Matching Items (15)
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- All Subjects: Cellular Biology
- All Subjects: Magnetic resonance imaging
- Creators: Kodibagkar, Vikram
- Creators: Roberson, Robert
Description
Cancer is the second leading cause of death in the United States and novel methods of treating advanced malignancies are of high importance. Of these deaths, prostate cancer and breast cancer are the second most fatal carcinomas in men and women respectively, while pancreatic cancer is the fourth most fatal in both men and women. Developing new drugs for the treatment of cancer is both a slow and expensive process. It is estimated that it takes an average of 15 years and an expense of $800 million to bring a single new drug to the market. However, it is also estimated that nearly 40% of that cost could be avoided by finding alternative uses for drugs that have already been approved by the Food and Drug Administration (FDA). The research presented in this document describes the testing, identification, and mechanistic evaluation of novel methods for treating many human carcinomas using drugs previously approved by the FDA. A tissue culture plate-based screening of FDA approved drugs will identify compounds that can be used in combination with the protein TRAIL to induce apoptosis selectively in cancer cells. Identified leads will next be optimized using high-throughput microfluidic devices to determine the most effective treatment conditions. Finally, a rigorous mechanistic analysis will be conducted to understand how the FDA-approved drug mitoxantrone, sensitizes cancer cells to TRAIL-mediated apoptosis.
ContributorsTaylor, David (Author) / Rege, Kaushal (Thesis advisor) / Jayaraman, Arul (Committee member) / Nielsen, David (Committee member) / Kodibagkar, Vikram (Committee member) / Dai, Lenore (Committee member) / Arizona State University (Publisher)
Created2013
Description
Magnetic Resonance Imaging using spiral trajectories has many advantages in speed, efficiency in data-acquistion and robustness to motion and flow related artifacts. The increase in sampling speed, however, requires high performance of the gradient system. Hardware inaccuracies from system delays and eddy currents can cause spatial and temporal distortions in the encoding gradient waveforms. This causes sampling discrepancies between the actual and the ideal k-space trajectory. Reconstruction assuming an ideal trajectory can result in shading and blurring artifacts in spiral images. Current methods to estimate such hardware errors require many modifications to the pulse sequence, phantom measurements or specialized hardware. This work presents a new method to estimate time-varying system delays for spiral-based trajectories. It requires a minor modification of a conventional stack-of-spirals sequence and analyzes data collected on three orthogonal cylinders. The method is fast, robust to off-resonance effects, requires no phantom measurements or specialized hardware and estimate variable system delays for the three gradient channels over the data-sampling period. The initial results are presented for acquired phantom and in-vivo data, which show a substantial reduction in the artifacts and improvement in the image quality.
ContributorsBhavsar, Payal (Author) / Pipe, James G (Thesis advisor) / Frakes, David (Committee member) / Kodibagkar, Vikram (Committee member) / Arizona State University (Publisher)
Created2013
Description
Sensitivity is a fundamental challenge for in vivo molecular magnetic resonance imaging (MRI). Here, I improve the sensitivity of metal nanoparticle contrast agents by strategically incorporating pure and doped metal oxides in the nanoparticle core, forming a soluble, monodisperse, contrast agent with adjustable T2 or T1 relaxivity (r2 or r1). I first developed a simplified technique to incorporate iron oxides in apoferritin to form "magnetoferritin" for nM-level detection with T2- and T2* weighting. I then explored whether the crystal could be chemically modified to form a particle with high r1. I first adsorbed Mn2+ ions to metal binding sites in the apoferritin pores. The strategic placement of metal ions near sites of water exchange and within the crystal oxide enhance r1, suggesting a mechanism for increasing relaxivity in porous nanoparticle agents. However, the Mn2+ addition was only possible when the particle was simultaneously filled with an iron oxide, resulting in a particle with a high r1 but also a high r2 and making them undetectable with conventional T1-weighting techniques. To solve this problem and decrease the particle r2 for more sensitive detection, I chemically doped the nanoparticles with tungsten to form a disordered W-Fe oxide composite in the apoferritin core. This configuration formed a particle with a r1 of 4,870mM-1s-1 and r2 of 9,076mM-1s-1. These relaxivities allowed the detection of concentrations ranging from 20nM - 400nM in vivo, both passively injected and targeted to the kidney glomerulus. I further developed an MRI acquisition technique to distinguish particles based on r2/r1, and show that three nanoparticles of similar size can be distinguished in vitro and in vivo with MRI. This work forms the basis for a new, highly flexible inorganic approach to design nanoparticle contrast agents for molecular MRI.
ContributorsClavijo Jordan, Maria Veronica (Author) / Bennett, Kevin M (Thesis advisor) / Kodibagkar, Vikram (Committee member) / Sherry, A Dean (Committee member) / Wang, Xiao (Committee member) / Yarger, Jeffery (Committee member) / Arizona State University (Publisher)
Created2012
Description
Contrast agents in medical imaging can help visualize structural details, distributions of particular cell types, or local environment characteristics. Multi-modal imaging techniques have become increasingly popular for their improved sensitivity, resolution, and ability to correlate structural and functional information. This study addresses the development of dual-modality (magnetic resonance/fluorescence) and dual-functional (thermometry/detection) nanoprobes for enhanced tissue imaging.
ContributorsHemzacek, Katherine Leigh (Author) / Kodibagkar, Vikram (Thesis director) / Stabenfeldt, Sarah (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2015-05
Description
Macrophage fusion resulting multinucleated giant cells (MGCs) formation is associated with numerous chronic inflammatory diseases including the foreign body reaction to implanted
biomaterials. Despite long-standing predictions, there have been attempts to use live-cell
imaging to investigate the morphological features initiating macrophage fusion because
macrophages do not fuse on clean glass required for most imaging techniques. Consequently,
the mechanisms of macrophage fusion remain poorly understood. The goal of this research
project was to characterize the early and late stages of macrophage multinucleation using
fusogenic optical quality substrate. Live-cell imaging with phase-contrast and lattice-light
sheet microscopy revealed that an actin-based protrusion initiates macrophage fusion. WASpdeficient macrophages and macrophages isolated from myeloid cell-specific Cdc42-/- mice
fused at very low rates. In addition, inhibiting the Arp2/3 complex impaired both the formation
of podosomes and macrophage fusion.
Analyses of the late stages of macrophage multinucleation on biomaterials implanted into
mice revealed novel actin-based zipper-like structures (ZLSs) formed at contact sites between
MGCs. The model system that was developed for the induction of ZLSs in vitro allowed for
the characterization of protein composition using confocal and super-resolution microscopy.
Live-cell imaging demonstrated that ZLSs are dynamic formations undergoing continuous
assembly and disassembly and that podosomes are precursors of these structures. It was further
found that E-cadherin and nectin-2 are involved in ZLS formation by bridging the plasma
membranes together. ii
Macrophage fusion on implanted biomaterials inherently involves their adhesion to the
implant surface. While biomaterials rapidly acquire a layer of host proteins, a biological
substrate that is required for macrophage fusion is unknown. It was shown that mice with
fibrinogen deficiency as well as mice expressing fibrinogen incapable of fibrin polymerization
displayed a dramatic reduction of macrophage fusion on biomaterials. Furthermore, these mice
were protected from the formation of the dense collagenous capsule enveloping the implant. It
was also found that the main cell type responsible for the deposition of collagen in the capsule
were mononuclear macrophages but not myofibroblasts. Together, these findings reveal a
critical role of the actin cytoskeleton in macrophage fusion and identify potential targets to
reduce the drawbacks of macrophage fusion on implanted biomaterials.
ContributorsBalabiyev, Arnat (Author) / Ugarova, Tatiana (Thesis advisor) / Roberson, Robert (Committee member) / Chandler, Douglas (Committee member) / Baluch, Page (Committee member) / Arizona State University (Publisher)
Created2021
Description
Male reproductive dysfunction accounts for almost half of male infertility cases, yet the signaling mechanisms involved in the male reproductive system remain unclear. Although the exact cause of male reproductive dysfunction varies, obtaining a better understanding of the modulators of smooth muscle contractions may provide new targets for the treatment of male reproductive conditions. The male reproductive tract, consisting of the testes, epididymis, vas deferens, and penis, is lined with innervated smooth muscle fibers that transport spermatozoa through the system. Contractions of these smooth muscle fibers can be modulated by neurotransmitters and hormones, like dopamine and norepinephrine, as well as biogenic amines. The focus of this study is on the biogenic amine tyramine, which is produced by the breakdown of tyrosine via decarboxylation. Tyramine has been shown to modulate vasoconstriction and increase blood pressure due to its effect on smooth muscle contractions. This study has found that tyramine localizes in male reproductive tissues and modulates smooth muscle contractions. Age and environment were also found to play a significant role in the expression of tyramine and its associated receptor, TAAR1.
ContributorsSteadman, Solange (Author) / Baluch, Debra (Thesis advisor) / Roberson, Robert (Committee member) / Sweazea, Karen (Committee member) / Arizona State University (Publisher)
Created2023
Description
Alpha herpesviruses are a family of neuroinvasive viruses that infect multiplevertebrate species. Alpha herpesviruses are responsible for human and livestock infections, most notably Herpes Simplex Virus (HSV), Varicella Zoster virus (VZV), and Pseudorabies Virus (PRV). PRV is a potent swine virus that can infect other mammals, and results in lethal encephalitis that can be devastating to livestock and of great financial expense to farmers. HSV, types 1 and 2, and VZV are widespread throughout the global human population, with estimates of the HSV-1 burden at about 60% of people worldwide. The hallmark of alpha herpesvirus infection is a persistent, lifelong infection that can reactivate throughout the lifespan of the host. Currently, the precise mechanisms of how these viruses undergo intracellular trafficking to emerge from the infected cell in epithelial tissues is not well understood. Many insights have been made with PRV in animal neurons, both in culture systems and animal models, about the viral genes and host factors involved in these processes. However, understanding of these mechanisms, and the interplay between viral and host proteins, in the human pathogen HSV-1 is even more lacking. Using recombinant fluorescent virus strains of HSV-1 and Total Internal Reflection Microscopy to image the transport of mature viral progeny in epithelial cells, it was determined that the egress of HSV-1 uses constitutive cellular secretory pathways. Specifically, the viral progeny traffic from the trans-Golgi network to the site of exocytosis at the plasma membrane via Rab6a secretory vesicles. This work will contribute to the understanding of how alpha herpesviruses complete their lifecycles in host cells, particularly at the sites where infection initially occurs and can spread to a new organism. Knowledge of these processes may lead to the development of therapeutics or prophylactics to reduce the burden of these viruses.
ContributorsBergeman, Melissa Hope (Author) / Hogue, Ian B (Thesis advisor) / Hogue, Brenda (Committee member) / Roberson, Robert (Committee member) / Varsani, Arvind (Committee member) / Arizona State University (Publisher)
Created2023
Description
A description of numerical and analytical work pertaining to models that describe the growth and progression of glioblastoma multiforme (GBM), an aggressive form of primary brain cancer. Two reaction-diffusion models are used: the Fisher-Kolmogorov-Petrovsky-Piskunov equation and a 2-population model that divides the tumor into actively proliferating and quiescent (or necrotic) cells. The numerical portion of this work (chapter 2) focuses on simulating GBM expansion in patients undergoing treatment for recurrence of tumor following initial surgery. The models are simulated on 3-dimensional brain geometries derived from magnetic resonance imaging (MRI) scans provided by the Barrow Neurological Institute. The study consists of 17 clinical time intervals across 10 patients that have been followed in detail, each of whom shows significant progression of tumor over a period of 1 to 3 months on sequential follow up scans. A Taguchi sampling design is implemented to estimate the variability of the predicted tumors to using 144 different choices of model parameters. In 9 cases, model parameters can be identified such that the simulated tumor contains at least 40 percent of the volume of the observed tumor. In the analytical portion of the paper (chapters 3 and 4), a positively invariant region for our 2-population model is identified. Then, a rigorous derivation of the critical patch size associated with the model is performed. The critical patch (KISS) size is the minimum habitat size needed for a population to survive in a region. Habitats larger than the critical patch size allow a population to persist, while smaller habitats lead to extinction. The critical patch size of the 2-population model is consistent with that of the Fisher-Kolmogorov-Petrovsky-Piskunov equation, one of the first reaction-diffusion models proposed for GBM. The critical patch size may indicate that GBM tumors have a minimum size depending on the location in the brain. A theoretical relationship between the size of a GBM tumor at steady-state and its maximum cell density is also derived, which has potential applications for patient-specific parameter estimation based on magnetic resonance imaging data.
ContributorsHarris, Duane C. (Author) / Kuang, Yang (Thesis advisor) / Kostelich, Eric J. (Thesis advisor) / Preul, Mark C. (Committee member) / Crook, Sharon (Committee member) / Gardner, Carl (Committee member) / Arizona State University (Publisher)
Created2023
Description
Microscopic algae have been investigated extensively by researchers for decades for their ability to bioremediate wastewater and flue gas while producing valuable biomass for use as feed, fuel, fertilizer, nutraceutical, and other specialty products. Reports of the exciting commercial potential of this diverse group of organisms started appearing in the literature as early as the 1940’s. However, nearly 80 years later, relatively few successful commercial microalgae installations exist and algae have not yet reached agricultural commodity status. This dissertation examines three major bottlenecks to commercial microalgae production including lack of an efficient and economical cultivation strategy, poor management of volatile waste nutrients, and costly harvesting and post processing strategies. A chapter is devoted to each of these three areas to gain a better understanding of each bottleneck as well as strategies for overcoming them.
The first chapter demonstrates the capability of two strains of Scenedesmus acutus to grow in ultra-high-density (>10 g L-1 dry weight biomass) cultures in flat panel photobioreactors for year-round production in the desert Southwest with record volumetric biomass productivity. The advantages and efficiency of high-density cultivation are discussed. The second chapter focuses on uptake and utilization of the volatile components of wastewater: ammonia and carbon dioxide. Scenedesmus acutus was cultured on wastewater from both municipal and agricultural origin and was shown to perform significantly better on flue gas as compared to commercial grade CO2 and just as well on waste nutrients as the commonly used BG-11 laboratory culture media, all while producing up to 50% lipids of the dry weight biomass suitable for use in biodiesel. The third chapter evaluates the feasibility of using gravity sedimentation for the harvesting of the difficult-to-separate Scenedesmus acutus green algae biomass followed by microfluidization to disrupt the cells. Lipid-extracted biomass was then studied as a fertilizer for plants and shown to have similar performance to a commercially available 4-6-6 fertilizer. Based on the work from these three chapters, a summary of modifications are suggested to help current and future microalgae companies be more competitive in the marketplace with traditional agricultural commodities.
The first chapter demonstrates the capability of two strains of Scenedesmus acutus to grow in ultra-high-density (>10 g L-1 dry weight biomass) cultures in flat panel photobioreactors for year-round production in the desert Southwest with record volumetric biomass productivity. The advantages and efficiency of high-density cultivation are discussed. The second chapter focuses on uptake and utilization of the volatile components of wastewater: ammonia and carbon dioxide. Scenedesmus acutus was cultured on wastewater from both municipal and agricultural origin and was shown to perform significantly better on flue gas as compared to commercial grade CO2 and just as well on waste nutrients as the commonly used BG-11 laboratory culture media, all while producing up to 50% lipids of the dry weight biomass suitable for use in biodiesel. The third chapter evaluates the feasibility of using gravity sedimentation for the harvesting of the difficult-to-separate Scenedesmus acutus green algae biomass followed by microfluidization to disrupt the cells. Lipid-extracted biomass was then studied as a fertilizer for plants and shown to have similar performance to a commercially available 4-6-6 fertilizer. Based on the work from these three chapters, a summary of modifications are suggested to help current and future microalgae companies be more competitive in the marketplace with traditional agricultural commodities.
ContributorsWray, Joshua (Author) / Dempster, Thomas (Thesis advisor) / Roberson, Robert (Thesis advisor) / Bingham, Scott (Committee member) / Neuer, Susanne (Committee member) / Arizona State University (Publisher)
Created2019
Description
Euendolithic cyanobacteria have the remarkable ability to actively excavate and grow within certain minerals. Their activity leads to increased erosion of marine and terrestrial carbonates, negatively affecting coral reef and bivalve ecology. Despite their environmental relevance, the boring mechanism has remained elusive and paradoxical, in that cyanobacteria alkalinize their surroundings, typically leading to carbonate precipitation, not dissolution. Thus, euendoliths must rely on unique adaptations to bore. Recent work using the filamentous model euendolith Mastigocoleus testarum strain BC008 indicated that excavation relied on transcellular calcium transport mediated by P-type ATPases, but the phenomenon remained unclear. Here I present evidence that excavation in M. testarum involves an unprecedented set of adaptations. Long-range calcium transport is achieved through the coordinated pumping of multiple cells, orchestrated by the localization of calcium ATPases in a repeating annular pattern, positioned at a single cell pole, adjacent to each cell septum along the filament. Additionally, specialized chlorotic cells that I named calcicytes, differentiate and accumulate calcium at concentrations more than 500 fold those of canonical cells, likely allowing for fast calcium flow at non-toxic concentrations through undifferentiated cells. I also show, using 13C stable isotope tracers and NanoSIMS imaging, that endolithic M. testarum derives most of its carbon from the mineral carbonates it dissolves, the first autotroph ever shown to fix mineral carbon, confirming the existence of a direct link between oxidized solid carbon pools and reduced organic pools in the biosphere. Finally, using genomic and transcriptomic approaches, I analyze gene expression searching for additional adaptations related to the endolithic lifestyle. A large and diverse set of genes (24% of 6917 genes) were significantly differentially regulated while boring, including several master regulators and genes expectedly needed under this condition (such as transport, nutrient scavenging, oxidative stress, and calcium-binding protein genes). However, I also discovered the up-regulation of several puzzling gene sets involved in alternative carbon fixation pathways, anaerobic metabolism, and some related to photosynthesis and respiration. This transcriptomic data provides us with several new, readily testable hypotheses regarding adaptations to the endolithic lifestyle. In all, my data clearly show that boring organisms show extraordinarily interesting adaptations.
ContributorsGuida, Brandon Scott (Author) / Garcia-Pichel, Ferran (Thesis advisor) / Chandler, Douglas (Committee member) / Bingham, Scott (Committee member) / Roberson, Robert (Committee member) / Arizona State University (Publisher)
Created2016