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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Characterizing different clinical settings for the diagnosis of idiopathic Rapid Eye Movement Sleep Behavior Disorder

Idiopathic Rapid Eye Movement Sleep Disorder (iRBD) is a disorder characterized by dream re-enactment. RBD is referred to as idiopathic when it occurs in isolation. A majority of iRBD patients will go on to receive a diagnosis of an a-synucleinopathy, a family of neurodegenerative disorders including Parkinson’s and Dementia with Lewy Bodies (DLB) [1]. In clinical settings, iRBD is likely to be diagnosed by a variety of medical providers including specialists in Neurology, Psychiatry, and Primary Care. iRBD patients often have 10-15 years in between the onset of iRBD and the onset of a neurodegenerative disorder, leaving a considerable length of time in which to intervene with therapeutic approaches. The problem is that as of yet, we are not sure in which clinical settings patients are receiving their diagnoses of iRBD. Our project aims to bridge this knowledge gap, which currently prevents us from recruiting iRBD patients into clinical trials aimed at preventing a-synucleinopathies such as Parkinson’s and DLB. In order to gather our data, we have conducted a retrospective chart review of UM medical records for relevant patients. We hope to gain a clear picture of where patients are receiving their iRBD diagnoses, in hopes of further research in the future. References [1] McKeith IG, Ferman TJ, Thomas AJ, Blanc F, Boeve BF, Fujishiro H, Kantarci K, Muscio C, O'Brien JT, Postuma RB, Aarsland D, Ballard C, Bonanni L, Donaghy P, Emre M, Galvin JE, Galasko D, Goldman JG, Gomperts SN, Honig LS, Ikeda M, Leverenz JB, Lewis SJG, Marder KS, Masellis M, Salmon DP, Taylor JP, Tsuang DW, Walker Z, Tiraboschi P (2020) Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology 94, 743-755.

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Relationship Between Depression and Subjective Executive Functioning in Parkinson’s Patients

In addition to physical symptoms, Parkinson’s patients are often diagnosed with mental complications including depression and cognitive dysfunction. However, little is known about the correlation between Parkinson’s patients’ depression and subjective cognitive skills, including executive functioning. This is important because executive dysfunction can cause difficulty in Parkinson’s patients’ ability to complete daily tasks. The main goal of this research is to examine how mental factors such as depression impact a Parkinson’s patient’s subjective executive functioning. In order to compare these two variables, archival clinical data was analyzed in a sample of 175 patients with Parkinson’s disease (PD; N(men) = 120, M(age) = 64.41, SD = 8.58). The Geriatric Depression Scale – Short Form (GDS-SF) was used to measure depression, the Frontal Systems Behavior Scale (FrSBe) was used to measure subjective executive functioning, and the Unified Parkinson Disease Rating Scale (UPDRS) Part III was used to measure PD severity. Pearson’s correlation revealed a significant relationship between the GDS and FrSBe scores, such that higher depression scores correlated with higher self-reported executive dysfunction, R = .42, p < .001. The partial correlation revealed that this relationship remained significant while controlling for UPDRS Part III, R = .45, p < .001. Findings were consistent with this study's hypothesis, such that Parkinson's patients with greater depression were more likely to self-report executive functioning problems. A possible explanation for this is that depressed Parkinson's patients are more likely to have negative self-perceptions, which may cause them to rate their executive functioning skills more poorly.

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Examining how COVID has affected African American women with Hypertension

Forty seven percent of African American women are living with hypertension, which increases their risk of contracting COVID-19. We asked 100 African American women living with hypertension (ages 21 to 64) to complete a questionnaire using qualtrics. Using a cross sectional descriptive survey, participants were asked to self-report their blood pressure during COVID. A portion of the survey was used to raise the questions of how paticipants have been maintaining their health through eating and exercise patterns as a result of the virus. Sixty one percent of participants reported that they have not had to change the way that they manage their blood pressure since COVID-19. Participants that reported that they did have to change the way that they managed their blood pressure, ensured that they have had to exercise more, practice healthier eating habits, and that they haven’t seen their physician since COVID-19. In addition, the majority of participants did not lose their job or income due to the “Stay at Home” mandate, nor are they concerned about their ability to get their medications and supplements used to control their blood pressure. Our findings raise the question regarding if participants are considering all factors that have been impacted in their lives by COVID and how participants have been managing their hypertension in the first place.

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Characterization of the Artemis Human Disease Gene in DNA repair

Mutations in DNA repair mechanisms can cause life-threatening conditions such as Severe Combined Immunodeficiency Disorder (SCID) or Omenn Syndrome (OS). The Artemis protein’s role in non-homologous end-joining (NHEJ) repair is especially crucial to cleave DNA hairpins during V(D)J recombination. A mutation in the Artemis gene can impair DNA repair mechanisms, increasing the possibility of SCID and/or OS in young patients. To study the hypomorph missense mutation from glycine to glutamate at position 6 in the Artemis gene, a Q5 mutagenesis kit was used to amplify the mutation plasmid, followed by bacterial transformation, restrictive digests, cell culture, Western Blot Analysis, and transient V(D)J recombination assays to observe what effects the Artemis mutation has on competent E.Coli cells. Recombination frequency calculated from the surviving cells on a double selection plate will be used to determine the effect the missense mutation has on Artemis gene survival. An in-depth analysis of the cells will reveal whether the change was an inversional or deletional phenomenon. Since little research has been done on this specific GGG to GAG at position 6 in the Artemis gene mutation, results will pave a path to further research on its characteristics.

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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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