Low oxygen tension reverses antineoplastic effect of iron chelator deferasirox in human glioblastoma cells

Background Overcoming resistance to treatment is an essential issue in many cancers including glioblastoma (GBM), the deadliest primary tumor of the central nervous system. As dependence on iron is a key feature of tumor cells, using chelators to reduce iron represents an opportunity to improve conventional GBM therapies. The aim of the present study was, therefore, to investigate the cytostatic and cytotoxic impact of the new iron chelator deferasirox (DFX) on human GBM cells in well-defined clinical situations represented by radiation therapy and mild-hypoxia. Results Under experimental normoxic condition (21 % O2), deferasirox (DFX) used at 10 μM for 3 days reduced proliferation, led cell cycle arrest in S and G2-M phases and induced cytotoxicity and apoptosis in U251 and U87 GBM cells. The abolition of the antineoplastic DFX effects when cells were co-treated with ferric ammonium sulfate supports the hypothesis that its effects result from its ability to chelate iron. As radiotherapy is the main treatment for GBM, the combination of DFX and X-ray beam irradiation was also investigated. Irradiation at a dose of 16 Gy repressed proliferation, cytotoxicity and apoptosis, but only in U251 cells, while no synergy with DFX was observed in either cell line. Importantly, when the same experiment was conducted in mild-hypoxic conditions (3 % O2), the antiproliferative and cytotoxic effects of DFX were abolished, and its ability to deplete iron was also impaired. Conclusions Taken together, these in vitro results could raise the question of the benefit of using iron chelators in their native forms under the hypoxic conditions often encountered in solid tumors such as GBM. Developing new chemistry or a new drug delivery system that would keep DFX active in hypoxic cells may be the next step toward their application

Rapid formation of large dust grains in the luminous supernova SN 2010jl

The origin of dust in galaxies is still a mystery. The majority of the refractory elements are produced in supernova explosions but it is unclear how and where dust grains condense and grow, and how they avoid destruction in the harsh environments of star-forming galaxies. The recent detection of 0.1-0.5 solar masses of dust in nearby supernova remnants suggests in situ dust formation, while other observations reveal very little dust in supernovae the first few years after explosion. Observations of the bright SN 2010jl have been interpreted as pre-existing dust, dust formation or no dust at all. Here we report the rapid (40-240 days) formation of dust in its dense circumstellar medium. The wavelength dependent extinction of this dust reveals the presence of very large (> 1 micron) grains, which are resistant to destructive processes. At later times (500-900 days), the near-IR thermal emission shows an accelerated growth in dust mass, marking the transition of the supernova from a circumstellar- to an ejecta-dominated source of dust. This provides the link between the early and late dust mass evolution in supernovae with dense circumstellar media.Comment: 62 pages, 13 figures, 1 table. Author version of the Letter to Nature, published online July 9 2014 (Nature, 511, 7509, pp. 326-329 (2014)), prior to the final editorial changes to conform to Journal style; includes Methods and Extended Data Figures and the Supplementary Information. See published version http://www.nature.com/nature/journal/v511/n7509/full/nature13558.htm

Discovery-dominance trade-off among widespread invasive ant species.

Ants are among the most problematic invasive species. They displace numerous native species, alter ecosystem processes, and can have negative impacts on agriculture and human health. In part, their success might stem from a departure from the discovery-dominance trade-off that can promote co-existence in native ant communities, that is, invasive ants are thought to be at the same time behaviorally dominant and faster discoverers of resources, compared to native species. However, it has not yet been tested whether similar asymmetries in behavioral dominance, exploration, and recruitment abilities also exist among invasive species. Here, we establish a dominance hierarchy among four of the most problematic invasive ants (Linepithema humile, Lasius neglectus, Wasmannia auropunctata, Pheidole megacephala) that may be able to arrive and establish in the same areas in the future. To assess behavioral dominance, we used confrontation experiments, testing the aggressiveness in individual and group interactions between all species pairs. In addition, to compare discovery efficiency, we tested the species' capacity to locate a food resource in a maze, and the capacity to recruit nestmates to exploit a food resource. The four species differed greatly in their capacity to discover resources and to recruit nestmates and to dominate the other species. Our results are consistent with a discovery-dominance trade-off. The species that showed the highest level of interspecific aggressiveness and dominance during dyadic interactions

Hip precautions after hip operation (HippityHop): protocol for a before and after study evaluating hip precautions following total hip replacement

Introduction Hip precautions are routinely used despite inconclusive evidence that they reduce dislocations, and concern that they impede activities of daily living. HippityHop compares a change in practice locally from implementing routine hip precautions to no routine precautions, in order to: 1. Compare patient outcomes in quality of life, functional performance, pain, sleep, mood and satisfaction. 2. Ascertain staff and patient perceptions of the two regimes. 3. Determine the cost of precautions. Methods Before and after study: phase one patients will receive hip precautions, while phase two patients will receive no routine precautions. We propose to collect data from 342 participants at baseline, and at one week, six weeks, and three months postoperatively. Interviews will be conducted with 20 staff and 20 patients, and data collected relating to costs. Results Statistical analysis will be conducted to compare the two groups to determine any differences in patient outcomes. Thematic analysis will be used to identify and report themes within the interview data. Conclusion If there are no additional advantages to hip precautions, patients could resume everyday activities more quickly, potentially improving their quality of life. Conversely, if withdrawing hip precautions is detrimental, evidence for precautions will be provided

Identification of plastic constitutive parameters at large deformations from three dimensional displacement fields

The aim of this paper is to provide a general procedure to extract the constitutive parameters of a plasticity model starting from displacement measurements and using the Virtual Fields Method. This is a classical inverse problem which has been already investigated in the literature, however several new features are developed here. First of all the procedure applies to a general three-dimensional displacement field which leads to large plastic deformations, no assumptions are made such as plane stress or plane strain although only pressure-independent plasticity is considered. Moreover the equilibrium equation is written in terms of the deviatoric stress tensor that can be directly computed from the strain field without iterations. Thanks to this, the identification routine is much faster compared to other inverse methods such as finite element updating. The proposed method can be a valid tool to study complex phenomena which involve severe plastic deformation and where the state of stress is completely triaxial, e.g. strain localization or necking occurrence. The procedure has been validated using a three dimensional displacement field obtained from a simulated experiment. The main potentialities as well as a first sensitivity study on the influence of measurement errors are illustrated

The Cytokine Release Inhibitory Drug CRID3 Targets ASC Oligomerisation in the NLRP3 and AIM2 Inflammasomes

Background: The Inflammasomes are multi-protein complexes that regulate caspase-1 activation and the production of the pro-inflammatory cytokine IL-1 beta. Previous studies identified a class of diarylsulfonylurea containing compounds called Cytokine Release Inhibitory Drugs (CRIDs) that inhibited the post-translational processing of IL-1 beta. Further work identified Glutathione S-Transferase Omega 1 (GSTO1) as a possible target of these CRIDs. This study aimed to investigate the mechanism of the inhibitory activity of the CRID CP-456,773 (termed CRID3) in light of recent advances in the area of inflammasome activation, and to clarify the potential role of GSTO1 in the regulation of IL-1 beta production

Getting the inactive active : implications for public health policy

Epidemiological data have established that a sedentary lifestyle increases the incidence of at least 17 medical conditions. The evidence is strongest for coronary heart disease. A sedentary lifestyle is now the normal lifestyle for the majority of the populations in developed countries and relapse from regular physical activity is also high. Thus there is clear need for public policy aimed at increasing the physical activity levels in the population. Policy makers have begun to respond to this need and recently Scottish and English plans for increasing physical activity levels in the populations have been published