MEDICA@MUSC (Medical University of South Carolina)
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Engineering CXCR2-Ligand-Based Fusion Proteins to Modulate Myeloid Cell Trafficking in Pancreatic Cancer
Get PDFPancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates of all cancers, and limited treatment options exist. Immunotherapy is effective in some cancer types, but the immunosuppressive tumor microenvironment (TME) of PDAC is a barrier to effective immunotherapy. CXCR2+ myeloid-derived suppressor cells (MDSCs) are abundant in PDAC tumors in humans and in mouse models. MDSCs suppress effector cell function, making them attractive targets for restoring anti-tumor immunity. The studies outlined in this dissertation (1) link tumor-intrinsic oncogenic signaling to dysregulated myeloid activity in PDAC, (2) describe a rationally designed fusion protein and potent inhibitor of CXCR2+ myeloid cell migration in PDAC, and (3) explore CXCL1-Fc as a modular platform for CXCR2-targeted therapeutics. We utilize cytokine arrays and quantitative ELISA to show that the most abundant soluble factors released from a genetically diverse set of human and mouse PDAC cells are CXCR2 ligands, including CXCL8, CXCL5, and CXCL1. Using engineered cell models, we showed that expression of CXCR2 ligands is at least partially driven by mutant KRAS and NF-κB signaling, which are two of the most commonly dysregulated pathways in PDAC. CyTOF and flow cytometry analyses revealed that myeloid cells are the dominant immune cell population in PDAC tumors, with MDSCs expressing high levels of CXCR2. Moreover, we observed that myeloid cells readily migrated toward conditioned media (CM) derived from PDAC cell cultures using Boyden chamber transwell assays. To therapeutically target immunosuppressive myeloid cells, we designed CXCR2 ligand-Fc fusion proteins. Unexpectedly, these fusion proteins were superior to native chemokines in binding and activation of CXCR2 on myeloid cells. These “superkines” were potent inhibitors of PDAC CM-induced myeloid cell migration and were superior to CXCR2 small-molecule inhibitors and neutralizing antibodies. Finally, we demonstrate that CXCL1-Fc can serve as a modular platform for delivering therapeutic payloads to CXCR2+ cells and may have applications beyond cancer, such as in wound healing. Together, these findings provide mechanistic insight into myeloid dysregulation in PDAC and introduce a promising class of immunotherapeutic agents capable of altering the myeloid landscape to improve treatment outcomes
Global ERK/MAPK Activation Determines Oncogenic Fitness in KRAS-Mutant Pancreatic Ductal Adenocarcinoma
No full textIn pancreatic ductal adenocarcinoma (PDAC), ~95% of cases harbor an activating KRAS mutation. The most common KRAS mutations in PDAC are KRASG12D (42%), KRASG12V (31%), and KRASG12R (15%). Patients harboring KRASG12R mutations have increased overall survival compared to those with KRASG12D/V-mutations. While KRASG12D/Vare common in all KRAS-mutant cancers, KRASG12Ris only common in PDAC.
KRASG12R is unable to activate the lipid kinase PIK3CA, a KRAS effector that is important for tumorigenesis in murine models. To investigate the tumorigenic potential of KRASG12R and the mechanisms that enable this mutation to drive PDAC, we developed both pancreas-specific and whole-body KRAS-mutant genetically engineered mouse models (GEMMs). Unlike their KrasG12D counterparts, KrasG12R-mutant mice exhibited extremely limited tumorigenesis. Using murine and human PDAC cell lines, GEMMs and patient-derived xenograft mouse models we showed that KRAS is not the primary driver of PI3K activity in human PDAC regardless of specific KRAS mutation. Overall, KRASG12R and KRASG12D activate a similar pancreas-specific transcriptional network, but KRASG12R promotes these pathways less robustly, due to limited activation of WT RAS isoforms and reduced ERK nuclear translocation. Additionally, KRASG12R-pancreatic tumors have an altered tumor microenvironment with reduced collagen deposition and metastatic liver invasion.
Further investigation of KRAS-independent mechanisms of PI3K activation revealed that PTEN, the negative regulator of PI3K signaling, is inactivated in PDAC through a redox-mediated modification that supports elevated basal PI3K signaling. All four PI3K Class I isoforms contribute to global PI3K signaling, and inhibition of any single isoform is insufficient to limit PDAC proliferation. Using proximity labeling alongside RNA sequencing analysis, we mapped early effector interactions of common and rare KRAS mutations to show that pancreatic cells are highly tolerant to overexpression of common mutations, but overexpression of the rare, constitutively active KRASQ61L leads to impaired proliferation and increased apoptosis through hyperactivation of the ERK/MAPK pathway. Overall, these findings reveal key mechanisms of KRAS-independent PI3K activation, define the role of KRAS-driven global ERK/MAPK signaling in determining oncogenic potential, and underscore the need for dual targeting of KRAS and PI3K/AKT pathways in pancreatic cancer
Enhancing Caregiver Understanding of Pediatric Spasticity Through Multimodal Educational Resources
No full textSpasticity is a highly complex neuromuscular impairment, which can make it a particularly difficult topic for caregivers to fully understand and manage without appropriate support and education. This capstone project was completed at a pediatric outpatient therapy clinic under the mentorship of an occupational therapist who specializes in neuro-related conditions. Following a clinical needs analysis, this project was designed to address a specific need: the limited availability of clear, accessible educational resources related to spasticity for caregivers.
The purpose of the project was to increase access to spasticity-related education by developing multimodal resources that rehabilitation therapists could easily distribute to caregivers The project had two primary goals: (1) to obtain advanced knowledge about pediatric spasticity and best practices for creating healthcare educational resources, and (2) to design sustainable and informative tools that support caregivers in understanding and managing spasticity in their child. The materials were intentionally written in clear, jargon-free language to ensure caregivers of all health literacy levels could understand and apply the information.
The final deliverables included a series of educational handouts and videos. These resources were reviewed and piloted at the clinic, where feedback was collected from participating caregivers. Project outcomes indicated that 100% of caregivers reported increased confidence and competence in understanding spasticity. They also expressed feeling better equipped to support their child’s needs at home using the knowledge provided.
This project highlights the value of accessible, family-centered spasticity educational tools in outpatient pediatric settings and supports occupational therapists in their role as educators and advocates for caregiver empowerment
OB/GYN Physician Perspectives on Maintenance of Certification (MOC)
No full textAbstract
Objective: To evaluate physician perspectives of the current maintenance of certification(MOC) activities utilized by the American Board of Obstetrics and Gynecology (ABOG).
Methods: We performed a convergent mixed methods study, using parallel quantitative and qualitative data collected via the internet plus paper surveys of a nationwide sample of Obstetrics and Gynecology (Ob/Gyn) physicians from November 12 to December 13, 2024. The questionnaire included 23 items about various aspects of maintenance of certification, physician burnout and demographics. Three open-ended questions regarding the pros and cons of MOC and recommendations for improvement were also included.
Results: Of the 5,083 requests sent, we received 503 responses (response rate 9.9%) of which 54 were excluded because they reported they do not participate in MOC through ABOG. Of the 449 remaining respondents, a significant majority of physicians reported that MOC was valuable relative to their time spent (62.8%) and relevant to caring for their patients (77.8%). Most respondents felt that MOC aided their professional development (70.3%), lifelong learning (64.3%) and patient safety (53.3%). Conversely, forty-six percent of respondents perceived MOC activities as a burden. Over half of physicians presently experience burnout (54.1%) and one-third of these felt MOC was a major contributor. Extending the recertification cycle to 2-years was supported by 61.8% of respondents and to a 3-year cycle by 46%. The most common suggestions for improving MOC were extending the time for recertification and scrapping or overhauling the Practice Improvement/Chart Review activities.
Conclusion: Most Ob/Gyn physicians view the current MOC process as valuable and relevant to their practice of Medicine. However, most respondents also felt the process could be improved
Expanding Health Literacy Among Community-Dwelling Older Adults: Developing and Delivering Educational Sessions
No full textOlder adults face numerous challenges in maintaining their health and independence, often due to limited access to health information that supports aging in place. This capstone project was executed in a community-based setting catered to older adults and focused on increasing health literacy to promote independence and overall well-being. Through interactive educational sessions, the project aimed to enhance participants’ understanding of key health topics relevant to their daily lives.
The overarching goals of this project were to provide accessible, engaging, and practical health education to older adults, empowering them to make informed decisions about their health. Specifically, the sessions addressed fall prevention and balance, stress management and mental health wellness, and joint protection strategies for individuals with arthritis. Each session incorporated a PowerPoint presentation, interactive activities, and printed handouts to reinforce key concepts. Additionally, participants engaged in guided exercises, such as box breathing and guided imagery techniques, to support mental well-being.
To assess the project\u27s impact on older adult health literacy, participant confidence in understanding health-related information was measured through post-session surveys available via QR code or paper format. The outcomes demonstrated an increase in self-reported confidence in recognizing fall risks, implementing stress management techniques, and utilizing joint protection strategies. Participants expressed greater awareness of available resources and reported feeling more empowered to manage their health proactively.
This capstone experience highlights the vital role of occupational therapy in promoting health literacy among older adults. By providing tailored education and interactive engagement, this project contributed to enhancing independence, safety, and overall quality of life for community-dwelling older adults
LC/MS Validation of Stool as an Analytical Matrix for Profiling Free Fatty Acids in Neonatal Patients
No full textABSTRACT
Healthy gut microbiota establishment in neonates is crucial for infant health. Influential to the establishment of a healthy immune system, a healthy gut is essential for improved long-term health outcomes, and in mitigating the risk for developing diseases later in life. Fecal matter formed in the digestive tract provide valuable data that may be useful in the detection of gut microbiota dysbiosis through the analysis of end metabolic products of digestion in the intestines. However, due to the complex nature of infant fecal material, proper sample collection, preparation and accurate analytical methods are vital in generating precise data in gut microbiome research. Quantitative and qualitative analyses of free fatty acid metabolites in several biological matrices (e.g., serum and urine) have been developed. However, standardized fecal matter sample preparation methodology for targeted free fatty acid analysis was not previously developed prior to this thesis. In this study, the stability and reliability of the fecal matrix in the development of a long-chain free fatty acid profile utilizing high performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS) was evaluated for future investigations into neonatal diseases and metabolic syndromes. An extraction and purification protocol was optimized using a liquid-liquid extraction assay developed to quantify several polyunsaturated fatty acid species in human stool. We modified the Bligh & Dyer liquid–liquid extraction protocol and compared differences due to internal standard recovery and resolute chromatographic separation. Our results indicate that a minimum fecal (wet) mass of 5.0 mg diluted in buffer solution accurately represents the complex texture of stool with consistent, reproducible results. Our method provides accurate, sensitive, and simultaneous quantification of long to very long chain free fatty acids, specifically, α-linolenic (ALA), eicosapentaenoic (EPA), docosahexaenoic acid (DHA), arachidonic (AA), and linoleic acids (LA)
Rural and Urban Disparities in Access to GLP-1 Agonists for Patients with Obesity
Get PDFThe increasing interest in glucagon-like peptide-1 (GLP-1) agonists, such as semaglutide, which are often prescribed as a first-line treatment for managing Type II diabetes, as well as for non-diabetic purposes—such as weight management and improving metabolic health—highlights their potential in preventive care. This promise inspires hope for a future where preventive healthcare is more effective and accessible to a wider audience. Nonetheless, significant geographic disparities in access to healthcare, especially between rural and urban areas, create obstacles that prevent numerous patients from reaping the benefits of these essential medications. In rural communities, challenges like cost, availability, and awareness are often more severe, which leaves many without the critical treatment they need. This study uses a quantitative, comparative design to examine disparities in GLP-1 agonist access among patients with obesity in rural and urban communities. It analyzes secondary data, sourced from the MarketScan database, is analyzed to explore access patterns related to GLP-1 agonists. The objective is to identify gaps in medication access for populations utilizing these treatments for preventive and non-diabetic purposes. This research will guide the development of targeted interventions that significantly influence healthcare policy, including policy changes to lower costs, improve provider education, and enhance medication availability in underserved areas. The ultimate goal is to develop strategies that ensure equitable healthcare access, allowing all individuals to benefit from the preventive advantages of GLP-1 agonists
Comparison of AI Tools that address Social Determinants of Health suggested to Reduce Maternal Mortality: A Systematic Review
No full textMaternal mortality remains a critical public health issue, disproportionately affecting underserved, low-income urban populations where systemic inequities exacerbate health disparities. The purpose of this study is two-fold; (1) conduct a systematic review of relevant literature on AI-powered digital healthcare tools aimed at improving maternal health outcomes, with a particular focus on how they integrate social determinants of health (SDOH) and (2) review and compare AI tools that incorporate key SDOH factors—such as transportation access, food security, and housing stability, to name a few—to assess their effectiveness in reducing maternal mortality. This review, based on the analysis of 48 studies and 51 reports, examines AI\u27s ability to address barriers to equitable care through tools such as predictive analytics, food delivery, and transport. These innovations demonstrate improvements in maternal outcomes by enhancing accessibility, precision, and care coordination. However, findings reveal substantial gaps in integrating multiple SDOH within AI frameworks, which limits their holistic impact on maternal health. Policy implications stress the need to prioritize the development of comprehensive, multi-SDOH AI solutions to reduce maternal mortality and advance health equity. This research underscores the urgency of deploying cost-effective, scalable AI tools tailored to the unique challenges of underserved populations, thereby fostering equitable and improved maternal healthcare outcomes
After-School Program for Teens with Intellectual and Developmental Disabilities
Get PDFIntroduction: According to the Centers for Disease Control and Prevention, 1 in 36 children have Autism Spectrum Disorder (ASD) (CDC, 2023) with 31% of children with ASD having an Intellectual Disability (ID) (Autism Speaks, 2023), and 1 in every 700 babies are born with Down Syndrome (CDC, 2023b). According to the National Longitudinal Transition Study-2 (Shattuck et al, 2011) nearly 40% of individuals with ASD after exiting high school were not receiving any services, such as occupational therapy, case management, medical assessments, etc. The purpose of this capstone is to implement an after-school program for teens with Intellectual and Developmental Disabilities (IDD). The aim of this project is to increase confidence, socialization, and independent living skills in teens with IDD. Additionally, this project aims to enhance socialization in teens with IDD to increase confidence in making friends and interacting with individuals in their job. Methods: a seven-week program for teens with IDD was implemented with alternating skills and social nights every Wednesday afternoon for two hours. The teens (n=4) learned various skills such as laundry, making a sandwich, and understanding emotions, while social nights included arts and crafts, movies, and games. Student volunteers from occupational therapy, physical therapy, and speech language pathology participated in social nights to increase teen engagement and socialization. An emotion check-in was given pre and post session to determine change in emotional regulation over time. Surveys were administered to caregivers of the teens at weeks four and seven. Results: Data from the emotion check-ins were inconclusive. This is due to varying factors, such as change in routine, weather, and independence with emotional regulation. Parent survey results concluded that 100% of the caregivers would recommend this program to someone else and would re-enroll their teen again. Conclusion: Although the emotional check-in data proved inconclusive, feedback from caregivers and teens indicated the program was successful and has good sustainability. The aims of this program were met- increased confidence, socialization, and independently living skills- assessed through observation, conversation with teens, and survey responses. Social activities in the future may include: yoga, dance, sports, art, and music, as well as community collaboration. Skills activities in consideration include: self-care, conversation skills, safety, social media, and money skills.
Centers for Disease Control and Prevention. (2023, April 4). Data & statistics on autism spectrum disorder. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/autism/data.html Autism statistics and facts.
Autism Speaks. (2023). https://www.autismspeaks.org/autism-statistics-asd#:~:text=Autism%20Prevalence&text=31%25%20of%20children%20with%20ASD,all%20ethnic%20and%20socioeconomic%20groups.
Centers for Disease Control and Prevention. (2023b, June 28). Data and statistics on Down Syndrome. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/birthdefects/downsyndrome/data.htm
Cultivating Resilience Through Play: An Educational Tool for Early Childhood Development
Get PDFEducating caregivers on early childhood development can empower them to use therapeutic play to support their child’s growth in life skills. This project aimed to enhance caregivers\u27 understanding of play-based strategies that promote resilience during early development. The educational tool was designed for occupational therapists to share with caregivers of children receiving OT services. It simplifies key developmental milestones related to play, social interaction, and the foundational skills needed to build resilience. The occupational therapy team reported that the tool is both relevant and practical for pediatric use, and they believe it will support therapeutic carryover at home