Investigating intratumour heterogeneity analysis methods and their application in GBM

Glioblastoma (GBM) is an incurable cancer with a median survival of 15 months. Despite debulking surgery, cancer cells are inevitably left behind in the surrounding brain, with a minority able to resist subsequent chemoradiotherapy and eventually form a recurrent tumour. This resistance is likely influenced by the cells’ genotypes, which show high variability (intratumour heterogeneity), as a result of tumour evolution. Characterising changes in the genetic architecture of tumours through therapy, may allow us to understand the effect that different mutations and pathways have on cell survival, and potentially identify novel targets for counteracting resistance in GBM. Such analyses involve detection of mutations from bulk tumour samples, and then delineating them into individual genetically distinct ‘subclones’, through subclonal deconvolution. This is a complex process, with no reliable guidelines for the best pipelines to use. I therefore developed methods to allow simulation and in silico sequencing of genomes from realistically complex, artificial tumour samples, so that I could benchmark such pipelines. This revealed that no tested pipelines, using single bulk samples, showed a high level of accuracy, though mutation calling with Mutect2 and FACETS, followed by subclonal deconvolution with Ccube, showed the best results. I then used alternative approaches with the largest longitudinal GBM dataset investigated to date. I found that evidence of strong subclonal selection is absent in many samples, and not associated with therapy. Nonetheless, this does not negate the possibility of smaller, or less frequent, pockets of altered fitness. Using pathway analysis combined with variants that are informative of tumour progression, I identified processes that may confer increased resistance, or sensitisation to therapy, and which warrant further investigation. Lastly, I apply subclonal deconvolution to investigate mouse-specific evolution in GBM patient-derived orthotopic xenografts and found no clear evidence to suggest these models are unsuitable for investigations relevant to humans

The mindful path to compassion in an adult mental health group

A naturalistic study was undertaken within an NHS setting to explore the effectiveness and satisfaction with a Mindfulness-Based Cognitive Therapy and Mindful Self-Compassion group programme in an adult mental health population. Outcome measures and qualitative feedback suggested beneficial effects and high levels of satisfaction

Observation-based modeling of ozone chemistry in the Seoul metropolitan area during the Korea-United States Air Quality Study (KORUS-AQ)

The Seoul Metropolitan Area (SMA) has a population of 24 million and frequently experiences unhealthy levels of ozone (O3). In this work, measurements taken during the Korea-United States Air Quality Study (KORUS-AQ, 2016) are used to explore regional gradients in O3 and its chemical precursors, and an observationally-constrained 0-D photochemical box model is used to quantify key aspects of O3 production including its sensitivity to precursor gases. Box model performance was evaluated by comparing modeled concentrations of select secondary species to airborne measurements. These comparisons indicate that the steady state assumption used in 0-D box models cannot describe select intermediate species, highlighting the importance of having a broad suite of trace gases as model constraints. When fully constrained, aggregated statistics of modeled O3 production rates agreed with observed changes in O3, indicating that the box model was able to represent the majority of O3 chemistry. Comparison of airborne observations between urban Seoul and a downwind receptor site reveal a positive gradient in O3 coinciding with a negative gradient in NOx, no gradient in CH2O, and a slight positive gradient in modeled rates of O3 production. Together, these observations indicate a radical-limited (VOC-limited) O3 production environment in the SMA. Zero-out simulations identified C7+ aromatics as the dominant VOC contributors to O3 production, with isoprene and anthropogenic alkenes making smaller but appreciable contributions. Simulations of model sensitivity to decreases in NOx produced results that were not spatially uniform, with large increases in O3 production predicted for urban Seoul and decreases in O3 production predicted for far-outlying areas. The policy implications of this work are clear: Effective O3 mitigation strategies in the SMA must focus on reducing local emissions of C7+ aromatics, while reductions in NOx emissions may increase O3 in some areas but generally decrease the regional extent of O3 exposure

Sources and characteristics of summertime organic aerosol in the Colorado Front Range: perspective from measurements and WRF-Chem modeling

Abstract. The evolution of organic aerosols (OAs) and their precursors in the boundary layer (BL) of the Colorado Front Range during the Front Range Air Pollution and Photochemistry Éxperiment (FRAPPÉ, July–August 2014) was analyzed by in situ measurements and chemical transport modeling. Measurements indicated significant production of secondary OA (SOA), with enhancement ratio of OA with respect to carbon monoxide (CO) reaching 0.085±0.003 µg m−3 ppbv−1. At background mixing ratios of CO, up to  ∼  1.8 µg m−3 background OA was observed, suggesting significant non-combustion contribution to OA in the Front Range. The mean concentration of OA in plumes with a high influence of oil and natural gas (O&G) emissions was  ∼  40 % higher than in urban-influenced plumes. Positive matrix factorization (PMF) confirmed a dominant contribution of secondary, oxygenated OA (OOA) in the boundary layer instead of fresh, hydrocarbon-like OA (HOA). Combinations of primary OA (POA) volatility assumptions, aging of semi-volatile species, and different emission estimates from the O&G sector were used in the Weather Research and Forecasting model coupled with Chemistry (WRF-Chem) simulation scenarios. The assumption of semi-volatile POA resulted in greater than a factor of 10 lower POA concentrations compared to PMF-resolved HOA. Including top-down modified O&G emissions resulted in substantially better agreements in modeled ethane, toluene, hydroxyl radical, and ozone compared to measurements in the high-O&G-influenced plumes. By including emissions from the O&G sector using the top-down approach, it was estimated that the O&G sector contributed to  <  5 % of total OA, but up to 38 % of anthropogenic SOA (aSOA) in the region. The best agreement between the measured and simulated median OA was achieved by limiting the extent of biogenic hydrocarbon aging and consequently biogenic SOA (bSOA) production. Despite a lower production of bSOA in this scenario, contribution of bSOA to total SOA remained high at 40–54 %. Future studies aiming at a better emissions characterization of POA and intermediate-volatility organic compounds (IVOCs) from the O&G sector are valuable

ENACT study : what has helped health and social care workers maintain their mental wellbeing during the COVID-19 pandemic?

A growing body of research has highlighted the adverse impact of COVID-19 stressors on health and social care workers’ (HSCWs) mental health. Complementing this work, we report on the psychosocial factors that have had both a positive and negative impact on the mental wellbeing of HSCWs during the third lockdown period in Scotland. Using a cross-sectional design, participants (n= 1364) completed an online survey providing quantitative data and free open-text responses. A multi-method approach to analysis was used. The majority of HSCWs were found to have low wellbeing scores, high levels of COVID-19 stress, worry, burnout and risk perception scores and almost half of HSCWs met the clinical cut off for acute stress (indicative of PTSD). HSCWs with higher scores on adaptive coping strategies and team resilience reported higher scores on mental wellbeing. HSCWs were significantly more likely to seek informal support for dealing with personal or emotional problems compared to formal supports. Barriers to formal help-seeking were identified including stigma and fear of the consequences of disclosure. HSCWs mostly valued peer support, workplace supports, visible leadership and teamwork in maintaining their mental wellbeing. Our findings illuminate the complexity of the effects of the COVID-19 pandemic on HSCWs’ wellbeing and will inform future intervention development seeking to increase positive adaptation and improve staff wellbeing. Addressing barriers to mental health help-seeking among HSCWs is essential. The implications emphasise the importance of lessons learned across health and social care contexts, planning and preparedness for future pandemics

The Stature of Boys Is Inversely Correlated to the Levels of Their Sertoli Cell Hormones: Do the Testes Restrain the Maturation of Boys?

The testes of preadolescent boys appear to be dormant, as they produce only trace levels of testosterone [1]. However, they release supra-adult levels of Müllerian Inhibiting Substance (MIS, anti-Müllerian hormone) and lesser levels of inhibin B (InhB), for unknown reasons [2], [3]. Boys have a variable rate of maturation, which on average is slower than girls. The height of children relative to their parents is an index of their maturity [4], [5]. We report here that a boy's level of MIS and InhB is stable over time and negatively correlates with his height and his height relative to his parent's height. This suggests that boy's with high levels of MIS and InhB are short because they are immature, rather than because they are destined to be short men. The levels of MIS and InhB in the boys did not correlate with known hormonal modulators of growth, and were additive with age and the growth hormone/IGF1 axis as predictors of a boy's height. If MIS and InhB were causal regulators of maturity, then the inter-boy differences in the levels of these hormone produces variation in maturation equivalent to 18-months of development. MIS and InhB may thus account for most of the variation in the rate of male development. If boys lacked these hormones, then an average 5-year-old boy would be over 5 cm taller than age-matched girls, making boys almost as dimorphic as men, for height. This indicates that boys have a high growth potential that is initially suppressed by their testes. The concept of the childhood testes suppressing an adult male feature appears paradoxical. However, the growth of children requires intergenerational transfer of nutrients. Consequently, the MIS/InhB slowing of male growth may have been historically advantageous, as it would minimizes any sex bias in the maternal cost of early child rearing