Medicine and Health Sciences Commons^™

Tak1 And Tbk1 Are Differentially Required By Gmp- And Lmpp-Like Leukemia Stem Cells, Austin P. Runde, Joseph Michael Cannova, Ryan Mack, Kanak Joshi, Mark Sellin, Allan Youmaran, Mattias Lenz, Rohit Thalla, Wei Wei, Peter Breslin S.J., Jiwang Zhang

School of Medicine

Acute myeloid leukemia (AML) encompasses a diverse group of cancers that originate in the blood-forming tissues of the bone marrow. Aside from the M3 subtype (PML-RARA⁺), AML carries a 5-year survival rate of 28% for patients 20+ years of age. AML is the most common cancer of the hematopoietic system and is slightly more common in biological males; the average age at diagnosis is 68 years. Standard frontline treatment for AML is a 2-phase regimen of intensive chemotherapy (CTx) employing daunorubicin and cytarabine. Despite 60-70% of patients achieving complete remission (CR), at least half of CR-achieving patients …

Role Of Ripk3 In The Pathogenesis Of Tet2 Mutant Hematopoietic Malignancies, Kanak Joshi

Dissertations

Hematopoiesis is dynamically controlled by an epigenetic landscape that regulates gene transcription. Ten-eleven translocation 2 (TET2) is a Fe2+ and α-ketoglutarate (α-KG)-dependent dioxygenase that regulates the transcriptional status of genes associated with hematopoietic stem cell self-renewal and multiple stages of lineage commitment and differentiation. TET2 mutations are commonly detected in almost all types of hematopoietic malignancies, including myeloproliferative disorder, acute myeloid leukemia, and peripheral T-cell lymphomas. In most cases, TET2 is a founder mutation that occurred in hematopoietic stem/progenitor cells (HSPCs). The mutant HSCs undergo clonal expansion and evolution with the accumulation of additional mutations for malignant transformation. Microbial-stimulated inflammatory …

Effect Of Selenof Loss In Combination With A Western Diet On Tumorigenesis, Brenna Joy Flowers

Master's Theses

SELENOF is an understudied selenium-containing protein that has previously been postulated to behave as a tumor suppressor in the breast. Examination of patient databases showed that SELENOF levels were lowest in tumors from patients with aggressive late-stage breast cancers. Whether loss of SELENOF drives breast tumorigenesis remains to be determined. To address this question, we used juvenile female wild type or systemic Selenof knockout mice and exposed them to 7,12-Dimethylbenz[a]anthracene (DMBA), a carcinogen that replicates the multistep process of breast tumorigenesis. Previous reports have shown that loss of Selenof led to glucose and metabolic dysregulation in mice suggesting a link …

Cellular Mechanisms Underlying State-Dependent Neural Inhibition With Magnetic Stimulation, Hui Ye, Vincent Chiun-Fan Chen, Jenna Hendee

Engineering Science Faculty Publications

Novel stimulation protocols for neuromodulation with magnetic fields are explored in clinical and laboratory settings. Recent evidence suggests that the activation state of the nervous system plays a significant role in the outcome of magnetic stimulation, but the underlying cellular and molecular mechanisms of state-dependency have not been completely investigated. We recently reported that high frequency magnetic stimulation could inhibit neural activity when the neuron was in a low active state. In this paper, we investigate state-dependent neural modulation by applying a magnetic field to single neurons, using the novel micro-coil technology. High frequency magnetic stimulation suppressed single neuron activity …

Axonal Blockage With Microscopic Magnetic Stimulation, Hui Ye

Biology: Faculty Publications and Other Works

Numerous neurological dysfunctions are characterized by undesirable nerve activity. By providing reversible nerve blockage, electric stimulation with an implanted electrode holds promise in the treatment of these conditions. However, there are several limitations to its application, including poor bio-compatibility and decreased efficacy during chronic implantation. A magnetic coil of miniature size can mitigate some of these problems, by coating it with biocompatible material for chronic implantation. However, it is unknown if miniature coils could be effective in axonal blockage and, if so, what the underlying mechanisms are. Here we demonstrate that a submillimeter magnetic coil can reversibly block action potentials …

Targeting Epha2 In Hepatocellular Carcinoma: Uncovering Its Therapeutic Potential And Beyond, Hao Wang

Dissertations

Hepatocellular Carcinoma (HCC) remains one of the deadliest malignancies worldwide. One major obstacle to treatment is a lack of effective molecular-targeted therapies. Here, we identify EphA2 receptor tyrosine kinase as a clinically relevant target for HCC. EphA2 expression and signaling is enriched in human HCC and associates with poor prognosis. Loss of EphA2 suppressed the initiation and growth of HCC in vitro and in vivo. Furthermore, CRISPR/CAS9 mediated EphA2 inhibition significantly delayed tumor development in a genetically-engineered murine model of HCC. Mechanistically, we discovered that targeting EphA2 simultaneously suppresses both JAK1/STAT3 and AKT signaling, two separate oncogenic pathways in HCC. …

Tumor Immunology: Understanding The Immune System And Cancer To Enhance The Efficacy Of Cancer Immunotherapies, Natasha Malibu Lenart

Master's Theses

Tumor cells are notorious for their ability to escape immune surveillance, but developments in the understanding of the tumor microenvironment and how the immune system can be re-activated in tumors have had significant clinical impact. Commercially available and experimental methods such as adoptive cellular therapy, cytokine stimulation, and immune checkpoint blockade are promising immunotherapies for a variety of cancers, including solid tumors and hematological malignancies. However, induction of persistent, long-term anti-tumor immunity after initial treatment is infamously difficult. as a result, scientists are searching for new approaches to improve established immunotherapies. by employing combination treatments or enhancing the functionality of …

Stratification Of Ovarian Tumor Pathology By Expression Of Programmed Cell Death-1 (Pd-1) And Pd-Ligand- 1 (Pd-L1) In Ovarian Cancer, Maureen L. Drakes, Swati Mehrotra, Monica Aldulescu, Ronald K. Potkul, Yueying Liu, Anne Grisoli, Cara Joyce, Timothy O'Brien, M. Sharon Stack, Patrick J. Stiff

Mathematics and Statistics: Faculty Publications and Other Works

Background

Ovarian cancer is the major cause of death among gynecologic cancers with 75% of patients diagnosed with advanced disease, and only 20% of these patients having a survival duration of five years. Treatments blocking immune checkpoint molecules, programmed cell death (PD-1) or its ligand PD-ligand- I (PD-L1) have produced a beneficial and prolonged effect in a subgroup of these patients. However, there is debate in the literature concerning the prognostic value of the expression of these molecules in tumors, with immunotherapy responsiveness, and survival.

We evaluated the immune landscape of the ovarian tumor microenvironment of patients, by measuring the …

Inhibition Of Insulin‐Like Growth Factor 1 Receptor Enhances The Efficacy Of Sorafenib In Inhibiting Hepatocellular Carcinoma Cell Growth And Survival, Fang Wang, Thomas Bank, George Malnassy, Maribel Arteaga, Na Shang, Annika Dalheim, Xianzhong Ding, Scott J. Cotler, Mitchell F. Denning, Michael I. Nishimura, Peter Breslin, Wei Qiu

Biology: Faculty Publications and Other Works

Hepatocellular carcinoma (HCC) is the fifth most common primary cancer and second largest cause of cancer‐related death worldwide. The first‐line oral chemotherapeutic agent sorafenib only increases survival in patients with advanced HCC by less than 3 months. Most patients with advanced HCC have shown limited response rates and survival benefits with sorafenib. Although sorafenib is an inhibitor of multiple kinases, including serine/threonine‐protein kinase c‐Raf, serine/threonine‐protein kinase B‐Raf, vascular endothelial growth factor receptor (VEGFR)‐1, VEGFR‐2, VEGFR‐3, and platelet‐derived growth factor receptor β, HCC cells are able to escape from sorafenib treatment using other pathways that the drug insufficiently inhibits. The aim …

Prevalence And Predictors Of Low Serum 25-Hydroxyvitamin D Among Female African-American Breast Cancer Survivors, Patricia M. Sheean, Claudia Arroyo, Jennifer Woo, Melinda Stolley

Nursing: School of Nursing Faculty Publications and Other Works

Background:

African-American breast cancer survivors commonly demonstrate low serum 25-hydroxyvitamin D (25(OH)D). Decreased cutaneous conversion, high levels of adiposity, and even breast cancer treatment may influence vitamin D status. Previous investigations have analyzed African-American women in aggregate with other breast cancer survivors and have not comprehensively addressed these influential factors.

Divergent Pro-Leukemic Effects Of Myd88 And Ticam-1/Trif Mediated Toll-Like Receptor Signaling, Joseph Michael Cannova

Dissertations

The goal of this study is to determine the role of Toll-like receptor (TLR) signaling in acute myeloid leukemia (AML). AML is a hematopoietic malignancy that predominately affects the elderly. The median age of AML diagnosis is 67 years old. The standard of care of AML is treatment with cytotoxic chemotherapy, which elderly patients are often unable to tolerate. To identify novel pathways as potential targets for treatment, a microarray on AML primary patient samples was performed to determine the expression of key inflammatory genes. This microarray, and other published datasets, showed that TLR are overexpressed in myelomonocytic (M4) and …

Inhibitory Or Excitatory? Optogenetic Interrogation Of The Functional Roles Of Gabaergic Interneurons In Epileptogenesis, Hui Ye

Biology: Faculty Publications and Other Works

Alteration in the excitatory/inhibitory neuronal balance is believed to be the underlying mechanism of epileptogenesis. Based on this theory, GABAergic interneurons are regarded as the primary inhibitory neurons, whose failure of action permits hyperactivity in the epileptic circuitry. As a consequence, optogenetic excitation of GABAergic interneurons is widely used for seizure suppression. However, recent evidence argues for the context-dependent, possibly “excitatory” roles that GABAergic cells play in epileptic circuitry. We reviewed current optogenetic approaches that target the “inhibitory” roles of GABAergic interneurons for seizure control. We also reviewed interesting evidence that supports the “excitatory” roles of GABAergic interneurons in epileptogenesis. …

Using Tcr Transgenic, Gp100 Reactive T Cells And Checkpoint Inhibition To Target Lymphangioleimyomatosis, Christian Ankney

Master's Theses

Lymphangioleiomyomatosis (LAM) is a low-grade neoplastic disease affecting primarily women. It is characterized by cystic lung disease as well as renal and retroperitoneal tumors called angiomyolipomas and lymphangiomas. Tumor cells have smooth muscle features as well as neuroendocrine cell surface markers, and the disease can be diagnosed by HMB45 staining of tumor cells. We questioned whether expression of melanocytic antigens, specifically gp100, creates an opportunity to treat LAM by adoptive T cell transfer. LAM lung lesions demonstrate poor immune surveillance, therefore adoptive T cell transfer could offer benefits in this disease.

A link was made between melanoma and depigmenting vitiligo …

Tissue- And Serum-Associated Biomarkers Of Hepatocellular Carcinoma, Ranjit Chauhan

School of Medicine

Hepatocellular carcinoma (HCC), one of the leading causes of cancer deaths in the world, is offering a challenge to human beings, with the current modes of treatment being a palliative approach. Lack of proper curative or preventive treatment methods encouraged extensive research around the world with an aim to detect a vaccine or therapeutic target biomolecule that could lead to development of a drug or vaccine against HCC. Biomarkers or biological disease markers have emerged as a potential tool as drug/vaccine targets, as they can accurately diagnose, predict, and even prevent the diseases. Biomarker expression in tissue, serum, plasma, or …

Separating Autoimmune And Anti-Tumor Responses With Hsp70iq435a, James Mahon

Master's Theses

Vitiligo and melanoma are both melanocyte-derived diseases; vitiligo progresses through the autoimmune-targeted destruction of healthy melanocytes while melanoma results from uncontrolled proliferation of cancerous melanocytes. Treatment of vitiligo with HSP70iQ435A inhibits the DC-mediated auto-immune response against melanocytes in vitiligo mouse models; this raises the concern that treatment with this modified HSP may also inhibit natural anti-tumor responses against melanocyte-derived melanoma tumor cells.

We hypothesized that HSP70iQ435A prevents migration of melanocyte-antigen reactive T cells to the skin in a way that is mechanistically different from anti-tumor responses to melanoma and therefore would not have a negative effect on anti-tumor responses. We …

Primary Seronegative But Molecularly Evident Hepadnaviral Infection Engages Liver And Induces Hepatocarcinoma In The Woodchuck Model Of Hepatitis B, Ranjit Chauhan

School of Medicine

Hepadnavirus at very low doses establishes in woodchucks asymptomatic, serologically undetectable but molecularly evident persistent infection. This primary occult infection (POI) preferentially engages the immune system and initiates virus-specific T cell response in the absence of antiviral antibody induction. The current study aimed to determine whether POI with time may culminate in serologically identifiable infection and hepatitis, and what are, if any, its pathological consequences. Juvenile woodchucks were intravenously injected with inocula containing 10 or 100 virions of woodchuck hepatitis virus (WHV) to induce POI and followed for life or up to 5.5 years thereafter. All 10 animals established molecularly …

Regulation And Targeting Of Fyn In Human Cutaneous Squamous Cell Carcinoma, Sarah Fenton

Dissertations

Fyn, a member of the Src family kinases, is an oncogene in murine epidermis and is associated with cell-cell adhesion turnover and migration. Introduction of active H-Ras(G12V) into the HaCaT human keratinocyte cell line resulted in upregulation of FYN mRNA (200-fold) and protein, but did not increase the expression of other SFKs. We identified two nucleotides 74 bases upstream of the human FYN gene transcription start site as necessary for FYN upregulation in HaCaT-Ras cells. Further studies identified Lef-1 as the transcription factor most likely binding to this site and mediating FYN upregulation.

Transduction of active Ras or Fyn was …

The Symptom Experience Of Patients Receiving Epidermal Growth Factor Receptor Inhibitors, Josephine Ann Howard-Ruben

Dissertations

This study explored the symptom experience of patients receiving epidermal growth factor receptor inhibitors (EGFRIs) for breast, colon, head and neck, and colon cancer. EGFRIs are targeted therapies used at various points along the treatment continuum for these solid tumors, and may be first, second or third-line agents which can be used as single agents or in combination with other therapies. The most common side effect of these agents include dermatologic effects, such as rashes, hair, and nail changes, but they can also contribute to other side effects such as fatigue, anxiety and diarrhea. Most previous work has addressed the …

Shades Of Grey: An Exploration Of The Student Learning Experience In Diagnostic Radiology Education, Kathleen Linda Linaker

Dissertations

Diagnostic radiology education is a specialty within healthcare education and encompasses education at both the undergraduate and resident level. There is little research regarding what constitutes effective radiology education. The broad purpose of this study was to investigate through the student perspective how chiropractic students learned diagnostic radiology within their curriculum and what contributed to this learning. This interview-based, qualitative research explored the learning experiences of 12 fourth-year chiropractic students at two colleges. Specifically this study investigated a) the learning strategies students believe both worked and didn't work in learning radiology, b) student perceptions of the effectiveness of instructional methods …

Notch-1 Activates Nf-Кb Activity In Cervical Cancer And Estrogen Receptor Negative Breast Cancer, Yin Peng

Dissertations

Breast and cervical cancer are two common cancers that severely endanger women's health. The fatality rates of breast and cervical cancer are ranked first and fifth, respectively, in cancer related deaths in women worldwide. Continuous dedication to cancer research is urgently required to elucidate the cancer cell survival mechanism that is responsible for disease aggressiveness and poor prognosis.

Emerging data indicate that Notch-1 is aberrantly regulated in human cervical and ER- breast cancer and inhibiting Notch-1 sensitizes cancer cells to apoptosis. However, the mechanism by which Notch-1 promotes cell survival is not known. NF-КB is also deregulated in these two …

Identification And Characterization Of Genotype A And D Recombinant Hepatitis B Virus From Indian Chronic Hbv Isolates, Ranjit Chauhan

School of Medicine

To confirm the presence of recombination, full-length hepatitis B virus (HBV) from chronic patients was sequenced and analyzed.Full-length HBV genomes from 12 patients were amplified and sequenced in an automated sequencer. Phylogenetic analysis was carried out on full-length, Core and preS2/Surface regions using MEGA software. SimPlot Boot Scanning and amino acid sequence analysis were performed for confirmation of recombination.Eight patients were infected with genotype D strain; one patient with genotype A and three patients had genotype A and D recombination; two of them had cirrhosis and one had hepatocellular carcinoma. Phylogenetic analysis of core and preS2/surface regions separately showed …

Integrative Theories Of Medicine: A (W)Holistic Vision, Kathryn B. Forestal

Master's Theses

No abstract provided.

Gatekeeping Access To Emergency Departments: A Survey Of Hmo Policies, Regina Conway Phillips

Master's Theses

No abstract provided.

A Study To Determine The Effects Of Client Participation In Care On Perceived Control/Powerlessness And Morale, Janis Marie Ormond

Master's Theses

No abstract provided.

Isolation And Characterization Of A Vulvar Carcinoma In Tissue Culture: Studies Of The Tumor Biology And Tumor-Host Interaction, Melvin G. Dodson

Dissertations

No abstract provided.