Hypoxia and hyperglycaemia determine why some endometrial tumours fail to respond to metformin

High expression of Ki67, a proliferation marker, is associated with reduced endometrial cancer-specific survival. Pre-surgical metformin reduces tumour Ki-67 expression in some women with endometrial cancer. Metformin's anti-cancer activity may relate to effects on cellular energy metabolism. Since tumour hypoxia and glucose availability are major cellular redox determinants, we evaluated their role in endometrial cancer response to metformin. Endometrial cancer biopsies from women treated with pre-surgical metformin were tested for the hypoxia markers, HIF-1α and CA-9. Endometrial cancer cell lines were treated with metformin in variable glucose concentrations in normoxia or hypoxia and cell viability, mitochondrial biogenesis, function and energy metabolism were assessed. In women treated with metformin (n = 28), Ki-67 response was lower in hypoxic tumours. Metformin showed minimal cytostatic effects towards Ishikawa and HEC1A cells in conventional medium (25 mM glucose). In low glucose (5.5 mM), a dose-dependent cytostatic effect was observed in normoxia but attenuated in hypoxia. Tumours treated with metformin showed increased mitochondrial mass (n = 25), while in cultured cells metformin decreased mitochondrial function. Metformin targets mitochondrial respiration, however, in hypoxic, high glucose conditions, there was a switch to glycolytic metabolism and decreased metformin response. Understanding the metabolic adaptations of endometrial tumours may identify patients likely to derive clinical benefit from metformin

Do CoSA work? A review of the literature

To ensure that CoSA projects continue to grow in both success and public confidence on an international scale, a solid research base is essential. In addition, to inform best practice the factors involved in the success of CoSA need to be identified (Wilson, Bates, & Völlm, 2010). The following chapter focuses upon the growing body of efficacy research surrounding CoSA projects. This will include the key statistical evaluations of the effect of CoSA on recidivism, along with more qualitative explorations of the psychosocial implications of being involved

The prison-based model of CoSA and its application in transitioning to the community

The barriers to successful reintegration those convicted of sexual offences face, often lead to social isolation and prevent desistance from crime being achieved (Tewksbury & Mustaine, Journal of Public Management & Social Policy, 15 (2), 215–239, 2009). Of those who commit these offences, the elderly and intellectually disabled face even greater barriers, often finding the transition from prison to community the most difficult. In 2014, a prison-model of CoSA was established to support these individuals specifically. A qualitative evaluation was commenced at the same time, involving interviews with the Core Members to explore their personal experience of the prison-based model. This chapter will explore some of the key themes derived from the data in relation to the support the prison-based model of CoSA provided the Core Members during their transition from prison to community

Supporting desistance through ambiguous practice: what can be learned from the first prison-based model of CoSA in England and Wales?

Circles of Support and Accountability (CoSA) are an initiative designed to support those previously convicted of sexual offences as they reintegrate back in to society, whilst still holding them accountable for their thoughts and behaviour (Cesaroni, 2002). The aim of the research was to explore the Core Member and volunteer experience of being involved in a CoSA that transitions from prison to community, with the objective being to focus upon what can be learnt from these initial experiences. The study included qualitative interviews with two separate groups of participants; Core Members (n=7) and volunteers (n=10) involved in the prison-model CoSA. Interpretative Phenomenological Analysis of the data was undertaken to consider the individual’s subjective experience of being involved in this initiative. A superordinate theme of ambiguous practice was identified, whereby volunteers appeared to overlook the importance of expressive support, described a lack of commitment from other fellow volunteers and demonstrated a confusion surrounding the accountability aspect of their role. Despite the confusion highlighted, however, the accountability aspect of the volunteers’ role was identified through their indirect support of Core members’ desistance. The second superordinate theme outlined the volunteers’ encouragement of the Core Members new pro-social lifestyle, thus helping to reinforce their crime -free identity. This led to a concern, however, of what would happen once the CoSA journey had come to an end. The learning derived from these findings can now be used to continue to develop and improve the use of prison-model CoSA across England and Wales

Sub-optical resolution of single spins using magnetic resonance imaging at room temperature in diamond

There has been much recent interest in extending the technique of magnetic resonance imaging (MRI) down to the level of single spins with sub-optical wavelength resolution. However, the signal to noise ratio for images of individual spins is usually low and this necessitates long acquisition times and low temperatures to achieve high resolution. An exception to this is the nitrogen-vacancy (NV) color center in diamond whose spin state can be detected optically at room temperature. Here we apply MRI to magnetically equivalent NV spins in order to resolve them with resolution well below the optical wavelength of the readout light. In addition, using a microwave version of MRI we achieved a resolution that is 1/270 size of the coplanar striplines, which define the effective wavelength of the microwaves that were used to excite the transition. This technique can eventually be extended to imaging of large numbers of NVs in a confocal spot and possibly to image nearby dark spins via their mutual magnetic interaction with the NV spin.Comment: 10 pages, 8 figures, Journal of Luminescence (Article in Press

Perspectives of frailty and frailty screening: Protocol for a collaborative knowledge translation approach and qualitative study of stakeholder understandings and experiences

Accompanying the unprecedented growth in the older adult population worldwide is an increase in the prevalence of frailty, an age-related clinical state of increased vulnerability to stressor events. This increased vulnerability results in lower social engagement and quality of life, increased dependency, and higher rates of morbidity, health service utilization and mortality. Early identification of frailty is necessary to guide implementation of interventions to prevent associated functional decline. Consensus is lacking on how to clinically recognize and manage frailty. It is unknown how healthcare providers and healthcare consumers understand and perceive frailty, whether or not they regard frailty as a public health concern; and information on the indirect and direct experiences of consumer and healthcare provider groups towards frailty are markedly limited.We will conduct a qualitative study of consumer, practice nurse, general practitioner, emergency department physician, and orthopedic surgeons' perspectives of frailty and frailty screening in metropolitan and non-metropolitan South Australia. We will use tailored combinations of semi-structured interviews and arts-based data collection methods depending on each stakeholder group, followed by inductive and iterative analysis of data using qualitative description.Using stakeholder driven approaches to understanding and addressing frailty and frailty screening in context is critical as the prevalence and burden of frailty is likely to increase worldwide. We will use the findings from the Perceptions of Frailty and Frailty Screening study to inform a context-driven identification, implementation and evaluation of a frailty-screening tool; drive awareness, knowledge, and skills development strategies across stakeholder groups; and guide future efforts to embed emerging knowledge about frailty and its management across diverse South Australian contexts using a collaborative knowledge translation approach. Study findings will help achieve a coordinated frailty and healthy ageing strategy with relevance to other jurisdictions in Australia and abroad, and application of the stakeholder driven approach will help illuminate how its applicability to other jurisdictions.Mandy M. Archibald, Rachel Ambagtsheer, Justin Beilby, Mellick J. Chehade, Tiffany K. Gill, Renuka Visvanathan, and Alison L. Kitso

Gluon flux-tube distribution and linear confinement in baryons

We have observed the formation of gluon flux-tubes within baryons using lattice QCD techniques. A high-statistics approach, based on translational and rotational symmetries of the four-dimensional lattice, enables us to observe correlations between vacuum action density and quark positions in a completely gauge independent manner. This contrasts with earlier studies which used gauge-dependent smoothing techniques. We used 200 O(a^2) improved quenched QCD gauge-field configurations on a 16^3x32 lattice with a lattice spacing of 0.123 fm. In the presence of static quarks flux tubes representing the suppression of gluon-field fluctuations are observed. We have analyzed 11 L-shapes and 8 T and Y shapes of varying sizes in order to explore a variety of flux-tube topologies, including the ground state. At large separations, Y-shape flux-tube formation is observed. T-shaped paths are observed to relax towards a Y-shaped topology, whereas L-shaped paths give rise to a large potential energy. We do not find any evidence for the formation of a Delta-shaped flux-tube (empty triangle) distribution. However, at small quark separations, we observe an expulsion of gluon-field fluctuations in the shape of a filled triangle with maximal expulsion at the centre of the triangle. Having identified the precise geometry of the flux distribution, we are able to perform quantitative comparison between the length of the flux-tube and the associated static quark potential. For every source configuration considered we find a universal string tension, and conclude that, for large quark separations, the ground state potential is that which minimizes the length of the flux-tube. The flux tube radius of the baryonic ground state potential is found to be 0.38 \pm 0.03 fm, with vacuum fluctuations suppressed by 7.2 \pm 0.6 %.Comment: 16 pages, final version as accepted for publication in Physical review D1. Abstract, text, references and some figures have been revise

Nasal Lipopolysaccharide Challenge and Cytokine Measurement Reflects Innate Mucosal Immune Responsiveness

<div><p>Background</p><p><b>P</b>ractical methods of monitoring innate immune mucosal responsiveness are lacking. Lipopolysaccharide (LPS) is a component of the cell wall of Gram negative bacteria and a potent activator of Toll-like receptor (TLR)-4. To measure LPS responsiveness of the nasal mucosa, we administered LPS as a nasal spray and quantified chemokine and cytokine levels in mucosal lining fluid (MLF).</p><p>Methods</p><p>We performed a 5-way cross-over, single blind, placebo-controlled study in 15 healthy non-atopic subjects (n = 14 <i>per protocol</i>). Doses of ultrapure LPS (1, 10, 30 or 100μg/100μl) or placebo were administered by a single nasal spray to each nostril. Using the recently developed method of nasosorption with synthetic adsorptive matrices (SAM), a series of samples were taken. A panel of seven cytokines/chemokines were measured by multiplex immunoassay in MLF. mRNA for intercellular cell adhesion molecule-1 (ICAM-1) was quantified from nasal epithelial curettage samples taken before and after challenge.</p><p>Results</p><p>Topical nasal LPS was well tolerated, causing no symptoms and no visible changes to the nasal mucosa. LPS induced dose-related increases in MLF levels of IL-1β, IL-6, CXCL8 (IL-8) and CCL3 (MIP-1α) (AUC at 0.5 to 10h, compared to placebo, p<0.05 at 30 and 100μg LPS). At 100μg LPS, IL-10, IFN-α and TNF-α were also increased (p<0.05). Dose-related changes in mucosal ICAM-1 mRNA were also seen after challenge, and neutrophils appeared to peak in MLF at 8h. However, 2 subjects with high baseline cytokine levels showed prominent cytokine and chemokine responses to relatively low LPS doses (10μg and 30μg LPS).</p><p>Conclusions</p><p>Topical nasal LPS causes dose-dependent increases in cytokines, chemokines, mRNA and cells. However, responsiveness can show unpredictable variations, possibly because baseline innate tone is affected by environmental factors. We believe that this new technique will have wide application in the study of the innate immune responses of the respiratory mucosa.</p><p>Key Messages</p><p>Ultrapure LPS was used as innate immune stimulus in a human nasal challenge model, with serial sampling of nasal mucosal lining fluid (MLF) by nasosorption using a synthetic absorptive matrix (SAM), and nasal curettage of mucosal cells. A dose response could be demonstrated in terms of levels of IL-1β, IL-6, CXCL8 and CCL3 in MLF, as well as ICAM-1 mRNA in nasal curettage specimens, and levels of neutrophils in nasal lavage. Depending on higher baseline levels of inflammation, there were occasional magnified innate inflammatory responses to LPS.</p><p>Trial Registration</p><p>Clinical Trials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT02284074?term=nasal+lipopolysaccharide&rank=1" target="_blank">NCT02284074</a></p></div

Teaching climate change and sustainability: A survey of teachers in England

This report shares detailed findings as to the current state of climate change and sustainability education in England in 2022-23, with a particular focus on teachers’ practice and professional development. The results reveal both strengths and gaps in the provision of climate change and sustainability education in England. The report serves as an evidence base for researchers, policymakers and practitioners who seek to support teachers to fulfil their important roles in society’s transformation to a sustainable future. UCL’s Centre for Climate Change and Sustainability Education (CCCSE) conducted a survey of teachers in England entitled ‘What do climate change and sustainability education have to do with me?’. Between October and December 2022, teachers were invited to respond to an online questionnaire about their views and experiences. Teachers were recruited through email lists, professional networks, social media and via the CCCSE website. The questionnaire investigated their teaching practice, professional development, and sense of confidence and preparedness to incorporate climate change and sustainability into their teaching. It included a range of question types and generated quantitative and qualitative data. The survey gathered 870 responses, with over two thirds (70.7%) teaching at secondary level, and geography (41.3%) and science (37.2%) being the most frequently reported subjects taught. Those who responded represented a wide range of teaching experience, from one year to 20+ years, with university-led PGCE programmes the most commonly reported route into teaching (87.2%). The significant majority of respondents were female (73.9%) and from white backgrounds (90.5%)