The Receptor AXL Diversifies EGFR Signaling and Limits the Response to EGFR-Targeted Inhibitors in Triple-Negative Breast Cancer Cells

The relationship between drug resistance, changes in signaling, and emergence of an invasive phenotype is well appreciated, but the underlying mechanisms are not well understood. Using machine learning analysis applied to the Cancer Cell Line Encyclopedia database, we identified expression of AXL, the gene that encodes the epithelial-to-mesenchymal transition (EMT)–associated receptor tyrosine kinase (RTK) AXL, as exceptionally predictive of lack of response to ErbB family receptor–targeted inhibitors. Activation of EGFR (epidermal growth factor receptor) transactivated AXL, and this ligand-independent AXL activity diversified EGFR-induced signaling into additional downstream pathways beyond those triggered by EGFR alone. AXL-mediated signaling diversification was required for EGF (epidermal growth factor)–elicited motility responses in AXL-positive TNBC (triple-negative breast cancer) cells. Using cross-linking coimmunoprecipitation assays, we determined that AXL associated with EGFR, other ErbB receptor family members, MET (hepatocyte growth factor receptor), and PDGFR (platelet-derived growth factor receptor) but not IGF1R (insulin-like growth factor 1 receptor) or INSR (insulin receptor). From these AXL interaction data, we predicted AXL-mediated signaling synergy for additional RTKs and validated these predictions in cells. This alternative mechanism of receptor activation limits the use of ligand-blocking therapies and indicates against therapy withdrawal after acquired resistance. Further, subadditive interaction between EGFR- and AXL-targeted inhibitors across all AXL-positive TNBC cell lines may indicate that increased abundance of EGFR is principally a means to transactivation-mediated signaling.United States. Dept. of Defense (Congressionally Directed Medical Research Programs, Breast Cancer Research Program (W81XWH-11-1-0088))National Science Foundation (U.S.) (Graduate Research Fellowship)Repligen Corporation (Fellowship in Cancer Research)National Cancer Institute (U.S.). Integrative Cancer Biology Program (1-U54-CA112967)David H. Koch Institute for Integrative Cancer Research at MIT (Frontier Research Program Initiator Award)National Institutes of Health (U.S.) (NIH R01-CA96504

Single cell imaging of Bruton's Tyrosine Kinase using an irreversible inhibitor

A number of Bruton's tyrosine kinase (BTK) inhibitors are currently in development, yet it has been difficult to visualize BTK expression and pharmacological inhibition in vivo in real time. We synthesized a fluorescent, irreversible BTK binder based on the drug Ibrutinib and characterized its behavior in cells and in vivo. We show a 200 nM affinity of the imaging agent, high selectivity, and irreversible binding to its target following initial washout, resulting in surprisingly high target-to-background ratios. In vivo, the imaging agent rapidly distributed to BTK expressing tumor cells, but also to BTK-positive tumor-associated host cells

Effects of Art Intervention on Pediatric Anxiety and Pain in the Medical Setting

Introduction: Hospitalization and illness can be a painful and stressful time for a child. There may be anxiety over procedures and inpatient stays disrupt normal routines. Previous research found that for pre-school aged children, having parents around, having the help of the hospital staff, and playing an active role in alleviating their fears were the most helpful in reducing anxiety. Another study found that visual creative expressions can be meaningful experiences for young adult cancer survivors. Additionally, there is abundant literature on formal art therapy and its favorable effects on children in the hospital, however, there are fewer studies investigating less standardized “art intervention” in the same population. The purpose of our project was to assess whether art intervention reduces anxiety and pain in inpatient and outpatient pediatric patients.https://scholarworks.uvm.edu/comphp_gallery/1224/thumbnail.jp

Order Effects of Ballot Position without Information-Induced Confirmatory Bias

Candidate list positions have been shown to influence decision making when voters have limited candidate information (e.g. Miller and Krosnick, 1998; Brockington, 2003). Here, a primacy advantage is observed due to a greater number of positive arguments generated for early list candidates (Krosnick, 1991). The present study examined list position effects when an absence of information precludes such a confirmatory bias heuristic. We report the first large scale low-information experimental election where candidate position is fully counterbalanced. Seven hundred and twenty participants voted in a mock election where the position of 6 fictitious and meaningless parties was counterbalanced across the electorate. Analysis by position revealed that significantly fewer votes were allocated to the terminal parties (Experiment 1). In addition, Experiment 1 reported preliminary evidence of an alphabetical bias (consistent with Bagley, 1966). However, this positional bias was not present in a methodological replication using six genuine UK political parties (Experiment 2). This suggests that in situations of pure guessing, the heuristic shifts from the primacy benefiting confirmatory bias to an alternative heuristic that prejudices the first and last parties. These findings suggest that whilst the UK general electoral process may be largely immune to positional prejudice, English local elections (in which there can be multiple candidates from the same party) and multiple preference ranking systems (Scottish Local Government and London Mayoral Elections) could be susceptible to both positional and alphabetical biases

Modular Design of Artificial Tissue Homeostasis: Robust Control through Synthetic Cellular Heterogeneity

Synthetic biology efforts have largely focused on small engineered gene networks, yet understanding how to integrate multiple synthetic modules and interface them with endogenous pathways remains a challenge. Here we present the design, system integration, and analysis of several large scale synthetic gene circuits for artificial tissue homeostasis. Diabetes therapy represents a possible application for engineered homeostasis, where genetically programmed stem cells maintain a steady population of β-cells despite continuous turnover. We develop a new iterative process that incorporates modular design principles with hierarchical performance optimization targeted for environments with uncertainty and incomplete information. We employ theoretical analysis and computational simulations of multicellular reaction/diffusion models to design and understand system behavior, and find that certain features often associated with robustness (e.g., multicellular synchronization and noise attenuation) are actually detrimental for tissue homeostasis. We overcome these problems by engineering a new class of genetic modules for ‘synthetic cellular heterogeneity’ that function to generate beneficial population diversity. We design two such modules (an asynchronous genetic oscillator and a signaling throttle mechanism), demonstrate their capacity for enhancing robust control, and provide guidance for experimental implementation with various computational techniques. We found that designing modules for synthetic heterogeneity can be complex, and in general requires a framework for non-linear and multifactorial analysis. Consequently, we adapt a ‘phenotypic sensitivity analysis’ method to determine how functional module behaviors combine to achieve optimal system performance. We ultimately combine this analysis with Bayesian network inference to extract critical, causal relationships between a module's biochemical rate-constants, its high level functional behavior in isolation, and its impact on overall system performance once integrated.National Institutes of Health (U.S.) (NIH NIGMS grant R01GM086881)National Science Foundation (U.S.) (NSF Award #1001092)National Science Foundation (U.S.) (NSF Graduate Research Fellowship Program)Swiss National Science Foundation (SystemsX.ch grant

MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer

Taxane therapy remains the standard of care for triple-negative breast cancer. However, high frequencies of recurrence and progression in treated patients indicate that metastatic breast cancer cells can acquire resistance to this drug. The actin regulatory protein MENA and particularly its invasive isoform, MENAINV , are established drivers of metastasis. MENAINV expression is significantly correlated with metastasis and poor outcome in human patients with breast cancer. We investigated whether MENA isoforms might play a role in driving resistance to chemotherapeutics. We find that both MENA and MENAINV confer resistance to the taxane paclitaxel, but not to the widely used DNA-damaging agents doxorubicin or cisplatin. Furthermore, paclitaxel treatment does not attenuate growth of MENAINV -driven metastatic lesions. Mechanistically, MENA isoform expression alters the ratio of dynamic and stable microtubule populations in paclitaxel-treated cells. MENA expression also increases MAPK signaling in response to paclitaxel treatment. Decreasing ERK phosphorylation by cotreatment with MEK inhibitor restored paclitaxel sensitivity by driving microtubule stabilization in MENA isoform-expressing cells. Our results reveal a novel mechanism of taxane resistance in highly metastatic breast cancer cells and identify a combination therapy to overcome such resistance

A Golf Programme for People with Severe and Enduring Mental Health Problems

This article reports a pioneering golf programme for people with severe and enduring mental health problems. Following a discussion of the problems and possibilities of golf as a form of physical activity for this group, we outline the structure, organisation, and ethos of the golf programme. Through an analysis of qualitative case study data collected during the programme, we discuss the response to the programme from service users and mental health professionals. We conclude by highlighting aspects of the programme which were critical to its success and offering suggestions for further initiatives in this area

The mass assembly of galaxy groups and the evolution of the magnitude gap

We investigate the assembly of groups and clusters of galaxies using the Millennium dark matter simulation and the associated gas simulations and semi-analytic catalogues of galaxies. In particular, in order to find an observable quantity that could be used to identify early-formed groups, we study the development of the difference in magnitude between their brightest galaxies to assess the use of magnitude gaps as possible indicators. We select galaxy groups and clusters at redshift z=1 with dark matter halo mass M(R200) > 1E13/h Msun, and trace their properties until the present time (z=0). We consider only the systems with X-ray luminosity L_X> 0.25E42/h^2 erg/s at z=0. While it is true that a large magnitude gap between the two brightest galaxies of a particular group often indicates that a large fraction of its mass was assembled at an early epoch, it is not a necessary condition. More than 90% of fossil groups defined on the basis of their magnitude gaps (at any epoch between 0<z<1) cease to be fossils within 4 Gyr, mostly because other massive galaxies are assembled within their cores, even though most of the mass in their haloes might have been assembled at early times. We show that, compared to the conventional definition of fossil galaxy groups based on the magnitude gap Delta m(12)> 2 (in the R-band, within 0.5R200 of the centre of the group), an alternative criterion Delta m(14)>2.5 (within the same radius) finds 50% more early-formed systems, and those that on average retain their fossil phase longer. However, the conventional criterion performs marginally better at finding early-formed groups at the high-mass end of groups. Nevertheless, both criteria fail to identify a majority of the early-formed systems.Comment: 16 pages, 11 figures, 2 tables. Accepted for publication in MNRA