Misregulation of DNA damage repair pathways in HPV-positive head and neck squamous cell carcinoma contributes to cellular radiosensitivity

Patients with human papillomavirus type 16 (HPV)-associated oropharyngealsquamous cell carcinomas (OPSCC) display increased sensitivity to radiotherapy andimproved survival rates in comparison to HPV-negative forms of the disease. Howeverthe cellular mechanisms responsible for this characteristic difference are unclear.Here, we have investigated the contribution of DNA damage repair pathways to thein vitro radiosensitivity of OPSCC cell lines. We demonstrate that two HPV-positiveOPSCC cells are indeed more radiosensitive than two HPV-negative OPSCC cells, whichcorrelates with reduced efficiency for the repair of ionising radiation (IR)-inducedDNA double strand breaks (DSB). Interestingly, we show that HPV-positive OPSCCcells consequently have upregulated levels of the proteins XRCC1, DNA polymerase β,PNKP and PARP-1 which are involved in base excision repair (BER) and single strandbreak (SSB) repair. This translates to an increased capacity and efficiency for therepair of DNA base damage and SSBs in these cells. In addition, we demonstratethat HPV-positive but interestingly more so HPV-negative OPSCC display increasedradiosensitivity in combination with the PARP inhibitor olaparib. This suggests thatPARP inhibition in combination with radiotherapy may be an effective treatmentfor both forms of OPSCC, particularly for HPV-negative OPSCC which is relativelyradioresistant

Modulation of outer bank erosion by slump blocks: Disentangling the protective and destructive role of failed material on the three-dimensional flow structure

The three-dimensional flow field near the banks of alluvial channels is the primary factor controlling rates of bank erosion. Although submerged slump blocks and associated large-scale bank roughness elements have both previously been proposed to divert flow away from the bank, direct observations of the interaction between eroded bank material and the 3-D flow field are lacking. Here we use observations from multibeam echo sounding, terrestrial laser scanning, and acoustic Doppler current profiling to quantify, for the first time, the influence of submerged slump blocks on the near-bank flow field. In contrast to previous research emphasizing their influence on flow diversion away from the bank, we show that slump blocks may also deflect flow onto the bank, thereby increasing local shear stresses and rates of erosion. We use our measurements to propose a conceptual model for how submerged slump blocks interact with the flow field to modulate bank erosion.UK Natural Environment Research Council (NERC

Seismotectonics and rupture process of the MW 7.1 2011 Van reverse-faulting earthquake, eastern Turkey, and implications for hazard in regions of distributed shortening

The 2011 October 23 MW 7.1 Van earthquake in eastern Turkey caused ~600 deaths and caused widespread damage and economic loss. The seismogenic rupture was restricted to 10-25 km in depth, but aseismic surface creep, coincident with outcrop fault exposures, was observed in the hours to months after the earthquake. We combine observations from radar interferometry, seismology, geomorphology and Quaternary dating to investigate the geological slip rate and seismotectonic context of the Van earthquake, and assess the implications for continuing seismic hazard in the region. Transient post-seismic slip on the upper Van fault started immediately following the earthquake, and decayed over a period of weeks; it may not fully account for our long-term surface slip-rate estimate of ≥ 0.5 mm yr-1. Post-seismic slip on the Bostaniçi splay fault initiated several days to weeks after the main shock, and we infer that it may have followed the MW 5.9 aftershock on the 9th November. The Van earthquake shows that updip segmentation can be important in arresting seismic ruptures on dip-slip faults. Two large, shallow aftershocks show that the upper 10 km of crust can sustain significant earthquakes, and significant slip is observed to have reached the surface in the late Quaternary, so there may be a continuing seismic hazard from the upper Van fault and the associated splay. The wavelength of folding in the hanging wall of the Van fault is dominated by the structure in the upper 10 km of the crust, masking the effect of deeper seismogenic structures. Thus, models of subsurface faulting based solely on surface folding and faulting in regions of reverse faulting may underestimate the full depth extent of seismogenic structures in the region. In measuring the cumulative post-seismic offsets to anthropogenic structures, we show that Structure-from-Motion can be rapidly deployed to create snapshots of postseismic displacement.We also demonstrate the utility of declassified Corona mission imagery (1960s-1970s) for geomorphic mapping in areas where recent urbanization has concealed the geomorphic markers

Healthier diet quality and dietary patterns are associated with lower risk of mobility limitation in older men

Purpose To investigate associations between diet quality, dietary patterns and mobility limitation 15 years later in a population-based sample of older British men. Methods We used longitudinal data from 1234 men from the British Regional Heart Study, mean age 66 years at baseline. Mobility limitation was defined as difficulty going up- or downstairs or walking 400 yards as a result of a long-term health problem. Dietary intake was measured using a food frequency questionnaire data from which the Healthy Diet Indicator (HDI), the Elderly Dietary Index (EDI), and three a posteriori dietary patterns were derived. The a posteriori dietary patterns were identified using principal components analysis: (1) high fat/low fibre, (2) prudent and (3) high sugar. Results Men with greater adherence to the EDI or HDI were less likely to have mobility limitation at follow-up, top vs bottom category odds ratio for the EDI OR 0.50, 95% CI 0.34, 0.75, and for the HDI OR 0.55, 95% CI 0.35, 0.85, after adjusting for age, social class, region of residence, smoking, alcohol consumption and energy intake. Men with a higher score for the high-fat/low-fibre pattern at baseline were more likely to have mobility limitation at follow-up, top vs bottom quartile odds ratio OR 3.28 95% CI 2.05, 5.24. These associations were little changed by adjusting for BMI and physical activity. Conclusion Our study provides evidence that healthier eating patterns could contribute to prevention or delay of mobility limitation in older British men

Early parental death and psychosocial risk factors for dementia: A case-control study in Europe

Objectives: To assess the association between early parental death and the risk of dementia in adult life, and to examine the risk factors associated with early parental death in people with and without dementia. Methods / Design: A population-based case-control study of a sample of 65,997 participants from the Survey of Health, Ageing and Retirement in Europe study. Early parental death was operationalized as parental death at the age of ≤ 16 years. Main analyses were conducted using bivariate and multivariate logistic regression analyses. Results: The odds ratio (OR) for dementia in individuals who experienced early parental death (father or mother) at the age of ≤ 16 years was 1.83 (95%CI 1.61-2.09) and 1.54 (95%CI 1.35-1.76) adjusted for age, gender, and education. In the multivariate logistic regression analysis carried out with the whole sample, early parental death increased the risk of dementia (OR = 1.50, 95%CI 1.31-1.72), along with older age (OR = 5.92, 95%CI 4.86-7.17), neuroticism (OR = 2.94,95%CI 2.61-3.31), low education level (OR = 1.84, 95%CI 1.64- 2.05) and low income (OR = 1.49, 95%CI 1.34-1.67). Discussion: Early parental death (< 16 years) was associated with an increased risk of dementia. We discuss the neurobiological markers associated with adverse childhood experiences (ACEs) and dementia as well as interventions to counteract the negative health effects on adults

Systematic review of treatment intensification using novel agents for chemoradiotherapy in rectal cancer

Background With the well established shift to neoadjuvant treatment for locally advanced rectal cancer, there is increasing focus on the use of radiosensitizers to improve the efficacy and tolerability of radiotherapy. There currently exist few randomized data exploring novel radiosensitizers to improve response and it is unclear what the clinical endpoints of such trials should be. Methods A qualitative systematic review was performed according to the PRISMA guidelines using preset search criteria across the PubMed, Cochrane and Scopus databases from 1990 to 2017. Additional results were generated from the reference lists of included papers. Results A total of 123 papers were identified, of which 37 were included; a further 60 articles were obtained from additional referencing to give a total of 97 articles. Neoadjuvant radiosensitization for locally advanced rectal cancer using fluoropyrimidine‐based chemotherapy remains the standard of treatment. The oral derivative capecitabine has practical advantages over 5‐fluorouracil, with equal efficacy, but the addition of a second chemotherapeutic agent has yet to show a consistent significant efficacy benefit in randomized clinical assessment. Preclinical and early‐phase trials are progressing with promising novel agents, such as small molecular inhibitors and nanoparticles. Conclusion Despite extensive research and promising preclinical studies, a definite further agent in addition to fluoropyrimidines that consistently improves response rate has yet to be found

Synthetizing Qualitative (Logical) Patterns for Pedestrian Simulation from Data

This work introduces a (qualitative) data-driven framework to extract patterns of pedestrian behaviour and synthesize Agent-Based Models. The idea consists in obtaining a rule-based model of pedestrian behaviour by means of automated methods from data mining. In order to extract qualitative rules from data, a mathematical theory called Formal Concept Analysis (FCA) is used. FCA also provides tools for implicational reasoning, which facilitates the design of qualitative simulations from both, observations and other models of pedestrian mobility. The robustness of the method on a general agent-based setting of movable agents within a grid is shown.Ministerio de Economía y Competitividad TIN2013-41086-

Survey of the quality of experimental design, statistical analysis and reporting of research using animals

For scientific, ethical and economic reasons, experiments involving animals should be appropriately designed, correctly analysed and transparently reported. This increases the scientific validity of the results, and maximises the knowledge gained from each experiment. A minimum amount of relevant information must be included in scientific publications to ensure that the methods and results of a study can be reviewed, analysed and repeated. Omitting essential information can raise scientific and ethical concerns. We report the findings of a systematic survey of reporting, experimental design and statistical analysis in published biomedical research using laboratory animals. Medline and EMBASE were searched for studies reporting research on live rats, mice and non-human primates carried out in UK and US publicly funded research establishments. Detailed information was collected from 271 publications, about the objective or hypothesis of the study, the number, sex, age and/or weight of animals used, and experimental and statistical methods. Only 59% of the studies stated the hypothesis or objective of the study and the number and characteristics of the animals used. Appropriate and efficient experimental design is a critical component of high-quality science. Most of the papers surveyed did not use randomisation (87%) or blinding (86%), to reduce bias in animal selection and outcome assessment. Only 70% of the publications that used statistical methods described their methods and presented the results with a measure of error or variability. This survey has identified a number of issues that need to be addressed in order to improve experimental design and reporting in publications describing research using animals. Scientific publication is a powerful and important source of information; the authors of scientific publications therefore have a responsibility to describe their methods and results comprehensively, accurately and transparently, and peer reviewers and journal editors share the responsibility to ensure that published studies fulfil these criteria

Fast fluorescence microscopy for imaging the dynamics of embryonic development

Live imaging has gained a pivotal role in developmental biology since it increasingly allows real-time observation of cell behavior in intact organisms. Microscopes that can capture the dynamics of ever-faster biological events, fluorescent markers optimal for in vivo imaging, and, finally, adapted reconstruction and analysis programs to complete data flow all contribute to this success. Focusing on temporal resolution, we discuss how fast imaging can be achieved with minimal prejudice to spatial resolution, photon count, or to reliably and automatically analyze images. In particular, we show how integrated approaches to imaging that combine bright fluorescent probes, fast microscopes, and custom post-processing techniques can address the kinetics of biological systems at multiple scales. Finally, we discuss remaining challenges and opportunities for further advances in this field