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    ABSTRACT: The prevalence of lower urinary tract storage disorders such as overactive bladder syndrome (OAB) and urinary incontinence (UI) significantly increase with age. Previous studies have shown alterations in detrusor function and urothelial transmitter release but there are few studies which have investigated how the urothelium and sensory pathways are affected. The aim of this study was to investigate the effect of ageing on urothelial-afferent signaling in the mouse bladder. To this aim, 3 month old control and 24 month old aged male mice were used in this study. In vivo natural voiding behaviour, sensory nerve activity, urothelial cell function, muscle contractility, transmitter release and gene protein expression were measured to identify how all three components of the bladder (neural, contractile and urothelial) were affected by ageing. In aged mice, increased voiding frequency and enhanced low threshold afferent nerve activity was observed suggesting that ageing induces overactivity and hypersensitivity of the bladder. These changes were concurrent with altered ATP and ACh bioavailability, measured as transmitter overflow into the lumen, increased purinergic receptor sensitivity and raised P2X3 receptor expression in the urothelium. Taken together these data suggest that ageing results in aberrant urothelial function, increased afferent mechanosensitivity, increased smooth muscle contractility and changes in gene and protein expression (including P2X3). These data are consistent with the hypothesis that ageing evokes changes in purinergic signalling from the bladder, however further studies are now required to fully validate this idea.
    The Journal of Physiology 12/2013;
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    ABSTRACT: Angiosarcomas are rare, aggressive vascular tumours known to express vascular endothelial growth factor (VEGF), a key pro-angiogenic growth factor. The aim of this study was to determine the potential effects of vascular-targeted agents for the treatment of angiosarcoma, using two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS), and human dermal microvascular endothelial cells (HuDMECs) for comparison. Protein arrays were used to assess the expression of angiogenesis-related proteins, and potential drug targets were assessed by ELISA and Western blotting. Response to vascular-targeted agents, including bevacizumab an anti-VEGF antibody, axitinib a VEGF-receptor tyrosine kinase inhibitor, everolimus an mTOR inhibitor, selumetinib a MEK inhibitor and vadimezan a vascular-disrupting agent were compared in functional in vitro cellular assays, including viability, differentiation and migration assays. ASM and ISO-HAS cells expressed a broad range of pro-angiogenic growth factors. ASM and ISO-HAS VEGF expression was significantly increased (p = 0.029) compared with HuDMECs. Striking responses were seen to vadimezan with an IC50 of 90 and 150 μg/ml for ASM and ISO-HAS cells, respectively. Selumetinib inhibited ASM with an IC50 of 1,750 ng/ml, but was not effective in ISO-HAS. Everolimus reduced both ASM and ISO-HAS viable cell counts by 20 % (p < 0.001). Minimal responses were observed to bevacizumab and axitinib in assays with ASM and ISO-HAS cells. Further studies are warranted to investigate mTOR inhibitors, MEK inhibitors and vascular-disrupting agents for the treatment of angiosarcoma.
    Cancer Chemotherapy and Pharmacology 11/2013;
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    ABSTRACT: Human pluripotent stem cells (PSCs), whether embryonic stem cells or induced PSCs, offer enormous opportunities for regenerative medicine and other biomedical applications once we have developed the ability to harness their capacity for extensive differentiation. Central to this is our ability to identify and characterize such PSC, but this is fraught with potential difficulties that arise from a tension between functional definitions of pluripotency and the more convenient use of 'markers', a problem exacerbated by ethical issues, our lack of knowledge of early human embryonic development, and differences from the mouse paradigm.
    Neuroreport 10/2013;
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    ABSTRACT: Conserved from humans to Drosophila, the JAK/STAT signaling cascade is essential for multiple developmental and homeostatic processes with regulatory molecules controlling pathway activity also highly conserved. Here we characterize the Drosophila JAK/STAT pathway regulator SOCS36E and show that it functions via two independent mechanisms. Firstly we show that Drosophila Elongin B/C and Cullin 5 act via the SOCS-box of SOCS36E, to reduce pathway activity specifically in response to ligand stimulation - a process that involves endocytic trafficking and lysosomal degradation of the Domeless receptor. In addition, SOCS36E also suppresses both stimulated and basal pathway activity via an Elongin/Cullin-independent mechanism which is mediated by the N-terminus of SOCS36E which is required for the physical interaction of SOCS36E with Domeless. Although some human SOCS proteins contain N-terminal kinase inhibitory domains, we do not identify such a region in SOCS36E and propose a model where the N-terminal of SOCS36E blocks access to tyrosine residues in Dome. Our biochemical analysis of a SOCS-family regulator from a lower organism highlights the fundamental conserved roles played by regulatory mechanisms in signal transduction.
    Molecular biology of the cell 07/2013;
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    ABSTRACT: The conservation of signaling cascades between humans and Drosophila, over more than 500 million years of evolutionary time, means that the genetic tractability of the fly can be used to its full advantage to understand the functional requirements for JAK-STAT pathway signaling across species. Here we review the background to how the pathway was first identified and the first characterization of JAK-STAT pathway phenotypes in the Drosophila system, highlighting the molecular, functional, and disease-related conservation of the pathway.
    JAK-STAT. 07/2013; 2(3):e25353.
  • Autonomic neuroscience: basic & clinical 06/2013;
  • European Urology 06/2013;
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    ABSTRACT: The development of neural circuits relies on spontaneous electrical activity that occurs during immature stages of development. In the developing mammalian auditory system, spontaneous calcium action potentials are generated by inner hair cells (IHCs), which form the primary sensory synapse. It remains unknown whether this electrical activity is required for the functional maturation of the auditory system. We found that sensory-independent electrical activity controls synaptic maturation in IHCs. We used a mouse model in which the potassium channel SK2 is normally overexpressed, but can be modulated in vivo using doxycycline. SK2 overexpression affected the frequency and duration of spontaneous action potentials, which prevented the development of the Ca(2+)-sensitivity of vesicle fusion at IHC ribbon synapses, without affecting their morphology or general cell development. By manipulating the in vivo expression of SK2 channels, we identified the "critical period" during which spiking activity influences IHC synaptic maturation. Here we provide direct evidence that IHC development depends upon a specific temporal pattern of calcium spikes before sound-driven neuronal activity.
    Proceedings of the National Academy of Sciences 05/2013;
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    BJU International 04/2013; 111(4):530-1.
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    ABSTRACT: Spontaneous electrical activity generated by developing sensory cells and neurons is crucial for the maturation of neural circuits. The full maturation of mammalian auditory inner hair cells (IHCs) depends on patterns of spontaneous action potentials during a 'critical period' of development. The intrinsic spiking activity of IHCs can be modulated by inhibitory input from cholinergic efferent fibres descending from the brainstem, which transiently innervate immature IHCs. However, it remains unknown whether this transient efferent input to developing IHCs is required for their functional maturation. We used a mouse model that lacks the α9-nicotinic acetylcholine receptor subunit (α9nAChR) in IHCs and another lacking synaptotagmin-2 in the efferent terminals to remove or reduce efferent input to IHCs, respectively. We found that the efferent system is required for the developmental linearization of the Ca(2+)-sensitivity of vesicle fusion at IHC ribbon synapses, without affecting their general cell development. This provides the first direct evidence that the efferent system, by modulating IHC electrical activity, is required for the maturation of the IHC synaptic machinery. The central control of sensory cell development is unique among sensory systems.
    Open Biology 01/2013; 3(11):130163.
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