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<p> Metals such as arsenic, cadmium, beryllium, and nickel are known human carcinogens; however, other transition metals, such as tungsten, remain relatively uninvestigated with regard to their potential carcinogenic activity. Tungsten production for industrial and military applications has almost doubled over the past decade and continues to increase. This work demonstrates tungsten&rsquo;s ability to induce carcinogenic-related endpoints including cell transformation, increased migration, xenograft growth in nude mice, and the activation of multiple cancer related pathways in transformed clones as determined by RNA sequencing. Human bronchial epithelial cell line (BEAS-2B) exposed to tungsten developed carcinogenic properties. In a soft agar assay, tungsten-treated cells formed more colonies than controls and the tungsten-transformed clones formed tumors in nude mice. RNA sequencing data revealed that the tungsten-transformed clones altered the expression of many cancer-associated genes when compared to control clones. Genes involved in lung cancer, leukemia, and general cancer genes were deregulated by tungsten. </p><p> In order to examine the epigenetic mechanisms that mediate tungsten&rsquo;s tumorigenicity, we investigated if tungsten alters the levels of global histone methylation and if these changes are due to tungsten influencing the histone demethylases. We found that cells acutely treated with tungsten displayed significantly increased numbers of H34me3 and H3K9me2 histone marks on a global scale. This increase was due to down-regulation in the protein levels of the histone demethylases JMJD1A and JARID1A. The increase in global histone methylation remained when cellular SAM levels were depleted. The decrease in histone demethylase proteins was found to be due to a reduction in their gene expression. Epigenetic alterations induced by tungsten in the histone demethylase genes caused the repression. </p><p> We also evaluated insoluble tungsten, tungsten oxide (WO₃). WO₃ is an occupational exposure hazard. The primary route of WO₃ exposure is inhalation and WO₃ is known as a pulmonary irritant. WO₃ exposure led to stochastic results, which were likely due to the random effects of the particles. </p><p> Given the carcinogenic potential of other metals, it is likely that tungsten will exert carcinogenic outcomes. This study evaluates cancer-associated endpoints induced by tungsten exposure in both <i>in vitro</i> and <i> in vivo</i> models. To evaluate the mechanisms that underlie tungsten-induced carcinogenesis, alterations to the epigenome are assessed. Arsenic, cadmium, nickel, and chromium (VI) are poor mutagens; however, they exert their carcinogenic potential via epigenetic mechanisms. The literature is currently void of investigations examining the epigenetic effects of tungsten. Given the evidence characterizing metals as epimutagens, it is likely that tungsten toxicity and carcinogenesis is mediated via epigenetic mechanisms.</p>

<p> Women with Type 2 diabetes (T2D) have a 49% increase in breast cancer related mortality compared to women without T2D. Epidemiological studies report that increased endogenous insulin levels and increased insulin receptor (IR) expression are associated with poor survival in breast cancer patients. Therefore, it is essential to investigate the role of endogenous hyperinsulinemia on breast cancer progression. Presented in this thesis are contributions to understanding the effect of insulin in a mouse model of hyperinsulinemia (MKR mouse). First, data is shown that highlights the significant increase in primary MVT-1 tumors and pulmonary metastasis in the MKR mouse compared to Wild Type mice. The studies presented show that the primary tumors from the MKR mice have significantly higher Vimentin protein expression compared to primary tumors from control mice. Next, the studies determine that silencing Vimentin expression in the tumor cells leads to either decreased number of pulmonary metastasis in the hyperinsulinemic mice. The work in this thesis also establishes a novel immunodeficient hyperinsulinemic (Rag/MKR) mouse model that enabled the study of the effects of endogenous insulin on the progression of human cancer cells. The hyperinsulinemia of the Rag/MKR mice promoted a significant increase in tumor growth of MDA-MB-231 and LCC6 cells. The knockdown of the insulin receptor in the LCC6 cells led to primary tumors that were significantly smaller in both the hyperinsulinemic Rag/MKR and Rag/WT control mice compared to the tumors from the LCC6 control cells. Finally, it is shown for the first time that the knockdown of the IR promotes a reversal of the epithelial-mesenchymal phenotype by repressing mesenchymal markers and re-expressing epithelial markers in the LCC6 insulin receptor knockdown tumors. The data presented in this thesis highlight a potential contribution to the understanding of the role of insulin in the setting of hyperinsulinemia and provide potential targets for therapy to improve survival in women with breast cancer and hyperinsulinemia.</p>

<p>Gliomagenesis is driven by a complex network of genetic alterations and while the glioma genome has been a focus of investigation for many years; critical gaps in our knowledge of this disease remain. The identification of novel molecular biomarkers remains a focus of the greater cancer community as a method to improve the consistency and accuracy of pathological diagnosis. In addition, novel molecular biomarkers are drastically needed for the identification of targets that may ultimately result in novel therapeutics aimed at improving glioma treatment. Through the identification of new biomarkers, laboratories will focus future studies on the molecular mechanisms that underlie glioma development. Here, we report a series of genomic analyses identifying novel molecular biomarkers in multiple histopathological subtypes of glioma and refine the classification of malignant gliomas. We have completed a large scale analysis of the WHO grade II-III astrocytoma exome and report frequent mutations in the chromatin modifier, alpha thalassemia mental retardation x-linked (<italic>ATRX<italic>), isocitrate dehydrogenase 1 and 2 (<italic>IDH1<italic> and <italic>IDH2<italic>), and mutations in tumor protein 53 (<italic>TP53<italic>) as the most frequent genetic mutations in low grade astrocytomas. Furthermore, by analyzing the status of recurrently mutated genes in 363 brain tumors, we establish that highly recurrent gene mutational signatures are an effective tool in stratifying homogeneous patient populations into distinct groups with varying outcomes, thereby capable of predicting prognosis. Next, we have established mutations in the promoter of telomerase reverse transcriptase (<italic>TERT<italic>) as a frequent genetic event in gliomas and in tissues with low rates of self renewal. We identify <italic>TERT<italic> promoter mutations as the most frequently mutated gene in primary glioblastoma. Additionally, we show that <italic>TERT<italic> promoter mutations in combination with <italic>IDH1<italic> and <italic>IDH2<italic> mutations are able to delineate distinct clinical tumor cohorts and are capable of predicting median overall survival more effectively than standard histopathological diagnosis alone. Taken together, these data advance our understanding of the genetic alterations that underlie the transformation of glial cells into neoplasms and we provide novel genetic biomarkers and multi &ndash; gene mutational signatures that can be utilized to refine the classification of malignant gliomas and provide opportunity for improved diagnosis.</p> / Dissertation

<p> Metastatic, castrate-resistant prostate cancer (mCRPC) is one of the most prevalent cancers and is the third leading cause of cancer death among men. Several treatment options have been developed to combat mCRPC, however none have produced any tangible benefits to patients' overall survivability. As part of a crowd-sourced algorithm development competition, participants were asked to develop new prognostic models for mCRPC patients treated with docetaxel. Such results could potentially assist in clinical decision making for future mCRPC patients. </p><p> In this thesis, we present a new ensemble prognostic model to perform risk prediction for mCRPC patients treated with docetaxel. We rely on traditional survival analysis model like the Cox Proportional Hazard model, as well as more recently developed boosting model that incorporates smooth approximation of the concordance index for direct optimization. Our model performs better than the the current state-of-the-art mCRPC prognostic models for the concordance index performance measure and is competitive with these models on the integrated time-dependent area under the receiver operating characteristic curve.</p>

<p> Hepatocellular carcinoma (HCC) is the second leading cause of cancer death in the world and the liver is a common site of metastases from other primary neoplasms. Many patients are not surgical candidates. Radioembolization is an intra-arterial therapy delivering high doses of radiation emitted from microspheres infused selectively into the tumor feeding arteries. These microspheres land in the tumor microcirculation and deposit radiation to the tumor tissues. Over the past ten years, radioembolization has become part of the treatment guidelines for unresectable HCC, liver-dominant metastatic colorectal cancer, and neuroendocrine liver metastases, and it is often used in the salvage setting for patients with hepatic malignancy progressing on other therapies. The overarching goal of the thesis work was to advance the basic science of ⁹⁰Y radioembolization based on existing clinical needs to ultimately improve patient outcomes. This included 1) setup of pre-clinical laboratory to study radioembolization, 2) optimization of radioembolization protocols in research animals, 3) validation of ⁹⁰Y PET/CT imaging techniques to monitor microsphere delivery and dosing, 4) blood oxygen-level dependent (BOLD) imaging and evaluation of tumor biology and physiology after radioembolization in the VX2 rabbit model at a fixed dose of 50 Gy, 5) evaluation of normal tissue pathology (fibrosis, atrophy) and biology (hepatocyte proliferation, microvessel density, stellate cell activation) in rats after ⁹⁰Y radiation lobectomy at clinically relevant dosing from 150 to >4,000 Gy, and 6) development of new yttrium microsphere compositions for combination therapy with electromagnetic hyperthermia.</p>

Psychologists have focused on the phenomenon of chemotherapy-related nausea because of the extent of its debilitating effects, which affect compliance with medical regimens, and the more-current belief that some of this nausea may be conditioned. Research with behavioral treatments began with and continue to apply relaxation training. However, attention has moved to distraction strategies recently, with the belief that one active ingredient of relaxation may be distraction. This two-experiment project tested distraction with two types of chemotherapy patients: those with chemotherapy experience (Experiment 1) and patients new to chemotherapy (Experiment 2). An induction and rationale for distraction was provided treatment patients along with a "package" of distractors that included hand-held games, tape recordings and magazines. Orders were given to begin use of distractors when symptoms of nausea began. It was hoped that with all patients the distraction would attenuate nausea. With patients new to chemotherapy, it was hoped distraction would also inhibit conditioning of nausea. The first experiment utilized a pre-test, post-test control group design with sequential assignment to treatment and control groups. Subjects (20 controls, 13 treatment) were followed for two hospitalizations, with treatment subjects given the distraction intervention on the second visit. A regressed change analysis with variables entered hierarchically found no significant differences between treatment and control subjects' levels of nausea. Experiment 2 used a repeated-measures posttest-only design with sequential assignment. Nine control and 10 treatment subjects were each followed for three hospital visits, with treatment subjects using distraction each visit. A mixed factoral design analysis of variance found no significant difference in nausea between control and treatment subjects. / Source: Dissertation Abstracts International, Volume: 49-07, Section: B, page: 2879. / Major Professor: Wallace Albert Kennedy. / Thesis (Ph.D.)--The Florida State University, 1988.

The most common type of thyroid cancer, differentiated thyroid cancer (DTC), is diagnosed by radioactive iodine whole body scanning (WBS) and treated with radiotherapy using iodine-131 (131I). The success of this diagnosis/treatment approach relies on the relatively selective localisation of the sodium/iodide symporter (NIS) in cells of the thyroid gland. However, in some de-differentiated thyroid cancers, NIS expression is lost. This results in the inability of WBS to stage the disease and it also decreases the effectiveness of treatment with 131I. A number of reports have shown that de-differentiated thyroid carcinomas, however, continue to express thyroid stimulating hormone receptor (TSHR). TSHR is, therefore, a potential target for the diagnosis and treatment of radioiodine resistant de-differentiated thyroid carcinoma. In this study an anti-TSHR monoclonal antibody (mAb9) and human recombinant TSH (rhTSH) were radiolabelled and evaluated for their potential use in the diagnosis and treatment of radioiodine resistant thyroid cancer. A number of radiolabelling methods and quality control experiments were initially carried out to ensure high purity radiolabelled mAb9 and rhTSH were produced. In vitro studies were conducted to assess the binding affinity of 125I-mAb9, 111In-mAb9 and 125I-rhTSH to the TSHR in thyroid cancer cell lines, TPC-1, FTC-133, and FRTL5, and in a TSHR transfected cell line, GPI. SPECT/CT animal studies were performed in mice to investigate whether 125I-mAb9, 111In-mAb9 and 125I-rhTSH bound to TSHR in the thyroid of mice in vivo. 125I-mAb9, 111In-mAb9 and 125I-rhTSH bound to GPI cells but did not bind specifically to the TSHR in FTC-133, TPC-1 and FRTL5 cells as well as to the thyroid of normal mice in vivo. Radiolabelled mAb9 and radiolabelled rhTSH are therefore unlikely to be of use in the diagnosis and treatment of radioiodine resistant de-differentiated thyroid cancer.