IL-1/IL-1R Signaling in head and neck cancer

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

Malignant odontogenic tumours : a systematic review of cases reported in literature

Background: Malignant odontogenic tumours (MOTs) arise either de novo from the tooth forming tissues, their developmental residues or from existing odontogenic epithelial or mesenchymal neoplasms in the jaws. Their management requires extensive surgery due to their infiltrative nature and risk of metastasis. There is a need to understand the clinical and pathological features of MOTs to inform both treatment algorithms and prognostication. This is an area of diagnostic pathology which presents substantial difficulties in diagnosis, compounded by inconsistent use of terminology. Thus, this systematic review aimed to describe the clinical and pathological features of MOTs with a view to consolidating the literature and defining problematic areas in diagnosis and classification. Methods: An electronic database search was conducted in Web of Science, PubMed/Medline, and Embase. Additionally, the grey literature and reference lists of selected papers searched for completeness. Nine hundred and sixty articles were initially identified. Following removal of duplicates and application of inclusion/exclusion criteria, 312 articles were included for qualitative analysis. Results: The 312 articles encompassed a total of 507 patients with most lesions located within the mandible (74.3%). The most common first histological diagnosis was ameloblastic carcinoma (25.7% of all diagnoses), but there is considerable variation in how and when various diagnostic terms are used, and several misdiagnoses were reported. An initial benign diagnosis was made in 24.7% of patients, followed by a later malignant diagnosis and in this sub-group, the most common benign first diagnosis was ameloblastoma (42.4%). Cervical lymph nodes were the most common site of metastasis (9.3% of patients). With respect to distant metastasis (DM), the lungs were the most common organ affected (11.2% of DM patients) with metastasising ameloblastoma the most commonly reported tumour which metastasised to the lungs. Overall, 26.8% of patients developed recurrence. Conclusion: Overall, the quality of the literature on MOTs is poor. This review of the literature has highlighted variations in diagnostic terms and criteria which has resulted in areas of confusion with potential for misdiagnosis. This consolidation of primary data has identified key areas for targeted research including further discussion on the malignant potential of ameloblastoma

Effect of Learning to Use a Mobility Aid on Gait and Cognitive Demands in People with Mild to Moderate Alzheimer\u27s Disease: Part I - Cane

BACKGROUND: People with Alzheimer\u27s disease (AD) exhibit balance and walking impairments that increase falls risk. Prescription of a mobility aid is done to improve stability, yet also requires increased cognitive resources. Single-point canes require unique motor sequencing for safe use. The effect of learning to use a single-point cane has not been evaluated in people with AD. OBJECTIVES: In people with AD and healthy adult controls: 1) examine changes in gait while using a cane under various walking conditions; and 2) determine the cognitive and gait costs associated with concurrent cane walking while multi-tasking. METHODS: Seventeen participants with AD (age 82.1±5.6 years) and 25 healthy controls (age 70.8±14.1 years) walked using a single-point cane in a straight (6 meter) and a complex (Figure of 8) path under three conditions: single-task (no aid), dual-task (walking with aid), and multi-task (walking with aid while counting backwards by ones). Velocity and stride time variability were recorded with accelerometers. RESULTS: Gait velocity significantly slowed for both groups in all conditions and stride time variability was greater in the AD group. Overall, multi-tasking produced a decrease in gait and cognitive demands for both groups, with more people with AD self-prioritizing the cognitive task over the gait task. CONCLUSION: Learning to use a cane demands cognitive resources that lead to detrimental changes in velocity and stride time variability. This was most pronounced in people with mild to moderate AD. Future research needs to investigate the effects of mobility aid training on gait performance

Effect of Learning to Use a Mobility Aid on Gait and Cognitive Demands in People with Mild to Moderate Alzheimer\u27s Disease: Part II - 4-Wheeled Walker.

BACKGROUND: Cognitive deficits and gait problems are common and progressive in Alzheimer\u27s disease (AD). Prescription of a 4-wheeled walker is a common intervention to improve stability and independence, yet can be associated with an increased falls risk. OBJECTIVES: 1) To examine changes in spatial-temporal gait parameters while using a 4-wheeled walker under different walking conditions, and 2) to determine the cognitive and gait task costs of walking with the aid in adults with AD and healthy older adults. METHODS: Twenty participants with AD (age 79.1±7.1 years) and 22 controls (age 68.5±10.7 years) walked using a 4-wheeled walker in a straight (6 m) and Figure of 8 path under three task conditions: single-task (no aid), dual-task (walking with aid), and multi-task (walking with aid while counting backwards by ones). RESULTS: Gait velocity was statistically slower in adults with AD than the controls across all conditions (all p values CONCLUSION: Learning to use a 4-wheeled walker is cognitively demanding and any additional tasks increases the demands, further adversely affecting gait. The increased cognitive demands result in a decrease in gait velocity that is greatest in adults with AD. Future research needs to investigate the effects of mobility aid training on gait performance

The experiences of people with Alzheimer’s dementia and their caregivers in acquiring and using a mobility aid_ a qualitative study

Purpose: Cognitive deficits and gait and balance problems are progressive in people with Alzheimer’s dementia. Yet, mobility aids are associated with an increased falls risk in people with dementia. Our objectives were to identify the perceptions of people living with mild-to-moderate Alzheimer’s dementia, and their caregivers, on the use of mobility aids. Methods: A qualitative study using semi-structured, face-to-face interviews was conducted. Community-dwelling older adults with dementia attending a day hospital program were recruited. Thematic analysis was conducted and the text was coded into broad themes aligned with the research questions. The coded text was examined for patterns and similarities, and grouped to form inductive themes. Results: Twenty-four people (12 living with dementia and their 12 caregivers) participated. Five themes were identified: (1) acknowledgement of need; (2) protecting a sense of self; (3) caregiver oversight and relief of burden; (4) healthcare professional involvement; (5) environment and design of aids. Conclusions: The findings suggest that people with Alzheimer’s dementia and their caregivers regard mobility aid use as increasing independence. There is a role for healthcare professionals to be involved in the prescription, provision and training for use of mobility aids among people living with dementia to ensure uptake and safety.IMPLICATIONS FOR REHABILITATION Mobility aid use is regarded as increasing independence by people with Alzheimer’s disease and their caregivers. Falls risk associated with mobility aid use was not well known and caregivers perceived mobility aids as a means to reduce falls. Most people do not see a healthcare professional when they acquire a mobility aid and there is a role for healthcare professionals to be involved in the prescription, provision and training of people living with dementia in the use of mobility aids in order to increase the uptake of aids and their safe use

Data Set for the Reporting of Malignant Odontogenic Tumors Explanations and Recommendations of the Guidelines From the International Collaboration on Cancer Reporting

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Does clinical management improve outcomes following self-Harm? Results from the multicentre study of self-harm in England

Background Evidence to guide clinical management of self-harm is sparse, trials have recruited selected samples, and psychological treatments that are suggested in guidelines may not be available in routine practice. Aims To examine how the management that patients receive in hospital relates to subsequent outcome. Methods We identified episodes of self-harm presenting to three UK centres (Derby, Manchester, Oxford) over a 10 year period (2000 to 2009). We used established data collection systems to investigate the relationship between four aspects of management (psychosocial assessment, medical admission, psychiatric admission, referral for specialist mental health follow up) and repetition of self-harm within 12 months, adjusted for differences in baseline demographic and clinical characteristics. Results 35,938 individuals presented with self-harm during the study period. In two of the three centres, receiving a psychosocial assessment was associated with a 40% lower risk of repetition, Hazard Ratios (95% CIs): Centre A 0.99 (0.90–1.09); Centre B 0.59 (0.48–0.74); Centre C 0.59 (0.52–0.68). There was little indication that the apparent protective effects were mediated through referral and follow up arrangements. The association between psychosocial assessment and a reduced risk of repetition appeared to be least evident in those from the most deprived areas. Conclusion These findings add to the growing body of evidence that thorough assessment is central to the management of self-harm, but further work is needed to elucidate the possible mechanisms and explore the effects in different clinical subgroups

Exploring the regulatory interactions between mutated genes and homeobox genes in the head and neck cancer progression.

ObjectiveUnderstanding 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.MethodsGenomic 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.ResultsSignificant 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.ConclusionThe 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

Senataxin modulates resistance to cisplatin through an R-loop mediated mechanism in HPV-associated Head and Neck Squamous Cell Carcinoma

AbstractIntroductionOropharyngeal Squamous Cell Carcinoma (OPSCC) is a site defined subtype of head and neck cancer with two distinct clinical subtypes: HPV-associated (HPV+) and HPV-independent (HPV-); both of which are commonly treated with chemoradiotherapy involving cisplatin. Cisplatin creates DNA crosslinks, which lead to eventual cell death via apoptosis. Clinical outcomes in HPV-OPSCC are poor and although HPV+ has an improved response to therapy, a subset of patients suffer from distant metastases, with a poor prognosis. Therefore, there is a need to understand the molecular basis underlying treatment resistance. A common mechanism of chemotherapy resistance is upregulation of DNA repair, and a major source of endogenous DNA damage are DNA/RNA hybrids, known as R-loops. R-loops are three stranded DNA/RNA hybrids formed in the genome as a by- product of transcription and are normally transient; however, they can persist and become a source of genomic instability. The contribution of R-loops to the development of cisplatin resistance in OPSCC is unknown.MethodsHPV+ and HPV- cisplatin resistant cell lines were developed, and RNA-sequencing was used to investigate changes in gene expression. Changes in R-loop dynamics were explored using slot blots and DRIP-qPCR. The effect of depleting known R-loop regulators on cisplatin sensitivity was assessed using siRNA. R-loop burden in a cohort of HPV+ and HPV- OPSCC tumours was explored using S9.6 immunohistochemistry.ResultsDevelopment of cisplatin resistant clones led to changes in gene expression consistent with resistance, alongside alterations in the expression of known R-loop regulators. Both HPV+ and HPV- resistant cells had elevated global R-loop levels and in HPV+ resistant cells there was a corresponding upregulation of the R-loop resolving protein, senataxin, which was not observed in HPV- resistant cells. Depletion of senataxin led to increased sensitivity to cisplatin in both HPV+ and HPV- resistant cells, however, the effect was greater in HPV+ cells. Quantification of R-loop levels by S9.6 immunohistochemistry revealed that HPV+ tumours and tumours with bone metastases had a higher R-loop burden.ConclusionR-loops are involved in modulating sensitivity to cisplatin and may represent a potential therapeutic target.</jats:sec