Health Sciences – Page 29 – UROP Spring Symposium 2021

Health Sciences

Sexual Education for Children With Spina Bifida

Sexual education in America has many gaps, but one of the most glaring is the lack of sexual education for adolescents with physical disabilities. Children with Spina Bifida often enter puberty earlier than their peers. Therefore, it is crucial for them to learn about and prepare for their adult bodies at a young age. A comprehensive sexual education program was developed for each stage of a child’s physical and mental development by, first, creating a preliminary curriculum based on an analysis of existing sexual education programs for able-bodied and physically-disabled children. Qualitative interviews with physicians of varying specialties and with adults living with Spina Bifida were then performed in order to adapt the program to the specific needs of children with Spina Bifida. The program is designed specifically for children, adolescents, and teenagers with Spina Bifida and incorporates information that is appropriate for each successive life stage: childhood, adolescence, and young adulthood. The curriculum is separated into these three stages, and each stage includes videos and discussion topics about changing bodies, navigating adulthood, and handling sexuality. Those who opt to engage with the program are encouraged to discuss these sensitive topics with their parents and doctors and find their agency regarding their sexuality and their independence. The program will be beta tested with a cohort of children ages 10-19 with Spina Bifida, who will be asked to complete surveys and knowledge tests, in order to determine the efficacy of the curriculum. This program is one of few that specifically address sexual education for children with disabilities. While students are left out of their sexual education programs due to their conditions, this campaign aims to normalize sexuality and aid young kids with Spina Bifida in preparing for adulthood.

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Risky On-the-road Driving in Night Shift Workers

This study investigates whether there is a relationship between risky driving behaviors in night shift workers and circadian rhythms, an internal biological clock in humans. The participants chosen for this study are night shift workers, meaning they work predominantly during the night hours. Data was collected through sleep diaries filled out by night shift workers for every time they went to sleep or took naps and actigraphs were worn to document rest and activity cycles as well as light exposure. Saliva samples were also collected and assayed for melatonin, a hormone important for elucidating circadian timing of sleep by determining the time of dim light melatonin onset and offset. As the data has not yet been analyzed, results have not yet been produced. However, the expected results for this study are that there will be a higher likelihood of risky driving behaviors shown through hard braking, aggressive acceleration, phone usage while driving, and speeding when driving during the time interval of dim light melatonin onset and offset compared to driving outside of this time interval. The main conclusion from the expected results would be that circadian misalignment independently from sleep affects driving behavior.

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Effects of Rapamycin on Age-Associated Vasculature Transcription Profiles

Rapamycin (Rapa), an mTOR1 inhibitor, is one of the few therapies shown to prolong lifespan. It also may mitigate the adverse effects of age on the vasculature. To explore the vascular transcription profiles of age-associated pathways in mice treated with Rapa, mice were 1? treated with varying dosing regimens of Rapa beginning at 20 months of age?. The mice were checked twice daily for health status and were euthanized at 22 months of age. The aortas of mice were collected, and RNA was extracted from the aortas. RNA was then tested to ensure the collected samples were of adequate quality for RNA-sequencing analysis. We expect that the mice experiencing prolonged lifespan in response to Rapa treatment will have differences in their transcription profiles compared to young and old mice which had not been treated with Rapa. This information may provide insight related to the effects of Rapa towards prolongation of lifespan and may direct future studies in humans.

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FADD amplification in lung cancer promotes G1 to S cell cycle transition

Glioblastoma multiforme (GBM) is the most malignant primary central nervous system tumor and once diagnosed, the patient outcome does not look good. Currently, there are no curative treatment options for GBM, and the survival rate of patients diagnosed with the disease remains low. RAD51 is highly expressed in response to radiation and chemotherapy which is required for DNA repair from after these genotoxic therapies. Using small molecule drugs that modulate the RAD51 function, we have shown that they enhance chemo- and radio-sensitization in GBM due to inhibition of DNA repair. My UROP project will involve the purification of RAD51 protein so that the binding site and mechanism by which the RAD51 targeted drugs function can be delineated using X-ray crystallography. We hypothesize that the inhibition of RAD51 will sensitize GSCs to radio and chemotherapy which will further improve the survival of GBM patients. Although there are currently no results, this research and experiment is valuable because there are no effective therapies for GBM.

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Short-term Self-regulation of COPD

Chronic Obstructive Pulmonary Disease creates long-term obstacles for patients, which can result in exacerbations and mortality. Previous clinical trials focus on a patient’s physical well-being, utilizing bronchodilators or inhaled therapy as an attempt to alleviate symptoms and prevent future exacerbations. Short-term Self-regulation of COPD is focused on a patient’s self-regulation and provides an alternative hypothesis that a more active lifestyle will result in improved diligence of self-regulation as a short-term outcome. Participants were recruited from the Ann Arbor and Flint area and severity of their disease was measured prior to randomization. As intense physical activity is not practical for these subjects, this study utilizes chair yoga and imagery in the control group and squats, leg lifts, arm curls, oblique twists, and similar activities led by a kinesiology specialist as part of the experimental group; while group placement is randomly generated, both groups participate in activities that have the potential to improve outcomes. Our analysis involves evaluations taken at baseline and an assessment taken approximately 3 months after completion of the 10-week training classes. This data is taken from the Active for Life with COPD data set that includes testing visits, seven-day activity monitoring, the Chronic Respiratory Disease Questionnaire Self-Administered Standardized (CRQ-SAS), Multidimensional Outcome Expectations for Exercise Scale, and the Self-Regulation for Physical Activity Scale responses. Intervention elements during weeks 1-10 consist of lab-based exercises and an educational program with further intervention elements measured at approximately six months into the study; coaching phone calls and a booster session also occur. Data collection is done with blind testing, surveys, and numerous physical measurements for fatigue and mastery of activities like the six-minute walk. This research aims to support the hypothesis that a less-sedentary lifestyle leads to improved self-regulation in COPD patients.

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Connections Between Cell Signaling, Neutrophils, and Tumor Metastasis

Triple negative breast cancer (TNBC) is a type of breast cancer that is defined by the absence of estrogen receptors, progesterone receptors, and the low expression of HER2. The combined absence of these markers, historically, led to TNBCs having poorer prognosis due to the lack of therapeutic targets. Recent research reported by the Egeblad group (Cold Spring Harbor Laboratory) was able to identify that neutrophil extracellular traps (NETs), a pathogen trapping structure comprised of DNA, histones, and various other neutrophil-associated proteins, typically produced in the presence of a pathogenic infection, are prompted to form by metastatic breast cancer cells in the absence of an active infection. By studying the effect of inhibiting neutrophil infiltration, NET production, and of breaking down NETs within a short time through the use of DNase I treatment in vivo; the Egeblad group demonstrated that metastasis of the traditionally-metastatic 4T1 cell line could be prevented/delayed simply by targeting the interaction between tumors and NETs – thereby establishing NETs as a potential therapeutic target for the treatment of TNBC. Using the same 4T1 and 4T07 cell lines examined by the Egeblad group, we have recently demonstrated that these two cell lines constitutively produce different levels of CXCR-2 ligands in vitro when grown in control/untreated conditions; but produce similar levels when cultured in the presence of a NET-like biomaterial we have developed that we refer to as DNA-histone mesostructures (DHMs). Because 4T1 and 4T07 cells are derived from the same spontaneously-occurring parental tumor, this difference in constitutive expression poses interesting questions: what mutational differences may be present in 4T1 cells (but not in the 4T07 cells) that contributes to their constitutive production of CXCR-2 ligands (which act as neutrophil chemoattractants and induce the production of NETs by infiltrating neutrophils), and what similarities exist between these cells that may underlie their shared response to DHMs in vitro. To address these questions, we have chosen to take a multi-faceted approach that examines transcriptomic data from 4T1 and 4T07 cells grown in vitro (+/- DHMs) and in vivo (+/- DHMs), conducting comprehensive literature reviews on cancer-related intracellular signaling pathways to see what genes and intracellular factors may shed light upon the source of the intrinsic difference between these cell lines.

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Connections Between Cell Signaling, Neutrophils, and Tumor Metastasis

Triple negative breast cancer (TNBC) is a type of breast cancer that is defined by the absence of estrogen receptors, progesterone receptors, and the low expression of HER2. The combined absence of these markers, historically, led to TNBCs having poorer prognosis due to the lack of therapeutic targets. Recent research reported by the Egeblad group (Cold Spring Harbor Laboratory) was able to identify that neutrophil extracellular traps (NETs), a pathogen trapping structure comprised of DNA, histones, and various other neutrophil-associated proteins, typically produced in the presence of a pathogenic infection, are prompted to form by metastatic breast cancer cells in the absence of an active infection. By studying the effect of inhibiting neutrophil infiltration, NET production, and of breaking down NETs within a short time through the use of DNase I treatment in vivo; the Egeblad group demonstrated that metastasis of the traditionally-metastatic 4T1 cell line could be prevented/delayed simply by targeting the interaction between tumors and NETs – thereby establishing NETs as a potential therapeutic target for the treatment of TNBC.

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Genetic Impact on Low Diversity Microbiomes in Patients with Inflammatory Bowel Disease

Inflammatory Bowel Disease (IBD), a term that is used to generalize Ulcerative Colitis (UC) and Crohn’s Disease, is a disorder that involves chronic inflammation in the digestive tracts. UC is restricted to the colon, while Crohn’s disease can involve all segments of the GI tract. The pathogenesis of IBD is still unclear but several proposed mechanisms are being investigated which lead to a loss of homeostatic host-microbe interaction in the GI tract. Our study focuses on one of those mechanisms whereby a mutation in a gene that encodes an NADPH oxidase called Duox2 might lead to a loss of host-microbe homeostasis in the gut. In addition, we aim to better understand the possible environmental and hereditary factors that may contribute to IBD. Our study aimed to recruit 100 sibling pairs to take a survey that asked questions about diet, sleep, exercise, and their living environment. One of the siblings had IBD while the other was a control subject. Each sibling pair had a first degree relative with IBD, indicating a possible genetic component (e.g., Duox2 mutation). There was a parallel study conducted in Taiwan to also compare differences in ethnicity. Through our survey, we predicted that results will show trends among families who have IBD. The second phase of the study, identified patients who may be more likely to have a mutation in the Duox2 gene by screening for congenital hypothyroidism known to share a common genetic risk gene in Duox2. By collecting a blood and stool sample from families, we predict that we will be able to better understand the determinants of genetics, environment, and gut microbiota in the pathogenesis of IBD.

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Precision Medicine for Patients with Glomerular Disease

Frequently relapsing/steroid dependent nephrotic syndrome (FR/SDNS) is a chronic health condition in children that is treated with long term immunosuppression therapies with variable response and significant treatment-associated toxicities. Precise, safe and effective therapies are needed. Objective: in order to address drug development needs, we undertook a project to prioritize FR/SDNS clinical trial outcomes and generate standard of care outcome estimates for use in clinical trial design. Methods: A clinician-investigator stakeholder group was polled to elicit input on FR/SDNS trial endpoint priorities. A literature review was conducted using PubMed and enriched with assessment of trial listings from Clinicaltrials.gov. Search terms included: Idiopathic Nephrotic Syndrome and Minimal Change Disease. Publications were required to be clinical trials in humans for inclusion. Data collection included population type, year of publication, age of participants, trial treatment groups, participants in each arm and the prioritized outcome relapse rate. A summary of the results by treatment arm was generated using forest plot of relapse rate point estimates and 95% confidence intervals by trial treatment arm. Results: Relapse rate was one of two prioritized FR/SDNS clinical trial endpoints. From published clinical trials, relapse rate point estimates varied by clinical trial treatment groups but were generally between 0.02 and 0.2 relapses per patient month. Conclusions: The identified relapse rates and distribution can be used in the design of FR/SDNS clinical trials for power and sample size estimations.

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