Medicine and Health Sciences Commons^™

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 …

Murine Tbk1 Is Required By Flt3+ Leukemia Stem Cells Yet Dispensable In Homeostatic Hematopoiesis, Austin Patrick Runde

Master's Theses

The TANK-binding kinase 1 (TBK1) is a cytoplasmic, serine/threonine kinase and a critical activator of the innate immune system. Reports have implicated TBK1 as a promoter of multiple cancer types. Acute myeloid leukemia (AML) is a cancer arising from the hematopoietic stem/progenitor cells (HSPCs). Although ~70% of AML patients achieve complete remission with chemotherapy, at least half will relapse due to the failure to eradicate leukemia stem cells (LSCs). As our previous data indicate the TLR-TAK1/TICAM-1 axes regulate LSCs, we suspect TBK1 also regulates LSCs. To study TBK1 in AML, we generated tamoxifen-inducible, Tbk1-knockout (Tbk1NULL) mice and Tbk1NULL MLL-AF9+ mouse …

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 …

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. …

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 …

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 …

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 …

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 …

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 …