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- All Subjects: Cellular Biology
- All Subjects: public health
- Creators: Jacobs, Bertram
- Member of: Theses and Dissertations
- Resource Type: Text
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
Flavivirus infections are emerging as significant threats to human health around the globe. Among them West Nile(WNV) and Dengue Virus (DV) are the most prevalent in causing human disease with WNV outbreaks occurring in all areas around the world and DV epidemics in more than 100 countries. WNV is a neurotropic virus capable of causing meningitis and encephalitis in humans. Currently, there are no therapeutic treatments or vaccines available. The expanding epidemic of WNV demands studies that develop efficacious therapeutics and vaccines and produce them rapidly and inexpensively. In response, our lab developed a plant-derived monoclonal antibody (mAb) (pHu-E16) against DIII (WNV antigen) that is able to neutralize and prevent mice from lethal infection. However, this drug has a short window of efficacy due to pHu-E16's inability to cross the Blood Brain Barrier (BBB) and enter the brain. Here, we constructed a bifunctional diabody, which couples the neutralizing activity of E16 and BBB penetrating activity of 8D3 mAb. We also produced a plant-derived E16 scFv-CH1-3 variant with equivalent specific binding as the full pHu-E16 mAb, but only requiring one gene construct for production. Furthermore, a WNV vaccine based on plant-derived DIII was developed showing proper folding and potentially protective immune response in mice. DV causes severe hemorrhaging diseases especially in people exposed to secondary DV infection from a heterotypic strain. It is hypothesized that sub-neutralizing cross-reactive antibodies from the first exposure aid the second infection in a process called antibody-dependent enhancement (ADE). ADE depends on the ability of mAb to bind Fc receptors (FcγRs), and has become a major roadblock for developing mAb-based therapeutics against DV. We aim to produce an anti-Dengue mAb (E60) in different glycoengineered plant lines that exhibit reduced/differential binding to FcγRs, therefore, reducing or eliminating ADE. We have successfully cloned the molecular constructs of E60, and expressed it in two plant lines with different glycosylation patterns. We demonstrated that both plant-derived E60 mAb glycoforms retained specific recognition and neutralization activity against DV. Overall, our study demonstrates great strives to develop efficacious therapeutics and potent vaccine candidates against Flaviviruses in plant expression systems.
ContributorsHurtado, Jonathan (Author) / Chen, Qiang (Thesis advisor) / Huffman, Holly A (Committee member) / Steele, Kelly P (Committee member) / Arizona State University (Publisher)
Created2014
Description
This study aims to unearth monological and monocultural discourses buried under the power of the dominant biomedical model governing the HIV/AIDS debate. The study responds to an apparent consensus, rooted in Western biomedicine and its "standardizations of knowledge," in the production of the current HIV/AIDS discourse, especially in Sub-Saharan Africa. As a result, biomedicine has become the dominant actor (in) writing and rewriting discourse for the masses while marginalizing other forms of medical knowledge. Specifically, in its development, the Western biomedical model has arguably isolated the disease from its human host and the social experiences that facilitate the disease's transmission, placing it in the realm of laboratories and scientific experts and giving full ownership to Western medical discourse. Coupled with Western assumptions about African culture that reproduce a one-sided discourse informing the social construction of HIV/AIDS in Africa, this Western monopoly thus constrained the extent and efficacy of international prevention efforts. In this context, the goal for this study is not to demonize the West and biomedicine in general. Rather, this study seeks an alternative and less monolithic understanding currently absent in scientific discourses of HIV/AIDS that frequently elevates Western biomedicine over indigenous medicine; the Western expert over the local. The study takes into account the local voices of Sub-Saharan Africa and how the system has affected them, this study utilizes a Foucauldian approach to analyze discourse as a way to explore how certain ways of knowledge are formed in relation to power. This study also examines how certain knowlege is maintaned and reinforced within specific discourses.
ContributorsAbdalla, Mohamed (Author) / Jacobs, Bertram (Thesis advisor) / Robert, Jason (Committee member) / Klimek, Barbara (Committee member) / Arizona State University (Publisher)
Created2014
Description
Is it possible to treat the mouth as a natural environment, and determine new methods to keep the microbiome in check? The need for biodiversity in health may suggest that every species carries out a specific function that is required to maintain equilibrium and homeostasis within the oral cavity. Furthermore, the relationship between the microbiome and its host is mutually beneficial because the host is providing microbes with an environment in which they can flourish and, in turn, keep their host healthy. Reviewing examples of larger scale environmental shifts could provide a window by which scientists can make hypotheses. Certain medications and healthcare treatments have been proven to cause xerostomia. This disorder is characterized by a dry mouth, and known to be associated with a change in the composition, and reduction, of saliva. Two case studies performed by Bardow et al, and Leal et al, tested and studied the relationships of certain medications and confirmed their side effects on the salivary glands [2,3]. Their results confirmed a relationship between specific medicines, and the correlating complaints of xerostomia. In addition, Vissink et al conducted case studies that helped to further identify how radiotherapy causes hyposalivation of the salivary glands [4]. Specifically patients that have been diagnosed with oral cancer, and are treated by radiotherapy, have been diagnosed with xerostomia. As stated prior, studies have shown that patients having an ecologically balanced and diverse microbiome tend to have healthier mouths. The oral cavity is like any biome, consisting of commensalism within itself and mutualism with its host. Due to the decreased salivary output, caused by xerostomia, increased parasitic bacteria build up within the oral cavity thus causing dental disease. Every human body contains a personalized microbiome that is essential to maintaining health but capable of eliciting disease. The Human Oral Microbiomics Database (HOMD) is a set of reference 16S rRNA gene sequences. These are then used to define individual human oral taxa. By conducting metagenomic experiments at the molecular and cellular level, scientists can identify and label micro species that inhabit the mouth during parasitic outbreaks or a shifting of the microbiome. Because the HOMD is incomplete, so is our ability to cure, or prevent, oral disease. The purpose of the thesis is to research what is known about xerostomia and its effects on the complex microbiome of the oral cavity. It is important that researchers determine whether this particular perspective is worth considering. In addition, the goal is to create novel experiments for treatment and prevention of dental diseases.
ContributorsHalcomb, Michael Jordan (Author) / Chen, Qiang (Thesis director) / Steele, Kelly (Committee member) / Barrett, The Honors College (Contributor) / College of Letters and Sciences (Contributor)
Created2015-05
Description
This study investigated the potential efficacy of HEAL International's prevention education program in inducing health behavior change in HIV/AIDS, malaria, and communicable disease to children in grade levels ranging from primary school to secondary school. The health education program was aimed at changing health behavior by increasing knowledge. This increase in knowledge was analyzed as a modifying factor in the Health Belief Model suggesting that knowledge, along with five other modifying factors, are directly responsible for an individual's health perceptions. These health perceptions ultimately result in an individual's health behavior. As a result, it is argued that an increase in knowledge can lead to health behavior change so long as it is coupled with a strong theoretical framework. Administering pre-evaluations at the beginning of the program, post evaluations at the end of the program, and a second post evaluation again two months later completed the evaluation. It was hypothesized that if there was a significant difference between the percent of correct answers at the pre-evaluation compared the second post-evaluation then there is evidence that HEAL's health education program is, or at least has the potential to, create sustainable health behavior change. A paired samples t-test was completed on the data and showed a statistically significant difference between the percent of correct answers at pre-evaluation and the percent of correct answers at second post-evaluation. These results indicated that the number of students with a comprehensive knowledge of the subjects that HEAL taught during the program had increased. It was concluded that the results of the study indicate evidence that HEAL's program has the potential to deliver sustainable health behavior change but that it will be more quantifiable once HEAL is able to adopt a theoretical framework on which to base future programs.
ContributorsWright, Mia Christina (Author) / Jacobs, Bertram (Thesis director) / Salamone, Damien (Committee member) / Ayers, Stephanie (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor) / School of Life Sciences (Contributor)
Created2014-05
Description
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) that emerged from a zoonotic host at the end of 2019 and caused a public health crisis. In this collection of studies, Nicotiana benthamiana plants are used to set the foundation for producing monoclonal antibodies (mAbs) with homogeneous glycosylation to neutralize SARS-CoV-2 and potentially address the immunopathology often observed with severe COVID-19. Specifically, a mAb against the human interleukin (IL)-6 receptor (sarilumab) was generated and evaluated in vitro for its potential to reduce IL-6 signaling that has been shown to be associated with more severe cases of COVID-19. Furthermore, multiple mAbs that bind to the receptor-binding domain (RBD) of SARS-CoV-2 and efficiently neutralize the virus were developed using plant-based expression. Several of these mAbs are from different classes of RBD-binding mAbs that have distinct binding sites from one another. Several mAbs from different classes showed synergy in neutralizing the ancestral strain of SARS-CoV-2 and a smaller subset showed synergy when tested against the highly mutated Omicron (B.1.1.529) variant. Of interest, a novel RBD-binding mAb, termed 11D7, that was raised against the ancestral strain and derived from a hybridoma, appears to have an epitope on the RBD that contributes more synergy to a mAb combination that efficiently neutralizes the B.1.1.529 variant of SARS-CoV-2. This epitope was partially mapped by competitive binding and shows that it overlaps with another known antibody that binds a cryptic, distal epitope, away from the receptor binding site, giving insight into the potential mechanism by which 11D7 neutralizes SARS-CoV-2, as well as potentially allowing it to resist SARS-CoV-2 immune evasion more efficiently. Furthermore, this mAb carries a highly homogeneous glycan pattern when expressed in N. benthamiana, that may contribute to enhanced effector function and provides a tool to elucidate the precise role of crystallizable fragment (Fc)-mediated protection in SARS-CoV-2 infection. Ultimately, these studies provide evidence of the utility of plant-made mAbs to be used as cocktail members, giving clarity to the use of less potent mAbs as valuable cocktail components which will spur further investigations into how mAbs with unique epitopes work together to efficiently neutralize SARS-CoV-2.
ContributorsJugler, Collin (Author) / Chen, Qiang (Thesis advisor) / Lake, Douglas (Committee member) / Steele, Kelly (Committee member) / Mason, Hugh (Committee member) / Arizona State University (Publisher)
Created2022
Description
Novel biological strategies for cancer therapy have recently been able to generate improved anti-tumor effects in the clinic. Of these new advancements, oncolytic virotherapy is a promising strategy through a dual mechanism of oncolysis and stimulation of tumor immunogenicity against the target cancer cells. Myxoma virus (MYXV) is an oncolytic poxvirus that has a natural tropism for Leporids, being nonpathogenic in humans and all other known vertebrates. MYXV is able to infect cancer cells due to mutations and defects in many innate signaling pathways, such as those involved in anti-viral responses. While MYXV alone infects and kills many classes of human cancer cells, recombinant techniques allow for the implementation of therapeutic transgenes, which have the potential of ‘arming’ the virus to enhance its potential as an oncolytic virus. The implementation of certain transgenes allows improved cancer cell killing and/or promotion of more robust anti-tumor immune responses. To investigate the potential of immune-inducing transgenes in MYXV, in vitro screening experiments were performed with several single transgene-armed recombinant MYXVs. As recent studies have shown the ability of MYXV to uniquely target malignant human hematopoietic stem cells, the potential of oncolytic MYXV armed with individual immune-enhancing transgenes was investigated through in vitro killing analysis using human acute myeloid leukemia (AML) and multiple myeloma (MM) cell lines. Additionally, in vitro experiments were performed using primary bone marrow (BM) cells obtained from human patients diagnosed with MM. Furthermore, the action of an engineered bispecific killer engager (huBIKE) was investigated through co-culture studies between the CD138 surface marker of target MM cells and the CD16 surface marker of primary effector peripheral blood mononuclear cells (PBMCs), particularly NK cells and neutrophils. In this study, several of the test armed MYXV-infected human AML and MM cell lines resulted in increased cell death compared to unarmed MYXV-infected cells. Additionally, increased killing of CD138+ MM cells from primary human BM samples was observed following infection with huBIKE-armed MYXV relative to infection with unarmed MYXV. Furthermore, analysis of co-culture studies performed suggests enhanced killing of target MM cells via engagement of NK cells with U266 MM cells by huBIKE.
ContributorsMamola, Joseph (Author) / McFadden, Grant (Thesis advisor) / Jacobs, Bertram (Committee member) / Blattman, Joseph (Committee member) / Arizona State University (Publisher)
Created2020
Description
Environmental stressors can perturb cellular homeostasis. Cells activate an integrated stress response that will alleviate the effects of the ongoing stress. Stress-activated protein kinases function to phosphorylate the eukaryotic translation initiation factor, eIF2α, which results in inhibition of translation of house-keeping genes. Following these events, formation of cytoplasmic messenger ribonucleoprotein complexes, known as stress granules, will take place. Stress granules typically have a pro-survival function. These studies demonstrate that assembly of stress granules can also lead to necroptosis. Necroptosis is a caspase-independent, receptor-interacting protein kinase 3 (RIPK3)-dependent cell death pathway executed by mixed lineage kinase domain-like (MLKL) protein. Cellular stress is induced using arsenite (oxidative stress) or by infection with vaccinia virus (VACV) E3 protein Z-DNA-binding domain mutant, VACV-E3LΔ83N. In both cases, RIPK3-dependent death was observed in interferon (IFN)-primed L929 cells. This death led to phosphorylation and trimerization of MLKL, indicative of necroptosis. Necroptosis induced by oxidative stress and VACV-E3LΔ83N infection was dependent on the host Z-form nucleic acid sensor, DNA-dependent activator of IFN-regulatory factors (DAI), as it was inhibited in DAI-deficient L929 cells. Under both cellular stresses, DAI associated with RIPK3 and formed high-molecular-weight complexes, consistent with formation of the necrosomes. DAI localized into stress granules during necroptosis induced by arsenite and the mutant virus, and the necrosomes formed only in presence of stress granule assembly. The significance of stress granules for cellular stress-induced necroptosis was demonstrated using knock-out (KO) cell lines unable to form granules: T cell-restricted intracellular antigen 1 (TIA-1) KO MEF cells and Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1/2) KO U2OS cells. Necroptosis was inhibited in absence of stress granule formation as no cell death or activation of MLKL was observed in the knock-out cell lines following arsenite treatment or VACV-E3LΔ83N infection. Furthermore, wild-type VACV was able to inhibit stress granule assembly, which coincided with the virus ability to inhibit necroptosis. These studies have led to a model of Z-form nucleic acids being involved in activation of the stress granule-mediated necroptosis following induction by environmental stressors. These results have significance for understanding the etiology of human diseases and the antiviral innate immunity.
ContributorsSzczerba, Mateusz Bartlomiej (Author) / Jacobs, Bertram L (Thesis advisor) / Langland, Jeffrey (Committee member) / Lake, Douglas (Committee member) / Chen, Qiang (Committee member) / Arizona State University (Publisher)
Created2021
Description
Brought on by extended survival due to Highly Active Anti-Retroviral Therapy and increased incidence among older adults, the demographic profile of the HIV epidemic has begun to shift towards the aging population. As people living with HIV (PLWH) begin to age and develop multiple comorbidities, their needs are no longer limited to HIV treatment and disease management; they may require aging services similar to those with a negative HIV status. Increased attention has been placed on HIV and aging to assess the unique needs of older PLWH, however, limited research exists on the preparedness of aging services to provide adequate care to this population. This study aims to assess HIV and aging within Maricopa County, where individuals aged 50 years and older account for nearly half the reported HIV/AIDS cases in the county, and 30% of cases in Arizona. Two focus groups – one with older PLWH and another with aging service professionals – were conducted to gather information about existing aging services and the perspectives of older PLWH regarding their growing needs. Older PLWH were found to experience challenges similar to those that have been well-documented in previous studies: most notably, PTSD and other mental health conditions; fear of the future and isolation; HIV status disclosure and stigma; and economics and financial security. An anonymous survey was developed in conjunction with Aunt Rita’s Foundation to evaluate Maricopa County aging services; it was discovered that providers lack experience with HIV and admit deficiencies in their preparation to address the age-related concerns of older PLWH. The results show that the majority of providers were supportive of offering care to older PLWH and expressed interest in improving their preparedness. Future research is necessary to obtain perspectives from additional aging services in Maricopa County and word towards the development of an aging services directory to connect older PLWH to care.
ContributorsLayon, Sarah (Author) / Jacobs, Bertram (Thesis director) / Coon, David (Committee member) / Spencer, Glen (Committee member) / School of Life Sciences (Contributor) / School of Human Evolution & Social Change (Contributor) / School of Art (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Human Immunodeficiency Virus, or HIV, is a global epidemic, costing over 9.51 million individuals their lives since 2000. There are different modes of transmission of HIV, one such mode being from an HIV positive woman to her child before, during, or after delivery (SIC Curriculum, 2006). Though a global epidemic, not all countries have the same prevalence of mother to child, or MTC, transmission of HIV. In 2016, over 160,000 children under the age of five were newly infected with HIV in sub-Saharan Africa. That is compared to the United States of America, where it is estimated that fewer than 150 new infant HIV infections occur yearly (Glaser Foundation, 2020). Those differences exist despite both countries having access to preventative medication as of 1998.
Additionally, the World Health Organization, or WHO, developed three treatment plans for prevention of MTC transmission of HIV, globally available as of 2010 (WHO, 2010). The goal of the WHO was to globally standardize care of HIV-positive pregnant women and their infants in order to decrease the global prevalence of HIV. The first plan was called Option A, then came Option B, and lastly Option B+. While preventative medication has been available for over twenty years and at least one of these theoretically effective treatment plans has been implemented and is readily available in each country of sub-Saharan Africa, the overall prevalence of MTC transmission of HIV in sub-Saharan Africa has continued to be notably high compared to other countries. Thus, the aim of this thesis is to explore some of the significant obstacles to implementation of the WHO’s treatment plans in sub-Saharan Africa that contribute to that high prevalence. I also suggest possible solutions to those barriers in order to effectively decrease the prevalence of MTC transmission of HIV.
Additionally, the World Health Organization, or WHO, developed three treatment plans for prevention of MTC transmission of HIV, globally available as of 2010 (WHO, 2010). The goal of the WHO was to globally standardize care of HIV-positive pregnant women and their infants in order to decrease the global prevalence of HIV. The first plan was called Option A, then came Option B, and lastly Option B+. While preventative medication has been available for over twenty years and at least one of these theoretically effective treatment plans has been implemented and is readily available in each country of sub-Saharan Africa, the overall prevalence of MTC transmission of HIV in sub-Saharan Africa has continued to be notably high compared to other countries. Thus, the aim of this thesis is to explore some of the significant obstacles to implementation of the WHO’s treatment plans in sub-Saharan Africa that contribute to that high prevalence. I also suggest possible solutions to those barriers in order to effectively decrease the prevalence of MTC transmission of HIV.
ContributorsJones, Sierra Hope (Author) / Jacobs, Bertram (Thesis director) / Maienschein, Jane (Committee member) / School of Molecular Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05