BaF2 LTCC as a potential solution for high-reliability packaged electronics. The BaSO4-BaF2 ceramics have the advantages of a wide low-temperature sintering range (650-850 °C), low loss, temperature stability, and Ag compatibility, ensuring excellent performance in LTCC technology. The 95 wt %BaSO4-5 wt %BaF2 ceramic has a εr of 9.1, a Q × f of 40,100 GHz @11.03 GHz (Q = 1/tan δ), a temperature coefficient of the resonant frequency of -11.2 ppm °C1-, a CTE of +21.8 ppm °C1-, and a thermal conductivity of 1.3 W mK-1 when sintered at 750 °C. Furthermore, a dielectric resonant antenna using BaSO4-BaF2 ceramics, a typically packaged component of LTCC and laminate, was designed and used to verify the excellent performance by a gain of 6.0 dBi at a central frequency of 8.97 GHz and a high radiation efficiency of 90% over a bandwidth of 760 MHz. Good match and low thermal stress were found in the packaged components of BaSO4-BaF2 ceramics, organic laminates, and Sn-based solders by finite element analysis, proving the potential of this LTCC for high-reliability packaged electronics.

Correlation analysis between physicians' evaluations of doctor-patient relationship and their preferences for shared decision-making in China.

Shared decision-making (SDM) is a scientific and reasonable decision-making model. However, whether physicians choose SDM is usually influenced by many factors. It is not clear whether the strained doctor-patient relationship will affect physicians' willingness to choose SDM. Through a survey by questionnaire, 304 physicians' evaluations of doctor-patient relationship (DPR) were quantified by the difficult DPR questionnaire-8. Their preferences for SDM and the reasons were also evaluated. The correlation between physicians' evaluations of DPR and their preferences for SDM were analyzed. 84.5% physicians perceived DPR as poor or strained, 53.3% physicians preferred SDM, mainly because of the influences of medical ethics and social desirability bias. Their preferences for SDM were not significantly correlated with their evaluations of DPR (P > 0.05). Physicians with different evaluations of DPR (good, poor, and strained) all had similar preferences for SDM (42.6, 56.4, and 42.9%), with no significant difference (P > 0.05). There was no correlation between physicians' evaluations of DPR and their preferences for SDM. Physicians' evaluations of poor DPR did not affect their preferences for SDM. This may be influenced by the medical ethics and social desirability bias.

Efficacy of Antibiotics Used as an Adjunct in the Treatment of Peri-implant Mucositis and Peri-implantitis: A Systematic Review and Meta-analysis.

PURPOSE: This systematic review aimed to assess the clinical efficacy of antibiotics when used as an adjunct in treating peri-implant diseases. MATERIALS AND METHODS: A systematic search of papers published between January 1980 and March 2020 was conducted. Randomized clinical trials with at least 10 patients who had peri-implant diseases, treated with or without adjunctive antibiotics in combination with surgical or nonsurgical therapies, and with a minimum of at least 3 months of follow-up were included. Meta-analyses were conducted to analyze weighted mean differences in probing depth reduction, radiographic bone level gain, and odds ratio of treatment success. RESULTS: From the 856 articles identified, 10 articles met the inclusion criteria and were selected. Of these, 7 articles were used for the meta-analysis. The adjunctive use of antibiotics in the treatment of peri-implant diseases yielded significantly greater probing depth reduction (weighted mean differences = 0.56 mm at 3 months, P = .001; 0.77 mm at 6 months, P < .00001; 0.92 mm at 12 months, P < .00001), radiographic bone level gain (weighted mean differences = 0.64 mm, P = .03), and treatment success (odds ratio = 1.74, P = .04) compared to the same treatment without antibiotics. CONCLUSION: Based on the existing evidence, the use of adjunctive antibiotics to treat peri-implant diseases, especially peri-implantitis, provided potential benefits in clinical outcomes for up to 12 months posttherapy.

Revisit incidence of complications after impacted mandibular third molar extraction: A nationwide population-based cohort study.

Most of complications after impacted mandibular third molar (iLM3) extraction surgeries are transient and resolved spontaneously within one or two weeks, but some of them are more complicated and required further treatments to alleviate the symptoms. The aim of study is to revisit incidence and predictors of complications after iLM3 surgery by reviewing previous literature and investigating a population-based data. From Taiwan National Health Insurance Research Database, records of 16,609 patients who had received iLM3 extraction under ambulatory settings were retrieved for analysis. Outcomes of interest included dry socket (DS), prolonged temporomandibular joint symptoms (TMD), and surgical site infection (SSI), which necessitated additional appointments to manage. Odds ratios of having those complications between different variables were analyzed. The incidence rates of DS, TMD, and SSI were 3.6%, 0.41%, 0.17%, respectively; while they ranged from 0.33-19.14% (DS), 0-4.17% (TMD), and 0.2-5.17% (SSI) in previous studies. Logistic regression revealed DS significantly correlated with complexity of odontectomy (2.5-fold of risk) and history of gingivitis or pericoronitis (1.3-fold of risk). More TMD was found in female than male patients (0.5% versus 0.3%). However, no factors associated with SSI was found; neither did we find aging as a risk in association with any of above complications. Compared to previous studies, our data supports that surgical intervention should be considered in iLM3 with risk of gingivitis or pericoronitis to reduce the occurrence of DS. The original information in this article, which provides a "real-world" evidence, along with the organizing data we summarized from previous article, can serve as a reference for clinicians in assessing the complication risks before treatment of iLM3.

Associations between aging and second molar diseases in patients having adjacent impacted third molar extraction.

PURPOSE: There is limited evidence available regarding when the best time to extract impacted lower third molars (iLM3). Thus, the current study is aimed to examine the association between the age of patients during the time of extraction of their iLM3 and the sequelae of their adjacent second molar (LM2) in order to find a better time to remove iLM3. METHODS: Retrospective cohort study was conducted with a total of 15,432 patients from ages 16-45 years old who had their first surgical extraction of iLM3. Statistical analysis was performed to evaluate variables in association with the sequalae of LM2. Adjusted odds ratios (AOR) were calculated to show the influence of the age of patients by multivariate regression model. RESULTS: Patients who had iLM3 extraction over 22 years of age had a significantly higher risk of having LM2 pulpal disease (AOR: from 2.84 in 23-25 age to 11.58 in >35 age). Significantly higher risk of having LM2 periodontal conditions was found in individuals over 31 years of age (AOR: 1.47 in 31-35 age, 1.90 in >35 age), with prior periodontitis (AOR: 1.97) or complicated odontectomy (AOR: 1.43). The risk of LM2 being extracted due to an untreatable condition was highest in patients more than 35 years old (AOR: 14.38). CONCLUSION: The age of patients having iLM3 extracted was independently associated with various LM2 sequelae. We suggest that patients can have their iLM3 extracted in their college/university age (19-22-year-old) to minimize complications on the adjacent LM2.

ATP dynamic regeneration strategy for enhancing co-production of glutathione and S-adenosylmethionine in Escherichia coli.

OBJECTIVES: In general, a sufficient supply of ATP can promote the synthesis of ATP-driven metabolites, but excessive ATP will lead to the inhibition of cell growth. For enhancing the co-production of glutathione(GSH) and S-adenosylmethionine(SAM), a dynamic ATP regeneration strategy was developed. RESULTS: The novel ATP regeneration strategy consisting of ATP-sensing riboswitch ydaO motif, polyphosphate kinase (PPK), and Vitreoscilla hemoglobin (VHb) was successfully applied in Escherichia coli. The intracellular ATP level was always around 0.60 mg/g dry cell weight during the fermentation process, resulting in significantly enhanced co-production of GSH and SAM. The GSH titer and SAM titer in the strain CGS-2 increased by 137.40% and 82.18% after fermentation for 24 h, compared with the control strain. CONCLUSIONS: The ATP regulation strategy is expected to be a favorable tool to improve the efficiency of microbial cell factories. The proposed ATP dynamic regeneration approach may be applicable for cost-effective, high-yield production of ATP-driven metabolites.

Botulinum Toxin A Might Be an Alternative or Adjunct Therapy for the Treatment of Trigeminal and Postherpetic Neuralgia.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: The efficacy of botulinum toxin for the treatment of trigeminal and postherpetic neuralgia: A systematic review with meta-analyses. Shackleton T, Ram S, Black M, Ryder J, Clark GT, Enciso R. Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122(1):61-71. SOURCE OF FUNDING: Information not available TYPE OF STUDY/DESIGN: Systematic review and meta-analysis.

Suppression of microRNA-135b-5p protects against myocardial ischemia/reperfusion injury by activating JAK2/STAT3 signaling pathway in mice during sevoflurane anesthesia.

The study aims to explore the effects of miR-135b-5p on myocardial ischemia/reperfusion (I/R) injuries by regulating Janus protein tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription (STAT) signaling pathway by mediating inhalation anesthesia with sevoflurane. A sum of 120 healthy Wistar male mice was assigned into six groups. Left ventricular ejection fraction (LVEF) and left ventricular shortening fraction (LVSF) were detected. Cardiomyocyte apoptosis was determined by terminal dexynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) assay. MiR-135b-5p expression, mRNA and protein expression of p-STAT3, p-JAK2, STAT3, JAK2, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein B (Bax) were detected by quantitative real-time PCR (qRT-PCR) and Western blotting. Target relationship between miR-135b-5p and JAK2 was confirmed by dual-luciferase reporter assay. The other five groups exhibited increased cardiomyocyte necrosis, apoptosis, miR-135b-5p and Bax expression, mRNA expression of JAK2 and STAT3, and protein expression of p-STAT3 and p-JAK2 compared with the sham group, but showed decreased LVEF, LVFS, and Bcl-2 expression. Compared with the model and AG490 + Sevo groups, the Sevo, inhibitor + Sevo and inhibitor + AG490 + Sevo groups displayed reduced cardiomyocyte necrosis, apoptosis, miR-135b-5p and Bax expression, but displayed elevated mRNA expression of JAK2 and STAT3, protein expression of p-STAT3 and p-JAK2, LVEF, LVFS and Bcl-2 expression. Compared with the Sevo and inhibitor + AG490 + Sevo groups, the AG490 + Sevo group showed decreased LVEF, LVFS, Bcl-2 expression, mRNA expressions of JAK2 and STAT3, and protein expressions of p-STAT3 and p-JAK2, but increased cardiomyocyte necrosis, apoptosis, and Bax expressions. MiR-135b-5p negatively targetted JAK2. Inhibition of miR-135b-5p can protect against myocardial I/R injury by activating JAK2/STAT3 signaling pathway through mediation of inhalation anesthesia with sevoflurane.

Engineered yeast with a CO2-fixation pathway to improve the bio-ethanol production from xylose-mixed sugars.

Bio-ethanol production from lignocellulosic raw materials could serve as a sustainable potential for improving the supply of liquid fuels in face of the food-to-fuel competition and the growing energy demand. Xylose is the second abundant sugar of lignocelluloses hydrolysates, but its commercial-scale conversion to ethanol by fermentation is challenged by incomplete and inefficient utilization of xylose. Here, we use a coupled strategy of simultaneous maltose utilization and in-situ carbon dioxide (CO2) fixation to achieve efficient xylose fermentation by the engineered Saccharomyces cerevisiae. Our results showed that the introduction of CO2 as electron acceptor for nicotinamide adenine dinucleotide (NADH) oxidation increased the total ethanol productivity and yield at the expense of simultaneous maltose and xylose utilization. Our achievements present an innovative strategy using CO2 to drive and redistribute the central pathways of xylose to desirable products and demonstrate a possible breakthrough in product yield of sugars.

Grafting and Dental Implantation in Patients With Jawbone Cavitation: Case Series and 3-Year Follow-Up.

PURPOSE: Jawbone cavitation (BC) is not uncommon and is considered to be related to some cases of unexpected implant displacement into deep jawbone space. Here, a series of cases with BC is described, in which the lesions were accidentally found and successfully treated by bone grafting and dental implantation. METHODS: Thirty-four partially edentulous patients who were found to have BC during dental implant surgeries were included in this study. Alloplast bone substitute (ß-tricalcium phosphate) grafting with immediate or staged locking-taper implant placement was performed. Bone filling and implants on BC were followed up to 36 months, and they were evaluated clinically and radiographically to verify treatment outcome. RESULTS: A total of 41 BCs were found at premolar and molar regions, which involved one or more teeth breadth. Nearly most of the lesions occurred in the mandible (95.1%, 39/41). Histologically, they were compatible with focal osteoporotic marrow defects. Fifty-two locking-taper implants and final restorations were delivered on 38 BCs. One implant failed due to loss of integration. The overall cumulative 3-year implant survival rate was 98.1%. CONCLUSION: By carefully examining and managing the surgical bed, the current treatment modality was shown to yield a satisfactory outcome for restoration of edentulous ridge with underneath BC.

Pretreatment pain predicts perineural invasion in oral squamous cell carcinoma: A prospective study.

OBJECTIVES: Perineural invasion (PNI) is an established poor prognostic pathological feature for oral squamous cell carcinoma (OSCC). The purpose of this study was to analyze the role of pretreatment parameters in predicting PNI for OSCC. MATERIALS AND METHODS: We prospectively enrolled into our study 102 newly diagnosed OSCC patients, who were surgically treated from 2011 to 2012. Before treatment, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire H&N35 and the visual analogue scale (VAS) for cancer pain. Pathological examination was performed to ascertain PNI status in all patients. Patients were divided into two groups, those with PNI and without PNI. Pretreatment parameters were compared between the two groups. RESULTS: In univariate analysis, clinical T classification (P<0.001), painkiller use (P=0.001), problem with social eating (P<0.001) and social contact (P=0.002), VAS scores of primary pain (P<0.001) and referred pain (P=0.004) were found to be associated with PNI. Multivariate logistic regression analysis further revealed VAS score of primary pain (P=0.001, OR 2.014) and T3-4 classification (P=0.014, OR 6.422) were independent predictors of PNI. A regression equation incorporating pretreatment pain was developed to predict the probability of having PNI. CONCLUSION: PNI can be predicted by higher pretreatment VAS score of primary pain, as well as more advanced clinical T classification. Careful evaluation of pretreatment pain of primary tumor can thus be helpful in improving treatment decision making for OSCC.

The effect of regenerative periodontal therapy in preventing periodontal defects after the extraction of third molars: A systematic review and meta-analysis.

BACKGROUND: Periodontal defect on the distal aspect of mandibular second molars is a common complication after mandibular third-molar extraction. Researchers have proposed different procedures, but no evidence has shown that a single effective method can prevent or treat this complication. METHODS: The authors conducted a systematic review and meta-analysis to answer this clinical question: what is the effect of regenerative periodontal therapy on the periodontal tissue healing of the distal site of the mandibular second molar after impacted mandibular third-molar extraction compared with extraction alone without using any biomaterials during a follow-up period of at least 6 months? The authors conducted an electronic search for randomized controlled trials using MEDLINE, Embase, and other databases, and they assessed the quality of selected articles. RESULTS: Among the 1,083 eligible articles found in the initial search, 7 studies fit all of the selection criteria. All of these studies had a follow-up period lasting at least 6 months. The authors found that regenerative periodontal therapy was significantly more effective in gaining clinical attachment level or reducing probing depth at the distal site of the mandibular second molar than extraction without therapy (weighted mean difference of clinical attachment level gain, 1.94 millimeters [95% confidence interval {CI}, 1.56-2.31]; weighted mean difference of probing depth reduction, 1.67 mm [95% CI, 1.15-2.19]). CONCLUSIONS AND PRACTICAL IMPLICATIONS: The results of our systematic review and meta-analysis demonstrated that regenerative periodontal therapy effectively prevents the periodontal defect associated with impacted mandibular third-molar extraction. Clinicians should consider performing guided tissue regeneration when the defect is anticipated.

Survival analysis of wide dental implant: systematic review and meta-analysis.

OBJECTIVE: Wide-diameter implants are frequently placed in molar sites to obtain appropriate restoration profiles, to rescue implants that lack stability, and to engage bone in extraction sites. However, studies of wide-diameter implant placement have provided conflicting evidence regarding clinical outcomes. This systematic review aims to analyze survival rates of wide-diameter implants (platform diameter ≥5 mm) and assess clinical variables potentially affecting failure rates. MATERIAL AND METHODS: Electronic search was conducted using MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL) and EMBASE from January 1980 to October 2014. Publication screening, data extraction, and quality assessment were performed. Failure rate per implant-year was analyzed using mix-effects Poisson regression model to obtain summary estimates of the 5-year survival rate. Relative risk (RR) was calculated to evaluate the association of different clinical variables with estimated failure rates. RESULTS: Eleven retrospective studies and eight prospective studies having at least 1-year follow-up period were included in the analysis. The estimated 5-year survival rate was 92.67% (95% confidence interval: [79.60, 97.50]) in the retrospective studies and 97.76% (Confidence interval: [93.25, 99.27]) in the prospective studies. Implant surface and implant diameter were significantly associated with the failure events in the retrospective studies. CONCLUSIONS: Placement of wide-diameter implants demonstrated a promising survival rate during 5-year follow-up. Further controlled trials with the control group and longer follow-up period are needed to provide the direct evidence comparing survival rates of wide implants with survival rates of narrower implants.

Forkhead factor FOXQ1 promotes TGF-ß1 expression and induces epithelial-mesenchymal transition.

Epithelial-mesenchymal transition (EMT) promotes tumor invasion and metastasis, but the coordination and integration mechanisms of these processes are still not fully understood. In this study, we used a cross-species expression profiling strategy of Hela cells to determine an important genetic program transfers. In particular, we have discovered a new transfer function, which is not previously known about transcription factor forkhead box Q1 (FOXQ1). The shRNA anti-FOXQ1 gene was synthesized and transfected into the Hela and EpRas cells. RT-PCR assay was performed to detect the mRNA levels in cells. Cell adhesion and separation assay were used to examine the cell-cell adhesion and separation among cells. Wound healing assay was utilized to examine cell migration and invasion ability. Chromatin immunoprecipitation assay was used to investigate the interaction between E-cadherin and N-cadherin and FOXQ1 promoter region. The results indicated that ectopic expression of FOXQ1 increased cell migration and invasion in vitro, enhanced mammary epithelial cells in vivo lung metastasis, and triggered significant EMT. In contrast, the opposite effects in vitro and in vivo of FOXQ1 knockdown phenotypes were caused by these mechanisms. Notably, FOXQ1 repressed core EMT regulation of the expression of TGF-ß1. FOXQ1 protein directly interacts with E-cadherin and N-cadherin promoter region. And surveys show that FOXQ1 expression regulation by TGF-ß1 and blockade induced EMT both morphological and molecular levels. Our findings emphasize the feasibility of cross-species expression profiles, as a strategy to identify metastasis-related genes. The induction of EMT by FOXQ1 defines a new transfer function in promoting cancer behind possible mechanisms.

TGF-ß1 mediates estrogen receptor-induced epithelial-to-mesenchymal transition in some tumor lines.

More and more studies have reported that epithelial-mesenchymal transition (EMT) involved in the process of cancer development and progression occurs. The EMT also plays an important role in the movement and transfer of the tumors. Transforming growth factor-ß (TGF-ß) could induce the EMT in some cancer cell types. However, the mechanism underlying this transition process has also not been entirely clarified. In this study, the results indicated that TGF-ß1-mediated EMT in the tumor was associated with the estrogen receptor (ER). The decreased expression of vimentin and snail resulted in the decrease of the ER expression by small interfering RNA-mediated silencing and preventing the TGF-ß-induced EMT. In conclusion, our results indicated that TGF-ß1 is an estrogen receptor signaling and essential novel downstream targets and could act as an important factor in the TGF-ß-induced EMT.

Oral health status of children with special health care needs receiving dental treatment under general anesthesia at the dental clinic of Taipei Veterans General Hospital in Taiwan.

BACKGROUND: Oral health is crucial to individual growth and development. However, oral health care is often overlooked in children with special health care needs (CSHCN). We investigated current oral health status and unmet dental needs of CSHCN in Taiwan. METHODS: We performed a retrospective study of consecutive CSHCN cases receiving first-time comprehensive dental treatment under general anesthesia at Taipei Veterans General hospital from 2001 to 2010. We retrieved clinical data including age, sex, types, and severity of disability, caries experience index [decayed, extracted, and filled teeth (deft) index for primary dentition/decayed, missing, and filled teeth (DMFT) index for permanent dentition], malocclusion, and treatment modalities from medical charts for analysis. The correlation between different groups of CSHCN regarding the deft/DMFT indices and treatment modalities was analyzed statistically. RESULTS: Our study included 96 children, ranging in age from 2.4 years to 14.3 years (mean age 6.8 ± 3.3 years). The deft/DMFT index was significantly higher in the younger age group (2-6 years; 13.8 ± 4.3) compared with the older group (> 6 years; 10.5 ± 5.3; p < 0.001). The mean number of total treated teeth was 14.2 ± 3.8, and no differences existed among disability groups (p = 0.528) and age groups (p = 0.992). For the treatment modality, the number of pulp therapies with crown restoration was higher in the younger age group than in the older group. At the time of the study, 53 CSHCN had reached their full permanent dentition. We observed significantly more malocclusion of full permanent dentition in the older age group (91%) than in the younger group (35%; p < 0.001). CONCLUSION: Unmet dental needs and caries experience indices remain high in CSHCN, regardless of the types and severity of disability. However, the younger the age at which CSHCN received their first dental treatment, the more effective the dental rehabilitation was. Parental education regarding early dental intervention and a preventive approach for enhanced oral care is mandatory.

Prognostic value of hypercalcaemia and leucocytosis in resected oral squamous cell carcinoma.

Hypercalcaemia and leucocytosis are common in our patients with progressive oral squamous cell carcinoma (SCC). However, the precise incidence, prognostic value, and correlation with the condition of the tumour remain obscure. A total of 618 patients with oral SCC who were treated primarily between 2007 and 2012 and had serum calcium concentrations and white blood cell count (WCC) measured postoperatively were included in the study. Primary TNM stage, pathological features, and the presence of locoregional recurrence or distant metastasis after comprehensive surgical treatment were recorded. The incidence of hypercalcaemia was 9.1% and that of leucocytosis 7.2%. Hypercalcaemia correlated significantly with size of primary tumour (T status), nodal involvement (N status), TNM stage, perineural invasion, lymphovascular permeation, and recurrence or metastasis of disease. Leucocytosis, however, correlated only with T status, lymphovascular permeation, and recurrence or metastasis. In multivariate analysis of survival, recurrence, metastasis, hypercalcaemia, and leucocytosis were strong independent prognostic factors. Median survival was low if the patient had hypercalcaemia or leucocytosis (179 (range 3-73) days if the patient had distant metastasis, and 43 (range 3-102) days if the patient had locoregional recurrence). The incidence of hypercalcaemia and leucocytosis was high during the course of the disease, and both conditions have an adverse impact on survival from oral SCC. Periodic evaluation of serum calcium concentrations and WCC should be routine during the postoperative period.

Histone modification patterns correlate with patient outcome in oral squamous cell carcinoma.

BACKGROUND: Patterns of global histone modifications have been suggested to be predictors of clinical outcome in many cancers. However, the role of global histone modification patterns in oral squamous cell carcinoma (OSCC) is unclear. METHODS: A retrospective clinicopathologic analysis was undertaken of 186 patients with oral squamous cell carcinoma who received complete ablative surgical treatment. Tissue arrays were made from those paraffin-embedded OSCC samples and examined by immunohistochemistry for histone 3 lysine 4 acetylation (H3K4ac), histone 3 lysine 18 acetylation (H3K18ac), histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 9 trimethylation (H3K9me3), and histone 3 lysine 27 trimethylation (H3K27me3). RESULTS: A low level of H3K4ac and a high level of H3K27me3 were associated with advanced T status, N status, tumor stage, and perineural invasion. They were also correlated with cancer-specific survival (CSS) and disease-free survival (DFS). The 5-year CSS and DFS in H3K4ac(low) vs. H3K4ac(high) were 74.8% versus 92.5% (P = .010), and 51.4% versus 76.2% (P = .001), respectively. The 5-year CSS and DFS in H3K27me3(low) versus H3K27me3(high) were 94.7% versus 62.3% (P < .001) and 76.4% versus 32.3% (P < .001), respectively. We also found improved prediction for DFS after combining the H3K4ac(low) and H3K27me3(high) profiles and comparing the scores with the other modification patterns (P < .0001). CONCLUSIONS: This research demonstrates the potential prognostic utility of global histone modification analysis for OSCC.

Chromosome instability modulated by BMI1-AURKA signaling drives progression in head and neck cancer.

Chromosomal instability (CIN) is widely considered a hallmark of cancer, but its precise roles in cancer stem cells (CSC) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatin-modifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stem-like properties associated with induction of epithelial-mesenchymal transition (EMT) that promotes invasion, metastasis, and poor prognosis. Here, we report that BMI1 mediates its diverse effects through upregulation of the mitotic kinase Aurora A, which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the ß-catenin/TCF4 transcription factor complex. Second, BMI1 repressed miRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let-7i suppression. AURKA upregulation by BMI1 exerts several effects, including centrosomal amplification and aneuploidy, antiapoptosis, and cell-cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting Aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that coamplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT, and CIN through the BMI1-AURKA axis and suggest therapeutic use from inhibiting Aurora A in head and neck cancers, which overexpress BMI1.