1,326 publications from this institution
<p>Effects of VEGFR-1 signaling ablation on E0771 tumor growth, vascular and immune environment in lean and obese mice.</p>
<p>Oligonucleotides used for site-directed mutagenesis of PTPA, and for genomic characterization of Ppp2r4 gene-trapped ES-cells and mice.</p>
The concept of inhibiting tumor neovessels has taken the hurdle from the bench to the bedside and now represents an extra pillar of anticancer treatment. So far, anti-angiogenic therapy prolongs survival in the order of months in some settings while failing to induce a survival benefit in others, in part because of intrinsic refractoriness or evasive escape. This review provides an update on recent mechanisms via which tumor and stromal cells induce resistance and discusses recent evolutions in the (pre)clinical development of novel third-generation anti-angiogenic agents to overcome this problem.
Abstract Impaired fibrinolysis, resulting from increased plasminogen activator inhibitor-1 (PAI-1) or reduced tissue-type plasminogen activator (t-PA) plasma levels, may predispose the individual to subacute thrombosis in sepsis and inflammation. The objective of these studies was to show that adenovirus-mediated gene transfer could increase systemic plasma t-PA levels and thrombolytic capacity in animal model systems. Recombinant adenovirus vectors were constructed that express either human wild type or PAI-1–resistant t-PA from the cytomegalovirus (CMV) promoter. Both t-PA-deficient (t-PA−/−) and PAI-1–overexpressing transgenic mice were infected by intravenous injection of these viruses. Intravenous injection of recombinant adenovirus resulted in liver gene transfer, t-PA synthesis, and secretion into the plasma. Virus dose, human t-PA antigen, and activity concentrations in plasma and extent of lysis of a 125I-fibrin–labeled pulmonary embolism were all closely correlated. Plasma t-PA antigen and activity were increased approximately 1,000-fold above normal levels. Clot lysis was significantly increased in mice injected with a t-PA–expressing virus, but not in mice injected with saline or an irrelevant adenovirus. Comparable levels of enzyme activity and clot lysis were obtained with wild type and inhibitor-resistant t-PA viruses. Adenovirus-mediated t-PA gene transfer was found to augment clot lysis as early as 4 hours after infection, but expression levels subsided within 7 days. Adenovirus-mediated transfer of a t-PA gene can effectively increase plasma fibrinolytic activity and either restore (in t-PA–deficient mice) or augment (in PAI-1–overexpressing mice) the thrombolytic capacity in simple animal models of defective fibrinolysis.
