A Review of the Repair of DNA Double Strand Breaks in the Development of Oral Cancer.

We explore the possibility that defects in genes associated with the response and repair of DNA double strand breaks predispose oral potentially malignant disorders (OPMD) to undergo malignant transformation to oral squamous cell carcinoma (OSCC). Defects in the homologous recombination/Fanconi anemia (HR/FA), but not in the non-homologous end joining, causes the DNA repair pathway to appear to be consistent with features of familial conditions that are predisposed to OSCC (FA, Bloom's syndrome, Ataxia Telangiectasia); this is true for OSCC that occurs in young patients, sometimes with little/no exposure to classical risk factors. Even in Dyskeratosis Congenita, a disorder of the telomerase complex that is also predisposed to OSCC, attempts at maintaining telomere length involve a pathway with shared HR genes. Defects in the HR/FA pathway therefore appear to be pivotal in conditions that are predisposed to OSCC. There is also some evidence that abnormalities in the HR/FA pathway are associated with malignant transformation of sporadic cases OPMD and OSCC. We provide data showing overexpression of HR/FA genes in a cell-cycle-dependent manner in a series of OPMD-derived immortal keratinocyte cell lines compared to their mortal counterparts. The observations in this study argue strongly for an important role of the HA/FA DNA repair pathway in the development of OSCC.

Role of CD44 in Chemotherapy Treatment Outcome: A Scoping Review of Clinical Studies.

Cluster of differentiation 44 (CD44), a cell surface adhesion molecule overexpressed in cancer stem cells, has been implicated in chemoresistance. This scoping review, following PRISMA-ScR guidelines, systematically identified and evaluated clinical studies on the impact of CD44 expression on chemotherapy treatment outcomes across various cancer types. The search encompassed PubMed (1985-2023) and SCOPUS (1936-2023) databases, yielding a total of 12,659 articles, of which 40 met the inclusion criteria and were included in the qualitative synthesis using a predefined data extraction table. Data collected included the cancer type, sample size, interventions, control, treatment outcome, study type, expression of CD44 variants and isoforms, and effect of CD44 on chemotherapy outcome. Most of the studies demonstrated an association between increased CD44 expression and negative chemotherapeutic outcomes such as shorter overall survival, increased tumor recurrence, and resistance to chemotherapy, indicating a potential role of CD44 upregulation in chemoresistance in cancer patients. However, a subset of studies also reported non-significant relationships or conflicting results. In summary, this scoping review highlighted the breadth of the available literature investigating the clinical association between CD44 and chemotherapeutic outcomes. Further research is required to elucidate this relationship to aid clinicians in managing CD44-positive cancer patients.

Prevalence and risk factors of oral potentially malignant disorders in Indonesia: a cross-sectional study undertaken in 5 provinces.

Detection of subjects with oral potentially malignant disorders in a population is key to early detection of oral cancer (OC) with consequent reduction of cancer-related morbidity and mortality. Our aim was to investigate the prevalence and associated risk factors for OPMD in representative provinces of Indonesia. This cross-sectional study was undertaken in five Indonesian provinces: West Java (WJ), Jakarta (JKT), West Papua (WP), West Kalimantan (WK) and Banda Aceh (BA). Respondents answered a previously validated questionnaire including information on ethnicity, occupation, socioeconomic status (SES), oral health practices, and behaviours associated with oral cancer. An oral examination was undertaken using WHO standardized methodology. Data were analysed using ANOVA, Chi-Square, and logistic regression to assess association between risk factors and mucosal disease. A total of 973 respondents between the ages of 17 and 82 years was enrolled (WJ 35.5%,JKT 13.3% WP 18.3%, WK 9%, BA 23.9%). Tobacco smoking (14.8%), Betel quid (BQ) chewing (12.6%) and alcohol drinking (4%) varied geographically. A well-established OPMD was detected in 137 (14.1%) respondents and 2 (0.2%) presented with chronic ulceration later diagnosed as OC. Leukoplakia was the most common OPMD found (9.7%), while the prevalence of oral submucous fibrosis (OSMF), not previously described in the nation, was 2.3%. Poor knowledge of OC risk factors, poor oral hygiene behaviours, low-income SES and ethnicity were significantly associated with the presence of an OPMD. There is a previously under-reported high prevalence of OPMD in Indonesia. Overall, we found a strong correlation between the presence of an OPMD and individual habituation to known risk factors.

Accuracy of Treatment Recommendations by Pragmatic Evidence Search and Artificial Intelligence: An Exploratory Study.

There is extensive literature emerging in the field of dentistry with the aim to optimize clinical practice. Evidence-based guidelines (EBGs) are designed to collate diagnostic criteria and clinical treatment for a range of conditions based on high-quality evidence. Recently, advancements in Artificial Intelligence (AI) have instigated further queries into its applicability and integration into dentistry. Hence, the aim of this study was to develop a model that can be used to assess the accuracy of treatment recommendations for dental conditions generated by individual clinicians and the outcomes of AI outputs. For this pilot study, a Delphi panel of six experts led by CoTreat AI provided the definition and developed evidence-based recommendations for subgingival and supragingival calculus. For the rapid review-a pragmatic approach that aims to rapidly assess the evidence base using a systematic methodology-the Ovid Medline database was searched for subgingival and supragingival calculus. Studies were selected and reported based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), and this study complied with the minimum requirements for completing a restricted systematic review. Treatment recommendations were also searched for these same conditions in ChatGPT (version 3.5 and 4) and Bard (now Gemini). Adherence to the recommendations of the standard was assessed using qualitative content analysis and agreement scores for interrater reliability. Treatment recommendations by AI programs generally aligned with the current literature, with an agreement of up to 75%, although data sources were not provided by these tools, except for Bard. The clinician's rapid review results suggested several procedures that may increase the likelihood of overtreatment, as did GPT4. In terms of overall accuracy, GPT4 outperformed all other tools, including rapid review (Cohen's kappa 0.42 vs. 0.28). In summary, this study provides preliminary observations for the suitability of different evidence-generating methods to inform clinical dental practice.

General dentists' knowledge, perceptions, and practices regarding oral potentially malignant disorders and oral cancer in Indonesia.

INTRODUCTION: The most effective means for reducing oral cancer (OC) mortality is by preventing late-stage disease. Early diagnosis can be improved by increasing awareness among healthcare providers, specifically general dental practitioners (GDP). Therefore, our study aimed to assess GDPs' knowledge of OC risk factors and perceived competence in performing conventional oral examination (COE) in routine dental practice. MATERIAL AND METHODS: This was a cross-sectional study conducted in five provinces of Indonesia, namely: Aceh, Banda Aceh (BA); Bandung, West Java (WJ); special district Jakarta (JKT), JKT; Pontianak, West Kalimantan (WK); and Sorong, West Papua (WP). The local Dental Association or Faculty of Dentistry invited the GDPs to attend an education program and complete the survey. RESULTS: One hundred seventy-seven GDPs completed the survey (WJ, n = 63; BA, n = 44, JKT, n = 27; WP, n = 23; and WP, n = 20). A large proportion (164 out of 177, 92.66%) of GDPs felt they had received insufficient training to equip them to diagnose OC and as many as 22.6% (n = 40) did not refer to specialists when they found suspicious mucosal lesions. Notwithstanding the significant regional variations, the majority of Indonesian GDPs self-reported inadequate knowledge and awareness of OC and scarce confidence in performing COE. CONCLUSION: GDP knowledge of OC risk factors and COE is key to improving early diagnosis of OC at a community level. Therefore, it is suggested that the lack of knowledge and confidence of GDPs reported here should be addressed through the national dental curriculum in Indonesia.

A Critical Interpretive Synthesis of the Role of Arecoline in Oral Carcinogenesis: Is the Local Cholinergic Axis a Missing Link in Disease Pathophysiology?

Arecoline is the primary active carcinogen found in areca nut and has been implicated in the pathogenesis of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF). For this study, we conducted a stepwise review process by combining iterative scoping reviews with a post hoc search, with the aim of identifying the specific mechanisms by which arecoline initiates and promotes oral carcinogenesis. Our initial search allowed us to define the current trends and patterns in the pathophysiology of arecoline-induced OSF and OSCC, which include the induction of cell proliferation, facilitation of invasion, adhesion, and migration, increased collagen deposition and fibrosis, imbalance in immune and inflammatory mechanisms, and genotoxicity. Key molecular pathways comprise the activation of NOTCH1, MYC, PRDX2, WNT, CYR61, EGFR/Pl3K, DDR1 signaling, and cytokine upregulation. Despite providing a comprehensive overview of potential pathogenic mechanisms of OSF, the involvement of molecules functioning as areca alkaloid receptors, namely, the muscarinic and nicotinic acetylcholine receptors (AChRs), was not elucidated with this approach. Accordingly, our search strategy was refined to reflect these evidence gaps. The results of the second round of reviews with the post hoc search highlighted that arecoline binds preferentially to muscarinic AChRs, which have been implicated in cancer. Consistently, AChRs activate the signaling pathways that partially overlap with those described in the context of arecoline-induced carcinogenesis. In summary, we used a theory-driven interpretive review methodology to inform, extend, and supplement the conventional systematic literature assessment workflow. On the one hand, the results of this critical interpretive synthesis highlighted the prevailing trends and enabled the consolidation of data pertaining to the molecular mechanisms involved in arecoline-induced carcinogenesis, and, on the other, brought up knowledge gaps related to the role of the local cholinergic axis in oral carcinogenesis, thus suggesting areas for further investigation.

The Hyaluronan/CD44 Axis: A Double-Edged Sword in Cancer.

Hyaluronic acid (HA) receptor CD44 is widely used for identifying cancer stem cells and its activation promotes stemness. Recent evidence shows that overexpression of CD44 is associated with poor prognosis in most human cancers and mediates therapy resistance. For these reasons, in recent years, CD44 has become a treatment target in precision oncology, often via HA-conjugated antineoplastic drugs. Importantly, HA molecules of different sizes have a dual effect and, therefore, may enhance or attenuate the CD44-mediated signaling pathways, as they compete with endogenous HA for binding to the receptors. The magnitude of these effects could be crucial for cancer progression, as well as for driving the inflammatory response in the tumor microenvironment. The increasingly common use of HA-conjugated drugs in oncology, as well as HA-based compounds as adjuvants in cancer treatment, adds further complexity to the understanding of the net effect of hyaluronan-CD44 activation in cancers. In this review, I focus on the significance of CD44 in malignancy and discuss the dichotomous function of the hyaluronan/CD44 axis in cancer progression.

Assessment of Oxidative Stress-Induced Oral Epithelial Toxicity.

Reactive oxygen species (ROS) are highly reactive molecules generated in living organisms and an excessive production of ROS culminates in oxidative stress and cellular damage. Notably, oxidative stress plays a critical role in the pathogenesis of a number of oral mucosal diseases, including oral mucositis, which remains one of cancer treatments' most common side effects. We have shown previously that oral keratinocytes are remarkably sensitive to oxidative stress, and this may hinder the development and reproducibility of epithelial cell-based models of oral disease. Here, we examined the oxidative stress signatures that parallel oral toxicity by reproducing the initial events taking place during cancer treatment-induced oral mucositis. We used three oral epithelial cell lines (an immortalized normal human oral keratinocyte cell line, OKF6, and malignant oral keratinocytes, H357 and H400), as well as a mouse model of mucositis. The cells were subjected to increasing oxidative stress by incubation with hydrogen peroxide (H2O2) at concentrations of 100 µM up to 1200 µM, for up to 24 h, and ROS production and real-time kinetics of oxidative stress were investigated using fluorescent dye-based probes. Cell viability was assessed using a trypan blue exclusion assay, a fluorescence-based live-dead assay, and a fluorometric cytotoxicity assay (FCA), while morphological changes were analyzed by means of a phase-contrast inverted microscope. Static and dynamic real-time detection of the redox changes in keratinocytes showed a time-dependent increase of ROS production during oxidative stress-induced epithelial injury. The survival rates of oral epithelial cells were significantly affected after exposure to oxidative stress in a dose- and cell line-dependent manner. Values of TC50 of 800 µM, 800 µM, and 400 µM were reported for H400 cells (54.21 ± 9.04, p < 0.01), H357 cells (53.48 ± 4.01, p < 0.01), and OKF6 cells (48.64 ± 3.09, p < 0.01), respectively. Oxidative stress markers (MPO and MDA) were also significantly increased in oral tissues in our dual mouse model of chemotherapy-induced mucositis. In summary, we characterized and validated an oxidative stress model in human oral keratinocytes and identified optimal experimental conditions for the study of oxidative stress-induced oral epithelial toxicity.

The Immune Cells in the Development of Oral Squamous Cell Carcinoma.

A still unresolved issue surrounding tumor formation concerns the role that the immune system plays in preventing the formation and progression of neoplasia, including oral squamous cell carcinoma (OSCC). Antitumor immunity has historically been seen as a critical barrier for cancer cells to develop, grow and spread, and this can be modulated using immunotherapies to achieve antitumor clinical responses. However, it has recently become clear that tumor-associated immunity, particularly the inflammatory microenvironment, has the paradoxical effect of enhancing tumorigenesis and progression. In this review, we discuss the multifaceted function of infiltrating immune cells in suppressing or promoting premalignancy and cancer. In particular, we report on the evidence supporting a role for T lymphocytes, dendritic cells, macrophages, and neutrophils in the development and progression of oral potentially malignant disorders (OPMD) and OSCC. We also draw attention to the clinical relevance of immune cell phenotypes and associated molecules for use as biomarkers and to the translatability of current research findings to improve classification systems and precision medicine in patients with OSCC.

High-risk TP53 mutations predict poor primary treatment response of patients with head and neck squamous cell carcinoma.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) poses a diagnostic and therapeutic challenge worldwide and is associated with a poor survival rate. Due to the variability in the efficacy of treatments for HNSCC, new predictive biomarkers of therapy outcomes are needed. Recently, we developed an algorithm that employs the mutational profile of TP53 as an independent prognostic factor in HNSCC. In this study, we investigated its role as a predictive biomarker of treatment outcomes in HNSCC patients. We also tested the usefulness of two classification systems for TP53 mutational landscapes. MATERIALS AND METHODS: Clinical and genomic data were retrieved from The Cancer Genome Atlas database. We built a multivariate stepwise backward binary regression model to assess the role of TP53 mutations in predicting therapeutic outcomes. RESULTS: Cases harbouring high-risk-of-death mutations reported an odds ratio of 3.301 for stable or progressive disease compared to wild-type cases, while no significant difference in treatment outcomes was found between cases with low-risk-of-death mutations and wild-type TP53. Our analysis found that older patients with a history of alcohol consumption had a higher risk of stable/progressive disease. CONCLUSIONS: This study improves current evidence on the role of TP53 mutations in treatment response in HNSCC patients.

High molecular weight hyaluronic acid drastically reduces chemotherapy-induced mucositis and apoptotic cell death.

Oral and intestinal mucositis (OIM) are debilitating inflammatory diseases initiated by oxidative stress, resulting in epithelial cell death and are frequently observed in cancer patients undergoing chemo-radiotherapy. There are currently few preventative strategies for this debilitating condition. Therefore, the development of a safe and effective mucositis mitigating strategy is an unmet medical need. Hyaluronic acid (HA) preparations have been tentatively used in oral mucositis. However, the protective effects of HA in chemotherapy-induced mucositis and their underlying mechanisms remain to be fully elucidated. This study aimed to assess these mechanisms using multiple formulations of enriched HA (Mucosamin®), cross-linked (xl-), and non-crosslinked high molecular weight HA (H-MW-HA) in an oxidative stress-induced model of human oral mucosal injury in vitro and an in vivo murine model of 5-flurouracil (5-FU)-induced oral/intestinal mucositis. All tested HA formulations protected against oxidative stress-induced damage in vitro without inducing cytotoxicity, with H-MW-HA also significantly reducing ROS production. Daily supplementation with H-MW-HA in vivo drastically reduced the severity of 5-FU-induced OIM, prevented apoptotic damage and reduced COX-2 enzyme activity in both the oral and intestinal epithelium. In 5-FU-injected mice, HA supplementation also significantly reduced serum levels of IL-6 and the chemokine CXCL1/KC, while the serum antioxidant activity of superoxide dismutase was elevated. Our data suggest that H-MW-HA attenuates 5-FU-induced OIM, at least partly, by impeding apoptosis, inhibiting of oxidative stress and suppressing inflammatory cytokines. This study supports the development of H-MW-HA preparations for preventing OIM in patients receiving chemotherapy.

Mechanisms underlying sex bias in oral immune-mediated conditions, an insight.

The predilection for women in systemic autoimmune diseases is well established. However, this sex bias in oral autoimmune diseases has been classically reported from an epidemiological perspective without any elaborate attempts to unveil the underlying mechanisms. The unique nature of the oral environment is likely to impose a combination of systemic and local factors that ultimately result in the sex bias in autoimmune diseases of the oral cavity. Variations of immune responses, target organ vulnerability, endocrine and genetic factors, sex chromosomes and modes of parental inheritance are potential systemic factors, while the oral microbiome, oral tolerance, saliva, and oral epithelial stem cells may account for local contributing factors. This review will discuss the preponderance of women in oral immune-mediated diseases, the potential systemic and local mechanisms underlying this predominance and highlight the crucial need for further research in this area.

Harnessing the power of collective intelligence in dentistry: a pilot study in Victoria, Australia.

BACKGROUND: In many dental settings, diagnosis and treatment planning is the responsibility of a single clinician, and this process is inevitably influenced by the clinician's own heuristics and biases. Our aim was to test whether collective intelligence increases the accuracy of individual diagnoses and treatment plans, and whether such systems have potential to improve patient outcomes in a dental setting. METHODS: This pilot project was carried out to assess the feasibility of the protocol and appropriateness of the study design. We used a questionnaire survey and pre-post study design in which dental practitioners were involved in the diagnosis and treatment planning of two simulated cases. Participants were provided the opportunity to amend their original diagnosis/treatment decisions after viewing a consensus report made to simulate a collaborative setting. RESULTS: Around half (55%, n = 17) of the respondents worked in group private practices, however most practitioners (74%, n = 23) did not collaborate when planning treatment. Overall, the average practitioners' self-confidence score in managing different dental disciplines was 7.22 (s.d. 2.20) on a 1-10 scale. Practitioners tended to change their mind after viewing the consensus response, particularly for the complex case compared to the simple case (61.5% vs 38.5%, respectively). Practitioners' confidence ratings were also significantly higher (p < 0.05) after viewing the consensus for complex case. CONCLUSION: Our pilot study shows that collective intelligence in the form of peers' opinion can lead to modifications in diagnosis and treatment planning by dentists. Our results lay the foundations for larger scale investigations on whether peer collaboration can improve diagnostic accuracy, treatment planning and, ultimately, oral health outcomes.

Role of Hemidesmosomes in Oral Carcinogenesis: A Systematic Review.

BACKGROUND: Oral cancers have limited diagnostic tools to aid clinical management. Current evidence indicates that alterations in hemidesmosomes, the adhesion complexes primarily involved in epithelial attachment to the basement membrane, are correlated to cancer phenotype for multiple cancers. This systematic review aimed to assess the experimental evidence for hemidesmosomal alterations, specifically in relation to oral potentially malignant disorders and oral squamous cell carcinomas. METHODS: We conducted a systemic review to summarise the available literature on hemidesmosomal components and their role in oral pre-cancer and cancer. Relevant studies were retrieved from a comprehensive search of Scopus, Ovid MEDLINE, Ovid Embase and Web of Science. RESULTS: 26 articles met the inclusion criteria, of which 19 were in vitro studies, 4 in vivo studies, 1 in vitro and in vivo study, and 2 in vitro and cohort studies. Among them, 15 studies discussed individual alpha-6 and/or beta-4 subunits, 12 studies discussed the alpha-6 beta-4 heterodimers, 6 studies discussed the entire hemidesmosome complex, 5 studies discussed bullous pemphigoid-180, 3 studies discussed plectin, 3 studies discussed bullous pemphigoid antigen-1 and 1 study discussed tetraspanin. CONCLUSION: Heterogeneity in cell type, experimental models, and methods were observed. Alterations in hemidesmosomal components were shown to contribute to oral pre-cancer and cancer. We conclude that there is sufficient evidence for hemidesmosomes and their components to be potential biomarkers for evaluating oral carcinogenesis.

The Role of Non-Neuronal Acetylcholine in the Autoimmune Blistering Disease Pemphigus Vulgaris.

The importance of acetylcholine (ACh) in keratinocyte adhesion and acantholysis has been investigated over the last three decades, particularly in the pathophysiology of autoimmune blistering dermatoses. Pemphigus vulgaris (PV) is an autoimmune blistering skin disease where autoantibody-mediated suprabasilar intraepidermal splitting causes flaccid blisters and non-healing erosions of the oral mucosa and sometimes also of the skin. Historically, acantholysis in PV was thought to be driven by anti-desmoglein (Dsg) antibodies. Herein, we describe the role of autoantibodies against keratinocyte muscarinic and nicotinic acetylcholine receptors, as well as the annexin-like molecule pemphaxin that also binds ACh, in the immunopathogenesis of PV. The identification of targets in this disease is important, as they may lead to novel diagnostic and therapeutic options in the future for this potentially deadly disease.

Determinants of Clinical Decision Making under Uncertainty in Dentistry: A Scoping Review.

Clinical decision-making for diagnosing and treating oral and dental diseases consolidates multiple sources of complex information, yet individual clinical judgements are often made intuitively on limited heuristics to simplify decision making, which may lead to errors harmful to patients. This study aimed at systematically evaluating dental practitioners' clinical decision-making processes during diagnosis and treatment planning under uncertainty. A scoping review was chosen as the optimal study design due to the heterogeneity and complexity of the topic. Key terms and a search strategy were defined, and the articles published in the repository of the National Library of Medicine (MEDLINE/PubMed) were searched, selected, and analysed in accordance with PRISMA-ScR guidelines. Of the 478 studies returned, 64 relevant articles were included in the qualitative synthesis. Studies that were included were based in 27 countries, with the majority from the UK and USA. Articles were dated from 1991 to 2022, with all being observational studies except four, which were experimental studies. Six major recurring themes were identified: clinical factors, clinical experience, patient preferences and perceptions, heuristics and biases, artificial intelligence and informatics, and existing guidelines. These results suggest that inconsistency in treatment recommendations is a real possibility and despite great advancements in dental science, evidence-based practice is but one of a multitude of complex determinants driving clinical decision making in dentistry. In conclusion, clinical decisions, particularly those made individually by a dental practitioner, are potentially prone to sub-optimal treatment and poorer patient outcomes.