• Targeting BCL2 and MYC DNA Secondary Structures by Novel Compounds to Lower Gene Expression in DLBCL

  Knight, Eric Victor (The University of Arizona., 2015)
• 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.
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  According to the Revolution: The Cuban Revolution in Cuban History and Cuban History in the Cuban Revolution

  Tschudy, James R. (The University of Arizona., 2005)

  This thesis combines the recent historiography on the Cuban Revolution with a theoretical approach to put forth a new mode of analysis for the ideological origin and guide of the Cuban Revolution. The role of Cuban history in the lexicon of the Cuban Revolution has been prominent, and it has provided the ideological background of the Revolution. The leadership's focus on Cuban history makes it organic in the Gramscian sense of organic versus traditional intellectuals. By analyzing the historical narrative with the assistance of the recent historiography, this thesis will show that the leadership of the 1959 Revolution had a blueprint for revolution, as well as a reference to the main obstacles to real change in Cuba: the power of the United States and the segment of the Cuban elite that willingly mortgaged sovereignty for economic and social stability in the vain of Cardoso and Falleto's analysis of dependency theory.
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  SAVAGES, SINNERS, AND SAINTS: THE HAWAIIAN KINGDOM AND THE IMPERIAL CONTEST, 1778-1839

  Kashay, Jennifer Fish (The University of Arizona., 2002)

  This dissertation uses the writings of sailors, traders, and diplomats, American missionaries, and Hawaiian chiefs, as well as anthropological theories and ethnographic insights about Hawaiian culture to examine the cultural milieu created by western sojourners in Hawaii, contestation over the interrelated issues of morality, sexuality, religion, economics, and politics that occurred with the arrival of American evangelists, and the ways in which Hawaiian chiefs and commoners negotiated a delicate and calculated path between the embattled imperialist forces in their islands. This study places Hawaiian experiences within the broader outlines of American social, religious, and expansionist history. It offers a distinctly new interpretation of imperial relations in Hawaii, one that others may choose to build upon. In the past two decades, scholars of postmodernism and subaltern studies have devised new approaches to examining western imperialism in Africa, India, and China. However, only a handful of scholarly works have focused on western imperialism in Hawaii. Following trends in colonial scholarship and anthropological theory, particularly the work of Marshall Sahlins, this study uses an ethnographic approach to explain how Hawaiians viewed the religious, social, political, and cultural changes that resulted from the presence of foreigners in their kingdom and their responses to the challenges of imperialism. As such, this dissertation is highly interdisciplinary and draws upon the secondary literature in anthropology, missiology, colonialism, and Native American history. The issue of Hawaiian sovereignty has received national attention in recent years. Most scholars date the loss of Hawaiian independence to the moment in 1893 when U.S. Marines helped dethrone Queen Lili'uokalani. In reality, the forces that led to the annexation of the islands to the United States began with Captain James Cook's 1778 arrival in Hawaii. By focusing on the complex relations between two polarized groups of foreigners-American missionaries and western traders, sailors, and diplomats-and Hawaiian chiefs and commoners, this study reveals how the combined effects of western economic, religious, cultural, and political imperialism, cultural disintegration, native factionalism, and chiefly miscalculation created the context for the loss of Hawaiian political and economic control after 1839, much earlier than previously asserted in the Iiterature.
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  THE POLITICAL HUMANISM OF THOMAS STARKEY: A STUDY OF HIS POLITICAL THOUGHT

  De Weese, Malcolm L. Jr. (The University of Arizona., 1967)
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  NOSOTRAS: GENDER AND THE CONTRUCTION OF ECUADORIAN TRANSNATIONAL IDENTITIES IN MADRID, SPAIN

  Algar, Araceli Masterson (The University of Arizona., 2004)
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  THE SPANISH CIVIL WAR: MYTHS AND REALITIES

  Bernal, Marisa Diana (The University of Arizona., 1999)
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  SAN FRANCISCO JOE: The Life Story of a Kibei

  Warnock, Marcia Dawn (The University of Arizona., 1993)
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  WESTERN NORTH CAROLINA MOUNTAIN MEN IN THE CONFEDERATE ARMY: AN ANALYSIS OF HOW BATTLEFIELD AND HOME FRONT EVENTS INFLUENCED THEIR PARTICIPATION DURING THE AMERICAN CIVIL WAR, 1861-1865

  Parson, Robert William (The University of Arizona., 2006)

  This "synthetic works narrative" effort1, examines how western North Carolina evolved through the experiences of its people on the home and war fronts in America's Civil War. Themes like race, class, gender, and ethnicity interacted in the political and social upheavals that caused this most cataclysmic war for and among Americans. Battlefield results directly and indirectly influenced the varying levels of commitment that mountain men and women made to sustain the Confederacy. Likewise home-front instability occurred as a result of policies implemented and actions taken to support the war effort against the Union invaders. Volunteers in 1861 knew why they were willing to fight. Some persisted but many did not as morale fell due to external pressures. Internal pressures wrought hard times at home, news of which adversely affected the commitment of those mountain soldiers who did not have the moral fiber to stay and chose to desert.
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  DIPLOMACY FAR REMOVED A REINTERPRETATION OF THE U.S. DECISION TO OPEN DIPLOMATIC RELATIONS WITH JAPAN

  Arnold, Bruce Makoto (The University of Arizona., 2005)

  On the morning of April28, 1849, the USS Preble, a sloop of war commanded by James Glynn, weighed anchor and sailed away from Nagasaki harbor. On board were fourteen men from the whaler Lagoda who had been held for over a year by Japanese authorities. Upon interrogation, the men stated that they were physically mistreated by the Japanese. Two years earlier, sailors from the whaler Lawrence) who were also forced onto Japanese shores and held captive, reported similar mistreatment. The story of these events comprised over fifty pages of the original Senate report used to persuade the United States Congress to approve a naval expedition to Japan. This study seeks to clarify the impact of the stories of the Lawrence and Lagoda on the decision to send the U.S. mission to Japan. Mter examining the actual narratives of the sailors and comparing them with Japanese reports in order to ascertain a factual baseline, the study examines the reaction to the Lawrence and Lagoda by prominent businessmen, naval officers, and politicians. Then, the reaction to the Lawrence and Lagoda is placed in the contextual framework of prevailing mid-nineteenth century American social, cultural, and legal attitudes in order to show that humanitarian concerns were, indeed, a prime consideration tor sending the Perry mission to Japan.
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  Temple E and Roman Identity in Early Roman Corinth

  Taga, Hayley (The University of Arizona., 2008)
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  "Thank God for the Deserts": Mormon Colonization, Environmental Change, and Climatic Variability in the Little Colorado River Watershed, 1873-1920

  Finger, Thomas David (The University of Arizona., 2006)

  Deep-seeded aspects of Mormon theology set ideological boundaries for how settlers in northern Arizona's Little Colorado River watershed could interact with the land and water. Rather than see the variable climate and hydrologic regime of the watershed as proof it could not support long-term intensive agriculture, the settlers viewed the desert through a religious lens. Deserts had to be redeemed into gardens if the settlers were to attain the Kingdom of God. A series of overlapping problems - social, economic, and environmental -beset the colony throughout the final two decades of the nineteenth century- among them a breakup of the communal order, the arrival of largescale cattle outfits, and prolonged drought. Faced with these difficulties, the settlers modified their ideology and transformed their environmental practices. Ironically, these efforts, based in contemporary scientific and secular understandings of water management also failed to remove settlers from their environmental constraints.
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  EL MANCO Y EL MARTIR: FUNERALS, THE FAMILY,AND POPULAR MEMORY OF THE ASSASSINATION OF ALVARO OBREGON, 1928-1929

  Lopez, Amanda Marie (The University of Arizona., 2004)

  This thesis explores the aftermath of the assassination of President-elect Alvaro Obregon in Mexico City on July 17, 1928. It recounts the details of his funeral ceremonies and the execution and funeral of his assassin, Jose de Leon Toral. The funerals present an opportunity to see how issues of nationality and gender are negotiated in cultural events. Furthermore, the thesis examines correspondence surrounding the assassination, including condolences and pardon requests, to demonstrate how men and women understood and accepted the concept of the reified Revolution. Finally, it discusses the memory of the assassination as expressed in corridos, literature, and commemorative events. This thesis demonstrates the effect of the assassination on the construction, reception, and memory of the myth of the Mexican Revolution and considers how issues of gender relate to the myth.
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  "We, too, Are Americans": African American Women, Class, and Citizenship in Detroit and Richmond, 1940-1954

  Shockley, Megan N. Taylor (The University of Arizona., 2000)
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  CONFLICT ON THE LINE: THE BATTLE OF AMBOS NOGALES

  Hayden, Paul Andrew (The University of Arizona., 1998)
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  BLACK GOLD & THE DEEP BLUE SEA: THE PROBLEM OF OIL POLLUTION IN THE MEDITERRANEAN SEA & THE HUMAN RESPONSE TO IT THROUGH THE 1970S

  Lloyd, Jennifer Ellen (The University of Arizona., 2007)
• A Two-Stage Estimation of Elasticities for Disaggregated Salad Products

  Lobo, Andrew (The University of Arizona., 2018)

  Demand elasticities are estimated for seven lettuce and leafy green products through two-stage estimation using data from the 2015 National Consumer Panel. Products are aggregated into categories by the amount of convenience they offer the consumer. The two least-convenient good categories—unprocessed lettuce and fresh-processed lettuce—are found to be inferior goods, while more convenient goods are found to be normal or even luxury goods. All seven categories are found to be own-price elastic.
• Application of Machine Learning Techniques for Prognosis of Traumatic Brain Injury Patients in Intensive Care Units

  Ehsani, Sina (The University of Arizona., 2018)

  With advances in digital health technologies and proliferation of big biomedical data in recent years, applications of Machine Learning (ML) in healthcare and medicine have gained significant attention. Modern Intensive Care Units (ICUs), in particular, are equipped to generate rich multimodal clinical data on critically-ill patients. In this thesis, we focus on applying machine learning techniques for prognostication of Traumatic Brain Injury (TBI) patients in ICU, which is the leading cause of death and disability among children and adults of age less than 44. We present two case studies to demonstrate the feasibility and applicability of machine learning techniques: one for mortality prediction in TBI patients and the second for extracting patterns from physiological data collected from TBI patients. For the case study I, clinical data including demographics, vital signs, and physiological data for the first 72 hours of TBI patients were extracted from the Medical Information Mart for Intensive Care III (MIMIC III) database. Several traditional supervised machine learning algorithms such as artificial neural network, support vector machine, and logistic regression were employed to construct prediction models. Bagging and Voting techniques were implemented to improve the performance of these algorithms. By comparing the performances of these algorithms, we showed that deploying voting techniques on several different ML models can improve the overall performance. These algorithms obtained the highest Area Under receiver operating characteristic Curve (AUC) of 0.91. For the case study II, an exploratory, secondary analysis of physiologic data of TBI patients from the Phase III trial of Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (PROTECT) was performed. Subspace clustering was used to extract relationships between various physiologic variables. For both studies, 10-fold cross validation was used for evaluation purposes.
• The Leucine-Repeat Rich Receptor-Like Kinases XIP1/CEPR1 and CEPR2 Control Lateral Root Initiation and Elongation in Arabidopsis

  Dimitrov, Ivan D. (The University of Arizona., 2018)

  Roots serve both to anchor plants in the soil, and to help plants acquire water and nutrients. Plants have to optimize the growth of their root system, as roots cost energy to expand and maintain. This is accomplished through short and long distance signaling pathways that connect environmental conditions of the roots and available energy in shoots. XIP1/CEPR1 and CEPR2 are two Leucine-Rich Repeat Receptor-Like Kinase that are important for root growth responses to differing nitrogen levels in the environment. While previous results implicated these two receptors in signaling from roots to shoots, here I have shown that they are part of a short-range pathway within roots that controls lateral root initiation. Furthermore, through the use of genetic tests I have connected a group of physically-interacting proteins to XIP1/CEPR1 and CEPR2-related phenotypes. I have shown that these receptors and interacting proteins play roles in controlling early growth, flowering time, silique maturation, and lateral root initiation, emergence and elongation.
• The Effect of Cortical Spreading Depression Induced Episodic Headache on Blood-Brain Barrier Structure and Function

  Cottier, Karissa Ellen (The University of Arizona., 2018)

  Previous research has demonstrated that BBB structure and function are altered as a result of various neurological disorders including ischemic stroke, traumatic brain injury, epilepsy, and infections of the brain. Additionally, the BBB has also been shown to alter its function in response to nociception. Despite the strong evidence for BBB alterations in both neurological disorders and pain, there is still debate on whether BBB permeability is altered in episodic headache disorders such as migraine. Cortical spreading depression (CSD) in the CNS is suggested as a common mechanism contributing to both headache production and BBB changes. In previous studies examining BBB changes in response to CSD, animals were anesthetized during the study, preventing any behavioral assessments. Additionally, in studies examining CSD induced nociceptive behaviors, BBB permeability was not assessed. Therefore, this work represents the first joint assessment of nociceptive responses and BBB integrity in response to CSD. In these studies, we observed a transient increase in BBB paracellular permeability in the cortex, but not brainstem, in response to KCl induced CSD. Additionally, at corresponding time points, we found that KCl induced CSD reduced periorbital withdrawal thresholds and rearing behavior, indicative of a state of facial mechanical allodynia. Despite strong evidence for CNS involvement in headache disorders, drug development for headache disorders remains focused on peripheral targets. Difficulty in delivering drugs across the BBB may partially account for this disparity. In this work, we demonstrated that KCl induced CSD increased the CNS uptake of radiolabeled sumatriptan in both the cortex and the brainstem. We also found that KCl induced CSD increased the expression of the putative sumatriptan transporter Oatp1a4 in the brainstem, which likely underlies the observed increased brainstem permeability to sumatriptan following CSD induction. Repeated CSD events may be harmful long-term. Therefore, we also investigated whether pre-treatment with the migraine prophylactic topiramate could prevent the CSD induced increase in BBB permeability. In these studies a single dose of topiramate was not able to block CSD induced BBB changes; importantly, topiramate and other migraine prophylactic drugs are typically given chronically to reduce the occurrence and severity of attacks. Therefore further studies should be conducted to determine if chronic topiramate treatment has any protective effects on the BBB in this model. Often, changes in BBB permeability are accompanied by decreases in tight junction protein expression, including occludin, claudin-5, and ZO-1. Here, however, we did not observe any changes in expression of either occludin or claudin-5 in response to cortical KCl induced CSD. BBB permeability can also be decreased through changes in TJ protein localization. We observed a change in claudin-5, but not occludin or ZO-1, localization in rats where CSD was induced with cortical KCl injections. This was recapitulated in an in vitro model using bEnd.3 mouse brain endothelial cells. Additionally, treatment of these cells with a CSD cocktail comprised of KCl, ATP, and glutamate with a pH of 6.8 was also able to cause claudin-5 relocalization. Interestingly, potassium influx mechanisms including the Na+/K+ ATPase and Kir6 channels have been implicated in BBB regulation. We found that blockade of these mechanisms with digoxin or AMP-PNP, respectively was able to prevent KCl or CSD cocktail-induced claudin-5 relocalization. Since claudin-5 is the component of the BBB which regulates permeability to ions and small molecules, these changes may represent the BBB’s effort to re-establish membrane ionic equilibrium. Finally, this work addresses sex differences in migraine, particularly as they relate to the BBB. In previous studies, female sex hormones have been shown to facilitate both nociception and CSD production. Here, we found that female rats had a more intense response to cortical KCl induced CSD. Additionally, we demonstrated that the female sex hormone 17-β-estradiol can, on its own, induce nociceptive behaviors in rats. Finally we observed several changes in BBB structure and function related to sex hormones. Consistent with previous studies, we found that ovariectomy increased BBB permeability. When investigating estradiol induced molecular changes at the BBB, we turned our attention to the sodium/hydrogen exchanger NHE1 due to its role in regulating cell excitability, its reported functional regulation by estradiol, and in vitro data implying expression may play a role in triptan uptake. Here, we found that estradiol reduces NHE1 expression in a concentration dependent manner in GPNT rat brain endothelial cells, but not other CNS cell types such as microglia or astrocytes. Additionally, we found that testosterone did not affect its expression. These data suggest that estradiol may control CNS ion balance and excitability due to its regulation of BBB ion exchangers such as NHE1. Together, the results presented herein demonstrate that CSD induces episodic headache-like behaviors that coincide with alterations in BBB structure and function. These changes can be taken advantage of clinically, by dosing drugs at specific times to increase their access to the CNS. On the other hand, episodic headache induced BBB changes may also produce long-term deleterious effects. Therefore, further studies should be conducted to fully elucidate the mechanisms behind headache induced BBB changes so that they may be prevented through appropriate therapeutic interventions.

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