The Role of Androgen Receptor Signalling in Endocrine Resistant Breast Cancer

Breast cancer (BCa) is the most prevalent cancer among women in the UK. The majority of BCas are endocrine sensitive and develop through the action of oestrogens, facilitated through the transcription factor Oestrogen Receptor alpha (ERα). Treatment for these patients usually involves endocrine therapies (Aromatase Inhibitors and antioestrogens), which are successful in many patients, but therapy resistance represents a major clinical issue. The Androgen Receptor (AR) is a transcription factor that is more highly expressed than ERα in BCa, and mediates the functions of androgens. In early forms of ERα-positive disease, AR is a positive indicator of prognostic outcome and suppresses ERα signalling. However, in ERα-negative disease AR has been demonstrated to drive cancer progression and recent evidence has suggested that AR can drive endocrine resistance. Reporter assays, gene expression analysis and Chromatin Immunoprecipitation assays demonstrated that AR and ERα inhibit each other’s activity and that antioestrogens can reverse this inhibition, resulting in an active AR. Importantly, long term colony formation assays demonstrated that androgen could induce anti-oestrogen resistant growth, but anti-androgens prevented this from developing. Co-treatment of tumours with anti-oestrogens and anti-androgens could therefore be a viable option to block this mechanism of resistance. Cell line models of endocrine resistant disease were used to investigate AR signalling in therapy resistance. The results demonstrated that AR levels were enhanced in several lines and that all cell lines were sensitive to androgen for growth. Importantly, anti-androgens could inhibit androgen-induced growth in all models. Anti-androgens could therefore also be a viable option for the treatment of tumours that have become resistant to endocrine therapies. This study therefore furthers our understanding of the role of the AR in BCa progression and suggests that it is a valid therapeutic target to prevent and/or treat endocrine resistant disease

Emplacement of inflated Pāhoehoe flows in the Naude’s Nek Pass, Lesotho remnant, Karoo continental flood basalt province: use of flow-lobe tumuli in understanding flood basalt emplacement

Physical volcanological features are presented for a 710-m-thick section, of the Naude’s Nek Pass, within the lower part of the Lesotho remnant of the Karoo Large Igneous Province. The section consists of inflated pāhoehoe lava with thin, impersistent sedimentary interbeds towards the base. There are seven discreet packages of compound and hummocky pāhoehoe lobes containing flow-lobe tumuli, making up approximately 50% of the section. Approximately 45% of the sequence consists of 14 sheet lobes, between 10 and 52-m-thick. The majority of the sheet lobes are in two packages indicating prolonged periods of lava supply capable of producing thick sheet lobes. The other sheet lobes are as individual lobes or pairs, within compound flows, suggesting brief increases in lava supply rate. We suggest, contrary to current belief, that there is no evidence that compound flows are proximal to source and sheet lobes (simple flows) are distal to source and we propose that the presence of flow-lobe tumuli in compound flows could be an indicator that a flow is distal to source. We use detailed, previously published, studies of the Thakurvadi Formation (Deccan Traps) as an example. We show that the length of a lobe and therefore the sections that are ‘medial or distal to source’ are specific to each individual lobe and are dependent on the lava supply of each eruptive event, and as such flow lobe tumuli can be used as an indicator of relative distance from source

Neutron halos in heavy nuclei -- relativistic mean field approach

Assuming a~simple spherical relativistic mean field model of the nucleus, we estimate the width of the antiproton--neutron annihilation ($\Gamma_n$) and the width of antiproton--proton ($\Gamma_p$) annihilation, in an antiprotonic atom system. This allows us to determine the halo factor $f$, which is then discussed in the context of experimental data obtained in measurements recently done on LEAR utility at CERN. Another quantity which characterizes the deviation of the average nuclear densities ratio from the corresponding ratio of the homogeneous densities is introduced too. It was shown that it is also a good indicator of the neutron halo. The results are compared to experimental data as well as to the data of the simple liquid droplet model of the nuclear densities. The single particle structure of the nuclear density tail is discusssed also.Comment: revtex, 12 pages + 6 postscript figure

Impact of picture archiving communication systems on rates of duplicate imaging: a before-after study

<p>Abstract</p> <p>Background</p> <p>Electronic health information systems, such as picture archiving communication systems (PACS), are commonly believed to reduce the need for duplicate testing. However, empirical data to support this belief are not available.</p> <p>Methods</p> <p>Before-after study using administrative claims data from the Ontario Health Insurance Plan to determine whether the introduction of PACS at 10 hospitals in the Thames Valley region of southwestern Ontario, Canada between June 2004 and December 2005 reduced the frequency of duplicate imaging examinations. The imaging modalities studied were: chest and abdominal X-ray; computed tomography of the abdomen/pelvis, head, and chest. The frequency of duplicate testing was examined at 3 different time frames: 7 days, 30 days, and 60 days after a given index test.</p> <p>Results</p> <p>Overall frequencies of duplicate imaging were: 2.7% within 7 days of an index imaging test, 6.7% within 30 days, and 9.8% within 60 days. Comparing the 12 months before and 12 months after PACS, absolute reductions in the frequency of duplicate X-rays using 7-day, 30-day, and 60-day time frames were: 0.2% (P = 0.01), 0.6% (P < 0.001), and 0.9% (P < 0.001), respectively. In contrast, there were absolute <it>increases </it>in the frequency of duplicate CT scans after PACS of 0.0% (P = 0.92), 0.5% (P = 0.01), and 0.5% (P = 0.01), respectively.</p> <p>Conclusion</p> <p>The frequency of duplicate imaging is relatively low and we did not find large reductions in duplicate imaging after the introduction of PACS. Independent evaluation of electronic medical systems should be conducted to confirm widely held beliefs of their potential benefits.</p

Genetic Analysis of the Functions and Interactions of Components of the LevQRST Signal Transduction Complex of Streptococcus mutans

Transcription of the genes for a fructan hydrolase (fruA) and a fructose/mannose sugar:phosphotransferase permease (levDEFG) in Streptococcus mutans is activated by a four-component regulatory system consisting of a histidine kinase (LevS), a response regulator (LevR) and two carbohydrate-binding proteins (LevQT). The expression of the fruA and levD operons was at baseline in a levQ mutant and substantially decreased in a levT null mutant, with lower expression with the cognate inducers fructose or mannose, but slightly higher expression in glucose or galactose. A strain expressing levQ with two point mutations (E170A/F292S) did not require inducers to activate gene expression and displayed altered levD expression when growing on various carbohydrates, including cellobiose. Linker-scanning (LS) mutagenesis was used to generate three libraries of mutants of levQ, levS and levT that displayed various levels of altered substrate specificity and of fruA/levD gene expression. The data support that LevQ and LevT are intimately involved in the sensing of carbohydrate signals, and that LevQ appears to be required for the integrity of the signal transduction complex, apparently by interacting with the sensor kinase LevS

A single-centre investigator-blinded randomised parallel-group study protocol to investigate the influence of an acclimatisation appointment on children’s behaviour during N2O/O2 sedation as measured by psychological, behavioural and real-time physiological parameters

Aims and objectives To describe a study protocol of a randomised control trial (RCT) assessing the effectiveness, in reducing dental anxiety, of an acclimatising nitrous oxide sedation (N2O) session prior to actual dental treatment with N2O. Materials and methods A single-centre investigator-blinded parallel-group RCT conducted in a postgraduate dental hospital in Dubai, United Arab Emirates (UAE). Anxious children requiring N2O (aged 5–15 years) will be randomly assigned to; a study group: children who will have a preparatory N2O trial experience or; a control group: children who will only have N2O explained to them. Treatment with N2O for both groups will start at the second visit. The following outcomes will be recorded: completion of dental treatment, anxiety scores at baseline and after treatment (using the Modified Child Dental Anxiety Scale faces), behaviour of the child (using Frankl Rating Behaviour Scale) and the acquisition of real-time physiological anxiety-related parameters (using E4® electronic wrist devices). Results The data will be analysed statistically. Discussion There is a paucity of research regarding dental N2O acclimatising appointments. This RCT will supplement existing literature. Conclusions This RCT will report whether prior acclimatising of a child to N2O sedation is effective, or not, in improving dental treatment behaviour

Annexin-A5 assembled into two-dimensional arrays promotes cell membrane repair

Eukaryotic cells possess a universal repair machinery that ensures rapid resealing of plasma membrane disruptions. Before resealing, the torn membrane is submitted to considerable tension, which functions to expand the disruption. Here we show that annexin-A5 (AnxA5), a protein that self-assembles into two-dimensional (2D) arrays on membranes upon Ca2+ activation, promotes membrane repair. Compared with wild-type mouse perivascular cells, AnxA5-null cells exhibit a severe membrane repair defect. Membrane repair in AnxA5-null cells is rescued by addition of AnxA5, which binds exclusively to disrupted membrane areas. In contrast, an AnxA5 mutant that lacks the ability of forming 2D arrays is unable to promote membrane repair. We propose that AnxA5 participates in a previously unrecognized step of the membrane repair process: triggered by the local influx of Ca2+, AnxA5 proteins bind to torn membrane edges and form a 2D array, which prevents wound expansion and promotes membrane resealing

Smoking and health-related quality of life in English general population: Implications for economic evaluations

Copyright @ 2012 Vogl 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.This article has been made available through the Brunel Open Access Publishing Fund.Background: Little is known as to how health-related quality of life (HRQoL) when measured by generic instruments such as EQ-5D differ across smokers, ex-smokers and never-smokers in the general population; whether the overall pattern of this difference remain consistent in each domain of HRQoL; and what implications this variation, if any, would have for economic evaluations of tobacco control interventions. Methods: Using the 2006 round of Health Survey for England data (n = 13,241), this paper aims to examine the impact of smoking status on health-related quality of life in English population. Depending upon the nature of the EQ-5D data (i.e. tariff or domains), linear or logistic regression models were fitted to control for biology, clinical conditions, socio-economic background and lifestyle factors that an individual may have regardless of their smoking status. Age- and gender-specific predicted values according to smoking status are offered as the potential 'utility' values to be used in future economic evaluation models. Results: The observed difference of 0.1100 in EQ-5D scores between never-smokers (0.8839) and heavy-smokers (0.7739) reduced to 0.0516 after adjusting for biological, clinical, lifestyle and socioeconomic conditions. Heavy-smokers, when compared with never-smokers, were significantly more likely to report some/severe problems in all five domains - mobility (67%), self-care (70%), usual activity (42%), pain/discomfort (46%) and anxiety/depression (86%) -. 'Utility' values by age and gender for each category of smoking are provided to be used in the future economic evaluations. Conclusion: Smoking is significantly and negatively associated with health-related quality of life in English general population and the magnitude of this association is determined by the number of cigarettes smoked. The varying degree of this association, captured through instruments such as EQ-5D, may need to be fed into the design of future economic evaluations where the intervention being evaluated affects (e.g. tobacco control) or is affected (e.g. treatment for lung cancer) by individual's (or patients') smoking status

Increasing condom use in heterosexual men: development of a theory-based interactive digital intervention

Increasing condom use to prevent sexually transmitted infections is a key public health goal. Interventions are more likely to be effective if they are theory- and evidence-based. The Behaviour Change Wheel (BCW) provides a framework for intervention development. To provide an example of how the BCW was used to develop an intervention to increase condom use in heterosexual men (the MenSS website), the steps of the BCW intervention development process were followed, incorporating evidence from the research literature and views of experts and the target population. Capability (e.g. knowledge) and motivation (e.g. beliefs about pleasure) were identified as important targets of the intervention. We devised ways to address each intervention target, including selecting interactive features and behaviour change techniques. The BCW provides a useful framework for integrating sources of evidence to inform intervention content and deciding which influences on behaviour to target

Influencia de la responsabilidad social corporativa en el desempe?o organizacional considerando como variable moderadora a la reputaci?n corporativa

La pr?ctica de la responsabilidad social corporativa por parte de las empresas se ha incrementado alrededor del mundo y en el Per?. Hoy en d?a se considera como una estrategia que puede contribuir al desempe?o financiero de la empresa; Sin embargo, las conclusiones obtenidas por la literatura de dicha relaci?n han variado. Bas?ndonos en la pir?mide de Carroll de las 4 dimensiones de la RSC: social, ?tica, legal y econ?mica, la presente investigaci?n busca determinar c?mo la responsabilidad social corporativa impacta en el desempe?o organizacional del sector financiero de Lima Metropolitana tomando como elemento moderador a la reputaci?n corporativa. Para la recolecci?n de datos se proponen cuestionarios estructurados como instrumento de medici?n. Para el procesamiento de la informaci?n se sugiere analizar los datos mediante el m?todo de an?lisis de varianza (ANOVA) y regresi?n lineal. Uno de los principales aportes de esta investigaci?n es plantear una base te?rica anal?tica sobre c?mo la reputaci?n corporativa modera la relaci?n entre la responsabilidad social corporativa y el desempe?o organizacional