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ESN Publications Improving outcome after stroke: overcoming the translational roadblock. Endres M, Engelhardt B, Koistinaho J, Lindvall O, Meairs S, Mohr JP, Planas A, Rothwell N, Schwaninger M, Schwab ME, Vivien D, Wieloch T, Dirnagl U. Cerebrovasc Dis. 2008;25(3):268-78. 2008 Feb 22. Stroke poses a massive burden of disease, yet we have few effective therapies. The paucity of therapeutic options stands contrary to intensive research efforts. The failure of these past investments demands a thorough re-examination of the pathophysiology of ischaemic brain injury. Several critical areas hold the key to overcoming the translational roadblock: (1) vascular occlusion: current recanalization strategies have limited effectiveness and may have serious side effects; (2) complexity of stroke pathobiology: therapy must acknowledge the 'Janus-faced' nature of many stroke targets and must identify endogenous neuroprotective and repair mechanisms; (3) inflammation and brain-immune-system interaction: inflammation contributes to lesion expansion, but is also instrumental in lesion containment and repair; stroke outcome is modulated by the interaction of the injured brain with the immune system; (4) regeneration: the potential of the brain for reorganization, plasticity and repair after injury is much greater than previously thought; (5) confounding factors, long-term outcome and predictive modelling. These 5 areas are linked on all levels and therefore need to be tackled by an integrative approach and innovative therapeutic strategies. Rudini, N., Felici, A., Giampietro, C., Lampugnani, M.G., Corada, M., Swirsding, K., Garre’, M., Liebner, S., Letarte, M., ten Dijke, P. and Dejana, E. VE-cadherin is a critical endothelial regulator of TGF-beta signalling. EMBO J. 2008 Apr 9;27(7):993-1004.
Taddei, A., Giampietro, C., Conti, A., Orsenigo, F., Breviario, F., Pirazzoli, V., Potente, M., Daly, C., Dimmeler, S., Dejana, E. Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nat Cell Biol. 2008;10(8):923-34. Liebner S, Corada M, Bangsow T, Babbage J, Taddei A, Czupalla CJ, Reis M, Felici A, Wolburg H, Fruttiger M, Taketo MM, von Melchner H, Plate KH, Gerhardt H, Dejana E. Wnt/beta-catenin signaling controls development of the blood-brain barrier. J Cell Biol. 2008 Nov 3;183(3):409-17. François M, Caprini A, Hosking B, Orsenigo F, Wilhelm D, Browne C, Paavonen K, Karnezis T, Shayan R, Downes M, Davidson T, Tutt D, Cheah KS, Stacker SA, Muscat GE, Achen MG, Dejana E, Koopman P. Sox18 induces development of the lymphatic vasculature in mice. Nature. 2008 456(7222):643-7. Nyqvist D, Giampietro C, Dejana E. Deciphering the functional role of endothelial junctions by using in vivo models. EMBO Rep. 2008 Aug;9(8):742-745. Dejana E , Orsenigo F, Lampugnani MG. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci. 2008 Jul 1;121(Pt 13):2115-22. Dejana E, Tournier-Lasserve E, Weinstein BM. The Control of Vascular Integrity by Endothelial Cell Junctions: Molecular Basis and Pathological Implications. Dev Cell. 2009;16(2):209-221. Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, Ruiz de Almodovar C, De Smet F, Vinckier S, Aragonés J, Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG, Dejana E, Simons M, Ratcliffe P, Maxwell P, Carmeliet P. Heterozygous Deficiency of PHD2 Restores Tumor Oxygenation and Inhibits Metastasis via Endothelial Normalization. Cell 2009 Feb 11. Woodfin A, Voisin MB, Imhof BA, Dejana E, Engelhardt B, Nourshargh S. Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A and PECAM-1. Blood 2009 Feb 10. Cera MR, Fabbri M, Molendini C, Corada M, Orsenigo F, Rehberg M, Reichel CA, Krombach F, Pardi R, Dejana E. JAM-A promotes neutrophil chemotaxis by controlling integrin internalization and recycling. J Cell Sci. 2009 Jan 15;122(Pt 2):268-77 |