Health Sciences – Page 3 – UROP Spring Symposium 2021

Health Sciences

State trends in medically unnecessary surgical births

Recent studies in the United States have shown that over one third of birthing women have primary cesarean (C-section) sections to deliver their children. C-section surgeries pose risks to the mother and her child, carrying a longer, more involved recovery than a traditional, noninvasive vaginal delivery. In many cases, a birth is considered ?NTSV (?Nulliparous, Term, Singleton, Vertex?), or low-risk, and a c-section is given despite a lack of medical indication. The United States has one of the highest incidences of NTSV c-sections in the western hemisphere. We are interested in examining the non-clinical and social factors that may influence c-section rates and interventions among women with low-risk pregnancies that end in cesarean section, NTSV c-sections. To do this, we collected data from all fifty states’ previous studies and statistics on births, c-sections, health collaboratives, and demographics, and compiled it into a database to find statistical significance with each factor. When comparing the states, we found that the access to information differed greatly depending on the state being studied. With these findings, we hope to then go further to identify specific nonclinical factors, socioeconomic status, race, insurance, and other demographics that may influence c-section rates within each state. These conclusions will inform improvements to the healthcare system that can aid the reduction of NTSV c-sections in the United States.

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State trends in medically unnecessary surgical births

Recent studies in the United States have shown that over one third of birthing women have primary Cesarean sections to deliver their children. C-section poses risk to the mother and her child, and carries a much longer recovery time than a vaginal delivery. In many cases, a birth is considered NTSV (Nulliparous, Term, Singleton, Vertex), or low-risk, and a c-section is given despite a lack of medical indication. The United States has one of the highest incidences of NTSV c-sections in the western hemisphere. In this study, we are interested in examining the non-clinical and social factors that may influence c-section rates and interventions among the NTSV or low-risk population. To do this, we collected data from all fifty states on births, c-sections, health collaboratives, and demographics, and compiled it into a database to make statistical analysis on each factor. When comparing the states, we found that the access to information differed greatly depending on the state being studied. With these findings, we hope to then go further to identify specific nonclinical factors that influence c-section rates within each state. These conclusions will then inform improvements in obstetric healthcare practices that can aid the reduction of NTSV c-sections in the United States.

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Tissue crosstalk in joint injury

Post-traumatic osteoarthritis (PTOA) is a debilitating disease that develops as a result of a joint injury. Overactivation of the Wnt signaling pathway has been implicated in progression of PTOA, however very little is known about this. This work is among the first to study Wnt signaling mechanisms in PTOA. R-spondin 2 is a secreted matricellular protein that functions as an agonist for the Wnt pathway, promoting Wnt signaling. Our preliminary data show that R-spondin 2 is greatly induced in the synovium in a mouse model of PTOA. We also showed that R-spondin 2 is secreted into the synovial fluid after joint injury. This deregulation of R-spondin 2 promotes over-stimulation of the Wnt pathway, which we hypothesize is an important mechanism in joint deterioration. Our aims are to understand the cellular and molecular mechanisms underlying R-spondin 2 and Wnt signaling in PTOA, and how we can manipulate these to inhibit further joint degeneration. To study gene expression in joint-resident cell types, we first analyzed bone marrow stromal cells – primary cells cultured from mice and differentiated into osteoblasts, a cell type present in the joint and relevant to PTOA progression. We isolated RNA, converted it to cDNA, and performed qPCR to analyze gene expression. In parallel, we employed microscopy to study joint pathology over the course of PTOA. Further investigation is now warranted, from which we hope to better understand the cellular and molecular mechanisms of Wnt signaling in PTOA, with the ultimate goal of developing novel therapeutics for treating PTOA.

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Evaluating Novel Cancer Drugs and Drug Delivery in Preclinical Studies

Cancer prevention and treatment in the United States has seen many advances over the last few years, however, breast cancer continues to be one of the most widespread diseases, affecting the lives of approximately one in every eight American women. There is a pressing need for a more effective and less invasive treatment for breast cancer, specifically those cancers that originate in the epithelial cells of the milk ducts or lobules, also known as adenocarcinomas. Heat shock protein 90 (HSP90) has become an important target of many drug treatments. At the molecular level, over-expressed signaling proteins that lead to uncontrollable cell growth are stabilized by HSP90. Recent in vitro studies of the specific HSP90 inhibitors, KU757 and KU758, suggest this drug is effective in treating certain types of cancer, such as thyroid cancer and triple negative breast cancer respectively. This study aims to investigate the efficacy of KU757 and KU758 in treating the breast adenocarcinoma cell line called MCF7. Cell proliferation will be measured by MTS assay, and drug efficacy will be analyzed by calculating inhibitory concentration 50 values.

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Testing a Novel Drug Agent on Glioblastoma multiforme

Glioblastoma multiforme (GBM) is one of the most aggressive forms of cancer which begins in the brain. In many GBM cases, there are mutations in Epidermal Growth Factor Receptor (EGFR), like EGFRvIII that is the most common variant. Currently, there are no treatments for GBM besides chemotherapy and surgery because a drug would need to cross the Blood-Brain Barrier (BBB) to target GBM. We have developed a novel small molecule, DPI503, that can cross the BBB, binds with EGFR, and promotes its degradation by blocking EGFR dimerization. Preliminary in vitro data show that DPI503 kills U87 glioblastoma cells stably transduced to express EGFRvIII with IC90 of 3 micro M. Therefore, we expect DPI503 to be effective against EGFRvIII expressing tumors. To test this, we will prepare an orthotopic brain tumor model by implanting luciferase-expressing U87-EGFRvIII tumor cells into the brains of SCID mice. The growth of the tumor will be monitored using an IVIS Lumina imaging system after intraperitoneal injection of Luciferin. After confirmation of established tumors, mice will be treated with 4 dose levels of DPI503 (0, 10, 30, 100 mg/kg) via daily oral gavage. We have found that DPI503 treatment is effective against EGFR driven HNSCC and lung flank xenograft model. We expect DPI503 to be effective against the GBM model as well. If single-agent activity is not curative, we would combine radiotherapy with DPI503 treatment in follow-up experiments.

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Developing a Novel Drug Agent for EGFR mutant Lung Cancer Patients

Mutant epidermal growth factor receptor(EGFR) spurs on lung cancer. Currently, tyrosine kinase activity inhibitors(TKI) have been used to combat this, however, unfortunately, roughly a year later patients develop resistance to this type of therapy and are left with no other intervention options which have proven to be deadly. So, our goal for the research we have conducted is to find a solution to this problem for patients in this position and give them a chance with a drug agent that is able to function regardless of kinase function. It has been shown by us, and others, that the degradation of EGFR has a very significant effect on whether or not cancer cells remain alive. So, the goal of our research was to test if a drug that causes the degradation of EGFR without anything to do with ATP will improve the odds for patients in these scenarios. In order to explore these ideas, we screened novel drug agent DGD1202 next to osimertinib in various lung cancer lines. We then took these results and were able to see their correlation with EGFR degradation. We currently are still working on this research, and we believe that once completed, a new, safe alternative intervention to lung cancer patients will be available that will greatly improve their odds.

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System for Opioid Overdose Surveillance (SOS): Genesee County Project

Background: The opioid epidemic has grown across Michigan with very few areas having access to real-time data on opioid overdoses. A project was conducted by the CDC-funded University of Michigan Injury Prevention Center and Michigan High Intensity Drug Trafficking Areas (HIDTA) to develop a system for near real-time opioid surveillance. This system, called the System for Opioid Overdose Surveillance (SOS) was designed to inform data-driven opioid overdose prevention and response efforts with the goal of reducing overdose injuries and fatalities. Methods: In a Genesee County project, community stakeholders composed of public health, public safety, and community outreach service providers were gathered for a focus group, and then interviewed to evaluate how near real-time opioid overdose data can inform prevention work and barriers to prevention efforts. Stakeholders received SOS data reports for their jurisdiction on a regular basis for eight weeks, and their feedback was solicited over time through a survey. A final focus group emphasized the mobilization of data-driven coordinated community responses through near real-time reports. Data was analyzed to create a coordinated community response toolkit. Results: Findings suggest SOS is being used to impact local planning and responses to opioid overdoses. One major finding from the Genesee County project was the application of zip codes in aiding community stakeholders. The use of zip codes, one of many data visualizations in the SOS, allowed for stakeholders to pinpoint locations most affected by opioid overdoses within the community. Conclusions: Through the Genesee County Project, the SOS dashboard helped aid in creating “best fit” strategies for specific areas within larger communities. The Genesee County Project also showcases how near real-time data surveillance can benefit communities. Keywords: Opioids, Surveillance, Genesee County

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Digital phenotyping and electrophysiology in mice

The molecular, synaptic, and neuromodulatory variations in a variety of brain regions, namely the the prefrontal cortex, nucleus accumbens, and the ventral hippocampus1, have been associated with changes in behavior quantified by metrics such as the Forced Swim Test (FST)2, Sucrose Preference Test3, and the Open Field Test4. While the behavior of mice exposed to chronic stress has been extensively studied, there is a need for more information regarding the behavior of these mice over a longer span of time. Additionally, due to the difficulty of recording electrical activity for extended periods of time in specific regions of the brain, there are few studies that analyze the longitudinal alterations in electrophysiology that may be correlated with exposure to chronic stress.

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Reducing racial disparities in pulmonary and critical care

Despite recent efforts and movements for racial equity and equality in the United States, racial disparities are evident in ICU care, specifically related to medical ventilation practices. Timely and effective care for respiratory failure is essential for saving lives in ICU care, however, the effectiveness of mechanical ventilation practices is underscored by the lives of racial and ethnic minorities, who are twice as likely to develop respiratory failure as Whites. This study grasps the enduring problem in critical care of detecting, understanding, and eliminating racial and ethnic inequities through a systematic review process and meta-analyses of medical literature. An analysis of this literature yields evidence of the pervasive disparities in rates of respiratory failure between Blacks and other ethnic groups and Whites as well as the rise of mortality rates among racial and ethnic minorities. There is an urgent need to wage the knowledge gap of understanding the decision-making process of ICU clinicians and intervention called for mitigating racial disparities in ICU care, which in turn can save lives. The overall objective of the research is to reduce inequitable outcomes of respiratory failure by improving ICU care. The results of analyzing the literature are a growing part of this research that involves designing an intervention to promote racial equity in respiratory failure, prototyping through patient, family, and clinician engagement and piloting at two ICUs.

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Reducing Racial Disparities in Pulmonary and Critical Care

Research has shown that racial minorities are twice as likely to develop respiratory failure than Whites, but remain inconclusive on whether minorities are more likely to die after respiratory failure. The COVID-19 pandemic has created a unique opportunity to study these disparities and what interventions are needed in the ICU. This research project will focus on how care processes in the ICU contribute to racial health disparities in mechanical ventilation for adult patients. Our central hypothesis is that care processes related to mechanical ventilation such as sedation, fluid balance and end-of-life practices are contributors to differences in survival rates among different races. For example, the level and frequency of sedation given to a patient has shown to impact survival rates during mechanical ventilation. Critically ill minorities disproportionately receive deep sedation, and there is an association between higher mortality and deep sedation. Furthermore, clinical decision-making such as end-of-life care and palliative care consultations can be influenced by race and result in differing health outcomes. Systematic searches for clinical processes contributing racial disparities in respiratory failure the US were identified through Pubmed, Google Scholar, and ProQuest. Literature that has met the inclusion criteria were then assessed by the two independent readers conducting the systematic review. The findings report care processes for mechanical ventilation contributing to variation in risk-standardized mortality for respiratory failure by race. These results will provide a basis for researchers studying care processes that contribute to racial disparities in respiratory failure and inform hospital administration and other stakeholders to implement interventions.

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