Health Sciences – Page 16 – UROP Spring Symposium 2021

Health Sciences

Determining the Mechanism Mediating the Upregulation of Chemokines by DHMs

Neutrophils, which are immune system cells, express the chemokine receptor CXCR2. It has been shown that the ligands of CXCR2 are found at higher levels in triple negative breast cancer. In a previous study about the interaction between a tumor and the immune system, it was found that stimulated neutrophils may lyse – releasing a material made up of DNA/protein referred to as neutrophil extracellular traps (NETs). It was recently found that these NETs can promote tumor metastasis in triple negative breast cancer. Previously in our lab, a DNA-histone mesostructure (DHM) was created to mimic the functions of a NET. A DHM is a simplified version of a NET containing only DNA and histones. Metastatic 4T1 cells and non-metastatic 4T07 cells have a similar genetic background (being derived from the same parental tumor), yet in vitro, 4T1 cells have been shown to constitutively produce CXCR2 ligands while 4T07 cells do not. However, in the presence of a DHMs the two cell lines produce similar levels of CXCR2 ligands – possibly recapitulating aspects of the interaction between NETs and these tumor cells in vivo. In order to determine what the mechanism is for the difference in neutrophil infiltration between 4T1 and 4T07 tumors in vivo, we are looking at multiple genes involved in the expression of CXCR2 ligands to better understand the interaction between NETs and these tumors. In these experiments, we will be examining gene variants and changes in the activity of three signaling pathways: PDGF R beta, SCF R, and FLT-3.

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Design of a PPI Inhibitor to Treat AAV

Many diseases, such as ANCA-associated vasculitis (AAV), are caused by mutated proteins involved in protein-protein interactions (PPIs) that can be inhibited by designer proteins that would serve as small molecule inhibitors. In the case of AAV, the targeted interaction is between TNF-alpha and its associated TNFR1 receptor, which induces the activation of neutrophils in endothelial cells, causing inflammation in AAV patients. By designing a protein which will bind to TNF-alpha, its interaction with TNFR1 can be decreased, thus decreasing patient inflammation. UniDesign from the Zhang Lab was used to design de novo protein sequences from a PDB model of the TNF-alpha and TNFR1 interaction. The results were then analyzed by comparing the binding energy of the designer protein against the native sequence. These results are very promising in the development of protein design as a viable treatment method for rare diseases. This new protein could provide a novel type of treatment to AAV patients that would mitigate the use of glucocorticoids, a common anti-inflammatory agent with long-term side-effects such as increased risk for infections, heart disease, etc.

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Design of novel proteins targeting the PD-1/PD-L1 pathway

The PPI being analyzed is PD-1 to PD-L1. Programmed cell death 1 (PD-1) is a protein involved in regulating the immune system’s T-cell induced apoptosis system by suppressing T-cells. Therefore, PD-1 suppresses and prevents cell apoptosis. PD-1 performs this function in unison with PD-L1 or Programmed Death Ligand 1. The suppression of T-cells can only occur when PD-1 is bound to PD-L1, therefore, this a very important protein-protein interaction. Because this PPI is highly involved in cell cycle regulation it is a common target of cancer treatments. One common cancer treatment is a drug that blocks PD-1 and prevents it from complexing with PD-L1. By hindering this PPI, T-cells’ ability to kill possibly cancerous cells is increased. Using an evolutionary-profile based approach program called UniDesign, 300 possible different peptide sequences were created for PD-1 while keeping PD-L1 the same. Although results have not been obtained we hope to show through the experimental analysis that the designed sequences will have a stronger binding affinity to PD-L1 than PD-1. This research is important because better understanding this PPI plays a large role in cancer treatment research.

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Computational design of protein binders to block the PD-1/PD-L1 pathway

The Programmed Cell Death Protein 1 (PD-1)/Programmed Cell Death Ligand 1 (PD-L1) pathway is crucial in the immune system’s response to cells in the human body. When PD-L1 binds to PD-1 it helps to prevent T-cells from killing other cells, including cancer cells which allows for tumor growth. We used an physics-based approach, EvoEF2, to create an artificial protein based on the structure of PD-1 to competitively bind to PD-L1. We are hoping to show through our binding experiment analyses that our designed proteins will have a stronger binding affinity to PD-L1 than PD-1. While PD-1 inhibitor drugs have been developed they are not completely effective, finding more effective ways to block this pathway could be an important step in future cancer drug research.

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Rapid Understanding of Best Practices in Rural Intensive Care (RUBRIC)

The U.S. has had great disparities between rural and urban hospital resources – particularly with intensive care. Rural ICUs have much less resources as compared to urban ICUs and as such, have been impacted differently by the COVID-19 pandemic. This study aims to work on characterizing adaptations made by rural ICUs in response to COVID-19 along with setting up for further studies which contribute to the development of a toolkit of methods used by high-functioning rural ICUs. This toolkit will provide knowledge and understanding of ways in which rural ICU care can be made more effective. The toolkit will be created by conducting a randomized, nationwide survey of ICU administrators who can answer questions regarding their ICU’s changes to resources including capacity, staffing, policies, and workflow in response to the pandemic. We hypothesize that high-performing rural ICUs have made particular adaptations that have aided them in providing effective patient care during the COVID-19 pandemic. Particularly, we predict that hospitals will respond by 1. Reducing barriers to inter-hospital transfer and 2. Expanding alternative care strategies. In order to identify these adaptations, we are conducting a randomized nationwide survey of ICU administrators at rural ICUs about their adaptations in response to COVID-19. Upon completion of the survey, the responses received will be analyzed and a toolkit of resources will be developed and rapidly disseminated. Our toolkit of resources will allow rural ICUs to prepare for future public health emergencies by optimizing resources and maximizing patient care.

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Wearable technology for evaluating asymmetries of the lower limb musculature

Asymmetries in strength and mobility can be detrimental to performance and may contribute to the development of musculoskeletal injuries. The aim of this study was to assess the effectiveness of using surface electromyography (sEMG) to detect imbalances between muscles of the lower limb during air squats. An additional aim was to determine the effect banded hip mobility exercises may have on decreasing muscle imbalances. To begin exploring these aims, one participant was evaluated during a series of lower body movements. Muscle recruitment patterns were evaluated using a commercially available “smart garment” with embedded sEMG sensors. The sEMG sensors were used to calculate the percent difference between left and right training load of the quadriceps, hamstrings, and glutes. Validation of the sEMG sensors to detect differences in load was conducted by performing single leg controlled movements. Air squats were performed before and after banded hip mobility exercises to observe any effect on muscle recruitment patterns. When used to calculate differences in load, sEMG sensors appear to be an effective way to evaluate asymmetries between muscle groups of the lower limb.

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The Impacts of Nuclear Radiation on DNA Repair Machinery

The field of nuclear radiation has been analyzed through time in order to further quantify the effects of nucleotide ionizing particles both in the environment and humans. The focus is often to not only understand the health impacts of radiation exposure, but to also innovate preventive measures for a heightened risk for cancer development during long-term physical exposure to high levels of ionizing radiation. To date, researchers have focused on a wide range of organisms and exposure levels for radiation-focused studies, making it difficult to quantify and summarize the status of this field to date. We aim to produce a useful review that summarizes the status of this research while focusing on the DNA repair pathways currently used to improve radiation cancer therapy. In our review, we found that the ability to optimize DNA repair mechanisms can lead to a higher chance of radioresistance in our cells and can potentially serve as a clinical treatment for ionizing radiation-induced damage in our genomic DNA. Ultimately researchers feel this should allow enough time for the DNA repair mechanisms to correct the damage in an error-free and timely manner.

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Student Learning of Qualitative Methods in a Team-Based Tiered Mentorship Approach Through Analysis of Police Role in Out-of-Hospital Cardiac Arrest

Qualitative analysis, and an associated team-based approach in learning these methods, has grown increasingly popular. However, many students find learning qualitative analysis difficult due to limited exposure in early higher education and the absence of a standardized process for qualitative inquiry. Prior studies on teaching and learning qualitative methods highlighted the importance of group work, asking questions, and openness to discussions. However, to the best of our knowledge, there is not much in the literature about the role of a tiered team-based mentorship program in it’s teaching. We sought to foster improved understanding of qualitative research for undergraduate trainees, as well as conduct exploration of the influence of a team-based approach on learning qualitative analysis. A core team of research mentors conducting qualitative analysis of data collected on police role in out-of-hospital cardiac arrest (OHCA) led trainings for four undergraduate students over the course of seven months. These training sessions leveraged data from the OHCA study to facilitate presentations and group discussions dedicated to qualitative methods. Mentors and trainees convened on a weekly basis for one hour to discuss aspects of qualitative research.

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Student Learning of Qualitative Methods in a Team-Based Tiered Mentorship Approach Through Analysis of Police Role in Out-of-Hospital Cardiac Arrest

Qualitative analysis, and an associated team-based approach in learning these methods, has grown increasingly popular. However, many students find learning qualitative analysis difficult due to limited exposure in early higher education and the absence of a standardized process for qualitative inquiry. Prior studies on teaching and learning qualitative methods highlighted the importance of group work, asking questions, and openness to discussions. However, to the best of our knowledge, there is not much in the literature about the role of a tiered team-based mentorship program in its teaching. We sought to foster improved understanding of qualitative research for undergraduate trainees, as well as conduct exploration of the influence of a team-based approach on learning qualitative analysis. A core team of research mentors conducting qualitative analysis of data collected on police role in out-of-hospital cardiac arrest (OHCA) led trainings for four undergraduate students over the course of seven months. These training sessions leveraged data from the OHCA study to facilitate presentations and group discussions dedicated to qualitative methods. Mentors and trainees convened on a weekly basis for one hour to discuss aspects of qualitative research.

Student Learning of Qualitative Methods in a Team-Based Tiered Mentorship Approach Through Analysis of Police Role in Out-of-Hospital Cardiac Arrest Read More »

Tolerance of Toxicities of Oral Anticancer Agents among Older Adults with Advanced Cancers

This project is focused on older adults taking oral anticancer agents, OAA. Specifically, capecitabine, an oral chemotherapy, is studied for its use in older adults with advanced cancer. Potentially, older patients may less tolerate OAA toxicities, which will impact the treatment effects and their quality of life. The overarching purpose is to explore the occurrence and effects of OAA toxicity-related symptoms in older adults taking capecitabine using real-world patient data from EHR. We will examine the potential differences in side effects of patients aged more than 65 years and patients less than 65 years from the use of capecitabine. From this data analysis, we will identify determinants through demographics, clinical characteristics, performance status, and the impact of OAA toxicity on treatment plan and performance status changes.

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