Matching Items (72)
Description
Bats (order Chiroptera) are the longest lived mammals for their size, with particularly extreme longevity evolving in the family Vespertilionidae, or vesper bats. Because of this, researchers have proposed using bats to study ageing and cancer suppression. Here, we study gene duplications across mammalian genomes and show that, similar to previous findings in elephants, bats have experienced duplications of the tumor suppressor gene TP53, including five genomic copies in the genome of the little brown bat (Myotis lucifugus) and two copies in Brandt's bat (Myotis brandtii). These species can live 37 and 41 years, respectively, despite having an adult body mass of only ~7 grams. We use evolutionary genetics and next generation sequencing approaches to show that positive selection has acted on the TP53 locus across bats, and two recently duplicated TP53 gene copies in the little brown bat are both highly conserved and expressed, suggesting they are functional. We also report an extraordinary genomic copy number expansion of the tumor suppressor gene FBXO31 in the common ancestor of vesper bats which accelerated in the Myotis lineage, leading to 34\u201457 copies and the expression of 20 functional FBXO31 homologs in Brandt's bat. As FBXO31 directs the degradation of MDM2, which is a negative regulator of TP53, we suggest that increased expression of both FBXO31 and TP53 may be related to an enhanced DNA-damage response to genotoxic stress brought on by long lifespans and rapid metabolic rates in bats.
ContributorsSchneider-Utaka, Aika Kunigunda (Author) / Maley, Carlo (Thesis director) / Wilson Sayres, Melissa (Committee member) / Tollis, Marc (Committee member) / School of Life Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2018-12
Description
Due to artificial selection, dogs have high levels of phenotypic diversity, yet, there appears to be low genetic diversity within individual breeds. Through their domestication from wolves, dogs have gone through a series of population bottlenecks, which has resulted in a reduction in genetic diversity, with a large amount of linkage disequilibrium and the persistence of deleterious mutations. This has led to an increased susceptibility to a multitude of diseases, including cancer. To study the effects of artificial selection and life history characteristics on the risk of cancer mortality, we collected cancer mortality data from four studies as well as the percent of heterozygosity, body size, lifespan and breed group for 201 dog breeds. We also collected specific types of cancer breeds were susceptible to and compared the dog cancer mortality patterns to the patterns observed in other mammals. We found a relationship between cancer mortality rate and heterozygosity, body size, lifespan as well as breed group. Higher levels of heterozygosity were also associated with longer lifespan. These results indicate larger breeds, such as Irish Water Spaniels, Flat-coated Retrievers and Bernese Mountain Dogs, are more susceptible to cancer, with lower heterozygosity and lifespan. These breeds are also more susceptible to sarcomas, as opposed to carcinomas in smaller breeds, such as Miniature Pinschers, Chihuahuas, and Pekingese. Other mammals show that larger and long-lived animals have decreased cancer mortality, however, within dog breeds, the opposite relationship is observed. These relationships could be due to the trade-off between cellular maintenance and growing fast and large, with higher expression of growth factors, such as IGF-1. This study further demonstrates the relationships between cancer mortality, heterozygosity, and life history traits and exhibits dogs as an important model organism for understanding the relationship between genetics and health.
ContributorsBalsley, Cassandra Sierra (Author) / Maley, Carlo (Thesis director) / Wynne, Clive (Committee member) / Tollis, Marc (Committee member) / School of Life Sciences (Contributor) / School of Human Evolution and Social Change (Contributor) / Barrett, The Honors College (Contributor)
Created2017-12
Description
Nucleic acid polymers have numerous applications in both therapeutics and research to control gene expression and bind biologically relevant targets. However, due to poor biological stability their clinical applications are limited. Chemical modifications can improve both intracellular and extracellular stability and enhance resistance to nuclease degradation. To identify a potential candidate for a highly stable synthetic nucleic acid, the biostability of α-L-threofuranosyl nucleic acid (TNA) was evaluated under simulated biological conditions. TNA contains a four-carbon sugar and is linked by 2’, 3’ phosphodiester bonds. We hypothesized that this distinct chemical structure would yield greater nuclease resistance in human serum and human liver microsomes, which were selected as biologically relevant nuclease conditions. We found that TNA oligonucleotides remained undigested for 7 days in these conditions. In addition, TNA/DNA heteropolymers and TNA/RNA oligonucleotide duplexes displayed nuclease resistance, suggesting that TNA has a protective effect over DNA and RNA. In conclusion TNA demonstrates potential as a viable synthetic nucleic acid for use in numerous clinical and therapeutic applications.
ContributorsCulbertson, Michelle Catherine (Author) / Maley, Carlo (Thesis director) / Mangone, Marco (Committee member) / Larsen, Andrew (Committee member) / School of Molecular Sciences (Contributor) / School of International Letters and Cultures (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Cancer rates in our nearest relatives are largely unknown. Comparison of human cancer rates with other primates should help us to understand the nature of our susceptibilities to cancer. Data from deceased primates was gathered from 3 institutions, the Duke Lemur Center, San Diego Zoo, and Jungle Friends primate sanctuary. This data contained over 400 unique individuals across 45 species with information on cancer incidence and mortality. Cancer incidence ranged from 0-71% and cancer mortality ranged from 0-67%. We used weighted phylogenetic regressions to test for an association between life history variables (specifically body mass and lifespan) and cancer incidence as well as mortality. Cancer incidence did not correlate with both body mass and lifespan (p>.05) however, cancer mortality did (p<.05). However, it is uncertain if the variables can be used as reliable predictors of cancer, because the data come from different organizations. This analysis presents cancer incidence rates and cancer mortality rates in species where it was previously unknown, and in some primate species, is surprisingly high. Microcebus murinus(grey mouse lemur) appear to be particularly vulnerable to cancer, mostly lymphomas. Further studies will be required to determine the causes of these vulnerabilities.
ContributorsWalker, William Charles (Author) / Maley, Carlo (Thesis director) / Boddy, Amy (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Adaptive therapy utilizes competitive interactions between resistant and sensitive cells by keeping some sensitive cells to control tumor burden with the aim of increasing overall survival and time to progression. The use of adaptive therapy to treat breast cancer, ovarian cancer, and pancreatic cancer in preclinical models has shown significant results in controlling tumor growth. The adaptive therapy model comes from the integrated pest management agricultural strategy, predator prey model, and the unique intra- and inter-tumor heterogeneity of tumors. The purpose of this thesis is to analyze and compare gemcitabine dose response on hormone refractory breast cancer cells retrieved from mice using an adaptive therapy strategy with standard therapy treatment. In this study, we compared intermittent (drug holiday) adaptive therapy with maximum tolerated dose therapy. The MCF7 resistant cell lines to both fulvestrant and palbociclib were injected into the mammary fat pads of 8 weeks old NOD/SCID gamma (NSG) mice which were then treated with gemcitabine. Tumor burden graphs were made to track tumor growth/decline during different treatments while Drug Dose Response (DDR) curves were made to test the sensitivity of the cell lines to the drug gemcitabine. The tumor burden graphs showed success in controlling the tumor burden with intermittent treatment. The DDR curves showed a positive result in using the adaptive therapy treatment method to treat mice with gemcitabine. Due to some fluctuating DDR results, the sensitivity of the cell lines to gemcitabine needs to be further studied by repeating the DDR experiment on the other mice cell lines for stronger results.
ContributorsConti, Aviona Christina (Author) / Maley, Carlo (Thesis advisor) / Blattman, Joseph (Committee member) / Anderson, Karen (Committee member) / Arizona State University (Publisher)
Created2022
Description
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, declared in March 2020 resulted in an unprecedented scientific effort that led to the deployment in less than a year of several vaccines to prevent severe disease, hospitalizations, and death from coronavirus disease 2019 (COVID-19). Most vaccine models focus on the production of neutralizing antibodies against the spike (S) to prevent infection. As the virus evolves, new variants emerge that evade neutralizing antibodies produced by natural infection and vaccination, while memory T cell responses are long-lasting and resilient to most of the changes found in variants of concern (VOC). Several lines of evidence support the study of T cell-mediated immunity in SARS-CoV-2 infections. First, T cell reactivity against SARS-CoV-2 is found in both (cluster of differentiation) CD4+ and CD8+ T cell compartments in asymptomatic, mild, and severe recovered COVID-19 patients. Second, an early and stronger CD8+ T cell response correlates with less severe COVID-19 disease [1-4]. Third, both CD4+ and CD8+ T cells that are reactive to SARS-CoV-2 viral antigens are found in healthy unexposed individuals suggesting that cross-reactive and conserved epitopes may be protective against infection.
The current study is focused on the T cell-mediated response, with special attention to conserved, non-spike-cross-reactive epitopes that may be protective against SARS-CoV-2. The first chapter reviews the importance of epitope prediction in understanding the T cell-mediated responses to a pathogen. The second chapter centers on the validation of SARS-CoV-2 CD8+ T cell predicted peptides to find conserved, immunodominant, and immunoprevalent epitopes that can be incorporated into the next generation of vaccines against severe COVID-19 disease. The third chapter explores pre-existing immunity to SARS-CoV-2 in a pre-pandemic cohort and finds two highly immunogenic epitopes that are conserved among human common cold coronaviruses (HCoVs). To end, the fourth chapter explores the concept of T cell receptor (TCR) cross-reactivity by isolating SARS-CoV-2-reactive TCRs to elucidate the mechanisms of cross-reactivity to SARS-CoV-2 and other human coronaviruses (HCoVs).
ContributorsCarmona, Jacqueline (Author) / Anderson, Karen S (Thesis advisor) / Lake, Douglas (Thesis advisor) / Maley, Carlo (Committee member) / Mangone, Marco (Committee member) / LaBaer, Joshua (Committee member) / Arizona State University (Publisher)
Created2023
Description
Can Body Height and BMI predict cancer trends in humans? Using a dataset of 220,181 individuals, with 31,822 individuals having malignancy records, we found that body height (p < 2e-16) and Body Mass Index (BMI) (p < 5.6e-05) are significant predictors of developing cancer. After stratifying by sex, we determined that men and women face an elevated risk of developing cancer with increases in body height, but a very slight increase in cancer risk with increases in BMI.
ContributorsMartins, Brian (Author) / Maley, Carlo (Thesis director) / Richker, Harley (Committee member) / Marquez Alcaraz, Gissel (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor) / School of Life Sciences (Contributor)
Created2023-12
Description
A big part of understanding cancer is understanding the cellular environment itthrives in by analyzing it from a microecological perspective. Humans and other species
are affected by different cancer types, and this highlights the notion that there may be a
correlation between specific tissues and neoplasia prevalence. Research shows that
humans are the most susceptible to adenocarcinomas and carcinomas which include the
following tissues: lungs, breast, prostate, and pancreas. Furthermore, research shows that
adenocarcinoma accounts for 38.5% of all lung cancer cases, 20% of small cell
carcinomas, and 2.9% of large cell carcinoma. The incidence of the most common cancer
types in humans is consistently increasing annually. This study analyzes trends of tissue-specific cancers across species to examine possible contributors to vulnerability to
cancer. I predicted that adenocarcinomas would be the most prevalent cancer type across
the tree of life. To test this hypothesis, I reviewed over 130 species that reported equal to
or greater than 50 individual necropsy pathology records across 4 classes (Mammalia,
amphibia, Reptilia, Aves) and ranked them by neoplasia prevalence. This information was
then organized in tables in descending order. The study’s resulting tables and data
concluded that the hypothesis was correct. I found that across all species
adenocarcinomas were the most common cancer type and account for 30.4% of
malignancies reported among species. Future research should investigate how organ size
contributes to neoplasia prevalence.
ContributorsPERAZA, ASHLEY (Author) / Maley, Carlo (Thesis advisor) / Boddy, Amy (Thesis advisor) / Baciu, Cristina (Committee member) / Arizona State University (Publisher)
Created2022
Description
Cancer is a problem of multicellularity, making it a problem across all species. This pervasiveness has led to much research into the defense and the pathology of the disease. Previously, studies have been limited in sample size, taxonomic breadth, and comparative methods to explain and understand the data available. Here, we have access to life history and cancer risk data of 17,563 individuals for 327 species, spanning across three monophyletic clades: Amphibians, Sauropsids, and Mammals. Comparative biology’s approach to cross-species cancer prevalence is crucial to the identification of species that are uniquely resistant to cancer as well as stratifying risk across a phylogeny based on the life history framework. Using the life history framework, alongside a multitude of life history data, was able to find that neoplasia prevalence increases with adult weight and longevity, but decreases with gestation time. It was also discovered that malignancy prevalence decreases with gestation time. Gestation and adult weight are also both significant predictors of neoplasia and malignancy prevalence when controlling for the other. On an evolutionary scale, cancer risk appears to be best described by sudden shifts in cancer prevalence followed by stabilizing selection of that trait. The understanding of increases and decreases of cancer risk across species could create better insight on human’s own cancer risk, as well as disease prevention in humans.
ContributorsMellon, Walker (Author) / Maley, Carlo (Thesis director) / Compton, Zachary (Committee member) / Mallo, Diego (Committee member) / Barrett, The Honors College (Contributor) / Department of Information Systems (Contributor) / Department of Economics (Contributor)
Created2022-12
Description
The Patient Guidance Project was created by a team of research assistants in the Arizona Cancer Evolution Center as a source of supplemental education and support for recently diagnosed cancer patients. Extensive background research in the form of literature reviews highlighted disparities between the information patients want and are receiving, as well as between average literacy levels of patients and the literacy levels at which cancer information is commonly provided. The Patient Guidance Project has published comprehensive guides for specific types of cancer, which so far include metastatic melanoma, glioblastoma, prostate cancer, oral cancer, kidney cancer, breast cancer, and colorectal cancer. The content of the guides is intended to bridge the gaps in information for patients with an emphasis on treatment options, treatment side effects, and psychological support resources, which surveys have identified as the topics patients want information on most. Written at a sixth-grade literacy level, which over half of adults in the U.S. read at, the guides are meant to be of benefit to as many people as possible. In the future, the team hopes to expand the Patient Guidance Project to include more cancer types, guides in different languages, and multimodal features to increase their effectiveness.
ContributorsWilliams, Erica (Author) / Maley, Carlo (Thesis director) / Baciu, Cristina (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2022-12