HER2-HER3 heterodimer quantification by FRET-FLIM and patient subclass analysis of the COIN colorectal trial

BACKGROUND: The phase 3 MRC COIN trial showed no statistically significant benefit from adding the EGFR-target cetuximab to oxaliplatin-based chemotherapy in first-line treatment of advanced colorectal cancer. This study exploits additional information on HER2-HER3 dimerization to achieve patient stratification and reveal previously hidden subgroups of patients who had differing disease progression and treatment response. METHODS: HER2-HER3 dimerization was quantified by "FLIM Histology" in primary tumor samples from 550 COIN trial patients receiving oxaliplatin and fluoropyrimidine chemotherapy +/-cetuximab. Bayesian latent class analysis (LCA) and covariate reduction was performed to analyze the effects of HER2-HER3 dimer, RAS mutation and cetuximab on progression-free survival (PFS) and overall survival (OS). All statistical tests were two-sided. RESULTS: LCA on a cohort of 398 patients revealed two patient subclasses with differing prognoses (median OS: 1624 days [95%CI=1466-1816] vs 461 [95%CI=431-504]): Class 1 (15.6%) showed a benefit from cetuximab in OS (HR = 0.43 [95%CI=0.25-0.76]; p = 0.004). Class 2 showed an association of increased HER2-HER3 with better OS (HR = 0.64 [95%CI=0.44-0.94]; p = 0.02). A class prediction signature was formed and tested on an independent validation cohort (N = 152) validating the prognostic utility of the dimer assay. Similar subclasses were also discovered in full trial dataset (N = 1,630) based on 10 baseline clinicopathological and genetic covariates. CONCLUSIONS: Our work suggests that the combined use of HER dimer imaging and conventional mutation analyses will be able to identify a small subclass of patients (>10%) who will have better prognosis following chemotherapy. A larger prospective cohort will be required to confirm its utility in predicting the outcome of anti-EGFR treatment

Systematic Conservation Planning in the Face of Climate Change: Bet-Hedging on the Columbia Plateau

Systematic conservation planning efforts typically focus on protecting current patterns of biodiversity. Climate change is poised to shift species distributions, reshuffle communities, and alter ecosystem functioning. In such a dynamic environment, lands selected to protect today's biodiversity may fail to do so in the future. One proposed approach to designing reserve networks that are robust to climate change involves protecting the diversity of abiotic conditions that in part determine species distributions and ecological processes. A set of abiotically diverse areas will likely support a diversity of ecological systems both today and into the future, although those two sets of systems might be dramatically different. Here, we demonstrate a conservation planning approach based on representing unique combinations of abiotic factors. We prioritize sites that represent the diversity of soils, topographies, and current climates of the Columbia Plateau. We then compare these sites to sites prioritized to protect current biodiversity. This comparison highlights places that are important for protecting both today's biodiversity and the diversity of abiotic factors that will likely determine biodiversity patterns in the future. It also highlights places where a reserve network designed solely to protect today's biodiversity would fail to capture the diversity of abiotic conditions and where such a network could be augmented to be more robust to climate-change impacts

Estimating how inflated or obscured effects of climate affect forecasted species distribution

Climate is one of the main drivers of species distribution. However, as different environmental factors tend to co-vary, the effect of climate cannot be taken at face value, as it may be either inflated or obscured by other correlated factors. We used the favourability models of four species (Alytes dickhilleni, Vipera latasti, Aquila fasciata and Capra pyrenaica) inhabiting Spanish mountains as case studies to evaluate the relative contribution of climate in their forecasted favourability by using variation partitioning and weighting the effect of climate in relation to non-climatic factors. By calculating the pure effect of the climatic factor, the pure effects of non-climatic factors, the shared climatic effect and the proportion of the pure effect of the climatic factor in relation to its apparent effect (r), we assessed the apparent effect and the pure independent effect of climate. We then projected both types of effects when modelling the future favourability for each species and combination of AOGCM-SRES (two Atmosphere-Ocean General Circulation Models: CGCM2 and ECHAM4, and two Special Reports on Emission Scenarios (SRES): A2 and B2). The results show that the apparent effect of climate can be either inflated (overrated) or obscured (underrated) by other correlated factors. These differences were species-specific; the sum of favourable areas forecasted according to the pure climatic effect differed from that forecasted according to the apparent climatic effect by about 61% on average for one of the species analyzed, and by about 20% on average for each of the other species. The pure effect of future climate on species distributions can only be estimated by combining climate with other factors. Transferring the pure climatic effect and the apparent climatic effect to the future delimits the maximum and minimum favourable areas forecasted for each species in each climate change scenario.Ministerio de Ciencia e Innovación and FEDER (project CGL2009-11316/BOS). D. Romero is a PhD student at the University of Malaga with a grant of the Ministerio de Educacio´n y Ciencia (AP 2007-03633

The effectiveness of modern cardiac rehabilitation : A systematic review of recent observational studies in non-attenders versus attenders

BACKGROUND: The beneficial effects of cardiac rehabilitation (CR) have been challenged in recent years and there is now a need to investigate whether current CR programmes, delivered in the context of modern cardiology, still benefit patients. METHODS: A systematic review of non-randomised controlled studies was conducted. Electronic searches of Medline, Embase, CINAHL, science citation index (web of science), CIRRIE and Open Grey were undertaken. Non-randomised studies investigating the effects of CR were included when recruitment occurred from the year 2000 onwards in accordance with significant CR guidance changes from the late 1990's. Adult patients diagnosed with acute myocardial infarction (AMI) were included. Non-English articles were considered. Two reviewers independently screened articles according to pre-defined selection criteria as reported in the PROSPERO database (CRD42015024021). RESULTS: Out of 2,656 articles, 8 studies involving 9,836 AMI patients were included. Studies were conducted in 6 countries. CR was found to reduce the risk of all-cause and cardiac-related mortality and improve Health-Related Quality of Life (HRQOL) significantly in at least one domain. The benefits of CR in terms of recurrent MI were inconsistent and no significant effects were found regarding re-vascularisation or re-hospitalisation following AMI. CONCLUSION: Recent observational evidence draws different conclusions to the most current reviews of trial data with respect to total mortality and re-hospitalisation, questioning the representativeness of historic data in the modern cardiological era. Future work should seek to clarify which patient and service level factors determine the likelihood of achieving improved all-cause and cardiac mortality and reduced hospital re-admissions

Pedometer use and self-determined motivation for walking in a cardiac telerehabilitation program: a qualitative study

BACKGROUND: Exercise-based cardiac rehabilitation reduces morbidity and mortality. Walking is a convenient activity suitable for people with cardiac disease. Pedometers count steps, measure walking activity and motivate people to increase physical activity. In this study, patients participating in cardiac telerehabilitation were provided with a pedometer to support motivation for physical activity with the purpose of exploring pedometer use and self-determined motivation for walking experienced by patients and health professionals during a cardiac telerehabilitation program. METHODS: A qualitative research design consisting of observations, individual interviews and patient documents made the basis for a content analysis. Data was analysed deductively using Self Determination Theory as a frame for analysis and discussion, focusing on the psychological needs of autonomy, competence and relatedness. Twelve cardiac patients, 11 health professionals, 6 physiotherapists and 5 registered nurses were included. RESULTS: The pedometer offered independence from standardised rehabilitation since the pedometer supported tailoring, individualised walking activity based on the patient’s choice. This led to an increased autonomy. The patients felt consciously aware of health benefits of walking, and the pedometer provided feedback on walking activity leading to an increased competence to achieve goals for steps. Finally, the pedometer supported relatedness with others. The health professionals’ surveillance of patients’ steps, made the patients feel observed, yet supported, furthermore, their next of kin appeared to be supportive as walking partners. CONCLUSION: Cardiac patients’ motivation for walking was evident due to pedometer use. Even though not all aspects of motivation were autonomous and self determined, the patients felt motivated for walking. The visible steps and continuous monitoring of own walking activity made it possible for each individual patient to choose their desired kind of activity and perform ongoing adjustments of walking activity. The immediate feedback on step activity and the expectations of health benefits resulted in motivation for walking. Finally, pedometer supported walking made surveillance possible, giving the patients a feeling of being looked after and supported. TRIAL REGISTRATION: Current study is a part of The Teledi@log project

SMARTphone-based, early cardiac REHABilitation in patients with acute coronary syndromes [SMART-REHAB Trial]: A randomized controlled trial protocol

© 2016 The Author(s). Background: There are well-documented treatment gaps in secondary prevention of coronary heart disease and no clear guidelines to assist early physical activity after acute coronary syndromes (ACS). Smartphone technology may provide an innovative platform to close these gaps. This paper describes the study design of a randomized controlled trial assessing whether a smartphone-based secondary prevention program can facilitate early physical activity and improve cardiovascular health in patients with ACS. Methods: We have developed a multi-faceted, patient-centred smartphone-based secondary prevention program emphasizing early physical activity with a graduated walking program initiated on discharge from ACS admission. The program incorporates; physical activity tracking through the smartphone's accelerometer with interactive feedback and goal setting; a dynamic dashboard to review and optimize cardiovascular risk factors; educational messages delivered twice weekly; a photographic food diary; pharmacotherapy review; and support through a short message service. The primary endpoint of the trial is change in exercise capacity, as measured by the change in six-minute walk test distance at 8-weeks when compared to baseline. Secondary endpoints include improvements in cardiovascular risk factor status, psychological well-being and quality of life, medication adherence, uptake of cardiac rehabilitation and re-hospitalizations. Discussion: This randomized controlled trial will use a smartphone-phone based secondary prevention program to emphasize early physical activity post-ACS. It will provide evidence regarding the feasibility and utility of this innovative platform in closing the treatment gaps in secondary prevention. Trial registration: The trial was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) on April 4, 2016. The registration number is ACTRN12616000426482

PPARα Deficiency in Inflammatory Cells Suppresses Tumor Growth

Inflammation in the tumor bed can either promote or inhibit tumor growth. Peroxisome proliferator-activated receptor (PPAR)α is a central transcriptional suppressor of inflammation, and may therefore modulate tumor growth. Here we show that PPARα deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of the endogenous angiogenesis inhibitor thrombospondin-1 and prevents tumor growth. Bone marrow transplantation and granulocyte depletion show that PPARα expressing granulocytes are necessary for tumor growth. Neutralization of thrombospondin-1 restores tumor growth in PPARα-deficient mice. These findings suggest that the absence of PPARα activity renders inflammatory infiltrates tumor suppressive and, thus, may provide a target for inhibiting tumor growth by modulating stromal processes, such as angiogenesis

ALIX Regulates Tumor-Mediated Immunosuppression by Controlling EGFR Activity and PD-L1 Presentation

This work was supported by Cancer Research UK (grants C1519/A6906 and C5255/A15935); by the King’s College London-UCL Comprehensive Cancer Imaging Centre (CRUK and EPSRC, grants C1519/A10331 and C1519/A16463), in association with the MRC and DoH (grant C1519/A10331); by the EU FP7 grants IMAGINT (EC grant: 259881); and by KCL Breast Cancer Now Unit funding (for F.F.-B.; grant KCL-Q2-Y5). J.G.C. is a Wellcome Trust Senior Research fellow (206346/Z/17/Z). The purchase of the siRNA library was possible thanks to a generous gift from Ms. Marianne B. Blake, who raised funds during the 2010 London Marathon through Dimbleby Cancer Care

Open-label study comparing the efficacy and tolerability of aripiprazole and haloperidol in the treatment of pediatric tic disorders

Due to its unique pharmacodynamic properties of dopamine partial agonist activity, and its association with few and mild side effects, aripiprazole is a candidate atypical antipsychotic for patients with tic disorders. This open-label study compared the efficacy and tolerability of aripiprazole with haloperidol, a typical antipsychotic widely used to treat patients with tic disorders. Forty-eight children and adolescents with tic disorders were recruited from the outpatient clinic at South Korea and treated with aripiprazole (initial dose, 5.0 mg/d; maximum dose 20 mg/d) or haloperidol (initial dose, 0.75 mg/d; maximum dose, 4.5 mg/d) for 8 weeks. Treatment efficacy was measured using the yale global tic severity scale (YGTSS), and tolerability was measured using the extrapyramidal symptom rating scale (ESRS) and an adverse effects checklist. Total tic scores as measured by the YGTSS decreased over time in both groups (p < 0.001) without any significant differences between groups. ESRS scores were significantly higher in the haloperidol group during the 4 weeks after commencement of medication (p < 0.05). These results indicate that aripiprazole may be a promising drug in the treatment of children and adolescents with tic disorders. Further controlled studies are needed to determine the efficacy and tolerability of aripiprazole in these patients

In Silico Identification of Specialized Secretory-Organelle Proteins in Apicomplexan Parasites and In Vivo Validation in Toxoplasma gondii

Apicomplexan parasites, including the human pathogens Toxoplasma gondii and Plasmodium falciparum, employ specialized secretory organelles (micronemes, rhoptries, dense granules) to invade and survive within host cells. Because molecules secreted from these organelles function at the host/parasite interface, their identification is important for understanding invasion mechanisms, and central to the development of therapeutic strategies. Using a computational approach based on predicted functional domains, we have identified more than 600 candidate secretory organelle proteins in twelve apicomplexan parasites. Expression in transgenic T. gondii of eight proteins identified in silico confirms that all enter into the secretory pathway, and seven target to apical organelles associated with invasion. An in silico approach intended to identify possible host interacting proteins yields a dataset enriched in secretory/transmembrane proteins, including most of the antigens known to be engaged by apicomplexan parasites during infection. These domain pattern and projected interactome approaches significantly expand the repertoire of proteins that may be involved in host parasite interactions