Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial : study protocol for a randomized controlled trial

Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI

HER2-family signalling mechanisms, clinical implications and targeting in breast cancer.

Approximately 20 % of human breast cancers (BC) overexpress HER2 protein, and HER2-positivity is associated with a worse prognosis. Although HER2-targeted therapies have significantly improved outcomes for HER2-positive BC patients, resistance to trastuzumab-based therapy remains a clinical problem. In order to better understand resistance to HER2-targeted therapies in HER2-positive BC, it is necessary to examine HER family signalling as a whole. An extensive literature search was carried out to critically assess the current knowledge of HER family signalling in HER2-positive BC and response to HER2-targeted therapy. Known mechanisms of trastuzumab resistance include reduced receptor-antibody binding (MUC4, p95HER2), increased signalling through alternative HER family receptor tyrosine kinases (RTK), altered intracellular signalling involving loss of PTEN, reduced p27kip1, or increased PI3K/AKT activity and altered signalling via non-HER family RTKs such as IGF1R. Emerging strategies to circumvent resistance to HER2-targeted therapies in HER2-positive BC include co-targeting HER2/PI3K, pan-HER family inhibition, and novel therapies such as T-DM1. There is evidence that immunity plays a key role in the efficacy of HER-targeted therapy, and efforts are being made to exploit the immune system in order to improve the efficacy of current anti-HER therapies. With our rapidly expanding understanding of HER2 signalling mechanisms along with the repertoire of HER family and other targeted therapies, it is likely that the near future holds further dramatic improvements to the prognosis of women with HER2-positive BC

Nothing Lasts Forever: Environmental Discourses on the Collapse of Past Societies

The study of the collapse of past societies raises many questions for the theory and practice of archaeology. Interest in collapse extends as well into the natural sciences and environmental and sustainability policy. Despite a range of approaches to collapse, the predominant paradigm is environmental collapse, which I argue obscures recognition of the dynamic role of social processes that lie at the heart of human communities. These environmental discourses, together with confusion over terminology and the concepts of collapse, have created widespread aporia about collapse and resulted in the creation of mixed messages about complex historical and social processes

Влияние фосфатных связующих на физико-механические свойства периклазохромитовых огнеупоров

У данній статті наведено та порівняно фізико-механічні властивості периклазо-хромітових матеріалів в залежності від різних типів фосфатних зв’язуючих та введення різних домішок. Визначено, що найбільш раціональним є введення триполіфосфату натрію.In given clause are resulted and the physycal-mechanical properties periclase-cgromite of materials are compared depending on different of types phosphate binding and introduction of the various additives. Is determined, that most rational is the introduction treepolyphosphate sodume

Lettuce Cultivar Mediates Both Phyllosphere and Rhizosphere Activity of Escherichia coli O157:H7

Plant roots and leaves can be colonized by human pathogenic bacteria, and accordingly some of the largest outbreaks of foodborne illness have been associated with salad leaves contaminated by E. coli O157. Integrated disease management strategies often exploit cultivar resistance to provide a level of protection from economically important plant pathogens; however, there is limited evidence of whether the genotype of the plant can also influence the extent of E. coli O157 colonization. To determine cultivar-specific effects on colonization by E. coli O157, we used 12 different cultivars of lettuce inoculated with a chromosomally lux-marked strain of E. coli O157:H7. Lettuce seedlings grown gnotobiotically in vitro did exhibit a differential cultivar-specific response to E. coli O157 colonization, although importantly there was no relationship between metabolic activity (measured as bioluminescence) and cell numbers. Metabolic activity was highest and lowest on the cultivars Vaila-winter gem and Dazzle respectively, and much higher in endophytic and tightly bound cells than in epiphytic and loosely bound cells. The cultivar effect was also evident in the rhizosphere of plants grown in compost, which suggests that cultivar-specific root exudate influences E. coli O157 activity. However, the influence of cultivar in the rhizosphere was the opposite to that in the phyllosphere, and the higher number and activity of E. coli O157 cells in the rhizosphere may be a consequence of them not being able to gain entry to the plant as effectively. If metabolic activity in the phyllosphere corresponds to a more prepared state of infectivity during human consumption, leaf internalization of E. coli O157 may pose more of a public health risk than leaf surface contamination alone

Terahertz photometer to observe solar flares in continuum

Solar observations at sub-THz frequencies detected a new flare spectral component peaking in the THz range, simultaneously with the well known microwaves component, bringing challenging constraints for interpretation. Higher THz frequencies observations are needed to understand the nature of the mechanisms occurring in flares. A THz photometer system was developed to observe outside the terrestrial atmosphere on stratospheric balloons or satellites, or at exceptionally transparent ground stations. The telescope was designed to observe the whole solar disk detecting small relative changes in input temperature caused by flares at localized positions. A Golay cell detector is preceded by low-pass filters to suppress visible and near IR radiation, a band-pass filter, and a chopper. A prototype was assembled to demonstrate the new concept and the system performance. It can detect temperature variations smaller than 1 K for data sampled at a rate of 10/second, smoothed for intervals larger than 4 seconds. For a 76 mm aperture, this corresponds to small solar burst intensities at THz frequencies. A system with 3 and 7 THz photometers is being built for solar flare observations on board of stratospheric balloon missions.Comment: 11 pages, 8 figures, accepted by Journal of Infrared, Millimeter, and Terahertz Waves, 9 December 201

Bats Avoid Radar Installations: Could Electromagnetic Fields Deter Bats from Colliding with Wind Turbines?

Large numbers of bats are killed by collisions with wind turbines, and there is at present no direct method of reducing or preventing this mortality. We therefore determine whether the electromagnetic radiation associated with radar installations can elicit an aversive behavioural response in foraging bats. Four civil air traffic control (ATC) radar stations, three military ATC radars and three weather radars were selected, each surrounded by heterogeneous habitat. Three sampling points matched for habitat type and structure, dominant vegetation species, altitude and surrounding land class were located at increasing distances from each station. A portable electromagnetic field meter measured the field strength of the radar at three distances from the source: in close proximity (<200 m) with a high electromagnetic field (EMF) strength >2 volts/metre, an intermediate point within line of sight of the radar (200–400 m) and with an EMF strength <2 v/m, and a control site out of sight of the radar (>400 m) and registering an EMF of zero v/m. At each radar station bat activity was recorded three times with three independent sampling points monitored on each occasion, resulting in a total of 90 samples, 30 of which were obtained within each field strength category. At these sampling points, bat activity was recorded using an automatic bat recording station, operated from sunset to sunrise. Bat activity was significantly reduced in habitats exposed to an EMF strength of greater than 2 v/m when compared to matched sites registering EMF levels of zero. The reduction in bat activity was not significantly different at lower levels of EMF strength within 400 m of the radar. We predict that the reduction in bat activity within habitats exposed to electromagnetic radiation may be a result of thermal induction and an increased risk of hyperthermia

Anti-erbB2 treatment induces cardiotoxicity by interfering with cell survival pathways

INTRODUCTION: Cardiac dysfunction is among the serious side effects of therapy with recombinant humanized anti-erbB2 monoclonal antibody. The antibody blocks ErbB-2, a receptor tyrosine kinase and co-receptor for other members of the ErbB and epidermal growth factor families, which is over-expressed on the surface of many malignant cells. ErbB-2 and its ligands neuregulin and ErbB-3/ErbB-4 are involved in survival and growth of cardiomyocytes in both postnatal and adult hearts, and therefore the drug may interrupt the correct functioning of the ErbB-2 pathway. METHODS: The effect of the rat-anti-erbB2 monoclonal antibody B-10 was studied in spontaneously beating primary myocyte cultures from rat neonatal hearts. Gene expression was determined by RT-PCR (reverse transcription polymerase chain reaction) and by rat stress-specific microarray analysis, protein levels by Western blot, cell contractility by video motion analysis, calcium transients by the FURA fluorescent method, and apoptosis using the TUNEL (terminal uridine nick-end labelling) assay. RESULTS: B-10 treatment induces significant changes in expression of 24 out of 207 stress genes analyzed using the microarray technique. Protein levels of ErbB-2, ErbB-3, ErbB-4 and neuregulin decreased after 1 day. However, both transcription and protein levels of ErbB-4 and gp130 increased several fold. Calreticulin and calsequestrin were overexpressed after three days, inducing a decrease in calcium transients, thereby influencing cell contractility. Apoptosis was induced in 20% cells after 24 hours. CONCLUSION: Blocking ErbB-2 in cultured rat cardiomyocytes leads to changes that may influence the cell cycle and affects genes involved in heart functions. B-10 inhibits pro-survival pathways and reduces cellular contractility. Thus, it is conceivable that this process may impair the stress response of the heart

Discovery of potent, novel, non-toxic anti-malarial compounds via quantum modelling, virtual screening and in vitro experimental validation

<p>Abstract</p> <p>Background</p> <p>Developing resistance towards existing anti-malarial therapies emphasize the urgent need for new therapeutic options. Additionally, many malaria drugs in use today have high toxicity and low therapeutic indices. Gradient Biomodeling, LLC has developed a quantum-model search technology that uses quantum similarity and does not depend explicitly on chemical structure, as molecules are rigorously described in fundamental quantum attributes related to individual pharmacological properties. Therapeutic activity, as well as toxicity and other essential properties can be analysed and optimized simultaneously, independently of one another. Such methodology is suitable for a search of novel, non-toxic, active anti-malarial compounds.</p> <p>Methods</p> <p>A set of innovative algorithms is used for the fast calculation and interpretation of electron-density attributes of molecular structures at the quantum level for rapid discovery of prospective pharmaceuticals. Potency and efficacy, as well as additional physicochemical, metabolic, pharmacokinetic, safety, permeability and other properties were characterized by the procedure. Once quantum models are developed and experimentally validated, the methodology provides a straightforward implementation for lead discovery, compound optimizzation and <it>de novo </it>molecular design.</p> <p>Results</p> <p>Starting with a diverse training set of 26 well-known anti-malarial agents combined with 1730 moderately active and inactive molecules, novel compounds that have strong anti-malarial activity, low cytotoxicity and structural dissimilarity from the training set were discovered and experimentally validated. Twelve compounds were identified <it>in silico </it>and tested <it>in vitro</it>; eight of them showed anti-malarial activity (IC50 ≤ 10 μM), with six being very effective (IC50 ≤ 1 μM), and four exhibiting low nanomolar potency. The most active compounds were also tested for mammalian cytotoxicity and found to be non-toxic, with a therapeutic index of more than 6,900 for the most active compound.</p> <p>Conclusions</p> <p>Gradient's metric modelling approach and electron-density molecular representations can be powerful tools in the discovery and design of novel anti-malarial compounds. Since the quantum models are agnostic of the particular biological target, the technology can account for different mechanisms of action and be used for <it>de novo </it>design of small molecules with activity against not only the asexual phase of the malaria parasite, but also against the liver stage of the parasite development, which may lead to true causal prophylaxis.</p