Thesis (Ph. D.)--School of Nursing. University of Missouri--Kansas City, 2007. / "A dissertation in nursing." Advisor: Peggy Ward-Smith. Typescript. Vita. Title from "catalog record" of the print edition Description based on contents viewed Dec. 19, 2007. Includes bibliographical references (leaves 74-83). Online version of the print edition.

No description available.

Thesis (M. Nurs.)--University of Hong Kong, 2006.

<p>The aim of the study is to compare the palliative efficacy of two saliva substitutes (Sinspeek and Xerostom) in patients during radiotherapy for cancer of the head and neck. This crossover randomised controlled clinical trial was carried out on twenty-five patients with malignant tumours of the head and neck, following four weeks of radiotherapy at tygerberg hospital. The benefit of saliva substitutes to ameliorate the effects of xerostomia is well established and proper advice and access to relevant preparations is essential.</p>

No description available.

Adult T-cell leukemia/lymphoma (ATLL) is an incurable peripheral T-cell malignancy where most patients succumb within the first year of diagnosis. Development of ATLL requires human T-cell lymphotrophic virus type 1 (HTLV-I) retroviral infection followed by accumulation of somatic mutations and changes in gene expression. The discovery of genes and pathways involved in the initiation of ATLL may provide novel therapeutic targets for treatment of this fatal disease. Since the IL-2 signaling pathway plays an important role in ATLL development, mutational analysis of IL-2 signaling pathway components should yield a better understanding of disease progression and outcome. Janus kinase 3 (JAK3), a nonreceptor tyrosine kinase is a key kinase upstream in the IL-2 signaling pathway. Activating somatic mutations in JAK3 have been described in leukemias and lymphomas including acute megakaryoblastic leukemia and natural killer/T-cell lymphoma. Three mutations in the regulatory FERM domain of JAK3 were identified in four of the thirty-six ATLL patients screened and no mutations were found in the twenty-four screened ethnically matched controls. These somatic, missense mutations occurred in the amino terminal regulatory FERM domain. JAK3 FERM domain may play an autoregulatory role by inhibiting kinase activity in the absence of IL-2. In cell culture assays all three FERM domain mutations induce gain of function in JAK3 and can be inhibited with a JAK specific kinase inhibitor, tofacitinib. One of the JAK3 FERM domain mutations (E183G) was characterized in vivo and found to be oncogenic in cooperation with the loss of cell cycle regulatory proteins p16(INK4a) and p14(ARF). These findings emphasize the importance of JAK3 activation in ATLL development and offer a novel therapeutic target for this incurable disease.

Mesenteric lymph node (ln) metastasis is the single most important prognostic characteristic in colorectal cancer (CRC). The ln status is used for staging and is a decisive selection criterion for postoperative adjuvant therapy. However, it is difficult to accurately determine ln status by routine histopathology (H&amp;E). Thus, ~25% of CRC patients, who by H&amp;E are considered to lack tumor cells in their lns, i.e. stage I+II, die from CRC. To explore the utility of biomarker mRNA analysis for staging and prognosis of CRC, lns were collected at surgery and mRNA levels for fourteen biomarkers, including carcinoembryonic antigen (CEA), kallikrein 6 (KLK6), cytokeratin 20 (CK20), guanylyl cyclase C (GCC), CEACAM1-S, CEACAM6 and mucin 2 (MUC2), were determined by quantitative RT-PCR with RNA copy standards. Results were compared to routine H&amp;E analysis. The biomarkers were analyzed for capacity to detect disseminated tumor cells in lns. mRNA levels were determined in CRC- and control lns, primary tumor, normal colon, immune cells and fibroblasts. Lack of expression in immune cells and fibroblasts and high and homogenous expression in primary tumors showed to be the determining factors. CEA fulfilled these criteria best, followed by KLK6, CK20, GCC, and MUC2. Utility of the biomarker mRNAs for staging and prognosis was examined in 174 CRC patients. CEA was the best predictor of disease-free survival time after surgery with a 71 months difference between CEA(+) and CEA(-) patients and a hazard ratio of 5.1 for risk of recurrence for CEA(+) patients. CEA, CK20 and MUC2 were more sensitive than H&amp;E in that these biomarkers identified patients who succumbed from recurrent CRC although H&amp;E analysis had failed to detect the disseminated tumor cells. Combined analysis of CEA and MUC2 mRNAs improved prediction of outcome. Patients with high risk for recurrence had low MUC2/CEA ratios. KLK6 mRNA was identified as a potential progression marker by genome-wide microarray analysis of gene expression. It was found to be ectopically expressed in CRC tumor cells. KLK6(+) lns was an indicator of poor prognosis (hazard ratio 3.7). Notably, the actual level was of importance for outcome. The higher the KLK6 mRNA levels the greater the risk of recurrence. At the 90 thpercentile the hazard risk ratio for KLK6(+) patients was 5.6. KLK6 positivity in lns with low numbers of tumor cells, as indicated by low CEA mRNA levels, indicated poor prognosis (hazard ratio 2.8). Thus, KLK6 adds prognostic information to CEA analysis. Increased levels of mRNA for the proinflammatory cytokine interferon- and the down-regulatory cytokine interleukin-10 in lns of CRC patients suggested ongoing immune reactions against the infiltrating tumor cells. Elevated TGF-1 levels correlated weakly with survival, suggesting protection by the antiproliferative effect of TGF-1 in sporadic cases. CEA mRNA was the best single biomarker for staging and prediction of disease-free survival time and risk of recurrence after surgery. In addition to CEA, KLK6 positivity and low MUC2/CEA ratio correlate with poor prognosis. Thus, CEA, MUC2 and KLK6 mRNAs form a strong "trio" for staging and prediction of outcome for CRC patients.

It has steadily become more recognized that even patients with progressively growing tumors are often mounting substantial immune responses against their tumor. The reasons why this immunity is unable to control the outgrowth of the tumor must be understood if we are to develop immunotherapeutic and preventative strategies against cancer. Experimental observations since the 1960s have suggested that cellular immunity generated against tumor antigens is protective, while some studies have led me to believe that humoral immunity may be associated with disease progression. This possibility has led me to test the hypothesis that the cause of immune failure is immune-deviation.<p>The experimental system I chose employs the P815 mastocytoma and L5178Y lymphoma tumors, both of which are of DBA origin. I have demonstrated that primary resistance to tumors correlates with Th1 responses, while primary progressive tumor growth is associated with a mixed Th1/Th2 immune response generated against tumor antigens. Such correlates were defined directly by assessing tumor-dependent cytokine secretion by T cells, and indirectly by assessing the relative abundance of tumor-specific IgG2a and IgG1 antibodies by western blot and enzyme-linked immunoassays. Moreover, I have demonstrated, utilizing these assays, that low doses of gamma irradiation, which have previously been shown to induce immune-mediated regression of established tumors, is associated with a phenotypic switch in the anti-tumor immune response from a mixed Th1/Th2 to a predominant Th1 response. The simplicity and reliability of using IgG isotypes to indirectly assess the Th1/Th2 nature of the anti-tumor immune response gives me hope that this work, in the long run, will result in a new way of guiding immunotherapy to effectively treat cancer.

LZAP (Cdk5rap3, C53) is a putative tumor suppressor lost in 30% of human head and neck squamous cell carcinoma. LZAP depletion enhances cell invasion, xenograft tumor growth and angiogenesis. Mechanistically, LZAP inhibits activity of NF-¦ÊB and Chk1 and Chk2 through binding and decreasing phosphorylation of critical proteins. LZAP has no known enzymatic activity, implying that its biological functions are likely mediated by protein-protein interactions. The focus of this dissertation is to better understand LZAP activity through discovery of LZAP-associated proteins. Immunoprecipitation followed by liquid chromatography¨Cmass spectrometry identified members of protein phosphatase 2C family, PPM1A and PPM1B, as LZAP binding proteins Wip1/PPM1D, a known RelA phosphatase is a member of this family. Here we show that PPM1A dephosphorylates S536 and S276 of RelA and selectively inhibits NF-¦ÊB transcriptional activity resulting in decreased expression of cytokines implicated in cancer metastases. In human prostate cancer, metastatic deposits had lower PPM1A mRNA compared to primary tumors without metastases. In xenograft models, PPM1A expression inhibited bony metastases, whereasPPM1A depletion enhanced tumor growth. Interestingly, activities of LZAP and PPM1A to inhibit RelA inhibition are mutually dependent. LZAP contains motifs predicted to bind the docking domain (D domain) of mitogen activated protein kinases (MAPKs). LZAP binds and inhibit p38 phosphorylation, alters p38 cellular localization, and inhibits basal and cytokine-stimulated p38 activity. LZAP binds the p38 phosphatase, Wip1, and facilitates Wip1 binding and dephosphorylation of p38. These data suggest that LZAP inhibition of p38 phosphorylation and activity depends, at least partially, on Wip1. Regulation of LZAP activity is not well understood; however, we found that LZAP protein is modified by phosphorylation and ubiquitination, forms dimers/oligomers, and may be a target of PPM family members. These findings provide insight into LZAP activity and may lead to mechanisms to restore LZAP activity. Together, this work suggests a common mechanism of LZAP activity to regulate important cancer-related proteins, namely interaction with and regulation of PPM phosphatase family members.

The overall survival for neuroblastoma remains dismal, in part due to the emergence of resistance to chemotherapeutic drugs resulting in aggressive, refractory disease. As a neuroendocrine tumor, neuroblastomas secrete a number of peptides; one such being the gastrin-releasing peptide (GRP). GRP antagonists have been used to inhibit the proliferation of cancer cells. Here, I demonstrate that GRP silencing induced apoptosis in neuroblastoma cells and, in combination, allowed the usage of sublethal doses of chemotherapeutic drugs to elicit responses similar to lethal doses of the same drugs when used alone. GRP silencing also decreased tumorigenesis in vitro and suppressed liver metastasis in vivo. Moreover, GRP silencing increased PTEN levels with a simultaneous inhibition of AKT/mTOR/FAK activation in neuroblastoma cells. Interestingly, PTEN overexpression inhibited GRP-mediated neuroblastoma progression in vitro. This placed PTEN as a critical negative regulator of the oncogenic effects of GRP in neuroblastoma progression. This study provides a rationale for the use of GRP antagonists in patients with aggressive, refractory neuroblastomas.