Medicine and Health Sciences Commons^™

Her4 Promotes A Stem-Like Phenotype In Osteosarcoma, Rocio K. Rivera-Valentin

Dissertations & Theses (Open Access)

Metastatic disease to the lungs is the primary cause of death for patients with pediatric osteosarcoma (OS). OS has a high degree of heterogeneity and genomic instability, making understanding the pathogenesis and drivers of metastasis of this disease challenging. In an effort to explain tumoral heterogeneity, the tumor initiating cell model (TIC) states that tumors are composed of cells that form the majority of the tumor and are terminally differentiated. This model however, attributes tumorigenesis, metastasis and chemoresistance to a distinct cell population with a stem-like phenotype that can be identified using selective markers. OS appears to follow this model …

Repetitive, Pre-Anesthetic Fasting And Malnutrition In A Pediatric Oncology Population Undergoing Radiation Therapy, Laura P. Santibáñez

Dissertations & Theses (Open Access)

Background: Pediatric oncology patients often experience nutritional status changes, particularly malnutrition, which may adversely affect their outcomes. Although the consequences of malnutrition are elucidated, its causes remain unclear. A possible cause of malnutrition in pediatric oncology patients is repetitive, pre-anesthetic fasting prior to non-invasive procedures and treatments, such as anesthesia-assisted radiation therapy (AART). This exploratory study investigated the association between repetitive, pre-anesthetic fasting and non-fasting days and malnutrition in pediatric oncology patients receiving AART.

Procedure: A retrospective cohort of 138 pediatric oncology patients (£ 10 years of age) who received any type of radiation therapy (RT) with or without anesthesia …

The Immune Microenvironment Of Microsatellite Instable Endometrial Cancer, Janelle B. Pakish

Dissertations & Theses (Open Access)

Limited treatment options are available for patients with advanced and recurrent endometrial cancer (EC) should standard chemotherapy fail. Recent studies in other tumor types have shown that tumors with high microsatellite instability (MSI-H) have increased immunogenicity and response to immunotherapy treatments compared to microsatellite stable (MSS) tumors. Patients with MSI-H EC may also benefit from these therapies; however, the tumor immune microenvironment in MSI-H EC has not yet been well described.

In order to evaluate the immune microenvironment of MSI-H EC, multiple approaches were used, including analysis of large publically available datasets and detailed characterization of patient tumor samples. Uterine …

Potentially Inappropriate Medication Use In Older Patient With Breast And Colorectal Cancer, Meghan S. Karuturi

Dissertations & Theses (Open Access)

Our objective was to determine predictors of potentially inappropriate medication (PIM) use and its impact on outcomes (including ER visits, hospitalization, all cause death, and composite of three) in breast and colorectal cancer patients receiving chemotherapy. We used data from the SEER database linked to Medicare claims. Our cohort included patients ≥ 66 years diagnosed with of Stage II/III breast or colorectal cancer between 7/1/2007-12/31/2009. Baseline PIM was defined using the Drugs to Avoid in the Elderly list (DAE) or Beers criteria. Univariate and multivariable logistic regression were used to determine the associations of baseline PIMs with different covariates. Event-free …

Epigenetic Modulation In Braf Mutated Metastatic Colorectal Cancer, Van Morris

Dissertations & Theses (Open Access)

Introduction: BRAF V600E mutations are associated with poor clinical outcomes for patients with metastatic colorectal cancer (mCRC). Unlike other tumors with the same mutation, BRAF inhibitors are ineffective as monotherapy. CRC tumors with BRAF V600E mutations are associated with global hypermethylation, which may turn off tumor suppressor gene expression. We studied demethylation in BRAF V600E mCRC to restore sensitivity to BRAF inhibitors.

Methods: Tumor databanks were investigated for genes differentially expressed according to BRAF mutation status to identify genes which may be particularly susceptible to epigenetic influence. Mouse xenograft models of BRAFV600E mCRC were treated with vemurafenib or azacitidine, alone …

Development Of Rational Combination Therapy With Parp Inhibitors And Kinase Inhibitors In Tnbc, Wen-Hsuan Yu

Dissertations & Theses (Open Access)

Poly (ADP-ribose) polymerase inhibitors (PARPi) emerge as potential targeting drugs for BRCA-deficient cancers including triple negative breast cancer (TNBC). However, it has been reported that a subgroup of patients even with BRCA mutation fails to respond to PARPi in multiple clinical trials. In this study, we identified c-Met, a tyrosine kinase, phosphorylates PARP1 at Y907 and that the phosphorylation increases PARP1 activity, thereby rendering cancer cells resistant to PARPi. The combination of c-Met inhibitors (METi) and PARPi has a synergistic effect for c-Met overexpressed TNBC in vitro and in vivo. In addition to c-Met, through functional analysis, we found …

A Phase I Dose-Escalation Study Of The Braf Inhibitor Vemurafenib In Combination With The Mtor Inhibitor Everolimus In Subjects With Advanced Cancer, Javier Munoz

Dissertations & Theses (Open Access)

Vemurafenib has been approved in the United States for the treatment of relapsed or refractory BRAF mutation positive malignant melanoma and is being investigated in various other malignancies. The RAS/RAF/MEK/ERK (MAPK) pathway is critical to cell proliferation in many human cancers. The mTOR inhibitors are well known to exert profound anticancer effects across malignancies through inhibition of the PTEN/PI3K/AKT/mTOR (mTOR) pathway. We hypothesize that the toxicity profile of the combination of vemurafenib and everolimus will be well tolerated. The primary objective is to find the maximum tolerated dose (MTD) and the toxicity of the combination of vemurafenib and everolimus following …

The Roles Of Malt1 In Nf-Κb Activation And Solid Tumor Progression, Deng Pan

Dissertations & Theses (Open Access)

The transcription factor NF-κB plays a central role in many aspects of biological processes and diseases, such as inflammation and cancer. Although it has been suggested thatNF-κB is critical in tumorigenesis and tumor progression, the molecular mechanism by which NF-κB is activated in solid tumor remains largely unknown. In the current work, we focus on growth factor receptor-induced NF-κB activation and tumor progression, including epidermal growth factor receptor (EGFR)-induced NF-κB in lung cancer and heregulin receptor (HER2)-induced NF-κB in breast cancer. We found that Mucosa-associated lymphoma translocation protein 1 (MALT1), also known as paracaspase, is required for EGFR-induced NF-κB activation …

The Role Of 5-Alpha Reductase 3 In Steroid Metabolism, Zahi Mitri

Dissertations & Theses (Open Access)

Background

The growth and development of prostate cancer is largely driven by androgen mediated signaling. The 5-alpha reductase family of enzymes plays an essential role in the conversion of testosterone to the more potent androgen, 5-alpha dihydrotestosterone (DHT), which is capable of binding the androgen receptor to activate gene targets and downstream signaling. This study aimed to evaluate the role of 5-alpha reductase 3 (SRD5A3), a novel member of the 5-alpha reductase family, in steroid metabolism and prostate carcinogenesis.

Materials and Methods

HEK293 cells were transfected with the SRD5A3 human cDNA ORF Clone from OriGene. Steroid substrates (testosterone, progesterone, androstenedione, …

The Psychosocial Effects Of The Li-Fraumeni Education And Early Detection (Lead) Program On Indivdiuals With Li-Fraumeni Syndrome, Jessica L. Ross

Dissertations & Theses (Open Access)

Li-Fraumeni syndrome (LFS) is a hereditary cancer syndrome that leads to an increased risk of multiple cancers. In the past five years new screening protocols have been developed that provide improved screening options for individuals with LFS. However, very little has been published on the psychosocial impact of these screening protocols. The goals of this study were to determine how participation in screening impacts individuals psychosocially, to examine the benefits and drawbacks of screening, and to evaluate possible barriers to continued screening. This qualitative study consisted of phone interviews with 20 individuals that took part in an LFS screening program …

Is Whole-Exome Sequencing An Ethically Disruptive Technology? Perspectives Of Pediatric Oncologists And Parents Of Pediatric Patients With Solid Tumors., Laurence B Mccullough, Melody J Slashinski, Amy L Mcguire, Richard L Street, Christine M Eng, Richard A Gibbs, D William Parsons, Sharon E Plon

Faculty Publications

BACKGROUND: It has been anticipated that physician and parents will be ill prepared or unprepared for the clinical introduction of genome sequencing, making it ethically disruptive.

PROCEDURE: As a part of the Baylor Advancing Sequencing in Childhood Cancer Care study, we conducted semistructured interviews with 16 pediatric oncologists and 40 parents of pediatric patients with cancer prior to the return of sequencing results. We elicited expectations and attitudes concerning the impact of sequencing on clinical decision making, clinical utility, and treatment expectations from both groups. Using accepted methods of qualitative research to analyze interview transcripts, we completed a thematic analysis …

Activation Of Signal Transduction Pathways During Hepatic Oncogenesis., W Chung, M Kim, S De La Monte, L Longato, R Carlson, B L. Slagle, X Dong, J R. Wands

Faculty Publications

BACKGROUND AND AIMS: Understanding the molecular pathogenesis of hepatocellular carcinoma (HCC) is essential to identify therapeutic targets. A hepatitis B virus (HBV) related double transgenic murine model was developed. METHODS: Liver specific expression of HBV X protein (HBx) and insulin receptor substrate 1 (IRS1) was achieved and transgenic mice were followed from birth to age 21 months. Liver and tumor tissue were assessed for histologic changes as well as activation of signal transduction pathways by qRT-PCR and multiplex ELISA protein assays. RESULTS: Overexpression of HBx and IRS1 stimulates liver cell proliferation in the double transgenic mice. Only the male mice …