In vivo selectivity and localization of reactive oxygen species (ROS) induction by osmium anticancer complexes that circumvent platinum resistance

YesPlatinum drugs are widely used for cancer treatment. Other precious metals are promising, but their clinical progress depends on achieving different mechanisms of action to overcome Pt-resistance. Here, we evaluate 13 organo-Os complexes: 16-electron sulfonyl-diamine catalysts [(η6-arene)Os(N,N′)], and 18-electron phenylazopyridine complexes [(η6-arene)Os(N,N’)Cl/I]+ (arene = p-cymene, biphenyl, or terphenyl). Their antiproliferative activity does not depend on p21 or p53 status, unlike cisplatin, and their selective potency toward cancer cells involves the generation of reactive oxygen species. Evidence of such a mechanism of action has been found both in vitro and in vivo. This work appears to provide the first study of osmium complexes in the zebrafish model, which has been shown to closely model toxicity in humans. A fluorescent osmium complex, derived from a lead compound, was employed to confirm internalization of the complex, visualize in vivo distribution, and confirm colocalization with reactive oxygen species generated in zebrafish.Wellcome Trust (grant no. 107691/Z/15/Z), ERC (grant nos. 247450, 324594), Science City (AWM and ERDF), WCPRS and Bruker Daltonics (Studentship for JPCC), Mike and Enfys Bagguley, and EPSRC (Studentship for HEB, and grant no. EP/F034210/1)

2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia

A correction has been published: European Heart Journal, Volume 39, Issue 22, 7 June 2018, Pages 2105Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017.info:eu-repo/semantics/publishedVersio

Identification, Replication, and Functional Fine-Mapping of Expression Quantitative Trait Loci in Primary Human Liver Tissue

The discovery of expression quantitative trait loci (“eQTLs”) can help to unravel genetic contributions to complex traits. We identified genetic determinants of human liver gene expression variation using two independent collections of primary tissue profiled with Agilent (n = 206) and Illumina (n = 60) expression arrays and Illumina SNP genotyping (550K), and we also incorporated data from a published study (n = 266). We found that ∼30% of SNP-expression correlations in one study failed to replicate in either of the others, even at thresholds yielding high reproducibility in simulations, and we quantified numerous factors affecting reproducibility. Our data suggest that drug exposure, clinical descriptors, and unknown factors associated with tissue ascertainment and analysis have substantial effects on gene expression and that controlling for hidden confounding variables significantly increases replication rate. Furthermore, we found that reproducible eQTL SNPs were heavily enriched near gene starts and ends, and subsequently resequenced the promoters and 3′UTRs for 14 genes and tested the identified haplotypes using luciferase assays. For three genes, significant haplotype-specific in vitro functional differences correlated directly with expression levels, suggesting that many bona fide eQTLs result from functional variants that can be mechanistically isolated in a high-throughput fashion. Finally, given our study design, we were able to discover and validate hundreds of liver eQTLs. Many of these relate directly to complex traits for which liver-specific analyses are likely to be relevant, and we identified dozens of potential connections with disease-associated loci. These included previously characterized eQTL contributors to diabetes, drug response, and lipid levels, and they suggest novel candidates such as a role for NOD2 expression in leprosy risk and C2orf43 in prostate cancer. In general, the work presented here will be valuable for future efforts to precisely identify and functionally characterize genetic contributions to a variety of complex traits

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

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

Priming food intake with weight control cues: systematic review with a meta-analysis

Background A growing number of studies suggest that exposure to cues which are associated with weight control can prime or prompt controlled food intake in tempting food environments. However, findings are mixed and understanding which types of cues and for whom such cues may be most effective is needed to inform subsequent research and societal applications. A systematic review and meta-analysis were conducted to evaluate the effects of exposure to weight control cues compared with control cues on food intake. Methods PsycINFO, Medline, Embase and Web of Science were searched using key terms. Hedge’s g was used to calculate effect sizes based on mean food intake, standard deviations and sample sizes extracted from relevant publications and, a random effects model was used for the meta-analysis. Results Twenty-five articles consisting of 26 studies were eligible. Data from 25 studies (31 effect sizes) were available for the meta-analysis. Overall, weight control cues reduced food intake, albeit to a trivial effect (ES: -0.149, 95% CI: -0.271 to − 0.027). Subgroup analyses when studies which induced negative affect were removed showed that for individuals with strong weight control goals the effect was small-to-moderate (ES: -0.440, 95% CI: -0.718 to − 0.163), whereas for individuals with weak weight control goals this effect was trivial and non-significant (ES: 0.014, 95% CI: -0.249 to 0.278). Cue type and level of engagement did not significantly moderate the effect; however, specific cues (low-calorie foods and thin models) and attended engagement yielded significant effects. Caution is needed interpreting these findings as most studies were rated with high risk of bias and a number of studies could not be included in the subgroup analyses. Conclusions Based on the data available, weight control cues reduce food intake in individuals with strong weight control goals. Further research is needed to explore longer term effects of cue exposure and confirm underlying mechanisms. PROSPERO registry#CRD42016052396

Calcium–iron–phosphate features in archaeological sediments: characterization through microfocus synchrotron X-ray scattering analyses

The occurrence of amorphous calcium (Ca)iron (Fe)phosphate infilling features in thin-section samples from archaeological stratigraphies is increasingly being reported and used in the cultural interpretations of sites. In some contexts, these materials are the product of dissolution and recrystallization of bone material within pores of the soil or sediment matrix. This study uses transmitted microfocus X-ray scattering to characterize and measure features of known cod fish bone (Gadus morhua) materials, and compare them to archaeological samples of amorphous Ca-Fe-phosphate infilling material found in thin section from early fishing community sites. The analyses characterize the structure of these features for the first time, and allow discussion of the diagenetic processes that lead to their formation