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Lung cancer is the leading cause of cancer-related deaths in the US. Low-dose computed tomography (LDCT) scans are speculated to reduce lung cancer mortality. However LDCT scans impose multiple risks including false-negative results, false- positive results, overdiagnosis, and cancer due to repeated exposure to radiation. Immunosignaturing is a new method proposed to screen and detect lung cancer, eliminating the risks associated with LDCT scans. Known and blinded primary blood sera from participants with lung cancer and no cancer were run on peptide microarrays and analyzed. Immunosignatures for each known sample collectively indicated 120 peptides unique to lung cancer and non-cancer participants. These 120 peptides were used to determine the status of the blinded samples. Verification of the results from Vanderbilt is pending.
ContributorsNguyen, Geneva Trieu (Author) / Woodbury, Neal (Thesis director) / Zhao, Zhan-Gong (Committee member) / Stafford, Phillip (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / Department of Psychology (Contributor)
Created2015-05
Description
Cancer remains one of the leading killers throughout the world. Death and disability due to lung cancer in particular accounts for one of the largest global economic burdens a disease presents. The burden on third-world countries is especially large due to the unusually large financial stress that comes from late tumor detection and expensive treatment options. Early detection using inexpensive techniques may relieve much of the burden throughout the world, not just in more developed countries. I examined the immune responses of lung cancer patients using immunosignatures – patterns of reactivity between host serum antibodies and random peptides. Immunosignatures reveal disease-specific patterns that are very reproducible. Immunosignaturing is a chip-based method that has the ability to display the antibody diversity from individual sera sample with low cost. Immunosignaturing is a medical diagnostic test that has many applications in current medical research and in diagnosis. From a previous clinical study, patients diagnosed for lung cancer were tested for their immunosignature vs. healthy non-cancer volunteers. The pattern of reactivity against the random peptides (the ‘immunosignature’) revealed common signals in cancer patients, absent from healthy controls. My study involved the search for common amino acid motifs in the cancer-specific peptides. My search through the hundreds of ‘hits’ revealed certain motifs that were repeated more times than expected by random chance. The amino acids that were the most conserved in each set include tryptophan, aspartic acid, glutamic acid, proline, alanine, serine, and lysine. The most overall conserved amino acid observed between each set was D - aspartic acid. The motifs were short (no more than 5-6 amino acids in a row), but the total number of motifs I identified was large enough to assure significance. I utilized Excel to organize the large peptide sequence libraries, then CLUSTALW to cluster similar-sequence peptides, then GLAM2 to find common themes in groups of peptides. In so doing, I found sequences that were also present in translated cancer expression libraries (RNA) that matched my motifs, suggesting that immunosignatures can find cancer-specific antigens that can be both diagnostic and potentially therapeutic.
ContributorsShiehzadegan, Shima (Author) / Johnston, Stephen (Thesis director) / Stafford, Phillip (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2015-12
Description
Misfolding and aggregation of alpha-synuclein (a-syn) has been strongly correlated with the pathogenesis of Parkinson's disease (PD). Reagents such as single chain antibody fragments (scFv) that can interact with specific aggregate forms of a-syn can be very useful to study how different aggregate forms affect cells. Here we utilize two scFvs, D5 and 10H, that recognize two distinct oligomeric forms of a-syn to characterize the presence of different a-syn aggregates in animal models of PD.
ContributorsAlam, Now Bahar (Author) / Sierks, Michael (Thesis director) / Pauken, Christine (Committee member) / Williams, Stephanie (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor) / Harrington Bioengineering Program (Contributor)
Created2013-05
Description
Methicillin-Resistant Staphylococcus aureus (MRSA) infections are a major challenge to healthcare professionals. Treatment of MRSA is expensive, and otherwise avoidable deaths occur every year in the United States due to MRSA infections. Additionally, such infections lengthen patients’ stays in hospitals, keeping them out of work and adversely affecting the economy. Beta lactam antibiotics used to be highly effective against S. aureus infections, but resistance mechanisms have rendered methicillin, oxacillin, and other beta lactam antibiotics ineffective against these infections. A promising avenue for MRSA treatment lies in the use of synthetic antibodies—molecules that bind with specificity to a given compound. Synbody 14 is an example of such a synbody, and has been designed with MRSA treatment in mind. Mouse model studies have even associated Syn14 treatment with reduced weight loss and morbidity in MRSA-infected mice. In this experiment, in vitro activity of Syn 14 and oxacillin was assessed. Early experiments measured Syn 14 and oxacillin’s effectiveness in inhibiting colony growth in growth media, mouse serum, and mouse blood. Syn14 and oxacillin had limited efficacy against USA300 strain MRSA, though interestingly it was noted that Syn14 outperformed oxacillin in mouse serum and whole mouse blood, indicating the benefits of its binding properties. A second experiment measured the impact that a mix of oxacillin and Syn 14 had on colony growth, as well as the effect of adding them simultaneously or one after the other. While use of either bactericidal alone did not show a major inhibitory effect on USA300 MRSA colony growth, their use in combination showed major decreases in colony growth. Moreover, it was found that unlike other combination therapies, Syn14 and oxacillin did not require simultaneous addition to MRSA cells to achieve inhibition of cell growth. They merely required that Syn14 be added first. This result suggests Syn14’s possible utility in therapeutic settings, as the time insensitivity of synergy removes a major hurdle to clinical use—the difficulty in ensuring that two drugs reach an affected area at the same time. Syn14 remains a promising antimicrobial agent, and further study should focus on its precise mechanism of action and suitability in clinical treatment of MRSA infections.
ContributorsMichael, Alexander (Author) / Diehnelt, Chris (Thesis director) / Stafford, Phillip (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor)
Created2015-05
Description
The research objective is to maintain the A4 nanobody stability during dialysis. Various dialysis buffers were tested and compared, including PBS with varying amounts of the detergent, Tween: low, high, none. Furthermore, PBS, Tris, and HEPES, were tested and compared. PBS without Tween was the worst for preserving A4 stability. PBS was determined to be a better dialysis buffer than Tris or HEPES. To find the optimum buffer, other buffers will be tested and compared with PBS; methods such as gravity filtration and lyophilization will be considered as alternatives to dialysis.
ContributorsTao, Kevin Huang (Author) / Sierks, Michael (Thesis director) / Williams, Stephanie (Committee member) / Barrett, The Honors College (Contributor) / Chemical Engineering Program (Contributor)
Created2015-05
Description
Five immunocompetent C57BL/6-cBrd/cBrd/Cr (albino C57BL/6) mice were injected with GL261-luc2 cells, a cell line sharing characteristics of human glioblastoma multiforme (GBM). The mice were imaged using magnetic resonance (MR) at five separate time points to characterize growth and development of the tumor. After 25 days, the final tumor volumes of the mice varied from 12 mm3 to 62 mm3, even though mice were inoculated from the same tumor cell line under carefully controlled conditions. We generated hypotheses to explore large variances in final tumor size and tested them with our simple reaction-diffusion model in both a 3-dimensional (3D) finite difference method and a 2-dimensional (2D) level set method. The parameters obtained from a best-fit procedure, designed to yield simulated tumors as close as possible to the observed ones, vary by an order of magnitude between the three mice analyzed in detail. These differences may reflect morphological and biological variability in tumor growth, as well as errors in the mathematical model, perhaps from an oversimplification of the tumor dynamics or nonidentifiability of parameters. Our results generate parameters that match other experimental in vitro and in vivo measurements. Additionally, we calculate wave speed, which matches with other rat and human measurements.
ContributorsRutter, Erica (Author) / Stepien, Tracy (Author) / Anderies, Barrett (Author) / Plasencia, Jonathan (Author) / Woolf, Eric C. (Author) / Scheck, Adrienne C. (Author) / Turner, Gregory H. (Author) / Liu, Qingwei (Author) / Frakes, David (Author) / Kodibagkar, Vikram (Author) / Kuang, Yang (Author) / Preul, Mark C. (Author) / Kostelich, Eric (Author) / College of Liberal Arts and Sciences (Contributor)
Created2017-05-31
Description
Peptides offer great promise as targeted affinity ligands, but the space of possible peptide sequences is vast, making experimental identification of lead candidates expensive, difficult, and uncertain. Computational modeling can narrow the search by estimating the affinity and specificity of a given peptide in relation to a predetermined protein target. The predictive performance of computational models of interactions of intermediate-length peptides with proteins can be improved by taking into account the stochastic nature of the encounter and binding dynamics. A theoretical case is made for the hypothesis that, because of the flexibility of the peptide and the structural complexity of the target protein, interactions are best characterized by an ensemble of possible bound configurations rather than a single “lock and key” fit. A model incorporating these factors is proposed and evaluated. A comprehensive dataset of 3,924 peptide-protein interface structures was extracted from the Protein Data Bank (PDB) and descriptors were computed characterizing the geometry and energetics of each interface. The characteristics of these interfaces are shown to be generally consistent with the proposed model, and heuristics for design and selection of peptide ligands are derived. The curated and energy-minimized interface structure dataset and a relational database containing the detailed results of analysis and energy modeling are made publicly available via a web repository. A novel analytical technique based on the proposed theoretical model, Virtual Scanning Probe Mapping (VSPM), is implemented in software to analyze the interaction between a target protein of known structure and a peptide of specified sequence, producing a spatial map indicating the most likely peptide binding regions on the protein target. The resulting predictions are shown to be superior to those of two other published methods, and support the validity of the stochastic binding model.
ContributorsEmery, Jack Scott (Author) / Pizziconi, Vincent B (Thesis advisor) / Woodbury, Neal W (Thesis advisor) / Guilbeau, Eric J (Committee member) / Stafford, Phillip (Committee member) / Taylor, Thomas (Committee member) / Towe, Bruce C (Committee member) / Arizona State University (Publisher)
Created2010
Description
Bacteria with antibiotic resistance are becoming a growing concern as the number of infections they are causing continue to increase. Many potential solutions are being researched in order to combat these pathogens. One such microbe is Pseudomonas aeruginosa, which causes acute and chronic human infections. It frequently colonizes the lungs of cystic fibrosis patients and is deadly. For these reasons, P. aeruginosa has been heavily studied in order to determine a solution to antibiotic resistance. One possible solution is the development of synbodies, which have been developed at the Biodesign Institute at Arizona State University. Synbodies are constructed from peptides that have antibacterial activity and were determined to have specificity for a target bacterium. These synbodies were tested in this study to determine whether or not some of them are able to inhibit P. aeruginosa growth. P. aeruginosa can also form multicellular communities called biofilms and these are known to cause approximately 65% of all human infections. After conducting minimum inhibitory assays, the efficacy of certain peptides and synbodies against biofilm inhibition was assessed. A recent study has shown that low concentrations of a specific peptide can cause biofilm disruption, where the biofilm structure breaks apart and the cells within it disperse into the supernatant. Taking into account this study and peptide data regarding biofilm inhibition from Dr. Aurélie Crabbé’s lab, screened peptides were tested against biofilm to see if dispersion would occur.
ContributorsPatel, Justin Hemant (Author) / Diehnelt, Chris (Thesis director) / Stafford, Phillip (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / School of Historical, Philosophical and Religious Studies (Contributor)
Created2015-05
Description
Complex human controls is a topic of much interest in the fields of robotics, manufacturing, space exploration and many others. Even simple tasks that humans perform with ease can be extremely complicated when observed from a controls and complex systems perspective. One such simple task is that of a human carrying and moving a coffee cup. Though this may be a mundane task for humans, when this task is modelled and analyzed, the system may be quite chaotic in nature. Understanding such systems is key to the development robots and autonomous systems that can perform these tasks themselves.
The coffee cup system can be simplified and modeled by a cart-and-pendulum system. Bazzi et al. and Maurice et al. present two different cart-and-pendulum systems to represent the coffee cup system [1],[2]. The purpose of this project was to build upon these systems and to gain a better understanding of the coffee cup system and to determine where chaos existed within the system. The honors thesis team first worked with their senior design group to develop a mathematical model for the cart-and-pendulum system based on the Bazzi and Maurice papers [1],[2]. This system was analyzed and then built upon by the honors thesis team to build a cart-and-two-pendulum model to represent the coffee cup system more accurately.
Analysis of the single pendulum model showed that there exists a low frequency region where the pendulum and the cart remain in phase with each other and a high frequency region where the cart and pendulum have a π phase difference between them. The transition point of the low and high frequency region is determined by the resonant frequency of the pendulum. The analysis of the two-pendulum system also confirmed this result and revealed that differences in length between the pendulum cause the pendulums to transition to the high frequency regions at separate frequency. The pendulums have different resonance frequencies and transition into the high frequency region based on their own resonant frequency. This causes a range of frequencies where the pendulums are out of phase from each other. After both pendulums have transitioned, they remain in phase with each other and out of phase from the cart.
However, if the length of the pendulum is decreased too much, the system starts to exhibit chaotic behavior. The short pendulum starts to act in a chaotic manner and the phase relationship between the pendulums and the carts is no longer maintained. Since the pendulum length represents the distance between the particle of coffee and the top of the cup, this implies that coffee near the top of the cup would cause the system to act chaotically. Further analysis would be needed to determine the reason why the length affects the system in this way.
The coffee cup system can be simplified and modeled by a cart-and-pendulum system. Bazzi et al. and Maurice et al. present two different cart-and-pendulum systems to represent the coffee cup system [1],[2]. The purpose of this project was to build upon these systems and to gain a better understanding of the coffee cup system and to determine where chaos existed within the system. The honors thesis team first worked with their senior design group to develop a mathematical model for the cart-and-pendulum system based on the Bazzi and Maurice papers [1],[2]. This system was analyzed and then built upon by the honors thesis team to build a cart-and-two-pendulum model to represent the coffee cup system more accurately.
Analysis of the single pendulum model showed that there exists a low frequency region where the pendulum and the cart remain in phase with each other and a high frequency region where the cart and pendulum have a π phase difference between them. The transition point of the low and high frequency region is determined by the resonant frequency of the pendulum. The analysis of the two-pendulum system also confirmed this result and revealed that differences in length between the pendulum cause the pendulums to transition to the high frequency regions at separate frequency. The pendulums have different resonance frequencies and transition into the high frequency region based on their own resonant frequency. This causes a range of frequencies where the pendulums are out of phase from each other. After both pendulums have transitioned, they remain in phase with each other and out of phase from the cart.
However, if the length of the pendulum is decreased too much, the system starts to exhibit chaotic behavior. The short pendulum starts to act in a chaotic manner and the phase relationship between the pendulums and the carts is no longer maintained. Since the pendulum length represents the distance between the particle of coffee and the top of the cup, this implies that coffee near the top of the cup would cause the system to act chaotically. Further analysis would be needed to determine the reason why the length affects the system in this way.
ContributorsZindani, Abdul Rahman (Co-author) / Crane, Kari (Co-author) / Lai, Ying-Cheng (Thesis director) / Jiang, Junjie (Committee member) / Electrical Engineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2019-12
Description
Approximately 248 million people in the world are currently living with chronic Hepatitis B virus (HBV) infection. HBV and HCV infections are the primary cause of liver diseases such as cirrhosis and hepatocellular carcinomas in the world with an estimated 1.4 million deaths annually. HBV in the Republic of Peru was used as a case study of an emerging and rapidly spreading disease in a developing nation. Wherein, clinical diagnosis of HBV infections in at-risk communities such the Amazon Region and the Andes Mountains are challenging due to a myriad of reasons. High prices of clinical diagnosis and limited access to treatment are alone the most significant deterrent for individuals living in at-risk communities to get the much need help. Additionally, limited testing facilities, lack of adequate testing policies or national guidelines, poor laboratory capacity, resource-limited settings, geographical isolation, and public mistrust are among the chief reasons for low HBV testing. Although, preventative vaccination programs deployed by the Peruvian health officials have reduced the number of infected individuals by year and region. To significantly reduce or eradicate HBV in hyperendemic areas and countries such as Peru, preventative clinical diagnosis and vaccination programs are an absolute necessity. Consequently, the need for a portable low-priced diagnostic platform for the detection of HBV and other diseases is substantial and urgent not only in Peru but worldwide. Some of these concerns were addressed by designing a low-cost, rapid detection platform. In that, an immunosignature technology (IMST) slide used to test for reactivity against the presence of antibodies in the serum-sample was used to test for picture resolution and clarity. IMST slides were scanned using a smartphone camera placed on top of the designed device housing a circuit of 32 LED lights at 647 nm, an optical magnifier at 15X, and a linear polarizing film sheet. Tow 9V batteries powered the scanning device LED circuit ensuring enough lighting. The resulting pictures from the first prototype showed that by lighting the device at 647 nm and using a smartphone camera, the camera could capture high-resolution images. These results conclusively indicate that with any modern smartphone camera, a small box lighted to 647 nm, and optical magnifier; a powerful and expensive laboratory scanning machine can be replaced by another that is inexpensive, portable and ready to use anywhere.
ContributorsMakimaa, Heyde (Author) / Holechek, Susan (Thesis director) / Stafford, Phillip (Committee member) / Jayasuriya, Suren (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05