Comparison of DC Bead-irinotecan and DC Bead-topotecan drug eluting beads for use in locoregional drug delivery to treat pancreatic cancer

DC Bead is a drug delivery embolisation system that can be loaded with doxorubicin or irinotecan for the treatment of a variety of liver cancers. In this study we demonstrate that the topoisomerase I inhibitor topotecan hydrochloride can be successfully loaded into the DC Bead sulfonate-modified polyvinyl alcohol hydrogel matrix, resulting in a sustained-release drug eluting bead (DEBTOP) useful for therapeutic purposes. The in vitro drug loading capacity, elution characteristics and the effects on mechanical properties of the beads are described with reference to our previous work with irinotecan hydrochloride (DEBIRI). Results showed that drug loading was faster when the solution was agitated compared to static loading and a maximum loading of ca. 40–45 mg topotecan in 1 ml hydrated beads was achievable. Loading the drug into the beads altered the size, compressibility moduli and colour of the bead. Elution was shown to be reliant on the presence of ions to perform the necessary exchange with the electrostatically bound topotecan molecules. Topotecan was shown by MTS assay to have an IC50 for human pancreatic adenocarcinoma cells (PSN-1) of 0.22 and 0.27 lM compared to 28.1 and 19.2 lM for irinotecan at 48 and 72 h, respectively. The cytotoxic efficacy of DEBTOP on PSN-1 was compared to DEBIRI. DEPTOP loaded at 6 & 30 mg ml-1, like its free drug form, was shown to be more potent than DEBIRI of comparable doses at 24, 48 & 72 h using a slightly modified MTS assay. Using a PSN-1 mouse xenograft model, DEBIRI doses of 3.3–6.6 mg were shown to be well tolerated (even with repeat administration) and effective in reducing the tumour size. DEBTOP however, was lethal after 6 days at doses of 0.83–1.2 mg but demonstrated reasonable efficacy and tolerability (again with repeat injection possible) at 0.2–0.4 mg doses. Care must therefore be taken when selecting the dose of topotecan to be loaded into DC Bead given its greater potency and potential toxicity

Critical Phenomena at the Antiferromagnetic Phase Transition of Azurite

We report on high-resolution acoustic, specific-heat and thermal expansion measurements in the vicinity of the antiferromagnetic phase transition at T_N = 1.88 K on a high-quality single crystal of the natural mineral azurite. A detailed investigation of the critical contribution to the various quantities at T_N is presented. The set of critical exponents and amplitude ratios of the singular contributions above and below the transition indicate that the system can be reasonably well described by a three-dimensional Heisenberg antiferromagnet.Comment: 9 pages, 3 figures, proceedings of ICM 2012, JKP

How Have Intravitreal Anti-VEGF and Dexamethasone Implant Been Used in Italy? A Multiregional, Population-Based Study in the Years 2010-2016

Purpose: To describe intravitreal anti-VEGF drug and dexamethasone use in four Italian regions.Methods: Four regional claims databases were used to measure drug prevalence, compare dosing intervals to those recommended in the summary of product characteristics (SPC), and identify switchers. Bilateral treatment and diabetic macular edema (DME) coding algorithms were validated, linking claims with a sample of prospectively collected ophthalmological data.Results: Overall, 41,836 patients received 651 study drug in 2010-2016 (4.8 per 10,000 persons). In 2016, anti-VEGF drug use ranged from 0.8 (Basilicata) to 5.7 (Lombardy) per 10,000 persons while intravitreal dexamethasone use ranged from 0.2 (Basilicata) to 1.4 (Lombardy) per 10,000 persons. Overall, 40,815 persons were incident users of study drugs. Among incident users with 651 year of follow-up (N = 30,745), 16.0% (N = 30,745), 16.0% (N = 30,745), 16.0% (.Conclusion: Study drug use increased over time in Lombardy, Basilicata, Calabria, and Sicily, despite a large heterogeneity in prevalence of use across regions. Drug treatment appeared to be partly in line with SPC, suggesting that improvement in clinical practice may be needed to maximize drug benefits

Overexpressed vs mutated Kras in murine fibroblasts: a molecular phenotyping study

Ras acts in signalling pathways regulating the activity of multiple cellular functions including cell proliferation, differentiation, and apoptosis. Amino-acid exchanges at position 12, 13, or 61 of the Kras gene convert the proto-oncogene into an activated oncogene. Until now, a direct comparison of genome-wide expression profiling studies of Kras overexpression and different Kras mutant forms in a single assay system has not been carried out. In our study, we focused on the direct comparison of global gene expression effects caused by mutations in codon 12 or 13 of the Kras gene and Kras overexpression in murine fibroblasts. We determined Kras cellular mRNA, Ras protein and activated Ras protein levels. Further, we compared our data to the proteome analysis of the same transfected cell lines. Both overexpression and mutations of Kras lead to common altered gene expression patterns. Only two genes, Lox and Col1a1, were reversely regulated in the Kras transfectants. They may contribute to the higher aggressiveness of the Kras codon 12 mutation in tumour progression. The functional annotation of differentially expressed genes revealed a high frequency of proteins involved in tumour growth and angiogenesis. These data further support the important role of these genes in tumour-associated angiogenesis

Dark energy survey year 1 results: the relationship between mass and light around cosmic voids

What are the mass and galaxy profiles of cosmic voids? In this paper, we use two methods to extract voids in the Dark Energy Survey (DES) Year 1 redMaGiC galaxy sample to address this question. We use either 2D slices in projection, or the 3D distribution of galaxies based on photometric redshifts to identify voids. For the mass profile, we measure the tangential shear profiles of background galaxies to infer the excess surface mass density. The signal-to-noise ratio for our lensing measurement ranges between 10.7 and 14.0 for the two void samples. We infer their 3D density profiles by fitting models based on N-body simulations and find good agreement for void radii in the range 15–85 Mpc. Comparison with their galaxy profiles then allows us to test the relation between mass and light at the 10 per cent level, the most stringent test to date. We find very similar shapes for the two profiles, consistent with a linear relationship between mass and light both within and outside the void radius. We validate our analysis with the help of simulated mock catalogues and estimate the impact of photometric redshift uncertainties on the measurement. Our methodology can be used for cosmological applications, including tests of gravity with voids. This is especially promising when the lensing profiles are combined with spectroscopic measurements of void dynamics via redshift-space distortions

Dark energy survey year 1 results: The lensing imprint of cosmic voids on the cosmic microwave background

Cosmic voids gravitationally lens the cosmic microwave background (CMB) radiation, resulting in a distinct imprint on degree scales. We use the simulated CMB lensing convergence map from the Marenostrum Institut de Ciencias de l’Espai (MICE) N-body simulation to calibrate our detection strategy for a given void definition and galaxy tracer density. We then identify cosmic voids in Dark Energy Survey (DES) Year 1 data and stack the Planck 2015 lensing convergence map on their locations, probing the consistency of simulated and observed void lensing signals. When fixing the shape of the stacked convergence profile to that calibrated from simulations, we find imprints at the 3σ significance level for various analysis choices. The best measurement strategies based on the MICE calibration process yield S/N ≈ 4 for DES Y1, and the best-fitting amplitude recovered from the data is consistent with expectations from MICE (A ≈ 1). Given these results as well as the agreement between them and N-body simulations, we conclude that the previously reported excess integrated Sachs–Wolfe (ISW) signal associated with cosmic voids in DES Y1 has no counterpart in the Planck CMB lensing map

On the relative bias of void tracers in the Dark Energy Survey

Luminous tracers of large-scale structure are not entirely representative of the distribution of mass in our Universe. As they arise from the highest peaks in the matter density field, the spatial distribution of luminous objects is biased towards those peaks. On large scales, where density fluctuations are mild, this bias simply amounts to a constant offset in the clustering amplitude of the tracer, known as linear bias. In this work we focus on the relative bias between galaxies and galaxy clusters that are located inside and in the vicinity of cosmic voids, extended regions of relatively low density in the large-scale structure of the Universe. With the help of mock data we verify that the relation between galaxy and cluster overdensity around voids remains linear. Hence, the void-centric density profiles of different tracers can be linked by a single multiplicative constant. This amounts to the same value as the relative linear bias between tracers for the largest voids in the sample. For voids of small sizes, which typically arise in higher density regions, this constant has a higher value, possibly showing an environmental dependence similar to that observed for the linear bias itself. We confirm our findings by analysing data obtained during the first year of observations by the Dark Energy Survey. As a side product, we present the first catalogue of three-dimensional voids extracted from a photometric survey with a controlled photo-z uncertainty. Our results will be relevant in forthcoming analyses that attempt to use voids as cosmological probes

Is media multitasking good for cybersecurity? Exploring the relationship between media multitasking and everyday cognitive failures on self-reported risky cybersecurity behaviors

The current study focused on how engaging in media multitasking (MMT) and the experience of everyday cognitive failures impact on the individual's engagement in risky cybersecurity behaviors (RCsB). In total, 144 participants (32 males, 112 females) completed an online survey. The age range for participants was 18 to 43 years (M = 20.63, SD = 4.04). Participants completed three scales which included an inventory of weekly MMT, a measure of everyday cognitive failures, and RCsB. There was a significant difference between heavy media multitaskers (HMM), average media multitaskers (AMM), and light media multitaskers (LMM) in terms of RCsB, with HMM demonstrating more frequent risky behaviors than LMM or AMM. The HMM group also reported more cognitive failures in everyday life than the LMM group. A regression analysis showed that everyday cognitive failures and MMT acted as significant predictors for RCsB. These results expand our current understanding of the relationship between human factors and cybersecurity behaviors, which are useful to inform the design of training and intervention packages to mitigate RCsB

Dark Energy Survey Year 1 results: weak lensing mass calibration of redMaPPer galaxy clusters

We constrain the mass--richness scaling relation of redMaPPer galaxy clusters identified in the Dark Energy Survey Year 1 data using weak gravitational lensing. We split clusters into 4×3 bins of richness λ and redshift z for λ≥20 and 0.2≤z≤0.65 and measure the mean masses of these bins using their stacked weak lensing signal. By modeling the scaling relation as ⟨M 200m |λ,z⟩=M 0 (λ/40) F ((1+z)/1.35) G , we constrain the normalization of the scaling relation at the 5.0 per cent level as M 0 =[3.081±0.075(stat)±0.133(sys)]⋅10 14 M ⊙ at λ=40 and z=0.35 . The richness scaling index is constrained to be F=1.356±0.051 (stat)±0.008 (sys) and the redshift scaling index G=−0.30±0.30 (stat)±0.06 (sys) . These are the tightest measurements of the normalization and richness scaling index made to date. We use a semi-analytic covariance matrix to characterize the statistical errors in the recovered weak lensing profiles. Our analysis accounts for the following sources of systematic error: shear and photometric redshift errors, cluster miscentering, cluster member dilution of the source sample, systematic uncertainties in the modeling of the halo--mass correlation function, halo triaxiality, and projection effects. We discuss prospects for reducing this systematic error budget, which dominates the uncertainty on M 0. Our result is in excellent agreement with, but has significantly smaller uncertainties than, previous measurements in the literature, and augurs well for the power of the DES cluster survey as a tool for precision cosmology and upcoming galaxy surveys such as LSST, Euclid and WFIRST