Potential sources of cessation support for high smoking prevalence groups: a qualitative study

Objective: This study aimed to: i) explore potential sources of cessation support as nominated by disadvantaged smokers; and ii) identify factors influencing decisions to use these sources. Methods: Semi-structured interviews were conducted with 84 smokers accessing community service organisations from the alcohol and other drugs, homeless, and mental health sectors. Transcripts were coded and thematically analysed. Results: Doctors emerged as the most commonly recognised source of cessation support, followed by Quitline, community service organisation staff; and online resources. The main factors contributing to the possible use of these sources of support were identified as awareness, perceived usefulness and anticipated emotional support. Conclusions: The results suggest that doctors are an important group to consider when developing cessation interventions for disadvantaged smokers due to their recognised ability to provide practical and emotional support. However, efforts are needed to ensure doctors are aware of the benefits of cessation for these groups. Community service organisations appear to be another potentially effective source of cessation support for disadvantaged smokers. Implications for public health The results indicate that cessation interventions among high-priority groups should endeavour to provide personalised emotional and practical support. Doctors and community service organisation staff appear to be well-placed to deliver this support

Simulation of heterogeneous tumour genomes with HeteroGenesis and in silico whole exome sequencing

Summary: Tumour evolution results in progressive cancer phenotypes such as metastatic spread and treatment resistance. To better treat cancers, we must characterize tumour evolution and the genetic events that confer progressive phenotypes. This is facilitated by high coverage genome or exome sequencing. However, the best approach by which, or indeed whether, these data can be used to accurately model and interpret underlying evolutionary dynamics is yet to be confirmed. Establishing this requires sequencing data from appropriately heterogeneous tumours in which the exact trajectory and combination of events occurring throughout its evolution are known. We therefore developed HeteroGenesis: a tool to generate realistically evolved tumour genomes, which can be sequenced using weighted-Wessim (w-Wessim), an in silico exome sequencing tool that we have adapted from previous methods. HeteroGenesis simulates more complex and realistic heterogeneous tumour genomes than existing methods, can model different evolutionary dynamics, and enables the creation of multi-region and longitudinal data

Benchmarking pipelines for subclonal deconvolution of bulk tumour sequencing data

Intratumour heterogeneity provides tumours with the ability to adapt and acquire treatment resistance. The development of more effective and personalised treatments for cancers, therefore, requires accurate characterisation of the clonal architecture of tumours, enabling evolutionary dynamics to be tracked. Many methods exist for achieving this from bulk tumour sequencing data, involving identifying mutations and performing subclonal deconvolution, but there is a lack of systematic benchmarking to inform researchers on which are most accurate, and how dataset characteristics impact performance. To address this, we use the most comprehensive tumour genome simulation tool available for such purposes to create 80 bulk tumour whole exome sequencing datasets of differing depths, tumour complexities, and purities, and use these to benchmark subclonal deconvolution pipelines. We conclude that i) tumour complexity does not impact accuracy, ii) increasing either purity or purity-corrected sequencing depth improves accuracy, and iii) the optimal pipeline consists of Mutect2, FACETS and PyClone-VI. We have made our benchmarking datasets publicly available for future use

A survey of UK optometry trainees' smoking cessation training

BACKGROUND: Smoking is a risk factor for a number of eye conditions, including age-related macular degeneration, cataracts and thyroid eye disease. Smoking cessation interventions have been shown to be highly cost-effective when delivered by a range of healthcare professionals. Optometrists are well placed to deliver smoking cessation advice to a wide population of otherwise healthy smokers. Yet optometrists remain a relatively neglected healthcare professional group in smoking cessation research and policy. Surveys of UK medical/nursing schools and of optometrists' training internationally demonstrate significant deficits in current curricular coverage regarding smoking cessation. This study aimed to identify the extent of smoking cessation training in UK optometry trainees' undergraduate and pre-registration training. METHODS: All undergraduate optometry schools in the UK (n = 9) were invited to participate in a web-based survey of their curricular coverage and assessment related to smoking cessation, and of perceived barriers to delivering smoking cessation training. A content analysis of the College of Optometrists Scheme for Registration Trainee Handbook 2014 was conducted to identify competence indicators related to smoking cessation. RESULTS: Nine undergraduate optometry schools (100%) responded to the survey. The majority reported dedicating limited hours (0-3) to teaching smoking cessation, and predominantly focused on teaching the harmful effects of smoking (89%). Only one school provides practical skills training for delivering evidence-based smoking cessation interventions, including very brief advice. The majority of schools (78%) reported that they did not formally examine students on their knowledge or skills for supporting smoking cessation, and rated confidence in their graduates' abilities to deliver smoking cessation interventions as 'poor' (78%). Lack of knowledge amongst staff was identified as the key barrier to teaching about smoking cessation support. The pre-registration competency framework does not include any competence indicators related to providing support for quitting smoking. CONCLUSIONS: There are substantial gaps in the current curricula of UK optometry training, particularly regarding practical skills for supporting smoking cessation. Increased curricular coverage of these issues is essential to ensure trainee optometrists are adequately trained and competent in supporting patients to quit smoking

Comparison of Tobacco Control Scenarios: Quantifying Estimates of Long-Term Health Impact Using the DYNAMO-HIA Modeling Tool

There are several types of tobacco control interventions/policies which can change future smoking exposure. The most basic intervention types are 1) smoking cessation interventions 2) preventing smoking initiation and 3) implementation of a nationwide policy affecting quitters and starters simultaneously. The possibility for dynamic quantification of such different interventions is key for comparing the timing and size of their effects

Elucidating drivers of oral epithelial dysplasia formation and malignant transformation to cancer using RNAseq

Oral squamous cell carcinoma (OSCC) is a prevalent cancer with poor prognosis. Most OSCC progresses via a non-malignant stage called dysplasia. Effective treatment of dysplasia prior to potential malignant transformation is an unmet clinical need. To identify markers of early disease, we performed RNA sequencing of 19 matched HPV negative patient trios: normal oral mucosa, dysplasia and associated OSCC. We performed differential gene expression, principal component and correlated gene network analysis using these data. We found differences in the immune cell signatures present at different disease stages and were able to distinguish early events in pathogenesis, such as upregulation of many HOX genes, from later events, such as down-regulation of adherens junctions. We herein highlight novel coding and non-coding candidates for involvement in oral dysplasia development and malignant transformation, and speculate on how our findings may guide further translational research into the treatment of oral dysplasia

RAD51 Is a Selective DNA Repair Target to Radiosensitize Glioma Stem Cells.

Patients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation. In GSCs, the small-molecule RAD51 inhibitors RI-1 and B02 prevent RAD51 focus formation, reduce DNA DSB repair, and cause significant radiosensitization. We further demonstrate that treatment with these agents combined with radiation promotes loss of stem cells defined by SOX2 expression. This indicates that RAD51-dependent repair represents an effective and specific target in GSCs

Identification of candidate mediators of chemoresponse in breast cancer through therapy-driven selection of somatic variants

Purpose: More than a third of primary breast cancer patients are treated with cytotoxic chemotherapy, typically without guidance from predictive markers. Increased use of neoadjuvant chemotherapy provides opportunities for identification of molecules associated with treatment response, by comparing matched tumour samples before and after therapy. Our hypothesis was that somatic variants of increased prevalence after therapy promote resistance, while variants with reduced prevalence cause sensitivity. Methods: We performed systematic analyses of matched pairs of cancer exomes from primary oestrogen receptor-positive/HER2-negative breast cancers (n = 6) treated with neoadjuvant epirubicin/cyclophosphamide. We identified candidate genes as mediators of chemotherapy response by consistent subclonal changes in somatic variant prevalence through therapy, predicted variant impact on gene function, and enrichment of specific functional pathways. Influence of candidate genes on breast cancer outcome was tested using publicly available breast cancer expression data (n = 1903). Results: We identified 14 genes as the strongest candidate mediators of chemoresponse: TCHH, MUC17, ARAP2, FLG2, ABL1, CENPF, COL6A3, DMBT1, ITGA7, PLXNA1, S100PBP, SYNE1, ZFHX4, and CACNA1C. Genes contained somatic variants showing prevalence changes in up to 4 patients, with up to 3 being predicted as damaging. Genes coding for extra-cellular matrix components or related signalling pathways were significantly over-represented among variants showing prevalence changes. Expression of 5 genes (TCHH, ABL1, CENPF, S100PBP, and ZFHX4) was significantly associated with patient survival. Conclusions: Genomic analysis of paired pre- and post-therapy samples resulting from neoadjuvant therapy provides a powerful method for identification of mediators of response. Genes we identified should be assessed as predictive markers or targets in chemo-sensitization