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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
The influenza virus, also known as "the flu", is an infectious disease that has constantly affected the health of humanity. There is currently no known cure for Influenza. The Center for Innovations in Medicine at the Biodesign Institute located on campus at Arizona State University has been developing synbodies as a possible Influenza therapeutic. Specifically, at CIM, we have attempted to design these initial synbodies to target the entire Influenza virus and preliminary data leads us to believe that these synbodies target Nucleoprotein (NP). Given that the synbody targets NP, the penetration of cells via synbody should also occur. Then by Western Blot analysis we evaluated for the diminution of NP level in treated cells versus untreated cells. The focus of my honors thesis is to explore how synthetic antibodies can potentially inhibit replication of the Influenza (H1N1) A/Puerto Rico/8/34 strain so that a therapeutic can be developed. A high affinity synbody for Influenza can be utilized to test for inhibition of Influenza as shown by preliminary data. The 5-5-3819 synthetic antibody's internalization in live cells was visualized with Madin-Darby Kidney Cells under a Confocal Microscope. Then by Western Blot analysis we evaluated for the diminution of NP level in treated cells versus untreated cells. Expression of NP over 8 hours time was analyzed via Western Blot Analysis, which showed NP accumulation was retarded in synbody treated cells. The data obtained from my honors thesis and preliminary data provided suggest that the synthetic antibody penetrates live cells and targets NP. The results of my thesis presents valuable information that can be utilized by other researchers so that future experiments can be performed, eventually leading to the creation of a more effective therapeutic for influenza.
ContributorsHayden, Joel James (Author) / Diehnelt, Chris (Thesis director) / Johnston, Stephen (Committee member) / Legutki, Bart (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor) / Department of Chemistry and Biochemistry (Contributor)
Created2014-05
Description
Background: National and international strategies to increase physical activity emphasize environmental and policy changes that can have widespread and long-lasting impact. Evidence from multiple countries using comparable methods is required to strengthen the evidence base for such initiatives. Because some environment and policy changes could have generalizable effects and others may depend on each country's context, only international studies using comparable methods can identify the relevant differences. Methods: Currently 12 countries are participating in the International Physical Activity and the Environment Network (IPEN) study. The IPEN Adult study design involves recruiting adult participants from neighborhoods with wide variations in environmental walkability attributes and socioeconomic status (SES). Results: Eleven of twelve countries are providing accelerometer data and 11 are providing GIS data. Current projections indicate that 14,119 participants will provide survey data on built environments and physical activity and 7145 are likely to provide objective data on both the independent and dependent variables. Though studies are highly comparable, some adaptations are required based on the local context. Conclusions: This study was designed to inform evidence-based international and country-specific physical activity policies and interventions to help prevent obesity and other chronic diseases that are high in developed countries and growing rapidly in developing countries.
ContributorsKerr, Jacqueline (Author) / Sallis, James F. (Author) / Owen, Neville (Author) / De Bourdeaudhuij, Ilse (Author) / Cerin, Ester (Author) / Sugiyama, Takemi (Author) / Reis, Rodrigo (Author) / Sarmiento, Olga (Author) / Froemel, Karel (Author) / Mitas, Josef (Author) / Troelsen, Jens (Author) / Christiansen, Lars Breum (Author) / Macfarlane, Duncan (Author) / Salvo, Deborah (Author) / Schofield, Grant (Author) / Badland, Hannah (Author) / Guillen-Grima, Francisco (Author) / Aguinaga-Ontoso, Ines (Author) / Davey, Rachel (Author) / Bauman, Adrian (Author) / Saelens, Brian (Author) / Riddoch, Chris (Author) / Ainsworth, Barbara (Author) / Pratt, Michael (Author) / Schmidt, Tom (Author) / Frank, Lawrence (Author) / Adams, Marc (Author) / Conway, Terry (Author) / Cain, Kelli (Author) / Van Dyck, Delfien (Author) / Bracy, Nicole (Author) / College of Health Solutions (Contributor) / School of Nutrition and Health Promotion (Contributor)
Created2013
Description
In this study, we demonstrate the effectiveness of a cancer type specific FrAmeShifT (FAST) vaccine. A murine breast cancer (mBC) FAST vaccine and a murine pancreatic cancer (mPC) FAST vaccine were tested in the 4T1 breast cancer syngeneic mouse model. The mBC FAST vaccine, both with and without check point inhibitors (CPI), significantly slowed tumor growth, reduced pulmonary metastasis and increased the cell-mediated immune response. In terms of tumor volumes, the mPC FAST vaccine was comparable to the untreated controls. However, a significant difference in tumor volume did emerge when the mPC vaccine was used with CPI. The collective data indicated that the immune checkpoint blockade therapy was only beneficial with suboptimal neoantigens. More importantly, the FAST vaccine, though requiring notably less resources, performed similarly to the personalized version of the frameshift breast cancer vaccine in the same mouse model. Furthermore, because the frameshift peptide (FSP) array provided a strong rationale for a focused vaccine, the FAST vaccine can theoretically be expanded and translated to any human cancer type. Overall, the FAST vaccine is a promising treatment that would provide the most benefit to patients while eliminating most of the challenges associated with current personal cancer vaccines.
ContributorsMurphy, Sierra Nicole (Author) / Johnston, Stephen (Thesis director) / Peterson, Milene (Committee member) / School of Mathematical and Statistical Sciences (Contributor) / School of Molecular Sciences (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Background
Increasing empirical evidence supports associations between neighborhood environments and physical activity. However, since most studies were conducted in a single country, particularly western countries, the generalizability of associations in an international setting is not well understood. The current study examined whether associations between perceived attributes of neighborhood environments and physical activity differed by country.
Methods
Population representative samples from 11 countries on five continents were surveyed using comparable methodologies and measurement instruments. Neighborhood environment × country interactions were tested in logistic regression models with meeting physical activity recommendations as the outcome, adjusted for demographic characteristics. Country-specific associations were reported.
Results
Significant neighborhood environment attribute × country interactions implied some differences across countries in the association of each neighborhood attribute with meeting physical activity recommendations. Across the 11 countries, land-use mix and sidewalks had the most consistent associations with physical activity. Access to public transit, bicycle facilities, and low-cost recreation facilities had some associations with physical activity, but with less consistency across countries. There was little evidence supporting the associations of residential density and crime-related safety with physical activity in most countries.
Conclusion
There is evidence of generalizability for the associations of land use mix, and presence of sidewalks with physical activity. Associations of other neighborhood characteristics with physical activity tended to differ by country. Future studies should include objective measures of neighborhood environments, compare psychometric properties of reports across countries, and use better specified models to further understand the similarities and differences in associations across countries.
Increasing empirical evidence supports associations between neighborhood environments and physical activity. However, since most studies were conducted in a single country, particularly western countries, the generalizability of associations in an international setting is not well understood. The current study examined whether associations between perceived attributes of neighborhood environments and physical activity differed by country.
Methods
Population representative samples from 11 countries on five continents were surveyed using comparable methodologies and measurement instruments. Neighborhood environment × country interactions were tested in logistic regression models with meeting physical activity recommendations as the outcome, adjusted for demographic characteristics. Country-specific associations were reported.
Results
Significant neighborhood environment attribute × country interactions implied some differences across countries in the association of each neighborhood attribute with meeting physical activity recommendations. Across the 11 countries, land-use mix and sidewalks had the most consistent associations with physical activity. Access to public transit, bicycle facilities, and low-cost recreation facilities had some associations with physical activity, but with less consistency across countries. There was little evidence supporting the associations of residential density and crime-related safety with physical activity in most countries.
Conclusion
There is evidence of generalizability for the associations of land use mix, and presence of sidewalks with physical activity. Associations of other neighborhood characteristics with physical activity tended to differ by country. Future studies should include objective measures of neighborhood environments, compare psychometric properties of reports across countries, and use better specified models to further understand the similarities and differences in associations across countries.
ContributorsDing, Ding (Author) / Adams, Marc (Author) / Sallis, James F. (Author) / Norman, Gregory J. (Author) / Hovell, Melbourn F. (Author) / Chambers, Christina D. (Author) / Hofstetter, C. Richard (Author) / Bowles, Heather R. (Author) / Hagstromer, Maria (Author) / Craig, Cora L. (Author) / Fernando Gomez, Luis (Author) / De Bourdeaudhuij, Ilse (Author) / Macfarlane, Duncan J. (Author) / Ainsworth, Barbara (Author) / Bergman, Patrick (Author) / Bull, Fiona C. (Author) / Carr, Harriette (Author) / Klasson-Heggebo, Lena (Author) / Inoue, Shigeru (Author) / Murase, Norio (Author) / Matsudo, Sandra (Author) / Matsudo, Victor (Author) / McLean, Grant (Author) / Sjostrom, Michael (Author) / Tomten, Heidi (Author) / Lefevre, Johan (Author) / Volbekiene, Vida (Author) / Bauman, Adrian E. (Author) / College of Health Solutions (Contributor) / School of Nutrition and Health Promotion (Contributor)
Created2013-05-14
Description
Background
Neighborhood environment studies of physical activity (PA) have been mainly single-country focused. The International Prevalence Study (IPS) presented a rare opportunity to examine neighborhood features across countries. The purpose of this analysis was to: 1) detect international neighborhood typologies based on participants’ response patterns to an environment survey and 2) to estimate associations between neighborhood environment patterns and PA.
Methods
A Latent Class Analysis (LCA) was conducted on pooled IPS adults (N=11,541) aged 18 to 64 years old (mean=37.5 ±12.8 yrs; 55.6% women) from 11 countries including Belgium, Brazil, Canada, Colombia, Hong Kong, Japan, Lithuania, New Zealand, Norway, Sweden, and the U.S. This subset used the Physical Activity Neighborhood Environment Survey (PANES) that briefly assessed 7 attributes within 10–15 minutes walk of participants’ residences, including residential density, access to shops/services, recreational facilities, public transit facilities, presence of sidewalks and bike paths, and personal safety. LCA derived meaningful subgroups from participants’ response patterns to PANES items, and participants were assigned to neighborhood types. The validated short-form International Physical Activity Questionnaire (IPAQ) measured likelihood of meeting the 150 minutes/week PA guideline. To validate derived classes, meeting the guideline either by walking or total PA was regressed on neighborhood types using a weighted generalized linear regression model, adjusting for gender, age and country.
Results
A 5-subgroup solution fitted the dataset and was interpretable. Neighborhood types were labeled, “Overall Activity Supportive (52% of sample)”, “High Walkable and Unsafe with Few Recreation Facilities (16%)”, “Safe with Active Transport Facilities (12%)”, “Transit and Shops Dense with Few Amenities (15%)”, and “Safe but Activity Unsupportive (5%)”. Country representation differed by type (e.g., U.S. disproportionally represented “Safe but Activity Unsupportive”). Compared to the Safe but Activity Unsupportive, two types showed greater odds of meeting PA guideline for walking outcome (High Walkable and Unsafe with Few Recreation Facilities, OR= 2.26 (95% CI 1.18-4.31); Overall Activity Supportive, OR= 1.90 (95% CI 1.13-3.21). Significant but smaller odds ratios were also found for total PA.
Conclusions
Meaningful neighborhood patterns generalized across countries and explained practical differences in PA. These observational results support WHO/UN recommendations for programs and policies targeted to improve features of the neighborhood environment for PA.
Neighborhood environment studies of physical activity (PA) have been mainly single-country focused. The International Prevalence Study (IPS) presented a rare opportunity to examine neighborhood features across countries. The purpose of this analysis was to: 1) detect international neighborhood typologies based on participants’ response patterns to an environment survey and 2) to estimate associations between neighborhood environment patterns and PA.
Methods
A Latent Class Analysis (LCA) was conducted on pooled IPS adults (N=11,541) aged 18 to 64 years old (mean=37.5 ±12.8 yrs; 55.6% women) from 11 countries including Belgium, Brazil, Canada, Colombia, Hong Kong, Japan, Lithuania, New Zealand, Norway, Sweden, and the U.S. This subset used the Physical Activity Neighborhood Environment Survey (PANES) that briefly assessed 7 attributes within 10–15 minutes walk of participants’ residences, including residential density, access to shops/services, recreational facilities, public transit facilities, presence of sidewalks and bike paths, and personal safety. LCA derived meaningful subgroups from participants’ response patterns to PANES items, and participants were assigned to neighborhood types. The validated short-form International Physical Activity Questionnaire (IPAQ) measured likelihood of meeting the 150 minutes/week PA guideline. To validate derived classes, meeting the guideline either by walking or total PA was regressed on neighborhood types using a weighted generalized linear regression model, adjusting for gender, age and country.
Results
A 5-subgroup solution fitted the dataset and was interpretable. Neighborhood types were labeled, “Overall Activity Supportive (52% of sample)”, “High Walkable and Unsafe with Few Recreation Facilities (16%)”, “Safe with Active Transport Facilities (12%)”, “Transit and Shops Dense with Few Amenities (15%)”, and “Safe but Activity Unsupportive (5%)”. Country representation differed by type (e.g., U.S. disproportionally represented “Safe but Activity Unsupportive”). Compared to the Safe but Activity Unsupportive, two types showed greater odds of meeting PA guideline for walking outcome (High Walkable and Unsafe with Few Recreation Facilities, OR= 2.26 (95% CI 1.18-4.31); Overall Activity Supportive, OR= 1.90 (95% CI 1.13-3.21). Significant but smaller odds ratios were also found for total PA.
Conclusions
Meaningful neighborhood patterns generalized across countries and explained practical differences in PA. These observational results support WHO/UN recommendations for programs and policies targeted to improve features of the neighborhood environment for PA.
ContributorsAdams, Marc (Author) / Ding, Ding (Author) / Sallis, James F. (Author) / Bowles, Heather R. (Author) / Ainsworth, Barbara (Author) / Bergman, Patrick (Author) / Bull, Fiona C. (Author) / Carr, Harriette (Author) / Craig, Cora L. (Author) / De Bourdeaudhuij, Ilse (Author) / Fernando Gomez, Luis (Author) / Hagstromer, Maria (Author) / Klasson-Heggebo, Lena (Author) / Inoue, Shigeru (Author) / Lefevre, Johan (Author) / Macfarlane, Duncan J. (Author) / Matsudo, Sandra (Author) / Matsudo, Victor (Author) / McLean, Grant (Author) / Murase, Norio (Author) / Sjostrom, Michael (Author) / Tomten, Heidi (Author) / Volbekiene, Vida (Author) / Bauman, Adrian (Author) / College of Health Solutions (Contributor) / School of Nutrition and Health Promotion (Contributor)
Created2013-03-07
Description
The objective of this thesis was to determine whether Zika Virus (ZIKV) can be effectively inactivated by Selective Photonic Disinfection (SEPHODIS) and determine whether key proteins involved in the infection process are preserved, making SEPHODIS a possible source for vaccine development. As of January 2018, there have been 3,720 confirmed cases of Congenital Zika Syndrome in infants, making a Zika Vaccine a high priority (Mitchell, 2018). SEPHODIS is a process that involves prolonged exposure of an object to a pulsing laser which can render it ineffective. Initially, ZIKV was subjected to laser inactivation for 6 hours, then a plaque assay was performed on both laser-treated and control samples. ZIKV was inactivated two-fold? after laser treatment, when compared with control, as indicated by the plaque assay results. Additionally, both samples were submitted to ELISA to evaluate antigenicity with a panel of monoclonal and human sera. As a second control, virus inactivated by formaldehyde (2%) was used. ELISA results showed that antigenicity of some proteins were preserved while others were probably disturbed. However, ELISA results show that ZIKV envelope protein (E-protein), the protein responsible for viral entry into cells, was effectively preserved after laser-treatment, implying that if laser parameters were tweaked to obtain more complete inactivation, then SEPHODIS may be an appropriate source for the development of a vaccine.
ContributorsViafora, Ataiyo Blue (Author) / Johnston, Stephen (Thesis director) / Tsen, Kong-Thon (Committee member) / School of Life Sciences (Contributor) / School of Sustainability (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
PD-L1 blockade has shown recent success in cancer therapy and cancer vaccine regimens. One approach for anti-PD-L1 antibodies has been their application as adjuvants for cancer vaccines. Given the disadvantages of such antibodies, including long half-life and adverse events related to their use, a novel strategy using synbodies in place of antibodies can be tested. Synbodies offer a variety of advantages, including shorter half-life, smaller size, and cheaper cost. Peptides that could bind PD-L1 were identified via peptide arrays and used to construct synbodies. These synbodies were tested with inhibition ELISA assays, SPR, and pull down assays. Additional flow cytometry analysis was done to determine the binding specificity of the synbodies to PD-L1 and the ability of those synbodies to inhibit the PD-L1/PD-1 interaction. Although analysis of permeabilized cells expressing PD-L1 indicated that the synbodies could successfully bind PD-L1, those results were not replicated in non-permeabilized cells. Further assays suggested that the binding of the synbodies was non-specific. Other tests were done to see if the synbodies could inhibit the PD-1/PD-L1 interaction. This assay did not yield any conclusive results and further experimentation is needed to determine the efficacy of the synbodies in inhibiting this interaction.
ContributorsMujahed, Tala (Author) / Johnston, Stephen (Thesis director) / Blattman, Joseph (Committee member) / Diehnelt, Chris (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
The devastating 2014 Ebola virus outbreak in Western Africa demonstrated the lack of therapeutic approaches available for the virus. Although monoclonal antibodies (mAb) and other molecules have been developed that bind the virus, no therapeutic has shown the efficacy needed for FDA approval. Here, a library of 50 peptide based ligands that bind the glycoprotein of the Zaire Ebola virus (GP) were developed. Using whole virus screening of vesicular stomatitis virus pseudotyped with GP, low affinity peptides were identified for ligand construction. In depth analysis showed that two of the peptide based molecules bound the Zaire GP with <100 nM KD. One of these two ligands was blocked by a known neutralizing mAb, 2G4, and showed cross-reactivity to the Sudan GP. This work presents ligands with promise for therapeutic applications across multiple variants of the Ebola virus.
ContributorsRabinowitz, Joshua Avraam (Author) / Diehnelt, Chris (Thesis director) / Johnston, Stephen (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Both technological and scientific fields continue to revolutionize in a similar fashion; however, a major difference is that high-tech corporations have found models to continue progressions while still keeping product costs low. The main objective was to identify which, if any, components of certain technological models could be used with the vaccine and pharmaceutical markets to significantly lower their costs. Smartphones and computers were the two main items investigated while the two main items from the scientific standpoint were vaccines and pharmaceuticals. One concept had the ability to conceivably decrease the costs of vaccines and drugs and that was "market competition". If the United States were able to allow competition within the vaccine and drug companies, it would allow for the product prices to be best affected. It would only take a few small companies to generate generic versions of the drugs and decrease the prices. It would force the larger competition to most likely decrease their prices. Furthermore, the PC companies use a cumulative density function (CDF) to effectively divide their price setting in each product cycle. It was predicted that if this CDF model were applied to the vaccine and drug markets, the prices would no longer have to be extreme. The corporations would be able to set the highest price for the wealthiest consumers and then slowly begin to decrease the costs for the middle and lower class. Unfortunately, the problem within the vaccine and pharmaceutical markets was not the lack of innovation or business models. The problem lied with their liberty to choose product costs due to poor U.S. government regulations.
ContributorsCalderon, Gerardo (Author) / Johnston, Stephen (Thesis director) / Diehnelt, Chris (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12