Health Sciences

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

itzeltv

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

pervezri

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

efischba

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

bczapla

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

gajja

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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A 5-year Longitudinal Observational Study of Management of Patients with Hepatocellular Carcinoma

hhakkani

Hepatocellular Carcinoma(HCC), a liver cancer that is linked with hepatitis A and B which are caused by liver cirrhosis, is an increasingly prevalent cancer that affects many people across the globe, majorly in the United States, Asia, and Africa. Treatments and remedies are currently very limited with nothing holding the capabilities of fully healing affected patients. The purpose of this research is to record and analyze the treatments currently used over the course of five years and create a database for future patients who face the cancer. Patients are searched for by project managers and are selected if they have HCC and commit to the project. The chosen patients undergo a health background check and provide documentation of their treatment and checkups every three months for a year and every six months for four more years. Over the course of five years, the patients are monitored and their medical documentation is used as data for the database. The database will allow physicians to categorize the effects of different treatments with the different types of patients to find the best solutions for future patients. After five years, the goal is not necessarily to find a cure or remedy, but rather to have an established database of information to allow doctors to better treat patients with HCC and create research further creating potential for a cure or remedy. The database’s main goal is to allow other researchers to take advantage of the material published and explore different methods of HCC treatment. Currently, the project remains partially complete and will require several years before the database becomes available for publication.

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Evaluating the efficacy of proteasome inhibitors in plasma cell leukemia

ahmedrah

Plasma cell leukemia (PCL) is a rare variant of multiple myeloma (MM), defined as >=20% plasma cells in peripheral blood by the International Myeloma Working Group (IMWG). Patients with PCL have worse outcomes than MM patients despite aggressive treatment with proteasome inhibitors, such as bortezomib, along with other agents. However, few studies have investigated the efficacy of proteosome inhibitors in PCL patients. This study is a single-center, retrospective study using previously collected data from 63 adult patients treated at Michigan Medicine between 1996 and 2019. Statistical analyses included Kaplan-Meier survival and Cox regression analyses. Patients were predominantly white (79%), with a mean age of 62 years, and received a median of four lines of treatment with 85% receiving bortezomib. Our study demonstrated that the use of bortezomib did not significantly improve overall survival (OS) compared to those that did not receive bortezomib (HR 0.85, p=0.7). The overall 12-month survival for PCL patients treated with bortezomib was 68% compared to 50% for those that did not receive bortezomib. We also investigated the efficacy of other treatments such as immunomodulators (IMID) and autologous stem cell transplant (ASCT). There was significantly improved OS in patients that received IMID therapy (HR 0.23, p=0.001), as well as those that received ASCT therapy (HR 0.31, p=0.0002). Our study demonstrates that bortezomib and other treatments have efficacy in PCL, though further studies with larger patient cohorts are warranted.

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A survey of Childhood Cancer Patients and Caregivers Experience during COVID

mmurillo

BACKGROUND The COVID-19 pandemic led to unprecedented change in healthcare delivery. In pediatric oncology, patients and providers were challenged to adapt to evolving circumstances while balancing adherence to well-established oncology treatment and monitoring plans in order to decrease exposure and prevent serious infections in this potentially immunosuppressed population. These changes may have affected healthcare behaviors. OBJECTIVE To evaluate the impact of the first 4 months of the COVID-19 pandemic on the timing of oncologic care and the overall experiences of pediatric oncology patients and families.

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Investigating the role of the Immune Microenvironment in Esophageal Adenocarcinoma

racheand

Esophageal adenocarcinoma (EAC) develops from chronic inflammation, termed Barrett’s Esophagus (BE), that then progresses through stages of increasing dysplasia before tumor development at the esophagogastric junction. The impact of the EAC immune microenvironment on patient survival at each stage has yet to be fully understood. This study provides quantitative descriptions of immune populations in EAC and surrounding tissue and its correlation with survival. Core tissue samples showing varying stages of dysplasia to cancer were stained for the T-cell proteins CD3 (general T-cell marker), CD4 (memory T-cells), CD8 (cytotoxic T-cells) or FOXP3 (T-regulatory cells). T-cells remove foreign and cancerous cells from the body. Immune checkpoint proteins normally regulate the immune system and suppress overactivity. In cancer, these proteins promote tumor survival. Immune checkpoint therapy, inhibiting checkpoint suppression, has shown promise in treating certain cancers. Tissue samples were stained for immune checkpoint markers, CTLA4, TIGIT and PD1. Linear regression and correlation matrices compared the overall makeup of the different T-cell and immune checkpoint microenvironment populations during each stage of disease progression and relationships between these populations. Cancer cells were also treated with two cytokines, IL6 and IL8. Previous studies indicate that IL-6 promotes tumor cell survival through chemo-resistance. Results from this study aim to understand if IL-8, which we have shown is upregulated in EAC, acts similarly. The goal of this project is to better understand immune cell interactions with EAC tumors. Our hypothesis is that high concentrations of T-cells in dysplastic or cancerous tissue could indicate a positive patient response to immunotherapy.

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