Creighton University Window Fall 1985

THE KNOTTY FARM PROBLEM / THE FARM CRISIS THROUGH THE EXPERTS' EYES | Dr. Herbert Funk, Creighton's own agriculture expert, Hugh Tinley, who heads the nation's top farm management company, and an alumna farmer look at the farm crisis. Page 4.YOU CAN BE AN AHN-TRA-PRE-NUR / DO YOU HAVE THE RIGHT ENTREPRENEUR STUFF? | Do you have what it takes to be a successful entrepreneur? Do you know what an entrepreneur is? Drs. Kathleen and William Brannen tell you. Page 10.COCA-COLA: DID THE MARKETING PAUSE REFRESH IT? / BEHIND THE SCENES OF THE COCA-COLA STORY OF 1985 | The Coca-Cola controversy of 1985 is examined by Dr. Guy Danville, who talked with Creighton alumnus and Coca-Cola president Don Keough. Page 14.ST. LOUIS JESUITS: MAKING A JOYFUL NOISE / SELLING LOTS OF ALBUMS, AND MAKING A JOYFUL NOISE | The "St. Louis Jesuits" make a joyful noise to the Lord, and they do it right here in Omaha at Sound Recorders, turning out best-selling record albums. Page 20.1

PEGylated DX-1000: Pharmacokinetics and Antineoplastic Activity of a Specific Plasmin Inhibitor

AbstractNovel inhibitors of the urokinase-mediated plasminogen (plg) activation system are potentially of great clinical benefit as anticancer treatments. Using phage display, we identified DX-1000 a tissue factor pathway inhibitor-derived Kunitz domain protein which is a specific high-affinity inhibitor of plasmin (pin) (Ki = 99 pM). When tested in vitro, DX-1000 blocks plasminmediated pro-matrix metal loproteinase-9 (proMMP-9) activation on cells and dose-dependently inhibits tube formation, while not significantly affecting hemostasis and coagulation. However, this low-molecular weight protein inhibitor (~ 7 kDa) exhibits rapid plasma clearance in mice and rabbits, limiting its potential clinical use in chronic diseases. After site-specific PEGylation, DX-1000 retains its activity and exhibits a decreased plasma clearance. This PEGylated derivative is effective in vitro, as well as potent in inhibiting tumor growth of green fluorescent protein (GFP)-labeled MDA-MB-231 cells. 4PEG-DX-1000 treatment causes a significant reduction of urokinase-type plasminogen activator (uPA) and plasminogen expressions, a reduction of tumor proliferation, and vascularization. 4PEG-DX-1000 treatment significantly decreases the level of active mitogenactivated protein kinase (MAPK) in the primary tumors and reduces metastasis incidence. Together, our results demonstrate the potential value of plasmin inhibitors as therapeutic agents for blocking breast cancer growth and metastasis

A Link between FXYD3 (Mat-8)-mediated Na,K-ATPase Regulation and Differentiation of Caco-2 Intestinal Epithelial Cells

FXYD3 (Mat-8) proteins are regulators of Na,K-ATPase. In normal tissue, FXYD3 is mainly expressed in stomach and colon, but it is also overexpressed in cancer cells, suggesting a role in tumorogenesis. We show that FXYD3 silencing has no effect on cell proliferation but promotes cell apoptosis and prevents cell differentiation of human colon adenocarcinoma cells (Caco-2), which is reflected by a reduction in alkaline phosphatase and villin expression, a change in several other differentiation markers, and a decrease in transepithelial resistance. Inhibition of cell differentiation in FXYD3-deficient cells is accompanied by an increase in the apparent Na+ and K+ affinities of Na,K-ATPase, reflecting the absence of Na,K-pump regulation by FXYD3. In addition, we observe a decrease in the maximal Na,K-ATPase activity due to a decrease in its turnover number, which correlates with a change in Na,K-ATPase isozyme expression that is characteristic of cancer cells. Overall, our results suggest an important role of FXYD3 in cell differentiation of Caco-2 cells. One possibility is that FXYD3 silencing prevents proper regulation of Na,K-ATPase, which leads to perturbation of cellular Na+ and K+ homeostasis and changes in the expression of Na,K-ATPase isozymes, whose functional properties are incompatible with Caco-2 cell differentiation