Medicine and Health Sciences Commons^™

Carhsp1 Is Required For Effective Tumor Necrosis Factor Alpha Mrna Stabilization And Localizes To Processing Bodies And Exosomes, Jason R. Pfeiffer, Bethany L. Mcavoy, Ryan E. Fecteau, Kristen M. Deleault, Seth A. Brooks

Dartmouth Scholarship

Tumor necrosis factor alpha (TNF-α) is a critical mediator of inflammation, and its production is tightly regulated, with control points operating at nearly every step of its biosynthesis. We sought to identify uncharacterized TNF-α 3' untranslated region (3'UTR)-interacting proteins utilizing a novel screen, termed the RNA capture assay. We identified CARHSP1, a cold-shock domain-containing protein. Knockdown of CARHSP1 inhibits TNF-α protein production in lipopolysaccharide (LPS)-stimulated cells and reduces the level of TNF-α mRNA in both resting and LPS-stimulated cells. mRNA stability assays demonstrate that CARHSP1 knockdown decreases TNF-α mRNA stability from a half-life (t(1/2)) of 49 min to a t(1/2) …

Comparing Implementations Of Magnetic-Resonance-Guided Fluorescence Molecular Tomography For Diagnostic Classification Of Brain Tumors, Scott C. Davis, Kimberley S. Samkoe, Julia A. O’Hara, Summer L. Gibbs-Strauss, Keith D. Paulsen, Brian W. Pogue

Dartmouth Scholarship

Fluorescence molecular tomography (FMT) systems coupled to conventional imaging modalities such as magnetic resonance imaging (MRI) and computed tomography provide unique opportunities to combine data sets and improve image quality and content. Yet, the ideal approach to combine these complementary data is still not obvious. This preclinical study compares several methods for incorporating MRI spatial prior information into FMT imaging algorithms in the context of in vivo tissue diagnosis. Populations of mice inoculated with brain tumors that expressed either high or low levels of epidermal growth factor receptor (EGFR) were imaged using an EGF-bound near-infrared dye and a spectrometer-based MRI-FMT …

Quantitative Imaging Reveals Heterogeneous Growth Dynamics And Treatment-Dependent Residual Tumor Distributions In A Three-Dimensional Ovarian Cancer Model, Jonathan P. Celli, Imran Rizvi, Conor L. Evans, Adnan O. Abu-Yousif, Tayyaba Hasan

Dartmouth Scholarship

Three-dimensional tumor models have emerged as valuable in vitro research tools, though the power of such systems as quantitative reporters of tumor growth and treatment response has not been adequately explored. We introduce an approach combining a 3-D model of disseminated ovarian cancer with high-throughput processing of image data for quantification of growth characteristics and cytotoxic response. We developed custom MATLAB routines to analyze longitudinally acquired dark-field microscopy images containing thousands of 3-D nodules. These data reveal a reproducible bimodal log-normal size distribution. Growth behavior is driven by migration and assembly, causing an exponential decay in spatial density concomitant with …

Identification Of Methylated Genes Associated With Aggressive Bladder Cancer, Carmen J. Marsit, E. Andres Houseman, Brock C. Christensen, Luc Gagne, Margaret R. Wrensch, Heather H. Nelson, Joseph Weimels, Shichun Zheng, John K. Wiencke, Angeline S. Andrew, Alan R. Schned, Margaret R. Karagas, Karl T. Kelsey

Dartmouth Scholarship

Approximately 500,000 individuals diagnosed with bladder cancer in the U.S. require routine cystoscopic follow-up to monitor for disease recurrences or progression, resulting in over $ 2 billion in annual expenditures. Identification of new diagnostic and monitoring strategies are clearly needed, and markers related to DNA methylation alterations hold great promise due to their stability, objective measurement, and known associations with the disease and with its clinical features. To identify novel epigenetic markers of aggressive bladder cancer, we utilized a high-throughput DNA methylation bead-array in two distinct population-based series of incident bladder cancer (n = 73 and n = 264, respectively). …

Deltanp63 Transcriptionally Regulates Atm To Control P53 Serine-15 Phosphorylation., Ashley L. Craig, Jitka Holcakova, Lee E. Finlan, Marta Nekulova, Roman Hrstka, Nuri Gueven, James Direnzo, Graeme Smith, Ted R. Hupp, Borivoj Vojtesek

Dartmouth Scholarship

Background: ΔNp63α is an epithelial progenitor cell marker that maintains epidermal stem cell self-renewal capacity. Previous studies revealed that UV-dam age induced p53 phosphorylation is confined to ΔNp63α-positive cells in the basal layer of human epithelium. Results: We now report that phosphorylatio n of the p53 tumour suppressor is po sitively regulated by ΔNp63α in immortalised human keratinocytes. ΔNp63α depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of ΔNp63α in p63-null tumour cells stimulates ATM transcription and p53 Seri ne-15 phosphorylation. We show that AT M is a …

Imaging Targeted-Agent Binding In Vivo With Two Probes, Brian W. Pogue, Kimberley S. Samkoe, Shannon Hextrum, Julia A. O'Hara, Michael Jermyn, Subhadra Srinivasan, Tayyaba Hasan

Dartmouth Scholarship

An approach to quantitatively image targeted-agent binding rate in vivo is demonstrated with dual-probe injection of both targeted and nontargeted fluorescent dyes. Images of a binding rate constant are created that reveal lower than expected uptake of epidermal growth factor in an orthotopic xenograft pancreas tumor (2.3×10−5 s−1), as compared to the normal pancreas (3.4×10−5 s−1). This approach allows noninvasive assessment of tumor receptor targeting in vivo to determine the expected contrast, spatial localization, and efficacy in therapeutic agent delivery.

Targeting therapeutic drugs to tumors based on their overexpression of cellular receptors is widely researched and has important clinical success. …

Proliferation Of Aneuploid Human Cells Is Limited By A P53-Dependent Mechanism, Sarah L. Thompson, Duane A. Compton

Dartmouth Scholarship

Most solid tumors are aneuploid, and it has been proposed that aneuploidy is the consequence of an elevated rate of chromosome missegregation in a process called chromosomal instability (CIN). However, the relationship of aneuploidy and CIN is unclear because the proliferation of cultured diploid cells is compromised by chromosome missegregation. The mechanism for this intolerance of nondiploid genomes is unknown. In this study, we show that in otherwise diploid human cells, chromosome missegregation causes a cell cycle delay with nuclear accumulation of the tumor suppressor p53 and the cyclin kinase inhibitor p21. Deletion of the p53 gene permits the accumulation …