ABSTRACT
Background: Mobile health (mHealth) has an emerging potential for remote assessment of traumatic dental injuries (TDI) and support of emergency care. This study aimed to determine the diagnostic accuracy of TDI detection from smartphone-acquired photographs. Methods: The upper and lower anterior teeth of 153 individuals aged ≥ 6 years were photographed using a smartphone camera app. The photos of 148 eligible participants were reviewed independently by a dental specialist, two general dentists, and two dental therapists, using predetermined TDI classification and criteria. The sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and inter-rater reliability were estimated to evaluate the diagnostic performance of the photographic method relative to the reference standard established by the dental specialist. Results: Of the 1,870 teeth screened, one-third showed TDI; and one-seventh of the participants had primary or mixed dentitions. Compared between the specialist's reference standard and four dental professionals' reviews, the diagnostic sensitivity and specificity for TDI versus non-TDI were 59-95% and 47-93%, respectively, with better performance for urgent types of TDI (78-89% and 99-100%, separately). The diagnostic consistency was also better for the primary/mixed dentitions than the permanent dentition. Conclusion: This study suggested a valid mHealth practice for remote assessment of TDI. A better diagnostic performance in the detection of urgent types of TDI and examination of the primary/mixed dentition was also reported. Future directions include professional development activities involving dental photography and photographic assessment, incorporation of a machine learning technology to aid photographic reviews, and randomized controlled trials in multiple clinical settings.
ABSTRACT
BACKGROUND: The use of Emergency Departments (EDs) for non-urgent medical conditions is a global public health concern. OBJECTIVES: A systematic review, guided by a registered protocol (PROSPERO: CRD42023398674), was conducted to interpret the association between distance as a measure of healthcare access and the utilization of EDs for non-urgent care in high- and middle-income countries. METHODS: The search was conducted on 22 August 2023 across five databases using controlled vocabulary and natural language keywords. Eligibility criteria included studies that examined non-urgent care, and featured concepts of emergency departments, non-urgent health services and distance, reported in English. Articles and abstracts where patients were transported by ambulance/paramedic services, referred/transferred from another hospital to an ED, or those that measured distance to an ED from another health facility were excluded. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework informed the quality of evidence. RESULTS: Fifteen articles met the inclusion criteria. All studies demonstrated satisfactory quality with regard to study design, conduct, analysis and presentation of results. Eight (53.3%) of the studies (1 paediatric, 4 all ages/adult, 3 ecological) found a moderate level of evidence of an inverse association between distance and ED visit volume or utilization for non-urgent medical conditions, while the remaining studies reported very low or low evidence. CONCLUSIONS: Half of the studies reported non-urgent ED use to be associated with shortest distance traveled or transportation time. This finding bears implications for healthcare policies aiming to reduce ED use for non-urgent care.
Main findings: Using the systematic review methodology, a qualitative synthesis of the prior literature showed moderate evidence of the negative role of distance on emergency departments use across middle- and high-income countries.Added knowledge: This systematic review adds to the literature by providing evidence that clarifies prior inconsistent findings on the association between distance, a measure of healthcare access, and non-urgent emergency department utilization.Global health impact for policy and action: Based on the main finding of negative role of distance, a three-tiered policy recommendation to reduce non-urgent use of emergency departments is provided that include: 1) public health systems reforms, 2) patient education, and 3) improved access to primary care providers.
Subject(s)
Emergency Service, Hospital , Health Services Accessibility , Emergency Service, Hospital/statistics & numerical data , Humans , Health Services Accessibility/statistics & numerical data , Patient Acceptance of Health Care/statistics & numerical dataABSTRACT
BACKGROUND: Oral health knowledge forms part of oral health literacy that enables individuals to inform appropriate oral health decisions and actions. Oral health-related quality of life (OHRQoL) characterizes self-perception of well-being influenced by oral health. This study aimed to examine the relationship between oral health knowledge and OHRQoL. METHODS: A random sample of 19-to-24-year-old first-year undergraduate students (n = 372) in Minnesota, United States of America was used. Each student was assessed with an online survey using the Comprehensive Measure of Oral Health Knowledge (CMOHK) and the OHRQoL items of the World Health Organization (WHO) Oral Health Questionnaire for Adults. Relationships between OHRQoL parameters and CMOHK together with other covariates were assessed using ordinal regression models. Associations between OHRQoL parameters were examined with the Kendall's tau-b method. RESULTS: Dry mouth (45%) was the most reported OHRQoL issue. The respondents showing good oral health knowledge were less likely to experience speech or pronunciation difficulty (ß=-1.12, p = 0.0006), interrupted sleep (ß=-1.43, p = 0.0040), taking days off (ß=-1.71, p = 0.0054), difficulty doing usual activities (ß=-2.37, p = 0.0002), or reduced participation in social activities due to dental or oral issues (ß=-1.65, p = 0.0078). CONCLUSIONS: This study suggested a protective effect of better oral health knowledge on specific OHRQoL issues. In addition to provision of affordable dental services, university-wide oral health education can be implemented to improve OHRQoL in undergraduate students.
Subject(s)
Oral Health , Quality of Life , Adult , Humans , United States , Young Adult , Universities , Surveys and Questionnaires , StudentsABSTRACT
OBJECTIVES: This study aimed to evaluate the splatter contamination generated by rotary instrumentation and irrigation during simulations of surgical extractions. Specifically, comparisons of the splatters generated were made between traditional assistant-based irrigation and self-irrigating drills and between saline and hydrogen peroxide irrigant. MATERIALS AND METHODS: A fluorescein solution was infiltrated into the irrigation system of high-speed drills, and the surgical extraction procedures were performed on manikins with the typodont teeth. Filter papers were placed at the predetermined locations around the operatory to absorb the fluorescein splatters; these samples underwent photographic image analysis. RESULTS: The patient chest showed the largest area of splatters, followed by the assistant's face shield. Procedures using the hydrogen peroxide irrigant generated a larger area of splatter than those using the saline irrigant. There was no difference between the splatters produced by assistant irrigation and self-irrigating drill procedures. CONCLUSIONS: Clinicians should observe and disinfect the locations contaminated by splatters to prevent the spread of infection, since using alternative irrigant or irrigation methods did not reduce the formation of splatters. CLINICAL RELEVANCE: Oral surgery drills with irrigation generate aerosols and splatters, which have potential to spread airborne pathogens. It is important to understand the patterns of splatters to mitigate contamination.
Subject(s)
Oral Surgical Procedures , Surgery, Oral , Humans , Hydrogen Peroxide , Infection Control , Therapeutic Irrigation/methods , FluoresceinsABSTRACT
OBJECTIVES: To examine the effect of individualized smartphone-recorded video review on dental student confidence in performing local anesthesia (LA) techniques, in a manikin-based simulation environment. METHODS: All University of Minnesota second-year dental students were invited to participate in this randomized trial developed following the Consolidated Standards of Reporting Trials statement, in 2020. With a parallel trial design, 104 students were randomly divided into two groups (52 per group) prior to the learning experience. Students and researchers were not blinded to group assignments. All students learned LA techniques in the same manikin-based simulation setting. The experimental group incorporated individualized smartphone filming into simulation training, and the control group did not. A paper-based questionnaire with 19 5-point Likert scale questions assessed the students' self-rated confidence levels in LA techniques before, immediately after, and approximately one month after the training. RESULTS: The final sample included 45 students in the experimental group (48.4%) and 48 in the control group (51.6%). In both groups, student confidence in performing LA techniques increased after completion of the training (p < 0.001), with no harm reported. The experimental group reported greater confidence in inferior alveolar nerve injection (p = 0.038), and in local anesthetic administration rate (p = 0.029), compared with the control group. CONCLUSIONS: This study suggested that the incorporation of smartphone-recorded video review in simulation training is beneficial for learning LA techniques. Further investigation on teaching methods to enhance student confidence and performance in LA administration is indicated.
Subject(s)
Anesthesia, Dental , Smartphone , Humans , Learning , Anesthetics, Local , Students, Dental , Clinical Competence , Anesthesia, Dental/methodsABSTRACT
With a higher pH level and being unlikely to erode the tooth, bottled water has been considered a safe alternative to acidic beverages. However, recent studies have reported some bottled water products in different countries to be acidic. The present paper aimed to examine the pH values of 42 bottled waters commercially available in Australia, using a pH meter and probe, and classify their risks to cause erosive tooth wear in comparison with the critical pH of enamel and dentine. Of the 42 bottled water samples collected, 81.0 and 73.8% were considered erosive to tooth dentine and enamel, respectively. Flavoured waters were the most acidic, followed by sparkling waters, spring waters, artesian waters, mineral waters, and alkaline waters. All sparkling waters and flavoured waters showed an erosive risk to the enamel and dentine. A portion of spring waters and artesian waters was also acidic enough to erode tooth structures. The findings of this work were of concern given the risk of sustaining erosive tooth wear from consuming bottled waters. Health promotion strategies including public awareness and education on oral health consequences related to the consumption of bottled water are needed. Future epidemiological and in vivo investigations are also warranted.
Subject(s)
Carbonated Water , Drinking Water , Tooth Wear , Drinking Water/chemistry , Humans , Hydrogen-Ion Concentration , Oral HealthABSTRACT
BACKGROUND: Erosive tooth wear has significant impacts on oral and general health. This study aimed to measure the awareness of dental erosion to establish the relationships among sociodemographic factors, awareness and knowledge of dental erosion, and beverage consumption behaviours, in a sample of university students in Australia. METHODS: All undergraduate students enrolled in the targeted programs at an Australian University were invited. A total of 418 students consented to participate. Each was assessed with an online questionnaire. RESULTS: The awareness rate of dental erosion was 92.1%. Soft drinks and fruit juice were most often perceived as acidic beverages by the respondents. The students of greater age, and studying pharmacy, paramedicine, physiotherapy or science, were less likely to be aware of dental erosion. Those students that were aware of dental erosion also had better knowledge of dental erosion, which was associated with a reduced quantity of daily acidic beverage consumption as well. The students that predominantly resided overseas had less knowledge of dental erosion. The students that were of greater age, that were studying clinical science, pharmacy, medical science, paramedicine, or science, and that correctly identified more types of acidic beverages, more often consumed acidic beverages in high-risk patterns. CONCLUSIONS: Erosive tooth wear is a relevant matter in dentistry, nutrition and public health. Within a university setting, the effect of education on oral health literacy and beverage consumption behaviour is confirmed. Dental and health professionals should actively educate the individuals and communities about dental erosion and motivate them to change acidic beverage consumption behaviours.
Subject(s)
Tooth Erosion , Australia , Beverages/adverse effects , Carbonated Beverages , Feeding Behavior , Humans , Surveys and Questionnaires , Tooth Erosion/etiology , Tooth Erosion/prevention & controlABSTRACT
This study uses a general formulation of integrated visual grading regression (IVGR) and applies it to cone beam computed tomography (CBCT) scan data related to anatomical landmarks for dental implantology. The aim was to assess and predict a minimum acceptable dose for diagnostic imaging and reporting. A skull phantom was imaged with a CBCT unit at various diagnostic exposures. Key anatomical landmarks within the images were independently reviewed by three trained observers. Each provided an overall image quality score. Statistical analysis was carried out to examine the acceptability of the images taken, using an IVGR analysis that was formulized as a three-stage protocol including defining an integrated score, development of an ordinal regression, and investigation of the possibility for dose reduction through estimated parameters. For a unit increase in the logarithm of radiation dose, the odds ratio that the integrated score for an image assessed by observers being rated in a higher category was 3.940 (95% confidence interval: 1.016-15.280). When assessed by the observers, the minimum dose required to achieve a 75% probability for an image to be classified as at least acceptable was 1346.91 mGy·cm2 dose area product (DAP), a 31% reduction compared to the 1962 mGy·cm2 DAP default dosage of the CBCT unit. The kappa values of the intra and inter-observer reliability indicated moderate agreements, while a discrepancy among observers was also identified because each, as expected, perceived visibility differently. The results of this work demonstrate the IVGR's predictive value of dose saving in the effort to reduce dose to patients while maintaining reportable diagnostic image quality.
Subject(s)
Spiral Cone-Beam Computed Tomography , Cone-Beam Computed Tomography , Humans , Phantoms, Imaging , Radiation Dosage , Reproducibility of ResultsABSTRACT
OBJECTIVES: This study was conducted to compare the use of intraoral photographs with the unaided visual dental examination as a means of dental caries detection in children. METHODS: Children aged 4- to 14-year-olds were visually examined at their schools. Following dental examinations, children had five photographs of their teeth taken using a smartphone camera. Four dental reviewers, who are different from those who visually examined the children, assessed intraoral photographs for dental caries. Sensitivity, specificity, and inter-rater reliability agreement were estimated to assess the diagnostic performance of the photographic method relative to the benchmark visual dental assessments. Caries prevalence was measured using dft/DFT (decayed and filled teeth) index. RESULTS: One hundred thirty-eight children (67 male and 71 female) were enrolled and had a mean age of 7.8 ± 2.1 years. The caries prevalence (dft/DFT > 0) using photographic dental assessments ranged from 30 percent to 39 percent but was not significantly different from the prevalence (42 percent) estimated with the visual dental examination (P ≥ 0.07). The sensitivity and specificity of the photographic method for detection of dental caries compared to visual dental assessments were 58-80 percent and 99.7-99.9 percent, respectively. The sensitivity for the photographic assessments was high in the primary dentition (63-82 percent) and children ≤7-year-olds (67-78 percent). The inter-rater reliability for the photographic assessment versus the benchmark ranged from substantial to almost perfect agreement (Kappa = 0.72-0.87). CONCLUSIONS: The photographic approach to dental screening, used within the framework of its limitations, yielded an acceptable diagnostic level of caries detection, particularly in younger children with primary dentition.
Subject(s)
Dental Caries , Child , Child, Preschool , Dental Care , Dental Caries/diagnosis , Dental Caries/epidemiology , Female , Humans , Male , Photography, Dental/methods , Reproducibility of Results , SmartphoneABSTRACT
Runt-related transcription factor 2 (Runx2)-deficient mice can be used to model congenital tooth agenesis in humans. Conversely, uterine sensitization-associated gene-1 (Usag-1)-deficient mice exhibit supernumerary tooth formation. Arrested tooth formation can be restored by crossing both knockout-mouse strains; however, it remains unclear whether topical inhibition of Usag-1 expression can enable the recovery of tooth formation in Runx2-deficient mice. Here, we tested whether inhibiting the topical expression of Usag-1 can reverse arrested tooth formation after Runx2 abrogation. The results showed that local application of Usag-1 Stealth small interfering RNA (siRNA) promoted tooth development following Runx2 siRNA-induced agenesis. Additionally, renal capsule transplantation of siRNA-loaded cationized, gelatin-treated mouse mandibles confirmed that cationized gelatin can serve as an effective drug-delivery system. We then performed renal capsule transplantation of wild-type and Runx2-knockout (KO) mouse mandibles, treated with Usag-1 siRNA, revealing that hindered tooth formation was rescued by Usag-1 knockdown. Furthermore, topically applied Usag-1 siRNA partially rescued arrested tooth development in Runx2-KO mice, demonstrating its potential for regenerating teeth in Runx2-deficient mice. Our findings have implications for developing topical treatments for congenital tooth agenesis.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Core Binding Factor Alpha 1 Subunit/genetics , Odontogenesis , RNA, Small Interfering/genetics , Tooth/growth & development , Animals , Gene Expression Regulation, Developmental , Mandible/transplantation , Mice , Mice, Inbred C57BL , Mice, Knockout , RNA Interference , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/pharmacology , Regeneration , Tooth/physiologyABSTRACT
PURPOSE: In response to COVID-19, dental educators have been tasked with maintaining the quality of education while reducing cost, increasing efficiency, and leveraging technology. METHODS: This collaborative, multisite virtual health policy course used the Staged Self-Directed Learning Model (SSDL) to lead a diverse group of students studying health policy. Twelve Core sessions were offered with three additional sessions in August or December for a total of 15 total synchronous Zoom sessions that covered policy issues on supply, demand, and need for dental care. RESULTS: Twenty-eight students, seven lead instructors, and two course directors from six schools reported positive feedback on the course format, use of technology and the SSDL model, and breadth of topics presented. Participation by universities in four states with differing health policies stimulated virtual classroom discussions. CONCLUSION: In conclusion, collaborative interinstitutional virtual teaching and learning is cost effective, efficient, and engaging for students. This model has the potential to continue even when institutions are no longer affected by COVID-19.
Subject(s)
COVID-19 , Universities , Curriculum , Dental Care , Health Policy , Humans , SARS-CoV-2 , TeachingABSTRACT
BACKGROUND: Non-nutritive sucking habits, bottle feeding, and facial hyperdivergency have been suggested as the influencing factors of anterior open bite (AOB). There was inconsistent reporting of prevalence and a gap of knowledge in the literature. AIM: The aim of this study was to investigate the prevalence of AOB in 7- to 12-year-olds, with a special interest to characterise the determinants of this malocclusion. DESIGN: A sample of 203 children aged 7 to 12 years were selected from a primary school in regional Australia. The legal guardian of each child completed a self-administered questionnaire. Data were assessed using methods of univariate statistics and neural analysis. RESULTS: The prevalence of AOB and thumb sucking was 24.1% and 23.2%, respectively. AOB was associated with the habit (correlation = 0.754) and duration (correlation = 0.574) of thumb sucking. Age, gender, birth order, feeding modality, sleep patterns, history of orthodontic treatment and tonsil, adenoid or grommet surgery, and parents' level of education were not related to AOB (correlation absolute value ≤ 0.474). CONCLUSIONS: Thumb sucking, specifically for prolonged duration, increases the risk of development of AOB. Cessation of thumb sucking habits should be encouraged at an early age to avoid the development of AOB.
Subject(s)
Malocclusion , Open Bite , Child , Cross-Sectional Studies , Humans , Neural Networks, Computer , Open Bite/epidemiology , Open Bite/etiology , Pacifiers , SchoolsABSTRACT
OBJECTIVE: This study aimed to investigate the prevalence of areca nut consumption and to identify social and behavioural determinants among a Taiwanese adolescent population. SUBJECTS AND METHODS: A random sample of 5,343 high school students aged between 15-18 years in Kaohsiung, Taiwan, participated in the study. Participants underwent a clinical dental examination and completed a self-administered questionnaire. Data analyses were performed using multivariate logistic regression to establish a relationship between areca nut consumption as well as social and behavioural characteristics. RESULTS: The prevalence of areca nut consumption was 3.0%. The chewing habit was more prevalent among older adolescents (p < .001, OR = 1.50, 95% CI: 1.26, 1.78), males (p < .001, OR = 17.91, 95% CI: 8.57, 37.40), pupils living with non-birth parent(s) (p = .003, OR = 2.13, 95% CI: 1.29, 3.50), children of family heads with primary (p = .001, OR = 2.90, 95% CI: 1.50, 5.59) or secondary level of education (p < .001, OR = 2.78, 95% CI: 1.74, 4.46), frequent risk takers (p < .001, OR = 1.35, 95% CI: 1.27, 1.43) and students of low physical fitness (p < .001, OR = 3.65, 95% CI: 1.81, 7.35). CONCLUSIONS: Areca nut consumption has become an ongoing pertinent issue in adolescent health. Future investigations into neurocognitive influences of risk-taking behaviour on areca nut consumption and social dependence of the habit are indicated.
Subject(s)
Areca , Nuts , Adolescent , Areca/adverse effects , Child , Humans , Male , Mastication , Prevalence , Taiwan/epidemiologyABSTRACT
BACKGROUND: Despite great improvement in child oral health, some children subgroups still suffer from higher levels of dental caries. Geographic and socioeconomic barriers and the lack of access to dental care services are among common reasons for poor oral health in children. Historically in Australia, oral health therapists or dental therapists have been responsible for providing dental care for school children through the School Dental Services (SDS). The current SDS has been unable to provide sustainable dental care to all school children due to a reduction in workforce participation and limited resources. We propose a paradigm shift in the current service through the introduction of user-friendly technology to provide a foundation for sustainable dental care for school children. METHODS/DESIGN: We describe an ongoing parallel, two-armed, non-inferiority randomised controlled trial that compares routine and teledental pathway of dental care in children aged 4-15 years (n = 250). Participating schools in Western Australia will be randomly assigned to the control or teledental group, approximately three schools in each group with a maximum of 45 children in each school. All participants will first receive a standard dental examination to identify those who require urgent referrals and then their teeth will be photographed using a smartphone camera. At the baseline, children in the control group will receive screening results and advice on the pathway of dental care based on the visual dental screening while children in the teledental group will receive screening results based on the assessment of dental images. At 9 months follow-up, all participants will undergo a final visual dental screening. The primary outcomes include decay experience and proportion of children become caries active. The secondary outcomes include the diagnostic performance of photographic dental assessment and costs comparison of two pathways of dental care. DISCUSSION: The current project seeks to take advantage of mobile technology to acquire dental images from a child's mouth at school settings and forwarding images electronically to an offsite dental practitioner to assess and prepare dental recommendations remotely. Such an approach will help to prioritise high-risk children and provide them with a quick treatment pathway and avoid unnecessary referrals or travel. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12619001233112. Registered 06 September 2019.
Subject(s)
Dental Care/trends , Dental Caries/prevention & control , Dentists/psychology , Telemedicine , Adolescent , Australia , Child , Child, Preschool , Humans , Professional Role , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Greater awareness and knowledge of oral cancer has been shown to increase patient presentation for opportunistic screening. This study aimed to identify the level of awareness and knowledge of oral cancer amongst adult patients in regional New South Wales. METHODS: A total of 444 adult dental patients participated in a self-administered questionnaire at one of five regional university dental clinics between 23rd May and 25th July. Data analyses were performed using the chi-square test and binary logistic regression to compare sociodemographic characteristics and the self-declared awareness and knowledge of oral cancer. RESULTS: The study revealed that 73.8% of patients were aware of oral cancer; however, only 28.8% knew that they had been previously screened for oral cancer. Being female (P < 0.001, OR = 2.57), having an excellent level of oral health (P = 0.042, OR = 3.34) and previous attendance at a dental clinic of the regional university (P = 0.014, OR = 2.89) significantly enhanced awareness of oral cancer. CONCLUSION: The findings of this study have broad implications for both clinicians and public health professionals, providing a platform for discussion regarding the sociodemographic factors contributing to reduced knowledge and awareness of oral cancer amongst patients. This study also identified an essential avenue to allow a more targeted approach in future campaigns to increase education.
Subject(s)
Mouth Neoplasms , Universities , Adult , Australia , Cross-Sectional Studies , Female , Health Knowledge, Attitudes, Practice , Humans , New South Wales , Risk Factors , Surveys and QuestionnairesABSTRACT
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been recognized as a therapeutic target for EML4-ALK fusion-positive nonsmall cell lung cancer (NSCLC) treatment using type I kinase inhibitors such as crizotinib to take over the ATP binding site. According to Shaw's measurements, ALK carrying G1202R mutation shows reduced response to crizotinib (IC50 = 382 nM vs. IC50 = 20 nM for wild-type), whereas L1198F mutant is more responsive (IC50 = 0.4 nM). Interestingly, the double mutant L1198F/G1202R maintains a similar response (IC50 = 31 nM) to the wild-type. Herein we conducted molecular modeling simulations to elucidate the varied crizotinib sensitivities in three mutants carrying L1198F and/or G1202R. Both L1198 and G1202 are near the ATP pocket. Mutation G1202R causes steric hindrance that blocks crizotinib accessibility, which greatly reduces efficacy, whereas mutation L1198F enlarges the binding pocket entrance and hydrophobically interacts with crizotinib to enhance sensitivity. With respect to the double mutant L1198F/G1202R, F1198 indirectly pulls R1202 away from the binding entrance and consequently alleviates the steric obstacle introduced by R1202. These results demonstrated how the mutated residues tune the crizotinib response and may assist kinase inhibitor development especially for ALK G1202R, analogous to the ROS1 G2302R and MET G1163R mutations that are also resistant to crizotinib treatment in NSCLC.
Subject(s)
Anaplastic Lymphoma Kinase/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Crizotinib/pharmacology , Drug Resistance, Neoplasm/genetics , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Adenosine Triphosphate/metabolism , Anaplastic Lymphoma Kinase/antagonists & inhibitors , Anaplastic Lymphoma Kinase/metabolism , Anaplastic Lymphoma Kinase/ultrastructure , Binding Sites/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Crizotinib/therapeutic use , Humans , Inhibitory Concentration 50 , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Molecular Dynamics Simulation , Protein Domains/genetics , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Proto-Oncogene Proteins c-met/geneticsABSTRACT
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in various cancers. In its basal state, the structure of ALK is in an autoinhibitory form stabilized by its A-loop, which runs from the N-lobe to the C-lobe of the kinase. Specifically, the A-loop adopts an inhibitory pose with its proximal A-loop helix (αAL-helix) to anchor the αC-helix orientation in an inactive form in the N-lobe; the distal portion of the A-loop is packed against the C-lobe to block the peptide substrate from binding. Upon phosphorylation of the first A-loop tyrosine (Y1278), the αAL-helix unfolds; the distal A-loop detaches from the C-lobe and reveals the P+1 pocket that accommodates the residues immediately after their phosphorylation, and ALK is activated accordingly. Recently, two neuroblastoma mutants, F1174L and R1275Q, have been determined to cause ALK activation without phosphorylation on Y1278. Notably, F1174 is located on the C-terminus of the αC-helix and away from the A-loop, whereas R1275 sits on the αAL-helix. In this molecular modeling study, we investigated the structural impacts of F1174L and R1275Q that lead to the gain-of-function event. Wild-type ALK and ALK with phosphorylated Y1278 were also modeled for comparison. Our modeling suggests that the replacement of F1174 with a smaller residue, namely leucine, moves the αC-helix and αAL-helix into closer contact and further distorts the distal portion of the A-loop. In wild-type ALK, R1275 assumes the dual role of maintaining the αAL-helixâ»αC-helix interaction in an inactive form and securing αAL-helix conformation through the D1276â»R1275 interaction. Accordingly, mutating R1275 to a glutamine reorients the αC-helix to an active form and deforms the entire A-loop. In both F1174L and R1275Q mutants, the A-loop rearranges itself to expose the P+1 pocket, and kinase activity resumes.
Subject(s)
Mutation/genetics , Receptor Protein-Tyrosine Kinases/chemistry , Receptor Protein-Tyrosine Kinases/genetics , AAA Domain/genetics , Anaplastic Lymphoma Kinase , Leucine/genetics , Models, Molecular , Phosphorylation/genetics , Protein Conformation, alpha-Helical/geneticsABSTRACT
Anterior open bite (AOB) is one of the most complex malocclusions to manage. AOB is caused by either by skeletal, genetic or environmental factors. Numerous treatment options are currently utilised to manage AOB. These vary from non-invasive behavioural shaping to orthodontic and surgical interventions. This paper reviews the available orthodontic and non-orthodontic interventions used in the management of AOB. The literature review was carried out using the PubMed search engine from the first of January 2000 to the first of June 2017. Two major keywords (open bite and anterior open bite) were used in addition to 23 minor keywords in the review. AOB is one of the most complex malocclusions to treat with high relapse rates. Long term outcome in treatments of patients with AOB was substantially low. Relapse rates were not taken into consideration for some of the literature reviewed. Despite limitations of the literature, it is recommended that orofacial myofunctional therapy (OMT) and non-orthodontic intervention (NOI) be used in conjunction as an effective treatment option for Anterior Open Bite.
Subject(s)
Fingersucking/therapy , Magnets , Myofunctional Therapy/methods , Open Bite/therapy , Child , Child, Preschool , Female , Fingersucking/psychology , Humans , Male , Open Bite/pathology , Open Bite/psychology , Recurrence , Treatment OutcomeABSTRACT
Adult Cebpb KO mice incisors present amelogenin-positive epithelium pearls, enamel and dentin allopathic hyperplasia, fewer Sox2-positive cells in labial cervical loop epitheliums, and reduced Sox2 expression in enamel epithelial stem cells. Thus, Cebpb acts upstream of Sox2 to regulate stemness. In this study, Cebpb KO mice demonstrated cementum-like hard tissue in dental pulp, loss of polarity by ameloblasts, enamel matrix in ameloblastic layer, and increased expression of epithelial-mesenchymal transition (EMT) markers in a Cebpb knockdown mouse enamel epithelial stem cell line. Runx2 knockdown in the cell line presented a similar expression pattern. Therefore, the EMT enabled disengaged odontogenic epithelial stem cells to develop supernumerary teeth. Cebpb and Runx2 knockdown in the cell line revealed higher Biglycan and Decorin expression, and Decorin-positive staining in the periapical region, indicating their involvement in supernumerary tooth formation. Cebpb and Runx2 acted synergistically and played an important role in the formation of supernumerary teeth in adult incisors.
Subject(s)
CCAAT-Enhancer-Binding Protein-beta/metabolism , Core Binding Factor Alpha 1 Subunit/metabolism , Epithelial-Mesenchymal Transition/physiology , Incisor/metabolism , Odontogenesis , Stem Cells/metabolism , Tooth, Supernumerary/metabolism , Ameloblasts/physiology , Animals , CCAAT-Enhancer-Binding Protein-beta/genetics , Cadherins/metabolism , Cell Line , Cell Polarity , Core Binding Factor Alpha 1 Subunit/genetics , Dental Cementum/metabolism , Dental Pulp/metabolism , Female , Gene Knockdown Techniques , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Normal Distribution , Phenotype , SOXB1 Transcription Factors/metabolism , Statistics, Nonparametric , Tooth Germ/metabolismABSTRACT
Oxygen homeostasis in normal and tumor cells is mediated by hypoxia-inducible factors (HIFs), which are active as heterodimer complexes, such as HIF-2α-aryl hydrocarbon receptor nuclear translocator (ARNT) and HIF-1α-ARNT. A series of mutations on the interfaces between HIF-2α and ARNT and on the domain-domain interface within HIF-2α has been reported to exert varying effects on HIF-2α-ARNT dimerization. In the present study, molecular dynamic simulations were conducted to evaluate HIF-2α mutations, namely R171A, V192D, and R171A/V192D, which are not involved in the interaction with ARNT but impede HIF-2α-ARNT dimerization. Our results indicate that these mutations induct local conformation leading to a shortened (by V192D) or widened (by R171A and R171A/V192D) Y91-E346 separation distance, where E346 and Y91 are located on the HIF-2α and interact with ARNT according to electrostatic and geometrical shape complementarity, respectively.