Journal of dental research最新文献

Head and neck squamous cell carcinoma (HNSCC) is one of the deadliest human cancers, with the overall 5-year survival rate stagnating in recent decades due to the lack of innovative treatment approaches. Apart from the recently Food and Drug Administration-approved epidermal growth factor receptor inhibitor and immune checkpoint inhibitor, alternative therapeutic strategies that target epigenetic abnormalities, an emerging cancer hallmark, remain to be fully explored. A pathological epigenetic landscape, characterized by widespread reprogramming of chromatin modifications such as DNA methylation and histone modifications, which drives transcription deregulation and genome reorganization, has been extensively documented in numerous cancers, including HNSCC. Growing evidence indicates that these frequent epigenomic alterations play pivotal roles in regulating malignant transformation, promoting metastasis and invasion, and reshaping the tumor microenvironment. Furthermore, these epigenetic changes also present unique vulnerabilities that open new avenues for identifying novel prognostic biomarkers and developing targeted antitumor therapies. In this review, we summarize recent discoveries of epigenetic dysregulations in HNSCC, with a focus on deregulated chromatin modifications, which include aberrant DNA methylation, oncohistone H3 lysine 36 to methionine (H3K36M) mutation, as well as recurrent mutations or altered expression of chromatin-modifying enzymes such as NSD1, EZH2, and KMT2C/D. Importantly, we discuss the various molecular mechanisms underlying the contributions of these epigenetic alterations to HNSCC development, particularly their involvement in deregulated cell proliferation and cell death, metabolic reprogramming, tumor immune evasion, and phenotypic plasticity. Finally, we conclude by highlighting the translational and clinical implications of targeting the epigenetic machinery, which offers promising prospects for overcoming resistance to conventional radiotherapy/chemotherapy and enhancing the response to immunotherapy in HNSCC.

It is important to maintain confidence in the risk and benefit balance of major caries-preventive programs using fluoride. The ongoing debate about potential effects of early-life exposures to fluoride on cognitive neurodevelopment requires high-quality scientific evidence. This study aimed to investigate the potential effects of fluoride exposure on cognitive neurodevelopment assessed with the Wechsler Adult Intelligence Scale 4th edition (WAIS-IV) in an Australian population-based sample. The sample was selected from the National Child Oral Health Study (NCOHS) 2012-2014. NCOHS collected data on socioeconomic factors, oral health behaviors, and residential history to estimate percentage lifetime exposure to fluoridated water during the first 5 y of life (%LEFW). NCOHS children were also examined by trained and calibrated examiners to assess dental fluorosis (a reliable and valid individual biomarker of total fluoride intake during early childhood). The sample was followed up in 2022-2023 to collect data on cognitive neurodevelopment (intelligence quotient [IQ]) using the WAIS-IV, which was administered by trained and calibrated qualified psychologists. Multivariable regression models were generated to investigate associations between the 2 exposure measurements (%LEFW and dental fluorosis) with full-scale IQ (FSIQ) scores, controlling for important confounding effects. Hypotheses of noninferiority were also tested, contrasting different levels of exposure to fluoride. Some 357 participants aged 16 to 26 y completed the WAIS-IV, with a mean FSIQ score of 109.2 (95% confidence interval [CI]: 107.8-110.5). The estimates of the multivariable regression models demonstrated slightly higher FSIQ scores among the exposed than the nonexposed. The adjusted β of 100%LEFW versus 0%LEFW was 1.07 (95% CI: -2.86, 5.01) and of having dental fluorosis versus no fluorosis was 0.28 (95% CI: -3.00, 3.57). The hypothesis of noninferiority tests found that FSIQ scores of those exposed and nonexposed to fluoride were equivalent. The study provided consistent evidence that early childhood exposure to fluoride does not have effects on cognitive neurodevelopment.

The long-term success of dental implants depends on the ability of soft tissues to form a protective barrier, limiting pathogen infiltration into peri-implant tissues. Here, we investigated the impact of an anodized surface modification on mucosal integration. Scanning electron microscopy and surface chemistry characterization were carried out on miniaturized implants. Following placement in fresh extraction sockets of mice, peri-implant tissues were examined at 4 time points. Histology along with quantitative immunohistochemistry for Keratin14, Vimentin, Laminin5, and CD68 were carried out on postimplant day (PID) 3 to assess early events in soft-tissue repair; on PID7, when peri-implant epithelialization was complete; at PID14, when osseointegration was complete; and at PID28, when soft-tissue maturation was nearing completion. In all cases, an intact junctional epithelium served as a reference. These analyses supported 3 conclusions: first, maturation of the peri-implant epithelium (PIE) is a protracted process, consistent with clinical observations. Second, maturation of the soft tissue-implant interface is slower than maturation of the bone-implant interface. Third, there is a benefit, albeit transient, to soft-tissue maturation around an anodized implant surface. Given its prolonged time course, strategies to improve and/or accelerate PIE maturation are likely to have significant clinical benefit.

Early childhood caries (ECC) is the most common noncommunicable childhood disease-an important health problem with known environmental and social/behavioral influences lacking consensus genetic risk loci. To address this knowledge gap, we conducted a genome-wide association study of ECC in a multiancestry population of U.S. preschool-age children (N = 6,103) ages 3 to 5 y participating in a community-based epidemiologic study of early childhood oral health. Calibrated examiners used International Caries Detection and Assessment System criteria to measure ECC; the primary trait was the number of primary tooth surfaces with caries experience (i.e., dmfs index). We estimated heritability and concordance rates and conducted genome-wide association analyses to estimate overall genetic effects as well as stratified by sex, household water fluoride, and dietary sugar and leveraged combined gene/gene-environment effects using 2-degree-of-freedom joint tests. Common genetic variants explained 24% of ECC phenotypic variance among unrelated individuals, while concordance rates were 0.64 (95% confidence interval [CI] = 0.42-0.79) among monozygotic twins and 0.44 (95% CI = 0.34-0.53) among first-degree relatives. Across all analyses, we identified 21 novel nonoverlapping genome-wide significant loci (P < 5 × 10^-8) and 1 genome-wide significant gene (TAAR6) associated with ECC. The taste receptor activity gene set, with known roles in chemosensing, bacterial recognition, and innate immunity in the oral cavity, was strongly associated with ECC. While no locus remained significant after studywise multiple-testing correction, 3 loci were nominally significant (P < 0.05) and directionally consistent in external cohorts of 285,248 adults (rs1442369, DLGAP1 and rs74606067, RP11-856F16.2) and 18,994 children (rs71327750, SLC41A3). Meanwhile, the strongest marker known to be associated with adult caries (rs1122171, tagging the long noncoding RNA PITX1-AS1) was nominally significant (P = 0.01) and directionally consistent with ECC in our study. Taken together, the results of this study add to the genomics knowledge base for early childhood caries, offer several plausible candidates for future mechanistic studies, and underscore the importance of accounting for sex and pertinent environmental exposures in genetic investigations.

High-quality prevalence and incidence studies of oral conditions are essential for estimation of disease burden and comparison of estimates among countries and over time, as well as for priority setting, resource allocation, and planning public health action. Existing systematic reviews of the epidemiology of untreated dental caries, severe periodontitis, and edentulism, carried out for the Global Burden of Disease study, showed inadequate and incomplete reporting of the measurement of oral conditions as well as a lack of consistency and comparability with other health conditions. These issues are more accentuated in studies from low- and middle-income countries. Studies must meet the highest standards so that these efforts do not waste resources. This report extends the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines to improve and standardize the reporting of descriptive oral epidemiologic studies of common oral conditions. The aim of the Guidelines for Reporting Oral Epidemiologic Studies to Inform Burden Estimation (GROESBE) is to promote transparency, clarity, and comparability of scientific reporting, specifically for prevalence and incidence studies of untreated caries, severe periodontitis, and edentulism. The GROESBE guidelines and checklist were developed following a structured and formal consultation process with a geographically diverse group of 23 individuals involved in the conduct and analysis of oral epidemiologic studies. GROESBE focuses on elements that are not included in STROBE, adding 14 specific recommendations to existing guidelines. They will facilitate reliable comparison of emerging prevalence and incidence data on untreated caries, severe periodontitis, and edentulism across settings worldwide and the synthesis of robust evidence to inform estimation of disease burden in future iterations of the Global Burden of Disease study.

Circadian rhythm disruption is thought to be associated with periodontitis, and molecular clock genes play critical roles in regulating bone homeostasis. However, the specific contribution of molecular clock genes to alveolar bone resorption caused by periodontitis is poorly understood. In this study, we introduced a novel Periodontitis Circadian Rhythm Score (PeriCRS) model that was established through machine learning using periodontal transcriptomic data from periodontitis clinical cohorts in the Gene Expression Omnibus (GEO) database. This approach revealed the potential regulatory role of circadian rhythm disruption in periodontitis and identified key molecular clock genes associated with alveolar bone destruction. Moreover, we established an experimental periodontitis model with circadian rhythm disturbance via periodontal ligation in mice exposed to a 6-h advanced LD12:12 cycle every 2 d. Our bioinformatics analysis revealed that NR1D1, which encodes REV-ERBα, is a pivotal factor in the impact of circadian rhythm disruption on periodontitis in periodontal tissues. Next, we confirmed the abnormal expression of the molecular clock gene Rev-erbα in inflammatory periodontal tissue in mice and confirmed that circadian rhythm disruption altered REV-ERBα expression. Furthermore, the activation of REV-ERBα with the agonist SR9009 notably decreased RANKL-induced osteoclast differentiation and suppressed the expression of osteoclast-related factors. Subsequent in vivo experiments demonstrated that SR9009 mitigated alveolar bone loss caused by periodontitis. Mechanistically, we found that the IL-22-STAT3 pathway inhibited REV-ERBα expression and modulated RANKL-induced osteoclast differentiation in vitro. Our results elucidate the role of REV-ERBα in osteoclastogenesis and suggest a potential new therapeutic avenue for addressing alveolar bone resorption associated with periodontitis.

Recent years have seen significant positive changes and developments in oral health-related policy and data on oral health and oral health care in Canada. Simultaneously, on the international stage, the momentum for oral health and related research continues to build. These changes have led to an initiative to create Canada's first National Oral Health Research Strategy (NOHRS), which was recently published by the Canadian Institutes of Health Research-Institute of Musculoskeletal Health and Arthritis (Allison and Rock 2024). In this communication, we describe the process that was used to undertake this work. We present the resulting guiding principles, the research priority areas, and the framework that emerged, which included 6 strategic priorities grouped into 3 themes: (A) Leading Issues: (1) access to care, (2) inequities, identities, and oral health; (B) Emerging Methods: (3) artificial intelligence, (4) omics; and (C) Overarching Approaches: (5) environmental sustainability, (6) knowledge mobilization and implementation science. In addition, NOHRS includes a series of proposed goals and a timeline over the coming years. The point is to encourage a broad range of individuals and groups of people to engage with this high-level strategy and create plans to implement it. This strategy directly answers the call by the World Health Organization for countries to establish a national oral health research strategy (World Health Organization 2024). We have engaged in an extensive, broad consultative process, resulting in a Canadian NOHRS that is tailored to the needs of our community. Its aim is to galvanize our community into action to address the priorities we have identified. By engaging in this process, we build upon multiple oral health-related initiatives in Canada and on the international stage. We hope to inspire and facilitate similar, much-needed work elsewhere.

Periodontal and peri-implant diseases are primarily biofilm-induced pathologies in susceptible hosts affecting the periodontium and dental implants. Differences in disease susceptibility, severity, and patterns of progression have been attributed to immune regulatory mechanisms such as epigenetics. DNA methylation is an essential epigenetic mechanism governing gene expression that plays pivotal roles in genomic imprinting, chromosomal stability, apoptosis, and aging. Clinical studies have explored DNA methylation inhibitors for cancer treatment and predictive methylation profiles for disease progression. In periodontal health, DNA methylation has emerged as critical, evidenced by clinical studies unraveling its complex interplay with inflammatory genes and its regulatory role in periodontitis contributing to disease severity. Human studies have shown that methylation enzymes associated with gene reactivation (e.g., ten-eleven translocation-2) are elevated in periodontitis compared with gingivitis. Dysregulation of these genes can lead to the production of inflammatory cytokines and an altered initial response to bacteria via the toll-like receptor signaling pathway in periodontal diseases. In addition, in peri-implant diseases, this dysregulation can result in altered DNA methylation levels and enzymatic activity influenced by the properties of the titanium surface. Beyond traditional perspectives, recent evidence highlights the involvement of RNA methylation (e.g., N6-methyladenosine [m6A], N6,2'-0-dimethyladenosine [m6Am]) in periodontitis and peri-implantitis lesions, playing vital roles in the innate immune response, production of inflammatory cytokines, and activation of dendritic cells. Both DNA and RNA methylation can influence the gene expression, virulence, and bacterial behavior of well-known periodontal pathogens such as Porphyromonas gingivalis. Alterations in bacterial methylation patterns result in changes in the metabolism, drug resistance, and gene expression related to survival in the host, thereby promoting tissue degradation and chronic inflammatory responses. In summary, the present state-of-the-art review navigates the evolving landscape of DNA and RNA methylation in periodontal and peri-implant diseases, integrating recent developments and mechanisms to reshape the understanding of epigenetic dynamics in oral health.

In population-based longitudinal studies, bias caused by nonresponse among eligible participants and attrition during follow-up thwarts conclusions. As this issue is not commonly addressed in dental studies, it is the aim of this study to examine the consequences of attrition with respect to tooth loss and mortality in a 10-y follow-up study. From the Study of Health in Pomerania (SHIP-0), a biological age (BA) score was constructed from 10 systemic biomarkers and related to one's actual chronological age (CA). The 3,417 dentate participants were stratified according to their BA-CA scores into tertiles: individuals with younger BA than their CA, those with concurrent BA and CA, and those with older BA than their CA. Baseline characteristics and propensity of leaving or remaining in the study were compared across these tertiles. We compared the characteristics within BA strata in the remainers of SHIP-2 (10-y follow-up) and their impact on tooth loss. Besides dropout by those who died, the attrition propensity of baseline study participants was dose dependent as related to BA-CA scores and socioeconomic factors. BA younger participants were underrepresented in dropouts but overrepresented in remaining follow-up participants. BA younger participants had a more favorable risk profile, better oral health, and a lower mortality rate than BA older participants. For the BA older participants, the opposite was observed. Remainers attaining the follow-up SHIP-2 were healthier and more health conscious. After 10 y, their tooth retention was still directed by BA constructed at baseline. The results support the assumption that individual risk profiles aggregated in BA constitute characteristic susceptibility patterns affecting perseverance or attrition in long-term follow-up studies. Attrition, which is common to follow-up studies, changes the study composition of participants depending on their BA and hence the transferability of results to the baseline population. The baseline BA gradient persists even after a long time.

Behavioral interventions can improve children's oral hygiene practices. The multiphase optimization strategy (MOST) offers a framework to prepare, optimize, and evaluate behavioral interventions. This optimization trial tested 3 intervention components-brief motivational interviewing (MI), storytelling videos (STVs), and oral health promotion messages (OHPMs)-in enhancing mother's self-reported brushing of their preschool children's teeth. A total of 128 mothers with children <5 y old were included in a 2³ factorial trial. The primary outcome was children's plaque accumulation, assessed using the modified Plaque Index of Silness and Löe, with scores ranging from 0 to 3. The secondary outcome was mothers' self-reported frequency of brushing their children's teeth, categorized as at least once daily or less than once daily. Mothers were randomized to 8 experimental conditions based on combinations of on-off levels of the 3 components. Linear regression and generalized linear regression with logit link function were used to assess the impact of the components and their interactions on plaque score and daily toothbrushing after 3 mo. Multiple imputation was used for missing values. The principle of effect hierarchy guided the selection of components for inclusion in the optimized package, giving priority to main effects and 2-way over 3-way interactions. Plaque was reduced from mean = 1.8 at baseline to mean = 1.5 and daily toothbrushing increased from 50.8% to 69.5% after 3 mo. MI led to non-significantly less plaque and non-significantly more daily toothbrushing. Combining OHPMs and STVs together without MI canceled each other. Neither the main effects nor the 2- or 3-way interactions significantly affected the 2 outcomes. Individual or combined components did not significantly reduce plaque or increase daily toothbrushing. MI had the greatest promise for behavior change, and the m-oral health components need modification before they can be combined with MI in a health promotion package.