Pub Date : 2025-10-18DOI: 10.1177/00220345251377014
J Aida,S Kiuchi,K Shirai,M A Peres,Y Matsuyama
Although studies have shown an association between oral health and dementia, causality and underlying mechanisms remain under debate. Reverse causality and unmeasured confounding factors, such as childhood cognitive function, raise questions about causality. Regarding theoretical mechanisms, essential oral functions such as eating and speaking are rarely discussed. The aim of this review was 2-fold: 1) to explain how recent epidemiologic studies tried to address these criticisms and 2) to suggest future research directions. To address reverse causality, studies used repeated surveys over time. Some studies considered the bidirectional relationship between oral health and dementia using appropriate methods. However, even in these studies, cognitive function prior to baseline was not incorporated. To infer the influence of unmeasured confounders, quantitative bias analysis using the E value is recommended, wherein the E value indicates the minimum strength of an unmeasured confounder needed to invalidate an observed association. Furthermore, methods that can ignore the effects of unmeasured confounding are good options, including fixed effect analysis and the instrumental variable method. However, few studies have applied these methods, yielding mixed results. Regarding mechanisms, although eating and speaking are essential oral functions, they have often been overlooked as potential mechanisms. These functions have a social aspect that facilitates interpersonal interactions and can reduce social isolation. The expert commission reported that social isolation in later life is 1 of the 14 modifiable risk factors for dementia. When we consider multilayered direct and indirect mechanisms of dementia throughout the life course in addition to the previously proposed mechanisms, such as periodontal inflammation, we find that poor oral health possibly increases dementia through social isolation via eating and speaking problems. In conclusion, based on causal inference studies and theoretical frameworks, oral health may be a modifiable risk factor for dementia. Methodologically and theoretically robust studies considering these points are needed to determine causality between oral health and dementia.
{"title":"Oral Health and Dementia: Causal Inference and Theoretical Mechanisms.","authors":"J Aida,S Kiuchi,K Shirai,M A Peres,Y Matsuyama","doi":"10.1177/00220345251377014","DOIUrl":"https://doi.org/10.1177/00220345251377014","url":null,"abstract":"Although studies have shown an association between oral health and dementia, causality and underlying mechanisms remain under debate. Reverse causality and unmeasured confounding factors, such as childhood cognitive function, raise questions about causality. Regarding theoretical mechanisms, essential oral functions such as eating and speaking are rarely discussed. The aim of this review was 2-fold: 1) to explain how recent epidemiologic studies tried to address these criticisms and 2) to suggest future research directions. To address reverse causality, studies used repeated surveys over time. Some studies considered the bidirectional relationship between oral health and dementia using appropriate methods. However, even in these studies, cognitive function prior to baseline was not incorporated. To infer the influence of unmeasured confounders, quantitative bias analysis using the E value is recommended, wherein the E value indicates the minimum strength of an unmeasured confounder needed to invalidate an observed association. Furthermore, methods that can ignore the effects of unmeasured confounding are good options, including fixed effect analysis and the instrumental variable method. However, few studies have applied these methods, yielding mixed results. Regarding mechanisms, although eating and speaking are essential oral functions, they have often been overlooked as potential mechanisms. These functions have a social aspect that facilitates interpersonal interactions and can reduce social isolation. The expert commission reported that social isolation in later life is 1 of the 14 modifiable risk factors for dementia. When we consider multilayered direct and indirect mechanisms of dementia throughout the life course in addition to the previously proposed mechanisms, such as periodontal inflammation, we find that poor oral health possibly increases dementia through social isolation via eating and speaking problems. In conclusion, based on causal inference studies and theoretical frameworks, oral health may be a modifiable risk factor for dementia. Methodologically and theoretically robust studies considering these points are needed to determine causality between oral health and dementia.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"11 1","pages":"220345251377014"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251372941
J.E. Gallagher, C. Guarnizo-Herreño, D. Kavanagh, Y. Makino, M. Mathur, P. Mossey, B. Varenne, B. O’Connell
Research-informed action is central to the mission of the International Association for Dental, Oral, and Craniofacial Research (IADR). The IADR Presidential Symposium in Bogotá, Colombia, in June 2023 explored the regional research agenda to support the WHO Global Strategy and Action Plan on Oral Health 2023–2030. Facilitated by the Global Oral Health Inequalities Research Network and supported through the participation of World Health Organization representatives, this symposium involved researchers and policy makers across 4 regions. Each presented the unique strengths, challenges, and opportunities for their region, highlighting key topics for research and methodological approaches for future consideration. This article presents a series of contrasting regional perspectives to inform collaborative action among the global research community and strategic organizations. IADR’s national and regional associations can play a vital role in ensuring that by 2030, at least 50% of countries will have a national oral health research agenda focused on public health and population-based interventions, supported by the breadth of dental, oral, and craniofacial research to improve population health and facilitate universal health coverage.
{"title":"Global Oral Health: Defining the Research Agenda in the Public Interest","authors":"J.E. Gallagher, C. Guarnizo-Herreño, D. Kavanagh, Y. Makino, M. Mathur, P. Mossey, B. Varenne, B. O’Connell","doi":"10.1177/00220345251372941","DOIUrl":"https://doi.org/10.1177/00220345251372941","url":null,"abstract":"Research-informed action is central to the mission of the International Association for Dental, Oral, and Craniofacial Research (IADR). The IADR Presidential Symposium in Bogotá, Colombia, in June 2023 explored the regional research agenda to support the WHO Global Strategy and Action Plan on Oral Health 2023–2030. Facilitated by the Global Oral Health Inequalities Research Network and supported through the participation of World Health Organization representatives, this symposium involved researchers and policy makers across 4 regions. Each presented the unique strengths, challenges, and opportunities for their region, highlighting key topics for research and methodological approaches for future consideration. This article presents a series of contrasting regional perspectives to inform collaborative action among the global research community and strategic organizations. IADR’s national and regional associations can play a vital role in ensuring that by 2030, at least 50% of countries will have a national oral health research agenda focused on public health and population-based interventions, supported by the breadth of dental, oral, and craniofacial research to improve population health and facilitate universal health coverage.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"131 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251372890
P R Arany,M Charles-Ayinde,M Fontana,G Huang,S M Levy,D V Messadi,R Moffat,S Naavaal,S L Tomar,Y H Yu,C H Fox
Topical fluorides play a critical role in the prevention and management of dental caries and have been a cornerstone of evidence-based oral health promotion for decades. A rigorous understanding of the improved acid resistance of fluorapatite, with more recent evidence of the antimicrobial actions of fluorides, has helped establish its key role in caries management. The American Association for Dental, Oral, and Craniofacial Research (AADOCR) recommends using fluoride-containing dentifrices at 1,000 to 1,500 ppm twice daily based on the current evidence. For preschool-aged children, only a small amount (a smear about the size of a grain of rice) should be used to effectively prevent caries while minimizing the risk of dental fluorosis from unintentional ingestion. Furthermore, for patients at increased caries risk, the use of topical fluoride agents, such as professionally applied gels, varnishes, and/or silver diamine fluoride, could be used at 6-mo intervals, along with daily or weekly fluoride mouth rinses and gels; frequency should be adjusted to individual risk status and other sources of fluorides. Due to their high fluoride concentration, mouth rinses and prescription gels are not recommended for preschool-aged children. The AADOCR supports continued high-quality research to refine clinical guidelines and ensure that topical fluoride use remains aligned with scientific understanding and public health priorities.
{"title":"The AADOCR Position Statement on Topical Fluoride.","authors":"P R Arany,M Charles-Ayinde,M Fontana,G Huang,S M Levy,D V Messadi,R Moffat,S Naavaal,S L Tomar,Y H Yu,C H Fox","doi":"10.1177/00220345251372890","DOIUrl":"https://doi.org/10.1177/00220345251372890","url":null,"abstract":"Topical fluorides play a critical role in the prevention and management of dental caries and have been a cornerstone of evidence-based oral health promotion for decades. A rigorous understanding of the improved acid resistance of fluorapatite, with more recent evidence of the antimicrobial actions of fluorides, has helped establish its key role in caries management. The American Association for Dental, Oral, and Craniofacial Research (AADOCR) recommends using fluoride-containing dentifrices at 1,000 to 1,500 ppm twice daily based on the current evidence. For preschool-aged children, only a small amount (a smear about the size of a grain of rice) should be used to effectively prevent caries while minimizing the risk of dental fluorosis from unintentional ingestion. Furthermore, for patients at increased caries risk, the use of topical fluoride agents, such as professionally applied gels, varnishes, and/or silver diamine fluoride, could be used at 6-mo intervals, along with daily or weekly fluoride mouth rinses and gels; frequency should be adjusted to individual risk status and other sources of fluorides. Due to their high fluoride concentration, mouth rinses and prescription gels are not recommended for preschool-aged children. The AADOCR supports continued high-quality research to refine clinical guidelines and ensure that topical fluoride use remains aligned with scientific understanding and public health priorities.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"1 1","pages":"220345251372890"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Resin–dentin bonding technology is the primary method for tooth restoration in clinical practice. However, the formation of a defect zone at the bonding interface due to inadequate moisture control at the interface remains a major challenge. Inspired by mussel wet-adhesion mechanisms, this study functionalized phosphoric acid etchants with catechol–lysine–methacrylate (CLM), a polymerizable small-molecule monomer. During dentin demineralization, catechol binding to demineralized dentin was confirmed using an incubation-rinsing technique, while lysine’s role in facilitating rapid water release at the bonding interface was validated by freeze-drying mass loss, surface charge distribution, and thermogravimetric analysis. Confocal laser scanning microscopy revealed increased resin tag lengths in the CLM-treated groups, indicating enhanced resin infiltration. Ultimate tensile strength, dry mass loss, sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and in situ zymography demonstrated catechol-enabled collagen stabilization via Schiff base/ester bonds and endogenous enzyme inhibition. Micro-tensile testing revealed that the 4- to 5-mg/mL CLM groups maintained bond strength after 10,000 thermal cycles. Thus, CLM-functionalized etchants may enhance bonding durability in vitro by improving moisture control and collagen stability.
{"title":"Mussel-Inspired Etchant with Catechol-Lys-Methacrylate for Bond Durability","authors":"Y.T. Hu, C.Y. Yang, D.J. Wang, X.R. Feng, F.R. Tay, J.H. Chen, X.D. Xing, Y.H. Xiao, L. Zhang","doi":"10.1177/00220345251376314","DOIUrl":"https://doi.org/10.1177/00220345251376314","url":null,"abstract":"Resin–dentin bonding technology is the primary method for tooth restoration in clinical practice. However, the formation of a defect zone at the bonding interface due to inadequate moisture control at the interface remains a major challenge. Inspired by mussel wet-adhesion mechanisms, this study functionalized phosphoric acid etchants with catechol–lysine–methacrylate (CLM), a polymerizable small-molecule monomer. During dentin demineralization, catechol binding to demineralized dentin was confirmed using an incubation-rinsing technique, while lysine’s role in facilitating rapid water release at the bonding interface was validated by freeze-drying mass loss, surface charge distribution, and thermogravimetric analysis. Confocal laser scanning microscopy revealed increased resin tag lengths in the CLM-treated groups, indicating enhanced resin infiltration. Ultimate tensile strength, dry mass loss, sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and in situ zymography demonstrated catechol-enabled collagen stabilization via Schiff base/ester bonds and endogenous enzyme inhibition. Micro-tensile testing revealed that the 4- to 5-mg/mL CLM groups maintained bond strength after 10,000 thermal cycles. Thus, CLM-functionalized etchants may enhance bonding durability in vitro by improving moisture control and collagen stability.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"142 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Temporomandibular joint osteoarthritis (TMJOA) is a progressive and debilitating degenerative joint disorder characterized by cartilage degradation. Its pathogenesis remains poorly understood, and current treatment strategies are insufficient to restore normal joint structure. Lipid metabolism disorders in condylar chondrocytes have been identified as key contributors to TMJOA development, with peroxisomes playing an essential regulatory role in this metabolic process. Although previous studies have suggested a role for peroxisomes in chondrocyte biology, their specific involvement in TMJOA pathogenesis remains unclear. This study is the first to demonstrate the involvement of peroxisomes in TMJOA and to elucidate the associated molecular mechanisms. A TMJOA mouse model was established via unilateral anterior crossbite surgery, revealing abnormal peroxisome quantity and function. In vitro experiments demonstrated that inhibiting peroxisome function alleviated mechanical stress-induced OA-like damage to chondrocytes. In Acan-CreERT2 Pex2f/f conditional knockout (KO) mice, Pex2 KO inhibited peroxisome function and significantly attenuated TMJOA pathology. Mechanistically, peroxisome functional inhibition led to decreased levels of palmitic acid (PA), whereas exogenous PA exposure induced an OA-like phenotype in chondrocytes. Further investigation revealed that PA activated the WNT/PCP pathway by activating the JNK/c-JUN signaling axis. Multiomics analysis revealed S100a4 as a key downstream effector gene, and further CUT&RUN quantitative polymerase chain reaction and dual-luciferase reporter assays confirmed that c-JUN directly bound to the S100a4 promoter region (-101 to -94 bp) to regulate its transcription. Knockdown of S100a4 expression significantly reduced PA-induced Mmp13 expression in chondrocytes. In vivo experiments confirmed that intra-articular injection of PA upregulated S100a4 levels and promoted TMJOA development. In conclusion, this study is the first to elucidate the critical role of the peroxisome/PA/JNK/c-JUN/S100a4 axis in cartilage degradation in TMJOA, providing a novel and promising therapeutic target for TMJOA.
{"title":"Peroxisome Functional Inhibition Alleviates TMJOA Cartilage Degradation.","authors":"R Ren,L Xiao,H Qi,S Tang,P Yue,Y Zhang,S Lin,L Xu,Y Li,K Zhou,Z Zhao,J Fang","doi":"10.1177/00220345251381299","DOIUrl":"https://doi.org/10.1177/00220345251381299","url":null,"abstract":"Temporomandibular joint osteoarthritis (TMJOA) is a progressive and debilitating degenerative joint disorder characterized by cartilage degradation. Its pathogenesis remains poorly understood, and current treatment strategies are insufficient to restore normal joint structure. Lipid metabolism disorders in condylar chondrocytes have been identified as key contributors to TMJOA development, with peroxisomes playing an essential regulatory role in this metabolic process. Although previous studies have suggested a role for peroxisomes in chondrocyte biology, their specific involvement in TMJOA pathogenesis remains unclear. This study is the first to demonstrate the involvement of peroxisomes in TMJOA and to elucidate the associated molecular mechanisms. A TMJOA mouse model was established via unilateral anterior crossbite surgery, revealing abnormal peroxisome quantity and function. In vitro experiments demonstrated that inhibiting peroxisome function alleviated mechanical stress-induced OA-like damage to chondrocytes. In Acan-CreERT2 Pex2f/f conditional knockout (KO) mice, Pex2 KO inhibited peroxisome function and significantly attenuated TMJOA pathology. Mechanistically, peroxisome functional inhibition led to decreased levels of palmitic acid (PA), whereas exogenous PA exposure induced an OA-like phenotype in chondrocytes. Further investigation revealed that PA activated the WNT/PCP pathway by activating the JNK/c-JUN signaling axis. Multiomics analysis revealed S100a4 as a key downstream effector gene, and further CUT&RUN quantitative polymerase chain reaction and dual-luciferase reporter assays confirmed that c-JUN directly bound to the S100a4 promoter region (-101 to -94 bp) to regulate its transcription. Knockdown of S100a4 expression significantly reduced PA-induced Mmp13 expression in chondrocytes. In vivo experiments confirmed that intra-articular injection of PA upregulated S100a4 levels and promoted TMJOA development. In conclusion, this study is the first to elucidate the critical role of the peroxisome/PA/JNK/c-JUN/S100a4 axis in cartilage degradation in TMJOA, providing a novel and promising therapeutic target for TMJOA.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"27 1","pages":"220345251381299"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251383829
J K Jeong,H Choi,T H Kim,D Adasooriya,S W Cho,E S Cho
Molar root morphogenesis, particularly the formation of the furcation that determines root number, is a complex process governed by precise epithelial-mesenchymal interactions. Although Wnt signaling is critical for tooth development, the mechanisms that spatially restrict its activity to ensure proper root architecture are not fully understood. In this study, to investigate the role of the secreted Wnt antagonist Notum in regulating molar root furcation, we analyzed Notum knockout (KO) mice. Temporospatial expression analysis revealed that Notum is specifically and transiently expressed in the differentiating odontoblasts of the apical mesenchyme during furcation formation. Notum KO mice exhibited a severe failure of molar root furcation with an enlarged pulp chamber. Mechanistically, particularly at the molar furcation region, Notum deficiency led to impaired extension of Hertwig's epithelial root sheath (HERS) and dysregulated signaling in the underlying mesenchyme, characterized by an upregulated Wnt pathway and, consequently, increased cell proliferation of apical pulp cells and reduced odontoblast differentiation. Notably, inducible deletion of Wntless (Wls) in the dental epithelium phenocopied the furcation defect and led to a dramatic loss of Notum expression, demonstrating that epithelial Wnt signaling is required for Notum induction at the mesenchymal apex of furcation region. These findings identify Notum as a critical regulator of molar root furcation. We propose a model in which HERS-derived Wnt signaling induces Notum expression in the adjacent mesenchyme, which, in turn, antagonizes the Wnt signal to orchestrate the switch from cell proliferation to odontoblastic differentiation, thereby driving the formation of the root furcation. This study provides novel insights into the molecular mechanisms underlying the negative feedback loop between Wnt and Notum through epithelial-mesenchymal interactions, contributing to a deeper understanding of tooth development.
{"title":"Notum Regulates Tooth Root Morphogenesis by Modulating Wnt Signaling.","authors":"J K Jeong,H Choi,T H Kim,D Adasooriya,S W Cho,E S Cho","doi":"10.1177/00220345251383829","DOIUrl":"https://doi.org/10.1177/00220345251383829","url":null,"abstract":"Molar root morphogenesis, particularly the formation of the furcation that determines root number, is a complex process governed by precise epithelial-mesenchymal interactions. Although Wnt signaling is critical for tooth development, the mechanisms that spatially restrict its activity to ensure proper root architecture are not fully understood. In this study, to investigate the role of the secreted Wnt antagonist Notum in regulating molar root furcation, we analyzed Notum knockout (KO) mice. Temporospatial expression analysis revealed that Notum is specifically and transiently expressed in the differentiating odontoblasts of the apical mesenchyme during furcation formation. Notum KO mice exhibited a severe failure of molar root furcation with an enlarged pulp chamber. Mechanistically, particularly at the molar furcation region, Notum deficiency led to impaired extension of Hertwig's epithelial root sheath (HERS) and dysregulated signaling in the underlying mesenchyme, characterized by an upregulated Wnt pathway and, consequently, increased cell proliferation of apical pulp cells and reduced odontoblast differentiation. Notably, inducible deletion of Wntless (Wls) in the dental epithelium phenocopied the furcation defect and led to a dramatic loss of Notum expression, demonstrating that epithelial Wnt signaling is required for Notum induction at the mesenchymal apex of furcation region. These findings identify Notum as a critical regulator of molar root furcation. We propose a model in which HERS-derived Wnt signaling induces Notum expression in the adjacent mesenchyme, which, in turn, antagonizes the Wnt signal to orchestrate the switch from cell proliferation to odontoblastic differentiation, thereby driving the formation of the root furcation. This study provides novel insights into the molecular mechanisms underlying the negative feedback loop between Wnt and Notum through epithelial-mesenchymal interactions, contributing to a deeper understanding of tooth development.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"54 1","pages":"220345251383829"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251378053
J Adeoye,H Wang,A W I Lo,U S Khoo,Y-X Su
Oral cancer often develops from oral potentially malignant disorders. Oral leukoplakia (OL) is the most common oral potentially malignant disorder. However, not all patients with OL develop oral cancer in their lifetimes, and cancer risk assessment is challenging. This study developed a time-to-event artificial intelligence-based model (termed OralCancerPredict) that integrated patient characteristics, histologic features, and immunohistochemical indicators for precise prediction of cancer progression in OL. We performed a retrospective analysis of patient data (n = 456) and tissue samples (n = 1,312) obtained before cancer progression or at last follow-up for patients with OL. KRT13 and p53 immunohistochemistry and quantitative analyses were performed for tissue samples, while independent prognostic features, including demographic characteristics, clinical information, and histopathologic findings, were obtained for patients in the cohort. KRT13 and p53 expression was combined with histologic and patient data for model training, testing, and external validation. Performance evaluation for OralCancerPredict included model discriminative ability, calibration, explainability, and net benefit analysis via decision curves. External validation was also performed to ensure model generalizability based on patient data (n = 119) and tissue samples (n = 322) unused for training and testing. Our findings showed that OralCancerPredict trained on multidimensional data had good concordance indices (0.855 to 0.867), areas under the curve (0.877 to 0.882), and integrated Brier scores (0.046 to 0.069) at testing and external validation. Explainability analysis confirmed the importance of KRT13 and p53 deregulated expression and World Health Organization dysplasia grading to OralCancerPredict in predicting the risk of cancerization and cancer progression-free survival. Moreover, the model had a better net benefit than the World Health Organization and binary dysplasia grading systems alone, which represent the current risk stratification methods in OL management. Overall, OralCancerPredict can predict the risk of cancer development and cancer progression-free survival for patients with OL, with good discrimination, calibration, and net benefit. The explainable artificial intelligence model has the potential to streamline intervention and close monitoring in the clinical management of OL.
{"title":"Multidimensional Artificial Intelligence-Based Cancer Progression Prediction in Oral Leukoplakia.","authors":"J Adeoye,H Wang,A W I Lo,U S Khoo,Y-X Su","doi":"10.1177/00220345251378053","DOIUrl":"https://doi.org/10.1177/00220345251378053","url":null,"abstract":"Oral cancer often develops from oral potentially malignant disorders. Oral leukoplakia (OL) is the most common oral potentially malignant disorder. However, not all patients with OL develop oral cancer in their lifetimes, and cancer risk assessment is challenging. This study developed a time-to-event artificial intelligence-based model (termed OralCancerPredict) that integrated patient characteristics, histologic features, and immunohistochemical indicators for precise prediction of cancer progression in OL. We performed a retrospective analysis of patient data (n = 456) and tissue samples (n = 1,312) obtained before cancer progression or at last follow-up for patients with OL. KRT13 and p53 immunohistochemistry and quantitative analyses were performed for tissue samples, while independent prognostic features, including demographic characteristics, clinical information, and histopathologic findings, were obtained for patients in the cohort. KRT13 and p53 expression was combined with histologic and patient data for model training, testing, and external validation. Performance evaluation for OralCancerPredict included model discriminative ability, calibration, explainability, and net benefit analysis via decision curves. External validation was also performed to ensure model generalizability based on patient data (n = 119) and tissue samples (n = 322) unused for training and testing. Our findings showed that OralCancerPredict trained on multidimensional data had good concordance indices (0.855 to 0.867), areas under the curve (0.877 to 0.882), and integrated Brier scores (0.046 to 0.069) at testing and external validation. Explainability analysis confirmed the importance of KRT13 and p53 deregulated expression and World Health Organization dysplasia grading to OralCancerPredict in predicting the risk of cancerization and cancer progression-free survival. Moreover, the model had a better net benefit than the World Health Organization and binary dysplasia grading systems alone, which represent the current risk stratification methods in OL management. Overall, OralCancerPredict can predict the risk of cancer development and cancer progression-free survival for patients with OL, with good discrimination, calibration, and net benefit. The explainable artificial intelligence model has the potential to streamline intervention and close monitoring in the clinical management of OL.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"1 1","pages":"220345251378053"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-18DOI: 10.1177/00220345251383901
P C Yelick
{"title":"Reimagining Dental, Oral, and Craniofacial Research: New Opportunities for the IADR's Efforts to Achieve Global Oral Health.","authors":"P C Yelick","doi":"10.1177/00220345251383901","DOIUrl":"https://doi.org/10.1177/00220345251383901","url":null,"abstract":"","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"194 1","pages":"220345251383901"},"PeriodicalIF":7.6,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1177/00220345251368346
Y Chiba,T Tian,K Yoshizaki,X Wang,A Yamada,S Fukumoto
The coordination of dental cells is essential for tooth development. Various dental epithelial cell types are involved in tooth development, and each cell type plays a distinct role; however, the functional role of the outer enamel epithelium (OEE) remains unclear. We performed single-cell RNA-sequence (scRNA-seq) analysis of postnatal day (P) 7 incisors and embryonic day (E) 14 P1 molars of the mouse tooth germ to reveal the gene expression profile and role of OEE during tooth development. We identified keratin 15 (Krt15) as a specific marker gene of OEE in the dental epithelium. Characterization of dental epithelial clusters using scRNA-seq suggested that Krt15-negative cycling inner enamel epithelial (IEE) cells give rise to Krt15-positive OEE cells, whereas the proliferative activity of dental epithelial cells decreases toward the development of OEE cells. We performed ex vivo organ cultures of the tooth germ to examine the effects of Krt15 knockdown on tooth development. Depletion of Krt15 in the tooth germ resulted in ectopic expression of Ki67 in OEE cells, leading to the development of an abnormal dental epithelial structure. We used the dental epithelial cell line CLDE to assess the molecular mechanisms regulated by Krt15. Krt15-depleted CLDE cells showed abnormal cellular morphology and dysregulated gene expression of cytokeratin family members. Furthermore, Krt15 knockdown in CLDE cells upregulated the expression of cell proliferation marker genes, such as Mki67. Furthermore, Krt15-depleted CLDE cells exhibited activation of the p38 MAP kinase (MAPK) pathway and high proliferative activity. This suggested that Krt15 may control tooth germ size, inhibits p38 activation, and may act as a suppressor of dental epithelial cell proliferation. These findings provide new insights into the role of OEE in tooth development and contribute to a better understanding of the mechanisms underlying tooth morphogenesis.
{"title":"Keratin 15 Regulates Cell Proliferation in Outer Enamel Epithelium.","authors":"Y Chiba,T Tian,K Yoshizaki,X Wang,A Yamada,S Fukumoto","doi":"10.1177/00220345251368346","DOIUrl":"https://doi.org/10.1177/00220345251368346","url":null,"abstract":"The coordination of dental cells is essential for tooth development. Various dental epithelial cell types are involved in tooth development, and each cell type plays a distinct role; however, the functional role of the outer enamel epithelium (OEE) remains unclear. We performed single-cell RNA-sequence (scRNA-seq) analysis of postnatal day (P) 7 incisors and embryonic day (E) 14 P1 molars of the mouse tooth germ to reveal the gene expression profile and role of OEE during tooth development. We identified keratin 15 (Krt15) as a specific marker gene of OEE in the dental epithelium. Characterization of dental epithelial clusters using scRNA-seq suggested that Krt15-negative cycling inner enamel epithelial (IEE) cells give rise to Krt15-positive OEE cells, whereas the proliferative activity of dental epithelial cells decreases toward the development of OEE cells. We performed ex vivo organ cultures of the tooth germ to examine the effects of Krt15 knockdown on tooth development. Depletion of Krt15 in the tooth germ resulted in ectopic expression of Ki67 in OEE cells, leading to the development of an abnormal dental epithelial structure. We used the dental epithelial cell line CLDE to assess the molecular mechanisms regulated by Krt15. Krt15-depleted CLDE cells showed abnormal cellular morphology and dysregulated gene expression of cytokeratin family members. Furthermore, Krt15 knockdown in CLDE cells upregulated the expression of cell proliferation marker genes, such as Mki67. Furthermore, Krt15-depleted CLDE cells exhibited activation of the p38 MAP kinase (MAPK) pathway and high proliferative activity. This suggested that Krt15 may control tooth germ size, inhibits p38 activation, and may act as a suppressor of dental epithelial cell proliferation. These findings provide new insights into the role of OEE in tooth development and contribute to a better understanding of the mechanisms underlying tooth morphogenesis.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"66 1","pages":"220345251368346"},"PeriodicalIF":7.6,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1177/00220345251364162
B Liu,F Cao,S Zheng,X Yuan,N Mandalapu,J S Park,M O Sugihara,Y Mishina,J A Helms
As a first line of defense against periodontal diseases, the junctional epithelium must establish a firm attachment to the tooth surface while allowing new cells arising from the stem cell niche to migrate through the tissue. How these static and dynamic cell behaviors are coordinated in the junctional epithelium is not clear; we hypothesize it involves the epithelial-to-mesenchymal transition (EMT). An intact junctional epithelium was interrogated via quantitative immunohistochemistry for molecular markers of EMT; since EMT is also critical for tissue repair, the junctional epithelium was also interrogated at multiple time points after ligature-induced periodontitis. These analyses revealed that junctional epithelial cells transition from a polarized, cell-adherent phenotype to one in which cytoskeletal remodeling and increased motility occur. To gain insights into molecular mechanisms regulating EMT, we used a genetic system to delete the BMP type I receptor (BMPR1a) in postnatal mice. Within 7 d of BMPR1a inactivation, multiple EMT signaling pathways including Wnt/β-catenin, transforming growth factor-β, and Notch signaling were upregulated in the junctional epithelium. The mutant junctional epithelium exhibited extensive EMT accompanied by downregulation of the hemidesmosomal proteins Laminin5, plectin, and β4 integrin. Together, these findings demonstrate that normal junctional epithelium turnover used EMT and that this physiological process is controlled in part by WNT/BMP signaling.
{"title":"BMP/WNT-Dependent Mechanisms of Junctional Epithelium Turnover.","authors":"B Liu,F Cao,S Zheng,X Yuan,N Mandalapu,J S Park,M O Sugihara,Y Mishina,J A Helms","doi":"10.1177/00220345251364162","DOIUrl":"https://doi.org/10.1177/00220345251364162","url":null,"abstract":"As a first line of defense against periodontal diseases, the junctional epithelium must establish a firm attachment to the tooth surface while allowing new cells arising from the stem cell niche to migrate through the tissue. How these static and dynamic cell behaviors are coordinated in the junctional epithelium is not clear; we hypothesize it involves the epithelial-to-mesenchymal transition (EMT). An intact junctional epithelium was interrogated via quantitative immunohistochemistry for molecular markers of EMT; since EMT is also critical for tissue repair, the junctional epithelium was also interrogated at multiple time points after ligature-induced periodontitis. These analyses revealed that junctional epithelial cells transition from a polarized, cell-adherent phenotype to one in which cytoskeletal remodeling and increased motility occur. To gain insights into molecular mechanisms regulating EMT, we used a genetic system to delete the BMP type I receptor (BMPR1a) in postnatal mice. Within 7 d of BMPR1a inactivation, multiple EMT signaling pathways including Wnt/β-catenin, transforming growth factor-β, and Notch signaling were upregulated in the junctional epithelium. The mutant junctional epithelium exhibited extensive EMT accompanied by downregulation of the hemidesmosomal proteins Laminin5, plectin, and β4 integrin. Together, these findings demonstrate that normal junctional epithelium turnover used EMT and that this physiological process is controlled in part by WNT/BMP signaling.","PeriodicalId":15596,"journal":{"name":"Journal of Dental Research","volume":"37 1","pages":"220345251364162"},"PeriodicalIF":7.6,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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