Staurosporine augments EGF-mediated EMT in PMC42-LA cells through actin depolymerisation, focal contact size reduction and Snail1 induction : a model for cross-modulation

Background A feature of epithelial to mesenchymal transition (EMT) relevant to tumour dissemination is the reorganization of actin cytoskeleton/focal contacts, influencing cellular ECM adherence and motility. This is coupled with the transcriptional repression of E-cadherin, often mediated by Snail1, Snail2 and Zeb1/δEF1. These genes, overexpressed in breast carcinomas, are known targets of growth factor-initiated pathways, however it is less clear how alterations in ECM attachment cross-modulate to regulate these pathways. EGF induces EMT in the breast cancer cell line PMC42-LA and the kinase inhibitor staurosporine (ST) induces EMT in embryonic neural epithelial cells, with F-actin de-bundling and disruption of cell-cell adhesion, via inhibition of aPKC. Methods PMC42-LA cells were treated for 72 h with 10 ng/ml EGF, 40 nM ST, or both, and assessed for expression of E-cadherin repressor genes (Snail1, Snail2, Zeb1/δEF1) and EMT-related genes by QRT-PCR, multiplex tandem PCR (MT-PCR) and immunofluorescence +/- cycloheximide. Actin and focal contacts (paxillin) were visualized by confocal microscopy. A public database of human breast cancers was assessed for expression of Snail1 and Snail2 in relation to outcome. Results When PMC42-LA were treated with EGF, Snail2 was the principal E-cadherin repressor induced. With ST or ST+EGF this shifted to Snail1, with more extreme EMT and Zeb1/δEF1 induction seen with ST+EGF. ST reduced stress fibres and focal contact size rapidly and independently of gene transcription. Gene expression analysis by MT-PCR indicated that ST repressed many genes which were induced by EGF (EGFR, CAV1, CTGF, CYR61, CD44, S100A4) and induced genes which alter the actin cytoskeleton (NLF1, NLF2, EPHB4). Examination of the public database of breast cancers revealed tumours exhibiting higher Snail1 expression have an increased risk of disease-recurrence. This was not seen for Snail2, and Zeb1/δEF1 showed a reverse correlation with lower expression values being predictive of increased risk. Conclusion ST in combination with EGF directed a greater EMT via actin depolymerisation and focal contact size reduction, resulting in a loosening of cell-ECM attachment along with Snail1-Zeb1/δEF1 induction. This appeared fundamentally different to the EGF-induced EMT, highlighting the multiple pathways which can regulate EMT. Our findings add support for a functional role for Snail1 in invasive breast cancer.

A systematic review of community-based interventions for emerging zoonotic diseases in Southeast Asia

Background Southeast Asia has been at the epicentre of recent epidemics of emerging and re-emerging zoonotic diseases. Community-based surveillance and control interventions have been heavily promoted but the most effective interventions have not been identified. Objectives This review evaluated evidence for the effectiveness of community-based surveillance interventions at monitoring and identifying emerging infectious disease; the effectiveness of community-based control interventions at reducing rates of emerging infectious disease; and contextual factors that influence intervention effectiveness. Inclusion criteria Participants Communities in Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, the Philippines, Singapore, Thailand and Viet Nam. Types of intervention(s) Non-pharmaceutical, non-vaccine, and community-based surveillance or prevention and control interventions targeting rabies, Nipah virus , dengue, SARS or avian influenza. Types of outcomes Primary outcomes: measures: of infection or disease; secondary outcomes: measures of intervention function. Types of studies Original quantitative studies published in English. Search strategy Databases searched (1980 to 2011): PubMed, CINAHL, ProQuest, EBSCOhost, Web of Science, Science Direct, Cochrane database of systematic reviews, WHOLIS, British Development Library, LILACS, World Bank (East Asia), Asian Development Bank. Methodological quality Two independent reviewers critically appraised studies using standard Joanna Briggs Institute instruments. Disagreements were resolved through discussion. Data extraction A customised tool was used to extract quantitative data on intervention(s), populations, study methods, and primary and secondary outcomes; and qualitative contextual information or narrative evidence about interventions. Data synthesis Data was synthesised in a narrative summary with the aid of tables. Meta-analysis was used to statistically pool quantitative results. Results Fifty-seven studies were included. Vector control interventions using copepods, environmental cleanup and education are effective and sustainable at reducing dengue in rural and urban communities, whilst insecticide spraying is effective in urban outbreak situations. Community-based surveillance interventions can effectively identify avian influenza in backyard flocks, but have not been broadly applied. Outbreak control interventions for Nipah virus and SARS are effective but may not be suitable for ongoing control. Canine vaccination and education is more acceptable than culling, but still fails to reach coverage levels required to effectively control rabies. Contextual factors were identified that influence community engagement with, and ultimately effectiveness of, interventions. Conclusion Despite investment in community-based disease control and surveillance in Southeast Asia, published evidence evaluating interventions is limited in quantity and quality. Nonetheless this review identified a number of effective interventions, and several contextual factors influencing effectiveness. Identification of the best programs will require comparative evidence of effectiveness acceptability, cost-effectiveness and sustainability.

Top-k retrieval using facility location analysis

The top-k retrieval problem aims to find the optimal set of k documents from a number of relevant documents given the user’s query. The key issue is to balance the relevance and diversity of the top-k search results. In this paper, we address this problem using Facility Location Analysis taken from Operations Research, where the locations of facilities are optimally chosen according to some criteria. We show how this analysis technique is a generalization of state-of-the-art retrieval models for diversification (such as the Modern Portfolio Theory for Information Retrieval), which treat the top-k search results like “obnoxious facilities” that should be dispersed as far as possible from each other. However, Facility Location Analysis suggests that the top-k search results could be treated like “desirable facilities” to be placed as close as possible to their customers. This leads to a new top-k retrieval model where the best representatives of the relevant documents are selected. In a series of experiments conducted on two TREC diversity collections, we show that significant improvements can be made over the current state-of-the-art through this alternative treatment of the top-k retrieval problem.

Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44HI/CD24lO/-stem cell phenotype in human breast cancer

We review here the recently emerging relationship between epithelial-mesenchymal transition (EMT) and breast cancer stem cells (BCSC), and provide analyses of published data on human breast cancer cell lines, supporting their utility as a model for the EMT/BCSC state. Genome-wide transcriptional profiling of these cell lines has confirmed the existence of a subgroup with mesenchymal tendencies and enhanced invasive properties ('Basal B'/Mesenchymal), distinct from subgroups with either predominantly luminal ('Luminal') or mixed basal/luminal ('Basal A') features (Neve et al. Cancer Cell, 2006). A literature-derived EMT gene signature has shown specific enrichment within the Basal B subgroup of cell lines, consistent with their over-expression of various EMT transcriptional drivers. Basal B cell lines are found to resemble BCSC, being CD44highCD24low. Moreover, gene products that distinguish Basal B from Basal A and Luminal cell lines (Basal B Discriminators) showed close concordance with those that define BCSC isolated from clinical material, as reported by Shipitsin et al. (Cancer Cell, 2007). CD24 mRNA levels varied across Basal B cell lines, correlating with other Basal B Discriminators. Many gene products correlating with CD24 status in Basal B cell lines were also differentially expressed in isolated BCSC. These findings confirm and extend the importance of the cellular product of the EMT with Basal B cell lines, and illustrate the value of analysing these cell lines for new leads that may improve breast cancer outcomes. Gene products specific to Basal B cell lines may serve as tools for the detection, quantification, and analysis of BCSC/EMT attributes.

Regulation of proliferation, invasion and growth factor synthesis in breast cancer by steroids

Endogenous ovarian estrogens and progestins appear to play a critical role in the development and progression of breast cancer. Local productions of growth factors probably also contribute to malignant proliferation, while production and activation of collagenolytic enzymes may be equally critical for local invasive processes. The current review focusses on characterization of growth factor-receptor systems operant in normal and malignant breast epithelium. In addition, the determinants of local invasion are reviewed: attachment, modality, and proteose secretion. Finally, data are discussed concerning the regulation of both proliferation and invasion by hormones and antihormonal agents in hormone-dependent breast cancer. The results suggest new potential pharmacologic targets to explore to suppress onset and progression of breast cancer.

The type I collagen induction of MT1-MMP-mediated MMP-2 activation is repressed by αVβ3 integrin in human breast cancer cells

The influence of αVβ3 integrin on MT1-MMP functionality was studied in human breast cancer cells of differing β3 integrin status. Overexpression of β3 integrin caused increased cell surface expression of αV integrin and increased cellular adhesion to extracellular matrix (ECM) substrates in BT-549, MDA-MB-231 and MCF-7 cells. β3 integrin expression also enhanced the migration of breast cancer cells on ECM substrates and enhanced collagen gel contraction. In vivo, αVβ3 cooperated with MT1-MMP to increase the growth of MCF-7 cells after orthotopic inoculation in immunocompromised mice, but had no influence on in vitro proliferation. Despite these stimulatory effects, overexpression of β3 integrin suppressed the type I collagen (Col I) induced MMP-2 activation in all breast cancer cell lines analyzed. This was also evident in extracts from the MCF-7 tumors in vivo, where MMP-2 activation was stimulated by MT1-MMP transfection, but attenuated with β3 integrin expression. Although our studies confirm important biological effects of αVβ3 integrin on enhancing cell adhesion and migration, ECM remodeling and tumor growth, β3 integrin caused reduced MMP-2 activation in response to Col I in vitro, which appears to be physiologically relevant, as it was also seen in tumor xenografts in vivo. The reduction of MMP-2 activation (and thus MT1-MMP activity) by αVβ3 in response to Col I may be important in scenarios where cells which are activated for matrix degradation need to preserve some pericellular collagen, perhaps as a substrate for cell adhesion and migration, thus maintaining a balanced level of proteolysis required for efficient tumor growth.

Orientation dependence of spatial memory acquired from auditory experience

The present study investigated whether memory for a room-sized spatial layout learned through auditory localization of sounds exhibits orientation dependence similar to that observed for spatial memory acquired from stationary viewing of the environment. Participants learned spatial layouts by viewing objects or localizing sounds and then performed judgments of relative direction among remembered locations. The results showed that direction judgments following auditory learning were performed most accurately at a particular orientation in the same way as were those following visual learning, indicating that auditorily encoded spatial memory is orientation dependent. In combination with previous findings that spatial memories derived from haptic and proprioceptive experiences are also orientation dependent, the present finding suggests that orientation dependence is a general functional property of human spatial memory independent of learning modality.

Rules of thumb for comparing multinomial logit and multinomial probit coefficients

A rule of thumb is suggested for comparing multinomial logit coefficients with multinomial probit coefficients in the special case where the normal errors are distributed N(0,1). The rule is a generalization of the '1.6' rule for comparing logit and probit coefficients. © 1989.

Extending FORK-256 attack to the full hash function

In a paper published in FSE 2007, a way of obtaining near-collisions and in theory also collisions for the FORK-256 hash function was presented [8]. The paper contained examples of near-collisions for the compression function, but in practice the attack could not be extended to the full function due to large memory requirements and computation time. In this paper we improve the attack and show that it is possible to find near-collisions in practice for any given value of IV. In particular, this means that the full hash function with the prespecified IV is vulnerable in practice, not just in theory. We exhibit an example near-collision for the complete hash function.

Surface insulation performance of epoxy resin/silica nanocomposite material

Composite polymer insulators provide many advantages over the traditional porcelain insulators and they are increasingly being used at both transmission and distribution levels. In the present paper, an epoxy resin/silica nanocomposite dielectric material (NDM) structure is proposed and fabricated. Hydrophobic fumed silica is incorporated in epoxy resin matrix and acetone is adopted as media agent to effectively achieve homogenous dispersion of the nano-scale silica filler. The acetone also acts as diluents to reduce viscosity before the curing phase of epoxy resin and enables bubbles to escape from being trapped. Through partial discharge (PD) and surface aging tests, it is illustrated that the inception of surface discharge of the proposed NDM is relatively higher than that of the non-filled counterpart, and a better PD resistivity was observed in the negative half cycle regarding to applied AC voltage. Results of surface aging test indicate that surface discharge activity is retarded over the test conducting time. By contrast, surface discharge developed to the opposite way on the non-filled sample. Therefore, the proposed NDM could provide better safety reliability and lower maintenance cost to industrial application compared with nonfilled conventional epoxy resin.

Rad51 supports triple negative breast cancer metastasis

In contrast to extensive studies on familial breast cancer, it is currently unclear whether defects in DNA double strand break (DSB) repair genes play a role in sporadic breast cancer development and progression. We performed analysis of immunohistochemistry in an independent cohort of 235 were sporadic breast tumours. This analysis suggested that RAD51 expression is increased during breast cancer progression and metastasis and an oncogenic role for RAD51 when deregulated. Subsequent knockdown of RAD51 repressed cancer cell migration in vitro and reduced primary tumor growth in a syngeneic mouse model in vivo. Loss of RAD51 also inhibited associated metastasis not only in syngeneic mice but human xenografts and changed the metastatic gene expression profile of cancer cells, consistent with inhibition of distant metastasis. This demonstrates for the first time a new function of RAD51 that may underlie the proclivity of patients with RAD51 overexpression to develop distant metastasis. RAD51 is a potential biomarker and attractive drug target for metastatic triple negative breast cancer, with the capability to extend the survival of patients, which is less than 6 months.

Oscillating magnetic field current drive in a spherical plasma device

The continuous steady-state current drive in a spherical argon plasma by transverse oscillating magnetic field (OMF) is investigated. The experimental results reveal that a rotating magnetic field is generated, and its amplitude depends linearly on the external steady vertical magnetic field. It has been shown that steady toroidal currents of up to about 400 A can be driven by a 490 kHz OMF with an input power of 1.4 kW. The generation of steady toroidal magnetic fields directed oppositely in the upper and lower hemispheres have been recorded. The measurements of time-varying magnetic fields unveil a strong nonlinear effect of the frequency-doubled field harmonics generation. The electron number density and temperature of up to 6.2×1018 m-3 and 12 eV have been obtained. The observed effects validate the existing theory of the OMF current drive in spherical plasmas.

Effects of intrinsic and extrinsic motivation on user-generated content

User-generated content where content is created and shared among consumers is of key importance to marketers. This study investigates consumer intrinsic and extrinsic motivation to understand why people create user-generated branded video content. Specifically, we examine the role of altruism (individual difference – intrinsic motivation), social benefits (extrinsic reward), and economic incentives (extrinsic reward) on intentions to create user-generated content. Results show that extrinsic rewards (economic incentives) result in more positive intentions to create user-generated content than intrinsic motivations. However, an effect for altruism is also evident revealing that high altruism consumers are more likely to create positive user-generated content. The implication of these findings is that marketers wanting to encourage user-generated content about their brands should target high altruism consumers and offer economic incentives for content creation.

Modelling total duration of traffic incidents including incident detection and recovery time

Traffic incidents are key contributors to non-recurrent congestion, potentially generating significant delay. Factors that influence the duration of incidents are important to understand so that effective mitigation strategies can be implemented. To identify and quantify the effects of influential factors, a methodology for studying total incident duration based on historical data from an ‘integrated database’ is proposed. Incident duration models are developed using a selected freeway segment in the Southeast Queensland, Australia network. The models include incident detection and recovery time as components of incident duration. A hazard-based duration modelling approach is applied to model incident duration as a function of a variety of factors that influence traffic incident duration. Parametric accelerated failure time survival models are developed to capture heterogeneity as a function of explanatory variables, with both fixed and random parameters specifications. The analysis reveals that factors affecting incident duration include incident characteristics (severity, type, injury, medical requirements, etc.), infrastructure characteristics (roadway shoulder availability), time of day, and traffic characteristics. The results indicate that event type durations are uniquely different, thus requiring different responses to effectively clear them. Furthermore, the results highlight the presence of unobserved incident duration heterogeneity as captured by the random parameter models, suggesting that additional factors need to be considered in future modelling efforts.

Factors contributing to crashes among young drivers

Young drivers are the group of drivers most likely to crash. There are a number of factors that contribute to the high crash risk experienced by these drivers. While some of these factors are intrinsic to the young driver, such as their age, gender or driving skill, others relate to social factors and when and how often they drive. This article reviews the factors that affect the risk of young drivers crashing to enable a fuller understanding of why this risk is so high in order to assist in developing effective countermeasures.