Crosstalk with insulin and dependence on PI3K/Akt/mTOR rather than MAPK pathways in upregulation of basal growth following long-term oestrogen deprivation in three human breast cancer cell lines

Background: MCF-7, T-47-D, ZR-75-1 human breast cancer cell lines are dependent on oestrogen for growth but can adapt to grow during long-term oestrogen deprivation. This serves as a model for identification of therapeutic targets in endocrine-resistant breast cancer. Methods: An overlooked complication of this model is that it involves more than non-addition of oestrogen, and inadequate attention has been given to separating molecular events associated with each of the culture manipulations. Results: Insulin and oestradiol were shown to protect MCF-7 cells against upregulation of basal growth, demonstrating a crosstalk in the growth adaptation process. Increased phosphorylation of p44/42MAPK and c-Raf reflected removal of insulin from the medium and proliferation of all three cell lines was inhibited to a lesser extent by PD98059 and U0126 following long-term oestrogen/insulin withdrawal, demonstrating a reduced dependence on the MAPK pathway. By contrast, long-term oestrogen/insulin deprivation did not alter levels of phosphorylated Akt and did not alter the dose-response of growth inhibition with LY294002 in any of the three cell lines. The IGF1R inhibitor picropodophyllin inhibited growth of all MCF-7 cells but only in the long-term oestrogen/insulin-deprived cells was this paralleled by reduction in phosphorylated p70S6K, a downstream target of mTOR. Long-term oestrogen/insulin-deprived MCF-7 cells had higher levels of phosphorylated p70S6K and developed increased sensitivity to growth inhibition by rapamycin. Conclusions: The greater sensitivity to growth inhibition by rapamycin in all three cell lines following long-term oestrogen/insulin deprivation suggests rapamycin-based therapies might be more effective in breast cancers with acquired oestrogen resistance. Keywords Akt, breast cancer cells, endocrine resistance, insulin, MAPK, MCF-7 cells, mTOR, oestrogen, oestrogen-deprived, PI3K, picropodophyllin, rapamycin, T-47-D cells, ZR-75-1 cells

How Twitter is studied in the medical professions: a classification of Twitter papers indexed in PubMed

Background: Since their inception, Twitter and related microblogging systems have provided a rich source of information for researchers and have attracted interest in their affordances and use. Since 2009 PubMed has included 123 journal articles on medicine and Twitter, but no overview exists as to how the field uses Twitter in research. // Objective: This paper aims to identify published work relating to Twitter indexed by PubMed, and then to classify it. This classification will provide a framework in which future researchers will be able to position their work, and to provide an understanding of the current reach of research using Twitter in medical disciplines. Limiting the study to papers indexed by PubMed ensures the work provides a reproducible benchmark. // Methods: Papers, indexed by PubMed, on Twitter and related topics were identified and reviewed. The papers were then qualitatively classified based on the paper’s title and abstract to determine their focus. The work that was Twitter focused was studied in detail to determine what data, if any, it was based on, and from this a categorization of the data set size used in the studies was developed. Using open coded content analysis additional important categories were also identified, relating to the primary methodology, domain and aspect. // Results: As of 2012, PubMed comprises more than 21 million citations from biomedical literature, and from these a corpus of 134 potentially Twitter related papers were identified, eleven of which were subsequently found not to be relevant. There were no papers prior to 2009 relating to microblogging, a term first used in 2006. Of the remaining 123 papers which mentioned Twitter, thirty were focussed on Twitter (the others referring to it tangentially). The early Twitter focussed papers introduced the topic and highlighted the potential, not carrying out any form of data analysis. The majority of published papers used analytic techniques to sort through thousands, if not millions, of individual tweets, often depending on automated tools to do so. Our analysis demonstrates that researchers are starting to use knowledge discovery methods and data mining techniques to understand vast quantities of tweets: the study of Twitter is becoming quantitative research. // Conclusions: This work is to the best of our knowledge the first overview study of medical related research based on Twitter and related microblogging. We have used five dimensions to categorise published medical related research on Twitter. This classification provides a framework within which researchers studying development and use of Twitter within medical related research, and those undertaking comparative studies of research relating to Twitter in the area of medicine and beyond, can position and ground their work.

Hypersensitivity and growth adaptation of oestrogen-deprived MCF-7 human breast cancer cells

Background: Efficacy of endocrine therapy is compromised when human breast cancer cells circumvent imposed growth inhibition. The model of long-term oestrogen-deprived MCF-7 human breast cancer cells has suggested the mechanism results from hypersensitivity to low levels of residual oestrogen. Materials and methods: MCF-7 cells were maintained for up to 30 weeks in phenol-red-free medium and charcoal-stripped serum with 10-8 M 17-oestradiol and 10 g/ml insulin (stock 1), 10-8 M 17-oestradiol (stock 2), 10 g/ml insulin (stock 3) or no addition (stock 4). Results: Loss of growth response to oestrogen was observed only in stock 4 cells. Long-term maintenance with insulin in the absence of oestradiol (stock 3) resulted in raised oestrogen receptor alpha (ERlevels (measured by western immunoblotting) and development of hypersensitivity (assayed by oestrogen-responsive reporter gene induction and dose response to oestradiol for proliferation under serum-free conditions), but with no loss of growth response to oestrogen. Conclusion: Hypersensitivity can develop without any growth adaptation and therefore is not a prerequisite for loss of growth response in MCF-7 cells.

Do early father–infant interactions predict the onset of externalising behaviours in young children? Findings from a longitudinal cohort study

Background Factors related to parents and parenting capacities are important predictors of the development of behavioural problems in children. Recently, there has been an increasing research focus in this field on the earliest years of life, however, relatively few studies have addressed the role of fathers, despite this appearing to be particularly pertinent to child behavioural development. This study aimed to examine whether father–infant interactions at age 3 months independently predicted child behavioural problems at 1 year of age. Method A sample of 192 families was recruited from two maternity units in the United Kingdom. Father–infant interactions were assessed in the family home and coded using the Global Rating Scales. Child behaviour problems were assessed by maternal report. Hierarchical and logistic regression analyses were used to examine associations between father–infant interaction and the development of behavioural problems. Results Disengaged and remote interactions between fathers and their infants were found to predict externalising behavioural problems at the age of 1 year. The children of the most disengaged fathers had an increased risk of developing early externalising behavioural problems [disengaged (nonintrusive) interactions – adjusted Odds Ratio 5.33 (95% Confidence Interval; 1.39, 20.40): remote interactions adj. OR 3.32 (0.92, 12.05)] Conclusions Disengaged interactions of fathers with their infants, as early as the third month of life, predict early behavioural problems in children. These interactions may be critical factors to address, from a very early age in the child’s life, and offer a potential opportunity for preventive intervention.

Exposure to parabens at the concentration of maximal proliferative response increases migratory and invasive activity of human breast cancer cells in vitro

Alkyl esters of p–hydroxybenzoic acid (parabens) are widely used as preservatives in personal care products, foods and pharmaceuticals. Their oestrogenic activity, their measurement in human breast tissue and their ability to drive proliferation of oestrogen-responsive human breast cancer cells has opened a debate on their potential to influence breast cancer development. Since proliferation is not the only hallmark of cancer cells, we have investigated the effects of exposure to parabens at concentrations of maximal proliferative response on migratory and invasive properties using three oestrogen-responsive human breast cancer cell lines (MCF-7, T-47-D, ZR-75-1). Cells were maintained short-term (1 week) or long-term (20±2 weeks) in phenol-red-free medium containing 5% charcoal-stripped serum with no addition, 10-8M 17-oestradiol, 1-5x10-4M methylparaben, 10-5M n-propylparaben or 10-5M n-butylparaben. Long-term exposure (20±2 weeks) of MCF-7 cells to methylparaben, n-propylparaben or n-butylparaben increased migration as measured using a scratch assay, time-lapse microscopy and xCELLigence technology: invasive properties were found to increase in matrix degradation assays and migration through matrigel on xCELLigence. Western immunoblotting showed an associated downregulation of E-cadherin and -catenin in the long-term paraben-exposed cells which could be consistent with a mechanism involving epithelial to mesenchymal transition. Increased migratory activity was demonstrated also in long-term paraben-exposed T-47-D and ZR-75-1 cells using a scratch assay and time-lapse microscopy. This is the first report that in vitro, parabens can influence not only proliferation but also migratory and invasive properties of human breast cancer cells.

Selective P4 activation by an organometallic nickel(I) radical: formation of a dinuclear nickel(II) tetraphosphide and related di- and trichalcogenides

The reaction of the 17e nickel(I) radical [CpNi(IDipp)] (1, IDipp = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) with P4 results in a nickel tetraphosphide [{CpNi(IDipp)}2(μ-η1:η1-P4)] with a butterfly-P42− ligand; related chalcogenides [{CpNi(IDipp)}2(μ-E2)] (E = S, Se, Te) and [{CpNi(IDipp)}2(μ-E3)] (E = S, Se) are formed with S8, Se∞ and Te∞.

Paying for long-term performance: restructuring bankers’ pay for risk regulation

The purpose of this paper is to propose hybrid capital securities as a new approach to compensation for senior bank executives and risk-takers instead of cash or equity-based compensation currently adopted by the industry. The global financial turmoil indicated that misaligned pay-for-performance compensation arrangements encouraged management short-termism and rewarded excessive risk-taking behaviour in Anglo-Saxon system. Rather than regulating specific instruments and processes, we believe that it is much more efficient to overhaul the compensation scheme to align it with risk management and governance. This empirical paper investigates the European hybrid market by employing data from the Merrill Lynch Global Index System from 2000 to 2010. Our paper contributes to both literature and practices by designing a structured scheme to tie the executive’s interests to long-term performance of the bank, the goal of regulators and the economy at large which consequently reduce the probability of future bank failures.

Meta-morphs: – being a mediator of the ‘thin’ place and ‘thin’ experience in the HE classroom. A paper on the experience of creating transformations in HE teaching and learning

The research which underpins this paper began as a doctoral project exploring archaic beliefs concerning Otherworlds and Thin Places in two particular landscapes - the West Coast of Wales and the West Coast of Ireland. A Thin Place is an ancient Celtic Christian term used to describe a marginal, liminal realm, beyond everyday human experience and perception, where mortals could pass into the Otherworld more readily, or make contact with those in the Otherworld more willingly. To encounter a Thin Place in ancient folklore was significant because it engendered a state of alertness, an awakening to what the theologian John O’ Donohue (2004: 49) called “the primal affection.” These complex notions and terms will be further explored in this paper in relation to Education. Thin Teaching is a pedagogical approach which offers students the space to ruminate on the possibility that their existence can be more and can mean more than the categories they believed they belonged to or felt they should inhabit. Central to the argument then, is that certain places and their inhabitants can become revitalised by sensitively considered teaching methodologies. This raises interesting questions about the role spirituality plays in teaching practice as a tool for healing in the twenty first century.

Trees for development? Articulating the ambiguities of power, authority and legitimacy in governing Ghana’s mineral rich forests

The growth of mining activities in Africa in the last decade has coincided with increased attention on the fate of the continent’s forests, specifically in the contexts of livelihoods and climate change. Although mining has serious environmental impacts, scant attention has been paid to the processes which shape decision-making in contexts where minerals and forests overlap. Focussing on the illustrative case of Ghana, this paper articulates the dynamics of power, authority and legitimacy of private companies, traditional authorities and key state institutions in governing mining activities in forests. The analysis highlights how mining companies and donors promote a neoliberal model of resource management which entrenches their ability to benefit from mineral exploitation and marginalises the role of state institutions and traditional authorities in decision-making. This subsequently erodes state authority and legitimacy and compounds the contested nature of traditional authorities’ legitimacy. A more nuanced examination of foundational governance questions concerning the relative role of the state, traditional authorities and private interests is needed.

Investigation of institutional investors’ responsible investment practices in UK

The focus of Corporate Governance is shifting from the role of directors to active ownership. Based on their fiduciary duty to other shareholders, it is believed that institutional investors have an important role to play in this regard. However, the Pension Funds and the Sovereign Wealth Organisations are not driven by the same set of objectives. In addition, Environmental Social and Governance (ESG) issues in investment decision-making are now becoming more important and they are capable of becoming the mainstream in the future. However, there are widespread variations in perception of fiduciary responsibilities, ESG issues appraisal, as well as the strategies adopted by institutional investors on shareholder engagement as responsible investors. Responsible Investment market is largely driven by institutional investors and they are expected to continue to lead the way. This research work investigates the role of the main asset owners and their advisors in responsible investment practices in the UK. It adopts a qualitative approach using semi-structured interviews, questionnaire and meetings observations. Gathered data is analysed using grounded theory and the findings highlight the perception of the various investor groups to corporate governance. The research work contributes to the body of knowledge by assessing the corporate governance perspectives of the various classes of institutional investors which may have practical implications for other countries.

An entirely new land? Italy’s post-war culture and its fascist past

Scholarship has for decades emphasised the significant continuities in Italian culture and society after Fascism, calling into question the rhetoric of post-war renewal. This essay proposes a reassessment of that rhetoric through the analysis of five key metaphors with which Italian intellectuals represented national recovery after 1945: parenthesis, disease, flood, childhood, and discovery. While the current critical consensus would lead us to expect a cultural conversation characterised by repression and evasion, an analysis of these five post-war metaphors instead reveals both a penetrating re-assessment of Italian culture after Fascism and an earnest adherence to the cause of national re-vitalisation. Foregrounding the inter-relation of Italy’s prospects for change and its continuities with Fascism, these metaphors suggest that post-war Italian intellectuals conceived of their country’s hopes for renewal, as well as its connections to the recent past, in terms that transcend the binary division favoured in many historical accounts.

A review of the cognitive effects observed in humans following acute supplementation with flavonoids, and their associated mechanisms of action

Flavonoids are polyphenolic compounds found in varying concentrations in many plant-based foods. Recent studies suggest that flavonoids can be beneficial to both cognitive and physiological health. Long term flavonoid supplementation over a period of weeks or months has been extensively investigated and reviewed, particularly with respect to cognitive ageing and neurodegenerative disease. Significantly less focus has been directed towards the short term effects of single doses of flavonoids on cognition. Here, we review 21 such studies with particular emphasis on the subclass and dose of flavonoids administered, the cognitive domains affected by flavonoid supplementation, and the effect size of the response. The emerging evidence suggests that flavonoids may be beneficial to attention, working memory, and psychomotor processing speed in a general population. Episodic memory effects are less well defined and may be restricted to child or older adult populations. The evidence also points towards a dose-dependent effect of flavonoids, but the physiological mechanisms of action remain unclear. Overall, there is encouraging evidence that flavonoid supplementation can benefit cognitive outcomes within an acute time frame of 0–6 h. But larger studies, combining cognitive and physiological measures, are needed to strengthen the evidence base.

Cacao swollen shoot virus in Nigeria: analysis of a pathogen and its vectors

Cacao swollen shoot virus (CSSV) causes the Cacao swollen shoot virus disease (CSSVD) and significantly reduces production in West African cacao. This study characterised the current status of the disease in the major cacao growing States in Nigeria and attempted a clarification on the manner of CSSV transmission. Two separate field surveys and sample collections were conducted in Nigeria in summer 2012 and spring 2013. PCR-based screening of cacao leaf samples and subsequent DNA sequencing showed that the disease continues to persist in Ondo and Oyo States and in new cacao sites in Abia, Akwa Ibom, Cross River and Edo States. Mealybug samples collected were identified using a robust approach involving environmental scanning electron microscopy, histology and DNA barcoding, which highlighted the importance of integrative taxonomy in the study. The results show that the genus Planococcus (Planococcus citri (Risso) and/or Planococcus minor (Maskell)) was the most abundant vector (73.5%) at the sites examined followed by Formicococcus njalensis (Laing) (19.0 %). In a laboratory study, the feeding behaviour of Pl. citri, Pseudococcus longispinus (Targioni-Tozzetti) and Pseudococcus viburni (Signoret) on cacao were investigated using electrical penetration graph (EPG) analysis. EPG waveforms reflecting intercellular stylet penetration (C), extracellular salivation (E1e), salivation in sieve elements (E1), phloem ingestion (E2), derailed stylet mechanics (F), xylem ingestion (G) and non-probing phase (Np) were analysed. Individual mealybugs exhibited marked variation within species and significantly differed (p ≤ .05) between species for E1e and E1. PCR-based assessments of the retention time for CSSV in viruliferous Pl. citri, Ps. longispinus and Ps. viburni fed on a non-cacao diet showed that CSSV was still detectable after 144 hours. These unusually long durations for a pathogen currently classified as a semi-persistent virus have implications for the design of non-malvaceous barrier crops currently being considered for the protection of new cacao plantings.