149 research outputs found
Novel combination therapies with the RNA Polymerase I-mediated transcription inhibitor CX-5461 improve efficacy in the treatment of multiple myeloma
No full text© 2019 Kylee Hannah MaclachlanMultiple myeloma (MM) is a malignant plasma cell disorder that is incurable with currently available therapy. The disease is genetically heterogeneous, with many recurrently mutated genes only seen in small numbers of patients and multiple clones present in each patient. This has limited potential approaches for designing widely applicable genetically targeted therapies.
rDNA transcription is consistently dysregulated in cancer, mediated through both oncogenic and tumour-suppressive pathways. RNA polymerase I (Pol I) transcriptional hyperactivity is observed in many cancers, with this dysregulation shown to provoke a survival checkpoint in haematological tumour cells. With the hypothesis that the therapeutic targeting of Pol I transcription may prove an effective strategy across a variety of malignant settings, our laboratory co-developed CX-5461; a highly selective small molecule Pol I-mediated transcription inhibitor, now in phase 1 clinical trials in relapsed / refractory malignancies.
We have previously demonstrated that single-agent treatment with CX-5461 provides a significant survival benefit in murine models of B-cell lymphoma and acute myeloid leukaemia. However, despite this improvement, drug resistance and relapse eventually occur, indicating combination drug therapy is essential for long term disease control and implementation in the clinic.
This thesis examines combination drug strategies in MM, centred on the therapeutic inhibition of Pol I transcription of ribosomal genes, with the aim of accelerating the clinical use of CX-5461 for MM. A boutique, high-throughput screen in human myeloma cell lines (HMCLs) of CX-5461 in combination with drugs having known clinical or promising preclinical efficacy in MM revealed that CX-5461 increases anti-proliferative effects when combined with a range of other agents, encompassing various targets. The histone deacetylase inhibitor panobinostat and the proteasome inhibitor (PI) carfilzomib demonstrated the most impressive synergy in vitro, both representing drug classes that are actively used to treat patients with MM.
In vivo testing demonstrated that the combination of CX-5461 with panobinostat increases survival compared with the single agents in both the Vκ*MYC murine model of MM and in C57BL-KaLwRij mice transplanted with 5T33 myeloma cells. Prolonged combination dosing in the Vκ*MYC model did not cause haematological toxicity beyond that seen with single agents. Investigating the molecular synergistic response to CX-5461 in combination with panobinostat indicated multiple potential mechanisms of synergy, including down-regulation of MYC and enhancement of the DDR elicited by CX-5461 alone.
To extend the translation of CX-5461 and its combination with panobinostat into the clinic for MM, where resistance to front-line PI treatment frequently develops, we investigated the synergistic relationship of CX-5461 with each of these drug classes. In addition to the screen finding that CX-5461 synergised with each of panobinostat and carfilzomib, we showed the triplet was synergistic in vitro beyond the individual combinations. Moreover, modelling clinical PI resistance, we generated a cell line that is resistant to the front-line PI bortezomib, and demonstrated that CX-5461 retains its impressive efficacy in this setting, both in vitro and in vivo, using the 5T33-C57BL6/KaLwRij model.
Taken together, the results described in this thesis will advance subsequent clinical trials utilising both CX-5461 and its combination with panobinostat in the treatment of relapsed multiple myeloma
Exploring experiences of postsecondary education for adult learners from communities of color in Oregon
No full textprepared by: Roberta Hunte, Gita Mehrotra, Miranda Mosier, Eva Skuratowicz, Kylee Sanders, Kevin Cherry, and Anita Gooding ; developed for the Higher Education Coordinating Commission.Title from PDF cover (viewed on June 15, 2021)."This report was completed by faculty and staff at Portland State University and Southern Oregon University, with support from HECC"--Page 3.This archived document is maintained by the State Library of Oregon as part of the Oregon Documents Depository Program. It is for informational purposes and may not be suitable for legal purposes.Includes bibliographical references.Funding for this report was made possible by Lumina FoundationMode of access: Internet from the Oregon Government Publications Collection.Text in English
Political knowledge and social media use in the digital media system
No full textMy dissertation explores how social media exposure affects political knowledge among the American public. Political knowledge is central to any understanding of citizen competence, yet key questions remain about how to best increase citizens’ information levels. My dissertation project assesses to what extent the dramatic rise in social media use has influenced how people receive, evaluate, and respond to information about politics. Previous research contends that although information about politics is increasingly accessible and available, the overall levels and social distribution of political knowledge within the American public has remained stable. However, the conception of political knowledge used most frequently in political science focuses on knowledge about the operation of government and key political players, which is only one of several types of political knowledge that citizens might possess.
My research begins with the premise that certain media types may be better or worse at facilitating learning of different types of knowledge, of which the familiar political science variety is only one. I introduce a knowledge typology that focuses on both knowledge content and type. In terms of knowledge content, most political behavior studies rely on a civics measure of knowledge (i.e. individuals’ understandings about what the government is). In addition to civics knowledge, this project also measures and tests current events knowledge (i.e. individuals’ understandings about what the government does). Even more importantly, the knowledge typology introduces subjective political knowledge as a distinct type of knowledge that individuals possess. Subjective political knowledge encompasses people’s perceptions about what they think they know about politics and their knowledge certainty. Assessing the relationship between objective and subjective political knowledge demonstrates that, although related, these knowledge types are not identical to one another. In an increasingly fragmented and polarized information environment, where people rely on sources like social media for political information, the assumed relationships between media exposure and political knowledge may no longer hold. Using survey and experimental data, I demonstrate that exposure to political information via social media platforms like Facebook can increase specific types of knowledge like subjective political knowledge, while having less of an impact on objective political knowledge. Ultimately this project introduces new types of knowledge and demonstrates how the rise of social media has important effects on people’s apparent levels of political knowledge.Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2020-05-01The student, Kylee Britzman, accepted the attached license on 2018-04-02 at 10:10.The student, Kylee Britzman, submitted this Dissertation for approval on 2018-04-02 at 10:16.This Dissertation was approved for publication on 2018-04-03 at 09:01.DSpace SAF Submission Ingestion Package generated from Vireo submission #12108 on 2018-08-31 at 17:18:08Made available in DSpace on 2018-09-04T20:33:57Z (GMT). No. of bitstreams: 2
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Motivational video vs self-selected song as a pre-task prime for maximal anaerobic performance
No full textMusic and video are widely used in pre-performance routines as motivational tools. Our study seeks to investigate if priming with a motivational video in comparison to priming with music will result in a greater anaerobic performance. Discussion: Neither of the motivational primes had a significantly greater anaerobic capacity, anaerobic power or a lower fatigue index. Music significantly increased perceived motivation, arousal and valence, but video only significantly increased motivation and valence. Video and music did not have a significant difference compared to each other for increasing perceived motivation, arousal and valence. Conclusion: Video and music used as a pre-performance motivational prime have no significant difference on maximal anaerobic performance and perceived motivation.Not peer reviewedStudent Research Day Poster (2019
Mindfulness-Based Stress Reduction: A Psychotherapeutic Intervention in Patients with Chronic Dermatological Diseases
No full textabstract: Psychological stress plays a vital role in skin disease. The worsening and reoccurrence of signs and symptoms of a wide array of skin diseases have been linked by various studies to stress. Together, stress and skin disease synergistically inhibit occupational, social, and emotional functioning resulting in diminished quality of life (Dixon, Witcraft, & Perry, 2019). Heightened levels of stress may contribute to an assortment of immediate and future adverse outcomes. These outcomes include triggering a skin outbreak, impairing function, behavioral avoidance, intense negative emotions such as shame and embarrassment, and emotional distress such as depression and anxiety (Dixon et al., 2019). The purpose of this paper is to discuss the relationship of stress, anxiety, and depression to the specific chronic skin diseases of acne vulgaris, psoriasis, vitiligo, rosacea, and atopic dermatitis. It will also discuss how a psychotherapeutic intervention called mindfulness-based stress reduction (MBSR) may decrease anxiety and depression in individuals affected by chronic skin diseases. This paper will also highlight the impact of MBSR on treatment adherence to dermatological prescription medications. A pilot program conducted in a dermatology clinic evaluates the effectiveness of an online mindfulness-based stress reduction intervention to decrease patient anxiety and depression. Results indicate clinical significance in that participants noted reduced anxiety and depression symptoms and scores, enjoyed MBSR and would continue MBSR. The potential benefits of this pilot program may include decreased patient anxiety and depression, increased patient satisfaction, increased treatment adherence, improved patient satisfaction of intervention, and improved patient outcomes
Managing History & Hauntings: The Spirit of Public History
No full textAuthor: Kylee Cole, public historian and historic preservationist at Arkansas State Parks. The Borden House at Prairie Grove Battlefield State Park, photo by Kylee Cole. Nestled in the heart of the rolling Ozark Mountains in Northwest Arkansas you’ll find Prairie Grove Battlefield State Park (PGBSP). This park, managed by Arkansas State Parks, is a sprawling collection of over 900 acres of rolling fields, tree-capped ridges, and nineteenth-century vernacular architecture. PGBSP pr..
Abstract IA10: Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers
No full textAbstract
Recent findings by our group have been instrumental in the development of the novel selective inhibitors of RNA Polymerase I (Pol I) (Drygin et al., Cancer Research, 2011; Bywater et al. Cancer Cell, 2012). This work has led to the fundamental discovery that ribosomal gene transcription by Pol I is not simply a “housekeeping” process in cancer cells but is highly regulated to maintain their viability (Bywater et al. Nature Reviews Cancer, 2013). Strikingly, inhibition of Pol I transcription shows a profound selectivity for malignant over normal cells in preclinical studies.
As with the majority of targeted therapies, despite initial favorable responses to approaches that target ribosome synthesis and/or function in MYC-driven lymphoma models, resistant disease emerges. It is increasingly clear that maximizing the inhibition of key signaling networks as a whole improves anti-tumor response. The well-established reliance of MYC-driven malignancies on elevated rates of ribosome biogenesis, mTORC1/eIF4E-driven protein synthesis, and cell growth makes them vulnerable to therapeutic strategies that target the ribosome. Thus we hypothesized that the simultaneous targeting of the ribosome at multiple points would antagonize the development of acquired resistance and consequently prolong survival in MYC-driven cancer models. We will present data to demonstrate that targeting both ribosome synthesis and function through the combination of novel inhibitors of RNA polymerase I transcription, and PI3K/AKT/mTOR signaling inhibitors or PIM Kinase inhibitors provides a significant increase in survival compared to treatment with single agents (Devlin et al., Cancer Discovery 2016; Rebello et al., Clinical Cancer Res. 2016). We will also discuss the molecular mechanism by which multipoint targeting of the ribosome synergizes to increase survival. Finally we will discuss our collaboration with Pimera, Inc. to develop highly selective second generation RNA Pol I inhibitors. The lead compound PMR-116 is showing exceptional activity in transgenic models of malignancy, including MLL-ENL AML and Vk*MYC driven multiple myeloma. We anticipate this compound will enter the clinic in 2017.
Citation Format: Ross D. Hannan, Nadine Hein, Katherine M. Hannan, Gretchen Poortinga, Elaine Sanij, Jirawas Sornkom, Kylee MacLachlan, Andrew Cuddihy, Carleen Cullinane, Luc Furic, Denis Drygin, Mustapha Haddach, Simon Harrison, Grant McArthur, Richard B. Pearson. Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA10.</jats:p
Abstract IA10: Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers
No full textRecent findings by our group have been instrumental in the development of the novel selective inhibitors of RNA Polymerase I (Pol I) (Drygin et al., Cancer Research, 2011; Bywater et al. Cancer Cell, 2012). This work has led to the fundamental discovery that ribosomal gene transcription by Pol I is not simply a “housekeeping” process in cancer cells but is highly regulated to maintain their viability (Bywater et al. Nature Reviews Cancer, 2013). Strikingly, inhibition of Pol I transcription shows a profound selectivity for malignant over normal cells in preclinical studies.
As with the majority of targeted therapies, despite initial favorable responses to approaches that target ribosome synthesis and/or function in MYC-driven lymphoma models, resistant disease emerges. It is increasingly clear that maximizing the inhibition of key signaling networks as a whole improves anti-tumor response. The well-established reliance of MYC-driven malignancies on elevated rates of ribosome biogenesis, mTORC1/eIF4E-driven protein synthesis, and cell growth makes them vulnerable to therapeutic strategies that target the ribosome. Thus we hypothesized that the simultaneous targeting of the ribosome at multiple points would antagonize the development of acquired resistance and consequently prolong survival in MYC-driven cancer models. We will present data to demonstrate that targeting both ribosome synthesis and function through the combination of novel inhibitors of RNA polymerase I transcription, and PI3K/AKT/mTOR signaling inhibitors or PIM Kinase inhibitors provides a significant increase in survival compared to treatment with single agents (Devlin et al., Cancer Discovery 2016; Rebello et al., Clinical Cancer Res. 2016). We will also discuss the molecular mechanism by which multipoint targeting of the ribosome synergizes to increase survival. Finally we will discuss our collaboration with Pimera, Inc. to develop highly selective second generation RNA Pol I inhibitors. The lead compound PMR-116 is showing exceptional activity in transgenic models of malignancy, including MLL-ENL AML and Vk*MYC driven multiple myeloma. We anticipate this compound will enter the clinic in 2017.
Citation Format: Ross D. Hannan, Nadine Hein, Katherine M. Hannan, Gretchen Poortinga, Elaine Sanij, Jirawas Sornkom, Kylee MacLachlan, Andrew Cuddihy, Carleen Cullinane, Luc Furic, Denis Drygin, Mustapha Haddach, Simon Harrison, Grant McArthur, Richard B. Pearson. Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA10.
©2017 American Association for Cancer Research
Creating a Safe Space: Therapeutic Relationships With Adolescents Who Have Experienced Childhood Emotional Abuse
No full textIn this capstone the author explores the experiences of adolescents who have endured childhood emotional abuse within the therapeutic relationship. Significant numbers of individuals experience childhood emotional abuse, with adolescence offering a developmental period of critical intervention. However, exploration of the impact on this population remains a gap in the literature. The author conducted a comprehensive literature review, analysis, and synthesis of various scholarly studies and found that adolescence holds an array of challenges that inhibit the ability to form and maintain strong therapeutic alliances through difficulties with trust, emotional dysregulation, rejection sensitivity, and the stigmatisation of mental health care. The negative effects of childhood emotional abuse often hinder the capacity to form therapeutic alliances because of challenges in trust, emotional dysregulation, and low psychological well-being. The intersection of these factors has significant negative implications for opportunities for adolescents who have experienced childhood emotional abuse to foster positive relationships and heal through the therapeutic process. Understanding the intersection of impacts on this population is vital to provide therapeutic supports competently and effectively. In consideration of the findings of the capstone project, the author has made suggestions for clinical applications and future areas of research
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