HDAC inhibitors increase NRF2-signaling in tumour cells and blunt the efficacy of co-adminstered cytotoxic agents

The NRF2 signalling cascade provides a primary response against electrophilic chemicals and oxidative stress. The activation of NRF2-signaling is anticipated to have adverse clinical consequences; NRF2 is activated in a number of cancers and, additionally, its pharmacological activation by one compound can reduce the toxicity or efficiency of a second agent administered concomitantly. In this work, we have analysed systematically the ability of 152 research, pre-clinical or clinically used drugs to induce an NRF2 response using the MCF7-AREc32 NRF2 reporter. Ten percent of the tested drugs induced an NRF2 response. The NRF2 activators were not restricted to classical cytotoxic alkylating agents but also included a number of emerging anticancer drugs, including an IGF1-R inhibitor (NVP-AEW541), a PIM-1 kinase inhibitor (Pim1 inhibitor 2), a PLK1 inhibitor (BI 2536) and most strikingly seven of nine tested HDAC inhibitors. These findings were further confirmed by demonstrating NRF2-dependent induction of endogenous AKR genes, biomarkers of NRF2 activity. The ability of HDAC inhibitors to stimulate NRF2-signalling did not diminish their own potency as antitumour agents. However, when used to pre-treat cells, they did reduce the efficacy of acrolein. Taken together, our data suggest that the ability of drugs to stimulate NRF2 activity is common and should be investigated as part of the drug-development process

Colon capsule endoscopy : an innovative method for detecting colorectal pathology during the Covid-19 pandemic?

Colorectal Disease © 2020 The Association of Coloproctology of Great Britain and Ireland.Peer reviewedPostprin

SDSSJ14584479+3720215: A Benchmark JHK Blazar Light Curve from the 2MASS Calibration Scans

Active galactic nuclei (AGNs) are well-known to exhibit flux variability across a wide range of wavelength regimes, but the precise origin of the variability at different wavelengths remains unclear. To investigate the relatively unexplored near-IR variability of the most luminous AGNs, we conduct a search for variability using well sampled JHKs-band light curves from the 2MASS survey calibration fields. Our sample includes 27 known quasars with an average of 924 epochs of observation over three years, as well as one spectroscopically confirmed blazar (SDSSJ14584479+3720215) with 1972 epochs of data. This is the best-sampled NIR photometric blazar light curve to date, and it exhibits correlated, stochastic variability that we characterize with continuous auto-regressive moving average (CARMA) models. None of the other 26 known quasars had detectable variability in the 2MASS bands above the photometric uncertainty. A blind search of the 2MASS calibration field light curves for AGN candidates based on fitting CARMA(1,0) models (damped-random walk) uncovered only 7 candidates. All 7 were young stellar objects within the {\rho} Ophiuchus star forming region, five with previous X-ray detections. A significant {\gamma}-ray detection (5{\sigma}) for the known blazar using 4.5 years of Fermi photon data is also found. We suggest that strong NIR variability of blazars, such as seen for SDSSJ14584479+3720215, can be used as an efficient method of identifying previously-unidentified {\gamma}-ray blazars, with low contamination from other AGN.Comment: 6 pages, 3 figures, ApJ Accepte

Geodynamic setting and origin of the Oman/UAE ophiolite

The ~500km-long mid-Cretaceous Semail nappe of the Sultanate of Oman and UAE (henceforth referred to as the Oman ophiolite) is the largest and best-preserved ophiolite complex known. It is of particular importance because it is generally believed to have an internal structure and composition closely comparable to that of crust formed at the present-day East Pacific Rise (EPR), making it our only known on-land analogue for ocean lithosphere formed at a fast spreading rate. On the basis of this assumption Oman has long played a pivotal role in guiding our conceptual understanding of fast-spreading ridge processes, as modern fast-spread ocean crust is largely inaccessible

The chaotic solar cycle II. Analysis of cosmogenic 10Be data

Context. The variations of solar activity over long time intervals using a solar activity reconstruction based on the cosmogenic radionuclide 10Be measured in polar ice cores are studied. Methods. By applying methods of nonlinear dynamics, the solar activity cycle is studied using solar activity proxies that have been reaching into the past for over 9300 years. The complexity of the system is expressed by several parameters of nonlinear dynamics, such as embedding dimension or false nearest neighbors, and the method of delay coordinates is applied to the time series. We also fit a damped random walk model, which accurately describes the variability of quasars, to the solar 10Be data and investigate the corresponding power spectral distribution. The periods in the data series were searched by the Fourier and wavelet analyses. The solar activity on the long-term scale is found to be on the edge of chaotic behavior. This can explain the observed intermittent period of longer lasting solar activity minima. Filtering the data by eliminating variations below a certain period (the periods of 380 yr and 57 yr were used) yields a far more regular behavior of solar activity. A comparison between the results for the 10Be data with the 14C data shows many similarities. Both cosmogenic isotopes are strongly correlated mutually and with solar activity. Finally, we find that a series of damped random walk models provides a good fit to the 10Be data with a fixed characteristic time scale of 1000 years, which is roughly consistent with the quasi-periods found by the Fourier and wavelet analyses.Comment: 8 pages, 11 figure

Measured Sensitivity of the First Mark II Phased Array Feed on an ASKAP Antenna

This paper presents the measured sensitivity of CSIRO's first Mk. II phased array feed (PAF) on an ASKAP antenna. The Mk. II achieves a minimum system-temperature-over-efficiency $T_\mathrm{sys}/\eta$ of 78 K at 1.23 GHz and is 95 K or better from 835 MHz to 1.8 GHz. This PAF was designed for the Australian SKA Pathfinder telescope to demonstrate fast astronomical surveys with a wide field of view for the Square Kilometre Array (SKA).Comment: 5 pages, 2 figures, accepted for publication in Electromagnetics in Advanced applications (ICEAA), 2015 International Conference o

Kampala Trauma Score (KTS): Is it a new triage tool?

In North America, injury surveillance has generated an accumulation of data regarding trauma events and outcomes through the implementation of trauma registries. Trauma registries have been predominantly instituted in response to the desire to be accredited by the American College of Surgeons (ACS). Committee on Trauma as an ACS Trauma Center1. These registries play a key role in research that determines epidemiological patterns of injury, advances injury prevention actions and finally, measures outcomes2. For example, they have been used extensively in the US to monitor reductions in mortality which has been attributed to the institution of “trauma systems”, coordinated hospital-based systems for the management of injured patients3. As interventions to reduce and prevent injuries are sought, registries allow the calculation of injury rates, identification of causes and measurement of outcomes produced by implementation of interventions4. Trauma registry data is made universally comparable across different strata through the routine use of trauma scores, such as the revised trauma score (RTS) and injury severity score (ISS)

Methanol Masers as Tracers of Circumstellar Disks

We show that in many methanol maser sources the masers are located in lines, with a velocity gradient along them which suggests that the masers are situated in edge-on circumstellar, or protoplanetary, disks. We present VLBI observations of the methanol maser source G309.92+0.48, in the 12.2 GHz transition, which confirm previous observations that the masers in this source lie along a line. We show that such sources are not only linear in space but, in many cases, also have a linear velocity gradient. We then model these and other data in both the 6.7 GHz and the 12.2 GHz transition from a number of star formation regions, and show that the observed spatial and velocity distribution of methanol masers, and the derived Keplerian masses, are consistent with a circumstellar disk rotating around an OB star. We consider this and other hypotheses, and conclude that about half of these methanol masers are probably located in edge-on circumstellar disks around young stars. This is of particular significance for studies of circumstellar disks because of the detailed velocity information available from the masers.Comment: 38 pages, 13 figures accepted by Ap