• A Comparative Study of Broadcast and Print Coverage in Three Criminal Cases

      Hudson, Lisa Rae (The University of Arizona., Not availa)
    • Liberation: The Story of a French Daily

      Herrera Cruz, Ignacio (The University of Arizona., Not availa)
    • Formative Assessment: Documenting Motor Vehicle Crashes and Local Perceptions with the Hualapai Tribe to Inform Injury Prevention Recommendations

      Mahal, Zeenat (The University of Arizona., 2020)
      Background: This research was designed to understand factors influencing Motor Vehicle Crashes (MVCs) on or near the Hualapai Tribe’s reservation in northwestern Arizona. The goal is to enable the Tribe to develop and implement a locally relevant MVC intervention program. The specific aims were to: i) compile and analyze 2010-2016 MVC data from Hualapai and federal sources to assess distributions of frequency, rates, high risk-locales, causes, days, times, age and sex of the drivers, in addition to assessing related conditions; ii) document local perceptions of environmental, social, and behavioral barriers to safe driving practices, and knowledge of MVC risk factors and existing tribal laws; and iii) provide evidence-based recommendations using the results from quantitative and qualitative data analyses. Approach/Methods: The research process applied a Community-Based Participatory Research approach and mixed methods using: a) secondary data analyses of records from six tribal programs and Indian Health Service (IHS), and b) qualitative analyses of data from two focus groups and field documents. Sensitivity analyses were conducted of IHS and Tribal Driving Under the Influence (DUI) data, using the 2010 U.S. Census as the denominator after adjusting for an undercount of up to 25%. Descriptive statistics, Fisher’s Exact Test, and linear and logistic regressions were used to examine significance. MVCs per 10 miles per year were estimated for State Route 66 and Diamond Bar Road/Grand Canyon West on or near the reservation due to higher numbers of crashes. Statistical process control charts, especially g-charts monitoring time between events, were plotted to examine the stability in the number of MVCs over time for each road. NVivo11Pro© was used to code and analyze the focus group data, guided by both inductive and deductive theories. Results: Driver’s seatbelt use in the Hualapai community increased from 2010 to 2012 (p < .0005), and reported DUIs decreased from 2010 to 2016 (p = .027). Similarly, car/booster seat use improved from 2014 to 2015 (p < .0005). Two hundred and fifty (N = 250) MVC-related injuries were registered at IHS facilities for Hualapai community members between 2006 and 2015. The highest rate, 22.4%, was observed in 15- to 24-year-olds, followed by 21.6% in 55- to 64-year-olds. For several combinations of numerators and denominators, sensitivity analysis of the IHS data shows a clear disparity between the Tribe’s MVC rate compared to the 2008 U.S. rate of 771.4 nonfatal injuries per 100,000 persons and the national goal for Healthy People 2020 (694.3 nonfatal injuries/100,000 persons). The major themes emerged from qualitative analyses of the focus groups were: i) unsafe traffic infrastructures, ii) DUI, iii) repeated DUI offenders driving on the reservation, and iv) a perception of lenient tribal traffic laws and enforcement on the reservation. Using study results, five Public Service Announcements were co-developed to inspire community-members to continue the trends noted from 2010-2016 and be aware of continued risks. Conclusions: MVCs are a multidimensional issue needing communitywide awareness of the range of risk factors. An intervention that addresses human and structural risks requires an alliance of tribal programs and external partners (e.g., IHS, university, federal, and state). Recommendations: Local recommendations include providing school- and institution-based education about alcohol/alcoholism and DUI consequences, and ongoing culturally and locally relevant communitywide education through the local newsletter and radio station.
    • Facebook pages and public spaces: Guatemala's 2015 movement and the years that followed

      Chikos, Michael (The University of Arizona., 2018-01)
      Guatemala’s 2015 Summer demonstrations were the largest public protest in the country since the Guatemalan Spring in 1944. These demonstrations were organized rapidly via social media, with Facebook Pages in particular playing a vital role, making them comparable to other digital mediated social movements and new forms of social protest in Latin America. The aims of this study are to explore the role of Facebook Pages in this historic moment, through an approach that considers both the cultural and political impacts of new technologies. Since the 1960s an emerging discourse around “New Social Movements” emphasizes the communicative and ideological nature of social movements, in contrast to social movements that seek purely political aims. This research found that while the Facebook Page should be understood as a Public Space where cultural forms are challenged and reshaped, it is also a highly political technology with real world effects.
    • Transition of Care: The Evaluation of Hand-off Communication Between Emergency Department and Medical/Surgical Nursing Units

      Naour, Michelle G. (The University of Arizona., 2018)
      Hand-off communication from the emergency department (ED) to inpatient nurses is an important process for transfer of safe and quality patient care from one department to another. Annually, there are130.4 million ED visits with 12.2 million of those visits resulting in hospital admission, providing ample opportunities for poor communication (Rui, Kang, & Albert, 2013). Miscommunications during patient hand-off are estimated to contribute to 80% of adverse events (The Joint Commission, 2012). This theory-driven, quality improvement project sought to evaluate the hand-off communication process between nurses from the ED and nurses in the inpatient Medical/Surgical units using human factors System Engineering Initiative for Patient Safety (SEIPS) approach, originally created by Pasqual Carayon in 2006. An online survey was created using an adapted SEIPS Model evaluating the interactive concepts of person, tools and technologies, tasks, organization, and environment and their impact on staff and patient outcomes. The survey was distributed to both the ED and Medical/Surgical nurses to gain their perspective on the interdepartmental hand-off communication process and how it impacts the staff and patient outcomes. There as an included option for the bedside nurses to provide recommendations on how to improve the hand-off communication process. Data was collected, anonymously, through an online database and descriptive statistics were used to analyze the results. The quality improvement project found that majority of nurses prefer verbal hand-off communication with a structured standard format of delivery in conjunction with the electronic health record. The project found that nurses perceive that the nurse-to-patient ratio and surrounding tasks impact the effectiveness and quality of hand-off communication. The most common suggested hand-off communication improvements were to not allow hand-off communication or transfer of the patient from the ED to the Medical/Surgical unit during peak times, such as shift change, and to follow up on tools and technology compliance. Overall, the person, the tools and technologies, the tasks, and the environment are contributing to ineffective hand-off, while the organization has adequately provided the resources the staff needs to perform an effective hand-off communication. All of which were concluded to have an impact on the staff and patient outcomes.
    • Robust Intelligent Agents for Wireless Communications: Design and Development of Metacognitive Radio Engines

      Asadi, Hamed (The University of Arizona., 2018)
      Improving the efficiency of spectrum access and utilization under the umbrella of cognitive radio (CR) is one of the most crucial research areas for nearly two decades. The results have been algorithms called cognitive radio engines which use machine learning (ML) to learn and adapt the communication's link based on the operating scenarios. While a number of algorithms for cognitive engine design have been identified, it is widely understood that significant room remains to grow the capabilities of the cognitive engines, and substantially better spectrum utilization and higher throughput can be achieved if cognitive engines are improved. This requires working through some difficult challenges and takes an innovative look at the problem. A tenet of the existing cognitive engine designs is that they are usually designed around one primary ML algorithm or framework. In this dissertation, we discover that it is entirely possible for an algorithm to perform better in one operating scenario (combination of channel conditions, available energy, and operational objectives such as max throughput, and max energy efficiency) while performing less effectively in other operating scenarios. This arises due to the unique behavior of an individual ML algorithm regardless of its operating conditions. Therefore, there is no individual algorithm or parameter sets that have superiority in performance over all other algorithms or parameter sets in all operating scenarios. Using the same algorithm at all times may present a performance that is acceptable, yet may not be the best possible performance under all operating scenarios we are faced with over time. Ideally, the system should be able to adapt its behavior by switching between various ML algorithms or adjusting the operating ML algorithm for the prevailing operating conditions and goal. In this dissertation, we introduce a novel architecture for cognitive radio engines, with the goal of better cognitive engines for improved link adaptation in order to enhance spectrum utilization. This architecture is capable of meta-reasoning and metacognition and the algorithms developed based on this architecture are called metacognitive engines (meta-CE). Meta-reasoning and metacognitive abilities provide for self-assessment, self-awareness, and inherent use and adaptation of multiple methods for link adaptation and utilization. In this work, we provide four different implementation instances of the proposed meta-CE architecture. First, a meta-CE which is equipped with a classification algorithm to find the most appropriate individual cognitive engine algorithm for each operating scenario. The meta-CE switches between the individual cognitive engine algorithms to decrease the training period of the learning algorithms and not only find the most optimal communication configuration in the fastest possible time but also provide the acceptable performance during its training period. Second, we provide different knowledge indicators for estimating the experience level of cognitive engine algorithms. We introduce a meta-CE equipped with these knowledge indicators extracted from metacognitive knowledge component. This meta-CE adjusts the exploration factors of learning algorithms to gain higher performance and decrease training time. The third implementation of meta-CE is based on the robust training algorithm (RoTA) which switches and adjusts the individual cognitive engine algorithms to guarantee a minimum performance level during the training phase. This meta-CE is also equipped with forgetting factor to deal with non-stationary channel scenarios. The last implementation of meta-CE enables the individual cognitive engine algorithms to handle delayed feedback scenarios. We analyze the impact of delayed feedback on cognitive radio engines' performances in two cases of constant and varying delay. Then we propose two meta-CEs to address the delayed feedback problem in cognitive engine algorithms. Our experimental results show that the meta-CE approach, when utilized for a CRS engine performed about 20 percent better (total throughput) than the second best performing algorithm, because of its ability to learn about its own learning and adaptation. In effect, the meta-CE is able to deliver about 70% more data than the CE with the fixed exploration rate in the 1000 decision steps. Moreover, the knowledge indicator (KI) autocorrelation plots show that the proposed KIs can predict the performance of the CEs as early as 100 time steps in advance. In non-stationary environments, the proposed RoTA based meta-CE guarantees the minimum required performance of a CRS while it’s searching for the optimal communication configurations. The RoTA based meta-CE delivers at least about 45% more data than the other algorithms in non-stationary scenarios when the channel conditions are often fluctuating. Furthermore, in delayed feedback scenarios, our results show that the proposed meta-CE algorithms are able to mitigate the adverse impact of delay in low latency scenarios and relieve the effects in high latency situations. The proposed algorithms show a minimum of 15% improvement in their performance compared to the other available delayed feedback strategies in literature. We also empirically tested the algorithms introduced in this dissertation and verified the results therein by designing an over the air (OTA) radio setup. For our experiments, we used GNU Radio and LiquidDSP as free software development toolkits that provide signal processing blocks to implement software-defined radios and signal-processing systems such as modulation, pulse-shaping, frame detection, equalization, and others. We also used two USRP N200 with WBX daughterboards, one as a transmitter and the other as a receiver. In these experiments, we monitored the packet success rate (PSR), throughput, and total data transferred as our key performance indicators (KPI). Then, we tested different proposed meta-CE algorithms in this dissertation to verify the productivity of the proposed algorithms in an OTA real-time radio setup. We showed that the experiments’ outputs support our simulations results as well.
    • The Estimation of Selected Physicochemical Properties of Organic Compounds

      Al-Antary, Doaa Tawfiq (The University of Arizona., 2018)
      Thermodynamic relationships are used to predict several physicochemical properties of organic compounds. As described in chapter one, the UPPER model (Unified Physicochemical Property Estimation Relationships) has been used to predict nine essential physicochemical properties of pure compounds. It was developed almost 25 years ago and has been validated by the Yalkowsky group for almost 2000 aliphatic, aromatic, and polyhalogenated hydrocarbons. UPPER is based on a group of additive and nonadditive descriptors along with a series of well-accepted thermodynamic relationships. In this model, the two-dimensional chemical structure is the only input needed. Chapter (1) extends the applicability of UPPER to hydrogen bonding and non-hydrogen bonding aromatic compounds with several functional groups such as alcohol, aldehyde, ketone, carboxylic acid, carbonate, carbamate, amine, amide, nitrile as well as aceto, and nitro compounds. The total data set includes almost 3000 compounds. Aside from the enthalpies and entropies of melting and boiling, no training set is used for the calculation of the properties. The results show that UPPER enables a reasonable estimation of all the considered properties. Chapter (2) uses modification of the van't Hoff equation to predict the solubility of organic compounds in dry octanol as explained in chapter two. The equation represents a linear relationship between the logarithm of the solubility of a solute in octanol to its melting temperature. More than 620 experimentally measured octanol solubilities, collected from the literature, are used to validate the equation without using any regression or fitting. The average absolute error of the prediction is 0.66 log units. Chapter (3) compares the use of a statistic based model for the prediction of aqueous solubility to the existing general solubility equation (GSE).
    • Evaluation of Practice Guidelines for Overweight and Obese Veterans: A Needs Assessment

      Chua, Justin (The University of Arizona., 2018)
      Purpose: With the obesity epidemic ever increasing, the purpose of this quality improvement project is to assess if Veteran’s Administration (VA) primary care providers have knowledge of and/or application barriers of the Veteran’s Administration/Department of Defense Clinical Practice Guideline for Screening and Management of Overweight and Obesity (SMOOG) in the VA primary care clinic in southern Arizona. Background: The prevalence of obesity seen in adults in the U.S. escalated from 15% to 34%, which is more than double from 1980 to 2008. Active military and Veterans obesity rates rose in similar fashion. The implementation of practice guidelines is critical to effective treatment to counteract the rising rates of overweight and obesity. Adherence to clinical practice guidelines often remains low causing an omission of therapies recommended in the guidelines. Methods: This quality improvement project used a descriptive methodology. Initially, SMOOG was evaluated using the AGREE II instrument. Next, a survey was administered to primary care providers to identify provider knowledge of and barriers to utilization of the SMOOG guidelines. Inclusion criteria for this study are: VA employed primary care provider and practicing primary care for at least 1 year. The 20-question survey measured providers’ knowledge and perceptions of their use of the VA/DoD SMOOG. Results: Evaluation using the AGREE II tool revealed the lowest possible quality scores observed in the Applicability domain. Based upon the results of the evaluation SMOOG is recommended for use with modifications specifically improving its applicability. Fifteen primary care providers participated in the survey. The results revealed that few primary care providers use SMOOG in clinical practice and barriers exist to implementation of SMOOG. Conclusions: Assessing providers’ knowledge, perceptions, and barriers to SMOOG provides insight towards the next steps in addressing the rising prevalence of obesity among U.S. Veterans. An appraisal of SMOOG revealed that the guideline was developed with a high quality in the areas of evidence and clear presentation, but is clearly deficient in its applicability of implementation of the recommendations. The data obtained serves as an initial step to inform future research into synthesizing and guiding an implementation strategy.
    • Describing the Needs of Advanced Practice Registered Nurses (APRNs) Who Plan to Specialize in Cardiology

      Stokes, Allison (The University of Arizona., 2018)
      Background: Cardiology is but one of the many clinical foci available to certified Advanced Practice Registered Nurses (APRNs). In fact, more acute care APRNs choose cardiology as their focus than any other. With such strong interest in cardiac advanced practice nursing, it is imperative to assess the adequacy of preparation for those who wish to follow this career path. Known barriers exist in the educational and clinical preparation of this APRN population, however, there is little research detailing the specifics of those barriers. Purpose: This study describes the needs of APRNs who plan to specialize in cardiology. Method and Sampling: A qualitative design was used to describe the motivation of APRNs specializing in cardiology, tools they currently utilize to achieve their specialization, and their needs based on the current approach. I recruited participants, APRNs specializing in cardiology, through meetings at a local cardiology practice. Seven APRNs specializing in cardiology with experience ranging from 10 months to 15 years, and currently working in a cardiac setting, participated in the study. Structured interviews were conducted to describe the needs of APRNs who plan to specialize in cardiology. The interviews were audiotaped and analyzed to reveal commonalities. Findings: After analyzing the audio recordings three major commonalities emerged: APRNs specializing in cardiology must overcome limited educational opportunities, APRNs specializing in cardiology require a higher level of skill than their formal training and licensing requirements provide, and the need to validate APRNs specializing in cardiology knowledge. Additional commonalities included availability and the type of degree programs, and a lack of cardiac focus in educational preparation. Conclusion: The findings showed the needs of APRNs who plan to specialize in cardiology are rooted in their educational preparation. There is a vast amount of variability among degree programs and a severe lack of cardiac focus in their educational preparation. In order to achieve competency, 100% of study participants secured a mentorship with an expert cardiac clinician for a minimum of one year post-graduation and without assistance from their educational programs. Additionally, APRNs specializing in cardiology believe a national certification or examination requirement would be beneficial to their practice.
    • Orogenic Evolution of the Pamir Mountains

      Chapman, James (The University of Arizona., 2018)
      This dissertation consists of two parts, the first focused on the Pamir orogenic system and the second focused on the use of petrology to understand tectonic processes more generally. The Pamir Mountains are located at the western end of the Tibetan Plateau and are part of the Alpine-Himalayan orogenic belt. The Pamir has evolved from a Cordilleran-style orogen during the Mesozoic into a continent-continent collisional orogen during the Cenozoic. The examination of the Pamir Mountains takes an orogenic systems approach and investigates the foreland basin system, the retro- fold and thrust belt, the orogenic plateau hinterland, and the magmatic arc in the Pamir. Methods of analysis include structural geology, geochronology, thermochronology, petrology, geochemistry, sedimentology, stratigraphy, and numerical modeling, Tectonic processes and phenomena investigated include; intracontinental subduction, lithospheric delamination, crustal shortening, low-angle subduction, thrust belt evolution, subduction rollback, crustal anatexis, mantle drips, hinterland extension, high-flux events, crustal assimilation, syntectonic sedimentation, decoupled upper-lower crustal deformation, foreland basin sedimentation, subsidence dynamics, and sediment routing. The second part of the dissertation is focused on convergent orogenic systems more broadly and the development of petrologic and geochemical methods for interpreting tectonic processes. Igneous rocks and accessory minerals are studied, focusing on major and trace elements, radiogenic isotopic systems, and stable isotopic systems. Specific methods investigated include; geochemical proxies for crustal thickness, relating zircon element concentrations to whole rock compositions, interpreting the origin of spatial and temporal trends in radiogenic isotopic data, estimating mantle melt source regions, and the role of crustal assimilation in continental arcs.
    • Adult Patients with Schizophrenia and Noncompliance with Antipsychotics

      Arceo, Jan Michael (The University of Arizona., 2018)
      Greater than half of the population of patients with schizophrenia struggle to comply with their antipsychotic medications due to various factors. Psychiatric providers heavily rely on their patients to comply with their antipsychotic medications to improve their overall quality of life. The purpose of this DNP Project was to implement Psychoeducation via a Teach-Back Method intervention in adult Schizophrenic patients who are voluntarily noncompliant with their antipsychotic medications among residents in Las Vegas, Nevada. The Model of Improvement framework was utilized to help develop the project’s aims, and goals and the Plan-Do-Study-Act (PDSA) cycle was used to develop the project’s intervention, implement the intervention, and evaluate the results. Psychoeducation was used to educate the patients about the pathophysiology and symptoms of schizophrenia and how antipsychotic medication counteract their symptoms to improve their overall quality of life. The Teach-Back Method helps psychiatric providers provide psychoeducation in layman’s term so patients can understand the information. Understanding can be assessed by asking patients to verbalize the educational information back to the provider. Five participants ages 18 years old and older, diagnosed with schizophrenia who are voluntarily noncompliant with their antipsychotic medications were included in the DNP Project. Each participant was assessed for their baseline medication noncompliance, and the Psychoeducation via Teach-Back Method was implemented. Each participant had a follow-up visit 2 weeks Post-Intervention to evaluate their medication compliance. The data was analyzed using descriptive statistics to determine if the participant was compliant or noncompliant with their antipsychotic medications per definition. The data showed that all five participants showed an improvement in medication compliance (Post-Intervention) compared to their baseline medication noncompliance (Pre-Intervention). The data also showed 3 out of the 5 participant’s Post-Intervention results indicate they were compliant with their antipsychotic medications per definition of medication compliance. Overall, psychiatric providers should implement the Psychoeducation via Teach-Back Method intervention in adult patients with Schizophrenia who are voluntarily noncompliant with their antipsychotic medications to improve medication compliance and improve their patients overall quality of life.
    • The Evolution and Comparative Genomics of the Reproductive Manipulator Cardinium hertigii

      Stouthamer, Corinne Marie (The University of Arizona., 2018)
      Many insects and other arthropods have symbiotic microorganisms that may influence key facets of their biology. Cardinium hertigii is an intracellular bacterial symbiont, (phylum Bacteroidetes) of arthropods and nematodes. This versatile symbiont has been shown to cause three of four reproductive manipulations of their arthropod hosts known to be caused by symbionts: parthenogenesis induction (PI), where genetic males are converted into genetic females; feminization, where genetic males become functional females; and cytoplasmic incompatibility (CI), the symbiont-induced death of offspring from matings of infected males and uninfected females. Here, I explored the evolution of this symbiont and its reproductive manipulations, and found that closely related Cardinium strains have a tendency to associate with closely related hosts and the reproductive manipulations do not display a clear phylogenetic signal. To further understand the possible genes underlying these reproductive manipulations, I sequenced four Cardinium genomes and compared these with the two genomes analyzed in the literature. In these comparisons, I found that, although closely related Cardinium strains tend to reside in closely related hosts, there is no evidence for a suite of genes associated with host specificity, as few differences separate two strains residing in different host orders, suggesting that ecological opportunity for horizontal transmission may be more limiting to Cardinium than genomic capability. I additionally identify some genes that may be associated with the Cardinium’s ability to induce PI and CI in its wasp host. Overall, this dissertation has led to a better understanding of Cardinium and its effects on its hosts.
    • Mutation-Specific Calcium Dysregulation in Hypertrophic Cardiomyopathy

      Lehman, Sarah (The University of Arizona., 2018)
      As the genetic causes of Hypertrophic Cardiomyopathy (HCM) have become widely recognized, considerable lag in the development of targeted therapeutics has limited interventions to symptom palliation. This is in part due to an oft-noted finding that similar point mutations within myofilament proteins are known to cause differential disease severity, highlighting the need to understand disease progression at the molecular level. One commonly described pathway in HCM progression is calcium homeostasis dysregulation, albeit little is understood about disruption of the pathway. This dissertation investigated the calcium homeostasis of two clinically relevant murine models of HCM expressing similar point mutations within myofilament proteins. A mutation-specific alteration in the calcium dissociation rate from the cardiac myofilament is proposed to as a primary mechanism of down-stream calcium disruption. Two modes of intervention in down-stream calcium homeostasis were tested to as a means of improving directed therapies in HCM progression. The clinically-utilized diltiazem hydrochloride, an L-type calcium channel blocker, revealed mutation-specific symptom palliation but an inability to target within the disease mechanism itself. Due to this insufficient response to diltiazem, we investigated the role of the calcium-dependent kinase, CaMKII, and its persistent (autonomous) activation resulting from calcium dysregulation. Partial inhibition of the autonomous activation of the kinase was shown to improve functional and morphological indices of failure in calcium-dependent HCM progression. Thus, we conclude a myofilament-linked derangement in calcium homeostasis that potentiates aberrant activation of CaMKII. Moreover, we position the kinase as a nodal point in disease progression and a potential therapeutic target for early, robust management of HCM in the clinical population.
    • Benzodiazepine Taper Guidelines for Older Adults in an Inpatient Geiatric/Psychiatric Unit

      Amanti, Cecilia (The University of Arizona., 2018)
      Benzodiazepine dependence is a significant national problem. Although benzodiazepines — a class of drugs that includes drugs such as alprazolam, lorazepam, temazepam, clonazepam, and diazepam—have a wide range of uses including the treatment of insomnia, anxiety, and seizures; they are addictive. Individuals taking these drugs can quickly develop dangerous tolerances. Therefore, these drugs should not be selected as first choice nor used for more than short periods, yet a significant portion of the population uses benzodiazepines for long periods. This problem is significantly more pronounced in the elderly, a population that scholars have agreed should not use these drugs outside of extreme circumstances. Because benzodiazepines may be wrongfully perceived as an easy treatment for so many common afflictions, providers continue to prescribe them, and patients may be reluctant to discontinue use due to the symptoms associated with withdrawal (i.e., insomnia and anxiety). To avoid these symptoms, the standard discontinuation approach seen in an outpatient setting is a long-term taper that may take eight to 12 weeks of gradual reduction. However, in an inpatient setting, this long-term approach is unfeasible due to the short length of patient stays. The literature has given little consideration to this problem. Thus, it was necessary to review evidence and develop a guideline for benzodiazepine tapering in elderly patients receiving inpatient psychiatric care. The purpose of this project was to develop a guideline to taper benzodiazepines in the elderly using the Johns Hopkins Nursing Evidence-Based Practice Model (JHNEBP). The guideline was validated by expert peer reviewers using the AGREE II instrument. The completed guidelines offer recommendations on the tapering of benzodiazepines in an inpatient geropsych unit and best practices for interventions to increase the success rate of discontinuation.
    • Characterizing Therapy Induced Polyploidy (TIP) Populations as a Resistance Mechanism in DH/DE-DLBCL and Identifying Synthetic Lethal Targeted Therapies

      Islam, Md Shariful (The University of Arizona., 2018)
      Lymphoma is a blood cancer that involves the lymphatic system and is the 7th most common cancer in USA. Diffuse large B-cell lymphoma (DLBCL) and Peripheral T-cell lymphoma (PTCL) are the most common types of aggressive B-cell and T-cell non-Hodgkin lymphomas (NHL) respectively. Double-Hit or Double-Expresser DH/DE-DLBCL are high grade B-cell lymphomas characterized by translocation or over expression of MYC and BCL-2 which are mostly incurable with standard chemo-immunotherapy. Therefore, there is an unmet need for novel targeted therapy. Aurora kinase inhibition (alisertib) induces ~30% cell death (in vitro), while a portion of the remaining ~70% cells at day-4 escape apoptosis through polyploid populations which we called therapy induced polyploid cells (TIP). These TIP cells exhibited a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway. TIP also showed increased levels of phospho-Hck and phospho-Akt indicating increased BCR signaling which is a rationale for combining ibrutinib (BTK inhibitor). Combined inhibition of AK + BTK reduced phosphorylation of AKT/mTOR and ERK-1/2, up-regulated phospho-H2A-X and Chk-2 (DNA damage), reduced Bcl-6 and decreased Bcl-2 and Bcl-xL results in induced apoptosis evident by PARP cleavage. In a DE-DLBCL SCID mouse xenograft model, ibrutinib alone was inactive, while alisertib + ibrutinib was additive with a tumor growth inhibition (TGI) rate of ~25%. However, TGI for ibrutinib + rituximab was ~50-60%. In contrast, triple therapy showed a TGI rate of >90%. Kaplan-Meier survival analysis showed 67% of mice were alive at day-89 with triple therapy versus only 20% with ibrutinib + rituximab. All treatments were well tolerated with no significant changes in body weights. Anti-DLBCL chemotherapy dosing schedules are intermittent, designed to avoid damage to normal tissue such as the mucous membranes, gut and the bone marrow. TIP are common in standard anti-DLBCL therapies (e.g. vincristine, doxorubicin) and thought to be responsible for disease relapse. Some of these TIP cells die but remaining of those are capable of re-entering the cell cycle during off-therapy periods. We discovered how these TIP cells can re-enter cell cycle and molecular mechanism underlying this resistance. We have purified AK inhibitor induced polyploid DH/DE-DLBCL cells by FACS. Time-lapse microscopy of single cells revealed that following drug removal, a subset of TIP cells divide and proliferate by reductive cell division(s). This includes multipolar mitosis, meiosis like nuclear fission or budding off daughter cells. RNA-Seq, Proteomics and Kinomics proling of TIP cells demonstrated that alisertib induced polyploid cells have up-regulated DNA damage response, replication and immune evasion; amplify receptor tyrosine kinase and T-cell receptor signaling; hijacks the spindle assembly checkpoint point control via MYC dysregulation of RanGAP1, TPX2 and KPNA2. We believe these up-regulated proteins are responsible for induction of aneuploid daughter cells and disease resistance and also provide potential opportunities for novel therapy combination that warrant further exploration. Lymphomas are systemic diseases that require a comprehensive knowledge of immune mechanism in cancer as well as targeted therapeutic approach for designing an optimal therapeutic strategy and desired synergy can be achieved by rational combination of small molecule inhibitors with immune modulatory agents that could enhance host immune response. In PTCL we have shown that expression of PD-L1 relative to PD-1 is high in PTCL biopsies ( 9-fold higher) and cell lines. Combination of alisertib with pan-PI3K inhibition or VCR significantly reduced PD-L1, NF-kB expression and inhibited phosphorylation of AKT, ERK1/2 and AK with enhanced apoptosis. In a syngeneic PTCL mouse xenograft model, alisertib demonstrated tumor growth inhibition (TGI) ~30%, whilst anti-PD-L1 therapy alone was ineffective. Alisertib + anti-PD-L1 resulted in TGI >90% indicative of a synthetic lethal interaction. PF-04691502 + alisertib + anti-PD-L1 + VCR resulted in TGI 100%. Overall, mice tolerated the treatments well. Co-targeting AK, PI3K and PD-L1 is a rational and novel therapeutic strategy for PTCL. In conclusion, we have identified therapeutic targets in aggressive B- and T-cell lymphoma which can be combined with immunotherapy that warrant investigation to disrupt rapid tumor evolution of TIP cells to mitigate disease relapse.
    • Regulation of Cancer Cell Invasion by the Estrogen Receptor in ER+ Breast Cancer

      Padilla-Rodriguez, Marco (The University of Arizona., 2018)
      Estrogen receptor-positive (ER+) breast tumors account for 75% of diagnosed breast cancer in the United States. These breast tumors are defined by their dependency on the hormone estrogen for continued growth. Adjuvant endocrine therapy is frequently used to treat patients afflicted with ER+ breast cancer, during which ER inhibitors are used to suppress tumor growth. However, several epidemiological studies examining ER+ breast cancer in patients treated with estrogen show a significant decrease in cancer cell invasion, suggesting ER signaling may play a role in regulating invasion. While the mitogenic effects of estrogen on ER+ breast cancer are well studied, the mechanisms of regulating cancer cell invasion by ER signaling have not been characterized. In this dissertation, we show that estrogen-ER signaling suppresses cancer cell dissemination through the generation of Suppressive Cortical Actin Bundles (SCABs) at the leading edge of the cell. The formation of these actin structures are facilitated by the expression of the Ena/VASP protein family member EVL, which is transcriptionally regulated by ERs, and suppresses cancer cell invasion both in vitro and in vivo. Additionally, we find that suppressing ER activity by using clinical ER inhibitors used during adjuvant endocrine therapy suppresses EVL expression and promotes invasion. From these results, we propose a model in which ER activity regulates invasion by suppressing cancer cell dissemination through EVL-mediated actin remodeling, highlighting ER as a regulator of both tumor growth and tumor invasion in ER+ breast cancer.
    • The Pre-miR-27a Gene Polymorphism Rs895819 and Risk of Prostate Cancer Progression

      Daw, Jennifer Nicole (The University of Arizona., 2018)
      Small single-stranded, non-coding RNA molecules known as microRNAs (miRNAs) are capable of regulating gene expression by suppressing translation or degrading mRNAs resulting in diverse consequences. MiRNAs are synthesized as an individual primary transcript or as a gene cluster and each can act alone or together to control a single gene or a network of genes. The miR-23a~27a~24-2 gene cluster are individually processed of each other and have their own unique mature miRNA expression profile in various prostate cancer cell lines. Previous studies have reported the dysregulation of mature miR-27a and corresponding gene targets to be associated with cancer. A single nucleotide polymorphism in pre-miR-27a at position 40 (chr.19p13.1, SNP rs895819 T>C) and is proposed to affect mature miR-27a biogenesis. Rs895819 has been associated with risk of various cancers in different ethnic groups, and depending on the allele may cause up-regulation or down-regulation of mature miRNAs and pose as a risk factor for cancer. The literature evaluating SNP rs895819 is not clear with respect to its effects on miRNA processing, targeting, and its associations with PCa. In this study, we focus on miRNAs -23a, -27a, and -24-2 individually and as a cluster, and in a case-only study genotyping of rs895819 in a PCa cohort from a southwest US population consisting of a mixed ancestral background. We used a TaqMan SNP assay for genotyping rs895819 (T>C) in germline DNA samples from PCa patients and cell lines. Our data suggest rs895819 is associated with higher Gleason score sum. Based on our data we plan to investigate the miR-23a~27a~24-2 gene cluster to determine mechanisms by which these microRNAs regulate epithelial plasticity pathways in PCa.
    • Error-Related Theta Dynamics and Single-Trial Cognitive Control in Sports-Related Concussion

      Smith, Ezra (The University of Arizona., 2018)
      Athletes in contact sports can sustain concussions that damage brain circuits important for cognitive control of behavior. When healthy participants err, a cascade of neural dynamics is apparent across the scalp, and this neural activity predicts participants’ learning from mistakes and inhibiting future responses. Theta dynamics are especially important in terms of error-related brain activity: increases in theta power, and increased connectivity between brain regions is mediated by synchronous theta rhythms. Previous investigations of error-related brain activity have noted decreases in neural responses in concussed athletes, but these previous studies used techniques that are less-than-optimal for examining theta-dynamics and cognitive control specifically. This study focused on changes in theta oscillatory dynamics important for cognitive control in athletes with concussion/mTBI. In Study 1, between–subjects analyses revealed that injured athletes were characterized by attenuated mPFC-lPFC connectivity and cognitive control compared to healthy athletes. In Study 2a, within-subjects analyses revealed that a season of rugby play resulted in an attenuation of connectivity; Study 2b demonstrated that connectivity and cognitive control measures were sensitive to effects of acute concussion at a single-subject level. Results imply that measures of connectivity and cognitive control may be a useful measure to track recovery from concussion and inform return-to-play or discontinuation decisions. Theoretically-relevant neuroscientific findings in healthy adults may have translational applications in patient populations, especially in regard to monitoring brain health.
    • Perceived Learning and Satisfaction Differences in Face-to-Face and Online Courses

      Perez, Rebecca (The University of Arizona., 2018)
      With the increased popularity of online courses, ensuring that students in online courses have equivalent learning experiences as their peers in face-to-face courses is paramount. Current research regarding the similarities and differences between the two course delivery mediums has resulted in contradictory findings, particularly in terms of how students perceive and rate the course. This analysis expands the focus comparison of student evaluation of teaching ratings means beyond that of a single course or department using correlational analysis, paired t-test, and MANOVAs. Significant differences were found between online and face-to-face courses for particular evaluation items, college, and academic level. These differences provide insight into the differences between the delivery mediums from the student perspective and can help identify pedagogical strategies to ensure equivalent learning experiences.