Androgen Receptor Activation in Glioblastoma Can Be Achieved by Ligand-Independent Signaling through EGFR-A Potential Therapeutic Target

Androgen receptor (AR) is a ligand-mediated transcription factor that belongs to the superfamily of steroid receptors. AR is overexpressed in most glioblastomas and is a potential therapeutic target. In prostate and breast cancers, AR activation can be achieved also by a ligand-independent signaling through receptor tyrosine kinases such as epidermal growth factor receptor (EGFR). Considering its major role in glioblastoma, we explored whether EGFR is involved in AR signaling in this tumor. Analysis of mRNA expression in 28 glioblastoma samples with quantitative real-time reverse-transcription polymerase chain reaction revealed a positive and significant correlation between AR and EGFR mRNA expression levels (R = 0.47, p = 0.0092), which was validated by The Cancer Genome Atlas dataset (n = 671) analysis (R = 0.3, p = 0.00006). Using Western blotting and immunofluorescence staining, we showed that the transduced overexpression of EGFR or its variant EGFRvIII in the U87MG cells induced AR protein overexpression and nuclear translocation and Protein kinase B (AKT) S473 and AR S210/213 phosphorylation. The EGFR kinase inhibitor afatinib and the AKT inhibitor MK2206 reduced AR nuclear translocation. Afatinib diminished AKT phosphorylation at 30 min and 6 h in the EGFR- and EGFRvIII-overexpressing cells, respectively, and decreased AR phosphorylation in EGFR-overexpressing cells at 4 h. Afatinib or MK2206 combination therapy with the AR antagonist enzalutamide in the EGFR and EGFRvIII-overexpressing cells had synergistic efficacy. Our findings suggest that EGFR signaling is involved in AR activation in glioblastoma and buttresses the concept of combining an EGFR signaling inhibitor with AR antagonists as a potential glioblastoma treatment

EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand

Background: The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment.Methods: Targeted DNA-sequencing and whole transcriptome analysis was performed on clinical trial samples. High-throughput, high-content imaging analysis was done to understand the molecular mechanism underlying the survival benefit.Results: We first define the tumor genomic landscape in this well-annotated patient population. We find that tumors harboring EGFR single-nucleotide variations (SNVs) have improved outcome in the depatux-m + TMZ combination arm. Such SNVs are common to the extracellular domain of the receptor and functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands. These hypersensitizing SNVs and the ligand-independent EGFRvIII variant are inversely correlated, indicating two distinct modes of evolution to increase EGFR signaling in glioblastomas. Ligand hypersensitivity can explain the therapeutic efficacy of depatux-m as increased ligand-induced activation will result in increased exposure of the epitope to the antibody-drug conjugate. We also identified tumors harboring mutations sensitive to "classical" EGFR tyrosine-kinase inhibitors, providing a potential alternative treatment strategy.Conclusions: These data can help guide treatment for recurrent glioblastoma patients and increase our understanding into the molecular mechanisms underlying EGFR signaling in these tumors.</p

Getting aligned on representational alignment

Biological and artificial information processing systems form representations that they can use to categorize, reason, plan, navigate, and make decisions. How can we measure the extent to which the representations formed by these diverse systems agree? Do similarities in representations then translate into similar behavior? How can a system's representations be modified to better match those of another system? These questions pertaining to the study of representational alignment are at the heart of some of the most active research areas in cognitive science, neuroscience, and machine learning. For example, cognitive scientists measure the representational alignment of multiple individuals to identify shared cognitive priors, neuroscientists align fMRI responses from multiple individuals into a shared representational space for group-level analyses, and ML researchers distill knowledge from teacher models into student models by increasing their alignment. Unfortunately, there is limited knowledge transfer between research communities interested in representational alignment, so progress in one field often ends up being rediscovered independently in another. Thus, greater cross-field communication would be advantageous. To improve communication between these fields, we propose a unifying framework that can serve as a common language between researchers studying representational alignment. We survey the literature from all three fields and demonstrate how prior work fits into this framework. Finally, we lay out open problems in representational alignment where progress can benefit all three of these fields. We hope that our work can catalyze cross-disciplinary collaboration and accelerate progress for all communities studying and developing information processing systems. We note that this is a working paper and encourage readers to reach out with their suggestions for future revisions.Comment: Working paper, changes to be made in upcoming revision

Management of congestive heart failure: a gender gap may still exist. Observations from a contemporary cohort

BACKGROUND: Unlike other cardiovascular diseases the incidence and prevalence of congestive heart failure (CHF) continues to increase. While gender differences in coronary artery disease have been well described, to date, there has been a relative paucity of similar data in patients with CHF. We conducted a pilot study to evaluate the profile and management of patients with CHF at a tertiary care centre to determine if a gender difference exists. METHODS: A chart review was performed at a tertiary care centre on consecutive patients admitted with a primary diagnosis of CHF between June 1997 and 1998. Co-morbidity, diagnostic investigations, and management of CHF were recorded. Comparisons between male and female patients were conducted. RESULTS: One hundred and forty five patients were reviewed. There were 80 male (M) and 65 female (F) patients of similar age [71.6 vs. 71.3 (M vs. F), p = NS]. Male patients were more likely to have had a previous myocardial infarction (66% vs. 35%, p < 0.01) and revascularization (41% vs. 20%, p < 0.05), and had worse left ventricular ejection fraction (LVEF) than women, [median LVEF 3 vs. 2 (M vs. F), p < 0.01]. Male patients were more likely to have a non-invasive assessment of left ventricular (LV) function [85% vs. 69%, (M vs. F), p < 0.05]. A logistic regression analysis suggests that amongst those without coronary disease, males were more likely to receive non-invasive testing. There were no differences in the use of prescribed medications, in this cohort. CONCLUSIONS: This pilot study demonstrated that there seem to be important gender differences in the profile and management of patients with CHF. Importantly women were less likely to have an evaluation of LV function. As assessment of LV function has significant implications on patient management, this data justifies the need for larger studies to assess gender differences in CHF profile and treatment

Re-visiting Meltsner: Policy Advice Systems and the Multi-Dimensional Nature of Professional Policy Analysis

10.2139/ssrn.15462511-2

The EGFRvIII transcriptome in glioblastoma, a meta-omics analysis.

BACKGROUND: EGFR is among the genes most frequently altered in glioblastoma, with exons 2-7 deletions (EGFRvIII) being amongst its most common genomic mutations. There are conflicting reports about its prognostic role and it remains unclear whether and how it differs in signalling compared with wildtype EGFR. METHODS: To better understand the oncogenic role of EGFRvIII, we leveraged four large datasets into one large glioblastoma transcriptome dataset (n=741) alongside 81 whole-genome samples from two datasets. RESULTS: The EGFRvIII/EGFR expression ratios differ strongly between tumours and ranges from 1% to 95%. Interestingly, the slope of relative EGFRvIII expression is near-linear, which argues against a more positive selection pressure than EGFR wildtype. An absence of selection pressure is also suggested by the similar survival between EGFRvIII positive and negative glioblastoma patients. EGFRvIII levels are inversely correlated with pan-EGFR (all wildtype and mutant variants) expression, which indicates that EGFRvIII has a higher potency in downstream pathway activation. EGFRvIII-positive glioblastomas have a lower CDK4 or MDM2 amplification incidence than EGFRvIII-negative (p=0.007), which may point towards crosstalk between these pathways. EGFRvIII-expressing tumours have an upregulation of 'classical' subtype genes compared to those with EGFR-amplification only (p=3.873e-6). Genomic breakpoints of the EGFRvIII deletions have a preference towards the 3' end of the large intron-1. These preferred breakpoints preserve a cryptic exon resulting in a novel EGFRvIII variant and preserve an intronic enhancer. CONCLUSIONS: These data provide deeper insights into the complex EGFRvIII biology and provide new insights for targeting EGFRvIII mutated tumours

The effects of measurement error on the relation between physical activity and cardiovascular disease mortality in the Canada Fitness Survey cohort

grantor: University of TorontoThe purposes of the present study were to examine the relation between physical activity and mortality in women and men in the Canada Fitness Survey cohort, to assess the reliability of the physical activity components of the Canada Fitness Survey questionnaire (CFSQ) and to adjust estimates of the hypothetical true associations between physical activity and mortality, using estimates of reliability for the CFSQ. Results indicate a significant inverse association between physical activity and mortality in women due mainly to the contribution of non-leisure (household chores) energy expenditure. The association between energy expenditure and mortality in men was not as strong as in women. The CFSQ is moderately reliable for most measures of physical activity. Estimates of reliability vary considerably among the various activities and components of these activities and between males and females. The adjustment procedure resulted in estimates which showed a stronger association with mortality than did the crude estimates. The change in the adjusted estimates and the width of their confidence intervals (CI) were related to the size of the measurement error. Results of simulation studies showed that when the error is too great, the adjustment procedure resulted in unpredictable estimators. Nevertheless, in the presence of moderate measurement error and large enough sample sizes, results from the current study indicate that, adjustment for measurement error is a feasible and desirable procedure.Ph.D

Sticky Glass - Structural bonded joints with acrylates

p. 2982-2989UV and light curing acrylates present a whole host of possibilities for designing glass construction with adhesively bonded joints. Their clear and colourless appearance produces a transparent and lightweight construction. Short curing times consisting of no more than mere minutes allow for quick production with minimal downtime within the overall process. Processing can resume immediately once bonding has occurred. The advantages of acrylates can be silhouetted against the characteristics and properties of adhesive silicone which has been widely approved by German building authorities for specific façade applications. These adhesives are analysed both generally as bulk material and in applications as a joint between glass and metal. The use of dog bone shaped specimens is recommended to analyze the material behaviour under a variety of influential factors such as temperature and testing speed. The bonded joints of test specimens provide an opportunity to examine the interaction between the adhesive and the materials to which they are adhered. Constructions having punctually bonded joints are tested to demonstrate the potential use of acrylic joints in glass treatments. Some components are exposed to natural weathering in order to examine the affects of ageing on the adhesive. Finally in short form commendations can be given to plan and design glass constructions with adhesively bonded joints of UV and light curing acrylates.Weller, B.; Vogt, I. (2009). Sticky Glass - Structural bonded joints with acrylates. Editorial Universitat Politècnica de València. http://hdl.handle.net/10251/670

The role of work stress as a moderating variable in the chronic pain and depression association

Objective This article aims to examine the role of work stress as a moderating variable in the chronic pain–depression association, as well as sex differences in this link. Methods The analyses were carried out using the Canadian Community Health Survey Cycle 1.1. Key variables were chronic pain conditions (fibromyalgia, arthritis/rheumatism, back problems, and migraine headaches), work stress, and depression. The total sample comprises 78,593 working individuals. Results In this working sample, 7.6% met criteria for major depression, but the prevalence increased to 12% in those also reporting chronic pain. Both depression and comorbid chronic pain and depression were twice as prevalent in women as in men. Having a chronic pain condition and overall work stress emerged as the strongest predictors of depression. Unexpectedly, however, none of the work stress domains moderated the chronic pain and depression association. Conclusion The impact of work stress should be considered in the etiology and management of major depression