Beyond BRAFV600: Clinical Mutation Panel Testing by Next-Generation Sequencing in Advanced Melanoma

The management of melanoma has evolved owing to improved understanding of its molecular drivers. To augment the current understanding of the prevalence, patterns, and associations of mutations in this disease, the results of clinical testing of 699 advanced melanoma patients using a pan-cancer next-generation sequencing (NGS) panel of hotspot regions in 46 genes were reviewed. Mutations were identified in 43 of the 46 genes on the panel. The most common mutations were BRAFV600 (36%), NRAS (21%), TP53 (16%), BRAFNon-V600 (6%), and KIT (4%). Approximately one-third of melanomas had >1 mutation detected, and the number of mutations per tumor was associated with melanoma subtype. Concurrent TP53 mutations were the most frequent events in tumors with BRAFV600and NRAS mutations. Melanomas with BRAFNon-V600mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAFV600 mutations (1.6%). The prevalence of BRAFV600 and KIT mutations were significantly associated with melanoma subtypes, and BRAFV600 and TP53 mutations were significantly associated with cutaneous primary tumor location. Multiple potential therapeutic targets were identified in metastatic unknown primary and cutaneous melanomas that lacked BRAFV600and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma

The influence of visual flow and perceptual load on locomotion speed

Visual flow is used to perceive and regulate movement speed during locomotion. We assessed the extent to which variation in flow from the ground plane, arising from static visual textures, influences locomotion speed under conditions of concurrent perceptual load. In two experiments, participants walked over a 12-m projected walkway that consisted of stripes that were oriented orthogonal to the walking direction. In the critical conditions, the frequency of the stripes increased or decreased. We observed small, but consistent effects on walking speed, so that participants were walking slower when the frequency increased compared to when the frequency decreased. This basic effect suggests that participants interpreted the change in visual flow in these conditions as at least partly due to a change in their own movement speed, and counteracted such a change by speeding up or slowing down. Critically, these effects were magnified under conditions of low perceptual load and a locus of attention near the ground plane. Our findings suggest that the contribution of vision in the control of ongoing locomotion is relatively fluid and dependent on ongoing perceptual (and perhaps more generally cognitive) task demands

The Sodium/Proton Exchanger NHE8 Regulates Late Endosomal Morphology and Function

The pH and lumenal environment of intracellular organelles is considered essential for protein sorting and trafficking through the cell. We provide the first evidence that a mammalian sodium (potassium)/proton exchanger, NHE8, plays a key role in the control of protein trafficking and endosome morphology

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

The significance of heat transport by shallow fluid flow at an active plate boundary; the Southern Alps, New Zealand

Fluid flow can influence fault behavior. Here we quantify the role of groundwater heat advection in establishing the thermal structure of the Alpine Fault, a major tectonic boundary in southern New Zealand that accommodates most of the motion between the Australian and Pacific Plates. Convergence on the Alpine Fault has rapidly uplifted the Southern Alps, resulting in high geothermal gradients and a thin seismogenic zone. A new equilibrium temperature profile from the 818 m‐deep Deep Fault Drilling Project 2B (DFDP‐2B) borehole has been interrogated using one‐dimensional analytical models of fluid and rock advection. Models indicate a total heat flux of 720 mW·m‐2 results from groundwater flow with Darcy velocities approximating to 7.8×10‐10 m·s‐1. Groundwaters advect significantly more heat than rock advection in the shallow orogen (<6 km depth) and are the major control on the subsurface temperature field

Catching a glimpse of working memory: top-down capture as a tool for measuring the content of the mind

This article outlines a methodology for probing working memory (WM) content in high-level cognitive tasks (e.g., decision making, problem solving, and memory retrieval) by capitalizing on attentional and oculomotor biases evidenced in top-down capture paradigms. This method would be of great use, as it could measure the information resident in WM at any point in a task and, hence, track information use over time as tasks dynamically evolve. Above and beyond providing a measure of information occupancy in WM, such a method would benefit from sensitivity to the specific activation levels of individual items in WM. This article additionally forwards a novel fusion of standard free recall and visual search paradigms in an effort to assess the sensitivity of eye movements in top-down capture, on which this new measurement technique relies, to item-specific memory activation (ISMA). The results demonstrate eye movement sensitivity to ISMA in some, but not all, cases

Using the memory activation capture (MAC) procedure to investigate the temporal dynamics of hypothesis generation

Research investigating top-down capture has demonstrated a coupling of working memory content with attention and eye movements. By capitalizing on this relationship, we have developed a novel methodology, called the memory activation capture (MAC) procedure, for measuring the dynamics of working memory content supporting complex cognitive tasks (e.g., decision making, problem solving). The MAC procedure employs briefly presented visual arrays containing task-relevant information at critical points in a task. By observing which items are preferentially fixated, we gain a measure of working memory content as the task evolves through time. The efficacy of the MAC procedure was demonstrated in a dynamic hypothesis generation task in which some of its advantages over existing methods for measuring changes in the contents of working memory over time are highlighted. In two experiments, the MAC procedure was able to detect the hypothesis that was retrieved and placed into working memory. Moreover, the results from Experiment 2 suggest a two-stage process following hypothesis retrieval, whereby the hypothesis undergoes a brief period of heightened activation before entering a lower activation state in which it is maintained for output. The results of both experiments are of additional general interest, as they represent the first demonstrations of top-down capture driven by participant-established WM content retrieved from long-term memory