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A case of localized, longstanding, asymptomatic ligneous gingivitis affecting the crest of the edentulous lower left posterior alveolar ridge (ligneous alveolar gingivitis) of a middle-aged Caucasian woman is presented. This patient did not have any associated ophthalmic lesions (ligneous conjunctivitis) and did not have a plasminogen deficiency. [ABSTRACT FROM AUTHOR]

Targeted therapy has the potential to be used in the neoadjuvant setting for odontogenic tumors, reducing the morbidities associated with major surgery. In this regard, the aim of this study was to summarize the current evidence on the different forms of targeted therapy, effectiveness, and drawbacks of this course of treatment. Four databases were searched electronically without regard to publication date or language. Grey literature searches and manual searches were also undertaken. Publications with sufficient clinical data on targeted therapy for odontogenic tumors were required to meet the criteria for eligibility. The analysis of the data was descriptive. A total of 15 papers comprising 17 cases (15 ameloblastomas and 2 ameloblastic carcinomas) were included. Numerous mutations were found, with BRAF V600E being most common. Dabrafenib was the most utilized drug in targeted therapy. Except for one case, the treatment reduced the size of the lesion (16/17 cases), showing promise. Most of the adverse events recorded were mild, such as skin issues, voice changes, abnormal hair texture, dry eyes, and systemic symptoms (e.g., fatigue, joint pain, and nausea). It is possible to reach the conclusion that targeted therapy for ameloblastoma and ameloblastic carcinoma may be a useful treatment strategy, based on the findings of the included studies., (© 2024 Wiley Periodicals LLC.)

Objectives: To describe the historical evolution and dissemination of the Oral Medicine and Oral and Maxillofacial Pathology international societies and associations across the globe, and to provide insights into their significant contributions toward oral health promotion., Study Design: This review was conducted in accordance with the JBI Scoping Review Methodology Group guidance. The reporting followed the Preferred Reporting Items for Systematic Reviews extension for Scoping Reviews (PRISMA-ScR)., Results: Search strategy was applied to 5 databases (MEDLINE/PubMed, Scopus, Embase, Web of Science, Latin American and Caribbean Health Sciences (LILACS)) and grey literature (Google Scholar, Open Grey and ProQuest), as well as additional sources, such as organization websites. Eighty-nine sources were included in this review. Forty-six professional associations/societies were identified, of which 39 represented a country or geopolitical region, 2 represented continents, 2 represented multinational organizations and 3 multinational study groups., Conclusions: Documentation of the historical establishment and development of Oral Medicine and Oral and Maxillofacial Pathology organizations worldwide is limited and describing these processes remains challenging. Analysis of global data reveals heterogeneous development and distribution, resulting in disparities in accessibility and standardization. Further efforts toward oral health promotion should be implemented., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Detection of extranodal extension on histopathology in surgically treated head and neck squamous cell carcinoma indicates poor prognosis. However, there is no consensus on the diagnostic criteria, interpretation, and reporting of histology detected extranodal extension, which has contributed to conflicting evidence in the literature, and likely clinical inconsistency. The Head and Neck Cancer International Group conducted a three-round modified Delphi process with a group of 19 international pathology experts representing 15 national clinical research groups to generate consensus recommendations for histology detected extranodal extension diagnostic criteria. The expert panel strongly agreed on terminology and diagnostic features for histology detected extranodal extension and soft tissue metastasis. Moreover, the panel reached consensus on reporting of histology detected extranodal extension and on nodal sampling. These consensus recommendations, endorsed by 19 organisations representing 34 countries, are a crucial development towards standardised diagnosis and reporting of histology detected extranodal extension, and more accurate data collection and analysis., Competing Interests: Declaration of interests HM is the Director and a shareholder of Warwickshire Head and Neck Clinic; chair of the Head and Neck Cancer International Group; past president of the British Association of Head and Neck Oncologists; reports receiving honoraria from AstraZeneca; is on the Speaker's Bureau for Merck Sharpe Dohme (MSD), Sanofi Pasteur, and Merck; received funding from GSK Biologicals, MSD, Sanofi Pasteur, GSK, and AstraZeneca; and received travel accommodation expenses from Sanofi Pasteur, MSD, and Merck. WML is the chair of American Joint Committee on Cancer 9th Version head and neck task force. RDC is a member of a steering committee for a phase 3 clinical trial of neoadjuvant pembrolizumab sponsored by Merck and also has a non-financial relationship with Caris Life Sciences as a member of their Precision Oncology Alliance. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) shows distinct biological and clinical behaviour when compared to HPV-negative OPSCC. The overall role of the tumour microenvironment (TME) in head and neck cancer progression and metastasis has been studied intensively, but differences in HPV-negative and HPV-positive OPSCCs are less understood., Objective: To investigate the role of cancer-associated fibroblasts (CAFs) and the functional interactions of normal tonsil fibroblasts (NTFs) and OP CAFs with HPV+ and HPV- OPSCC cells and explore novel candidates in tumour-fibroblast crosstalk., Materials and Methods: A retrospective cohort of 143 primary OPSCCs was characterised using HPV16/18 RNAScope assay, p16 IHC and ɑ-SMA. Four OPSCC, three NTF and 2 new OPSCC CAF cultures were used to assess the cytokine-based interactions using cytokine arrays on conditioned media (CM), followed by co-culture approaches to identify the role of individual cell types and the role of OPN (SPP1) and IL-6 in SCC/fibroblast communication., Results: HPV status was associated with better overall survival. Although ɑ-SMA expression was observed in both OPSCC subtypes, it provided survival stratification only in the HPV-positive group (Log-Rank p  = 0.02). Three normal tonsillar fibroblast cultures (NTFs) were characterised by induction of myofibroblastic and senescent phenotypes with similar reactivity to our published NOF phenotype. The OPSCC-derived CAF cultures were characterised and their baseline myofibroblastic and senescence phenotypes varied. Cytokine array analysis of CM to identify novel candidates in the crosstalk between OPSCC tumour cells and NTFs/CAFs identified differences in the cytokine profiles on comparison of HPV+ and HPV- OPSCC cells. Osteopontin (OPN/SPP1) was identified, particularly in HPV-negative OPSCC cell analyses. We have demonstrated that OPN was produced by the OPSCC cells and revealed an associated upregulation of IL-6 in fibroblasts. Treatment of NTFs with rOPN showed alteration in phenotype, including increased contraction and IL-6 production. Antibody-mediated inhibition of CD44v6 attenuated the production of IL-6 by OPN in NTFs., Conclusion: This investigation with OPSCC fibroblasts provides novel insights into the role of CAFs in OPSCC mediated by IL-6 stimulated release of OPN from HPV negative OPSCC cells. The details of HPV-positive SCC cell/fibroblast cytokine crosstalk remain elusive., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Hendawi, Crane, Mehanna, Bolt, Lambert and Hunter.)

Ameloblastoma (AM) is a benign, although aggressive, epithelial odontogenic tumour originating from tooth-forming tissues or remnants. Its aetiopathogenesis remains unclear; however, molecular analysis techniques have allowed researchers to progress in understanding its genetic basis. The high frequency of BRAF p.V600E as a main driver mutation in AM is well established; nevertheless, it is insufficient to explain its tumourigenesis. In this review, we aimed to integrate the current knowledge about the biology of AM and to describe the main genetic alterations reported, focusing on the findings of large-scale sequencing and gene expression profiling techniques. Current evidence shows that besides BRAF mutation and activation of the MAPK pathway, alterations in Hedgehog and Wnt/β-catenin pathway-related genes are also involved in AM pathogenesis. Recently, a tumour suppressor gene, KMT2D, has been reported as mutated by different research groups. The biological impact of these mutations in the pathogenesis of AM has yet to be elucidated. Further studies are needed to clarify the impact of these findings in the identification of novel biomarkers that could be useful for diagnosing, classifying, and molecular targeting this neoplasm., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.

Objective: Understanding the regulatory role of homeobox (HOX) and mutated genes in the progression of head and neck cancers is essential, although their interaction remains elusive. This study aims to decipher the critical regulation of mutation driven effects on homeobox genes to enhance our understanding of head and neck cancer progression., Methods: Genomic mutation data from The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma were analyzed using VarScan2 for somatic variant detection. Mutational clustering, driver mutation identification, and cancer signaling pathway analysis were performed using the OncodriveCLUST method. Harmonizome datasets were retrieved to identify critical cancer driver genes affecting HOX genes. The effects of HPV infection on HOX and mutated genes were assessed using the oncoviral database. Altered pathway activity due to the effects of cancer drivers on HOX genes was analyzed with Gene Set Cancer Analysis. Functional enrichment analysis of gene ontology biological processes and molecular functions was conducted using the ClusterProfiler R package., Results: Significant alterations in HOX genes were observed in head and neck cancer cohorts with mutated TP53, FAT1, and CDKN2A. HOX genes were identified as functionally downstream targets of TP53, signifying transcriptionally mediated regulation. The interaction between HOX genes and mutated TP53, FAT1, and CDKN2A dysregulated the epithelial-to-mesenchymal transition, cell cycle, and apoptosis pathways in head and neck cancer progression., Conclusion: The interplay between cancer driver genes and HOX genes is pivotal in regulating the oncogenic processes underlying the pathogenesis of head and neck squamous cell carcinoma., Competing Interests: Declaration of Competing Interest All the authors of the manuscript hereby state that there is no financial implication or personal relationship with other people or organization that could inappropriately influence the outcome of this work., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Ameloblastic carcinoma (AC) is the most common odontogenic malignancy, constituting approximately 30% of cases in this category. Literature is sparse on malignant odontogenic neoplasms, with a large proportion of current knowledge derived from case reports or small case series., Methods: A systematic review of case series/case reports of AC was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement guidelines. Demographic and clinical information, including duration of the lesion, location, clinical presentation and radiologic features, were analysed. Additionally, the origin of the lesion (primary/secondary), Ki-67 proliferation index, treatment performed, metastasis, tumour recurrence and prognosis were collected for analysis., Results: A total of 126 studies, including 285 individual cases of AC, were included in this review. Patients presented with a near-equal distribution of painless and painful swellings. ACs presented at a median age of 45 years, with a male-to-female ratio of 1:2. The mandible was most frequently involved, with rare cases extending to involve more than one region, including crossing the midline. Although most lesions presented with poorly-demarcated borders (52.6%), unilocular lesions with well-demarcated borders (47.4%) comprised a substantial number in the sample. The proliferation index was only reported in 27 cases, with a mean score of 42% and a wide range. The probability of tumour recurrence increased, and the survival probability decreased with prolonged follow-up duration., Conclusion: This study provides more comprehensive, up-to-date descriptive data on these rare odontogenic malignancies, aiding clinicians and Pathologists with the diagnosis and surgeons in their management of cases., (© 2024 The Authors. Journal of Oral Pathology & Medicine published by John Wiley & Sons Ltd.)

Objective: This systematic review aimed to describe the method followed during physical examination and the anatomical structures of the head and neck assessed in screening for oral cancer and oral potentially malignant disorders (OPMDs)., Study Design: An extensive literature search was carried out using MEDLINE/PubMed, EMBASE, Scopus, LILACS, Web of Science, Cochrane databases, and gray literature. The risk of bias was available in all papers included., Results: Of 9,688 records identified, 27 were included in this review, reporting data from 356,250 individuals screened and distributed across 11 countries. Most of these (n = 19) were based on 1 round of screening conducted by a dental professional or other health care workers. Most screening programs included visual inspection and palpation of the lips, oral cavity, and the most visible oropharyngeal sites, but the descriptions reported were imprecise. Additional inspection and palpation of the neck (submental, submandibular, cervical, and supraclavicular regions) to assess for the presence of swellings and any palpable neck nodes were also performed in 15 programs., Conclusion: In conclusion, there was considerable heterogeneity in the method of physical examination in screening programs for oral cancer and OPMDs among the included studies., Competing Interests: Declaration of interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC., Experimental Design: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort., Results: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73., Conclusions: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Rhabdomyosarcoma (RMS) harboring EWSR1/FUS-TFCP2 fusions has been recently described as a distinct form of RMS with an aggressive course and predilection for the craniofacial bones, especially the jaws., Methods: We report three new cases of this rare entity, two from Brazil and one from Guatemala, with detailed clinicopathologic, immunohistochemical, and molecular descriptions. Additionally, we explored the English-language literature searching RMS with TFCP2 rearrangement or typical immunophenotype with co-expression of AE1/AE3 and ALK in the head and neck region., Results: Case 1 is a 58-year-old male with a 3-month history of painful swelling in the anterior maxilla. Case 2 is a 22-year-old male presenting with right facial swelling and proptosis. Case 3 is a 43-year-old female with a rapidly growing tumor located in the zygomatic region. Imaging examinations revealed highly destructive intraosseous masses in the first two cases, and a soft tissue tumor with bone invasion in case 3. Microscopically, all cases showed a hybrid spindle and epithelioid phenotype of tumor cells which expressed desmin, myogenin and/or Myo-D1, AE1/AE3, and ALK. FISH confirmed molecular alterations related to TFCP2 rearrangement in Cases 1-2. In case 3, there was no available material for molecular analysis. The patients were subsequently referred to oncologic treatment. Additionally, we summarized the clinicopathologic, immunohistochemical, and molecular features of 27 cases of this rare RMS variant in the head and neck region reported in the English-language literature., Conclusion: RMS with TFCP2 rearrangement is a rare and aggressive tumor with a particular predilection for craniofacial bones, especially the jaws. Knowing its clinicopathologic and immunohistochemical profile can avoid misdiagnosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mast cells are granulocytic immune sentinels present in vascularized tissues that drive chronic inflammatory mechanisms characteristic of allergic pathologies. IgE-mediated mast cell activation leads to a rapid mobilization of Ca 2+ from intracellular stores, which is essential for the release of preformed mediators via degranulation and de novo synthesized proinflammatory cytokines and chemokines. Given its potent signaling capacity, the dynamics of Ca 2+ localization are highly regulated by various pumps and channels controlling cytosolic Ca 2+ concentrations. Among these is sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA), which functions to maintain low cytosolic Ca 2+ concentrations by actively transporting cytosolic Ca 2+ ions into the endoplasmic reticulum. In this study, we characterized the role of SERCA in allergen-activated mast cells using IgE-sensitized bone marrow-derived mast cells (BMMCs) treated with the SERCA activating compound, CDN1163, and simultaneously stimulated with allergen through FcεRI under stem cell factor (SCF) potentiation. Acute treatment with CDN1163 was found to attenuate early phase mast cell degranulation along with reactive oxygen species (ROS) production. Additionally, treatment with CDN1163 significantly reduced secretion of IL-6, IL-13, and CCL3, suggesting a role for SERCA in the late phase mast cell response. The protective effects of SERCA activation via CDN1163 treatment on the early and late phase mast cell response may be driven by the selective suppression of p38 MAPK signaling. Together, these findings implicate SERCA as an important regulator of the mast cell response to allergen and suggest SERCA activity may offer therapeutic potential targeting allergic pathologies, warranting further investigation., (© 2023 Federation of American Societies for Experimental Biology.)

The Nobel Prize awarded gene editing system, CRISPR-Cas9, is probably one of the greatest achievements of the last decades. CRISPR-Cas9 can introduce irreversible genomic changes in its target DNA by simple specifying a 20-nucleotide sequence within its RNA guide. Due to its simplicity, efficacy, and relative low cost in comparison with other genome editing systems, it has become the most common gene editing system used in research laboratories. Here we describe a step-by-step protocol to produce genetically edited primary oral keratinocytes using the CRISPR-Cas9 system., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Although there has been substantial improvement in the treatment modalities, cancer remains the major cause of fatality worldwide. Metastasis, recurrence, and resistance to oncological therapies are the leading causes of cancer mortality. Epithelial-mesenchymal transition (EMT) is a complex biological process that allows cancer cells to undergo morphological transformation into a mesenchymal phenotype to acquire invasive potential. It encompasses reversible and dynamic ontogenesis by neoplastic cells during metastatic dissemination. Hence, understanding the molecular landscape of EMT is imperative to identify a reliable clinical biomarker to combat metastatic spread. Accumulating evidence reveals the role of HOX (homeobox) cluster-embedded long non-coding RNAs (lncRNAs) in EMT and cancer metastasis. They play a crucial role in the induction of EMT, modulating diverse biological targets. The present review emphasizes the involvement of HOX cluster-embedded lncRNAs in EMT as a molecular sponge, chromatin remodeler, signaling regulator, and immune system modulator. Furthermore, the molecular mechanisms behind therapy resistance and the potential use of novel drugs targeting HOX cluster-embedded lncRNAs in the clinical management of distant metastasis will be discussed., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Background: Keratoameloblastoma (KA) is an uncommon and controversial variant of ameloblastoma exhibiting central keratinisation. Due to their rarity, there is limited information in the literature on their clinical, radiologic and histologic features. This study adds seven additional cases of KA to the literature, and reviews the current published literature on this rare entity., Methods: KAs were retrospectively reviewed over a 20-year period from three Oral and Maxillofacial Pathology Laboratories. Included cases were examined and the diagnosis confirmed under conventional microscopy. Immunohistochemistry with the use of a monoclonal antibody against calretinin was performed on included cases. The clinical, radiologic and histologic features of the seven new cases of KA were analysed and compared to existing cases in the literature., Results: KAs presented at a mean age of 40 years with a nearly equal gender distribution and a mandibular predilection (65%). The majority (92%) of cases presented with localised swelling with associated pain in 32% of cases. Mixed density or internal calcifications were noted in 40% of cases. All tumours presented with bony expansion, with cortical destruction noted in 62% of cases. Histologically, all tumours consisted of solid and cystic follicles with surface parakeratinisation and lamellated accumulations of central keratin. In areas the cystic follicles had an epithelial lining suggestive of an OKC. There were focal luminal areas of loosely arranged polygonal cells reminiscent of the stellate reticulum. The basal cells consisted of columnar cells with evidence of palisading and prominent subnuclear vacuolisation. Of the cases treated via tumour resection, 27% presented with tumour recurrence., Conclusion: This case series reports seven additional cases of KA, taking the total to 26 reported cases. The identification of subtle histologic features, including focal stellate reticulum-like central areas, subnuclear vacuolisation and lamellated-type central keratinisation, are key in diagnosing KA. The radiologic features will often indicate signs of aggressiveness such as cortical destruction, differentiating KA from OKC. All cases were completely negative for calretinin IHC, limiting its use in distinguishing KA from OKC. Further large series are needed to expand the current understanding of this rare variant of ameloblastoma., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A multiscale modelling approach has been applied to the simulation of the electrical properties of oral tissue, for the purpose of informing an electrical impedance-based method of oral potential malignant disorder (OPMD) diagnosis. Finite element models of individual cell types, with geometry informed by histological analysis of human oral tissue (normal, hyperplastic and dysplastic), were generated and simulated to obtain electrical parameters. These were then used in a histology-informed tissue scale model, including the electrode geometry of the ZedScan tetrapolar impedance-measurement device. The simulations offer insight into the feasibility of distinguishing moderate dysplasia from severe dysplasia or healthy tissue. For some oral sites, simulated spectra agreed with real measurements previously collected using ZedScan. However, similarities between simulated spectra for dysplastic, keratinised and non-dysplastic but hyperkeratinised tissue suggest that significant keratinisation could cause some OPMD tissues to exhibit larger than expected impedance values. This could lead to misidentification of OPMD spectra as healthy. Sources of uncertainty within the models were identified and potential remedies proposed.

Potentially pre-malignant oral lesions (PPOLs) are composed of keratinocytes that are either mortal (MPPOL) or immortal (IPPOL) in vitro. We report here that MPPOL, but not generally IPPOL, keratinocytes upregulate various extracellular tumor-promoting cytokines (interleukins 6 and 8) and prostaglandins E1 (ePGE1) and E2 (ePGE2) relative to normal oral keratinocytes (NOKs). ePGE upregulation in MPPOL was independent of PGE receptor status and was associated with some but not all markers of cellular senescence. Nevertheless, ePGE upregulation was dependent on the senescence program, cyclo-oxygenase 2 (COX2) and p38 mitogen-activated protein kinase and was partially regulated by hydrocortisone. Following senescence in the absence of p16 INK4A , ePGEs accumulated in parallel with a subset of tumor promoting cytokine and metalloproteinase (MMP) transcripts, all of which were ablated by ectopic telomerase. Surprisingly, ataxia telangiectasia mutated (ATM) function was not required for ePGE upregulation and was increased in expression in IPPOL keratinocytes in line with its recently reported role in telomerase function. Only ePGE1 was dependent on p53 function, suggesting that ePGEs 1 and 2 are regulated differently in oral keratinocytes. We show here that ePGE2 stimulates IPPOL keratinocyte proliferation in vitro. Therefore, we propose that MPPOL keratinocytes promote the progression of IPPOL to oral SCC in a pre-cancerous field by supplying PGEs, interleukins and MMPs in a paracrine manner. Our results suggest that the therapeutic targeting of COX-2 might be enhanced by strategies that target keratinocyte senescence.

Oral potentially malignant disorders (OPMD) may precede oral squamous cell carcinoma (OSCC). Reported rates of malignant transformation of OPMD range from 3 to 50%. While some clinical, histological, and molecular factors have been associated with a high-risk OPMD, they are, to date, insufficiently accurate for treatment decision-making. Moreover, this range highlights differences in the clinical definition of OPMD, variation in follow-up periods, and molecular and biological heterogeneity of OPMD. Finally, while treatment of OPMD may improve outcome, standard therapy has been shown to be ineffective to prevent OSCC development in patients with OPMD. In this perspective paper, several experts discuss the main challenges in oral cancer prevention, in particular the need to (i) to define an OPMD classification system by integrating new pathological and molecular characteristics, aiming (ii) to better identify OPMD at high risk of malignant transformation, and (iii) to develop treatment strategies to eradicate OPMD or prevent malignant transformation.

This systematic review evaluates the diagnostic accuracy of conventional oral examination (COE) versus incisional or excisional biopsy for the diagnosis of malignant and/or dysplastic lesions in patients with clinically evident lesions. Searches were conducted across five electronic databases from inception to January 2020. Meta-analyses were undertaken, where appropriate. Among 18 included studies, 14 studies were included in the meta-analysis, giving summary estimates for COE of 71% sensitivity and 85% specificity for the diagnosis of dysplastic and/or malignant lesions. The pooled diagnostic accuracy of identifying malignant-only lesions was reported in seven studies, giving a pooled estimate of 88% sensitivity and 81% specificity. Diagnostic accuracy of different types of dental/medical professionals in identifying dysplastic or malignant lesions gave varying estimates of sensitivity and specificity across three studies. Further research is needed to improve the diagnostic accuracy of COE for early detection of dysplastic and malignant oral lesions., (© 2022 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Homeobox (HOX) genes encode highly conserved homeotic transcription factors that play a crucial role in organogenesis and tissue homeostasis. Their deregulation impacts the function of several regulatory molecules contributing to tumor initiation and progression. A functional bridge exists between altered gene expression of individual HOX genes and tumorigenesis. This review focuses on how deregulation in the HOX-associated signaling pathways contributes to the metastatic progression in cancer. We discuss their functional significance, clinical implications and ascertain their role as a diagnostic and prognostic biomarker in the various cancer types. Besides, the mechanism of understanding the theoretical underpinning that affects HOX-mediated therapy resistance in cancers has been outlined. The knowledge gained shall pave the way for newer insights into the treatment of cancer., (© 2021. The Author(s).)

Objective: The objective of this review is to decipher the biological implications of the immune factors in the tumour microenvironment in oral cancer. The restoration of balance between tumour tolerance and tumour eradication by the host immune cells is critical to provide effective therapeutic strategies., Design: The specific role of the stromal and the immune components in oral cancer was reviewed with a tailored search strategy using relevant keywords. The articles were retrieved from bibliometric databases indexed in PubMed, Scopus, and Embase. An in silico analysis was performed to identify potential drug candidates for immunotherapy, by accessing the Drug-Gene Interactions Database (DGIdb) using the rDGIdb package., Results: There is compelling evidence for the role of the cellular and extracellular components of the tumour microenvironment in inducing immunosuppression and progression of oral cancer. The druggable candidates specifically targeting the immune system are a viable option in the treatment of oral cancer as they can regulate the tumour microenvironment., Conclusion: A complex interaction between the tumour and the immunological microenvironment influences the disease outcome in oral cancer. Targeting specific components of the immune system might be relevant, as immunotherapy may become the new standard of care for oral cancer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The essential role HOX-associated non-coding RNAs play in chromatin dynamics and gene regulation has been well documented. The potential roles of these microRNAs and long non-coding RNAs in oral cancer development, with their attendant involvement in various cellular processes including proliferation, invasion, migration, epithelial-mesenchymal transition and metastasis is gaining credence. An interaction network of HOX-embedded non-coding RNAs was constructed to identify the RNA interaction landscape using the arena-Idb platform and visualized using Cytoscape. The miR-10a was shown to interact with HOXA1, miR-10b with HOXD10, miR-196a1 with HOXA5, HOXA7, HOXB8, HOXC8, HOXD8, and miR-196a2 with HOXA5. The lncRNAs, HOTAIR interacted with HOXC11, HOTAIRM1 with HOXA1 and HOXA4, HOTTIP with HOXA13, HOXA-AS2 with HOXA3, HOXA11-AS with HOXA11 and HOXD-AS1 with HOXB8. Changes in the HOX cluster-embedded non-coding RNAs have implications for prognosis and overall disease survival. Our review aims to analyze the functional significance and clinical relevance of non-coding RNAs within the HOX cluster in the context of oral carcinogenesis. Elucidating these interactions between the non-coding RNAs and HOX genes in oral cancer development and progression could pave the way for the identification of reliable biomarkers and potential therapeutic targets., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Over recent decades, the field of cellular senescence has attracted considerable attention due to its association with aging, the development of age-related diseases and cancer. Senescent cells are unable to proliferate, as the pathways responsible for initiating the cell cycle are irreversibly inhibited. Nevertheless, senescent cells accumulate in tissues and develop a pro-inflammatory secretome, known as the senescence-associated secretory phenotype (SASP), which can have serious deleterious effects if not properly regulated. There is increasing evidence suggesting senescent cells contribute to different stages of carcinogenesis in different anatomical sites, mainly due to the paracrine effects of the SASP. Thus, a new therapeutic field, known as senotherapeutics, has developed. In this review, we aim to discuss the molecular mechanisms underlying the senescence response and its relationship with cancer development, focusing on the link between senescence-related inflammation and cancer. We will also discuss different approaches to target senescent cells that might be of use for cancer treatment.

Senescence is a common denominator in wound healing, fibrosis, and cancer. Although, senescence is transiently antifibrotic, when prolonged, promotes fibrosis and malignant transformation. Eligible studies indexed in MEDLINE, Embase and Web of Science were searched to understand the role of cellular senescence in the pathogenesis of oral submucous fibrosis (OSF) and its malignant transformation. The senescence-associated secretory phenotype (SASP) components like IL-1, IL-6, and GRO-α induce double-strand DNA breaks in keratinocytes and drive genetic instability. SASP derived from myofibroblasts induces epithelial-mesenchymal transition in OSF and facilitates cancer progression. The use of senolytics has been shown to eliminate senescent cells from the areas of fibrosis, thereby preventing malignancy. Naturally occurring agents such as apigenin and kaempferol inhibit SASP. Mechanistic insight into the emerging role of senescence in the pathogenesis of OSF and modalities to inhibit senescence-associated antiapoptotic pathways as a supplementary therapy to prevent malignant transformation of OSF is underlined., (© 2021 Wiley Periodicals LLC.)

Decades ago, the study of cancer biology was mainly focused on the tumor itself, paying little attention to the tumor microenvironment (TME). Currently, it is well recognized that the TME plays a vital role in cancer development and progression, with emerging treatment strategies focusing on different components of the TME, including tumoral cells, blood vessels, fibroblasts, senescent cells, inflammatory cells, inflammatory factors, among others. There is a well-accepted relationship between chronic inflammation and cancer development. Interleukin-1 (IL-1), a potent pro-inflammatory cytokine commonly found at tumor sites, is considered one of the most important inflammatory factors in cancer, and has been related with carcinogenesis, tumor growth and metastasis. Increasing evidence has linked development of head and neck squamous cell carcinoma (HNSCC) with chronic inflammation, and particularly, with IL-1 signaling. This review focuses on the most important members of the IL-1 family, with emphasis on how their aberrant expression can promote HNSCC development and metastasis, highlighting possible clinical applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Niklander, Murdoch and Hunter.)

Loss of RARβ2 expression by promoter methylation is an early event in oral carcinogenesis. Understanding the mechanisms and consequences of RARβ loss may aid in understanding the disappointing results of retinoid chemoprevention trials. This study aimed to describe the effects of all-trans retinoic acid (ATRA) and the de-methylating agent 5-Aza-2' deoxycytidine (5-AZA-CdR) on a panel of immortal potentially malignant oral lesion (PMOL) cell cultures. RARβ expression was assessed in PMOL tissues by immunohistochemistry. Cells were treated with ATRA ± 5-AZA-CdR, and the effects on the cell cycle and senescence were assessed. In PMOL tissues, RARβ expression was variable, but lower in biopsies which gave rise to immortal cell cultures. Treatment of iPMOL cells with ATRA resulted in little change in RARβ expression, but the addition of 5-AZA-CdR resulted in significant increases. The effects on the cell cycle and senescence were variable and may be related to 5-AZA-CdR, as this has wider effects on the cell cycle. Overall, the response of iPMOL cells to ATRA and 5-AZA-CdR treatment was variable and is dependent on several factors, including RARβ-promoter methylation. These findings may help to explain the lack of consistent effect of retinoids in PMOLs seen in chemoprevention trials.

During oral pathology daily practice, true amyloid may be identified in oral amyloidosis and several odontogenic tumors. However, histologic examination often reveals other oral and perioral diseases with similar eosinophilic, acellular, amorphous substances. These include extensive areas of collagenous sclerosis, fibrin deposition, elastic fiber degeneration, and dentinoid material, which may resemble amyloid under light microscopic examination. These materials are often termed "amyloid-like" due to their close histologic resemblance to true amyloid. The rarity of most of these conditions and their strong histologic similarity may hamper an accurate diagnosis. Definitive diagnosis of these lesions may require clinical correlation; laboratory evaluation; histochemical or immunohistochemical reactions; and, in some cases, genetic investigation. In this review, we describe the main clinicopathologic features of this group of diseases that may manifest in the oral and/or perioral regions and that have in common the presence of amyloid-like material deposition., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective(s): The objective of the present manuscript is to elucidate the role of matrix stiffness in the malignant transformation of oral submucous fibrosis., Design: The role of matrix stiffness in several cancers including oral cancer was reviewed with a tailored search strategy using relevant keywords as per the Medline format. The role of molecular mediators, Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) was weighed in the context of OSF along two distinct pathways., Results: Increased matrix stiffness activates the transcriptional coactivators, YAP and TAZ shuttling between the nucleus and cytoplasm. YAP and TAZ, serve as mechanical transducers in promoting cell migration, invasion and epithelial-mesenchymal transition (EMT). The hypoxic microenvironment in the advanced stage of OSF promotes the migratory phenotype through mechanical memory., Conclusions: Reprogramming of a stiff matrix has the potential to restore the Hippo-YAP/TAZ tumor suppressor pathway and reverse fibrosis-associated tumor development., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Although uncommon, mature small B-cell lymphomas may arise in the oral/maxillofacial area and oral pathologists must be aware of the key characteristics of these neoplasms to perform an accurate diagnosis. In this manuscript, we attempted to integrate the currently available data on the clinicopathological features of follicular lymphoma (FL), mantle cell lymphoma (MCL), extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT-L), and chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) affecting these anatomical regions., Methods: An updated descriptive literature review was carried out and a detailed electronic search was done in multiple databases to gather all cases affecting the oral/maxillofacial region and palatine tonsils., Results: We observed that MALT-L was the most frequently reported subtype, followed by FL, MCL, and CLL/SLL. The palate was affected in a high proportion of cases and the most usual clinical presentation was an asymptomatic swelling. MALT-L and CLL/SLL neoplastic cells were strongly associated with small salivary glands. FL showed no gender preference, while MCL and CLL/SLL were more prevalent in males and MALT-L in females. Overall, cases were more common in elderly individuals. Patients' treatment and outcome varied, with MCL being the most aggressive neoplasm with a dismal prognosis in comparison to FL and MALT-L., Conclusion: Despite the poor documentation in many of the cases available, especially regarding the microscopic and molecular features of tumors, this review demonstrated that the oral mature small B-cell lymphomas investigated share similar clinical presentation, but carry different prognostic significance, demanding an accurate diagnosis., (© 2021 The Authors. Journal of Oral Pathology & Medicine published by John Wiley & Sons Ltd.)

Objective: The objective of this study was identification of the transcription factor binding sites (TFBS) in the promoter of HOX genes and elucidation of the comprehensive interaction of transcription factors (TFs)/genes with HOX., Methodology: Promoter sequences of HOXA3, HOXA5, HOXA9, HOXA10, HOXA13, HOXB5, HOXC10, HOXC12, and HOXD10 were analyzed to predict the TFBS and their targets using TRANSFAC, TRRUST, and Harmonizome. Functional analysis of the processed data sets was carried out using DAVID and GATHER gene annotation tools. A network of regulatory interactions was constructed using NetworkAnalyst and a comprehensive illustration of the TF-gene network was constructed with HOX as a central hub using the Encyclopedia of DNA Elements chromatin immunoprecipitation sequencing data. Further, the enriched network was constructed to elucidate the roles of these genes in the various pathways., Results: Binding sites for E2F1, HNF3α, SP3, and KLF6 were common to promoter regions of all of the HOX genes. The functional annotation and pathway analysis elucidated the regulatory activity of a distinct set of TF-genes in interaction with HOX. A P value ≤.05 and false discovery rate ≤0.01 were considered statistically significant., Conclusion: We have confirmed that the predicted TFBSs in the HOX gene promoters function in transcriptional regulation by modulating target gene activity. TF-gene interactions are crucial to understanding oral carcinogenesis., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumour in both adults and children. Histological grading of MEC is subjective, but plays an important role in predicting patient prognosis. Epithelial mucin (MUC) status may aid in establishing a more accurate grade. This study aimed to investigate the expression of various mucins (MUC1, MUC2, MUC4 and MUC5AC) in MECs to determine a possible correlation with tumour grade. Fifteen cases of each tumour grade (low-, intermediate-, and high-grade) were retrieved from the pathology archives of the Department of Oral Pathology and Oral Biology at the University of Pretoria. The patients included 23 men and 22 women, and ranged from 13 to 85 years (mean 49.8 years). Sections from formalin-fixed paraffin-embedded (FFPE) tissue were used for fluorescence in situ hybridization (FISH) for MAML2 rearrangements and MUC immunohistochemical analysis. The percentage immunohistochemical expression of the neoplastic mucous cells was evaluated first, followed by the overall percentage expression of all tumour cells. The results indicated that MUC1 overexpression may be a reliable marker of high-grade MECs, whereas MUC4 overexpression may be more indicative of low-grade tumours. MUC5AC expression was considered an unreliable marker in determining grade. MUC2 was only expressed in a single case of MEC and may be considered a useful marker to exclude MEC as a diagnostic possibility. This study demonstrates that MECs show an altered MUC expression pattern that can be used for diagnostic purposes and to aid in establishing a more accurate tumour grade.

Objective: The aim of this study was to report the clinicopathologic features of 62 cases of central odontogenic fibroma (COdF)., Study Design: Clinical and radiographic data were collected from the records of 13 oral pathology laboratories. All cases were microscopically reviewed, considering the current World Health Organization classification of tumors and were classified according to histopathologic features., Results: There were 43 females and 19 males (average age 33.9 years; range 8-63 years). Clinically, COdF lesions appeared as asymptomatic swellings, occurring similarly in the maxilla (n = 33) and the mandible (n = 29); 9 cases exhibited palatal depression. Imaging revealed well-defined, interradicular unilocular (n = 27), and multilocular (n = 12) radiolucencies, with displacement of contiguous teeth (55%) and root resorption (46.4%). Microscopically, classic features of epithelial-rich (n = 33), amyloid (n = 10), associated giant cell lesion (n = 7), ossifying (n = 6), epithelial-poor (n = 3), and granular cell (n = 3) variants were seen. Langerhans cells were highlighted by CD1a staining in 17 cases. Most patients underwent conservative surgical treatments, with 1 patient experiencing recurrence., Conclusions: To the best of our knowledge, this study represents the largest clinicopathologic study of COdF. Most cases appeared as locally aggressive lesions located in tooth-bearing areas in middle-aged women. Inactive-appearing odontogenic epithelium is usually observed within a fibrous/fibromyxoid stroma, occasionally exhibiting amyloid deposits, multinucleated giant cells, or granular cells., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Allergic inflammatory diseases are a steadily growing health concern. Mast cells, a driving force behind allergic pathologies, modulate metabolic pathways to carry out various functions following IgE-FcεRI-mediated activation. Tafazzin (TAZ) is a cardiolipin transacylase that functions to remodel, and thereby mature, cardiolipin, which is important for efficient energy production through oxidative phosphorylation. In this study, we aimed to evaluate the contribution of TAZ in IgE-mediated mast cell activation. Fetal liver-derived mast cells (FLMCs) were differentiated from mice with a doxycycline (dox)-inducible TAZ short hairpin RNA (shRNA) cassette ( TAZ shRNA +/+ ) and littermate wild-types (WTs). TAZ knockdown in FLMCs following dox treatment was confirmed by Western blotting (99.1% by day 5), whereas flow cytometry confirmed FLMC phenotype (c-kit + FcεRI + ) and retention of receptor expression post-dox. Five-day dox-treated WT and TAZ shRNA +/+ FLMCs were activated via allergen-bound IgE cross-linking of FcεRI under stem cell factor potentiation. With dox, and in response to allergen, TAZ shRNA +/+ FLMCs displayed a 25% reduction in oxygen consumption and a significant 31% reduction in mast cell degranulation compared with dox-treated WT FLMCs. Secretion of TNF, CCL1, and CCL2 were significantly reduced, with CCL9 also impaired. Notably, gene expression was not impaired for any inflammatory mediator measured. Functionally, this suggests that TAZ is a contributor to mast cell degranulation and inflammatory mediator secretion. Given unimpacted induced gene expression for mediators measured, we propose that TAZ reduction impairs mast cell exocytosis mechanisms. We thus identify a potential new contributor to immunometabolism that enhances our understanding of mast cell signaling metabolic pathway interactions during allergic inflammation., (Copyright © 2021 The Authors.)

Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER + ) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth.

This article reviews odontogenic and developmental oral lesions encountered in the gnathic region of pediatric patients. The process of odontogenesis is discussed as it is essential to understanding the pathogenesis of odontogenic tumors. The clinical presentation, microscopic features, and prognosis are addressed for odontogenic lesions in the neonate (dental lamina cysts/gingival cysts of the newborn, congenital (granular cell) epulis of the newborn, melanotic neuroectodermal tumor, choristoma/heterotopia, cysts of foregut origin), lesions associated with unerupted/erupting teeth (hyperplastic dental follicle, eruption cyst, dentigerous cyst, odontogenic keratocyst/keratocystic odonogenic tumor, buccal bifurcation cyst/inflammatory collateral cyst) and pediatric odontogenic hamartomas and tumors (odontoma, ameloblastic fibroma, ameloblastoma, adenomatoid odontogenic tumor, primordial odontogenic tumor). Pediatric odontogenic and developmental oral lesions range from common to rare, but familiarity with these entities is essential due to the varying management implications of these diagnoses.

The first detailed description of calcifying epithelial odontogenic tumor (CEOT) are ascribed to Jens Pindborg, but this tumor was described some years previously. Subsequently, CEOT was included in the 1971 WHO classification of odontogenic tumors and a since then number of variants have been described, which have added confusion to the diagnostic criteria. We aimed to survey the literature on the variants of CEOT, in parallel with a review of our single institution experience of CEOTs. Cases identified were collated, including available clinical, radiological and histological information and then reviewed, taking into account changes in the understanding and classifications of odontogenic tumors since initial diagnosis. We identified 26 cases from 1975 to 2017 for which histological material was available. Of these, only 13 (50%) showed the "classic" histological appearance, whilst two cases were identified as recognized variants. In 11 cases, other diagnoses or a differential diagnosis were preferred, with no agreed diagnosis in four of these. The proliferation fraction (Ki67) in the 10 cases tested was 2.1% ± 0.18. These findings illustrate the diagnostic challenges in this group of tumors and highlight the gaps in knowledge. Techniques, such as EWSR1 gene cytogenetic analysis, may be helpful in cases with clear cells. However, in other areas of controversy, including the non-calcifying and Langerhans cell rich variants, further investigation, perhaps utilizing sequencing technologies may be needed to refine the classification. Owing to the relative rarity of these lesions it would be beneficial if future work could be pursued as an international collaboration.

There is compelling evidence that senescent cells, through the senescence-associated secretory phenotype (SASP), can promote malignant transformation and invasion. Interleukin-1 (IL-1) is a key mediator of this cytokine network, but the control of its activity in the senescence programme has not been elucidated. IL-1 signalling is regulated by IL-1RA, which has four variants. Here, we show that expression of intracellular IL-1RA type 1 (icIL-1RA1), which competitively inhibits binding of IL-1 to its receptor, is progressively lost during oral carcinogenesis ex vivo and that the pattern of expression is associated with keratinocyte replicative fate in vitro We demonstrate that icIL-1RA1 is an important regulator of the SASP in mortal cells, as CRISPR/Cas9-mediated icIL-1RA1 knockdown in normal and mortal dysplastic oral keratinocytes is followed by increased IL-6 and IL-8 secretion, and rapid senescence following release from RhoA-activated kinase inhibition. Thus, we suggest that downregulation of icIL-1RA1 in early stages of the carcinogenesis process can enable the development of a premature and deregulated SASP, creating a pro-inflammatory state in which cancer is more likely to arise., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

The incidence of human papillomavirus (HPV)-associated cancer is increasing and HPV is now implicated in the aetiology of more than 60% of all oropharyngeal squamous cell carcinomas (OPSCC). In OPSCC, innate immune cells such as neutrophils and macrophages generally correlate with poor prognosis, whilst adaptive immune cells, such as lymphocytes, tend to correlate with improved prognosis. This may, in part, be due to differences in the immune response within the tumour microenvironment leading to the recruitment of specific tumour-associated leukocyte sub-populations. In this study, we aimed to examine if differences exist in the levels of infiltrated leukocyte sub-populations, with particular emphasis on tumour-associated neutrophils (TAN), and to determine the mechanism of chemokine-induced leukocyte recruitment in HPV-positive compared to HPV-negative OPSCC. Immunohistochemical analysis showed that HPV-negative OPSCC contained significantly more neutrophils than HPV-positive tumours, whilst levels of CD68+ macrophages and CD3+ lymphocytes were similar. Using a 3D tissue culture model to represent tumour-stromal interactions, we demonstrated that HPV-negative tumour-stromal co-cultures expressed significantly higher levels of CXCL8, leading to increased neutrophil recruitment compared to their HPV-positive counterparts. HPV-negative OPSCC cells have previously been shown to express higher levels of IL-1 than their HPV-positive counterparts, indicating that this cytokine may be responsible for driving increased chemokine production in the HPV-negative 3D model. Inhibition of IL-1R in the tumour-stromal models using the receptor-specific antagonist, anakinra, dramatically reduced chemokine secretion and significantly impaired neutrophil and monocyte recruitment, suggesting that this tumour-stromal response is mediated by the IL-1/IL-1R axis. Here, we identify a mechanism by which HPV-negative OPSCC may recruit more TAN than HPV-positive OPSCC. Since TAN are associated with poor prognosis in OPSCC, our study identifies potential therapeutic targets aimed at redressing the chemokine imbalance to reduce innate immune cell infiltration with the aim of improving patient outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Al-Sahaf, Hendawi, Ollington, Bolt, Ottewell, Hunter and Murdoch.)

Senescent cells accumulate in different organs and develop a senescence-associated secretory phenotype (SASP), associated with the development of age-related pathologies. The constitution of the SASP varies among cell types and with the method of senescence induction; nevertheless, there is substantial overlap among SASPs, especially the presence of pro-inflammatory cytokines such as IL-1β, IL-1α, IL-6 and IL-8. These cytokines are highly conserved among SASPs and are implicated in the development of several cancers. Here, we report that ROCK inhibition by Y-27632 reduces levels of IL-1α, IL-1β, IL-6 and IL-8 secreted by senescent normal and dysplastic oral keratinocytes without affecting the permanent cell growth arrest. The data indicate some inflammatory genes downregulated by Y-27632 remain downregulated even after repeated passage in the absence of Y-27632. We propose ROCK kinase inhibition as a novel alternative to current strategies to modulate the inflammatory components of the SASP, without compromising the permanent cell growth arrest. This observation potentially has wide clinical applications, given the involvement of senescence in cancer and a wide range of age-related disease. It also suggests care should be exercised when using Y-27632 to facilitate cell expansion of primary cells, as its effects on gene expression are not entirely reversible., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)