Concordance of judgement: A tool to foster the development of professionalism in dentistry.

INTRODUCTION: Developing professionalism notably involves learning how to make professional judgements in ambiguous situations. The Concordance of Judgement Test (CJT) is a learning tool that was proposed to develop professionalism competencies, but it was never performed in dentistry or used with a synchronous methodology. The present study evaluated the feasibility of the use of CJT in the context of dental education, to foster professionalism and stimulate reflexivity and discussion. MATERIALS AND METHODS: After different steps of optimization, a questionnaire presenting 12 vignettes was submitted to 33 Canadian students. Second, after an additional optimization, a questionnaire of 7 vignettes was submitted to 87 French students. An immediate educational feedback was proposed after each vignette to promote reflexivity and discussions during the experience. RESULTS: The overall experience of the students was reported as good, thanks to the feedback of real-life situations. This promoted reflexivity and stimulated discussion between students and educators regarding professionalism issues. The students considered CJT as a relevant and well-adapted tool, and reported positive feelings regarding the inter-university aspect of the activity. The mean score of the panel members was close to 80/100 and the mean score of the students was 5 to 10 points lower, which is in agreement with docimological performance. CONCLUSION: The results suggested that the use of CJT in a synchronous way was a feasible and relevant tool to motivate the students to improve their professionalism, and to stimulate their reflexivity and discussion. The students reported positive experience with CJT, and we believe that this tool can be integrated in the dental curriculum.

Diverging incidence trends of oral tongue cancer compared to other head and neck cancers in young adults in France.

While head and neck cancer incidence decreased worldwide due to reduced tobacco and alcohol consumption, oral tongue cancer (OTC) incidence has been reported to be increasing in several countries. Our study examines the incidence trends of OTC in France from 1990 to 2018, globally and by age; and compares the incidence trends with the evolution of the incidence of other human papilloma virus-unrelated head and neck squamous cell carcinoma, that is, cancers of the remaining subsites of the oral cavity (RSOCC) and laryngeal cancers for the period 1990 to 2018. World age-standardized incidence rates of oral tongue cancers (C02), cancers of the remaining subsites of the oral cavity (RSOCC, C03-06) and laryngeal cancers (C32) were estimated using the French National Network of Cancer Registries for the period 1990 to 2018. Trends in national incidence rates were estimated from a mixed-effect Poisson model including age and year effects using penalized splines and a district-random effect. In women aged 30 and 40, a significant increase in OTC incidence was observed, while ROSCC showed a nonsignificant incidence decrease. In young men aged 25, a marginally significant increase of OTC incidence years was observed, while incidence rates of RSOCC significantly declined. The results suggest a tendency towards diverging incidence trends for OTC compared to RSOCC and laryngeal cancer in young adults. The observed trends may reflect changes in underlying exposures or emerging exposures not yet identified, and stress the need to further investigate the etiology of oral tongue cancers.

Oral cavity squamous cell carcinomas in patients with no identified risk factors: Feeling like an outsider.

OBJECTIVES: Head and neck squamous cell carcinomas (HNSCCs) mainly affect smokers and drinkers. However, oral cavity squamous cell cancers (OCSCCs) are increasingly affecting patients with no identified risk factors (NIRFs). This study aimed at characterising their experience of the disease. METHODS: Qualitative study based on semi-structured interviews of 20 survivors of OCSCC with NIRF. Methods used in grounded theory approach were applied. RESULTS: Patients with NIRF had a similar experience to that of patients with risk factors regarding treatments. The absence of identified causes led to stigma and led the patients to distance themselves, both from the stereotypic HNSCC cancer patient and the identity as a cancer patient. Furthermore, having no identified risk factors seemed to reinforce the fear of recurrence. CONCLUSION: This study is the first to address key gaps in knowledge regarding patients with NIRF having survived OCSCC. Their experience is similar to that of patients with orphan diseases. Owing to confrontation with other patients and the repeated questions of caregivers about tobacco/alcohol consumption, these patients felt stigmatised during their treatment. OCSCC patients with NIRF may benefit from guidance and support on how to engage in prevention.

Oral tongue squamous cell carcinomas in young patients according to their smoking status: a GETTEC study.

BACKGROUND: Incidence of oral tongue squamous cell carcinoma (OTSCC) is increasing, especially in young adults, despite decreasing tobacco and alcohol consumption. METHODS: This multicentric retrospective study of 185 young adults with OTSCC (median follow-up 43 months), investigated risk factors, tumour characteristics and oncological outcomes according to the smoking status. RESULTS: Overall, 38% of patients were smokers (S). Non-smokers (NS) were significantly younger than S. Sex ratios were 1.1 for N and 1.8 for S. NS patients were less frequently cannabis or alcohol users than S, but were more likely to have a history of leukoplakia. Second primaries were observed in NS (4.4%) and in S (12.7%). Despite more frequent local relapse in NS (p = 0.018), there was no difference in diagnostic stage and overall survival between groups. CONCLUSION: OTSCC affects differently young S and NS patients suggesting the existence of a specific clinical entity of OTSCC in non-smoking young adults.

Improving digital scans by using a peripheral custom tray: A dental technique.

A digital dental technique is described for registering functional borders of immediate complete dentures, by using an intraoral scanner, a dental computer-aided design software program, and a peripheral custom tray. This article also illustrates how to virtually match the recorded information in order to transform the initial intraoral scan into definitive digital scans.

Digital prosthodontic management of a young patient with Papillon-Lefèvre syndrome: A clinical report.

Papillon-Lefèvre syndrome (PLS) is a rare disorder that leads to symptoms including the early progressive loss of deciduous and permanent teeth. Prosthodontic management of children and adolescents affected by PLS sometimes requires an immediate complete denture. Tooth mobility presents a challenge to the dentist, especially during impression-making. This clinical report describes the management of a 14-year-old boy with PLS by using an intraoral scanner to prevent conventional impressions and a fully digital workflow for the design and fabrication of immediate complete dentures.

CAD-CAM immediate to definitive complete denture transition: A digital dental technique.

The present article describes a digital workflow for the fabrication of definitive complete dentures in 2 appointments by reproducing the cameo surface and tooth arrangement of computer-aided design and computer-aided manufacturing (CAD-CAM) immediate dentures. This straightforward technique, which requires limited time and effort, can be easily applied by using an intraoral scanner, a dental CAD software program, and a milling machine.

Manufacturing of an immediate removable partial denture with an intraoral scanner and CAD-CAM technology: a case report.

BACKGROUND: Incisor loss constitutes a strong aesthetic and psychologic traumatism for the patient and it remains a challenging situation for the dental practitioner because of the necessity to rapidly replace the lacking tooth. Various therapeutic procedures have been proposed to replace the incisor concerned, for example by using a removable partial denture. However, the manufacturing of such a denture with classical procedures is often subject to processing errors and inaccuracies. The computer-aided design and computer-aided manufacturing (CAD-CAM) technology could represent a good alternative, but it is currently difficult because of the lack of dental softwares able to design easily immediate removable partial dentures. CASE PRESENTATION: A 30-year- patient complained about pain caused by a horizontally and vertically mobile maxillary right central incisor. After all options were presented, extraction of the traumatized incisor was decided due to its very poor prognosis, and the patient selected the realization of a removable denture for economic reasons. The present paper proposes an innovative procedure for immediate removable denture, based on the use of an intraoral scanner, CAD with two different softwares used sequentially, and CAM with a 5-axis machine. CONCLUSIONS: We show in this report that associating an intraoral scanner and CAD-CAM technology can be extended to immediate dentures manufacturing, which could be a valuable procedure for dental practitioners and laboratories, and also for patients.

Cleaved/associated TLR3 represents the primary form of the signaling receptor.

TLR3 belongs to the family of intracellular TLRs that recognize nucleic acids. Endolysosomal localization and cleavage of intracellular TLRs play pivotal roles in signaling and represent fail-safe mechanisms to prevent self-nucleic acid recognition. Indeed, cleavage by cathepsins is required for native TLR3 to signal in response to dsRNA. Using novel Abs generated against TLR3, we show that the conserved loop exposed in LRR12 is the single cleavage site that lies between the two dsRNA binding sites required for TLR3 dimerization and signaling. Accordingly, we found that the cleavage does not dissociate the C- and N-terminal fragments, but it generates a very stable "cleaved/associated" TLR3 present in endolysosomes that recognizes dsRNA and signals. Moreover, comparison of wild-type, noncleavable, and C-terminal-only mutants of TLR3 demonstrates that efficient signaling requires cleavage of the LRR12 loop but not dissociation of the fragments. Thus, the proteolytic cleavage of TLR3 appears to fulfill function(s) other than separating the two fragments to generate a functional receptor.

Dual function of MyD88 in inflammation and oncogenesis: implications for therapeutic intervention.

PURPOSE OF REVIEW: Inflammation is emerging as a new hallmark of cancer, and the toll-like receptor and interleukin-1 receptor adaptor molecule MyD88 has been linked to tumorigenesis. The purpose of this review is to give a brief overview of the latest advances in understanding the complexity of MyD88 implication in tumorigenesis. RECENT FINDINGS: MyD88 is shown to play a protumorigenic role through two mechanisms. First, it activates the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway in the hematopoietic compartment and in tumor cells, inducing an inflammatory environment favorable to carcinogenesis. Second, it plays a cell-autonomous role in Ras signaling and transformation, independently of its role in inflammatory signaling. MyD88 mediates the optimal activation of the Ras/extracellular signal-regulated kinase (ERK) pathway by binding to ERK and protecting it from dephosphorylation. This optimal activation of the Ras pathway is essential for the expression of important DNA repair enzymes, allowing cancer cells to efficiently repair damaged DNA. MyD88 is also shown in certain cases to play an antitumoral role through modulation of the immune response SUMMARY: These findings present a new dual function model for MyD88 implication in carcinogenesis making it a potential therapeutic target in cancer.

Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis.

Systemic sclerosis is a connective tissue disorder characterized by excessive fibrosis that primarily affects women, and can present as a multisystem pathology. Roughly 4-22% of patients with systemic sclerosis develop cancer, which drastically worsens prognosis. However, the mechanisms underlying systemic sclerosis initiation, propagation, and cancer development are poorly understood. We hypothesize that the inflammation and immune response associated with systemic sclerosis can trigger DNA damage, leading to elevated somatic mutagenesis, a hallmark of pre-cancerous tissues. To test our hypothesis, we culture clonal lineages of fibroblasts from the lung tissues of controls and systemic sclerosis patients and compare their mutation burdens and spectra. We find an overall increase in all major mutation types in systemic sclerosis samples compared to control lung samples, from small-scale events such as single base substitutions and insertions/deletions, to chromosome-level changes, including copy-number changes and structural variants. In the genomes of patients with systemic sclerosis, we find evidence of somatic hypermutation or kategis (typically only seen in cancer genomes), we identify mutation signatures closely resembling the error-prone translesion polymerase Polη activity, and observe an activation-induced deaminase-like mutation signature, which overlaps with genomic regions displaying kataegis.

Genome-scale mutational signature analysis in fixed archived tissues.

Mutation spectra and mutational signatures in cancerous and non-cancerous tissues can be identified by various established techniques of massively parallel sequencing (or next-generation sequencing) including whole-exome or whole-genome sequencing, and more recently by error-corrected/duplex sequencing. One rather underexplored area has been the genome-scale analysis of mutational signatures as markers of mutagenic exposures, and their impact on cancer driver events applied to formalin-fixed or alcohol-fixed paraffin embedded archived biospecimens. This review showcases successful applications of the next-generation sequencing methodologies in archived fixed tissues, including the delineation of the specific tissue fixation-related DNA damage manifesting as artifactual signatures, distinguishable from the true signatures that arise from biological mutagenic processes. Overall, we discuss and demonstrate how next-generation sequencing techniques applied to archived fixed biospecimens can enhance our understanding of cancer causes including mutagenic effects of extrinsic cancer risk agents, and the implications for prevention efforts aimed at reducing avoidable cancer-causing exposures.

Molecular and cell phenotype programs in oral epithelial cells directed by co-exposure to arsenic and smokeless tobacco.

Chronic arsenic exposure can lead to various health issues, including cancer. Concerns have been mounting about the enhancement of arsenic toxicity through co-exposure to various prevalent lifestyle habits. Smokeless tobacco products are commonly consumed in South Asian countries, where their use frequently co-occurs with exposure to arsenic from contaminated groundwater. To decipher the in vitro molecular and cellular responses to arsenic and/or smokeless tobacco, we performed temporal multi-omics analysis of the transcriptome and DNA methylome remodelling in exposed hTERT-immortalized human normal oral keratinocytes (NOK), as well as arsenic and/or smokeless tobacco genotoxicity and mutagenicity investigations in NOK cells and in human p53 knock-in murine embryonic fibroblasts (Hupki MEF). RNAseq results from acute exposures to arsenic alone and in combination with smokeless tobacco extract revealed upregulation of genes with roles in cell cycle changes, apoptosis and inflammation responses. This was in keeping with global DNA hypomethylation affecting genes involved in the same processes in response to chronic treatment in NOK cells. At the phenotypic level, we observed a dose-dependent decrease in NOK cell viability, induction of DNA damage, cell cycle changes and increased apoptosis, with the most pronounced effects observed under arsenic and SLT co-exposure conditions. Live-cell imaging experiments indicated that the DNA damage likely resulted from induction of apoptosis, an observation validated by a lack of exome-wide mutagenesis in response to chronic exposure to arsenic and/or smokeless tobacco. In sum, our integrative omics study provides novel insights into the acute and chronic responses to arsenic and smokeless tobacco (co-)exposure, with both types of responses converging on several key mechanisms associated with cancer hallmark processes. The generated rich catalogue of molecular programs in oral cells regulated by arsenic and smokeless tobacco (co-)exposure may provide bases for future development of biomarkers for use in molecular epidemiology studies of exposed populations at risk of developing oral cancer.

Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK.

Tobacco usage is linked to multiple cancer types and accounts for a quarter of all cancer-related deaths. Tobacco smoke contains various carcinogenic compounds, including polycyclic aromatic hydrocarbons (PAH), though the mutagenic potential of many tobacco-related chemicals remains largely unexplored. In particular, the highly carcinogenic tobacco-specific nitrosamines NNN and NNK form pre-mutagenic pyridyloxobutyl (POB) DNA adducts. In the study presented here, we identified genome-scale POB-induced mutational signatures in cell lines and rat tumors, while also investigating their role in human cancer. These signatures are characterized by T>N and C>T mutations forming from specific POB adducts damaging dT and dC residues. Analysis of 2,780 cancer genomes uncovered POB signatures in ∼180 tumors; from cancer types distinct from the ones linked to smoking-related signatures SBS4 and SBS92. This suggests that, unlike PAH compounds, the POB pathway may contribute uniquely to the mutational landscapes of certain hematological malignancies and cancers of the kidney, breast, prostate and pancreas.

Targeting ERK-MYD88 interaction leads to ERK dysregulation and immunogenic cancer cell death.

The quest for targeted therapies is critical in the battle against cancer. The RAS/MAP kinase pathway is frequently implicated in neoplasia, with ERK playing a crucial role as the most distal kinase in the RAS signaling cascade. Our previous research demonstrated that the interaction between ERK and MYD88, an adaptor protein in innate immunity, is crucial for RAS-dependent transformation and cancer cell survival. In this study, we examine the biological consequences of disrupting the ERK-MYD88 interaction through the ERK D-recruitment site (DRS), while preserving ERK's kinase activity. Our results indicate that EI-52, a small-molecule benzimidazole targeting ERK-MYD88 interaction induces an HRI-mediated integrated stress response (ISR), resulting in immunogenic apoptosis specific to cancer cells. Additionally, EI-52 exhibits anti-tumor efficacy in patient-derived tumors and induces an anti-tumor T cell response in mice in vivo. These findings suggest that inhibiting the ERK-MYD88 interaction may be a promising therapeutic approach in cancer treatment.

Oral Cavity Squamous Cell Carcinoma Risk Factors: State of the Art.

Head and neck (HN) squamous cell carcinomas (SCCs) originate from the epithelial cells of the mucosal linings of the upper aerodigestive tract, which includes the oral cavity, the pharynx, the larynx, and the sinonasal cavities. There are many associated risk factors, including alcohol drinking coupled with tobacco use, which accounts for 70% to 80% of HNSCCs. Human papilloma virus (HPV) is another independent risk factor for oropharyngeal SCC, but it is only a minor contributor to oral cavity SCC (OSCC). Betel quid chewing is also an established risk factor in southeast Asian countries. However, OSCC, and especially oral tongue cancer, incidence has been reported to be increasing in several countries, suggesting risk factors that have not been identified yet. This review summarizes the established risk factors for oral cavity squamous cell carcinomas and examines other undemonstrated risk factors for HNSCC.

Molecular landscapes of oral cancers of unknown etiology.

The incidence of the mobile tongue cancer in young patients has been rising. This oral cancer (OC) type has no identified risk factors (NIRF), no established molecular markers and is not yet recognized as a distinct clinical entity. To understand this emerging malignancy, we innovatively analyzed the public head and neck cancer multi-omics data. We identified mutational signatures that successfully stratified 307 OC and 109 laryngeal cancer cases according to their clinico-pathological characteristics. The NIRF OCs exhibited significantly increased activities of endogenous clock-like and APOBEC-associated mutagenesis, alongside specific cancer driver gene mutations, distinct methylome patterns and prominent antimicrobial transcriptomic responses. Furthermore, we show that mutational signature SBS16 in OCs reflects the combined effects of alcohol drinking and tobacco smoking. Our study characterizes the unique disease histories and molecular programs of the NIRF OCs revealing that this emerging cancer subtype is likely driven by increased endogenous mutagenesis correlated with responses to microbial insults.

Confined migration promotes cancer metastasis through resistance to anoikis and increased invasiveness.

Mechanical stress is known to fuel several hallmarks of cancer, ranging from genome instability to uncontrolled proliferation or invasion. Cancer cells are constantly challenged by mechanical stresses not only in the primary tumour but also during metastasis. However, this latter has seldom been studied with regards to mechanobiology, in particular resistance to anoikis, a cell death programme triggered by loss of cell adhesion. Here, we show in vitro that migrating breast cancer cells develop resistance to anoikis following their passage through microporous membranes mimicking confined migration (CM), a mechanical constriction that cancer cells encounter during metastasis. This CM-induced resistance was mediated by Inhibitory of Apoptosis Proteins, and sensitivity to anoikis could be restored after their inhibition using second mitochondria-derived activator of caspase (SMAC) mimetics. Anoikis-resistant mechanically stressed cancer cells displayed enhanced cell motility and evasion from natural killer cell-mediated immune surveillance, as well as a marked advantage to form lung metastatic lesions in mice. Our findings reveal that CM increases the metastatic potential of breast cancer cells.

Immersive 3D Educational Contents: A Technical Note for Dental Educators.

Three-dimensional files featuring patients' geometry can be obtained through common tools in dental practice, such as an intraoral scanner (IOS) or Cone Beam Computed Tomography (CBCT). The use of 3D files in medical education is promoted, but only few methodologies were reported due to the lack of ease to use and accessible protocols for educators. The aim of this work was to present innovative and accessible methodologies to create 3D files in dental education. The first step requires the definition of the educational outcomes and the situations of interest. The second step relies on the use of IOS and CBCT to digitize the content. The last "post-treatment" steps involve free software for analysis of quality, re-meshing and simplifying the file in accordance with the desired educational activity. Several examples of educational activities using 3D files are illustrated in dental education and discussed. Three-dimensional files open up many accessible applications for a dental educator, but further investigations are required to develop collaborative tools and prevent educational inequalities between establishments.

A Gender-Dependent Molecular Switch of Inflammation via MyD88/Estrogen Receptor-Alpha Interaction.

INTRODUCTION: Most Toll-like receptors and IL-1/IL-18 receptors activate a signaling cascade via the adaptor molecule MyD88, resulting in NF-κB activation and inflammatory cytokine and chemokine production. Females are less susceptible than males to inflammatory conditions, presumably due to protection by estrogen. The exact mechanism underlying this protection is unknown. METHODS: MCF7 cells expressing wild-type or mutated LXXLL motif were used to determine MyD88/estrogen receptor (ER)-a interaction by immunoprecipitation and cell activation by ELISA and luciferase reporter assay. IL-1b and/or E2 were used to activate MCF7 cells expressing normal or knocked down levels of PRMT1. Finally, in situ proximity ligation assay with anti-MyD88 and anti-methylated ER-a (methER-a) antibodies was used to evaluate MyD88/methylated ER-a interaction in THP1 cells and histological sections. RESULTS: We show that MyD88 interacts with a methylated, cytoplasmic form of estrogen receptor-alpha (methER-α). This interaction is required for NF-κB transcriptional activity and pro-inflammatory cytokine production, and is dissociated by estrogen. Importantly, we show a strong gender segregation in gametogenic reproductive organs, with MyD88/methER-α interactions found in testicular tissues and in ovarian tissues from menopausal women, but not in ovaries from women age 49 and less - suggesting a role for estrogen in disrupting this complex in situ. DISCUSSION: Collectively, our results indicate that the formation of MyD88/methER-α complexes during inflammatory signaling and their disruption by estrogen may represent a mechanism that contributes to gender bias in inflammatory responses.