Dual PI3K/mTOR Inhibition with BEZ235 Augments the Therapeutic Efficacy of Doxorubicin in Cancer without Influencing Cardiac Function

Cancer continues to be a leading cause death in the United States despite improved treatments. Cancerous lesions form after acquiring oncogenic driver mutations or losing tumor suppressor function in normal cells. Traditional therapies have included use of genotoxic substances that take advantage of the increased growth rate and loss of tumor suppressor function to cause cell death. One such drug is the anthracycline antibiotic doxorubicin (DOX). DOX interchelates into DNA and disrupts transcriptional machinery while also poisoning topoisomerase II. This results in single and double stranded DNA breaks, which if severe enough leads to either necrotic or apoptotic cell death. DOX has been very effective at treating several different cancers and is still widely used today however its clinical use is limited due to cumulative dose dependent cardiotoxicity. Therefore, combination therapy targeting survival pathways is utilized to minimize the cumulative dose of DOX without ameliorating its anti-tumor effects. We investigated the potential anti-cancer effects of combining the dual PI3K/mTOR inhibitor, BEZ235 (BEZ), with DOX in pancreatic, breast and other cancer cells lines as well as its associated effects on the heart. Our results showed that co-treatment of BEZ with DOX increased apoptosis in a manner that was dependent on inhibition of the AKT survival pathway. Moreover, BEZ co-treatment with DOX had additive effects towards cell viability while it significantly enhanced necrotic cell death compared to either drug alone. Furthermore, we observed that physiological concentrations of BEZ inhibited ABCB1 efflux resulting in increased intracellular accumulation of DOX, which led to increased DNA damage. In addition, BEZ in combination with gemcitabine (Gem) reduced cell proliferation but did not enhance necrosis or apoptosis. Treatment with BEZ and DOX in mice bearing tumor xenographs reduced tumor growth as compared to BEZ, DOX or Gem. Moreover, BEZ reduced DOX toxicity in rat myoblast cells and did not potentiate the effects of DOX in tumor-bearing mice. We propose that combining BEZ with DOX could be a novel therapeutic approach for the treatment of patients with cancer in the hope of improving the prognosis of this deadly disease

The contribution of Teacher education to universities:a case study for international teacher educators

This paper reports on the initial stage of a research project which aims to develop deeper understanding of the contribution teacher education, as a sub-discipline within Education, makes to Higher Education in England. The study is located in the intersection between the domains of teacher education and higher education scholarship, which in England represents a contested and ambiguous professional space. Tensions between competing accountability measures, pulling away from university-based to exclusively school-based teacher education, are exacerbated by proposed policy changes arising from the government's recent market review. Findings drawn from analysis of qualitative data from a national survey are discussed in the context of Elizabeth Povinelli's critique of late liberalism and previous scholarship on the nature of teacher educators’ work. Evidence from the study demonstrates numerous benefits to higher education of hosting teacher education departments, including contributions to standard metrics, regional development and knowledge exchange within a strategic social justice agenda. However, teacher educators themselves may find articulating these benefits difficult, because of marginalisation from the dominant ways of achieving and accounting for excellence in the modern university. These findings offer a cautionary tale to international colleagues whose governments may be embarking on equivalent paths of teacher education reform.<br/

Gene expression in Leishmania is regulated predominantly by gene dosage

ABSTRACT Leishmania tropica, a unicellular eukaryotic parasite present in North and East Africa, the Middle East, and the Indian subcontinent, has been linked to large outbreaks of cutaneous leishmaniasis in displaced populations in Iraq, Jordan, and Syria. Here, we report the genome sequence of this pathogen and 7,863 identified protein-coding genes, and we show that the majority of clinical isolates possess high levels of allelic diversity, genetic admixture, heterozygosity, and extensive aneuploidy. By utilizing paired genome-wide high-throughput DNA sequencing (DNA-seq) with RNA-seq, we found that gene dosage, at the level of individual genes or chromosomal “somy” (a general term covering disomy, trisomy, tetrasomy, etc.), accounted for greater than 85% of total gene expression variation in genes with a 2-fold or greater change in expression. High gene copy number variation (CNV) among membrane-bound transporters, a class of proteins previously implicated in drug resistance, was found for the most highly differentially expressed genes. Our results suggest that gene dosage is an adaptive trait that confers phenotypic plasticity among natural Leishmania populations by rapid down- or upregulation of transporter proteins to limit the effects of environmental stresses, such as drug selection. IMPORTANCE Leishmania is a genus of unicellular eukaryotic parasites that is responsible for a spectrum of human diseases that range from cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) to life-threatening visceral leishmaniasis (VL). Developmental and strain-specific gene expression is largely thought to be due to mRNA message stability or posttranscriptional regulatory networks for this species, whose genome is organized into polycistronic gene clusters in the absence of promoter-mediated regulation of transcription initiation of nuclear genes. Genetic hybridization has been demonstrated to yield dramatic structural genomic variation, but whether such changes in gene dosage impact gene expression has not been formally investigated. Here we show that the predominant mechanism determining transcript abundance differences (>85%) in Leishmania tropica is that of gene dosage at the level of individual genes or chromosomal somy

Towards the improvement of methane production in CO2 photoreduction using Bi2WO6/TiO2 heterostructures

Russelite bismuth tungstate (Bi2WO6) has been widely reported for the photocatalytic degradation and mineralization of a myriad of pollutants as well as organic compounds. These materials present perovskite-like structure with hierarchical morphologies, which confers excellent optoelectronic properties as potentials candidates for photocatalytic solar fuels production. Here, we propose the development of Bi2WO6/TiO2 heterojunctions for CO2 photoreduction, as a promising solution to produce fuels, alleviate global warming and tackle fossil fuel shortage. Our results show an improvement of the photocatalytic activity of the heterojunctions compared to the pristine semiconductors. Near Ambient Pressure X-ray Photoelectron Spectroscopy (NAP-XPS) experiments reveals a preferential CO2 adsorption over TiO2. On the other hand, transient absorption spectroscopy measurements show that the charge transfer pathway in Bi2WO6/TiO2 hybrids leads to longer-lived photogenerated carriers in spatially separated redox active sites, which favor the reduction of CO2 into highly electron demanding fuels and chemicals, such as CH4 and C2H6Financial support has been received from the European Research Council (ERC), through HYMAP project (grant agreement No. 648319), under the European Union's Horizon 2020 research and innovation program, as well as from the Marie Sklodowska-Curie grant agreement No. 754382. L.C. acknowledges funding from the project ARMONIA (PID2020–119125RJ-I00) funded by MCIN/AEI/10.13039/ 501100011033. Financial support has also been received from AEIMINECO/FEDER (Nympha Project, PID2019–106315RB-I00), "Comunidad de Madrid" regional government, and the European Structural Funds (FotoArt-CM project, S2018/NMT-4367). Authors also acknowledge financial support from the grant PLEC2021–007906 funded by MCIN/AEI/10.13039/501100011033 and the "European Union NextGenerationEU/PRTR"

Modulation of the Rate of Electron Injection in Dye-Sensitized Nanocrystalline TiO

We present a study of the kinetics of electron injection in ruthenium(II) cis-(2,2‘-bipyridyl-4,4‘-dicarboxylate)2(NCS)2-sensitized nanocrystalline TiO2 films as a function of electrical potential applied to the TiO2 film and as a function of the composition of the electrolyte in which the film is immersed. At moderate applied potentials (−0.2 V vs Ag/AgCl), and in the presence of potential determining ions (0.1 M Li+) in the electrolyte, the electron injection kinetics were found to be multiphasic, with a half time for electron injection of 500 fs. These injection kinetics were retarded by either the omission of potential determining ions or the application of more negative potentials. Omission of Li+ ions from the electrolyte resulted in a 7-fold retardation of the injections kinetics. The application of −0.7 V to the TiO2 electrode resulted in a 25-fold retardation of the injection kinetics. These observations are discussed in terms of nonadiabatic interfacial electron transfer theory. The retardation of the injection kinetics in the absence of potential determining ions is attributed to the influence of these ions upon the electronic density of states of the TiO2 electrode. The retardation of the injection kinetics at negative applied potentials is attributed to the increased occupancy of this density of states. Fits to the potential dependence of the injection kinetics following nonadiabatic theory yield a reorganizational energy for the electron injection process of 0.25 ± 0.05 eV

Quantitative conversations: the importance of developing rapport in standardised interviewing

© 2014, The Author(s). When developing household surveys, much emphasis is understandably placed on developing survey instruments that can elicit accurate and comparable responses. In order to ensure that carefully crafted questions are not undermined by ‘interviewer effects’, standardised interviewing tends to be utilised in preference to conversational techniques. However, by drawing on a behaviour coding analysis of survey paradata arising from the 2012 UK Poverty and Social Exclusion Survey we show that in practice standardised survey interviewing often involves extensive unscripted conversation between the interviewer and the respondent. Whilst these interactions can enhance response accuracy, cooperation and ethicality, unscripted conversations can also be problematic in terms of survey reliability and the ethical conduct of survey interviews, as well as raising more basic epistemological questions concerning the degree of standardisation typically assumed within survey research. We conclude that better training in conversational techniques is necessary, even when applying standardised interviewing methodologies. We also draw out some theoretical implications regarding the usefulness of the qualitative–quantitative dichotomy

Media Reporting of Health Interventions: Signs of Improvement, but Major Problems Persist

Background: Studies have persistently shown deficiencies in medical reporting by the mainstream media. We have been monitoring the accuracy and comprehensiveness of medical news reporting in Australia since mid 2004. This analysis of more than 1200 stories in the Australian media compares different types of media outlets and examines reporting trends over time. Methods and Findings: Between March 2004 and June 2008 1230 news stories were rated on a national medical news monitoring web site, Media Doctor Australia. These covered a variety of health interventions ranging from drugs, diagnostic tests and surgery to dietary and complementary therapies. Each story was independently assessed by two reviewers using ten criteria. Scores were expressed as percentages of total assessable items deemed satisfactory according to a coding guide. Analysis of variance was used to compare mean scores and Fishers exact test to compare proportions. Trends over time were analysed using un-weighted linear regression analysis. Broadsheet newspapers had the highest average satisfactory scores: 58% (95% CI 56–60%), compared with tabloid newspapers and online news outlets, 48% (95% CI 44–52) and 48% (95% CI 46–50) respectively. The lowest scores were assigned to stories broadcast by human interest/current affairs television programmes (average score 33% (95% CI 28–38)). While there was a non- significant increase in average scores for all outlets, a significant improvement was seen in the online news media: a rise of 5.1% (95%CI 1.32, 8.97; P 0.009). Statistically significant improvements were seen in coverage of the potential harms of interventions, the availability of treatment or diagnostic options, and accurate quantification of benefits. Conclusion: Although the overall quality of medical reporting in the general media remains poor, this study showed modest improvements in some areas. However, the most striking finding was the continuing very poor coverage of health news by commercial current affairs television programs

The PHENIX Experiment at RHIC

The physics emphases of the PHENIX collaboration and the design and current status of the PHENIX detector are discussed. The plan of the collaboration for making the most effective use of the available luminosity in the first years of RHIC operation is also presented.Comment: 5 pages, 1 figure. Further details of the PHENIX physics program available at http://www.rhic.bnl.gov/phenix