Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT Inhibitor Decitabine

Mutation in the IDH1 or IDH2 genes occurs frequently in gliomas and other human malignancies. In intermediate grade gliomas, IDH1 mutation is found in over 70% of tumors. These mutations impart the mutant IDH enzyme with a neomorphic activity – the ability to synthesize 2-hydroxyglutarate (2-HG). This ability leads to a reprogramming of chromatin state, a block in differentiation, and the establishment of the glioma hypermethylator phenotype (G-CIMP). It has been hypothesized but not proven that the extensive DNA methylation that occurs in G-CIMP tumors helps maintain and “lock in” glioma cancer cells in a dedifferentiated state. Here, we tested this hypothesis by treating patient derived IDH1 mutant glioma initiating cells (GIC) with non-cytotoxic, epigenetically targeted doses of the DNMT inhibitor decitabine. Global methylome analysis of treated IDH1 mutant GICs showed that DAC treatment resulted in reversal of DNA methylation marks induced by IDH and the re-expression of genes associated with differentiation. Accordingly, treatment of IDH1 mutant glioma cells resulted in a dramatic loss of stem-like properties and efficient adoption of markers of differentiation, effects not seen in decitabine treated IDH wild-type GICs. Induction of differentiation was much more efficient than that seen following treatment with a specific inhibitor of mutant IDH enzyme (Agios). Decitabine also decreased replicative potential and tumor growth in vivo. Reexpression of polycomb regulated genes accompanied these DAC-induced phenotypes. In total, our data indicates that targeting the pathologic DNA methylation in IDH mutant cells can reverse mutant IDH induced hypermethylation and block in differentiation and promote tumor control. These findings have substantial impact for exploring new treatment strategies for patients with IDH mutant gliomas.     

Beliefs and values about intra-operative teaching and learning: a case study of surgical teachers and trainees

Surgeons require advanced psychomotor skills, critical decision-making and teamwork skills. Much of surgical skills training involve progressive trainee participation in supervised operations where case variability, operating team interaction and environment affect learning, while surgical teachers face the key challenge of ensuring patient safety. Using a theoretical framework of situated learning including cognitive apprenticeship, we explored teachers’ and trainees’ beliefs and values about intra-operative training and reasons for any differences. A qualitative case study method was used where five teacher-trainee pairs participating in an observed teaching operation were separately interviewed about the same operation. Thematic analysis of transcribed interviews and observations was performed with iterative refinement and a reflexive approach was adopted throughout the study. We found that in all cases, teachers and trainees had shared recognition of learning about technical skills whereas they differed in three cases regarding non-technical skills such as surgical reasoning and team management. Factors contributing to teacher and trainee satisfaction with the process were successful trainee completion of operation without need for surgeon take-over, a positive learning environment and learning new things. Teaching–learning behaviours observed and discussed were modeling, coaching and scaffolding, while exploration, reflection and articulation were less common. Our study reveals differing teacher and trainee perspectives of some aspects of intra-operative training and surfaces new reasons other than amount of feedback and autonomy given. Factors contributing to different perspectives include teacher and trainee abilities, values and situational influences. Targeted teaching–learning strategies could enhance intra-operative learning.     

Acute-phase inflammatory response to periodontal disease in the US population

Moderate elevation of serum C-reactive protein (CRP) is a risk factor for cardiovascular disease among apparently healthy individuals, although factors that create this inflammatory response in the absence of systemic illness have not been clarified. This study aimed to: (1) evaluate associations among periodontal disease, established risk factors for elevated CRP, and CRP levels within the US population; and (2) determine whether total tooth loss is associated with reduced CRP. Data were obtained from the third National Health and Nutrition Examination Survey. A random sample of the US population was interviewed in their homes and examined at mobile examination centers. CRP was quantified from peripheral blood samples and analyzed as a continuous variable and as the prevalence of elevated CRP (> or = 10 mg/L). Some 12,949 people aged 18+ years who had periodontal examinations and an additional 1,817 edentulous people aged 18+ years were included in the analysis. Dentate people with extensive periodontal disease (> 10% of sites with periodontal pockets 4+ mm) had an increase of approximately one-third in mean CRP and a doubling in prevalence of elevated CRP compared with periodontally healthy people. Raised CRP levels among people with extensive periodontal disease persisted in multivariate analyses (P < 0.01), with established risk factors for elevated CRP (diabetes, arthritis, emphysema, smoking, and anti-inflammatory medications) and sociodemographic factors controlled for. However, CRP levels were similarly raised in edentulous people. Furthermore, the established risk factors for elevated CRP modified relationships between oral status and CRP levels. Periodontal disease and edentulism were associated with systemic inflammatory response in the US population, most notably among people who had no established risk factors for elevated CRP.     

Comparison of United States and Korean dental hygiene students using the Hiroshima university-dental behavioural inventory(HU-DBI)

OBJECTIVE: To compare cross-national differences of dental health behaviour among dental hygiene students. DESIGN: Cross-cultural differences. Setting: United States (USA) and Korea. SUBJECTS AND METHODS: One hundred and twenty-six dental hygiene students in USA and 246 in Korea were surveyed using the Hiroshima University-Dental Behavioural Inventory (HU-DBI) (in English and Korean versions respectively). RESULTS: There were considerable differences in oral health behaviour between USA and Korean dental hygiene students. Of great significance were findings that while only a small proportion of the USA students (1%) reported gum bleeding when they brushed their teeth, 37% of the Korean students did so (P<0.001). Furthermore, only 19% of the Korean students had been told by their dentist that they were performing a high level of plaque control, contrasted with 76% of the USA students. Logistic regression model showed that it was possible to distinguish USA students from Korean peers with a probability of more than 90% by using the HU-DBI. CONCLUSIONS: There were considerable differences in dental health attitudes/behaviour among dental hygiene students in the two countries. The variation in the favourable attitudes/behaviour toward oral health appeared to reflect the students' clinical training experience in Korea.     

Factors Influencing the Appropriateness of Restorative Dental Treatment: an Epidemiologic Perspective

Objectives : An epidemiologic analysis was performed to identify patient and dentist factors influencing over- and undertreatment of restorative services in a sample of insured adults. Methods : At baseline, 681 Washington State employees and their spouses, aged 20 to 34 years and residing in the Olympia or Pullman areas, were interviewed by telephone. Oral assessments were conducted to measure personal characteristics, oral disease, and restoration quality. Adults were followed for two years to measure use of restorative services from dental insurance claims. Each adult's baseline and claims data were linked with provider and practice variables collected from the dentist who provided treatment. Results : For overtreatment, 39 percent of adults received one or more replacement restorations in nondecayed teeth with satisfactory fillings at baseline, while 18 percent of adults had one or more restorations placed in teeth with no decay and fillings. An adult's probability of overtreatment was higher if the adult had more fillings at baseline, or if an adult's dentist was younger, had a busy practice, advertised, charged higher fees, had less continuing education, or had a solo practice. For undertreatment, about 16 percent of adults either received no replacement restorations in teeth with unsatisfactory fillings at baseline, or had decayed teeth at baseline that were not filled or crowned. An adult's probability of undertreatment was higher if an adult had less decayed or more missing surfaces at baseline, or if an adult's dentist believed in sharing information with patients, had a busy practice, or reported not placing fillings when radiographic evidence of new caries was present. Conclusion : A minority of adults aged 20 to 34 experienced potential over- or undertreatment of restorative services, which are influenced by both patient and dentist factors.     

Unaltered strong immunohistochemical expression of CD44-v6 and -v5 isoforms during development and progression of oral squamous cell carcinomas

The present study was designed to immunolocalize CD44-v6 and -v5 isoforms in normal, dysplastic and malignant oral mucosa as well as in primary and meta-static oral squamous cell carcinomas. Routinely formalin-fixed and paraffin-embedded tissues of 100 oral carcinoma patients were immunohistochemically investigated following wet autoclave antigen retrieval. Both CD44-v6 and -v5 epitopes were uniformly strongly expressed on the cell surface of basal and intermedial epithelial cells of normal and dysplastic mucosa and in all primary and melastatic squamous cell carcinomas with the exception of end-differentiated keratinizing cells. Our results strongly suggest that CD44-v6 and-v5 isoform expression is not altered during development and progression of oral carcinomas. Thus, they seem to be irrelevant factors in the prediction of prognosis in this type of cancer.