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This manuscript critically examines the current classification of oral potentially malignant disorders, questioning the practicality and implications of labeling such a large population as precancerous, given that the actual progression to oral cancer is significantly low for most disorders. The paper advocates for a revised classification system that accurately reflects the varying malignancy risks associated with different disorders. It suggests a reassessment of the diagnostic and management approaches to mitigate overdiagnosis and alleviate patient burdens. We propose categorizing diseases with oral malignant potential as follows: Oral Precancerous Diseases, encompassing high‐risk lesions and conditions like erythroplakia, non‐homogeneous leukoplakia, proliferative leukoplakia, and actinic keratosis; Oral Potentially Premalignant Diseases, covering lesions, conditions, and systemic diseases with distinct oral manifestations harboring a limited or undefined risk of transformation, such as homogeneous leukoplakia, oral submucous fibrosis, oral lichenoid diseases, chronic hyperplastic candidosis, keratosis of known aetiology (smokeless tobacco, khat), palatal lesions in reverse smokers, and dyskeratosis congenita; and Systemic Conditions with Oral Malignant Potential including Fanconi's anemia, xeroderma pigmentosum, and chronic immunosuppression (including patients post‐bone marrow transplantation), which are associated with an increased risk of oral cancer without preceding precursor lesions. We provide illustrative examples to demonstrate how this framework offers practical guidance for research, policy‐making, and clinical practice. [ABSTRACT FROM AUTHOR]

Background: ANXA5, a notable tumor marker, displays irregular expression in diverse solid cancers, and links to local recurrence and metastasis rates. We aimed study the expression of ANXA5 in oral squamous cell carcinoma (OSCC) and its diagnostic and prognostic values. Methods: 520 head and neck squamous cell carcinoma (HNSCC) patients in TCGA database and 124 OSCC patients in Nanjing stomatology hospital were enrolled in our study. Immunohistochemical analyses were performed using ANXA5 antibodies. Chi‐square test was used to analyze the clinicopathological features. Survival rates were determined using the Kaplan–Meier method and log‐rank test. Results: Our results showed significantly elevated ANXA5 at the gene and protein levels in HNSCC and OSCC compared to non‐tumor tissues. Histopathologically, ANXA5 was broadly present in OSCC tumor cells and fibroblast‐like cells but absent in tumor‐infiltrating lymphocytes, particularly at the invasive tumor front. Patients exhibiting high ANXA5 expression in these cells demonstrated poor differentiation, aggressive invasion patterns, and heightened lymph node metastasis risk, contributing to poorer postoperative outcomes. Remarkably, ANXA5 in fibroblast‐like cells emerged as an independent risk factor impacting survival in OSCC patients. Gene set enrichment analysis (GSEA) highlighted ANXA5's involvement in key pathways like epithelial‐mesenchymal transformation (EMT), TGF‐beta signaling, and hypoxia, which correlated with adverse clinical outcomes in OSCC. Conclusion: ANXA5 emerges as a significant prognostic biomarker for OSCC, potentially influencing its metastasis via the EMT pathway. [ABSTRACT FROM AUTHOR]

Symmetry properties of solutions to elliptic quasilinear equations have been widely studied in the context of Dirichlet boundary conditions. We show that, in the context of Robin boundary conditions, the symmetry property á la Gidas, Ni, and Nirenberg does not hold in dimension n ≥ 2, even for superharmonic functions, and we provide an explicit example. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study was to assess the prognostic value of muscle invasion (MI), a key histopathological feature of tumor aggressiveness, and construct a superior prognostic prediction model combining the current TNM staging system. Materials and Methods: MI was analyzed in the whole‐slide images from a total of 301 patients with primary buccal mucosa squamous cell carcinoma (BMSCC). Survival times of patients with/without MI were evaluated by Kaplan–Meier analysis. MI was further combined with the TNM staging system to explore its predictive value for prognosis. Moreover, 204 cases of head and neck carcinoma from the TCGA database were included. Results: MI positive rate reached to 76% (229/301) in patients with BMSCC. MI was associated with poor overall survival (p = 0.012) and disease‐free survival (p = 0.022). The novel system (TNM staging combined with MI) revealed strong predictive performance, with the largest area under the curve (OS: p < 0.001, DFS: p < 0.004). MI and the established classification system were also had good predictive ability in the TCGA cohort. Conclusions: MI is an independent predictor of poor prognosis of BMSCC. The inclusion of MI in prediction system can augment the risk stratification of patients with oral squamous cell carcinoma and may assist in the clinical decision‐making process. [ABSTRACT FROM AUTHOR]

Introduction: Special needs dentistry (SND) is an emerging dental specialty, with ongoing developments in education and clinical practice focused towards the tailored management of individuals with special needs (SN). Patients with SN have a higher prevalence of oral diseases and unmet dental needs compared to the general population. Although inadequate training and experience in managing patients with SN has been highlighted as a significant barrier to accessing care, there is limited data about the extent of SND teaching at the entry‐to‐practice or higher levels. Methods: This work is the first to map SND curricula globally, across 180 countries and 1265 dental schools. Results: Although 74.62% of dental schools were found in developing economies, the distribution of programs that reported SND in their courses was highly skewed towards developed countries. In terms of advanced degrees, beyond basic entry‐to‐practice training, the USA delivered 60% of the SND programs, followed by Canada (15.56%), UK (13.33%), and Australia (8.89%). The term SND appeared in 33.95% of entry‐to‐practice level program curricula and was less commonly used in transitioning economies. Only 112 SND‐specialized practitioners enter the workforce globally each year from developed economies, and all but three advanced degrees are found in G7 countries. Conclusion: By exploring the impact of economic status on its distribution, this paper highlighted the lack of SND representation in dental curricula, especially amongst programs in transitioning or developing economies. Education of both general dentists and specialists is critical as a collaborative effort is needed to manage the growing population of patients with SN. [ABSTRACT FROM AUTHOR]

Objectives: Special needs dentistry (SND) is a vast and fragmented field of study. This comprehensive bibliometric analysis aimed to evaluate the scope of SND, including the existing knowledge base, distribution structure, quantitative relationships, and research trends. Material and Methods: A systematic search was conducted on March 10, 2022, using the Web of Science Core Collection database, covering the period from 1985 to 2021, focusing on studies reporting on special needs populations in a dentally relevant context. Records were title‐screened and analyzed for key bibliometric indicators. Results: Among 48,374 articles, 13,869 underwent bibliometric analysis. Peak SND research occurred during 1985–1997. United States led in productivity, trailed by Brazil and Japan. University of Sao Paulo excelled in Brazil, University of Washington and University of North Carolina in the United States. The Journal of Dental Research was the most productive source of research and also had the highest number of citations, followed by Community Dentistry and Oral Epidemiology. Keyword analysis revealed that "elderly", "caries", and "epidemiology" were the most commonly used author keywords. Conclusions: This study represents the first bibliometric analysis of SND literature. It emphasizes the need for increased collaboration between institutions and authors. Furthermore, it suggests focusing on research input from non‐dental disciplines and populations with rarer intellectual or developmental conditions. [ABSTRACT FROM AUTHOR]

Mucositis is a pathological condition characterised by inflammation and ulceration of the mucous membranes lining the alimentary canal, particularly in the mouth (oral mucositis) and the gastrointestinal tract. It is a common side effect of cancer treatments, including chemotherapy and radiotherapy, and it is sometimes responsible for treatment interruptions. Preventing mucositis throughout the alimentary tract is therefore crucial. However, current interventions mainly target either oral or gastrointestinal side effects. This review aimed to investigate the use of systemically administered anti-inflammatory agents to prevent mucositis in cancer patients undergoing cancer treatment. PubMed, Ovid, Scopus, Web of Science, WHO ICTRP and ClinicalTrials.gov were screened to identify eligible randomised controlled trials (RCTs). The published literature on anti-inflammatory agents provides mixed evidence regarding the degree of efficacy in preventing/reducing the severity of mucositis in most anticancer treatments; however, sample size continued to be a significant limitation, alongside others discussed. Our review yielded a list of several anti-inflammatory agents that exhibit potential mucositis-preventive effects in cancer patients undergoing cancer treatment, which can be used to inform clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Disease metabolomes have been studied for identifying diagnostic and predictive biomarkers of pathology. Oral tongue squamous cell carcinoma (OTSCC) is one of the most prevalent subtypes of head and neck squamous cell carcinoma, yet the profile and diagnostic value of its tissue metabolite are unclear. Subjects and Methods: Tumor tissue samples and matched normal mucosal tissue samples were collected from 40 OTSCC patients. Untargeted metabolic analysis by liquid chromatography–mass spectrometry/mass spectrometry, in positive and negative ion modes, was used to identify dysregulated metabolites in OTSCC. Further, utilizing LASSO regression and receiver operating characteristic analyses, biomarker metabolites were selected and validated, and a diagnostic model was established. Results: One hundred and ninety metabolites were detected. The OTSCC had a total of 89 dysregulated metabolites, of which 73 were elevated. A diagnostic panel of nine metabolites was subsequently created that could accurately identify OTSCC with 100% sensitivity of 100%, 100% specificity and an AUC of 1.00. Conclusions: This study identified distinct metabolic characteristics of OTSCC and established a diagnostic model. Our research also contributes to the investigation of the pathogenesis of OTSCC. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the biological characteristics of oral cancer cells co‐cultured with cancer‐associated fibroblasts (CAFs)‐HSVtk and to assess the reliability of the CAFs‐HSVtk suicide system in a co‐culture model. Methods: CAFs were lentivirus‐transfected with PCDH‐HSVtk. Ganciclovir (GCV) was added and the survival rates of the CAFs‐HSVtk were measured. In parallel with the selective elimination of CAFs, comparison was made of the effects of CAF‐HSVtk on tumor cell proliferation/migration in a CAFs‐tumor co‐cultural system. Cell death of co‐cultured oral cancer cells was evaluated by flow cytometry. Results: Q‐PCR analysis showed that the expression of HSVtk in the CAFs‐HSVtk group was significantly higher than in the control group (p < 0.01). The survival rates of CAFs‐HSVtk with GCV were significantly reduced (p < 0.01). Following selective depletion of CAFs‐HSVtk, the growth and migration rates of oral cancer cells co‐cultured with CAFs‐HSVtk were reduced in a mixture ratio of 1:2 (p < 0.01, p < 0.01). Conclusions: Enhanced proliferation and migration rates of oral cancer cells in co‐culture were seriously impaired after deleting CAFs using the HSVtk suicide system, while oral tumor cell death was not affected. Therefore, CAFs‐HSVtk can be utilized as a valid model for CAF signature identification. [ABSTRACT FROM AUTHOR]

The prevalence of diseases characterised by eosinophilia is on the rise, emphasising the importance of understanding the role of eosinophils in these conditions. Eosinophils are a subset of granulocytes that contribute to the body's defence against bacterial, viral, and parasitic infections, but they are also implicated in haemostatic processes, including immunoregulation and allergic reactions. They contain cytoplasmic granules which can be selectively mobilised and secrete specific proteins, including chemokines, cytokines, enzymes, extracellular matrix, and growth factors. There are multiple biological and emerging functions of these specialised immune cells, including cancer surveillance, tissue remodelling and development. Several oral diseases, including oral cancer, are associated with either tissue or blood eosinophilia; however, their exact mechanism of action in the pathogenesis of these diseases remains unclear. This review presents a comprehensive synopsis of the most recent literature for both clinicians and scientists in relation to eosinophils and oral diseases and reveals a significant knowledge gap in this area of research. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. There is mounting evidence to suggest that several components of the coagulation system directly affect carcinogenesis. Our recent in vitro studies demonstrated, for the first time, that various anticoagulants have anticancer effects on OSCC. They also showed the need for the immediate translation of these experimental conditions from bench to preclinical animal models. Here, we carried out a systematic review to summarise existing evidence on murine models built around the interactions between anticoagulants and oral cancer. Only one preclinical murine study was included in our systematic review, investigating the role of heparins in tumour pathophysiology. The paucity of evidence regarding the interactions between oral squamous cell carcinoma and anticoagulants emphasises the urgency with which further preclinical research should be conducted. [ABSTRACT FROM AUTHOR]

Background: Coffee is one of the most consumed beverages in the world. Containing an abundance of bioactive molecules including polyphenols and flavonoids, the constituents of this beverage may exert antiproliferative, antioxidant and anti‐inflammatory effects. Methods: We conducted a systematic review to summarise the available evidence on the anticancer effects of coffee constituents and their potential therapeutic use for oral squamous cell carcinoma (OSCC). Studies were identified through a comprehensive search of OVID MEDLINE, OVID EMBASE and Web of Science, including articles from any year up to 15 May 2023. Results: Of the 60 reviewed papers, 45 were in vitro, 1 was in silico and 8 were in vivo exclusively. The remaining studies combined elements of more than one study type. A total of 55 studies demonstrated anti‐proliferative effects, whilst 12 studies also investigated migration and invasion of neoplastic cells. The constituents studied most frequently were quercetin and epigallocatechin gallate (EGCG), demonstrating various cytotoxic effects whilst also influencing apoptotic mechanisms in cancer cell lines. Dose‐dependent responses were consistently found amongst the studied constituents. Conclusion: Whilst there was heterogeneity of study models and methods, consistent use of specific models such as SCC25 for in vitro studies and golden hamsters for in vivo studies enabled relative comparability. The constituents of coffee have gained significant interest over the last 30 years, particularly in the last decade, and present an area of interest with significant public health implications. Currently, there is a paucity of literature on utilization of active coffee constituents for the therapeutic treatment of oral cancers. [ABSTRACT FROM AUTHOR]

A betel quid (BQ) chewing habit has been strongly associated with the development of several oral mucosal diseases. In order to investigate whether individual components of BQ mixtures have distinct physio-pathological effects on oral mucosal cells, we examined the impact of areca nut (AN), Piper betle leaf (Leaf), Piper betle stem inflorescence (SI), areca husk (Husk) and the complete BQ mixture on the growth of oral keratinocytes (OKF-6) and primary oral fibroblasts (MMF-1). Based on their known chemical properties, we selected BQ samples from Banda Aceh (BA) and West Papua (WP) regions for our in vitro study. We used a fluorescein diacetate assay (FDA) to assess the cell viability of BQ components on OKF-6 and MMF-1 cells. The cytotoxic effect of WP-AN on the OKF-6 cell line was observed at a concentration of 100 μg/mL, resulting in a 50% reduction in cell viability (IC50) after a 2-day incubation. Similarly, BA-AN exhibited cytotoxic effect, although at a higher concentration (500 μg/mL). WP-SI also displayed cytotoxic effects at a concentration of 500 μg/mL following 2 days of incubation. In contrast, Leaf, BQ mixture and husk extracts did not show any cytotoxic effects even after 3 days of incubation. No cytotoxic effects were observed at any concentration of BQ components when exposed to MMF-1 cells. Regarding cell proliferation, MMF-1 cells exposed to BA-AN and WP-AN showed increased growth on day 1, followed by decreased growth on day 2, in a dose- and time-dependent manner. Overall, our study indicates that BQ components induce distinctive cytotoxic effects on stromal and epithelial cells from the oral cavity. [ABSTRACT FROM AUTHOR]

Background: Micronutrients are vital for general and oral health, and their potential anti-cancer properties are documented. We explore beneficial vitamins for oral potentially malignant disorders (OPMDs) and oral cancer (OC), assessing the therapeutic impacts of essential vitamin supplementation. Methods: We systematically review evidence on vitamin supplementation's therapeutic effects for OPMDs and OC. Relevant studies were identified through comprehensive searches of MEDLINE, Evidence-Based Medicine, and Web of Science until 16 May 2023. All studies underwent risk of bias using criteria modified from the Office of Health Assessment and Translation (OHAT) tool. Results: We analysed 80 papers. Vitamin K, studied in vitro, shows promising therapeutic potential. Vitamin C, investigated in vivo (animals and humans), demonstrated mixed animal results and generally positive human trial effects. Vitamin A's efficacy varied, with positive monotherapy or adjunct effects. Vitamins B and D showed therapeutic benefits. Oral cancer research was extensive, with a focus on oral lichen planus and oral leukoplakia among the 11 OPMDs. All bias levels were reported in 'selective reporting' and 'performance', except for "definitely high" in the 'selection', 'detection', and 'attrition/exclusion' domains. Conclusions: Evidence of vitamin interventions for OPMDs and OC ranges from mixed to promising. Standardizing the study design and outcomes would enhance future research. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Invasive dental treatment in patients exposed to antiresorptive and antiangiogenic drugs can cause medication-related osteonecrosis of the jaw (MRONJ). Currently, the exact pathogenesis of this disease is unclear. Methods: In March 2022, Medline (Ovid), Embase (Ovid), Scopus, and Web of Science were screened to identify eligible in vitro studies investigating the effects of antiresorptive and antiangiogenic compounds on orally derived cells. Results: Fifty-nine articles met the inclusion criteria. Bisphosphonates were used in 57 studies, denosumab in two, and sunitinib and bevacizumab in one. Zoledronate was the most commonly used nitrogen-containing bisphosphonate. The only non-nitrogen-containing bisphosphonate studied was clodronate. The most frequently tested tissues were gingival fibroblasts, oral keratinocytes, and alveolar osteoblasts. These drugs caused a decrease in cell proliferation, viability, and migration. Conclusions: Antiresorptive and antiangiogenic drugs displayed cytotoxic effects in a dose and time-dependent manner. Additional research is required to further elucidate the pathways of MRONJ. [ABSTRACT FROM AUTHOR]

Simple Summary: Hemidesmosomes are junctional complexes that contribute to the attachment of epithelial cells to the underlying basement membrane. Importantly, detachment from the basement membrane, migration and invasion through the connective tissues represent early steps in oral carcinogenesis. Therefore, it is possible that these processes involve alterations of hemidesmosomes. The results of our systematic review provide evidence that oral potentially malignant disorders and oral cancer are associated with structural and molecular modifications of hemidesmosomes. We conclude that these cell adhesion structures represent potential candidates for use as biomarkers. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: TNF-α is of interest in oral squamous cell carcinoma (OSCC), with its demonstrated presence affecting both tumour and stromal inflammatory cells to enhance proliferation and facilitate invasion. TNF-α gene polymorphisms have also been associated with an increased risk for both oral pre-cancer and cancer development. Here we present a review of the current knowledge of the role of TNF-α in the aetiology, pathogenesis, and potential therapy of OSCC. Uncovering the inflammatory mechanisms underpinning initiation, progression, and promotion of oral squamous cell carcinoma (OSCC) development is fundamental to the rational pursuit of targeted therapeutics. Here we present a review of the current knowledge of the role of TNF-α in the aetiology, pathogenesis, and potential therapies with regards to OSCC. TNF-α is worthy of particular attention in OSCC, with its presence demonstrated to enhance cell proliferation and its downregulation demonstrated to inhibit proliferation and migration in other carcinomas in both in vitro and in vivo models and oral cancer patients. Increased TNF-α in the OSCC tumour microenvironment has been demonstrated to favour invasion through promotion of firstly the pro-inflammatory, pro-invasive phenotypes of OSCC cells and secondly its paracrine mechanism mediating recruitment and activation of inflammatory cells. Polymorphisms affecting the gene expression of TNF-α have been strongly associated with an increased risk for oral squamous cell carcinoma. A number of studies have considered TNF-α within biofluids, including saliva and serum, as a potential biomarker for the early detection of OSCC, as well as its staging, differentiation, and prognosis. The broad and multifaceted role that TNF-α plays in many inflammatory states presents an obvious confounder, particularly with demonstrated increased TNF-α levels in common oral disease states. Lastly, biologic agents targeting TNF-α are currently in clinical use for immune-mediated inflammatory rheumatological and gastrointestinal diseases. There is the potential that these biological agents might have an adjunctive role in OSCC prevention and treatment. [ABSTRACT FROM AUTHOR]

The increased glucose uptake observed in cancer cells is mediated by glucose transporters (GLUTs), a class of transmembrane proteins that facilitate the transport of glucose and other substrates across the plasma membrane. Despite the important role of glucose in the pathophysiology of oral squamous cell carcinoma (OSCC), there is very limited data regarding the expression of GLUTs in normal or malignant cells from the oral mucosa. We analysed the messenger RNA (mRNA) expression of all 14 GLUTs in two OSCC (H357/H400) and one non-malignant oral keratinocyte (OKF6) cell line using a quantitative polymerase chain reaction. GLUT expression was evaluated at baseline and after treatment with two specific GLUT inhibitors, namely, BAY876 (GLUT1) and WZB117 (GLUT1, GLUT3 and GLUT4). Here, we show that GLUT1, GLUT3, GLUT4, GLUT5, GLUT6, GLUT8, GLUT12 and GLUT13 transcripts were measurably expressed in all cell lines while GLUT2, GLUT7, GLUT9, GLUT11 and GLUT14 were not expressed. GLUT10 was only found in H357. In the presence of BAY876 and WZB117, OSCC cells exhibited significant alterations in the transcriptional profile of GLUTs. In particular, we observed distinct proliferationdependent changes of mRNAs to GLUT1, GLUT3, GLUT4, GLUT5 and GLUT6 in response to selective GLUT inhibitors. In summary, we documented for the first time the expression of GLUT5, GLUT6 and GLUT12 in normal and malignant oral keratinocytes. Whilst regulation of GLUT transcripts was cell line and inhibitor specific, GLUT3 was consistently upregulated in actively proliferating OSCC cell lines, but not in OKF6, regardless of the inhibitor used, suggesting that modulation of this transporter may act as one of the primary compensation mechanisms for OSCC cells upon inhibition of glucose uptake. [ABSTRACT FROM AUTHOR]

Simple Summary: Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide with 840,000 new cases and 420,000 deaths in 2020. Anticoagulants are widely prescribed medications routinely administered to help prevent blood clots. Despite the great relevance of these two topics, there is complete lack of knowledge regarding the potential effects that these drugs could exert on oral cancer patients. In this in vitro study, we comprehensively investigated the effect of anticoagulants on OSCC activity. This includes the effect of these drugs on cancer cell ability to survive, migrate to colonise distant sites, and resist treatment with conventional chemotherapy. We have demonstrated for the first time that various anticoagulants have anticancer effects on OSCC. Moreover, some of the anticoagulants tested were able to reduce the migratory ability of cancer cells. Finally, the great majority of anticoagulants studied reduced the effectiveness of the tested chemotherapeutic agent, allowing an increase in cancer cell proliferation. Our results highlight the need for urgent further research in the field, to improve the anticoagulant strategies in patients with oral cancer, and in turn their prognosis. Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. With anticoagulant usage on the rise, it is important to elucidate their potential effects on tumour biology and interactions with chemotherapeutics. The aim of the present study was to investigate the effects of anticoagulants on OSCC cell lines and their interactions with the drug 5-fluorouracil (5-FU). Cell proliferation was assessed using an MTS in vitro assay in two human OSCC cell lines (H357/H400) and in normal oral keratinocytes (OKF6) treated with the 5-FU (0.2/1/5/10 μg/mL), conventional anticoagulants warfarin (1/5/10/20 μM) and heparin (5/20/80 U), as well as four new oral anticoagulants, dabigatran (5/10/20 μM), rivaroxaban (5/10/20 μM), apixaban (0.1/1/5 μg/mL), and edoxaban (5/10/20 μM). Cell migration was assessed at 3 h intervals up to18 h using a wound healing assay. Our results clearly demonstrate, for the first time, that commonly prescribed anticoagulants exert in vitro antiproliferative effects on OSCC cells. Furthermore, treatment with some anticoagulants reduced the migration of OSCC cell lines. Nevertheless, most of the anticoagulants tested reduced the effectiveness of the chemotherapeutic agent tested, 5-FU, highlighting potential flaws in the current pharmacological management of these patients. Our findings showed the need for the immediate translation of this research to preclinical animal models. [ABSTRACT FROM AUTHOR]

Background: Oropharyngeal Neisseria gonorrhoeae (NG) infections are common, increasing, and have a higher treatment failure compared with other infection sites. Due to antimicrobial resistance, NG has become a global public health threat as available treatments remain scarce. Little is known about where NG colonizes in the oral mucosa and therefore, where antibiotics need to be distributed to cure infection. A recent review also highlighted the lack of oral cell models available for investigating NG infection. We recently started creating an in-vitro co-culture model for NG strains with human oral epithelial cells to understand patterns of NG growth in the mouth and examine antibiotic uptake by oral cell types supporting NG growth. Methods: NG strains were grown on Chocolate agar with IsoVitaleX and in modified Fastidious broth media in optimised conditions. NG colonies were assessed using a colony counter (Scan1200, Interscience technology). In a 2D model, NG were cocultured with 4 human oral keratinocyte cell lines isolated from different anatomical subsites of the oral cavity. Intra- and extra-cellular NG was quantified, and intracellular spatial distribution was assessed with confocal microscopy and immunocytochemistry. Invasion into 3D spheroids was characterised with penetration depth assessed via histological analysis (haematoxylin and eosin staining) and immunocytochemistry with images taken on a Zeiss Axioscan7 slide scanner or LSM800 confocal microscope. Real time invasion into spheroids was imaged using a MuviCyte live-cell imaging system. Lastly, host cell viability in response to NG infection was also assessed. Results: We created the first-of-its-kind in-vitro model for NG oral infection demonstrating that it is possible to co-culture NG with oral derived cells. NG survives and infects oral cells in an in vitro setting in both 2D and 3D models. Different strains of NG infected oral cells to significantly different degrees. Conclusion: Our presented model can be used to explore the interactions of NG with oral tissues and to investigate current and new therapeutics against oropharyngeal gonorrhoea. [ABSTRACT FROM AUTHOR]

The article discusses the appointment of a new Editor-in-Chief for the Journal of Oral Pathology & Medicine (JOPM). The new editor reflects on the previous editor's tenure and aims to uphold and build upon the high standards set. The new editor plans to introduce changes such as an editorial dedicated to the journal's history, unveiling the profiles of the editorial board members, expanding and diversifying the board, implementing a rigorous statistical review process, and addressing gender imbalance within the board. The editor also plans to optimize workflow and systems to improve efficiency. The appointment is for a 3-year term, during which the editor aims to earn the community's trust and preserve the journal's integrity. [Extracted from the article]

Objective: To systematically review retrospective studies examining prognostic potentials of candidate biomarkers to stratify malignant progression of oral leukoplakia (OL) and proliferative verrucous leukoplakia (PVL). Materials and Methods: A systematic literature search of PubMed, EMBASE, Evidence‐Based Medicine and Web of Science databases targeted literature published through 29 March 2018. Inter‐rater agreement was ascertained during title, abstract and full‐text reviews. Eligibility evaluation and data abstraction from eligible studies were guided by predefined PICO questions and bias assessment by the Quality in Prognosis Studies tool. Reporting followed Preferred Reporting Items for Systematic Review and Meta‐Analysis criteria. Biomarkers were stratified based on cancer hallmarks. Results: Eligible studies (n = 54/3,415) evaluated 109 unique biomarkers in tissue specimens from 2,762 cases (2,713 OL, 49 PVL). No biomarker achieved benchmarks for clinical application to detect malignant transformation. Inter‐rater reliability was high, but 65% of included studies had high "Study Confounding" bias risk. Conclusion: There was no evidence to support translation of candidate biomarkers predictive of malignant transformation of OL and PVL. Systematically designed, large, optimally controlled, collaborative, prospective and longitudinal studies with a priori‐specified methods to identify, recruit, prospectively follow and test for malignant transformation are needed to enhance feasibility of prognostic biomarkers predicting malignant OL or PVL transformation. [ABSTRACT FROM AUTHOR]

Background: Matrix metalloproteinases (MMPs) play a crucial role in the malignant phenotype of cancer cells. In particular, active levels of MMP2 in cancer cells have been associated with invasion and metastasis through the degradation of basement membrane extracellular matrix proteins. However, little is known about the role of this potential biomarker in oral cancer. Our aim was to investigate the effect of MMP2 inhibition on OSCC activity in vitro, as well as to assess MMP2 dysregulation in oral cancer samples.Methods: Human OSCC cell lines H357 and H400 were tested with the selective MMP2 inhibitor ARP101 and the MMP2 neutralising monoclonal antibody MA5-13590 to assess cell proliferation in vitro using MTS assay. Cell migration at 12/24 h was assessed using a Transwell migration assay. Cell invasion was assessed at 24 h using a Corning Matrigel invasion assay. MMP2 expression was assessed in 208 tissue samples (related to 60 OSCC cases and nine normal control) using tissue microarray (TMA) and further analysed via TCGA.Results: Both ARP101 and MA5-13590 monoclonal antibody reduced cell proliferation in both the cell lines tested. Treatment with 4μg/mL of MMP2 monoclonal antibody showed a significant decrease in cell migration at 24 hours. The administration of ARP101 and monoclonal antibody to H357 and H400 cell lines induced a drastic reduction in cell invasion at 24 h compared to the control. In patients, TCGA analysis demonstrated that oral cancer tissues express significantly higher levels of MMP2 mRNA compared to normal oral tissues. Further, IHC analysis on TMA showed significant difference in MMP2 protein expression between low and high histopathological grade OSCC.Conclusions: We have demonstrated, for the first time, that MMP2 inhibition affects oral cancer cells ability to survive, migrate and invade in vitro. Differences between MMP2 expression in normal and malignant tissues varied. Further research on the role of MMP2 in OSCC and novel mechanisms to inhibit MMP2-dependent pathways should be encouraged. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the effects of the nuclear factor of kappa B (NF-kB1) and c-Rel subunit loss in the oral carcinogen 4-nitroquinoloine-1 oxide (4-NQO) model of oral squamous cell carcinoma (OSCC). Topics include the risk factors of OSCC like pro-inflammatory agents and carcinogens such as alcohol and tobacco, as well as the use of mice in the study.

Tumour progression allows for aberrant angiogenesis. Consequently, cancer‐associated thrombosis is a prevalent complication that is coupled with poor prognosis. Anticoagulants have therefore been prescribed with chemotherapeutic agents to target potential thrombo‐embolic risk. A systematic review was carried out to summarise existing evidence on the interactions between anticoagulants and oral cancer. This treatment paradigm has demonstrated beneficial results in some oncology patients, thus associating anticoagulants with anticancer effects. Increasing prevalence of oral cancer presents a need to source alternative therapeutic means to prevent disease progression, and thus the use of anticoagulants in these patients may provide an avenue for this to occur. The paucity of evidence regarding the interactions between oral squamous cell carcinoma and anticoagulants emphasises the urgency with which further research should be conducted. [ABSTRACT FROM AUTHOR]

Current risk stratification of individuals for the development of oral squamous cell carcinoma (OSCC), including those with oral potentially malignant disorders (OPMD), remains based on clinical detection of visibly abnormal mucosa and tissue biopsy with histological assessment for the presence of OSCC or oral epithelial dysplasia (OED). In OPMD, the presence of OED remains the only prognostic tool used in standard care for the development of future OSCC, despite its ample limitations. There is assured potential that the analysis of the genome, transcripts and proteome can provide insight into what is occurring at a cellular level preceding the appearance of clinically observable change. The landscape of the role of the genome and its transcriptome on the development of OSCC and relationships with OPMDs are immense with exploration occurring on several fronts. For clinicians involved in the diagnosis and care of patients with OSCC and OPMD, understanding of commonly used molecular diagnostic techniques is imperative to gain useful insight from the expanding literature investigating the development of OSCC and the relationship with the clinical presentations which encompass OPMDs. Here we present an introduction to molecular diagnostic methods used in the study of OSCC and OPMD. [ABSTRACT FROM AUTHOR]

Background: Kava is a beverage made from the ground roots of the plant Piper Methysticum and has long-held a significant place within Pacific island communities. Active compounds were extracted from kava, and secondary metabolites include kavalactones, chalcones, cinnamic acid derivatives and flavanones. It is thought that components of kava may exert an antiproliferative effect through cell cycle arrest and promotion of apoptosis.Methods: We conducted a systematic review to summarize available evidence of the anticancer effects of kava components and investigate their potential use for oral squamous cell carcinoma (OSCC) treatment. Eligible studies were identified through a comprehensive search of OVID EMBASE, OVID MEDLINE and Web of Science, as at April 2018.Results: Of 39 papers that met the inclusion criteria, 32 included in vitro models and 13 included animal studies. A total of 26 different cancers were assessed with 32 studies solely assessing epithelial cancers, 6 mesenchymal cancers and 1 study including both. There was only one report assessing an OSCC cell line. Antiproliferative properties were demonstrated in 32 out of 39 papers. The most researched constituent of kava was flavokavain B followed by flavokavain A. Both were associated with increased expression of pro-apoptotic proteins and decreased expression of anti-apoptotic proteins. Further, they were associated with a dose-dependent reduction of angiogenesis.Conclusion: There was heterogeneity of study models and methods of investigation across the studies identified. Components of kava appear to present an area of interest with chemotherapeutic potential in cancer prevention and treatment, particularly for epithelial neoplasms. To date, there is a paucity of literature of the utility of kava components in the prevention and treatment of oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Objective: To identify the prognostic biomarker candidates for stratification and long‐term surveillance of oral leukoplakia progressing to cancer via a systematic literature review. Materials and Methods: Systematic searches with no date restrictions were conducted on March 29, 2018, targeting the databases PubMed (Ovid), EMBASE (Ovid), EBM (Ovid), and Web of Science (ISI). Bias was assessed using the Quality in Prognosis Studies tool. Biomarkers were stratified based on hallmarks of cancer. Results: Inclusion criteria were met by 25 of 3,415 studies. A range of biomarkers were evaluated experimentally for risk stratification, prognosis, and surveillance of oral leukoplakia in tissue, blood, and saliva. However, the studies were highly heterogeneous and require further validation. Biomarkers reported in these studies included inflammatory or oxidative markers, growth factors, ion channels, genetic and cellular regulatory factors, and epigenetic biomarkers. Studies tended to include small sample sizes, under‐reported or variably reported histopathological data, did not address potential confounding, reported limited/variable follow‐up data, or lacked a control group. Inclusion of subsets from chemoprevention trials may have introduced bias regarding reported malignant transformation rates and accuracy of prognostic biomarkers. Conclusions: This review identified insufficient longitudinal evidence to support validated prognostic biomarkers for oral leukoplakia. Further studies are needed to identify molecular targets with the potential to mitigate risk of malignant transformation. [ABSTRACT FROM AUTHOR]

Objective: To conduct a systematic review of studies exploring potential biomarkers for development, course, and efficacy of treatment of lymphomas in salivary glands of patients with Sjögren's syndrome. Material and Methods: Eligible studies were identified through a comprehensive search of two databases, that is, PubMed and EMBASE. Quality of included articles was assessed with the "Quality In Prognosis Studies" (QUIPS) tool. The "CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies" (CHARMS) was used to facilitate data extraction. Results: Fifty‐eight studies met the inclusion criteria. Only one study assessed the progression of lymphoma. Moderate risk of bias was detected in "outcome measurement," "study participation," and "study confounding" domains. Parotid gland enlargement, mixed monoclonal cryoglobulins, and low C4 levels represented strongest predictors of lymphoma development. The role of histological biomarkers, and specifically germinal centers, remains controversial. Clinical and methodological heterogeneity across studies precluded conduct of a meta‐analysis. Conclusions: Specific biomarkers in combination with clinical manifestations represent potential candidates for advancing precision medicine approaches to lymphoma prediction in patients with Sjögren's syndrome. Current focus has increasingly been on genetic and epigenetic markers as candidate predictors. Predictive accuracy of key biomarker candidates remains to be tested in well‐designed prospectively followed Sjögren's syndrome cohorts. [ABSTRACT FROM AUTHOR]

Synthetic corticosteroids are routinely administered during the treatment of several diseases, including malignancies. However, recent evidence suggests that corticosteroids may have tumor‐promoting effects, particularly in epithelial neoplasms. Our aim was to assess the role of the recently characterized cancer‐associated glucocorticoid (GC) system in the resistance to chemotherapy of oral malignant keratinocytes. Human malignant oral keratinocyte cell lines H314/H357/H400/BICR16/BICR56 were tested with: two chemotherapeutic agents, doxorubicin (DOXO) and 5‐fluorouracil (5‐FU), as well as hydrocortisone (HC), adrenocorticotropic hormone (ACTH), 5‐pregnen‐3‐beta‐ol‐20‐one‐16‐alfa‐carbonitrile (PCN), and two glucose uptake inhibitors, Fasentin and WZB. Both DOXO and 5‐FU induced apoptosis in a dose‐dependent and time‐dependent manner. HC administration (100 nM) reduced the effectiveness of both chemotherapeutic agents to a variable extent in all 5 oral squamous cell carcinoma cell lines. ACTH also reduced the effectiveness of DOXO on 2 cell lines tested (H357 and BICR56). The glucose uptake inhibitors Fasentin and WZB were able to partially block the increased resistance to the cytotoxic drugs induced by HC. In summary, we have demonstrated, for the first time, the importance of cortisol on oral cancer cells ability to proliferate and combat the effectiveness of chemotherapeutic agents. This effect appears to be glucose dependent. Synthetic corticosteroids are routinely administered during the treatment of several diseases, including malignancies. However, recent evidence suggests that corticosteroids may have tumor‐promoting effects, particularly in epithelial neoplasms. We have demonstrated, for the first time, the importance of cortisol on oral cancer cells ability to proliferate and combat the effectiveness of chemotherapeutic agents. [ABSTRACT FROM AUTHOR]