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Description
Random peptide microarrays are a powerful tool for both the treatment and diagnostics of infectious diseases. On the treatment side, selected random peptides on the microarray have either binding or lytic potency against certain pathogens cells, thus they can be synthesized into new antimicrobial agents, denoted as synbodies (synthetic antibodies). On the diagnostic side, serum containing specific infection-related antibodies create unique and distinct "pathogen-immunosignatures" on the random peptide microarray distinct from the healthy control serum, and this different mode of binding can be used as a more precise measurement than traditional ELISA tests. My thesis project is separated into these two parts: the first part falls into the treatment side and the second one focuses on the diagnostic side. My first chapter shows that a substitution amino acid peptide library helps to improve the activity of a recently reported synthetic antimicrobial peptide selected by the random peptide microarray. By substituting one or two amino acids of the original lead peptide, the new substitutes show changed hemolytic effects against mouse red blood cells and changed potency against two pathogens: Staphylococcus aureus and Pseudomonas aeruginosa. Two new substitutes are then combined together to form the synbody, which shows a significantly antimicrobial potency against Staphylococcus aureus (<0.5uM). In the second chapter, I explore the possibility of using the 10K Ver.2 random peptide microarray to monitor the humoral immune response of dengue. Over 2.5 billion people (40% of the world's population) live in dengue transmitting areas. However, currently there is no efficient dengue treatment or vaccine. Here, with limited dengue patient serum samples, we show that the immunosignature has the potential to not only distinguish the dengue infection from non-infected people, but also the primary dengue infection from the secondary dengue infections, dengue infection from West Nile Virus (WNV) infection, and even between different dengue serotypes. By further bioinformatic analysis, we demonstrate that the significant peptides selected to distinguish dengue infected and normal samples may indicate the epitopes responsible for the immune response.
ContributorsWang, Xiao (Author) / Johnston, Stephen Albert (Thesis advisor) / Blattman, Joseph (Committee member) / Arntzen, Charles (Committee member) / Arizona State University (Publisher)
Created2013
Description
Cancer is one of the most serious global diseases. We have focused on cancer immunoprevention. My thesis projects include developing a prophylactic primary and metastatic cancer vaccines, early cancer detection and investigation of genes involved in tumor development. These studies were focused on frame-shift (FS) antigens. The FS antigens are generated by genomic mutations or abnormal RNA processing, which cause a portion of a normal protein to be translated out of frame. The concept of the prophylactic cancer vaccine is to develop a general cancer vaccine that could prevent healthy people from developing different types of cancer. We have discovered a set of cancer specific FS antigens. One of the FS candidates, structural maintenance of chromosomes protein 1A (SMC1A) FS, could start to accumulate at early stages of tumor and be specifically exposed to the immune system by tumor cells. Prophylactic immunization with SMC1A-FS could significantly inhibit primary tumor development in different murine tumor models and also has the potential to inhibit tumor metastasis. The SMC1A-FS transcript was detected in the plasma of the 4T1/BALB/c mouse tumor model. The tumor size was correlated with the transcript ratio of the SMC1A-FS verses the WT in plasma, which could be measured by regular RT-PCR. This unique cancer biomarker has a practical potential for a large population cancer screen, as well as clinical tumor monitoring. With a set of mimotope peptides, antibodies against SMC1A-FS peptide were detected in different cancer patients, including breast cancer, pancreas cancer and lung cancer with a 53.8%, 56.5% and 12.5% positive rate respectively. This suggested that the FS antibody could be a biomarker for early cancer detection. The characterization of SMC1A suggested that: First, the deficiency of the SMC1A is common in different tumors and able to promote tumor initiation and development; second, the FS truncated protein may have nucleolus function in normal cells. Mis-control of this protein may promote tumor development. In summary, we developed a systematic general cancer prevention strategy through the variety immunological and molecular methods. The results gathered suggest the SMC1A-FS may be useful for the detection and prevention of cancer.
ContributorsShen, Luhui (Author) / Johnston, Stephen Albert (Thesis advisor) / Chang, Yung (Committee member) / Miller, Laurence (Committee member) / Sykes, Kathryn (Committee member) / Jacobs, Bertram (Committee member) / Arizona State University (Publisher)
Created2012
Description
The majority of non-small cell lung cancer (NSCLC) patients (70%) are diagnosed with adenocarcinoma versus other histological subtypes. These patients often present with advanced, metastatic disease and frequently relapse after treatment. The tumor suppressor, Liver Kinase B1, is frequently inactivated in adenocarcinomas and loss of function is associated with a highly aggressive, metastatic tumor (1). Identification of the mechanisms deregulated with LKB1 inactivation could yield targeted therapeutic options for adenocarcinoma patients. Re-purposing the immune system to support tumor growth and aid in metastasis has been shown to be a feature in cancer progression (2). Tumor associated macrophages (TAMs) differentiate from monocytes, which are recruited to the tumor microenvironment via secretion of chemotaxic factors by cancer cells. We find that NSCLC cells deficient in LKB1 display increased secretion of C-C motif ligand 2 (CCL2), a chemokine involved in monocyte recruitment. To elucidate the molecular pathway regulating CCL2 up-regulation, we investigated inhibitors of substrates downstream of LKB1 signaling in A549, H23, H2030 and H838 cell lines. Noticeably, BAY-11-7082 (NF-κB inhibitor) reduced CCL2 secretion by an average 92%. We further demonstrate that a CCR2 antagonist and neutralizing CCL2 antibody substantially reduce monocyte migration to NSCLC (H23) cell line conditioned media. Using an in vivo model of NSCLC, we find that LKB1 deleted tumors demonstrate a discernible increase in CCL2 levels compared to normal lung. Moreover, tumors display an increase in the M2:M1 macrophage ratio and increase in tumor associated neutrophil (TAN) infiltrate compared to normal lung. This M2 shift was significantly reduced in mice treated with anti-CCL2 or a CCR2 antagonist and the TAN infiltrate was significantly reduced with the CCR2 antagonist. These data suggest that deregulation of the CCL2/CCR2 signaling axis could play a role in cancer progression in LKB1 deficient tumors.
ContributorsFriel, Jacqueline (Author) / Inge, Landon (Thesis advisor) / Lake, Douglas (Thesis advisor) / Blattman, Joseph (Committee member) / Arizona State University (Publisher)
Created2015
Description
Immunosignaturing is a technology that allows the humoral immune response to be observed through the binding of antibodies to random sequence peptides. The immunosignaturing microarray is based on complex mixtures of antibodies binding to arrays of random sequence peptides in a multiplexed fashion. There are computational and statistical challenges to the analysis of immunosignaturing data. The overall aim of my dissertation is to develop novel computational and statistical methods for immunosignaturing data to access its potential for diagnostics and drug discovery. Firstly, I discovered that a classification algorithm Naive Bayes which leverages the biological independence of the probes on our array in such a way as to gather more information outperforms other classification algorithms due to speed and accuracy. Secondly, using this classifier, I then tested the specificity and sensitivity of immunosignaturing platform for its ability to resolve four different diseases (pancreatic cancer, pancreatitis, type 2 diabetes and panIN) that target the same organ (pancreas). These diseases were separated with >90% specificity from controls and from each other. Thirdly, I observed that the immunosignature of type 2 diabetes and cardiovascular complications are unique, consistent, and reproducible and can be separated by 100% accuracy from controls. But when these two complications arise in the same person, the resultant immunosignature is quite different in that of individuals with only one disease. I developed a method to trace back from informative random peptides in disease signatures to the potential antigen(s). Hence, I built a decipher system to trace random peptides in type 1 diabetes immunosignature to known antigens. Immunosignaturing, unlike the ELISA, has the ability to not only detect the presence of response but also absence of response during a disease. I observed, not only higher but also lower peptides intensities can be mapped to antigens in type 1 diabetes. To study immunosignaturing potential for population diagnostics, I studied effect of age, gender and geographical location on immunosignaturing data. For its potential to be a health monitoring technology, I proposed a single metric Coefficient of Variation that has shown potential to change significantly when a person enters a disease state.
ContributorsKukreja, Muskan (Author) / Johnston, Stephen Albert (Thesis advisor) / Stafford, Phillip (Committee member) / Dinu, Valentin (Committee member) / Arizona State University (Publisher)
Created2012
Description
Immunotherapy has been revitalized with the advent of immune checkpoint blockade
treatments, and neo-antigens are the targets of immune system in cancer patients who
respond to the treatments. The cancer vaccine field is focused on using neo-antigens from
unique point mutations of genomic sequence in the cancer patient for making
personalized cancer vaccines. However, we choose a different path to find frameshift
neo-antigens at the mRNA level and develop broadly effective cancer vaccines based on
frameshift antigens.
In this dissertation, I have summarized and characterized all the potential frameshift
antigens from microsatellite regions in human, dog and mouse. A list of frameshift
antigens was validated by PCR in tumor samples and the mutation rate was calculated for
one candidate – SEC62. I develop a method to screen the antibody response against
frameshift antigens in human and dog cancer patients by using frameshift peptide arrays.
Frameshift antigens selected by positive antibody response in cancer patients or by MHC
predictions show protection in different mouse tumor models. A dog version of the
cancer vaccine based on frameshift antigens was developed and tested in a small safety
trial. The results demonstrate that the vaccine is safe and it can induce strong B and T cell
immune responses. Further, I built the human exon junction frameshift database which
includes all possible frameshift antigens from mis-splicing events in exon junctions, and I
develop a method to find potential frameshift antigens from large cancer
immunosignature dataset with these databases. In addition, I test the idea of ‘early cancer
diagnosis, early treatment’ in a transgenic mouse cancer model. The results show that
ii
early treatment gives significantly better protection than late treatment and the correct
time point for treatment is crucial to give the best clinical benefit. A model for early
treatment is developed with these results.
Frameshift neo-antigens from microsatellite regions and mis-splicing events are
abundant at mRNA level and they are better antigens than neo-antigens from point
mutations in the genomic sequences of cancer patients in terms of high immunogenicity,
low probability to cause autoimmune diseases and low cost to develop a broadly effective
vaccine. This dissertation demonstrates the feasibility of using frameshift antigens for
cancer vaccine development.
treatments, and neo-antigens are the targets of immune system in cancer patients who
respond to the treatments. The cancer vaccine field is focused on using neo-antigens from
unique point mutations of genomic sequence in the cancer patient for making
personalized cancer vaccines. However, we choose a different path to find frameshift
neo-antigens at the mRNA level and develop broadly effective cancer vaccines based on
frameshift antigens.
In this dissertation, I have summarized and characterized all the potential frameshift
antigens from microsatellite regions in human, dog and mouse. A list of frameshift
antigens was validated by PCR in tumor samples and the mutation rate was calculated for
one candidate – SEC62. I develop a method to screen the antibody response against
frameshift antigens in human and dog cancer patients by using frameshift peptide arrays.
Frameshift antigens selected by positive antibody response in cancer patients or by MHC
predictions show protection in different mouse tumor models. A dog version of the
cancer vaccine based on frameshift antigens was developed and tested in a small safety
trial. The results demonstrate that the vaccine is safe and it can induce strong B and T cell
immune responses. Further, I built the human exon junction frameshift database which
includes all possible frameshift antigens from mis-splicing events in exon junctions, and I
develop a method to find potential frameshift antigens from large cancer
immunosignature dataset with these databases. In addition, I test the idea of ‘early cancer
diagnosis, early treatment’ in a transgenic mouse cancer model. The results show that
ii
early treatment gives significantly better protection than late treatment and the correct
time point for treatment is crucial to give the best clinical benefit. A model for early
treatment is developed with these results.
Frameshift neo-antigens from microsatellite regions and mis-splicing events are
abundant at mRNA level and they are better antigens than neo-antigens from point
mutations in the genomic sequences of cancer patients in terms of high immunogenicity,
low probability to cause autoimmune diseases and low cost to develop a broadly effective
vaccine. This dissertation demonstrates the feasibility of using frameshift antigens for
cancer vaccine development.
ContributorsZhang, Jian (Author) / Johnston, Stephen Albert (Thesis advisor) / Chang, Yung (Committee member) / Stafford, Phillip (Committee member) / Chen, Qiang (Committee member) / Arizona State University (Publisher)
Created2018
Description
Environmental changes are occurring at an unprecedented rate, and these changes will undoubtedly lead to alterations in resource availability for many organisms. To effectively predict the implications of such changes, it is critical to better understand how organisms have adapted to coping with seasonally limited resources. The vast majority of previous work has focused on energy balance as the driver of changes in organismal physiology. While energy is clearly a vital currency, other resources can also be limited and impact physiological functions. Water is essential for life as it is the main constituent of cells, tissues, and organs. Yet, water has received little consideration for its role as a currency that impacts physiological functions. Given the importance of water to most major physiological systems, I investigated how water limitations interact with immune function, metabolism, and reproductive investment, an almost entirely unexplored area. Using multiple species and life stages, I demonstrated that dehydrated animals typically have enhanced innate immunity, regardless of whether the dehydration is a result of seasonal water constraints, water deprivation in the lab, or high physiological demand for water. My work contributed greatly to the understanding of immune function dynamics and lays a foundation for the study of hydration immunology as a component of the burgeoning field of ecoimmunology. While a large portion of my dissertation focused on the interaction between water balance and immune function, there are many other physiological processes that may be impacted by water restrictions. Accordingly, I recently expanded the understanding of how reproductive females can alter metabolic substrates to reallocate internal water during times of water scarcity, an important development in our knowledge of reproductive investments. Overall, by thoroughly evaluating implications and responses to water limitations, my dissertation, when combined previous acquired knowledge on food limitation, will enable scientists to better predict the impacts of future climate change, where, in many regions, rainfall events are forecasted to be less reliable, resulting in more frequent drought.
ContributorsBrusch, George, IV (Author) / DeNardo, Dale F (Thesis advisor) / Blattman, Joseph (Committee member) / French, Susannah (Committee member) / Sabo, John (Committee member) / Taylor, Emily (Committee member) / Arizona State University (Publisher)
Created2019
Description
For as long as humans have been working, they have been looking for ways to get that work done better, faster, and more efficient. Over the course of human history, mankind has created innumerable spectacular inventions, all with the goal of making the economy and daily life more efficient. Today, innovations and technological advancements are happening at a pace like never seen before, and technology like automation and artificial intelligence are poised to once again fundamentally alter the way people live and work in society. Whether society is prepared or not, robots are coming to replace human labor, and they are coming fast. In many areas artificial intelligence has disrupted entire industries of the economy. As people continue to make advancements in artificial intelligence, more industries will be disturbed, more jobs will be lost, and entirely new industries and professions will be created in their wake. The future of the economy and society will be determined by how humans adapt to the rapid innovations that are taking place every single day. In this paper I will examine the extent to which automation will take the place of human labor in the future, project the potential effect of automation to future unemployment, and what individuals and society will need to do to adapt to keep pace with rapidly advancing technology. I will also look at the history of automation in the economy. For centuries humans have been advancing technology to make their everyday work more productive and efficient, and for centuries this has forced humans to adapt to the modern technology through things like training and education. The thesis will additionally examine the ways in which the U.S. education system will have to adapt to meet the demands of the advancing economy, and how job retraining programs must be modernized to prepare workers for the changing economy.
ContributorsCunningham, Reed P. (Author) / DeSerpa, Allan (Thesis director) / Haglin, Brett (Committee member) / School of International Letters and Cultures (Contributor) / Department of Finance (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
This paper considers what factors influence student interest, motivation, and continued engagement. Studies show anticipated extrinsic rewards for activity participation have been shown to reduce intrinsic value for that activity. This might suggest that grade point average (GPA) has a similar effect on academic interests. Further, when incentives such as scholarships, internships, and careers are GPA-oriented, students must adopt performance goals in courses to guarantee success. However, performance goals have not been shown to correlated with continued interest in a topic. Current literature proposes that student involvement in extracurricular activities, focused study groups, and mentored research are crucial to student success. Further, students may express either a fixed or growth mindset, which influences their approach to challenges and opportunities for growth. The purpose of this study was to collect individual cases of students' experiences in college. The interview method was chosen to collect complex information that could not be gathered from standard surveys. To accomplish this, questions were developed based on content areas related to education and motivation theory. The content areas included activities and meaning, motivation, vision, and personal development. The developed interview method relied on broad questions that would be followed by specific "probing" questions. We hypothesize that this would result in participant-led discussions and unique narratives from the participant. Initial findings suggest that some of the questions were effective in eliciting detailed responses, though results were dependent on the interviewer. From the interviews we find that students value their group involvements, leadership opportunities, and relationships with mentors, which parallels results found in other studies.
ContributorsAbrams, Sara (Author) / Hartwell, Lee (Thesis director) / Correa, Kevin (Committee member) / Department of Psychology (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Nuclear weapons possess enormous potential to inflict damage on our world. The majority of countries in the world denounce the proliferation of these weapons, but a minority of countries have a desire to proliferate. This essay analyzes the impact of regime type and alliance strength to a nuclear state on protégé proliferation decisions. Prior research focuses on single factors in proliferation decisions and fails to take in to account the multi-faceted factors that influence the international system that states operate in. The analysis finds that regime type gives an indication about a state’s likelihood to proliferate, but does not explain proliferation choices comprehensively. Alliance strength plays a large role in a state’s security calculations and must be analyzed in conjunction to regime type to understand proliferation decisions.
ContributorsHsu, Kai Nalu (Author) / Wright, Thorin (Thesis director) / Thies, Cameron (Committee member) / W.P. Carey School of Business (Contributor) / Department of Finance (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
#VanLife is a long-time, up and coming lifestyle movement on social media centered around the process of leaving the traditional nine-to-five work week for a life on the road in a camper van. While the ‘hippie-esque’ vagabond lifestyle has its humble roots long before the turn of the century, the inception of social media platforms such as Instagram and Pinterest have fueled the more recent popularization of a full-time life on the road. #VanLifers often freelance on the road, work part time jobs, or gain sponsorships to help fund their traveling and humble lifestyle.
As the #VanLife craze continues to grow, new businesses are finding ways to meet the demand in the market. For #Vanlifers who own and operate their own camper vans, specialized companies like GoWesty, Vanagain, and Boxeer offer a full range of parts, upgrades, and custom mechanical and systems conversion kits to keep these vans on the road as OE manufacturers discontinue production on these parts. For those who have an itch to try out the #VanLife for a shorter period and without the financial commitment, companies like Roamerica, TontoTrails, and adventureRIGS offer nightly and weekly rental opportunities on fully-outfitted campervans ready to hit the road.
For my Honors Project I wrote a complete analysis on the history, development, and modernization of the #VanLife movement. With plans to take to the road for an extended period of time after graduation, I also developed a complete financial plan for a one-year #VanLife experience. The financial plan includes a comprehensive set of budgets that scrutinize the start-up an operational costs of the #VanLife and associated travel.
As the #VanLife craze continues to grow, new businesses are finding ways to meet the demand in the market. For #Vanlifers who own and operate their own camper vans, specialized companies like GoWesty, Vanagain, and Boxeer offer a full range of parts, upgrades, and custom mechanical and systems conversion kits to keep these vans on the road as OE manufacturers discontinue production on these parts. For those who have an itch to try out the #VanLife for a shorter period and without the financial commitment, companies like Roamerica, TontoTrails, and adventureRIGS offer nightly and weekly rental opportunities on fully-outfitted campervans ready to hit the road.
For my Honors Project I wrote a complete analysis on the history, development, and modernization of the #VanLife movement. With plans to take to the road for an extended period of time after graduation, I also developed a complete financial plan for a one-year #VanLife experience. The financial plan includes a comprehensive set of budgets that scrutinize the start-up an operational costs of the #VanLife and associated travel.
ContributorsRischitelli, Noah Gary (Author) / Garverick, Michael (Thesis director) / Dawson, Gregory (Committee member) / WPC Graduate Programs (Contributor) / School of Accountancy (Contributor) / Department of Finance (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05