Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer

Introduction Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach. Methods Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n = 84), gene expression profiling (n = 47), matched pre- and post-AI aCGH (n = 19 pairs) and Ki67-based AI-response analysis (n = 39). Results Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1). Conclusions These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response

Mechanisms and Impacts of Earth System Tipping Elements

Tipping elements are components of the Earth system which may respond nonlinearly to anthropogenic climate change by transitioning toward substantially different long-term states upon passing key thresholds or “tipping points.” In some cases, such changes could produce additional greenhouse gas emissions or radiative forcing that could compound global warming. Improved understanding of tipping elements is important for predicting future climate risks and their impacts. Here we review mechanisms, predictions, impacts, and knowledge gaps associated with 10 notable Earth system components proposed to be tipping elements. We evaluate which tipping elements are approaching critical thresholds and whether shifts may manifest rapidly or over longer timescales. Some tipping elements have a higher risk of crossing tipping points under middle-of-the-road emissions pathways and will possibly affect major ecosystems, climate patterns, and/or carbon cycling within the 21st century. However, literature assessing different emissions scenarios indicates a strong potential to reduce impacts associated with many tipping elements through climate change mitigation. The studies synthesized in our review suggest most tipping elements do not possess the potential for abrupt future change within years, and some proposed tipping elements may not exhibit tipping behavior, rather responding more predictably and directly to the magnitude of forcing. Nevertheless, uncertainties remain associated with many tipping elements, highlighting an acute need for further research and modeling to better constrain risks

Adapted motivational interviewing to improve the uptake of treatment for glaucoma in Nigeria: study protocol for a randomized controlled trial.

BACKGROUND: Glaucoma is a chronic eye disease associated with irreversible visual loss. In Africa, glaucoma patients often present late, with very advanced disease. One-off procedures, such as laser or surgery, are recommended in Africa because of lack of or poor adherence to medical treatment. However, acceptance of surgery is usually extremely low. To prevent blindness, adherence to treatment needs to improve, using acceptable, replicable and cost-effective interventions. After reviewing the literature and interviewing patients in Bauchi (Nigeria) motivational interviewing (MI) was selected as the intervention for this trial, with adaptation for glaucoma (MIG). MI is designed to strengthen personal motivation for, and commitment to a specific goal by eliciting and exploring a person's reasons for change within an atmosphere of acceptance and compassion. The aim of this study is to assess whether MIG increases the uptake of laser or surgery amongst glaucoma patients where this is the recommended treatment. The hypothesis is that MIG increases the uptake of treatment. This will be the first trial of MI in Africa. METHODS: This is a hospital based, single centre, randomized controlled trial of MIG plus an information sheet on glaucoma and its treatment (the latter being "standard care") compared with standard care alone for glaucoma patients where the treatment recommended is surgery or laser.Those eligible for the trial are adults aged 17 years and above who live within 200 km of Bauchi with advanced glaucoma where the examining ophthalmologist recommends surgery or laser. After obtaining written informed consent, participants will be randomly allocated to MIG plus standard care, or standard care alone. Motivational interviewing will be delivered in Hausa or English by one of two MIG trained personnel. One hundred and fifty participants will be recruited to each arm. The primary outcome is the proportion of participants undergoing laser or surgery within two months of the date given to re attend for the procedure. MIG quality will be assessed using the validated MI treatment integrity scale. DISCUSSION: Motivational interviewing may be an important tool to increase the acceptance of treatment for glaucoma. The approach is potentially scalable and may be useful for other chronic conditions in Africa. TRIAL REGISTRATION: ISRCTN79330571 (Controlled-Trials.com)

Electro-Magnetic Nucleon Form Factors and their Spectral Functions in Soliton Models

It is demonstrated that in simple soliton models essential features of the electro-magnetic nucleon form factors observed over three orders of magnitude in momentum transfer $t$ are naturally reproduced. The analysis shows that three basic ingredients are required: an extended object, partial coupling to vector mesons, and relativistic recoil corrections. We use for the extended object the standard skyrmion, one vector meson propagator for both isospin channels, and the relativistic boost to the Breit frame. Continuation to timelike $t$ leads to quite stable results for the spectral functions in the regime from the 2- or 3-pion threshold to about two rho masses. Especially the onset of the continuous part of the spectral functions at threshold can be reliably determined and there are strong analogies to the results imposed on dispersion theoretic approaches by the unitarity constraint.Comment: 24 pages, (RevTeX), 5 PS-figures; Data points in fig.2 and corresponding references added. Final version, to be published in Z.Physik

Design and feasibility testing of a novel group intervention for young women who binge drink in groups

BackgroundYoung women frequently drink alcohol in groups and binge drinking within these natural drinking groups is common. This study describes the design of a theoretically and empirically based group intervention to reduce binge drinking among young women. It also evaluates their engagement with the intervention and the acceptability of the study methods.MethodsFriendship groups of women aged 18–35 years, who had two or more episodes of binge drinking (>6 UK units on one occasion; 48g of alcohol) in the previous 30 days, were recruited from the community. A face-to-face group intervention, based on the Health Action Process Approach, was delivered over three sessions. Components of the intervention were woven around fun activities, such as making alcohol free cocktails. Women were followed up four months after the intervention was delivered. Results The target of 24 groups (comprising 97 women) was recruited. The common pattern of drinking was infrequent, heavy drinking (mean consumption on the heaviest drinking day was UK 18.1 units). Process evaluation revealed that the intervention was delivered with high fidelity and acceptability of the study methods was high. The women engaged positively with intervention components and made group decisions about cutting down. Twenty two groups set goals to reduce their drinking, and these were translated into action plans. Retention of individuals at follow up was 87%.ConclusionsThis study successfully recruited groups of young women whose patterns of drinking place them at high risk of acute harm. This novel approach to delivering an alcohol intervention has potential to reduce binge drinking among young women. The high levels of engagement with key steps in the behavior change process suggests that the group intervention should be tested in a full randomised controlled trial

A whole-ecosystem method for experimentally suppressing ants on a small scale

Funder: Sinar Mas Agro Resources Technology Research Institute (SMARTRI)Funder: The Isaac Newton Trust Cambridge; Id: http://dx.doi.org/10.13039/501100004815Ant suppression experiments have emerged as a powerful method for assessing the role of ants in ecosystems. However, traditional methods have been limited to canopy ants, and not assessed the role of ants on and below ground. Recent advances have enabled whole-ecosystem ant suppression in large plots, but large-scale experiments are not always feasible. Here, we develop a small-scale, whole-ecosystem suppression method. We compare techniques for monitoring suppression experiments, and assess whether habitat complexity in oil palm influences our method’s effectiveness. We conducted ant suppression experiments in oil palm agroforestry in Sumatra, Indonesia. We used targeted poison baits, a physical barrier, and canopy isolation to suppress ants in 4m-radius arenas around single palms. We sequentially tested three suppression methods that increased in intensity over 18 months. We sampled ant abundance before and after suppression by fogging, using pitfall traps, and extracting soil monoliths. We also monitored ants throughout the experiment by baiting. We tested the soil for residual poison and monitored other invertebrates (Araneae, Coleoptera, Orthoptera, and Chilopoda) to test for cross-contamination. Plots were established under four oil palm management treatments that varied in their habitat complexity: reduced, intermediate, and high understory complexity treatments in mature plantation, and a recently-replanted plantation. Post-treatment ant abundance was 92% lower in suppression than control plots. Only the most intensive suppression method, which ran for the final nine months, worked. Baiting rarely reflected the other monitoring methods. The treatment negatively affected Orthoptera, but not other taxa. We detected no residual poison in the soil. Coleoptera abundance increased in suppression plots post-treatment, potentially due to reduced competition with ants. Our findings were consistent across management treatments.Whitten Studentship, Department of Zoolog

Using functional genomics to decipher the complexity of microbial pathogenicity

From the first identification of bacteria as a causative agent of disease, researchers have been developing methods and techniques to understand their pathogenic processes. For decades, this work has been limited to looking at a small number of genetically manipulatable isolates in in vitro assays or animal models of infection. Despite these limitations such work has facilitated the development of successful therapeutic strategies, most notably vaccines that target specific virulence-related features. There are however many antimicrobial resistant pathogens for which vaccination strategies have not worked, as we simply do not know enough about how they cause disease. We are however at the dawn of a new era in the study of microbial pathogenicity, where large collections of bacteria isolated directly from human infections can be sequenced and assayed to identify the bacterial features that affect disease severity in humans. Here, we describe our attempt to perform such a study focussed on the major human pathogen Staphylococcus aureus, which demonstrates the step changes such approaches can make to understanding microbial pathogenicity

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

Recipient and donor thrombophilia and the risk of portal venous thrombosis and hepatic artery thrombosis in liver recipients

<p>Abstract</p> <p>Background</p> <p>Vascular complications, such as HAT, are an important cause of graft loss and recipient mortality. We aimed to characterize post-transplant thrombotic events in a cohort of liver transplant recipients, and identify independent risk factors for these complications.</p> <p>Methods</p> <p>We conducted a thrombophilic study of 293 orthotopic liver transplants performed in the Digestive Surgery Department of the 12 de Octubre Hospital (Madrid, Spain) between January 2001 and December 2006.</p> <p>Results</p> <p>The most frequent post-transplant thrombotic events were HAT (9%) and PVT (1.7%). The one variable associated with post-transplant thrombotic event was a high fibrinogen level in the global cohort of liver transplantation. But toxicity as event post-OLT has been associated with post-transplant thrombotic event in the retrospective group and high fibrinogen level and low protein C levels were associated post-transplant thrombotic event in the prospective group. Liver disease relapse (HR 6.609, p < 0.001), high levels of FVIII (HR 1.008, p = 0.019)) and low levels of antithrombin (HR 0.946, p < 0.001) were associated with poor overall survival (OS).</p> <p>In conclusion, high fibrinogen and decreased protein C levels were associated with allograft thrombosis. Further studies are required in order to assess the clinical relevance of these parameters in prospective studies and to study the effect of anticoagulation prophylaxis in this group of risk.</p