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

The RRAT Trap: Interferometric Localization of Radio Pulses from J0628+0909

We present the first blind interferometric detection and imaging of a millisecond radio transient with an observation of transient pulsar J0628+0909. We developed a special observing mode of the Karl G. Jansky Very Large Array (VLA) to produce correlated data products (i.e., visibilities and images) on a time scale of 10 ms. Correlated data effectively produce thousands of beams on the sky that can localize sources anywhere over a wide field of view. We used this new observing mode to find and image pulses from the rotating radio transient (RRAT) J0628+0909, improving its localization by two orders of magnitude. Since the location of the RRAT was only approximately known when first observed, we searched for transients using a wide-field detection algorithm based on the bispectrum, an interferometric closure quantity. Over 16 minutes of observing, this algorithm detected one transient offset roughly 1' from its nominal location; this allowed us to image the RRAT to localize it with an accuracy of 1.6". With a priori knowledge of the RRAT location, a traditional beamforming search of the same data found two, lower significance pulses. The refined RRAT position excludes all potential multiwavelength counterparts, limiting its optical luminosity to L_i'<1.1x10^31 erg/s and excluding its association with a young, luminous neutron star.Comment: Submitted to ApJ, 7 pages, 5 figure

New Tests for Disruption Mechanisms of Star Clusters: The Large and Small Magellanic Clouds

We compare the observed bivariate distribution of masses(M) and ages(t) of star clusters in the LMC with the predicted distributions g(M,t) from 3 idealized models for the disruption of star clusters: (1)sudden mass-dependent disruption;(2)gradual mass-dependent disruption; and (3)gradual mass-independent disruption. The model with mass-{\em in}dependent disruption provides a good, first-order description of these cluster populations, with g(M,t) propto M^{beta} t^{gamma}, beta=-1.8+/-0.2 and gamma=-0.8+/-0.2, at least for clusters with ages t<10^9 yr and masses M<10^3 M_sol (more specifically, t<10^7(M/10^2 M_sol)^{1.3} yr). This model predicts that the clusters should have a power-law luminosity function, dN/dL propto L^-1.8, in agreement with observations. The first two models, on the other hand, fare poorly when describing the observations, refuting previous claims that mass-dependent disruption of star clusters is observed in the LMC over the studied M-t domain. Clusters in the SMC can be described by the same g(M,t) distribution as for the LMC, but with smaller samples and hence larger uncertainties. The successful g(M,t) model for clusters in the Magellanic Clouds is virtually the same as the one for clusters in the merging Antennae galaxies, but extends the domain of validity to lower masses and to older ages. This indicates that the dominant disruption processes are similar in these very different galaxies over at least t<10^8 yr and possibly t<10^9 yr. The mass functions for young clusters in the LMC are power-laws, while that for ancient globular clusters is peaked. We show that the observed shapes of these mass functions are consistent with expectations from the simple evaporation model presented by McLaughlin & Fall.Comment: 46 pages, 17 figures, published ApJ, vol 711, page 126

A Comparison of Methods for Determining the Age Distribution of Star Clusters: Application to the Large Magellanic Cloud

The age distribution of star clusters in nearby galaxies plays a crucial role in evaluating the lifetimes and disruption mechanisms of the clusters. Two very different results have been found recently for the age distribution chi(t) of clusters in the Large Magellanic Cloud (LMC). We found that chi(t) can be described approximately by a power law chi(t) propto t^{gamma}, with gamma -0.8, by counting clusters in the mass-age plane, i.e., by constructing chi(t) directly from mass-limited samples. Gieles & Bastian inferred a value of gamma~, based on the slope of the relation between the maximum mass of clusters in equal intervals of log t, hereafter the M_max method, an indirect technique that requires additional assumptions about the upper end of the mass function. However, our own analysis shows that the M_max method gives a result consistent with our direct counting method for clusters in the LMC, namely chi(t) propto t^-0.8 for t<10^9 yr. The reason for the apparent discrepancy is that our analysis includes many massive (M>1.5x10^3 M_sol), recently formed (t<10^7 yr) clusters, which are known to exist in the LMC, whereas Gieles & Bastian are missing such clusters. We compile recent results from the literature showing that the age distribution of young star clusters in more than a dozen galaxies, including dwarf and giant galaxies, isolated and interacting galaxies, irregular and spiral galaxies, has a similar declining shape. We interpret this approximately "universal" shape as due primarily to the progressive disruption of star clusters over their first ~few x 10^8 yr, starting soon after formation, and discuss some observational and physical implications of this early disruption for stellar populations in galaxies.Comment: 21 pages, 5 figures, published in the Astrophysical Journal, volume 713, page 134

Cessation of deliberate self harm following eye movement desensitisation and reprocessing: A case report

We present a case report of an eighteen year old female patient presenting with a psychological trauma related complaint. Part of the manifestation of the complaint included acts of self cutting over a number of years. Following two sessions of Eye Movement Desensitization & Reprocessing with one of the authors (DM) her self cutting ceased. This is maintained at thirteen months follow up. We conclude that Eye Movement Desensitization & Reprocessing may be an effective treatment option in reducing repeat self harm where traumatic events are noted to be the precursor to deliberate self harm

Recovery from PTSD following Hurricane Katrina

Background: We examined patterns and correlates of speed of recovery of estimated posttraumatic stress disorder (PTSD) among people who developed PTSD in the wake of Hurricane Katrina. Method: A probability sample of prehurricane residents of areas affected by Hurricane Katrina was administered a telephone survey 7–19 months following the hurricane and again 24–27 months posthurricane. The baseline survey assessed PTSD using a validated screening scale and assessed a number of hypothesized predictors of PTSD recovery that included sociodemographics, prehurricane history of psychopathology, hurricane‐related stressors, social support, and social competence. Exposure to posthurricane stressors and course of estimated PTSD were assessed in a follow‐up interview. Results: An estimated 17.1% of respondents had a history of estimated hurricane‐related PTSD at baseline and 29.2% by the follow‐up survey. Of the respondents who developed estimated hurricane‐related PTSD, 39.0% recovered by the time of the follow‐up survey with a mean duration of 16.5 months. Predictors of slow recovery included exposure to a life‐threatening situation, hurricane‐related housing adversity, and high income. Other sociodemographics, history of psychopathology, social support, social competence, and posthurricane stressors were unrelated to recovery from estimated PTSD. Conclusions: The majority of adults who developed estimated PTSD after Hurricane Katrina did not recover within 18–27 months. Delayed onset was common. Findings document the importance of initial trauma exposure severity in predicting course of illness and suggest that pre‐ and posttrauma factors typically associated with course of estimated PTSD did not influence recovery following Hurricane Katrina. Depression and Anxiety, 2011.  © 2011 Wiley‐Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87167/1/20790_ftp.pd

The Luminosity, Mass, and Age Distributions of Compact Star Clusters in M83 Based on HST/WFC3 Observations

The newly installed Wide Field Camera 3 (WFC3) on the Hubble Space Telescope has been used to obtain multi-band images of the nearby spiral galaxy M83. These new observations are the deepest and highest resolution images ever taken of a grand-design spiral, particularly in the near ultraviolet, and allow us to better differentiate compact star clusters from individual stars and to measure the luminosities of even faint clusters in the U band. We find that the luminosity function for clusters outside of the very crowded starburst nucleus can be approximated by a power law, dN/dL \propto L^{alpha}, with alpha = -2.04 +/- 0.08, down to M_V ~ -5.5. We test the sensitivity of the luminosity function to different selection techniques, filters, binning, and aperture correction determinations, and find that none of these contribute significantly to uncertainties in alpha. We estimate ages and masses for the clusters by comparing their measured UBVI,Halpha colors with predictions from single stellar population models. The age distribution of the clusters can be approximated by a power-law, dN/dt propto t^{gamma}, with gamma=-0.9 +/- 0.2, for M > few x 10^3 Msun and t < 4x10^8 yr. This indicates that clusters are disrupted quickly, with ~80-90% disrupted each decade in age over this time. The mass function of clusters over the same M-t range is a power law, dN/dM propto M^{beta}, with beta=-1.94 +/- 0.16, and does not have bends or show curvature at either high or low masses. Therefore, we do not find evidence for a physical upper mass limit, M_C, or for the earlier disruption of lower mass clusters when compared with higher mass clusters, i.e. mass-dependent disruption. We briefly discuss these implications for the formation and disruption of the clusters.Comment: 36 pages, 13 figures, 1 table; accepted for publication in the Astrophysical Journa