FAK Is a Critical Regulator of Neuroblastoma Liver Metastasis

Neuroblastomas express increased levels of gastrin-releasing peptide receptor (GRP-R). However, the exact molecular mechanisms involved in GRP-R-mediated cell signaling in neuroblastoma growth and metastasis are unknown. Here, we report that focal adhesion kinase (FAK), as a critical downstream target of GRP-R, is an important regulator of neuroblastoma tumorigenicity. We found that FAK expression correlates with GRP-R expression in human neuroblastoma sections and cell lines. GRP-R overexpression in SK-N-SH cells increased FAK, integrin α3 and β1 expressions and cell migration. These cells demonstrated flatter cell morphology with broad lamellae, in which intense FAK expression was localized to the leading edges of lamellipodia. Interestingly, FAK activation was, in part, dependent on integrin α3 and β1 expression. Conversely, GRP-R silencing decreased FAK as well as Mycn levels in BE(2)-C cells, which displayed a denser cellular morphology. Importantly, rescue experiments in GRP-R silenced BE(2)-C cells showed FAK overexpression significantly enhanced cell viability and soft agar colony formation; similarly, FAK overexpression in SK-N-SH cells also resulted in increased cell growth. These effects were reversed in FAK silenced BE(2)-C cells in vitro as well as in vivo. Moreover, we evaluated the effect of FAK inhibition in vivo. FAK inhibitor (Y15) suppressed GRP-induced neuroblastoma growth and metastasis. Our results indicate that FAK is a critical downstream regulator of GRP-R, which mediates tumorigenesis and metastasis in neuroblastoma

Conditional müller cell ablation causes independent neuronal and vascular pathologies in a novel transgenic model

Müller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Müller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional Müller cell ablation and the consequences of primary Müller cell dysfunction have been studied in adult mice. We found that selective ablation of Müller cells led to photoreceptor apoptosis, vascular telangiectasis, blood-retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium-derived factor. Intravitreal injection of ciliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that Müller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuropro-tective and anti-angiogenic therapies may be required to treat Müller cell deficiency in retinal diseases and in other parts of the CNS associated with glial dysfunction

Vereckei criteria as a diagnostic tool amongst emergency medicine residents to distinguish between ventricular tachycardia and supra-ventricular tachycardia with aberrancy

SummaryBackgroundAccurate electrocardiographic (ECG) differentiation of ventricular tachycardia (VT) from supraventricular tachycardia with aberrancy (SVT-A) on ECG is key to therapeutic decision-making in the emergency department (ED) setting.ObjectiveThe goal of this study was to test the accuracy and agreement of emergency medicine residents to differentiate VT from SVT-A using the Vereckei criteria.MethodsSix emergency medicine residents volunteered to participate in the review of 114 ECGs from 86 patients with a diagnosis of either VT or SVT-A based on an electrophysiology study. The resident reviewers initially read 12-lead ECGs blinded to clinical information, and then one week later reviewed a subset of the same 12-lead ECGs unblinded to clinical information.ResultsOne reviewer was excluded for failing to follow study protocol and one reviewer was excluded for reviewing less than 50 blinded ECGs. The remaining four reviewers each read 114 common ECGs blinded to clinical data and their diagnostic accuracy for VT was 74% (sensitivity 70%, specificity 80%), 75% (sensitivity 76%, specificity 73%), 61% (sensitivity 81%, specificity 25%), and 68% (sensitivity 84%, specificity 40%). The intraclass correlation coefficient (ICC) was 0.31 (95% CI 0.22–0.42). Eliminating two of the four reviewers who left a disproportionately high number of ECGs unclassified resulted in an increase in overall mean diagnostic accuracy (70–74%) and agreement (0.31–0.50) in the two remaining reviewers. Three reviewers read 45 common ECGs unblinded to clinical information and had accuracies for VT 93%, 93% and 78%.ConclusionThe new single lead Vereckei criteria, when applied by emergency medicine residents achieved only fair-to-good individual accuracy and moderate agreement. The addition of clinical information resulted in substantial improvement in test characteristics. Further improvements (accuracy and simplification) of algorithms for differentiating VT from SVT-A would be helpful prior to clinical implementation

Differences in Trauma-Related Guilt in Females with History of Sexual Violence Based on Insomnia Severity

Background and Objective Females with history of sexual violence report a high percentage of insomnia. Guilt is a common symptom among this group. This study investigated differences in trauma-related guilt cognition between females of sexual violence with high or low symptoms of insomnia. Methods Participants were 43 females who reported having a history of sexual violence (mean age 26.56±7.81). All participants completed questionnaires about insomnia symptoms (Insomnia Severity Index, ISI), Posttraumatic stress disorder (PTSD) symptoms (PTSD Symptom Scale Self-Report), trauma-related guilt (Trauma-related Guilt Inventory, TRGI), depression (Beck Depression Inventory) and trauma-related information. The TRGI is consisted by global guilt, distress and guilt cognitions. Guilt cognitions can further be divided into Hindsight-Bias/Responsibility, Wrongdoing, and Lack of Justification subscales. Analyses were conducted using Pearson’s correlation coefficient and analysis of covariance. Results Results indicated ISI scores were significantly positively associated with PSS scores (r = 0.620, p < 0.01) and the distress subscale of the TGRI (r = 0.488, p < 0.01), and negatively associated with guilt cognitions (r = −0.423, p < 0.01). 53.5% (n = 23) of the sample met criteria for clinical insomnia using ISI cut-off scores of 15. Participants in the insomnia group scored significantly lower in overall guilt cognitions (p < 0.001) and significantly higher in distress (p = 0.001) than the non-insomnia group after controlling for depression. Among the subscales of guilt cognitions, hindsight-bias/responsibility was significantly lower in the insomnia group (p < 0.001). Conclusions Guilt can sometimes be adaptive in trauma patients as it may work as a catalyst in cognitively processing their trauma. Our results indicate that individuals with insomnia report lower guilt cognition. This may subsequently interfere with their ability to process the traumatic experience and effectively cope with their situation

Loss of Trop2 causes ErbB3 activation through a neuregulin-1-dependent mechanism in the mesenchymal subtype of HNSCC

In head and neck squamous cell cancer (HNSCC), four intrinsic subtypes (or groups) have been identified, and each one possesses a unique biology that will require specific treatment strategies. We previously reported that mesenchymal (group 2) tumors exhibit reduced levels of Trop2 expression. In this study, we investigated the functional role of Trop2 in HNSCC and find that loss results in autocrine activation of the EGFR family member ErbB3 via neuregulin-1. Trop2 localizes to both the cell surface and cytosol of HNSCC cells and forms a complex with neuregulin-1, which is predominantly cytosolic. Inactivation of Trop2 increases the concentration of neuregulin-1 at the cell surface where it is cleaved to activate ErbB3. In primary HNSCC, detection of ErbB3 activation was limited to Trop2 negative tumors. An analysis of the Cancer Genome Atlas (TCGA) HNSCC dataset confirms enrichment for ErbB3 activity in mesenchymal tumors. Notably, Trop2 loss triggers sensitivity to anti-ErbB3 antibodies, which results in reduced proliferation and tumorigenic growth of Trop2 negative HNSCC cancer cells. These results uncover a molecular mechanism by which tumor cells control the amount of cell-surface neuregulin-1 available for cleavage and ErbB3 activation. Moreover, we demonstrate that Trop2 is a potential surrogate biomarker to identify tumors with ErbB3 activation and may therefore respond to anti-ErbB3 therapeutics

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Building Japan-ROK relations through East Asian maritime security

For more about the East-West Center, see http://www.eastwestcenter.org/Amanda Conklin, Sora Chung, Grace Kim, and Nicole Goertzen-Tang, recent graduates from the Elliott School of International Affairs at George Washington University, explain that "Maritime hotspots in the South China Sea have created an opportunity for Japan and South Korea to work together with the U.S. to establish a more stable region." The authors would like to thank all the policymakers and academics whose interviews were indispensable to the development of these policy recommendations

Synthesis and physicochemical characterization of acyl myricetins as potential anti-neuroexocytotic agents

Abstract Acyl myricetins (monopropionyl-, dipropionyl-, and monooctanoyl-myricetin, termed as MP1, MP2, and MO1, respectively) were synthesized through enzymatic or non-enzymatic esterification reaction of myricetin aglycone. Structure study indicated the hydroxyl group at C4′ in B-ring was highly susceptible to acylation. Over its parental myricetin, acylated compounds showed enhanced lipophilicity (from 7.4- to 26.3-fold) and oxidative stability (from 1.9- to 3.1-fold) on the basis of logP and decay rate, respectively. MO1, presenting the physicochemical superiority compared to the others, provided lowest EC50 value of 2.51 μM on inhibition of neutrotransmitter release and CC50 value of 59.0 μM, leading to widest therapeutic window. All myricetin esters did not show any irritation toxicity when assessed with a chicken embryo assay. This study describes information on acylation of myricetin that has not yet been explored, and suggests that MO1 has membrane fusion-arresting and anti-neuroexocytotic potential for industrial application due to its enhanced biological properties