Plasma-Independent Thrombin Production by Glioma Stem Cells Drives the Bidriectional Interaction Between GSCs and Platelets to Promote GBM Tumorigenesis

Sloan, Anthony R Case Western Reserve University ProQuest Dissertat 2023 해외박사(DDOD)

The effect of platelets on oncogenesis has been studied extensively in cancer metastasis, but less so in glioblastoma (GBM), where metastasis is rare. Here we identify the unique crosstalk between glioma stem cells (GSCs) and platelets within GBM solid tumors that enhance disease progression. Many experts consider targeting GSCs a promising therapeutic approach; however, no clear method has been identified. High platelet counts have been associated with poor clinical outcome in many cancers including ovarian, endometrial cancer, lung and colon cancers. While platelets are known to affect progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Excitingly our lab addresses a central, yet poorly understood problem in cancer biology: the interaction between cancer cells and non-cancer cells. We show that brain cancer stem cells promote their own proliferation by co-opting and activating platelets, ubiquitous blood cells that are normally involved in blood clotting.Our clinical studies suggest elevated platelet counts positively correlate with GSC proliferation and negatively correlate with overall survival in patients with GBM. Patients with high platelet counts (>350k/µl) had a median survival time of 9 months compared to 16 months median survival for patients with normal platelet count (150-350/µl) (p<0.05). We demonstrate platelet and GSC co-localization in GBM solid tissue and that cancer stems cells activate platelets without blood plasma, by endogenously producing all the factors of the intrinsic and extrinsic coagulation cascades, to produce thrombin, resulting in platelet activation. Secondly, we demonstrate that these cancer stem cells endogenous coagulation cascades are oncogenic: they promote stemness and proliferation in vitro and pharmacological inhibition delays oncogenesis in an in vivo model.We believe that our observations mark a paradigm shift in the understanding of how cancer cells co-opt non-cancer cells for their own advantage. It is possible and perhaps even likely that endogenous thrombin production is not limited to glioblastoma stem cells, but used by other cancer cells and possibly other diseases. Our findings also provide a framework for novel therapeutics targeting the platelet-GSC axis in GBM and potentially in other cancers.

The Atala Mosque : Between polity and culture in medieval Jaunpur (India)

Sloan, Anna J University of Pennsylvania 2001 국내박사

The organization of collection development in large university research libraries

Sloan, Elaine Carol Frank 1973 국내박사

Case study of how nine executives learn informally to develop strategy in a global context

Sloan, Julia A Columbia University Teachers College 2002 해외박사(DDOD)

The purpose of this study was to acquire greater insight into how top-tier executives of three global companies learn to make strategy. The business phenomenon of engaging in commerce across national borders is referred to in this study as “global” business. The following three research questions guided the study: What learning strategies were employed by the executives? How did they learn these strategies? What factors facilitated or impeded their learning?. The study was an interpretive case study consisting of in-depth interviews with nine top-tier executives representing three companies located in three different countries (United States, Japan and Poland), and three diverse industry sectors: finance, manufacturing and technology. Data collection methods included document analysis, personal data forms and in-depth interviews. A data analysis process was developed to examine the perceived linkage between the executives' learning and how they made strategy. The executives were asked to describe how they gained the knowledge, skills and affect they perceived as necessary for making strategy, and to reflect on what and how they had learned what they described. The result of the data analysis was a thematic description of factors that influenced their learning to make strategy. The study's findings were analyzed according to a three-stage model of reflective learning: preparation, experience and re-evaluation derived from the selected literature. The findings confirmed the usage of the three-stage informal, non-linear learning process found in the model. It also determined that regardless of age, culture or industry sector, all nine of the executives described prior success experience, reflective processes and five attributes as essential components for learning to make global strategy. Executives who had a prior successful life (non-business related) experience continued to use it as an “anchor” to test subsequent experiences against. The five critical attributes identified as requisites for successful global strategy making were: Imagination, Broad Perspective, Multi-tasking, No Control Over, and Desire-to-Win. Recommendations were offered to facilitate the informal learning aspect of strategy development within the companies.

A model for effective leadership in community colleges committed to continuous quality improvement

Sloan, Barbara Robinson University of Florida 2002 해외박사(DDOD)

To remain competitive in the future, community colleges must embrace change and respond to worldwide influences. Continuous Quality Improvement (CQI) is an organizational and philosophical approach to addressing change through continuous improvement, yet the successful implementation of CQI has been difficult for many colleges. Proponents of CQI have emphasized the central importance of leadership, but very little research has been conducted to explore what leadership attributes and styles best complement a continuous quality organization. To address the complexities of leadership and the leadership situation in a CQI college, this study considered multiple criteria including the leadership situation and intervening variables affecting the leadership situation as well as the personality attributes, leadership styles, and team styles of the presidents and other senior leaders. The purpose of this study was to develop a theoretical construct of effective leadership in a community college that has adopted or wants to adopt the principles of continuous quality improvement. Two institutions were identified as successful based on an assessment of their degree of implementation of the Malcolm Baldrige Education Criteria for Performance Excellence. The Occupational Personality Questionnaire (OPQ was used to determine the critical personality attributes, team types, and leadership styles of the presidents and their senior team members. Questionnaires, institutional reports and semi-structured interviews were used to understand the practices of the CEO's and to explore the organizational structure. The results of the study suggest a number of leadership traits and behaviors important to successful implementation of CQI. Although CQI can be successful in diverse environments, implementation requires a long-term commitment, as much as 10 to 15 years. The president should be committed to empowering others and should embrace the concept of leadership in which leaders and followers exert mutual influence. Cross-functional teams and horizontal work structures should be developed. A CQI environment requires a relations-oriented leadership. The colleges studied exhibited a high level of shared leadership; therefore, the leadership attributes of both presidents and other college leaders were examined.

Examination of endogenous and exogenously influenced physiological patterns of post-transplant Quercus rubra seedlings

Sloan, Joshua L Purdue University 2011 해외박사(DDOD)

Northern red oak (Quercus rubra L.) comprises a large portion of the seedlings planted in the Central Hardwood Forest region and constitutes a significant component of existing forest ecosystems. Members of the genus Quercus exhibit a recurrently flushing, episodic growth pattern different from and more complex than co-occurring non- Quercus species. This episodic growth pattern results in complex physiological patterns, which have been shown to vary with seedling ontogeny. For this reason, the Quercus morphological index (QMI) was developed, providing a means of identifying ontological growth stages using simple morphological measurements; it has subsequently proven useful for the description of endogenous patterns of physiological development within firstyear, pre-transplant northern red oak seedlings and for the distinction of exogenous influences from effects of these endogenous patterns. This dissertation describes a series of experiments designed to examine the validity of long-standing, yet largely untested, assumptions of the QMI and to assess post-transplant carbon allocation and physiological patterns in northern red oak seedlings as they occur endogenously and in response to exogenous factors, such as fertilization at time of transplant and environmental stresses commonly experienced by transplanted seedlings. Post-transplant physiological patterns relative to seedling ontogeny were found to resemble those of first-year, pre-transplant seedlings and to remain highly consistent across genotypes, thus supporting post-transplant use of the QMI. Post-transplant interactions between endogenous physiological patterns and flooding were demonstrated, as well as positive physiological effects of controlled release fertilizer (CRF) application at the time of transplant. Controlled release fertilizer was not found to interact with moisture availability in the present study, and post-transplant moisture stress was observed to influence seedling physiology independently of nutrient-availability effects. Patterns of observed post-transplant physiology of northern red oak seedlings resulted primarily from endogenous phenomena associated with episodic ontological development, although such patterns were demonstrably alterable by exogenous influences.

Exploring Novel PRMT5 Inhibitors for the Treatment of Human and Canine Lymphomas

Sloan, Shelby L The Ohio State University ProQuest Dissertations & 2023 해외박사(DDOD)

Lymphoma is a cancer that affects white blood cells called "lymphocytes" found in the lymphatic system. Each year approximately 580,000 people are diagnosed with lymphoma. Lymphoma is further categorized as a Hodgkin lymphoma (HL) or a non-Hodgkin lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are two distinct subtypes of NHL that originate from abnormal growth of B-lymphocytes. DLBCL is the most common subtype of NHL whereas MCL is rare, representing ~6% of non-Hodgkin disease. Patients are commonly diagnosed with DLBCL and MCL at a median age of 65 years and present with enlarged or swollen lymph nodes. Other common symptoms are fevers, night sweats, weight loss, loss of appetite, and fatigue. Similarly, lymphoma is one of the most common cancers in dogs with DLBCL being the most common subtype of NHL. MCL is comparatively rare in dogs; however, it tends to be a more indolent disease in dogs and lacks the hallmark translocation of cyclin D1.Treatment for both human and canine lymphoma involves multi-agent cytotoxic combination chemotherapy, with radiation, small molecule targeted therapy, and immunotherapy. Patients with DLBCL and MCL have a highly variable clinical course; and while most patients respond initially to immuno-chemotherapy many patients do not achieve a durable remission and relapse with drug-resistant disease. There remains an unmet need for more durable and tolerable therapeutic options for the relapsed and refractory patient population.Protein arginine methyltransferase 5 (PRMT5) is a protein that catalyzes the addition of methyl groups to arginine residues on numerous target proteins. PRMT5 is overexpressed in human and canine lymphomas and plays an important oncogenic role by epigenetic and post-translational modification of cell cycle regulators, DNA repair genes, pro-survival signaling components, and RNA splicing. In this dissertation, we explored targeting PRMT5 as a treatment for human and canine lymphomas with small molecule inhibitors of PRMT5 (C220 and PRT-382). Specifically, our studies focused on human MCL and canine DLBCL subtypes. In summary, targeting PRMT5 in vitro led to growth arrest and apoptotic cell death of cell lines and patient samples. Inhibition of PRMT5 resulted in the global loss of PRMT5 prost-translational modifications of symmetrically dimethylated arginine (SDMA) residues. We interrogated whole transcriptomic changes upon PRMT5 inhibition using gene expression microarrays and RNA-sequencing and highlighted key mechanisms of drug action. This work validates targeting PRMT5 in both human and canine lymphomas as a promising therapeutic strategy and supports the continued development of PRMT5 inhibitors in pre-clinical and clinical trials.

The role of safety behaviors in the maintenance of anxiety

Sloan, Tracy Beth The University of Texas at Austin 2001 해외박사(DDOD)

The concept of safety behaviors has taken an increasingly important role in our understanding of pathological fear and its modification. As early as 1978, Bandura emphasized the importance of fading patient's “response aids” during exposure so as to enhance a patient's sense of personal mastery. Recent interest in mechanisms of fear reduction has led to theorizing about the role of safety behaviors in fear reduction. Rachman (1984) suggests that safety-seeking behaviors may reduce the immediate experience of fear. Other theorists propose that the utilization of safety seeking behavior maintains pathological fear. They suggest that patients' use of safety behaviors interferes with threat disconfirmation, because patients mistakenly believe that their safety behaviors protect them from harm (Salkovskis, 1991; Teich, 1991). The present study examined the effects of safety-seeking behavior on fear reduction during exposure. Undergraduates (N = 60) displaying claustrophobic fear were randomized to one of three 30-min self-guided exposure conditions: (a) guided threat focus and reappraisal, (b) safety-behavior utilization, or (c) guided threat reappraisal plus safety behavior utilization. Measures of suffocation fear, entrapment fear, and peak fear during two distinct claustrophobic challenge tests were collected at pre-treatment, post-treatment, and two-week follow-up. Treatment process measures consisting of peak fear, expected anxiety, danger expectancies, and self-efficacy were collected at 5-min intervals throughout treatment. Also, safety-seeking behavior and attentional focus were collected to assess treatment integrity. Consistent with prediction, safety-seeking behavior exerted a detrimental effect on fear reduction at post-treatment and follow-up, while guided threat reappraisal was found to enhance fear reduction. Moreover, process analyses indicated that safety-behavior utilization exerted a detrimental effect on between-trial habituation but had no significant effect on either initial fear activation or within-trial habituation. Research and treatment implications of the findings will be discussed.

Loop quantum cosmology and the early universe

Sloan, David The Pennsylvania State University 2010 해외박사(DDOD)

In this dissertation we explore two issues relating to Loop Quantum Cosmology (LQC) and the early universe. The first is expressing the Belinkskii, Khalatnikov and Lifshitz (BKL) conjecture in a manner suitable for loop quantization. The BKL conjecture says that on approach to space-like singularities in general relativity, time derivatives dominate over spatial derivatives so that the dynamics at any spatial point is well captured by a set of coupled ordinary differential equations. A large body of numerical and analytical evidence has accumulated in favor of these ideas, mostly using a framework adapted to the partial differential equations that result from analyzing Einstein's equations. By contrast we begin with a Hamiltonian framework so that we can provide a formulation of this conjecture in terms of variables that are tailored to non-perturbative quantization. We explore this system in some detail, establishing the role of 'Mixmaster' dynamics and the nature of the resulting singularity. Our formulation serves as a first step in the analysis of the fate of generic space-like singularities in loop quantum gravity. The second issue is that of the role of inflation in LQC. In LQC the big bang singularity is replaced by a quantum bounce which is followed by a robust phase of super-inflation. We establish the behavior of effective equations for LQC in a generic setting then investigate in detail the particular case of early universe inflation caused by the slow roll of a scalar field down its potential. A natural measure is formed on the space of solutions to the equations of motion and it is established that in this scenario the a priori probability of seeing the required 68 efolds of inflation is in fact very high which stands in stark contrast to the results that have been presented in the classical case. In doing so we show that inflation in LQC suffers from no 'fine tuning' issue and is in fact a generic feature.

The Atala Mosque: Between polity and culture in medieval Jaunpur (India)

Sloan, Anna J University of Pennsylvania 2001 해외박사(DDOD)

This dissertation examines the role of architectural patronage, production, and documentation in the formulation of a new polity under the Sharqī sultans of Jaunpur (796–884/1394–1479). At the center of this inquiry is the Atala Mosque, the first monumental structure built under independent Sharqī rule, and the prototype for mosques subsequently built in the capital city of Jaunpur and the broader Sharqī realm. Although the mosque has been construed throughout the nineteenth and twentieth centuries as the product of materials plundered from a Hindu temple formerly occupying its site, this work presents archaeological and epigraphic evidence to indicate not only that the mosque was constructed from new materials, but also that its originality and craftsmanship were central to the articulation of a new Sharqī identity. This work combines a close inspection of the formal, symbolic, and artisanal formation of the new Sharqī mosque with a detailed analysis of the inscriptional evidence surviving from the period of transition from Tughluq to Sharqī hegemony in the Gangetic Plains region. The presentation and analysis of previously undocumented sites and inscriptions in the region, not only from the era of Sharqī rule, but also from the previous century, exposes the dialectic relationship between culture and polity in a period of dramatic historical change. It suggests that in two highly constructed languages—the image and the word—the transition from one polity to the next was revealed in conscious deviations from standard rhetorical strategies. Through the investigation of multiple facets of architectural production, this study offers new insight into the mechanisms by which the altered political landscape of post-Tughluq India was manifest in the emergence of distinctive regional cultures.