Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.

Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease

Dead or alive: sediment DNA archives as tools for tracking aquatic evolution and adaptation

DNA can be preserved in marine and freshwater sediments both in bulk sediment and in intact, viable resting stages. Here, we assess the potential for combined use of ancient, environmental, DNA and timeseries of resurrected long-term dormant organisms, to reconstruct trophic interactions and evolutionary adaptation to changing environments. These new methods, coupled with independent evidence of biotic and abiotic forcing factors, can provide a holistic view of past ecosystems beyond that offered by standard palaeoecology, help us assess implications of ecological and molecular change for contemporary ecosystem functioning and services, and improve our ability to predict adaptation to environmental stress

Interpreting and acting upon home blood pressure readings: A qualitative study

This article is made available through the Brunel Open Access Publishing Fund. Copyright @ 2013 Vasileiou et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Recent guidelines recognize the importance of home blood pressure monitoring (HBPM) as an adjunct to clinical measurements. We explored how people who have purchased and use a home blood pressure (BP) monitor make sense of, and act upon, readings and how they communicate with their doctor about the practice of home monitoring. Methods: A qualitative study was designed and participants were purposively recruited from several areas in England, UK. Semi-structured in-depth interviews were conducted with 18 users of home BP monitors. The transcribed data were thematically analysed. Results: Interpretation of home BP readings is complex, and is often characterised by uncertainty. People seek to assess value normality using ‘rules of thumb’, and often aim to identify the potential causes of the readings. This is done by drawing on lay models of BP function and by contextualising the readings to personal circumstances. Based on the perceived causes of the problematic readings, actions are initiated, mostly relating to changes in daily routines. Contacting the doctor was more likely when the problematic readings persisted and could not be easily explained, or when participants did not succeed in regulating their BP through their other interventions. Most users had notified their doctor of the practice of home monitoring, but medical involvement varied, with some participants reporting disinterest or reservations by doctors. Conclusions: Involvement from doctors can help people overcome difficulties and resolve uncertainties around the interpretation of home readings, and ensure that the rules of thumb are appropriate. Home monitoring can be used to strengthen the patient-clinician relationship

Mass extinctions and supernova explosions

A nearby supernova (SN) explosion could have negatively influenced life on Earth, maybe even been responsible for mass extinctions. Mass extinction poses a significant extinction of numerous species on Earth, as recorded in the paleontologic, paleoclimatic, and geological record of our planet. Depending on the distance between the Sun and the SN, different types of threats have to be considered, such as ozone depletion on Earth, causing increased exposure to the Sun's ultraviolet radiation, or the direct exposure of lethal x-rays. Another indirect effect is cloud formation, induced by cosmic rays in the atmosphere which result in a drop in the Earth's temperature, causing major glaciations of the Earth. The discovery of highly intensive gamma ray bursts (GRBs), which could be connected to SNe, initiated further discussions on possible life-threatening events in Earth's history. The probability that GRBs hit the Earth is very low. Nevertheless, a past interaction of Earth with GRBs and/or SNe cannot be excluded and might even have been responsible for past extinction events.Comment: Chapter for forthcoming book: Handbook of Supernovae, P. Murdin and A. Alsabeti (eds.), Springer International Publishing (in press

The role of passion in exercise addiction, exercise volume, and exercise intensity in long-term exercisers

Recent studies have shown a relationship between the risk for exercise addiction (REA) and passion. This research examined whether levels of REA, volume of exercise (in weekly hours), and self-reported exercise intensities yield differences in obsessive passion and harmonious passion among individuals with long history of exercise. Respondents (n = 360) completed the Exercise Addiction Inventory, Passion Scale, and Borg Scale (assessing their usual exercise intensity), and reported their volume of exercise (hours per week). Regression analysis demonstrated that exercise intensity, obsessive passion, and harmonious passion were significant predictors (r2 = .381, p < .001) of the REA scores with obsessive passion being the strongest predictor (r2 = .318). Exercisers classified as at REA reported higher obsessive passion, harmonious passion, and exercise intensity (p ≤ .001) than those classified as symptomatic, who in turn scored higher on these measures (p ≤ .006) than asymptomatic exercisers. Participants reporting greater volumes of exercise also scored higher on obsessive passion, harmonious passion (p < .001), exercise intensity (p = .032), and REA scores (p = .042) than individuals who exercised less. Finally, women exercising between low and high intensities exhibited greater obsessive passion, as well as harmonious passion (p ≤ .005) than men reporting similar exercise intensities. These findings support the recently reported relationship between passion and REA. They also expand the current knowledge by demonstrating that obsessive passion and harmonious passion are greater in the individuals who exercise at higher volumes and with higher intensities

Cirsium species show disparity in patterns of genetic variation at their range-edge, despite similar patterns of reproduction and isolation

Genetic variation was assessed across the UK geographical range of Cirsium acaule and Cirsium heterophyllum. A decline in genetic diversity and increase in population divergence approaching the range edge of these species was predicted based on parallel declines in population density and seed production reported seperately. Patterns were compared with UK populations of the widespread Cirsium arvense.Populations were sampled along a latitudinal transect in the UK and genetic variation assessed using microsatellite markers. Cirsium acaule shows strong isolation by distance, a significant decline in diversity and an increase in divergence among range-edge populations. Geographical structure is also evident in C. arvense, whereas no such patterns are seen in C.heterophyllum. There is a major disparity between patterns of genetic variation in C. acaule and C. heterophyllum despite very similar patterns in seed production and population isolation in these species. This suggests it may be misleading to make assumptions about the geographical structure of genetic variation within species based solely on the present-day reproduction and distribution of populations

Structure, chemistry, and charge transfer resistance of the interface between Li7La3Zr2O12 electrolyte and LiCoO2 cathode

All-solid-state batteries promise significant safety and energy density advantages over liquid-electrolyte batteries. The interface between the cathode and the solid electrolyte is an important contributor to charge transfer resistance. Strong bonding of solid oxide electrolytes and cathodes requires sintering at elevated temperatures. Knowledge of the temperature dependence of the composition and charge transfer properties of this interface is important for determining the ideal sintering conditions. To understand the interfacial decomposition processes and their onset temperatures, model systems of LiCoO2 (LCO) thin films deposited on cubic Al-doped Li7La3Zr2O12 (LLZO) pellets were studied as a function of temperature using interface-sensitive techniques. X-ray photoelectron spectroscopy (XPS), secondary ion mass spectroscopy (SIMS), and energy-dispersive X-ray spectroscopy (EDS) data indicated significant cation interdiffusion and structural changes starting at temperatures as low as 300°C. La2Zr2O7 and Li2CO3 were identified as decomposition products after annealing at 500°C by synchrotron X-ray diffraction (XRD). X-ray absorption spectroscopy (XAS) results indicate the presence of also LaCoO3, in addition to La2Zr2O7 and Li2CO3. Based on electrochemical impedance spectroscopy, and depth profiling of the Li distribution upon potentiostatic hold experiments on symmetric LCO|LLZO|LCO cells, the interfaces exhibited significantly increased impedance, up to 8 times that of the as-deposited samples after annealing at 500°C. Our results indicate that lower-temperature processing conditions, shorter annealing time scales, and CO2-free environments are desirable for obtaining ceramic cathode-electrolyte interfaces that enable fast Li transfer and high capacity

Presumed stromal graft rejection after automated lamellar therapeutic keratoplasty: case report

PURPOSE: To describe the development of presumed immune-mediated stromal rejection after automated lamellar therapeutic keratoplasty (ALTK) and its reversal after initiation of intensive topical corticosteroid therapy. METHODS: Observational case report. RESULTS: Stromal edema localized in the graft developed 42 days after ALTK for Avellino corneal dystrophy in a 65-year-old man. After one week of intensive topical corticosteroids, complete reversal of graft edema occurred, with full recovery of visual function. CONCLUSION: The clinical appearance and response to therapy in this case supported the diagnosis of immune-mediated stromal rejection. Ophthalmologists should be aware that stromal rejection may occur in lamellar corneal grafts

Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: a blinded crossover study

Nausea is a subjective sensation which is difficult to measure in non-verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18 mg/m2 cisplatin intravenously, followed 45 min later by a 15 min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5 mg/kg; 5-HT3 antagonist), maropitant (1 mg/kg; NK1 antagonist) or metoclopramide (0.5 mg/kg; D2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15 min for 8 h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations

Effect of different UCOE-promoter combinations in creation of engineered cell lines for the production of Factor VIII

<p>Abstract</p> <p>Background</p> <p>The most common approach used in generating cell lines for the production of therapetic proteins relies on gene amplification induced by a drug resistance gene e. g., DHFR and glutamine synthetase. Practically, this results in screening large number of clones for the one that expresses high levels of the biologic in a stable manner. The inefficiency of mammalian vector systems to express proteins in a stable manner typically involves silencing of the exogenous gene resulting from modifications such as methylation of CpG DNA sequences, histone deacetylation and chromatin condensation. The use of un-methylated CpG island fragments from housekeeping genes referred to as UCOE (ubiquitous chromatin opening elements) in plasmid vectors is now well established for increased stability of transgene expression. However, few UCOE-promoter combinations have been studied to date and in this report we have tested 14 different combinations.</p> <p>Findings</p> <p>In this report we describe studies with two different UCOEs (the 1.5 Kb human RNP fragment and the 3.2 Kb mouse RPS3 fragment) in combination with various promoters to express a large protein (B domain deleted factor VIII; BDD-FVIII) in a production cell line, BHK21. We show here that there are differences in expression of BDD-FVIII by the different UCOE-promoter combinations in both attached and serum free suspension adapted cells. In all cases, the 1.5 Kb human RNP UCOE performed better in expressing BDD-FVIII than their corresponding 3.2 Kb mouse RPS3 UCOE. Surprisingly, in certain scenarios described here, expression from a number of promoters was equivalent or higher than the commonly used and industry standard human CMV promoter.</p> <p>Conclusion</p> <p>This study indicates that certain UCOE-promoter combinations are better than others in expressing the BDD-FVIII protein in a stable manner in BHK21 cells. An empirical study such as this is required to determine the best combination of UCOE-promoter in a vector for a particular production cell line.</p