Matching Items (2)
Description
The long-term survival of patients with glioblastoma multiforme is compromised by the tumor's proclivity for local invasion into the surrounding normal brain. These invasive cells escape surgery and display resistance to chemotherapeutic- and radiation-induced apoptosis. We have previously shown that tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell invasion and survival via binding to the fibroblast growth factor-inducible 14 (Fn14) receptor and subsequent activation of the Rac1/NF-kappaB pathway. In addition, we have reported previously that Fn14 is expressed at high levels in migrating glioma cells in vitro and invading glioma cells in vivo. Here we demonstrate that TWEAK can act as a chemotactic factor for glioma cells, a potential process to drive cell invasion into the surrounding brain tissue. Specifically, we detected a chemotactic migration of glioma cells to the concentration gradient of TWEAK. Since Src family kinases (SFK) have been implicated in chemotaxis, we next determined whether TWEAK:Fn14 engagement activated these cytoplasmic tyrosine kinases. Our data shows that TWEAK stimulation of glioma cells results in a rapid phosphorylation of the SFK member Lyn as determined by multiplex Luminex assay and verified by immunoprecipitation. Immunodepletion of Lyn by siRNA oligonucleotides suppressed the chemoattractive effect of TWEAK on glioma cells. We hypothesize that TWEAK secretion by cells present in the glioma microenvironment induce invasion of glioma cells into the brain parenchyma. Understanding the function and signaling of the TWEAK-Fn14 ligand-receptor system may lead to development of novel therapies to therapeutically target invasive glioma cells.
ContributorsJameson, Nathan Meade (Author) / Anderson, Karen (Thesis director) / Lake, Douglas (Committee member) / Tran, Nhan (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2013-05
Description
In the medical industry, there have been promising advances in the increase of new types of healthcare to the public. As of 2015, there was a 98% Premarket Approval rate, a 38% increase since 2010. In addition, there were 41 new novel drugs approved for clinical usage in 2014 where the average in the previous years from 2005-2013 was 25. However, the research process towards creating and delivering new healthcare to the public remains remarkably inefficient. It takes on average 15 years, over $900 million by one estimate, for a less than 12% success rate of discovering a novel drug for clinical usage. Medical devices do not fare much better. Between 2005-2009, there were over 700 recalls per year. In addition, it takes at minimum 3.25 years for a 510(k) exempt premarket approval. Plus, a time lag exists where it takes 17 years for only 14% of medical discoveries to be implemented clinically. Coupled with these inefficiencies, government funding for medical research has been decreasing since 2002 (2.5% of Gross Domestic Product) and is predicted to be 1.5% of Gross Domestic Product by 2019. Translational research, the conversion of bench-side discoveries to clinical usage for a simplistic definition, has been on the rise since the 1990s. This may be driving the increased premarket approvals and new novel drug approvals. At the very least, it is worth considering as translational research is directly related towards healthcare practices. In this paper, I propose to improve the outcomes of translational research in order to better deliver advancing healthcare to the public. I suggest Best Value Performance Information Procurement System (BV PIPS) should be adapted in the selection process of translational research projects to fund. BV PIPS has been shown to increase the efficiency and success rate of delivering projects and services. There has been over 17 years of research with $6.3 billion of projects and services delivered showing that BV PIPS has a 98% customer satisfaction, 90% minimized management effort, and utilizes 50% less manpower and effort. Using University of Michigan \u2014 Coulter Foundation Program's funding process as a baseline and standard in the current selection of translational research projects to fund, I offer changes to this process based on BV PIPS that may ameliorate it. As concepts implemented in this process are congruent with literature on successful translational research, it may suggest that this new model for selecting translational research projects to fund will reduce costs, increase efficiency, and increase success. This may then lead to more Premarket Approvals, more new novel drug approvals, quicker delivery time to the market, and lower recalls.
ContributorsDel Rosario, Joseph Paul (Author) / Kashiwagi, Dean (Thesis director) / Kashiwagi, Jacob (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05