MEDICA@MUSC (Medical University of South Carolina)
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Utilizing Monobody Technology to Investigate RAS Signaling Mechanisms and Potential Therapeutic Vulnerabilities
No full textThe RAS family of small GTPases, consisting of HRAS, KRAS and NRAS, represent the most frequently mutated oncogenes in human cancers. As such, targeting RAS has remained at the forefront of efforts for cancer therapeutic development. For decades, these efforts were largely unsuccessful. However, recent seminal discoveries led to the development of the first clinically-approved inhibitors of a common oncogenic RAS mutant. While a major milestone, most oncogenic RAS mutants remain without inhibitors. One emerging theme over the past several years has been the notion that RAS multimerization plays a critical role in RAS function and that this process may represent a therapeutic vulnerability. Our lab has previously developed a synthetic binding protein, the NS1 monobody, that inhibits RAS through disruption of RAS–RAS interactions. NS1 binds to the α4-α5 allosteric lobe of HRAS and KRAS, which was previously proposed to be the interface for RAS dimerization. However, several groups reported conflicting evidence on the effect of mutating residues in the α4-α5 region on RAS function, igniting debate on the nature of these interactions and whether bona fide RAS dimerization is a prerequisite for RAS activity. We thus sought to determine the role of individual amino acids in the α4-α5 allosteric lobe on RAS activity through stringent cell signaling, biological transformation, and protein–protein interaction assays (Chapter 2). In addition, we developed a new monobody that binds and inhibits NRAS in a similar manner as NS1, which to our knowledge, is the first NRAS-specific inhibitory reagent (Chapter 3). In summary, we demonstrate that residues in the α4-α5 allosteric lobe of RAS do not mediate RAS dimerization. Instead, RAS–RAS interactions necessary for viii function are likely in the form of transient clustering at the cytoplasmic face of the cell membrane, and these interactions are likely driven by the membrane anchors (hypervariable regions) of RAS, not the G-domain
Hospital Characteristics Impact on Left Without Being Seen
Get PDFEmergency Department (ED) care is provided to patients for urgent and life-threatening emergencies. Inefficiency and overcrowding of ED continues to be a problem for the U.S. Health systems threaten the ability to provide care for the most vulnerable patients. The inefficiency of ED and hospital throughput creates challenges in being able to provide timely and effective care for ED patients. Prolonged ED wait times can be related to the availability of ED and hospital beds, inefficiencies in the emergency department, staffing, and other factors. Timely and effective care is important to providing high-quality care and decreases the risk of serious injury or illness. When a patient leaves without being seen (LWBS), the ED physician does not have an opportunity to provide a medical screening exam to evaluate the patient’s condition and assess the reason for seeking emergency care. Limited research has been conducted to understand if there is a positive relationship between hospital characteristics and LWBS rates in CMS patients using national-level data.The goal of the current project is to examine the potential impact of hospital characteristics on ED efficiency as measured by LWBS rates using currently available Medicare data from the data source of Timely and Effective Care National from emergency department visits. The limited dataset from the survey period of 2019 and 2022 was used to extract all records for Medicare beneficiaries
Developing A Blueprint for Health Equity Programs and Investigating Interventions and Metrics
Get PDFRacial and ethnic minority groups and rural and low-income populations are examples of populations who continue to experience health disparities despite policy mandates to eliminate them. This doctoral project will provide a foundational blueprint to aid health plans in addressing and improving health equity internally and with external stakeholders. The blueprint will be based on research comparing the robust health equity initiatives of four states to the NCQA national guidelines. The barriers to achieving and recommendations for advancing the field of health equity by implementing and analyzing policies and data that target health disparities through improved access to quality care and services will be addressed. This health equity guideline will contain suggestions and templates that may be used to supplement current NCQA Health Equity Standards as a guideline for developing a health equity program for small managed care organizations
Obesity and Kidney Transplantation: a Review of High Bmi Pre-kidney Transplant Patients Referred to Bariatrics
No full textThis project is a quality review project of the Medical University of South Carolina kidney transplant program that focuses on obese, high body mass index (BMI) patients who were referred to bariatrics. One hundred and eighteen pre-kidney transplant patients who were referred to bariatrics were identified through the EHR, though not all patients were required to see bariatrics for listing. Chart review demonstrated that 28% of the patients were below the departmental BMI cutoff, 43% could lose weight independently (enough to affect their listing), and only 15% underwent bariatric surgery. Body mass index appears to be an access to transplant issue affecting more African Americans and females than other groups. Bariatric surgery resulted in patients getting transplants quicker than their counterparts who lost weight on their own. These savings could offset the costs associated with surgery and improve long-term transplant outcomes
