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This study addressed gaps in the literature regarding the lack of information about the degree and extent of the relationships among symptom burden, specific symptoms, and health-related quality of life (HRQL). The sample included 89 adults receiving care for colorectal cancer in an outpatient setting. Data for this cross-sectional study were collected over a four month period using the Modified Ambulatory Care Flow Sheet (MACFS), the Rotterdam Symptom Checklist- Modified, numerical rating scales for pain and coping, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Cancer 30. Results showed that the MACFS was reasonably valid and internally consistent and that symptom burden and number of symptoms were significantly abut weakly correlated with HRQL. Specific symptoms most significantly correlated with HRQL were insomnia, fatigue, pain, nausea and vomiting. Findings support the use of the MACFS to assess symptoms and HRQL in the study population.

Introduction: There is uncertainty whether low-risk febrile neutropenia (FN) episodes in children with cancer are best managed in the inpatient or outpatient setting. Methods: A cost-utility model was created to compare four different treatment strategies for low-risk FN in pediatric cancer patients. Outcome measures were quality-adjusted FN episodes (QAFNE), costs (Canadian dollar), and incremental cost-effectiveness ratios (ICER). Results: The most cost-effective strategy was outpatient treatment with intravenous antibiotics. It was cost saving ($2,732 versus $2,757) and more effective (0.66 QAFNE versus 0.55 QAFNE) as compared to outpatient treatment with oral antibiotics. An early discharge strategy after 48 hours in hospital was slightly more effective but significantly more expensive than outpatient treatment with intravenous antibiotics resulting in an unacceptably high ICER of more than $130,000 per QAFNE. Inpatient care was the least cost-effective strategy. Conclusions: Outpatient strategies for treatment of low-risk FN in children are more cost-effective than traditional inpatient care.

Introduction: There is uncertainty whether low-risk febrile neutropenia (FN) episodes in children with cancer are best managed in the inpatient or outpatient setting. Methods: A cost-utility model was created to compare four different treatment strategies for low-risk FN in pediatric cancer patients. Outcome measures were quality-adjusted FN episodes (QAFNE), costs (Canadian dollar), and incremental cost-effectiveness ratios (ICER). Results: The most cost-effective strategy was outpatient treatment with intravenous antibiotics. It was cost saving ($2,732 versus $2,757) and more effective (0.66 QAFNE versus 0.55 QAFNE) as compared to outpatient treatment with oral antibiotics. An early discharge strategy after 48 hours in hospital was slightly more effective but significantly more expensive than outpatient treatment with intravenous antibiotics resulting in an unacceptably high ICER of more than $130,000 per QAFNE. Inpatient care was the least cost-effective strategy. Conclusions: Outpatient strategies for treatment of low-risk FN in children are more cost-effective than traditional inpatient care.

Prostatic carcinoma is the most frequently diagnosed cancer in men in the United States, however, its etiology is largely unknown. The mechanisms of invasion and metastases of prostate carcinoma are currently topics of intense study. Our research focused on IL-1β induced expression of the matrix metalloproteinase, matrilysin, in the prostate. Matrilysin is suspected to be involved with invasive and/or metastatic properties of prostate carcinoma cells and has been shown to be up regulated in prostate cancer. Inhibition of NFκB completely abrogated IL-1β induced promatrilysin expression, however, inhibition of protein synthesis with cyclohexamide completely blocked induction of IL-1β stimulated matrilysin mRNA which indicated that synthesis of one or more signaling factors was required for potentiation of promatrilysin expression by IL-1β. IL-1β also induced expression of IL-6 by LNCaP cells; and, recombinant IL-6 stimulated promatrilysin expression. Cyclohexamide did not inhibit induction of promatrilysin by IL-6 indicating that IL-6 induced promatrilysin expression was direct and did not require new protein synthesis. In addition, our data revealed that inhibition of IL-6 activity with a neutralizing antibody directed against the IL-6 ligand, blocked IL-1β induced promatrilysin expression. Further investigation of this pathway suggested that STAT3 acts downstream to regulate IL-6 induced matrilysin expression. Dominant negative STAT3 inhibited both IL-1β and IL-6 induced activity of a co-transfected matrilysin-luciferase reporter construct. Because of their relevance to prostate cancer, we next examined the effect of androgens on IL-1β induced promatrilysin expression. We found that the androgens, testosterone and dihydrotestosterone blocked IL-1β induced promatrilysin and IL-6 expression through inhibition of NFκB. Androgens showed no effect on IL-6 induced promatrilysin expression indicating that STAT3 is not regulated by androgens in our system. Therefore, our data indicate that IL-1β induced promatrilysin expression is regulated by NFκB mediated synthesis of IL-6 and STAT3 signaling; and, through inhibition of NFκB, androgens can block IL-1β induced promatrilysin. Degradation of the extracellular matrix by MMPs is thought to play a role in prostate cancer invasion and metastatasis. These data provide evidence that IL-1β and IL-6 mediated expression of matrilysin may be involved in prostate cancer progression.

In response to signals mediated by receptor tyrosine kinases (RTKs), G protein-coupled receptors or oncogenes, the two ubiquitously expressed isoforms of class IA phosphatidylinositol-3-kinases (PI3Ks), \(p110\alpha\) and \(p110\beta\), generate lipid second messengers at plasma membrane, which elicit multiple signal transduction cascades that regulate a broad range of cellular processes such as cell survival, proliferation, adhesion, motility, and transformation. Despite their similarity in sequence, expression pattern and regulatory subunits, growing evidence suggests that \(p110\alpha\) and \(p110\beta\) have distinct and redundant functions in normal physiological and disease conditions. For instance, activating mutations in \(p110\alpha\) have been frequently found in human tumors, while mutations in \(p110\beta\) have not been reported. \(p110\alpha\) is required for tumor formation induced by oncogenic RTKs, RAS, or polyoma middle T antigen (MT), whereas \(p110\beta\) seems to be essential for PTEN-deficient tumors. The objective of my dissertation has been to investigate the mechanisms underlying isoform selectivity and functional redundancy of \(p110\alpha\) and \(p110\beta\). First, we performed tandem affinity purification and mass spectrometry to look for \(p110\alpha\)- and \(p110\beta\)-interacting proteins. We found that CRKL preferentially binds to \(p110\beta\) at least under overexpression conditions. We further demonstrated that CRKL is an important regulator of PI3K activity in \(p110\beta\)-dependent PTEN-deficient tumor cells. Depletion of CRKL attenuates PI3K signaling and cell growth in PTEN-deficient prostate and breast cancer cell lines, but does not impair AKT activation in HER2 amplified and PIK3CA mutant cancer cells. Moreover, downregulation of CRKL does not inhibit AKT activation stimulated by insulin, suggesting that CRKL might regulate \(p110\beta\) activity in PTEN-null tumors independent of RTK stimulation. In the second part of this thesis, we used knockout fibroblasts and pharmacological inhibitors to dissect functional redundancy of \(p110\alpha\) and \(p110\beta\) in PDGF signaling. Our results suggest that both isoforms function downstream of PDGFR (abundant receptors): \(p110\alpha\) is the major isoform to mediate weak signals while both play a role when the signal is strong. When one isoform is ablated, the other isoform can play a compensatory role in the signal transduction. Such functional redundancy of class IA PI3K isoforms may have implications for the choice of the selectivity of PI3K inhibitors in cancer.

<p> This project involved the development of a funding database and grant library for the organization Project Pink Ink. Interviews with stakeholders in the organization were conducted to garner information to inform grant selection as well as program need. Content analysis was applied to the transcripts of the interviews. The interviews suggest a great need for a complementary program for oncology patients. After all of the information garnered was synthesized, a grant application was completed and a grant was submitted to obtain funding for the Project Pink Ink organization.</p>

Bile acids, known for millennia to play a role in health and disease, are currently being studied for their pivotal contribution to the development and possible prevention of colon cancer. Some bile acids have long been suspected to play a role in the development of colon cancer. Particularly, highly hydrophobic bile acids, such as deoxycholic acid (DCA), are known to promote the formation of colon tumors in animal models. However, one moderately hydrophobic bile acid, ursodeoxycholic acid (UDCA), has been shown to be a colon cancer chemopreventive agent, although its mechanism of action is unknown. Originally, it was believed that increased hydrophobicity caused high levels of cell membrane perturbation and digestion, thus resulting in cell death. In addition, it was believed that bile acids could cross membranes to a level related to their hydrophobicity and interact with intracellular molecules to induce biological responses. My studies have shown that while bile acid biological activity is related to hydrophobicity, bile acids do not have the innate ability to cross colon cell membranes. While highly hydrophobic bile acids cause a rapid induction of apoptosis and moderately hydrophobic bile acids cause growth arrest in colon cells, no evidence could be found to show that bile acids could enter colon cells. In fact, my data indicate that bile acids activate signaling cascades through transmembrane receptors on the plasma membrane. It is the activation of these signaling pathways, which result in DCA-induced apoptosis or UDCA-induced growth arrest. My studies have shown that DCA has the ability to activate GADDI53, FADD, and caspase 8 and that activation of these molecules is necessary to produce apoptosis. Additionally, I discovered that UDCA activates Rb and GADD153 and has the ability to induce GI growth arrest and protect cells from DCA induced apoptosis. Interestingly, I found that while DCA and UDCA cause drastically different cellular responses, my data suggest that they signal through shared pathways. I show that UDCA could abrogate DCA activity. These studies also show two possible by which UDCA acts as a chemo-preventive agent: by causing growth arrest and by preventing DCA-induced apoptosis.

The ultraviolet (UV) component of sunlight has been identified as a major etiological factor in the development of non-melanoma skin cancer (NMSC). Upregulation of Activator Protein-1 (AP-1) and Cyclooxygenase-2 (COX-2) have clearly demonstrated a functional role in skin tumor promotion. The goal of this work was to contribute to the growing knowledge of UVA and UVB induced signaling events leading to increases in AP-1 and COX-2. We show that UVA induces COX-2 expression in the human keratinocyte cell line, HaCaT through a post-transcriptional mechanism involving the 3 ' untranslated region (3'UTR). Use of a pharmacological inhibitor of p38 MAPK, SB202190, decreased UVA-induced COX-2 steady-state mRNA and protein levels. The stability of COX-2 mRNA is increased in UVA-irradiated cells and dependent upon p38 MAPK activity. We further explored the role of UVA-induced p38 MAPK activity in apoptosis in both HaCaT cells and primary keratinocytes. Dramatic increases in apoptosis were observed in UVA-irradiated cells treated with SB202190 or through the use of a dominant-negative construct. UVA induced expression of Bcl-X L with abrogation of expression using SB202190. Overexpression of Bcl-X L prevented PARP (Poly ADP-ribose Polymerase) cleavage induced by the combination of UVA and p38 MAPK inhibition. We further demonstrated that UVA enhanced the stability of Bcl-XL mRNA through increases in p38 MAPK activity mediated through the 3' UTR. p38 MAPK and Bcl-XL expression play critical roles in the survival of UVA-irradiated keratinocytes. Previous investigations from the laboratory identified p38 MAPK and PI3-Kinase as the major mediators of UVB-induced AP-1 and COX-2 in the HaCaT cell line. To further validate p38 MAPK and PI3-Kinase as potential molecular targets we investigated whether an acute UVB dose activated the p38 MAPK and PI3-Kinase pathways in vivo. We observed rapid increases in both p38 MAPK and PI3-Kinase signaling in mouse epidermis. Activation of these pathways resulted in the phosphorylation of cyclic AMP response element binding protein (CREB). Topical treatment with SB202190 or LY294002 (a specific inhibitor of PI3-Kinase) significantly decreased UVB-induced COX-2 expression and AP-1 activation in vivo. Our data suggest that p38 MAPK and PI3-Kinase may serve as significant molecular targets for the chemoprevention of UVB-induced NMSC.

Our laboratory had previously developed an in vitro tumor progression model which demonstrated that elevation of Reactive Oxygen Species (ROS) played a functional role in the development and maintenance of malignantly transformed mouse skin keratinocytes. The elevation of ROS levels were attributed to the repression of the anti-oxidant enzyme catalase. We hypothesized that repression of catalase, a potential tumor suppressor gene, led to the elevation of hydrogen peroxide which functions as a secondary messenger to active mitogenic signaling in the malignant cells. The first goal of these studies was to further characterize the repression of catalase in vivo. Using tumor samples generated by the mouse skin chemical carcinogenesis protocol, we determined that papillomas expressed higher levels of catalase protein and message than carcinomas. These results recapitulated the observations we made in the in vitro tumor progression model. The next goal was to determine the mechanism(s) behind the repression of catalase. Nuclear run-on analysis showed that catalase repression in the malignantly transformed cells was dependent on transcription. Results from luciferase reporter assays indicated that malignant cells have lower catalase promoter activities than benign papilloma cells, in part through the Wilm's tumor suppressor (WT1) binding site within the proximal promoter region. We concluded that WT1 element acts as a transcriptional repressor of catalase in this tumor progression model. The second part of this dissertation is focused on the role of the Rac1 signaling in tumor progression. Rac1 has been shown to activate NADPH oxidase to produce superoxide, potentially contributing to the elevation of ROS. We found that conditional expression of a dominant negative Rac1 was able to decrease multiple markers of malignancy including: growth, migration and invasion potential. In addition, these phenotypic changes were accompanied by a decrease in mitogenic signaling. Furthermore, we showed that inhibition of Rac1 signaling could reduce tumor growth in vivo. However, we were unable to show any decrease in intracellular levels of ROS. Based on these results, we concluded that Rac1 signaling plays a key role in mouse skin tumor progression through a ROS independent manner.