Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer

High-grade serous cancer (HGSC) accounts for ~67% of all ovarian cancer deaths. Although initially sensitive to platinum chemotherapy, resistance is inevitable and there is an unmet clinical need for novel therapies that can circumvent this event. We performed a drug screen with 1177 FDA-approved drugs and identified the hydroxyquinoline drug, chloroxine. In extensive validation experiments, chloroxine restored sensitivity to both cisplatin and carboplatin, demonstrating broad synergy in our range of experimental models of platinum-resistant HGSC. Synergy was independent of chloroxine’s predicted ionophore activity and did not relate to platinum uptake as measured by atomic absorption spectroscopy. Further mechanistic investigation revealed that chloroxine overrides DNA damage tolerance in platinum-resistant HGSC. Co-treatment with carboplatin and chloroxine (but not either drug alone) caused an increase in γH2AX expression, followed by a reduction in platinum-induced RAD51 foci. Moreover, this unrepaired DNA damage was associated with p53 stabilisation, cell cycle re-entry and triggering of caspase 3/7- mediated cell death. Finally, in our platinum-resistant, intraperitoneal in vivo model, treatment with carboplatin alone resulted in a transient tumour response followed by tumour regrowth. In contrast, treatment with chloroxine and carboplatin combined, was able to maintain tumour volume at baseline for over 4 months. In conclusion, our novel results show that chloroxine facilitates platinum-induced DNA damage to restore platinum sensitivity in HGSC. Since chloroxine is already licensed, this exciting combination therapy could now be rapidly translated for patient benefit

Magnetohydrodynamics dynamical relaxation of coronal magnetic fields. I. Parallel untwisted magnetic fields in 2D

Context. For the last thirty years, most of the studies on the relaxation of stressed magnetic fields in the solar environment have onlyconsidered the Lorentz force, neglecting plasma contributions, and therefore, limiting every equilibrium to that of a force-free field. Aims. Here we begin a study of the non-resistive evolution of finite beta plasmas and their relaxation to magnetohydrostatic states, where magnetic forces are balanced by plasma-pressure gradients, by using a simple 2D scenario involving a hydromagnetic disturbance to a uniform magnetic field. The final equilibrium state is predicted as a function of the initial disturbances, with aims to demonstrate what happens to the plasma during the relaxation process and to see what effects it has on the final equilibrium state. Methods. A set of numerical experiments are run using a full MHD code, with the relaxation driven by magnetoacoustic waves damped by viscous effects. The numerical results are compared with analytical calculations made within the linear regime, in which the whole process must remain adiabatic. Particular attention is paid to the thermodynamic behaviour of the plasma during the relaxation. Results. The analytical predictions for the final non force-free equilibrium depend only on the initial perturbations and the total pressure of the system. It is found that these predictions hold surprisingly well even for amplitudes of the perturbation far outside the linear regime. Conclusions. Including the effects of a finite plasma beta in relaxation experiments leads to significant differences from the force-free case

Pre-flare activity and magnetic reconnection during the evolutionary stages of energy release in a solar eruptive flare

In this paper, we present a multi-wavelength analysis of an eruptive white-light M3.2 flare which occurred in active region NOAA 10486 on November 1, 2003. Excellent set of high resolution observations made by RHESSI and TRACE provide clear evidence of significant pre-flare activities for ~9 minutes in the form of an initiation phase observed at EUV/UV wavelengths followed by the X-ray precursor phase. During the initiation phase, we observed localized brightenings in the highly sheared core region close to the filament and interactions among short EUV loops overlying the filament which led to the opening of magnetic field lines. The X-ray precursor phase is manifested in RHESSI measurements below ~30 keV and coincided with the beginning of flux emergence at the flaring location along with early signatures of the eruption. From the RHESSI observations, we conclude that both plasma heating and electron acceleration occurred during the precursor phase. The main flare is consistent with the standard flare model. However, after the impulsive phase, intense HXR looptop source was observed without significant footpoint emission. More intriguingly, for a brief period the looptop source exhibited strong HXR emission with energies up to 100 keV and significant non-thermal characteristics. The present study indicates a causal relation between the activities in the preflare and main flare. We also conclude that pre-flare activities, occurred in the form of subtle magnetic reorganization along with localized magnetic reconnection, played a crucial role in destabilizing the active region filament leading to solar eruptive flare and associated large-scale phenomena.Comment: 31 pages, 13 figures; Accepted in The Astrophysical Journa

Carvedilol targets beta-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy

Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer. We use a drug-repurposing approach to identify existing drugs that enhance the activity of oncolytic adenoviruses. This reveals that carvedilol, a β-arrestin-biased β-blocker, synergises with both wild-type adenovirus and the E1A-CR2-deleted oncolytic adenovirus, dl922-947. Synergy is not due to β-adrenergic blockade but is dependent on β-arrestins and is reversed by β-arrestin CRISPR gene editing. Co-treatment with dl922-947 and carvedilol causes increased viral DNA replication, greater viral protein expression and higher titres of infectious viral particles. Carvedilol also enhances viral efficacy in orthotopic, intraperitoneal murine models, achieving more rapid tumour clearance than virus alone. Increased anti-cancer activity is associated with an intratumoural inflammatory cell infiltrate and systemic cytokine release. In summary, carvedilol augments the activity of oncolytic adenoviruses via β-arrestins to re-wire cytokine networks and innate immunity and could therefore improve oncolytic viruses for cancer patient treatment

Conjugate Hard X-ray Footpoints in the 2003 October 29 X10 Flare: Unshearing Motions, Correlations, and Asymmetries

We present a detailed imaging and spectroscopic study of the conjugate hard X-ray (HXR) footpoints (FPs) observed with RHESSI in the 2003 October 29 X10 flare. The double FPs first move toward and then away from each other, mainly parallel and perpendicular to the magnetic neutral line, respectively. The transition of these two phases of FP unshearing motions coincides with the direction reversal of the motion of the loop-top (LT) source, and with the minima of the estimated loop length and LT height. The FPs show temporal correlations between HXR flux, spectral index, and magnetic field strength. The HXR flux exponentially correlates with the magnetic field strength, which also anti-correlates with the spectral index before the second HXR peak's maximum, suggesting that particle acceleration sensitively depends on the magnetic field strength and/or reconnection rate. Asymmetries are observed between the FPs: on average, the eastern FP is 2.2 times brighter in HXR flux and 1.8 times weaker in magnetic field strength, and moves 2.8 times faster away from the neutral line than the western FP; the estimated coronal column density to the eastern FP from the LT source is 1.7 times smaller. The two FPs have marginally different spectral indexes. The eastern-to-western FP HXR flux ratio and magnetic field strength ratio are anti-correlated only before the second HXR peak's maximum. Neither magnetic mirroring nor column density alone can explain the totality of these observations, but their combination, together with other transport effects, might provide a full explanation. We have also developed novel techniques to remove particle contamination from HXR counts and to estimate effects of pulse pileup in imaging spectroscopy, which can be applied to other RHESSI flares in similar circumstances.Comment: 22 pages, 14 figures, 4 tables; ApJ 2009, in pres

Eruptions of Magnetic Ropes in Two Homologous Solar Events on 2002 June 1 and 2: a Key to Understanding of an Enigmatic Flare

The goal of this paper is to understand the drivers, configurations, and scenarios of two similar eruptive events, which occurred in the same solar active region 9973 on 2002 June 1 and 2. The June 2 event was previously studied by Sui, Holman, and Dennis (2006, 2008), who concluded that it was challenging for popular flare models. Using multi-spectral data, we analyze a combination of the two events. Each of the events exhibited an evolving cusp-like feature. We have revealed that these apparent ``cusps'' were most likely mimicked by twisted magnetic flux ropes, but unlikely to be related to the inverted Y-like magnetic configuration in the standard flare model. The ropes originated inside a funnel-like magnetic domain whose base was bounded by an EUV ring structure, and the top was associated with a coronal null point. The ropes appear to be the major drivers for the events, but their rise was not triggered by reconnection in the coronal null point. We propose a scenario and a three-dimensional scheme for these events in which the filament eruptions and flares were caused by interaction of the ropes.Comment: 22 pages, 11 figure

Re-examination of the Perturbative Pion Form Factor with Sudakov Suppression

The perturbative pion form factor with Sudakov suppression is re-examined. Taking into account the multi-gluon exchange in the law $Q^2$ regions, we suggest that the running coupling constant should be frozen at $\alpha_s(t=\sqrt{})$ and $\sqrt{}$ is the average transverse momentum which can be determined by the pionic wave function. In addition, we correct the previous calculations about the Sudakov suppression factor which plays an important role in the perturbative predictions for the pion form factor.Comment: 11 pages, LaTex file, 2 figures as uu-encoded postscript file

The effectiveness of anaerobic digestion in removing estrogens and nonylphenol ethoxylates

This is the post-print version of the final paper published in Journal of Hazardous Materials. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2011 Elsevier B.V.The fate and behaviour of two groups of endocrine disrupting chemicals, steroid estrogens and nonylphenol ethoxylates, have been evaluated during the anaerobic digestion of primary and mixed sewage sludge under mesophilic and thermophilic conditions. Digestion occurred over six retention times, in laboratory scale reactors, treating sludges collected from a sewage treatment works in the United Kingdom. It has been established that sludge concentrations of both groups of compounds demonstrated temporal variations and that concentrations in mixed sludge were influenced by the presence of waste activated sludge as a result of transformations during aerobic treatment. The biodegradation of total steroid estrogens was >50% during primary sludge digestion with lower removals observed for mixed sludge, which reflected bulk organic solids removal efficiencies. The removal of nonylphenol ethoxylates was greater in mixed sludge digestion (>58%) compared with primary sludge digestion and did not reflect bulk organic removal efficiencies. It is apparent that anaerobic digestion reduces the concentrations of these compounds, and would therefore be expected to confer a degree of protection against exposure and transfer of both groups of compounds to the receiving/re-use environment.Thames Water, Yorkshire Water, and EPSRC

Evolution of Magnetic Field and Energy in A Major Eruptive Active Region Based on SDO/HMI Observation

We report the evolution of magnetic field and its energy in NOAA active region 11158 over 5 days based on a vector magnetogram series from the Helioseismic and Magnetic Imager (HMI) on board the Solar Dynamic Observatory (SDO). Fast flux emergence and strong shearing motion led to a quadrupolar sunspot complex that produced several major eruptions, including the first X-class flare of Solar Cycle 24. Extrapolated non-linear force-free coronal fields show substantial electric current and free energy increase during early flux emergence near a low-lying sigmoidal filament with sheared kilogauss field in the filament channel. The computed magnetic free energy reaches a maximum of ~2.6e32 erg, about 50% of which is stored below 6 Mm. It decreases by ~0.3e32 erg within 1 hour of the X-class flare, which is likely an underestimation of the actual energy loss. During the flare, the photospheric field changed rapidly: horizontal field was enhanced by 28% in the core region, becoming more inclined and more parallel to the polarity inversion line. Such change is consistent with the conjectured coronal field "implosion", and is supported by the coronal loop retraction observed by the Atmospheric Imaging Assembly (AIA). The extrapolated field becomes more "compact" after the flare, with shorter loops in the core region, probably because of reconnection. The coronal field becomes slightly more sheared in the lowest layer, relaxes faster with height, and is overall less energetic.Comment: Eq. (A1) correcte

Ion Trap in a Semiconductor Chip

The electromagnetic manipulation of isolated atoms has led to many advances in physics, from laser cooling and Bose-Einstein condensation of cold gases to the precise quantum control of individual atomic ion. Work on miniaturizing electromagnetic traps to the micrometer scale promises even higher levels of control and reliability. Compared with 'chip traps' for confining neutral atoms, ion traps with similar dimensions and power dissipation offer much higher confinement forces and allow unparalleled control at the single-atom level. Moreover, ion microtraps are of great interest in the development of miniature mass spectrometer arrays, compact atomic clocks, and most notably, large scale quantum information processors. Here we report the operation of a micrometer-scale ion trap, fabricated on a monolithic chip using semiconductor micro-electromechanical systems (MEMS) technology. We confine, laser cool, and measure heating of a single 111Cd+ ion in an integrated radiofrequency trap etched from a doped gallium arsenide (GaAs) heterostructure.Comment: 4 pages, 4 figure