Experimental observation of the amplitude death effect in two coupled nonlinear oscillators

The amplitude death phenomenon has been experimentally observed with a pair of thermo-optical oscillators linearly coupled by heat transfer. A parametric analysis has been done and compared with numerical simulations of a time delayed model. The role of the coupling strength is also discussed from experimental and numerical results

CREB Inhibits AP-2α Expression to Regulate the Malignant Phenotype of Melanoma

The loss of AP-2alpha and increased activity of cAMP-responsive element binding (CREB) protein are two hallmarks of malignant progression of cutaneous melanoma. However, the molecular mechanism responsible for the loss of AP-2alpha during melanoma progression remains unknown.Herein, we demonstrate that both inhibition of PKA-dependent CREB phosphorylation, as well as silencing of CREB expression by shRNA, restored AP-2alpha protein expression in two metastatic melanoma cell lines. Moreover, rescue of CREB expression in CREB-silenced cell lines downregulates expression of AP-2alpha. Loss of AP-2alpha expression in metastatic melanoma occurs via a dual mechanism involving binding of CREB to the AP-2alpha promoter and CREB-induced overexpression of another oncogenic transcription factor, E2F-1. Upregulation of AP-2alpha expression following CREB silencing increases endogenous p21(Waf1) and decreases MCAM/MUC18, both known to be downstream target genes of AP-2alpha involved in melanoma progression.Since AP-2alpha regulates several genes associated with the metastatic potential of melanoma including c-KIT, VEGF, PAR-1, MCAM/MUC18, and p21(Waf1), our data identified CREB as a major regulator of the malignant melanoma phenotype

How Coupling Determines the Entrainment of Circadian Clocks

Autonomous circadian clocks drive daily rhythms in physiology and behaviour. A network of coupled neurons, the suprachiasmatic nucleus (SCN), serves as a robust self-sustained circadian pacemaker. Synchronization of this timer to the environmental light-dark cycle is crucial for an organism's fitness. In a recent theoretical and experimental study it was shown that coupling governs the entrainment range of circadian clocks. We apply the theory of coupled oscillators to analyse how diffusive and mean-field coupling affects the entrainment range of interacting cells. Mean-field coupling leads to amplitude expansion of weak oscillators and, as a result, reduces the entrainment range. We also show that coupling determines the rigidity of the synchronized SCN network, i.e. the relaxation rates upon perturbation. %(Floquet exponents). Our simulations and analytical calculations using generic oscillator models help to elucidate how coupling determines the entrainment of the SCN. Our theoretical framework helps to interpret experimental data

GAS41 interacts with transcription factor AP-2β and stimulates AP-2β-mediated transactivation

Transcription factor AP-2 regulates transcription of a number of genes involving mammalian development, differentiation and carcinogenesis. Recent studies have shown that interaction partners can modulate the transcriptional activity of AP-2 over the downstream targets. In this study, we reported the identification of GAS41 as an interaction partner of AP-2β. We documented the interaction both in vivo by co-immunoprecipitation as well as in vitro through glutathione S-transferase (GST) pull-down assays. We also showed that the two proteins are co-localized in the nuclei of mammalian cells. We further mapped the interaction domains between the two proteins to the C-termini of both AP-2β and GAS41, respectively. Furthermore, we have identified three critical residues of GAS41 that are important for the interaction between the two proteins. In addition, by transient co-expression experiments using reporter containing three AP-2 consensus binding sites in the promoter region, we found that GAS41 stimulates the transcriptional activity of AP-2β over the reporter. Finally, electrophoretic mobility shift assay (EMSA) suggested that GAS41 enhances the DNA-binding activity of AP-2β. Our data provide evidence for a novel cellular function of GAS41 as a transcriptional co-activator for AP-2β

Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression

Abstract Purpose: VEGF-targeted therapies have modest efficacy in cancerpatients, butacquiredresistance iscommon. Themechanisms underlying such resistance are poorly understood. Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance. Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized roleofmacrophagesinsuchresistance.Macrophageswereactively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophagedeficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy. Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current antiangiogenesis therapies and identify new opportunities for combinationapproachesforovarianandothercancers. ClinCancerRes; 23(22); 7034–46. �2017 AACR

Phase II trial of imatinib mesylate in patients with metastatic melanoma

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined

Increased expression of transcription factor TFAP2α correlates with chemosensitivity in advanced bladder cancer

<p>Abstract</p> <p>Background</p> <p>The standard treatment for patients with advanced transitional cell carcinoma of the bladder is platin based chemotherapy. Only approximately 50% of the patients respond to chemotherapy. Therefore, molecular predictive markers for identification of chemotherapy sensitive subgroups of patients are highly needed. We selected the transcription factor <it>TFAP2α </it>from a previously identified gene expression signature for chemotherapy response.</p> <p>Methods</p> <p><it>TFAP2α </it>expression and localization was assessed by immunohistochemistry using a tissue microarray (TMA) containing 282 bladder cancer tumors from patients with locally advanced (pT2-T4_band N_1-3) or metastatic (M₁) disease. All patients had received cisplatin containing chemotherapy. Furthermore, QPCR analysis of three <it>TFAP2α </it>isoforms was performed on tumor specimens of advanced muscle invasive bladder cancers (T2-4). Using the bladder cell lines T24 and SW780 the relation of <it>TFAP2α </it>and cisplatin and gemcitabine sensitivity as well as cell proliferation was examined using siRNA directed <it>TFAP2α </it>knockdown.</p> <p>Results</p> <p>TFAP2α protein expression was analyzed on a TMA with cores from 282 advanced bladder cancer tumors from patients treated with cisplatin based combinational chemotherapy. <it>TFAP2α </it>was identified as a strong independent predictive marker for a good response and survival after cisplatin-containing chemotherapy in patients with advanced bladder cancer. Strong TFAP2α nuclear and cytoplasmic staining predicted good response to chemotherapy in patients with lymph node metastasis, whereas weak TFAP2α nuclear staining predicted good response in patients without lymph node metastasis. In vitro studies showed that siRNA mediated knockdown of TFAP2α increased the proliferation of SW780 cells and rendered the cells less sensitive to cisplatin and gemcitabine. In contrast to that T24 bladder cells with mutated p53 showed to be more drug sensitive upon TFAP2α depletion.</p> <p>Conclusions</p> <p>High levels of nuclear and cytoplasmic TFAP2α protein were a predictor of increased overall survival and progression free survival in patients with advanced bladder cancer treated with cisplatin based chemotherapy. TFAP2α knockdown increased the proliferation of the SW780 bladder cells and reduced cisplatin and gemcitabine induced cell death. The inverse effect was observed in the <it>TP53 </it>mutated T24 cell line where TFAP2α silencing augmented cisplatin and gemcitabine sensitivity and did not stimulate proliferation.</p

On winning the “lottery”: psychological preparation for football penalty shoot-outs

© 2015 Taylor & Francis. Abstract: The outcome of penalty shoot-outs is often referred to as a “lottery”, suggesting that luck, rather than the skill level of the player, predetermines outcome success. Throughout this article, we hope to show why such attitudes towards physical and psychological preparation can increase anxiety, diminish perceptions of control and negatively affect the behaviour and subsequent performance of penalty takers. From the synthesis of this evidence, we provide task-specific recommendations that are structured around the dynamic nature of emotions that players are likely to experience during each phase of the shoot-out and which can be implemented or adapted to suit the individual needs of the player. These recommendations are designed to provide a framework to help applied professionals to optimise the psychological preparation for this scenario with the overall aim of helping players to (re)gain control of this situation

AP2α controls the dynamic balance between miR-126&126∗ and miR-221&222 during melanoma progression

Accumulating evidences have shown the association between aberrantly expressed microRNAs (miRs) and cancer, where these small regulatory RNAs appear to dictate the cell fate by regulating all the main biological processes. We demonstrated the responsibility of the circuitry connecting the oncomiR-221&222 with the tumor suppressors miR-126&126∗ in melanoma development and progression. According to the inverse correlation between endogenous miR-221&222 and miR-126&126∗, respectively increasing or decreasing with malignancy, their enforced expression or silencing was sufficient for a reciprocal regulation. In line with the opposite roles of these miRs, protein analyses confirmed the reverse expression pattern of miR-126&126∗-targeted genes that were induced by miR-221&222. Looking for a central player in this complex network, we revealed the dual regulation of AP2α, on one side directly targeted by miR-221&222 and on the other a transcriptional activator of miR-126&126∗. We showed the chance of restoring miR-126&126∗ expression in metastatic melanoma to reduce the amount of mature intracellular heparin-binding EGF like growth factor, thus preventing promyelocytic leukemia zinc finger delocalization and maintaining its repression on miR-221&222 promoter. Thus, the low-residual quantity of these two miRs assures the release of AP2α expression, which in turn binds to and induces miR-126&126∗ transcription. All together these results point to an unbalanced ratio functional to melanoma malignancy between these two couples of miRs. During progression this balance gradually moves from miR-126&126∗ toward miR-221&222. This circuitry, besides confirming the central role of AP2α in orchestrating melanoma development and/or progression, further displays the significance of these miRs in cancer and the option of utilizing them for novel therapeutics

Refining and regaining skills in fixation/diversification stage performers: The Five-A Model

Technical change is one of many factors underpinning success in elite, fixation/diversification stage performers. Surprisingly, however, there is a dearth of research pertaining to this process or the most efficacious methods used to bring about such a change. In this paper we highlight the emergent processes, yet also the lack in mechanistic comprehension surrounding technical change, addressing issues within the motor control, sport psychology, coaching and choking literature. More importantly, we seek an understanding of how these changes can be made more secure to competitive pressure, and how this can be embedded within the process of technical change. Following this review, we propose The Five-A Model based on successful coaching techniques, psychosocial concomitants, the avoidance of choking and principles of effective behaviour change. Specific mechanisms for each stage are discussed, with a focus on the use of holistic rhythm-based cues as a possible way of internalising changes. Finally, we suggest the need for further research to examine these five stages, to aid a more comprehensive construction of the content and delivery of such a programme within the applied setting