Claire Marie Healy

Non-tuberculous mycobacterial (NTM) lung disease is now recognized as a chronic condition with considerable morbidity and mortality with incidence rising globally. This is concerning as these infections are often mis- or undiagnosed and currently available treatment regimens have lengthy (>1 year) treatment courses with variable to poor success rates. Identification of vulnerable targets and pathways in NTM pathogens is urgently needed to develop improved therapeutics. Itaconic acid (ITA), a macrophage-produced metabolite with immunomodulatory and antibacterial activity, inhibits growth of mycobacteria and here, we provide further important insights into the activity and mechanism of action for ITA. ITA displayed robust bactericidal activity against the prominent NTM pathogens Mycobacterium avium ( M. avium ) and M. abscessus in a pH- and fatty acid-dependent manner, conditions that these bacteria experience within phagosomes during infection. Using a genetically encoded intrabacterial pH reporter, we demonstrate that ITA induces intracellular acidification in a pH-dependent manner. This work reveals that disruption of NTM pH homeostasis is a vulnerability in these difficult-to-treat pathogens which could be exploited for therapeutic benefit.

Background: Tobacco, alcohol, and human papillomavirus (HPV) are major risk factors for oral cavity and oropharyngeal cancers, yet their specific contributions to the tumor molecular landscape remain incompletely understood. Methods: We analyzed somatic alterations in 1086 tumors (606 oral cavity cancers and 480 oropharyngeal cancers, including 287 HPV-positive oropharyngeal cancers) profiled with a 1109-gene panel and evaluated their associations with exposures. Results: PIK3CA alterations were widespread but context specific: HPV-positive oropharyngeal cancers featured APOBEC-driven mutations and co-occurrence of FGFR3 mutations in a subset of cases, while HPV-negative oropharyngeal cancers and oral cavity cancers were marked by 3q26/28 (PIK3CA/TP63/SOX2) amplifications. TP53 was the most frequently mutated gene in HPV-negative tumors, with strong enrichment among smokers in HPV-negative oropharyngeal cancers, whereas TP53 mutation frequencies in oral cavity cancers were consistently high, regardless of smoking status. CCND1 amplifications were largely restricted to HPV-negative tumors and were most frequent in individuals reporting combined tobacco and alcohol use. This combined effect was replicated in The Cancer Genome Atlas oral cavity cancer–oropharyngeal cancer cohort and mirrored at the transcriptomic level, where CCND1 messenger RNA expression was highest in dual tobacco-alcohol users. Within oral cavity cancers, characterization of 1 of the largest cohorts of tumors from never smoker–never drinkers to date (n = 100) showed that patients were more likely to be female and to exhibit enrichment for FAT1 and CASP8 mutations compared with tumors from ever smoker–ever drinkers (n = 353). Conclusions: Together, these findings define distinct, exposure-driven patterns of somatic alterations by subsite and HPV status and provide a molecular framework that may inform etiological-based risk stratification in head and neck cancer.

Nontuberculous mycobacterial infections are associated with persistent inflammation and prolonged treatment, yet host-directed therapeutic strategies remain lacking. Using metabolic flux analysis, we show dexamethasone suppressed Mycobacterium avium-induced glycolysis in human monocyte-derived macrophages. Furthermore, dexamethasone reduced metabolic enzyme expression and proinflammatory cytokines, without affecting bacterial control in human macrophages. These findings indicate that suppression of glycolytic metabolism can occur without impacting bacterial control in human macrophages and supports further investigation of dexamethasone as a potential host-directed strategy to limit inflammation while preserving host defense in nontuberculous mycobacterial disease.

Background: Cholesterol pathways may influence head and neck squamous cell carcinoma (HNSCC) progression, but evidence on prognosis is inconsistent. We used Mendelian randomization (MR) to test whether genetically proxied inhibition of major LDL-C–lowering drug targets and circulating lipid traits affects overall survival (OS) in HPV-positive and non-HPV driven HNSCC. Methods: We proxied lifelong LDL-C lowering using 55 cis-acting SNPs in HMGCR, NPC1L1, PCSK9, and LDLR from the updated 2021 Global Lipids Genetics Consortium, and instrumented circulating lipid traits. Two-sample MR estimated effects on OS in 4,869 multi-centre HNSCC cases (1,291 HPV-positive; 3,578 non-HPV driven) using minimally adjusted Cox models. Sensitivity analyses additionally adjusted for tumour stage and treatment, assessed collider bias using an external HNSCC incidence GWAS, and examined between-centre heterogeneity and colocalization. Results: Using the updated GLGC 2021 instruments, genetically proxied HMGCR inhibition showed a directionally protective but non-significant association with OS in HPV-positive oropharyngeal HNSCC in the primary analysis (IVW HR=0.19, 95% CI 0.03–1.18; P=0.08), with directionally concordant weighted median results. No corresponding protective association was observed for HMGCR in non-HPV-driven disease (IVW HR=1.68, 95% CI 0.78–3.63; P=0.19). No clear evidence of association was observed for NPC1L1, PCSK9, LDLR, or circulating lipid traits in either HPV stratum. Colocalization did not support a shared causal variant. Conclusions: These analyses provide suggestive evidence that genetically proxied HMGCR inhibition may influence survival in HPV-positive oropharyngeal HNSCC. Impact: HMGCR-related pathways may be relevant to prognosis in HPV-positive oropharyngeal HNSCC, whereas clear survival effects of other cholesterol-lowering targets were not supported.

Mycobacterium tuberculosis withstands acidic conditions to survive and replicate within macrophages. To define the genetic determinants of this adaptation, we performed a transposon screen in a lipid-rich, acidic medium that mimics the host environment and supports robust M. tuberculosis growth. This screen identified ldtB , encoding an L,D-transpeptidase, as essential for growth and survival under acid stress. Loss of LdtB decreased 3–3 peptidoglycan cross-linking, disrupted cell wall architecture, and impaired intrabacterial pH homeostasis, resulting in increased susceptibility to cell wall–active antibiotics. Notably, M. tuberculosis lacking LdtB displayed heightened sensitivity to meropenem within macrophages, suggesting that targeting this enzyme could potentiate β-lactam efficacy during infection. These findings establish LdtB as a key mediator linking peptidoglycan homeostasis to acid stress resistance and underscores the importance of in vitro culture models that recapitulate the host microenvironment for uncovering new in vivo active therapeutic targets. Teaser: Disabling a key peptidoglycan cross-linking enzyme compromises M. tuberculosis survival under acidic stress and antibiotic exposure.

Head and neck squamous cell carcinoma (HNSCC) includes diverse cancers arising in the oral cavity, oropharynx, and larynx, with the main risk factors being environmental exposures such as tobacco, alcohol, and human papillomavirus (HPV) infection. The genetic factors contributing to susceptibility across different populations and tumour subsites remain incompletely understood. Here we show, through a genome-wide association and fine mapping study of over 19,000 HNSCC cases and 38,000 controls from multiple ancestries, 18 genetic risk variants and 11 signals from fine mapping of the human leukocyte antigen (HLA) region, all previously unreported. rs78378222, a regulatory variant for TP53 is associated with a 40% reduction in overall HNSCC risk. We also identify gene-environment interactions, with BRCA2 and ADH1B variants showing effects modified by smoking and alcohol use. Subsite-specific analysis of the HLA region reveals distinct immune-related associations across HPV-positive and HPV-negative tumours. These findings refine the genetic architecture of HNSCC and highlight mechanisms linking inherited variation, immunity, and environmental exposures.

Amyloidosis is a complex disease which rarely affects the oral cavity. While localized and systemic variants have a similar clinical presentation, these entities differ vastly in their natural history and prognosis. There is a need for practitioners to be aware of the diverse presentation of this disease and the need for further workup. We present two cases of localised oral amyloidosis, outline their investigation and management and review the related literature.

Objective: This study aimed to determine if the oral potentially malignant disorder, oral leukoplakia (OLK), exhibited microbiome changes that predict the degree of dysplasia and the risk of malignant progression. Results: We examined the microbiome in 216 swabs of OLK from 177 patients. Compared to healthy controls ( n = 120 swabs from 61 patients), who were less likely to smoke and had better oral health, OLK patients exhibited an increased abundance of Rothia mucilaginosa , Streptococcus parasanguinis and S. salivarius , resembling acetaldehyde generating communities described previously. Compared to the patients' healthy contralateral normal (CLN) mucosa ( n = 202), which acts as a matched control for oral health parameters, OLK exhibited increased S. infantis , Leptotrichia spp., Bergeyella spp., Porphyromonas spp. and F. nucleatum . Machine learning with clinical and microbiome data could discriminate high‐risk dysplasia (moderate to severe) from low‐risk dysplasia (none or mild) (sensitivity 87.4%; specificity 76.5%). Follow‐up swabs were recovered from 58 patients, eight of whom progressed to a higher grade of dysplasia or OSCC and these eight patients exhibited a higher abundance of Fusobacterium species at their initial presentation. Conclusions: Our study suggests that the OLK microbiome has potential to be an aid to the prediction of dysplasia grade and the risk of malignant transformation.

Syphilis is an infectious disease which can present with multitudinous mucocutaneous manifestations. Often referred to as the ‘great mimicker', syphilis can present with non-specific symptoms and has a tropism for various organ systems. The oral cavity has been identified as a site commonly affected in the early stages of syphilis infection. Identification of the diverse presentations seen across the different stages of syphilis infection can assist in early diagnosis and treatment for this cohort of patients. Despite accurate diagnostic tools and the susceptibility of the infection to standard antimicrobial therapy, syphilis infections continue to rise worldwide.We present the clinical features and management of six cases of oral syphilis who presented to our unit. One case presented in 2008, but the other five cases presented between 2016 and 2023, reflecting the increasing incidence of syphilis infection. Five cases presented in the secondary stage of the infection while one presented with a primary infection in the form of a single chancre.The documented cases demonstrate the non-specific and variable clinical features of oral syphilis and highlight the importance of awareness in the dental profession of these manifestations. Dentists have an important role to play in recognising the disease and arranging appropriate testing for early intervention. This will not only reduce the incidence of the devastating consequences of tertiary infections but will also result in reduced spread of the disease.

Background: Head and neck cancer (HNC) incidence is on the rise, often diagnosed at late stage and associated with poor prognoses. Risk prediction tools have a potential role in prevention and early detection. Methods: The IARC‐ARCAGE European case–control study was used as the model development dataset. A clinical HNC risk prediction model using behavioral and demographic predictors was developed via multivariable logistic regression analyses. The model was then externally validated in the UK Biobank cohort. Model performance was tested using discrimination and calibration metrics. Results: 1926 HNC cases and 2043 controls were used for the development of the model. The development dataset model including sociodemographic, smoking, and alcohol variables had moderate discrimination, with an area under curve (AUC) value of 0.75 (95% CI, 0.74–0.77); the calibration slope (0.75) and tests were suggestive of good calibration. 384 616 UK Biobank participants (with 1177 HNC cases) were available for external validation of the model. Upon external validation, the model had an AUC of 0.62 (95% CI, 0.61–0.64). Conclusion: We developed and externally validated a HNC risk prediction model using the ARCAGE and UK Biobank studies, respectively. This model had moderate performance in the development population and acceptable performance in the validation dataset. Demographics and risk behaviors are strong predictors of HNC, and this model may be a helpful tool in primary dental care settings to promote prevention and determine recall intervals for dental examination. Future addition of HPV serology or genetic factors could further enhance individual risk prediction.