The interaction between cytosine methylation and processes of DNA replication and repair shape the mutational landscape of cancer genomes

© The Author(s) 2017. Methylated cytosines (5mCs) are frequently mutated in the genome. However, no studies have yet comprehensively analysed mutation-methylation associations across cancer types. Here we analyse 916 cancer genomes, together with tissue type-specific methylation and replication timing data. We describe a strong mutation-methylation association across colorectal cancer subtypes, most interestingly in samples with microsatellite instability (MSI) or Polymerase epsilon (POLE) exonuclease domain mutations. By analysing genomic regions with differential mismatch repair (MMR) efficiency, we suggest a possible role for MMR in the correction of 5mC deamination events, potentially accounting for the high rate of 5mC mutation accumulation in MSI tumours. Additionally, we propose that mutant POLE asserts a mutator phenotype specifically at 5mCs, and we find coding mutation hotspots in POLE-mutant cancers at highly-methylated CpGs in the tumour-suppressor genes APC and TP53. Finally, using multivariable regression models, we demonstrate that different cancers exhibit distinct mutation-methylation associations, with DNA repair influencing such associations in certain cancer genomes. Taken together, we find differential associations with methylation that are vital for accurately predicting expected mutation loads across cancer types. Our findings reveal links between methylation and common mutation and repair processes, with these mechanisms defining a key part of the mutational landscape of cancer genomes.Link_to_subscribed_fulltex

Ethical hurdles in the prioritization of oncology care

With finite resources, healthcare payers must make difficult choices regarding spending and the ethical distribution of funds. Here, we describe some of the ethical issues surrounding inequity in healthcare in nine major European countries, using cancer care as an example. To identify relevant studies, we conducted a systematic literature search. The results of the literature review suggest that although prevention, access to early diagnosis, and radiotherapy are key factors associated with good outcomes in oncology, public and political attention often focusses on the availability of pharmacological treatments. In some countries this focus may divert funding towards cancer drugs, for example through specific cancer drugs funds, leading to reduced expenditure on other areas of cancer care, including prevention, and potentially on other diseases. In addition, as highly effective, expensive agents are developed, the use of value-based approaches may lead to unacceptable impacts on health budgets, leading to a potential need to re-evaluate current cost-effectiveness thresholds. We anticipate that the question of how to fund new therapies equitably will become even more challenging in the future, with the advent of expensive, innovative, breakthrough treatments in other therapeutic areas

Strategic value-directed learning and memory in Alzheimer's disease and behavioural-variant frontotemporal dementia

In healthy adults, the ability to prioritize learning of highly valued information is supported by executive functions and enhances subsequent memory retrieval for this information. In Alzheimer's disease (AD) and behavioural-variant frontotemporal dementia (bvFTD), marked deficits are evident in learning and memory, presenting in the context of executive dysfunction. It is unclear whether these patients show a typical memory bias for higher valued stimuli. We administered a value-directed word-list learning task to AD (n = 10) and bvFTD (n = 21) patients and age-matched healthy controls (n = 22). Each word was assigned a low, medium or high point value, and participants were instructed to maximize the number of points earned across three learning trials. Participants’ memory for the words was assessed on a delayed recall trial, followed by a recognition test for the words and corresponding point values. Relative to controls, both patient groups showed poorer overall learning, delayed recall and recognition. Despite these impairments, patients with AD preferentially recalled high-value words on learning trials and showed significant value-directed enhancement of recognition memory for the words and points. Conversely, bvFTD patients did not prioritize recall of high-value words during learning trials, and this reduced selectivity was related to inhibitory dysfunction. Nonetheless, bvFTD patients showed value-directed enhancement of recognition memory for the point values, suggesting a mismatch between memory of high-value information and the ability to apply this in a motivationally salient context. Our findings demonstrate that value-directed enhancement of memory may persist to some degree in patients with dementia, despite pronounced deficits in learning and memory

Planetesimal Compositions in Exoplanet Systems

We have used recent surveys of the composition of exoplanet host stars to investigate the expected composition of condensed material in planetesimals formed beyond the snow line in the circumstellar nebulae of these systems. Of the major solid forming elements, we find that, as for the Sun, the C and O abundances (and particularly the C/O abundance ratio) have the most significant effect on the composition of icy planetesimals formed in these systems. The calculations use a self-consistent model for the condensation sequence of volatile ices from the nebula gas after refractory (silicate and metal) phases have condensed. The resultant proportions of refractory phases and ices were calculated for a range of nebular temperature structure and redox conditions. Planetesimals in systems with sub-solar C/O should be water ice-rich, with lower than solar mass fractions of refractory materials, while in super-solar C/O systems planetesimals should have significantly higher fractions of refractories, in some cases having little or no water ice. C-bearing volatile ices and clathrates also become increasingly important with increasing C/O depending on the assumed nebular temperatures. These compositional variations in early condensates in the outer portions of the nebula will be significant for the equivalent of the Kuiper Belt in these systems, icy satellites of giant planets and the enrichment (over stellar values) of volatiles and heavy elements in giant planet atmospheres.Comment: Accepted for publication in The Astrophysical Journa

Influence of the synthetic method on the properties of two-photon-sensitive mesoporous organosilica nanoparticles

International audienceHerein we report the modulation of the properties of mesoporous silica nanoparticles (NPs) via various synthetic approaches. Three types of elaborations were compared, one in aqueous media at 25 °C, and the other two at 80 °C in water or in a water–ethanol mixture. For all these methods, an alkoxysilylated two-photon photosensitizer (2PS) was co-condensed with tetraethylorthosilicate (TEOS) in the presence of cetyltrimethylammonium bromide (CTAB), leading to five two-photon-sensitive mesoporous silica (M2PS) NPs. The M2PS NP porous structure could be tuned from radial to worm-like and MCM-41 types of organization. Besides, the 2PS precursor spatial dispersion was found to be highly dependent on both the 2PS initial concentration and the elaboration process. As a result, two-photon properties were modulated by the choice of the synthesis, the best results being found in aqueous media at 25 or 80 °C. Finally, the M2PS NPs were used for in vitro two-photon imaging of cancer cells

Studying the Hurdles of Insulin Prescription (SHIP©): development, scoring and initial validation of a new self-administered questionnaire

<p>Abstract</p> <p>Background</p> <p>Although insulin therapy is well-accepted by symptomatic diabetic patients, it is still often delayed in less severe patients, in whom injectable insulin remains under-used. A better understanding of patients' perception of insulin would eventually help physicians to adopt the most appropriate dialogue when having to motivate patients to initiate or to intensify insulin injection.</p> <p>Methods</p> <p>The 'Studying the Hurdles of Insulin Prescription' (SHIP) questionnaire was developed based on a list of concepts derived from three diabetic patients' focus groups, and was included into two cross-sectional studies with similar design: SHIP Oral study and SHIP Premix study. Diabetic patients treated with oral hypoglycaemic agents (OHA; n = 1,494) and patients already treated with insulin (n = 1,150) completed the questionnaire at baseline, 6- and 12 months. Psychometric properties were assessed: 1) structure analysis by Principal Component Analysis (PCA) with Varimax rotation, 2) internal consistency reliability (Cronbach's alpha), and 3) concurrent validity (Spearman correlation coefficients with the Fear of Self-Injecting (FSI) score of the Diabetes Fear of Injecting and Self-testing Questionnaire. Reluctance/motivation towards insulin was assessed. Scores' ability to predict patients' insulin injection reluctance/motivation and initiation/intensification was evaluated with the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC).</p> <p>Results</p> <p>PCA analysis confirmed the structure of the 14 items grouped into 3 dimensions: 'acceptance and motivation', 'fear and constraints', and 'restraints and barriers' towards insulin injection. Internal consistency reliability was excellent (Cronbach's alpha > 0.70); concurrent validity was good. The three scores were significantly predictive of patients' reluctance/motivation towards insulin injection initiation, as they were of patients' actual switch, except for the 'restraints and barriers' dimension. 'Acceptance and motivation' and 'fears and constraints' dimensions were also significantly predictive of patients' reluctance/motivation towards insulin intensification. By the end of the 12-month study, 179 of the initially OHA-treated patients had started insulin injections; 186 of the patients already treated with insulin had increased their injections.</p> <p>Conclusion</p> <p>The SHIP questionnaire provides reliable and valid assessment of diabetic patients' attitude towards insulin and injections. The predictive power of scores for patients' reluctance/motivation and actual treatment decisions demonstrates encouraging potential for further application in clinical practice.</p

The Robo-AO-2 facility for rapid visible/near-infrared AO imaging and the demonstration of hybrid techniques

We are building a next-generation laser adaptive optics system, Robo-AO-2, for the UH 2.2-m telescope that will deliver robotic, diffraction-limited observations at visible and near-infrared wavelengths in unprecedented numbers. The superior Maunakea observing site, expanded spectral range and rapid response to high-priority events represent a significant advance over the prototype. Robo-AO-2 will include a new reconfigurable natural guide star sensor for exquisite wavefront correction on bright targets and the demonstration of potentially transformative hybrid AO techniques that promise to extend the faintness limit on current and future exoplanet adaptive optics systems.Comment: 15 page

Boundary Attention Mapping (BAM): Fine-grained saliency maps for segmentation of Burn Injuries

Burn injuries can result from mechanisms such as thermal, chemical, and electrical insults. A prompt and accurate assessment of burns is essential for deciding definitive clinical treatments. Currently, the primary approach for burn assessments, via visual and tactile observations, is approximately 60%-80% accurate. The gold standard is biopsy and a close second would be non-invasive methods like Laser Doppler Imaging (LDI) assessments, which have up to 97% accuracy in predicting burn severity and the required healing time. In this paper, we introduce a machine learning pipeline for assessing burn severities and segmenting the regions of skin that are affected by burn. Segmenting 2D colour images of burns allows for the injured versus non-injured skin to be delineated, clearly marking the extent and boundaries of the localized burn/region-of-interest, even during remote monitoring of a burn patient. We trained a convolutional neural network (CNN) to classify four severities of burns. We built a saliency mapping method, Boundary Attention Mapping (BAM), that utilises this trained CNN for the purpose of accurately localizing and segmenting the burn regions from skin burn images. We demonstrated the effectiveness of our proposed pipeline through extensive experiments and evaluations using two datasets; 1) A larger skin burn image dataset consisting of 1684 skin burn images of four burn severities, 2) An LDI dataset that consists of a total of 184 skin burn images with their associated LDI scans. The CNN trained using the first dataset achieved an average F1-Score of 78% and micro/macro- average ROC of 85% in classifying the four burn severities. Moreover, a comparison between the BAM results and LDI results for measuring injury boundary showed that the segmentations generated by our method achieved 91.60% accuracy, 78.17% sensitivity, and 93.37% specificity

Quantitative analysis of single particle trajectories: mean maximal excursion method

An increasing number of experimental studies employ single particle tracking to probe the physical environment in complex systems. We here propose and discuss new methods to analyze the time series of the particle traces, in particular, for subdiffusion phenomena. We discuss the statistical properties of mean maximal excursions, i.e., the maximal distance covered by a test particle up to time t. Compared to traditional methods focusing on the mean squared displacement we show that the mean maximal excursion analysis performs better in the determination of the anomalous diffusion exponent. We also demonstrate that combination of regular moments with moments of the mean maximal excursion method provides additional criteria to determine the exact physical nature of the underlying stochastic subdiffusion processes. We put the methods to test using experimental data as well as simulated time series from different models for normal and anomalous dynamics, such as diffusion on fractals, continuous time random walks, and fractional Brownian motion.Comment: 10 pages, 7 figures, 2 tables. NB: Supplementary material may be found in the downloadable source file