Indiana University Medical Student Program for Research and Scholarship (IMPRS)

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Activation of the oncogene ERG by the Ras/ERK and PI3K/AKT pathways
(2019-08) Willhite, Sydney; Strittmatter, Brady; Hollenhorst, Peter
Background and Hypothesis: The TMPRSS2-ERG re-arrangement occurs in ~50% of prostate cancers and results in aberrant expression of the transcription factor ERG in the prostate. ERG is known to be activated by the Ras/ERK and PI3K/AKT pathways, however, the exact mechanism of this activation is not fully understood. The aim of this project is to identify how activation of these signaling pathways differentially effect transcription of ERG target genes. Experimental Design or Project Methods: In order to test how the Ras/ERK and PI3K/AKT pathways effect ERG target gene transcription, normal prostate epithelial cells (RWPE1) were transfected with constitutively active AKT in combination with phospho-mutants of ERG. These cell lines were then used to conduct Quantitative Reverse Transcription PCR and Western blotting of known downstream ERG target genes to identify how the activation status of these signaling pathways affected transcription and protein production. Results: Overall, our results demonstrate that ERG mediated transcription of the VIM gene, a marker of EMT, was activated by the Ras/ERK pathway and was repressed by the PI3K/AKT pathway. In addition, we found that ERG expression decreased FOXO1 protein expression in our cell lines regardless of Ras/ERK and PI3K/AKT status. Transcription and protein quantification was also measured for ERG target gene VEGFA, a critical regulator of angiogenesis. Conclusion and Potential Impact: This project helps identify the molecular mechanisms by which a common oncogene in prostate cancer is activated. Our results demonstrate how upstream signaling pathways differentially regulate oncogenic transcription and cell transformation. Overall, this project will provide insight to the molecular mechanisms of possible therapeutic targets in prostate cancer, the most common cancer amongst men.
Analysis of Factors Contributing to Antenatal Corticosteroid Administration in Threatened Preterm Labor
(2022-07) Bode, Leah; McKinzie, Alexandra; Gidia, Nadia; Ibrahim, Sherrine; Haas, David
Introduction: Antenatal corticosteroids (ACS) are recommended for pregnant persons who are between 24 and 36+6/7 weeks’ gestational age (GA) and at risk for imminent delivery within 7 days. Many individuals diagnosed as having threatened preterm labor (tPTL) are given ACS but do not deliver until they reach term. This study aimed to describe characteristics of those seen for tPTL who receive ACS to better understand clinical decision-making. Methods: This retrospective cohort study consisted of mothers seen in triage at Eskenazi Hospital in 2021 for tPTL during pregnancy. Multiple demographic variables were evaluated against the primary outcome of ACS administration including maternal age, race/ethnicity, and prior preterm delivery, as well as obstetrical variables such as cervical dilation, effacement, membrane rupture, and tocolytic administration. Results: After exclusions, a cohort of 290 pregnant people with 372 unique encounters remained. The average maternal age was 26.7, and 15.6% of patients had a history of prior preterm birth. 107 patients in 111 encounters received ACS, which were associated with lower BMI, greater cervical dilation, greater effacement, membrane rupture, and more frequent contractions (all p<0.01). The mean GA at triage was 33.5 weeks. Logistic regression, adjusting for significant factors in the univariable analysis, found that BMI (OR 0.93, 0.89-0.97), cervical dilation (OR 1.34, 1.07-1.71), and cervical effacement (OR 1.02, 1.01-1.03) were significantly associated with giving ACS. 44% of those receiving ACS delivered within 7 days, compared to 11% of those who did not receive ACS (p<0.001). Conclusion: Greater cervical dilation and effacement and a lower BMI were associated with ACS administration, though most patients receiving ACS still did not deliver within 7 days. These findings will be further categorized and used to develop a clinical decisional model for administering ACS in those likely to imminently deliver preterm. Presentation recording available online: https://media.dlib.indiana.edu/media_objects/3b5922009
Are newborn outcomes different for term babies who are exposed to antenatal corticosteroids?
(2021-07-31) McKinzie, AH; Yang, Z; Teal, E; Tepper, RS; Quinney, SK; Rhoads, E; Haneline, LS; Haas, DM
Assessing Disparities in Care Utilization and Outcomes Among Pregnant Women with T2D Based on Race and Ethnicity
(2022-07-29) Pelton, Sarah; Izewski, Joanna; Scifres, Christina
Background/Objective: Disparities faced by individuals with type 2 diabetes (T2D) or gestational diabetes mellitus have been identified. However, because less is known about disparities faced by pregnant women with T2D and since the prevalence of T2D is increasing, we sought to investigate this issue. Methods: We performed a retrospective cohort study that included 369 women with singleton gestation and T2D that delivered from 2018-2020. Using maternal self-reported race and ethnicity abstracted from the electronic medical record, we categorized the women as Non-Hispanic White, Non-Hispanic Black, or Hispanic. Demographics, health care utilization, and maternal and neonatal outcomes were also abstracted. One way ANOVA and chi-squared tests were utilized to compare outcomes among the groups, and logistic regression was used to control for co-variates. Results: Non-Hispanic White and Non-Hispanic Black women had a higher BMI at their first prenatal visit and were more likely to be nulliparous. They were also more likely to have a prior caesarean delivery and chronic hypertension. Non-Hispanic Black women were more likely to have ≥12 prenatal visits compared to Non-Hispanic White and Hispanic women (70 vs. 43 vs. 45%, p<0.001), and non-Hispanic Black women had the lowest early pregnancy HbA1c (7.0±1.6 vs. 7.9±2.1 vs. 7.5±1.7%, p<0.001). Additionally, caesarean delivery rates were lowest for Hispanic women compared to Non-Hispanic White and Non-Hispanic Black women (45 vs. 63 vs. 71%, p<0.001); this difference persisted after controlling for co-variates (aOR 0.53, 95% CI 0.30-0.92). Conversely, there were no differences in birth weight category, preterm birth <37 weeks, hypertensive disorders of pregnancy, or NICU admission. Conclusion and Potential Impact: Pregnancies complicated by T2D have an increased risk of poor maternal and neonatal outcomes. For some outcomes, there is a significant difference among Non-Hispanic White, Non-Hispanic Black, and Hispanic women. Future studies are therefore needed to investigate causative factors and potential interventions. Presentation recording available online: https://purl.dlib.indiana.edu/iudl/media/h04d673g6h
Brain folding increases in sharpness and complexity over third trimester-equivalent development
(2022-07-28) Basinski, Christopher; Garcia, Kara
Brain folding increases in sharpness and complexity over third trimester-equivalent development Christopher Basinski [1], Kara Garcia [2] [1] Indiana University School of Medicine; [2] Indiana University School of Medicine, Department of Radiology and Imaging Sciences >> Background and Hypothesis: Gyrification, or convolution, of the cerebral cortex is a promising transdiagnostic marker for early neurodevelopment. Previous studies have related differences in sulcogyral shape to schizophrenia, bipolar disorder, and autism spectrum disorder, but the physical mechanisms underlying these differences remain poorly understood. The focus of this study was to explore decomposed curvature metrics, the principal curvatures, as physically meaningful quantitative biomarkers to track brain development. We hypothesize that the average sharpness and complexity of sulci and gyri, reflected by principal curvatures, increase throughout third trimester-equivalent development. Methods: Cortical surfaces generated from magnetic resonance imaging (MRI) were obtained from the developing Human Connectome Project. Global sharpness was calculated from the principal curvature of maximum magnitude, with average sharpness defined separately for gyral (positive) and sulcal (negative) curvatures. Global complexity of folds (eg., curviness along the length of a fold) was calculated from variance in the principal curvature with minimum magnitude. Trajectory of each summary metric was fit over time using polynomial regression. Results: Forty-three subjects were removed due to incomplete curvature analysis or missing subject information, such that 541 preterm and term-born infants were evaluated with scan age ranging from 27 to 45 weeks postmenstrual age (PMA). Across this developmental range, sharpness and complexity increased until a plateau around term-equivalent. Average sharpness of gyri was best correlated with age of scan (R2 = 0.877). Conclusion and Potential Impact: During the pre- and postnatal development period, total cortical surface area continues to increase after birth, but the overall sharpness and complexity of folding plateaus at ~37 weeks post-menstrual age. Exploring these physically meaningful curvature metrics can provide improved parameters for comparison to mechanistic models of brain folding.
Clinical Characteristics and Complications in Patients with Complex Vascular Anomalies
(2022-07-29) Johnson, Megan; Haggstrom, Anita
BACKGROUND/OBJECTIVE: Vascular anomalies are rare complications of development, with some forms affecting less than 1% of the population. In addition to visible manifestations, they may cause pain, swelling, bleeding, thrombosis, and infection. These conditions often require more than one field of medical expertise, so incorporating multidisciplinary care is essential for optimizing management strategies. In an effort to better describe a cohort of these patients requiring complex interventions and understand the spectrum of care they need, we captured demographic, clinical, and quality-of-life data to serve as a launching point for future studies. METHODS: We designed a RedCap database and conducted a retrospective chart review of 100 patients who presented at the Vascular Lesions Clinic (VLC) at Riley Children’s Hospital from May 2020 to May 2022. Demographic, clinical, and quality-of-life data using the OVAMA scale was obtained from Cerner and captured on RedCap. Excel and RedCap software were used to characterize this patient population. RESULTS: The majority of patients had diagnoses of venous malformations and lymphatic malformations. These anomalies showed no male or female predominance and most lesions were segmental. Sclerotherapy was the most common intervention, with venous malformations receiving a higher median number of treatments than lymphatic malformations. Lymphatic malformations were associated with lower appearance satisfaction and a younger median age at the time of the VLC visit than venous malformations. Older age, larger lesion size, female sex, and lesion location on the lower extremities also correlated with worse quality-of-life outcomes. CONCLUSION AND POTENTIAL IMPACT: The characterization of this cohort will guide broader studies of treatments and quality-of-life trends among patients with complex vascular anomalies. Future directions could explore patient outcomes, complication rates, and influences on quality-of-life in a prospective study design.
Clinical Features Distinguishing Diabetic Retinopathy Severity Using Artificial Intelligence
(2022-07-29) Happe, Michael; Gill, Hunter; Salem, Doaa Hassan; Janga, Sarath Chandra; Hajrasouliha, Amir
BACKGROUND AND HYPOTHESIS: 1 in 29 American diabetics suffer from diabetic retinopathy (DR), the weakening of blood vessels in the retina. DR goes undetected in nearly 50% of diabetics, allowing DR to steal the vision of many Americans. We hypothesize that increasing the rate and ease of diagnosing DR by introducing artificial intelligence-based methods in primary medical clinics will increase the long-term preservation of ocular health in diabetic patients. PROJECT METHODS: This retrospective cohort study was conducted under approval from the Institutional Review Board of Indiana University School of Medicine. Images were deidentified and no consent was taken due to the nature of this retrospective study. We categorized 676 patient files based upon HbA1c, severity of non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR). Retinal images were annotated to identify common features of DR: microaneurysms, hemorrhages, cotton wool spots, exudates, and neovascularization. The VGG Image Annotator application used for annotations allowed us to save structure coordinates into a separate database for future training of the artificial intelligence system. RESULTS: 228 (33.7%) of patients were diagnosed with diabetes, and 143 (62.7%) of those were diagnosed with DR. Two-sample t tests found significant differences between the HbA1c values of all diabetics compared to diabetics without retinopathy (p<0.007) and between all severities of DR versus diabetics without retinopathy (p<0.002). 283 eyes were diagnosed with a form of DR in this study: 37 mild NPDR, 42 moderate NPDR, 56 severe NPDR, and 148 PDR eyes. POTENTIAL IMPACT: With the dataset of coordinates and HbA1c values from this experiment, we aim to train an artificial intelligence system to diagnose DR through retinal imaging. The goal of this system is to be conveniently used in primary medical clinics to increase the detection rate of DR to preserve the ocular health of millions of future Americans.
Combinatorial Inhibition of Epigenetic Regulators to Treat Glioblastoma
(2022-07-29) Burket, Noah; Koenig, Jenna; Saratsis, Amanda
Glioblastoma (GBM) is a deadly primary brain cancer that affects 12,000 patients in the US annually with a median survival time of 15 months. Temozolomide is the standard-of-care chemotherapy for GBM; however, many tumors are resistant, necessitating the expansion of therapeutic options. EZH2 and JMJD3 are two proteins responsible for epigenetic regulation of the genome via histone methylation, with EZH2 also affecting non-histone targets. Prior studies showed that inhibition of these proteins decreased cell counts and induced radiosensitivity in GBM cells. Thus, we investigated combined use of EZH2 inhibitor, EPZ6438, and JMJD3 inhibitor, GSK-J4, in the treatment of temozolomide-resistant GBM10 cells. Non-irradiated cells were treated with both drugs singly and combined, and counted at 24-, 48-, and 72-hour intervals. Irradiated cells were pre-treated with each drug and combination therapy for three days, irradiated, and then counted at 24-, 48-, and 72-hour intervals. Western blot was used to investigate dsDNA damage biomarker y-H2AX, gene-silencing modification H3K27me3, tumor suppressor p53, EZH2, and JMJD3 expression in non-irradiated and irradiated cells following drug treatment. Single EPZ-6438 and GSK-J4 treatments reduced cell counts with increasing concentration and time. GSK-J4 appears to reduce cell counts more than EPZ-6438 alone, and combinatorial use reduces this further. Western blot reveals increased H3K27me3 expression with GSK-J4 treatment following radiation, but not with EPZ-6438. y-H2AX expression is increased after EPZ-6438 treatment but is not further increased with radiation. Meanwhile, GSK-J4 increased y-H2AX, but only after irradiation. Reduced cell counts following treatment with GSK-J4 may be due to its effects on gene silencing from inhibition of H3K27 demethylation. Additionally, increased dsDNA breaks seen in EPZ-6438 and GSK-J4 supports their roles in radiosensitizing GBM cells. This study highlights the importance of further investigation into GSK-J4 and EPZ-6438 combination therapy in temozolomide-resistant GBM tumors.
Comparing Long-term Patient-reported Outcomes after Cranial Vault Remodeling and Strip Craniectomies with the FACE-Q Craniofacial Module—a Retrospective Study
(2024-01-31) Bello, Margaret A.; Mercho, Patrick F.; Gupta, Salil; Shirrell, Mariah; Tran, Khoa D.; Cordes, Emma J; Tholpady, Sunil; Ackerman, Laurie; Makar, Katelyn G.
Comparing the Impact of Youth Violence upon Mental Health Before and During COVID-19 Pandemic vs the Effects of a Violence Prevention Program in a Cohort of Students in Gary, IN
(Indiana University, 2020) Omari, Deeb; McGee, Michael

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