SACM - United States of America
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Item Restricted Development of a novel therapeutic intervention for p53-mutant advanced cancers leveraging their DNA damage response liabilities(University at Buffalo, 2025-05) Alruwaili, Mohammed Muharrab; Andrei, BakinColorectal Cancer (CRC) and Pancreatic Ductal Adenocarcinoma (PDAC) are among most lethal cancers worldwide. Despite initial response to standard-of-care therapy, a significant proportion of CRC/PDAC cancers relapse and progress to metastatic disease with poor overall survival (OS). Thus, better treatment options are urgently needed. Genetic alterations in the tumor suppressor p53 gene (TP53) are found in most CRC and PDAC cases and contribute to cancer relapse, progression, and metastasis. Even though the functional consequences of p53 mutations have been extensively studied, there are no FDA-approved drug or their combination targeting p53-mutant cancers. This thesis work is aimed at the development of effective therapeutic approaches for p53-mutant cancers. The initial concept of the two-drug strategy, working as an inducer-amplifier pair, was suggested for selectively targeting p53-mutant triple-negative breast cancer (Zonneville at al., Commun. Biology, 2021). The current thesis research investigated the mechanisms underlying the efficacy and selectivity of our two-drug strategy using p53-mutant CRC and PDAC models. Our two-drug strategy utilizes thymidine analogue TAS102, acting as an inducer of single-strand DNA breaks through a post-replicative DNA repair, and poly (ADP-ribose) polymerase (PARP) inhibitor, acting by delaying repair of single-strand breaks in DNA. This two-drug concept is based on the following rationale. Our analysis of the genomic data from the Cancer Genome Atlas (TCGA) showed high expression levels of Base-Excision Repair (BER) and elevated tumor mutational burden (TMB) in p53-mutant CRC and PDAC, suggesting impairment in BER. The BER activity in CRC and PADC cells was examined by a new methodology with thymidine analogues (ethynyl-deoxyuridine (EdU) or trifluorothymidine (TFT, a component of TAS102)). The analysis revealed a significant delay in the removal of genomic EdU or TFT in p53-mutant cells compared to isogenic p53 wildtype (p53WT) cells. We also noted that p53-mutant cells accumulated in the late S/G2 phase while p53WT accumulated in G1. Thymidine analogues (EdU, TFT) induced buildup of DNA breaks in p53-mutant cancer cells, while non-tumor p53WT cells showed only a transient DNA damage. Further, addition of a PARP inhibitor (PARPi) increased DNA double-strand breaks (DSBs) and cell death selectively in p53-mutant cells, while PARPi alone did not induce DNA damage. Cytotoxicity analysis showed that thymidine analogues synergized with PARP inhibitors selectively in p53-mutant cells. In preclinical vivo models, the TAS102-PARPi combination was far more effective than either drug alone in p53-mutant Cell-Derived Xenograft (CDX) and Patient-Derived Xenograft (PDX) models. Immunohistochemistry data showed that the two-drug treatment increased DNA damage and cell death while decreasing cell proliferation. The two-drug combination and TAS102 exhibited comparable tumor control in the p53WT PDX model. Importantly, the TAS102-PARPi therapy did not exhibit major side toxic effects in mice even after prolonged drug administration. Our two-drug TAS102-PARPi strategy is now being tested in the first-in-human phase I study with TAS102 and talazoparib in refractory CRC (NCT04514497, PI Dr. Fountzilas). The dose-escalation part of the study showed that the TAS102-talazoparib treatment is well-tolerated, and no major dose-limiting toxicities were observed. The analysis showed that the addition of talazoparib to TAS102 increased TFT-positive cells in peripheral blood mononuclear cells (PBMCs) and in tumor tissues. The median progression-free survival (mPFS) was 5.7 months in the DL3 group compared to 1.9 months for historical TAS102 alone. Investigation of the mechanism behind the two-drug strategy showed that incorporation of thymidine analogues into DNA provoked post-replicative BER-mediated repair, generating DNA single-strand breaks (SSBs). As SSB repair is assisted by PARP, the inhibition of PARP increased more lethal DSBs. Non-tumor p53WT cells responded with activation of the p53-p21 axis, leading to G1-arrest and efficient removal of thymidine analogues. In contrast, p53-mutant cells, lacking the G1 checkpoint, accumulated DNA damage and were arrested in G2 for a prolonged time. Investigation of DNA damage response (DDR) revealed that TAS102-PARPi induced signaling pathways mediated by ATM (Ataxia-Telangiectasia Mutated) and ATR (Ataxia-Telangiectasia Rad3-related) kinases. Our study showed that ATM kinase-controlled activation of the p53-p21 axis, whereas ATR kinase-controlled activation of CHK1 and WEE1 kinases, which mediate induction of the G2-checkpoint, blocking the entrance to mitosis. Furthermore, the cell-cycle analysis demonstrated that the TAS102-PARPi treatment induced G2-arrest and high levels of DSBs selectively in p53-mutant cells while p53WT cells were transiently arrested in G1 and resumed the cell cycle after drug withdrawal. This finding suggested that blockade of ATR kinase or its downstream effectors may release p53-mutant cells with unrepaired DNA into mitosis, leading to cell death. This hypothesis was examined using several approaches, including cytotoxicity, immunofluorescence microscopy, and flow cytometry. We found that the blockade of ATM reduced sensitivity to TAS102-talazoparib in all tested cell lines. In contrast, blockade of ATR kinase markedly enhanced the cytotoxicity of TAS102-talazoparib in p53-mutant cells and increased levels of γH2AX and phospho-H3 in cells treated with TAS102-talazoparib, indicating increased DNA damage and entrance to mitosis. Similar effects were observed by blockade of downstream effector kinase WEE1. Furthermore, blockade of WEE1 markedly increased cell death in p53-mutant cells treated with TAS102-talazoparib. Based on these data, we developed a triple-drug strategy combining the TAS102-PARPi treatment with a sequential delayed application of the G2 checkpoint kinase inhibitors. This sequential triple-drug combination works as an inducer–amplifier–terminator trio to induce cell death in p53-mutant cells selectively. The in vivo studies showed that this sequential triple-drug strategy was more effective in tumor growth control compared to the TAS102-PARPi treatment or WEE1i alone. In the CRC HT29 tumor xenograft model, the triple-drug treatment reduced tumor growth by 63%, compared to 18% by WEE1i or 43% by TAS102-talazoparib alone. Likewise, the triple-drug regimen showed greater tumor control in the CRC-PDX-03-26-RP model carrying p53H178T/Ter67fs and KRAS-G12D. In the PDAC PDX-14312 model, carrying p53R175H, a triple-drug treatment reduced tumor growth by ~80%, whereas WEE1i monotherapy by ~30% or TAS102-talazoparib by ~43%. Importantly, neither of the treatments exhibited major side toxic effects or caused changes in major organs (kidney, liver, lungs, heart) based on the pathology analysis of mice. These preclinical data provide strong support for a sequential triple-drug treatment strategy that works as an inducer–amplifier–terminator trio to induce cell death in p53-mutant cancers. This novel triple-drug therapeutic strategy for p53-mutant cancers has strong potential to improve the management of CRC and PDAC and meaningfully impact the health of cancer patients.10 0Item Restricted WORLD ENGLISHES: THE ATTITUDES AND PERCEPTIONS OF STUDENTS AT A SAUDI UNIVERSITY WITH IMPLICATIONS FOR ENGLISH LANGUAGE PEDAGOGY(The University of Mississippi, 2025-05) Aldawsari, Abdullah; Schaefer, VanceThis study investigates the attitudes and perceptions of English department students at a Saudi university towards varieties of World Englishes (WEs) based on Kachru’s (1985, 1992) three concentric circles model. The study is guided by four central research questions; it investigates Saudi university students’ awareness of WEs varieties. It also explores their attitudes towards several varieties of WEs, specifically American English (AE), Indian English (IE), and Saudi English (SE). Furthermore, it investigates their attitudes and perceptions towards learning WEs varieties. Lastly, it explores their perceptions of key dimensions of WEs, including legitimacy and ownership as they pertain to SE. Using a mixed-methods approach, the study employs a verbal guise task (VGT), a semantic differential scale (SDS), a Likert-scale questionnaire (LSQ), and semi-structured interviews. The research design consists of a pilot study and a main study. Findings seem to indicate a preference for Inner Circle varieties (e.g., AE), perceiving them as more competent and legitimate. Notably, there appears to be a growing recognition of SE by Saudi learners within the Kingdom of Saudi Arabia (KSA) as a legitimate English variety. This may highlight an emerging endonormative orientation in the Saudi context. However, perceptions of ownership of English appear to remain contested within the KSA due to the continued influence of exonormative orientations in educational curricula and the limited institutional recognition or exposure to SE. This study contributes to applied linguistics by expanding attitudinal research within the Expanding Circle, specifically in the Saudi context. It highlights the pedagogical relevance of incorporating locally recognized English varieties, such as SE, into language curricula in the KSA. This study calls for a more pluralistic approach to English language pedagogy in the KSA, which reflects the sociolinguistic realities of English use and empowers learners to claim ownership of their local variety (SE). At the same time, it underscores the need to reflect on the reliance on Inner Circle norms within the context of the KSA.11 0Item Restricted Liquidity Creation, Bank Funding, and Risk-Taking: The Role of ESG(University of New Orleans, 2025-05) Bin Kowibeen, Sattam; Hassan, M. KabirThis dissertation explores two critical types of risks faced by banks that include liquidity risk and credit risk. Furthermore, it tests whether bank regulations such as adopting the environmental, social, and governance (ESG) standards in addition to diversifying funding resources play crucial roles in mitigating them. Also, this dissertation aims to provide evidence of whether these risks vary depending on banks sizes. The final sample consists of 136 U.S. commercial banks covering the period from 2005 to 2022. Furthermore, a variety of econometric methods are applied that include OLS regression, random effects (RE), two-step system Generalized Method of Moments (GMM), regression discontinuity (RD), the bias-corrected Least- Squares with Dummy Variables (LSDVC), and the Two-Stage Least Squares regression (2SLS). The first chapter investigates whether ESG performance plays a mediating role in the effect of funding costs on bank liquidity creation. The findings of this chapter reveal that funding costs significantly reduce liquidity creation, implying that higher funding costs decrease banks’ ability to create liquidity. Additionally, adopting ESG principles increases banks’ ability to create more liquidity. Moreover, ESG performance of the sampling banks plays a significant role in mediating the relationship between funding costs and liquidity creation, which implies that depositors accept low interest payments due to the good ESG performance of the sampling banks, which suggests increasing the ability of the sampling banks to create liquidity. The second chapter examines the effect of bank liquidity creation and bank funding diversification on bank risk-taking, as represented by non-performing loans (NPLs). Moreover, the chapter aims to explore the mediating role of bank size in these relationships. The findings of this chapter show that NPLs increase significantly as the sampling banks create more liquidity. Furthermore, funding diversification significantly reduces NPLs and enhances the stability of the sampling banks. Finally, bank size significantly moderate the impact of bank liquidity creation and bank funding diversification on NPLs, which is more evident for the case of large banks.66 0Item Restricted COORDINATED CONTROL OF DISTRIBUTED ENERGY RESOURCES IN POWER DISTRIBUTION SYSTEM(Colorado School of Mines, 2025) N. Almazroui, Abdulrahman; Mohagheghi, SalmanRecent advancements in photovoltaic (PV) and battery technologies, along with significant improvements in the efficiency of power electronic converters, have led to a rapid increase in the penetration of rooftop PV systems and electric vehicles (EVs) within distribution networks. While the integration of these technologies offers substantial economic and environmental benefits and supports the transition toward a more sustainable energy future, it also introduces new operational challenges for power systems. These challenges may include voltage fluctuations, increased system losses, and occurrences of overvoltage or undervoltage, particularly under high PV and EV adoption levels. Traditionally, voltage and reactive power regulation in distribution systems has been managed through Voltage and Var Control (VVC) schemes using equipment such as substation on-load tap changers (OLTCs), voltage regulators, and shunt capacitors. However, with increasing PV and EV penetration, it becomes essential to consider these distributed energy resources in coordination with conventional control devices. This shift necessitates the development of a unified framework for Voltage, Var, and Watt Control (VVWC) to ensure reliable and efficient grid operation. The primary objective of this study is to propose a comprehensive and realistic solution for the coordinated control of PV and EV resources in unbalanced power distribution systems, while considering sustainability and energy justice objectives. To achieve this, a mixed-integer nonlinear multi-objective optimization model is developed, employing a Chebyshev goal programming approach to ensure Pareto-optimal solutions. The model incorporates multiple objectives, including minimizing PV active power curtailment, reducing system losses, flattening the voltage profile, and minimizing unserved demand weighted based on social vulnerability. The formulation accounts for the inherent asymmetries and phase imbalances in distribution systems. To further enhance the study, a seasonal hosting capacity analysis was conducted using correlated hourly sampling, capturing system behavior across different seasons. The proposed VVWC framework is validated through simulations on a modified version of the IEEE 123-bus test feeder, demonstrating its effectiveness in supporting high PV and EV penetration levels while maintaining grid stability and operational efficiency. Most importantly, the study confirms that only through coordinated control strategies can power systems achieve higher integration of distributed energy resources.6 0Item Restricted Mindfulness as a Culturally Sensitive Moderator Between Stress and Anxiety in Saudi Female International Students(University of Cincinnati, 2024) Aldosari, Hend Abdullah; Brubaker, MichaelInternational students studying in the U.S. are becoming increasingly more common as students take advantage of new and existing educational opportunities. One of the larger populations of international students in the U.S. are Saudi students. While students face a number of stressors and anxieties related to schooling, Saudi international students face additional stressors related to adapting and acclimating to the new cultural environment. This is especially exacerbated in Saudi women, as they face discrimination based on the way they dress and have additional burdens such as family and childcare. However, culturally sensitive counseling approaches which address this unique population have yet to be fully investigated or developed. Mindfulness is a technique which involves quieting one’s mind and body and reflecting on one’s situation and circumstances without self-judgment. This approach has been used extensively as a technique to reduce and moderate the relationship between stress and anxiety generally and has been found to be effective in international students as well. Furthermore, mindfulness intersects directly with the principles of Islam through its focus on self-reflection and calming one’s mind, making it a culturally sensitive approach for Muslim clients, such as Saudi women. However, the moderating effects of mindfulness on stress and anxiety in Saudi female international students has yet to be investigated. The goal of this dissertation is to review what is known on the effects of mindfulness on stress and anxiety in international students and to investigate the moderating effects of mindfulness on stress and anxiety in Saudi female students in the U.S.11 0Item Restricted Resilience and Reality: Exploring the Lived Experiences of People Living with HIV in Texas During the COVID-19 Pandemic – A Qualitative Study.(The University of Texas at Arlington, 2025-05) Alanazi, Ahmed; Eusebius, SmallThis study investigated the lived experiences of individuals living with HIV (PLWH) in the Dallas-Fort Worth (DFW) area of Texas during the COVID-19 pandemic, using an Interpretative Phenomenological Analysis (IPA) framework. The research examined the intersection of health, social dynamics, and psychological resilience among PLWH, who faced compounded vulnerabilities due to systemic inequities and the dual public health crises of HIV and COVID-19. Through semi-structured interviews with ten participants from diverse backgrounds, the study captured the profound impacts of disrupted healthcare systems, heightened stigma, and social isolation on this marginalized population. The findings reveal that the pandemic exacerbated existing inequities in access to antiretroviral therapy (ART) and mental health services, while simultaneously highlighting the remarkable resilience of the participants. Adaptive coping mechanisms, community support, and advocacy efforts emerged as critical strategies for navigating the layered challenges of living with HIV during a global health crisis. The study identified key themes such as social isolation and estrangement, the emotional toll of the diagnosis, resilience in navigating health crises, and redefining possibilities through HIV services, with each theme branching into sub-themes that offer deeper interpretations. Participants' narratives underscore the necessity for tailored interventions that address the broad-ranging needs of PLWH, including the integration of mental health services into HIV care and the development of socially-led education campaigns to combat stigma. By focusing on the unique experiences of PLWH, this research contributes to the broader understanding of syndemic health crises, where HIV/AIDS interacts synergistically with other social, economic, and health issues, exacerbating the overall impact on affected communities. The study calls for a paradigm shift in public health policy, emphasizing the need for inclusive and intersectional approaches that prioritize equity, resilience, and community empowerment. The findings also provide actionable insights for healthcare providers, policymakers, and community organizations, advocating for robust telemedicine infrastructure, stigma reduction initiatives, and comprehensive support systems that ensure continuity of care during public health emergencies. As the global community still grapples with the lasting impacts of the COVID-19 pandemic, this study underlines the urgency of reimagining public health strategies. By centering the voices of those living at the intersection of HIV and COVID-19, it challenges existing paradigms and paves the way for innovative solutions that transcend individual health crises, offering a blueprint for more equitable, inclusive, and resilient healthcare systems. The research not only highlights the structural inequities that deepen health disparities but also illuminates the resilience and adaptive capacities of PLWH, providing a foundation for policies and practices that uphold dignity, wellbeing, and social inclusion for all.13 0Item Restricted Open Banking Framework: A Comparative Study of Evolving Law in the Kingdom of Saudi Arabia and the United States of America(Indiana University, 2025-05) Alatram, Abdulhamid; Henderson, WilliamOpen banking is reshaping the financial sector by enabling third-party access to consumer financial data and; fostering innovation while raising regulatory challenges. This study compares the legal frameworks that governs open banking in the Kingdom of Saudi Arabia (KSA) and the United States (US), focusing on consumer protection, data privacy, and compliance. KSA adopts a centralized regulatory model under the Saudi Central Bank (SAMA), ensuring uniform compliance, while the US follows a fragmented, market-driven approach with multiple regulators. Through a comparative legal analysis, the study identifies key differences, regulatory gaps, and areas for improvement in transparency, dispute resolution, and responsible data-sharing practices. The findings of this dissertation highlight the need for balanced regulatory frameworks that promote financial innovation while safeguarding consumer rights. This research provides insights for policymakers and industry stakeholders that; advocate for legal reforms that enhance security, efficiency, and consumer trust in open banking ecosystems.11 0Item Restricted Evolutionary Design with Freedom and Rhythm for Heat Transfer, Strength, and Power Utilization(Duke University, 2024) Almahmoud, Hamad; Bejan, AdrianThe thesis combines fundamental studies on the evolution of design and performance in flow fields. The first study investigates the evolving architecture of a composite material with configurable inserts, comparing different shapes such as plates, forks, chains, and diamonds. The inserts, having higher thermal conductivity and lower elasticity than the base material, lead to better performance in thermal conductance and mechanical strength when distributed wisely. Next, the thesis explores tree-shaped flow in a dendritic heat exchanger, examining two flow architectures: parallel orifices and sequential slits. It provides theoretical and numerical analysis on the step-down ratio in the size of the orifices and channels, contributing key design principles for future dendritic heat exchanger systems. The third study broadens the design of heat transfer systems by varying both the fin and flow channel aspect ratios. This comprehensive approach allows for predicting the complete design of high-density heat transfer architectures, providing higher heat transfer rates and lower pumping power. The fourth study is about periodic in-and-out airflow through a single orifice into an enclosure to refresh air quality. Two scenarios of airflow rhythm are analyzed, with findings indicating the optimal time intervals for maximum air replacement and minimal energy expenditure. The fifth study explores animal locomotion and the rhythm of propulsion in frogs and swimmers. The cyclic nature of work and energy dissipation is analyzed, revealing that evolutionary changes in body design and locomotion rhythm enhance power utilization and speed. Together, these studies highlight the role of evolving design principles in optimizing both natural and engineered systems, demonstrating how freedom in configuration and design leads to improved performance across a variety of applications.3 0Item Restricted Islamic Finance, Dividend Policy, and Performance of Insurance Firms(The University of New Orleans, 2025-05) Almoaheem, Yazeed; Hassan, KabirThe dissertation investigates the impact of Covid-19 pandemic and dividend policy on the performance of insurance firms. It examines the impact of the Covid-19 pandemic on the performance of Islamic insurance versus conventional insurance firms in the Organization of Islamic Cooperation (OIC) member countries. Using Dynamic Capabilities theory and Resource Dependence Theory, the study examines the reasons behind the more significant performance reduction in Islamic insurance firms during the pandemic. Using firm- and country-level panel data from 425 insurance firms for 7 years (2016-2022) and employing different regression models, the analysis focuses on Return of Assets (ROA) and Asset Turnover Ratio as performance measures. The results indicate that Islamic insurance firms exhibited a greater reduction in performance, during the pandemic, compared to conventional firms, primarily due to weaker liquidity management and operational flexibility. Cash from operating activities (COA) was the key factor of lack of liquidity management, contributing to the underperformance of Islamic insurance firms during the pandemic. The findings highlight the need for improved liquidity management approaches in Islamic insurance firms to increase their resilience to future economic shocks. The dissertation also investigates the impact of dividend policy on the performance of 688 insurance firms globally from 2014 to 2022. Employing different econometric models, we find that dividend policy significantly increases both accounting (ROAA) and market (MKTCAP) performance. The findings align with the Dividend Signaling Theory and the Agency Theory of Free Cash Flow, which emphasize that dividend payouts signal a stable financial health and mitigate agency problems. Our findings demonstrate that consistent dividend payments (CONDIV) increase ROAA and MKTCAP by 0.007 and 0.139, respectively, which underlines the importance of consistent dividends. Channel analysis shows that corporate governance board committees, CEO duality, and board gender diversity amplify the positive effect of dividend policy, while larger board size diminishes it. This provides a global understanding of dividend policy significant impact on insurance firm performance. Jointly, the dissertation’s findings provide a complete picture to understand the financial decisions and governance structures that affect the performance of insurance firms during economic shocks such as Covid-19 pandemic and on the global stage.45 0Item Restricted Firm Performance Sustainability and Reputation(University of New Orleans, 2025-05) Alharbi, Mohammed; Hassan, M.KabirThe first essay investigates the impact of the COVID-19 pandemic on the performance of Sharia-compliant and non-compliant firms within the Organization of Islamic Cooperation (OIC) member countries. Employing panel data from 337 publicly listed non-financial firms between 2016 and 2022, the research compares profitability and growth metrics, specifically Return on Assets (ROA), Return on Equity (ROE), and firm growth rates. Using ordinary least squares (OLS) and random effects (RE) regression models, the analysis incorporates firm-specific variables. The findings indicate that both Shari'ah compliance and the COVID-19 pandemic negatively impacted firm performance. Sharia-compliant firms experienced significantly greater declines in ROA and ROE compared to non-compliant firms. Furthermore, compliant firms exhibited reduced growth rates, which highlights potential vulnerabilities stemming from ethical financing constraints and conservative investment practices. The interaction between Shari’ah compliance and the COVID-19 pandemic further worsened these adverse outcomes, indicating an increased vulnerability among compliant firms during times of economic disruption. A comprehensive regional analysis has identified that firms in Asia were particularly affected, thereby emphasizing the geographic variations in the impacts observed. The second essay is an empirical study of the relationship between Environmental, Social, and Governance (ESG) performance and corporate reputation. The goal is to address the existing gap in sustainability literature. This study employs a comprehensive panel dataset that includes 4,000 US firms from 2014 to 2023. The aim of this study is to investigate how ESG performance influences corporate reputation through annual and cumulative corporate responsibility awards. The study utilizes various econometric techniques to tackle issues concerning endogeneity and sample selection bias. The econometric techniques include logistic regression, Ordinary Least Squares (OLS), Two-Stage Least Squares (2SLS), Propensity Score Matching (PSM), Entropy Balancing, and Heckman selection models. The results consistently show that companies with better ESG performance are significantly more likely to be acknowledged with corporate responsibility awards. The strength of these findings is supported by various robustness analyses. The study examines how firm-specific characteristics, including company size, financial performance, and research and development, influence the relationship between ESG engagement and reputation outcomes. The evidence indicates that these factors enhance the positive impact of ESG performance on corporate reputation. The findings highlight the strategic value of ESG initiatives for corporate leaders and policymakers, which emphasizes their role in enhancing stakeholder trust and securing long-term competitive advantages.28 0