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Title: MANIPULATING AKTIVATED METABOLISM VIA MTORC1.
Creator: von Hack-Prestinary, Ivan, Altomare, Deborah, University of Central Florida
Abstract / Description: Although poorly understood, normal cells and cancerous cells of the same type exhibit different patterns of nutrient consumption, processing and utility of metabolic substrates. Differences in substrate uptake, preference, and alternately emphasized metabolic pathways offer opportunities for selective targeting of cancer versus stroma. This may be accomplished by using a sequential approach of nutrient deprivation and pharmaceutical perturbation of metabolic pathways to inhibit cellular...
Show moreAlthough poorly understood, normal cells and cancerous cells of the same type exhibit different patterns of nutrient consumption, processing and utility of metabolic substrates. Differences in substrate uptake, preference, and alternately emphasized metabolic pathways offer opportunities for selective targeting of cancer versus stroma. This may be accomplished by using a sequential approach of nutrient deprivation and pharmaceutical perturbation of metabolic pathways to inhibit cellular proliferation. The purpose of this study was to investigate the effects of restricting glucose and glutamine concentrations, in vitro, to levels that resemble a potential human fasting state. The mammalian target of rapamycin (mTOR), a mediator of nutrient sensation, was then inhibited with rapamycin in the nutrient-restricted conditions. Because active Akt/mTOR is implicated in cancer cell pro-survival, the hypothesis is that pharmaceutical inhibition of active Akt/mTOR signaling in combination with the stress of restricted nutrient supply will be more effective than nutrient deprivation alone at disrupting metabolic processes to impair cancer cell proliferation and/or pro-survival mechanisms. Untreated and treated conditions were tested to determine if an additive or synergistic effect would result from a sequential insult of nutrient deprivation followed by inhibited mTORC1 signaling. The cell line used for this study was cultivated from a murine pancreatic intraepithelial neoplasia (PANIN) derived from a transgenic mouse with pancreatic tissue-specific expression of constitutively active Akt. The transgene of Akt, isoform 1, contains a myristoyl tag that facilitates co-localization of Akt to the plasma membrane, thereby promoting the activation of this signaling protein. This aberrantly activated Akt represents a prosurvival condition observed in most cancers, and impacts metabolic balance with increased downstream signaling to metabolic sensors and regulators, including mTORC1. Several methods were used to evaluate changes in metabolic and physiological response to nutrient deprivation and mTORC1 inhibition. These included tetrazolium reduction/absorbance readings to qualitatively evaluate differences in cell proliferation, and Western immunoblots for observing changes in protein expression and phosphorylation. ATP luminescence assays were applied to quantify intracellular ATP content, and citrate synthase spectrophotometry used to quantify specific activity/indicate changes in the TCA/OXPHOS production of ATP. Results from the above methods suggest that, individually, nutrient deprivation and rapamycin treatment share some similar effects on metabolically-related protein phosphorylation and in reducing cellular proliferation. Collectively, nutrient deprivation plus rapamycin treatment, however, resulted in unanticipated metabolic alterations under conditions used for this study, the complexities of which would need to be delineated in future studies.
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Date Issued: 2013
Identifier: CFH0004373, ucf:45006
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH0004373

Title: GOLD (III) MACROCYCLES ARE DNA INTERCALATORS THAT INHIBIT TOPOISOMERASE I AND II.
Creator: Fagenson, Alexander, Muller, Mark, University of Central Florida
Abstract / Description: Human Topoisomerase IB (TOP1) and Topoisomerase IIα (TOP2α) are essential nuclear enzymes that control DNA topology during DNA replication, gene transcription and cell division. These enzymes carry out their catalytic function by making transient single-strand (type I) or double-strand (type II) breaks in the DNA. In vivo, these complexes are short-lived but can be exploited by anti-cancer drugs to mechanistically kill cancer cells. Two general classes of compounds can kill cancer cells...
Show moreHuman Topoisomerase IB (TOP1) and Topoisomerase IIα (TOP2α) are essential nuclear enzymes that control DNA topology during DNA replication, gene transcription and cell division. These enzymes carry out their catalytic function by making transient single-strand (type I) or double-strand (type II) breaks in the DNA. In vivo, these complexes are short-lived but can be exploited by anti-cancer drugs to mechanistically kill cancer cells. Two general classes of compounds can kill cancer cells through a topo-targeted mechanism. Interfacial Poisons (IFPs) act at the enzyme-DNA interface to inhibit the religation reaction, resulting in the accumulation of DNA double-stand breaks (DSBs) in the genomic setting. Catalytic Inhibitor Compounds (CICs) act by interfering with other steps of the catalytic cycles such as DNA/protein binding or the cleavage reaction. In this work we identify new Au3+ macrocyclic gold complexes that act as CICs of both TOP1 and TOP2α. The complexes exhibit square planar geometry with an aromatic system that allows for DNA intercalation with binding affinities in the low micromolar range. A cytotoxicity screen across 60 human cancer cell lines performed by the National Cancer Institute (NCI, USA) reveals significant anti-tumor potential. Our lead compound (butyl gold(III) macrocycle, cmpd 3.) is currently undergoing further studies in animal models at the NCI. In vitro assays with purified DNA and enzyme reveal the Au3+ ion to be the quintessential switch that allows for DNA intercalation and subsequent inhibition of TOP1 and TOP2α.
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Date Issued: 2012
Identifier: CFH0004161, ucf:44823
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH0004161

Title: AN INVESTIGATION OF SELF-CARE MODALITIES FOR THE EFFECTIVE TREATMENT OF LYMPHEDEMA.
Creator: Major, Amber, Heglund, Stephen, University of Central Florida
Abstract / Description: The purpose of this literature review is to investigate the most effective forms of self-care that patients can perform to reduce swelling caused by lymphedema. Lymphedema may occur secondary to lymph node trauma, which makes it difficult for lymph fluid to leave an extremity. Even though lymphedema is more recognized as a side effect of breast cancer treatment, it can also be the result of many other ailments or treatments and can be present in any part of the body. By knowing which...
Show moreThe purpose of this literature review is to investigate the most effective forms of self-care that patients can perform to reduce swelling caused by lymphedema. Lymphedema may occur secondary to lymph node trauma, which makes it difficult for lymph fluid to leave an extremity. Even though lymphedema is more recognized as a side effect of breast cancer treatment, it can also be the result of many other ailments or treatments and can be present in any part of the body. By knowing which therapies are most effective, nurses and other health care professionals can educate patients to help ease the burden caused by this debilitating condition. This thesis discusses the results of clinical trials that studied different methods of self-care including exercises, bandaging, compression garments, sequential compression devices, and performing manual lymphatic drainage. The conclusion derived from the review of multiple studies is that participating in a combination of multiple therapies is the most effective means of lymphedema management and should be considered the ideal standard of care.
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Date Issued: 2011
Identifier: CFH0004065, ucf:44812
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH0004065

Title: Role of Kruppel-like Factor 8 (KLF8) in Cancer and Cardiomyopathy.
Creator: Lahiri, Satadru, Zhao, Jihe, Parthasarathy, Sampath, Masternak, Michal, Siddiqi, Shadab, University of Central Florida
Abstract / Description: Cancer and cardiovascular diseases are two most fatal diseases causing innumerable death each year. Understanding the mechanisms underlying these diseases is critical for developing proper therapeutic approach. Kr(&)#252;ppel-like factor 8 (KLF8) is a member of Kr(&)#252;ppel-like family transcription factors that is overexpressed in many types of cancers. There is no report on role of KLF8 in cardiovascular diseases to date. KLF8 transcriptionally activates or represses a host of target...
Show moreCancer and cardiovascular diseases are two most fatal diseases causing innumerable death each year. Understanding the mechanisms underlying these diseases is critical for developing proper therapeutic approach. Kr(&)#252;ppel-like factor 8 (KLF8) is a member of Kr(&)#252;ppel-like family transcription factors that is overexpressed in many types of cancers. There is no report on role of KLF8 in cardiovascular diseases to date. KLF8 transcriptionally activates or represses a host of target genes to promote cancer cell proliferation, migration, invasion and epithelial to mesenchymal transition during tumor progression. Studies proposed in this thesis identified a novel posttranslational modification of KLF8 essential for its role in promoting cancer cell migration and discovered a novel function of KLF8 in cardiomyopathy. In our first study, we identified serine 48 (S48) as a novel phosphorylation site on KLF8. Pharmacological and genetic manipulations of various potential kinases further revealed ERK2 as the kinase responsible for this novel phosphorylation. Functional studies indicated that this phosphorylation is crucial for protecting KLF8 protein from degradation in the nucleus and promoting cancer cell migration. Preclinical xenograft models have indicated an important role of KLF8 for tumor progression. To investigate role of KLF8 in spontaneous tumorigenesis better recapitulating pathology in patients, we established the first Cre-regulated conditional KLF8 transgenic mouse model. Upon induction of global expression of the KLF8 transgene, spontaneous mammary and testicular tumors were formed in a small population of the mice by their mid-age, as expected considering the long latency required for tumor progression. Surprisingly, however, nearly 100% of KLF8 the mice died with a significantly enlarged heart, which did not occur to any littermate control mouse. Further characterization of the mice revealed that the global expression of the transgene caused striking systolic dysfunction leading to fatal dilated cardiomyopathy. Importantly, these similar phenotypes were reproduced in heart-specific KLF8 transgenic mice. Cardiovascular disease PCR array identified a number of genes potentially mediating KLF8-induced cardiac pathology. These results identified a previously unimagined function of KLF8 in the heart, shed new light on the mechanisms of cardiac diseases and provide novel preclinical mouse models for future translational research.
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Date Issued: 2016
Identifier: CFE0006692, ucf:51914
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0006692

Title: THE SHEDDASE ACTIVITY OF ADAM10/ADAM17 ON CXCL16 INCREASES PROLIFERATION AND SURVIVAL OF COLORECTAL CANCER CELLS.
Creator: Talton, Tamu, von Kalm, Laurance, University of Central Florida
Abstract / Description: CXCL16 is an interferon-inducible chemokine of the CXC-subfamily and functions as an adhesion molecule, when membrane bound, and a chemoattractant when soluble. Upregulation of cell associated CXCL16 (cCXCL16) in colorectal cancer is associated with increased tumor infiltrating lymphocytes and good prognosis. ADAM10 and ADAM17 are metalloproteinases responsible for cleaving CXCL16, releasing soluble CXCL16 (sCXCL16) and contributing to proliferation and migration of mesangial cells, in kidney...
Show moreCXCL16 is an interferon-inducible chemokine of the CXC-subfamily and functions as an adhesion molecule, when membrane bound, and a chemoattractant when soluble. Upregulation of cell associated CXCL16 (cCXCL16) in colorectal cancer is associated with increased tumor infiltrating lymphocytes and good prognosis. ADAM10 and ADAM17 are metalloproteinases responsible for cleaving CXCL16, releasing soluble CXCL16 (sCXCL16) and contributing to proliferation and migration of mesangial cells, in kidney inflammatory disease. We hypothesize that cCXCL16 is a substrate for ADAM10 and ADAM17 cleavage in colorectal cancer, releasing sCXCL16, which mediates cell proliferation. To this end, we first identified CXCL16 in the human colon carcinoma cell line, RKO, by immunohistochemistry. cCXCL16 was found in the membrane, cytoplasm and nucleus. We treated RKO, in vitro, with an inflammatory cytokine mix containing 1.4 nM rhIFN³, 2.0 nM rhTNFα and 2.0 nM rhIL1² to increase the cleavage of cCXCL16 to sCXCL16. Overnight incubation with the cytokine mix significantly (P=.004) increased the release of sCXCL16 compared to normal conditions. To confirm that a metalloproteinase is responsible for the cleavage of cCXCL16, we used a broad spectrum metalloproteinase inhibitor, GM6001, in combination with inflammatory stimulation, in cell culture. We assayed the supernatant using ELISA for sCXCL16. GM6001 at 100 ¼M decreased sCXCL16 to levels indistinguishable from the background. Using siRNA, we knocked down the expression of ADAM10 and ADAM17, independently, to determine if the activity of each on cCXCL16 was mediated by inflammatory stimulation. It was shown that ADAM10 constitutively cleaved cCXCL16, and ADAM17 cleavage activity was induced by inflammatory stimulation. To determine if sCXCL16 increased colorectal cancer cell (CRC) proliferation through ligand-receptor binding, we treated cells with a range of rhCXCL16 from 3.125-100 ng/mL. rhCXCL16 did not increase RKO proliferation at doses up to 100 ng/mL. We used GM6001, to inhibit the cleavage of cCXCL16 into sCXCL16 then performed an ATPase assay and 6 day cell cycle analysis, under inflammatory stimulation. Increased cleavage of cCXCL16 induced by inflammatory stimulation with the cytokine mix containing 1.4 nM rhIFN³, 2.0 nM rhTNFα and 2.0 nM rhIL1², increased RKO proliferation and reduced apoptosis. We conclude that ADAM10 and ADAM17 cleavage of cCXCL16 to sCXCL16 is increased by ADAM17 activation with inflammatory stimulation. The cleavage of the extracellular portion from cCXCL16 is associated with increased proliferation and decreased apoptosis of colorectal cancer cells.
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Date Issued: 2011
Identifier: CFE0003587, ucf:48909
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0003587

Title: The Dynamic Functions of Bax are Dependent on Key Structural and Regulatory Features.
Creator: Boohaker, Rebecca, Khaled, Annette, Cole, Alexander, Zervos, Antonis, Tatulian, Suren, University of Central Florida
Abstract / Description: Bax is an essential mediator of cell fate. Since its discovery in 1985 as a protein that interacts with the anti-apoptotic protein, Bcl-2, key elements related to its function, structure and regulation remains to be determined. To this end, mitochondrial metabolism was examined in non-apoptotic Bax-deficient HCT-116 cells as well as primary hepatocytes from Bax-deficient mice. Although mitochondrial density and mitochondrial DNA content was the same in Bax-containing and Bax -deficient cells,...
Show moreBax is an essential mediator of cell fate. Since its discovery in 1985 as a protein that interacts with the anti-apoptotic protein, Bcl-2, key elements related to its function, structure and regulation remains to be determined. To this end, mitochondrial metabolism was examined in non-apoptotic Bax-deficient HCT-116 cells as well as primary hepatocytes from Bax-deficient mice. Although mitochondrial density and mitochondrial DNA content was the same in Bax-containing and Bax -deficient cells, MitoTracker staining patterns differed, suggesting the existence of Bax -dependent functional differences in mitochondrial physiology. Oxygen consumption and cellular ATP levels were reduced in Bax -deficient cells, while glycolysis was increased. These results suggest that cells lacking Bax have a deficiency in the ability to generate ATP through cellular respiration, supported by detection of reduced citrate synthase activity in Bax -deficient cells. Expression of either full length or C-terminal truncated Bax in Bax -deficient cells rescued ATP synthesis and oxygen consumption and reduced glycolytic activity, suggesting that this metabolic function of Bax was not dependent upon its C-terminal helix. Expression of BCL-2 in Bax-containing cells resulted in a subsequent loss of ATP measured, implying that, even under non-apoptotic conditions, an antagonistic interaction exists between the two proteins. Bax is composed of nine alpha-helices. While three of these helices have features of a trans-membrane region, the contribution of each domain to the apoptotic or non-apoptotic functions of Bax remains unknown. To examine this, we focused on the C-terminal alpha-9 helix, an amphipathic domain with putative membrane binding properties and discovered that it has an inherent membrane-binding and cytotoxic capacity. A peptide based on the last twenty amino acids (CT20p) of the alpha-9 helix was synthesized and proved a potent inducer of cell death independent of any apoptotic stimuli. The solubility of CT20p allowed it to be encapsulated in polymeric nanoparticles (NPs), and these CT20p-NPs caused the death of colon and breast cancer cells in vitro and induced tumor regression in vivo, using a murine breast cancer tumor model. CT20p caused increased mitochondrial membrane potential followed by cell death via membrane rupture, without the characteristic membrane asymmetry associated with apoptosis. Hence, while CT20p is based on Bax, its innate cytotoxic activity is unlike the parent protein and could be a powerful anti-cancer agent that bypasses drug resistance, can be encapsulated in tumor-targeted nanoparticles and has potential application in combination therapies to activate multiple death pathways in cancer cells. While previous work revealed novel aspects of the biology of Bax that were unrecognized, new structural information is needed to fully elucidate the complexity of Bax's function. One approach is to use computational modeling to assess the solved structure of Bax and provide insight into the structural components involved in the activity of the protein. Use of molecular dynamics simulators such as GROMACS, as well as other computational tools provides a powerful means by which to test the feasibility of certain modifications in defined parameters. Such work revealed that the removal of the C-terminal alpha-9 helix of Bax, which normally resides within a hydrophobic pocket, significantly destabilized the protein, perhaps explaining how the protein transitions from soluble to membrane-bound form and maintain energy production via aerobic respiration or, conversely, how the C-terminus helix conveys cytotoxicity. Collectively, this work reveals that Bax is more than an inducer of cell death but has complex activities yet to be determined.
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Date Issued: 2012
Identifier: CFE0004521, ucf:49285
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0004521

Title: Diabetes Phenotypes in Transgenic Pancreatic Cancer Mouse Models.
Creator: Albury, Toya, Altomare, Deborah, Zhao, Jihe, Masternak, Michal, Khaled, Annette, University of Central Florida
Abstract / Description: Protein Kinase B/AKT, a serine/threonine kinase with three isoforms (AKT1-3), is downstream of phosphatidylinositol 3-kinase (PI3K), and signals through the phosphorylation and subsequent activation or inhibition of downstream substrates, such as mammalian target of rapamycin complex 1 (mTORC1) or glycogen synthase kinase 3 beta (GSK-3?), respectively. The AKT1 isoform is predominantly recognized for regulation of cell survival, growth, and proliferation, due to its constitutive activation in...
Show moreProtein Kinase B/AKT, a serine/threonine kinase with three isoforms (AKT1-3), is downstream of phosphatidylinositol 3-kinase (PI3K), and signals through the phosphorylation and subsequent activation or inhibition of downstream substrates, such as mammalian target of rapamycin complex 1 (mTORC1) or glycogen synthase kinase 3 beta (GSK-3?), respectively. The AKT1 isoform is predominantly recognized for regulation of cell survival, growth, and proliferation, due to its constitutive activation in pancreatic cancers (e.g., islet cell carcinoma and pancreatic adenocarcinoma). The progression of pancreatic ductal adenocarcinoma (PDAC), the most lethal common cancer, is initiated by activation mutations of the KRas oncogene. This leads to additional molecular changes, such as activation of the AKT1 oncogene, which drives PDAC progression and tumor formation. By mating transgenic mice with activation of KRas (Pdx- Cre;LSL-KRasG12D) and mice with activation of AKT1 (Pdx- Tta;TetO-MyrAKT1) we were able to produce mice with two activated oncogenes (AKT1Myr/KRasG12D) for comparative studies. Kaplan-Meier survival curves, histology, and genomic/proteomic analysis were used to characterize the incidence and frequency of histological (e.g. presence of mucin-4 in pancreatic intraepithelial neoplasms) and genetic (e.g. loss of tumor suppressors p16Ink4a and p19Arf) alterations known to commonly occur in human pancreatic cancer, as well as delineate the role of AKT1 in accelerating pancreatic tumor progression and metastasis. We determined that AKT1Myr/KRasG12D mice, unlike other PDAC mouse models, accurately mimic the human PDAC progression molecularly, structurally, and temporally. Interestingly, the AKT1Myr and AKT1Myr/KRasG12D models both exhibit a pre-tumor, diabetic phenotype. While, AKT1 hyperactivation in various cancers has been thoroughly studied, its role in glucose metabolism has been noted, but comparatively overlooked. As early as the 1900s a relationship between diabetes and pancreatic cancer has been proposed. With 80% of PDAC patients suffering from hyperglycemia or diabetes prior to diagnosis, one prevailing theory is that new onset diabetes is an early marker for pancreatic cancer. This is also supported by experimental and clinical studies, such as the resolution of diabetes with tumor removal and the induction of hyperglycemia with the implantation of cancer cell lines. To better understand the role of AKT1 and its hyperactivation in glucose metabolism, AKT1Myr mice were characterized via metabolic (e.g. glucose/insulin tolerance test) and histological (e.g. immunohistochemistry) studies. Beginning at weaning, 3 weeks of age, the glucose intolerant AKT1Myr mice exhibited non-fasted hyperglycemia, which progressed to fasted hyperglycemia by 5 months of age. The glucose intolerance was attributed to a fasted hyperglucagonemia, and hepatic insulin resistance detectable by reduced phosphorylation of the insulin receptor following insulin injection into the inferior vena cava. Additionally, AKT1Myr/KRasG12D mice currently being studied, appear to display a more severe diabetic phenotype, with fasted hyperglycemia noticeable at an earlier age, fasted hyperglucagonemia, polyuria, muscle wasting, and bloating. Treatment of both models with doxycycline diet, to turn-off the transgene, caused attenuation of the non-fasted and fasted hyperglycemia, thus affirming AKT1 hyperactivation as the trigger. These newly revealed roles of AKT1, along with future studies of these mouse models, will better delineate the molecular mechanisms responsible for the individual and joint roles of AKT1 and KRas in pancreatic cancer oncogenesis, the initiation of cancer associated diabetes, and the association of these two diseases.
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Date Issued: 2015
Identifier: CFE0006245, ucf:51081
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0006245

Title: Variations in Health Services Utilization by Patients with Prostate Cancer.
Creator: McKee, Roberta, Wan, Thomas, Martin, Lawrence, Zhang, Ning, Sivo, Stephen, University of Central Florida
Abstract / Description: Among men living in the United States, prostate cancer is the second leading cause of cancer death, and, excluding skin cancers, it is the cancer diagnosed most frequently. While incidence and mortality rates have been declining, the American Cancer Society estimated that there were 220,800 men diagnosed with prostate cancer and more than 27,500 prostate cancer deaths in 2015. Various patient-level and community-level factors have been shown to influence the differential patterns of diagnosis...
Show moreAmong men living in the United States, prostate cancer is the second leading cause of cancer death, and, excluding skin cancers, it is the cancer diagnosed most frequently. While incidence and mortality rates have been declining, the American Cancer Society estimated that there were 220,800 men diagnosed with prostate cancer and more than 27,500 prostate cancer deaths in 2015. Various patient-level and community-level factors have been shown to influence the differential patterns of diagnosis, care, and outcomes for men with prostate cancer. Detailed information regarding the utilization of health services by prostate cancer patients, particularly those with higher propensity for health services use, could be used to inform efforts intended to improve the coordination and delivery of care to work towards the elimination of disparities. The purpose of the study is to facilitate a better understanding of the determinants of health services utilization by older males with prostate cancer in the United States by examining the relative influence and interaction effects of factors characterizing individual patients and their county of residence. Andersen's behavioral model of health services utilization is used as a framework to guide this study. A cross-sectional design is used to analyze administrative claims data from the 2008 Medicare Provider Analysis Review (MEDPAR) file (n=5,754). County-level data from Area Health Resources File (ARHF) are merged to include the community and contextual characteristics. American Hospital Association (AHA) annual survey data are also used to examine the importance of hospital attributes in a subset analysis (n=555). A two-stage approach is used for analyzing the data. First, several social and demographic variables are included in automatic interaction detector (AID) analysis to identify relatively homogenous subgroups of patients with similar service utilization patterns for emergency room visits and hospital length of stay. Second, regression analysis is performed in the full dataset including all patients, and in each subgroup to determine the amount of variance explained by predictor variables categorized as predisposing, enabling, and need-for-care factors. Hierarchical logistic regression is performed to analyze the variability in emergency room use, and hierarchical multiple regression is performed to analyze the variability in hospital length of stay. The results show that the need-for-care factors are dominant predictors of service use. However, the relative importance of the predictor variables varies by subgroups of prostate cancer patients identified in the initial AID analysis. The findings lend some support of the use of an integrated approach to examine the personal and social determinants of health services utilization by prostate cancer patients enrolled in the U.S. Medicare program. The theoretical framework and analytic approach employed in this study make it possible to obtain an in-depth understanding of the influential factors associated with emergency room use and length of stay for all-cause hospitalizations, which can be used to inform future research and efforts aimed at developing targeted interventions to improve the coordinated care and to reduce health disparities among Medicare beneficiaries with prostate cancer.
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Date Issued: 2016
Identifier: CFE0006352, ucf:51523
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0006352

Title: The development of motuporamine derivatives and an investigation into their biological properties.
Creator: Skruber, Kristen, Phanstiel, Otto, Teter, Kenneth, Vonkalm, Laurence, University of Central Florida
Abstract / Description: This project investigates the synthesis of a class of compounds derived from a marine-based natural product and probes how iterative changes to its structure affect its derivatives' biological efficacy. The compound class of interest are the motuporamines which were isolated from the sea sponge Xestospongia exigua collected off the coast of Motupore island in Papua, New Guinea. The compounds for this project are predicated upon dihydromotuporamine C (Motu33), the compound that has been shown...
Show moreThis project investigates the synthesis of a class of compounds derived from a marine-based natural product and probes how iterative changes to its structure affect its derivatives' biological efficacy. The compound class of interest are the motuporamines which were isolated from the sea sponge Xestospongia exigua collected off the coast of Motupore island in Papua, New Guinea. The compounds for this project are predicated upon dihydromotuporamine C (Motu33), the compound that has been shown to be both cytotoxic to MDA-MB231 breast carcinoma cells and has antimetastatic efficacy. The motuporamine scaffold contains a large fifteen-membered saturated macrocycle and an appended polyamine component. A series of Motu33 derivatives were synthesized and evaluated for their ability to target the polyamine transport system as well as inhibit cell migration of human pancreatic cancer cells in vitro. By altering the polyamine component of the system we attempted to build smart antimetastatic compounds which target the upregulated polyamine transport system of human pancreatic cancers and block their migration.
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Date Issued: 2016
Identifier: CFE0006505, ucf:51390
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0006505

Title: Role of KLF8-CXCR4 signaling in Breast Cancer Metastasis.
Creator: Mukherjee, Debarati, Zhao, Jihe, Khaled, Annette, Altomare, Deborah, Siddiqi, Shadab, University of Central Florida
Abstract / Description: Kr(&)#252;ppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. In this study we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of...
Show moreKr(&)#252;ppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. In this study we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of the cells towards the ligand CXCL12. On the other hand, knockdown of KLF8 in MDA-MB-231 cells reduced CXCR4 expression associated with decreased cell migration, invasion and TEM towards CXCL12. Histological and database mining analyses of independent cohorts of patient tissue microarrays revealed a correlation of aberrant co-elevation of KLF8 and CXCR4 with metastatic potential. Promoter analysis indicated that KLF8 directly binds and activates the human CXCR4 gene promoter. Furthermore, CXCR4-CXCL12 engagement downstream of KLF8 leads to the feed-forward activation of FAK. Interestingly, KLF8 expression, through CXCR4 engagement, triggered the formation of filopodium-like protrusions (FLP) and thereby enhanced the proliferation rate of breast cancer cells in 3D Matrigel-on-Top culture, under prolonged treatment with CXCL12. This indicates that KLF8 plays a major role in promoting aggressive colonization of tumor cells in a CXCL12-enriched foreign tissue microenvironment, thereby aiding in secondary macrometastasis formation. Xenograft studies showed that overexpression of CXCR4, but not a dominant-negative mutant of it, in the MDA-MB-231 cells prevented the invasive growth of primary tumor and lung metastasis from inhibition by knockdown of KLF8. Apart from lung, KLF8 overexpression also induced spontaneous secondary metastasis to other CXCL12-rich organs through CXCR4 signaling. These results collectively suggest a critical role for KLF8 and the CXCR4-CXCL12 pathway in promoting breast cancer metastasis and shed new light on potentially more effective anti-cancer strategies.
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Date Issued: 2016
Identifier: CFE0006149, ucf:51127
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0006149

Title: Family Care Giver Knowledge, Patient Illness Characteristics, and Unplanned Hospital Admissions in Older Adults with Cancer.
Creator: Geddie, Patricia, Loerzel, Victoria, Sole, Mary Lou, Gammonley, Denise, Norris, Anne, University of Central Florida
Abstract / Description: Unplanned hospital admissions (UHA) in older adult populations are a recurring problem in older adults with cancer. Older adults comprise approximately 60% of cancer diagnoses and receive the majority of cancer treatment. However, little is known about why older adults under treatment for cancer experience a high number of unplanned hospital admissions. A review of the literature provided few study findings and a gap in the current knowledge was identified regarding the factors associated...
Show moreUnplanned hospital admissions (UHA) in older adult populations are a recurring problem in older adults with cancer. Older adults comprise approximately 60% of cancer diagnoses and receive the majority of cancer treatment. However, little is known about why older adults under treatment for cancer experience a high number of unplanned hospital admissions. A review of the literature provided few study findings and a gap in the current knowledge was identified regarding the factors associated with unplanned hospital admissions in older adults under treatment for cancer. A conceptual framework based on the literature and this researcher's clinical experienced guided this study. The purpose of this study was to explore the factors related to unplanned hospital admissions and determine if one or more factors are predictive of unplanned hospital admissions of older adults with cancer. A convenience sample of 129 dyads of older adults with cancer and their family caregivers were approached and enrolled in the adult oncology outpatient infusion centers and inpatient units within a community cancer center in central Florida. Patient demographic and clinical data were obtained through a retrospective medical record review. Family caregiver demographic and side effect knowledge data was collected prospectively during interviews with family caregivers using a newly developed tool, Nurse Assessment of Family Caregiver Knowledge and Action Tool (NAFCKAT). The NAFCKAT contains 11 items to determine baseline knowledge about side effects and plan for managing side effects. A fever subsection consists of 4 knowledge and 2 action questions and a dehydration subsection consists of 2 knowledge and 2 action questions. Preliminary research was conducted to determine reliability and validity of the NAFCKAT. Excellent inter-reliability was found for the tool and preliminary support for validity was determined for the fever subscale. Descriptive statistics and logistic regression analyses were used to evaluate data collected from patient medical records and NAFCKAT scores. Study findings revealed that unplanned hospital admissions were more likely to occur when older adults had the presence of impaired function prior to treatment initiation and/or experienced side effects of infection /fever and vomiting/diarrhea during treatment. The presence of impaired function and family caregiver support (knowledge and availability) did not moderate the relationship between side effects and unplanned hospital admissions. Findings suggest that the presence of impaired function and side effects of infection and fever, and vomiting and diarrhea, predict unplanned hospital admissions in older adults during the active cancer treatment phase. Nurses should advocate for and conduct targeted assessments to identify the presence of functional impairments prior to cancer treatment initiation. In addition, nurses should actively monitor for the presence of cancer treatment-related side effects during the treatment phase of the cancer trajectory. Information gained from these assessments will assist nurses to provide practical and tailored strategies to support older adults and their family caregivers during cancer treatment and reduce the risk for unplanned hospital admissions.
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Date Issued: 2015
Identifier: CFE0005618, ucf:50214
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0005618

Title: IDENTIFICATION OF EPITHELIAL STROMAL INTERACTION 1 AND EPIDERMAL GROWTH FACTOR RECEPTOR AS NOVEL KR(&)#220;PPEL-LIKE FACTOR 8 TARGETS IN PROMOTING BREAST CANCER PROGRESSION.
Creator: Li, Tianshu, Zhao, Jihe, Khaled, Annette, Altomare, Deborah, Lambert, Stephen, University of Central Florida
Abstract / Description: Breast cancer is the major cause of cancer death among women worldwide. Understanding the mechanisms underlying breast cancer progression remains urgent for developing effective treatment strategies to eliminate breast cancer mortality. Our recent studies have demonstrated that Kr(&)#252;ppel-like transcriptional factor 8 (KLF8) plays a critical role for breast cancer progression. Other studies have shown that Epithelial stromal interaction 1 (EPSTI1), a recently identified stromal fibroblast...
Show moreBreast cancer is the major cause of cancer death among women worldwide. Understanding the mechanisms underlying breast cancer progression remains urgent for developing effective treatment strategies to eliminate breast cancer mortality. Our recent studies have demonstrated that Kr(&)#252;ppel-like transcriptional factor 8 (KLF8) plays a critical role for breast cancer progression. Other studies have shown that Epithelial stromal interaction 1 (EPSTI1), a recently identified stromal fibroblast-induced gene in non-invasive breast cancer cells and epidermal growth factor receptor (EGFR) are highly overexpressed in aggressively invasive breast carcinomas including triple negative breast cancers. In this thesis project, we demonstrate high co-overexpression of KLF8 with EPSTI1 as well as EGFR in invasive breast cancer cells and patient tumors. We also show that KLF8 upregulates the expression of EPSTI1 by directly binding and activating the EPSTI1 gene promoter, and KLF8 upregulates the expression of EGFR not only by directly activating the EGFR gene promoter but also by preventing EGFR translation from microRNA141-dependent inhibition. Genetic, signaling and animal cancer model analyses indicate that downstream of KLF8, EPSTI1 promotes the tumor invasion and metastasis by activating NF-?B through binding valosin containing protein (VCP) and subsequent degradation of I?B?, whereas EGFR promotes tumor growth and metastasis via activation of ERK. Taken together, these data identify EPSTI1 and EGFR as novel KLF8 targets in breast cancer and suggest that KLF8 may be targeted for new effective treatment of breast cancer.
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Date Issued: 2013
Identifier: CFE0005366, ucf:50474
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0005366

Title: Design, Synthesis, and Biological Evaluation of Novel Polyamine Transport System Probes and their Application to Human Cancers.
Creator: Muth, Aaron, Phanstiel, Otto, Ye, Jingdong, Elsheimer, Seth, Miles, Delbert, Vonkalm, Laurence, University of Central Florida
Abstract / Description: The mammalian polyamine transport system (PTS) has been of interest due to its roles in cancer and maintaining cellular homeostasis. Polyamines are essential growth factors which are tightly controlled via a balance of biosynthesis, metabolism, import, and export. This work focused on the development and biological testing of polyamine transport probes to help understand the molecular requirements of the PTS. This was mediated through the use of a CHO (PTS active) and CHO-MG* (PTS deficient)...
Show moreThe mammalian polyamine transport system (PTS) has been of interest due to its roles in cancer and maintaining cellular homeostasis. Polyamines are essential growth factors which are tightly controlled via a balance of biosynthesis, metabolism, import, and export. This work focused on the development and biological testing of polyamine transport probes to help understand the molecular requirements of the PTS. This was mediated through the use of a CHO (PTS active) and CHO-MG* (PTS deficient) screen, where compounds demonstrating high toxicity in CHO and low toxicity in CHO-MG* were considered PTS selective. The first chapter focused on the development of polyamine-based drugs which are both metabolically stable to polyamine oxidase (PAO) activity and are hyperselective for targeting the PTS. This approach was optimized by combining a di-substituted aryl design with terminal N-methylation of the appended polyamine chains to generate a new class of superior PTS agonists. The metabolic stability of these compounds was demonstrated in CHO and CHO-MG* in the presence and absence of a known PAO inhibitor, aminoguanidine (AG). Highly PTS selective compounds were then tested in the NCI-60 cell line screen to demonstrate the effectiveness of polyamine-based drugs in cancer therapy. During this screen, the MALME-3M (human melanoma) cell line was identified as being very sensitive to these PTS targeting drugs. Further studies using MALME-3M and its normal counterpart, MALME-3, showed excellent targeting of the cancer line over MALME-3. For example, The MeN44Nap44NMe compound showed 59-fold higher toxicity in MALME-3M over MALME-3.The second chapter focused on the development of potential polyamine transport inhibitors (PTIs) for use in combination therapy with ?-difluoromethylornithine (DFMO). This therapy is predicated upon reducing sustained polyamine depletion within cells by inhibiting both polyamine biosynthesis with DFMO and polyamine transport with the PTI ligand. Potential PTIs were identified by blocking the uptake of spermidine in DFMO-treated CHO and L3.6pl cells. Previous work has identified a tri-substituted polyamine-based design as an effective PTI. Low toxicity and a low Ki value in a L1210 screen were good predictors for PTI efficacy. The structural requirements for a potent PTI were explored by modulating the toxicity through the introduction of amide bonds, and also by determining the number and orientation of the polyamine messages (appended to an aryl core) required for efficient inhibition of polyamine uptake. These experiments showed that a tri-substituted design and a triamine message (homospermidine) appended was optimal for PTI potency. The final chapter focused on the development of Dihydromotuporamine C derivatives as non-toxic anti-metastatic agents. Dihydromotuporamine C demonstrated good anti-invasive properties with tumor cells. Derivatives were made in an effort to reduce the cytotoxicity of the parent and improve the anti-migration potency. The motuporamine derivatives all have a polyamine message (norspermidine or homospermidine) appended to make a macrocycle core, making them prime targets to evaluate as potential PTS ligands in the CHO and CHO-MG* screen. Each compound was also tested in the highly metastatic pancreatic cancer cell line L3.6pl to determine both its IC50 value and maximum tolerated dose (MTD). The anti-migration assay was performed at the lowest MTD obtained (0.6 (&)#181;M) in order to compare the series at the same non-toxic dose. The results suggested that as the N1-amine center was moved further from the macrocyclic ring, an increased ability to inhibit cell migration and reduced toxicity was observed. These collective findings provide new tools for cell biologists to modulate and target polyamine transport in mammalian cells. Future applications of these technologies include new cancer therapies which are cell-selective and inhibit the spread of tumors.
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Date Issued: 2012
Identifier: CFE0004636, ucf:49895
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0004636

Title: The Influence of Stigma on Quality of Life and Relationship Satisfaction for Prostate Cancer Survivors and Their Partners.
Creator: Wood, Andrew, Barden, Sejal, Daire, Andrew, Lambie, Glenn, Munyon, Matthew, Conley, Abigail, University of Central Florida
Abstract / Description: The purpose of this study was to examine the relationships between stigma, quality of life (QoL), and relationships satisfaction for prostate cancer (PCa) survivors and their intimate and/or romantic partners. The investigator tested a theoretical model that stigma (as measured by the Social Impact Scale [SIS; Fife (&) Wright, 2000]) influenced QoL (as measured by the Functional Assessment of Cancer Therapy (-) Prostate [FACT-P; Esper et al., 1997] and the Functional Assessment of Cancer...
Show moreThe purpose of this study was to examine the relationships between stigma, quality of life (QoL), and relationships satisfaction for prostate cancer (PCa) survivors and their intimate and/or romantic partners. The investigator tested a theoretical model that stigma (as measured by the Social Impact Scale [SIS; Fife (&) Wright, 2000]) influenced QoL (as measured by the Functional Assessment of Cancer Therapy (-) Prostate [FACT-P; Esper et al., 1997] and the Functional Assessment of Cancer Therapy (-) General Population [FACT-GP; Cella et al., 1993]) and relationship satisfaction (as measured by the Couples Satisfaction Index [CSI; Funk (&) Rogge, 2007]) for both PCa survivors and their partners (N = 72 couples). The investigator hypothesized that stigma would have a negative influence on both QoL and relationship satisfaction. Further, exploratory research questions pertained to the influence of race on stigma, QoL, and relationship satisfaction, as well as examining difference in experiences of stigma based on demographic variables (e.g., age and income).The results of the structural equation model analyses identified that stigma negatively influenced QoL (R2 = .84, p (<) .05) and relationship satisfaction (R2 = .19, p (<) .05) for both PCa survivors and their partners. Race did not have statistically significant (p (>) .05) relationships with stigma, QoL, or relationship satisfaction and stigma was not found to be statistically different (p (>) .05) based on demographic variables. Implications of the results of the study include (a) practical implications for PCa survivors and their partners; (b) strategies for effective individual, group, and couples-based counseling; (c) need for counselor educators to prepare counselors to work with medically ill populations and cancer survivors; (d) PCa stigma instrument development; and (e) the necessity to examine research with couples in a dyadic fashion.
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Date Issued: 2015
Identifier: CFE0005742, ucf:50112
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0005742

Title: MICRORNA REGULATION OF PROSTATE CANCER DESENSITIZATION TO ANDROGEN RECEPTOR ANTAGONIST DRUGS DURING ANDROGEN DEPRIVATION THERAPY.
Creator: Lorch, Robert, Chakrabarti, Ratna, University of Central Florida
Abstract / Description: The current standard treatment of prostate cancer by androgen deprivation therapy involves using drugs such as bicalutamide (Casodex) to antagonistically block androgen receptors that are normally present within prostate cells. Usually, the therapy is successful in the short run at limiting the growth of prostate cancer. However, in virtually all cases tumors begin to grow aggressively again after several months of treatment and new therapies must be started. The mechanism by which these...
Show moreThe current standard treatment of prostate cancer by androgen deprivation therapy involves using drugs such as bicalutamide (Casodex) to antagonistically block androgen receptors that are normally present within prostate cells. Usually, the therapy is successful in the short run at limiting the growth of prostate cancer. However, in virtually all cases tumors begin to grow aggressively again after several months of treatment and new therapies must be started. The mechanism by which these prostate cells transform from androgen sensitive to androgen independent and anti-androgen resistant is unclear. In this study, we investigated the role of microRNAs, small 15 to 18 nucleotide regulatory RNAs, in regulating the desensitization of prostate cancer cells to the androgen receptor antagonist drug bicalutamide. In order to identify significant microRNAs, quantitative PCR was used to obtain genome-wide microRNA expression levels of 885 human microRNAs at different timepoints for androgen sensitive LNCaP cancer cells treated with bicalutamide and for untreated control cells in tissue culture. Analysis of microRNA expression by clustering analysis and by statistical comparisons of treatment groups resulted in identification of 28 microRNAs that have altered expression in the progression process. In silico target prediction analysis was performed with the microRNAs shown to have altered expression, and a group of genes predicted to be under microRNA regulatory control during cancer progression to resistance was identified. A microRNA expression profile can be useful in developing more effective prognostic and therapeutic tools for prostate cancer.
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Date Issued: 2011
Identifier: CFH0003826, ucf:44740
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH0003826

Title: LIM KINASE 1 MODULATES EXPRESSION OF MATRIX METALLOPROTEINASES AND ASSOCIATES WITH GAMMA-TUBULIN: DUAL ROLE IN INVASION AND MITOTIC PROCESSES.
Creator: Tapia, Tenekua, Chakrabarti, Ratna, University of Central Florida
Abstract / Description: LIM kinase 1 (LIMK1) is a unique dual specificity serine/threonine kinase containing two N-terminal LIM domains in tandem, a PDZ domain and a C-terminal catalytic domain. LIMK1 is involved in modulation of actin cytoskeleton through inactivating phosphorylation of the ADF (actin depolymerization factor) family protein cofilin. Recent studies have shown that LIMK1 is upregulated in breast and prostate cancer cells and tissues, promotes metastasis in animals and induces acquisition of an...
Show moreLIM kinase 1 (LIMK1) is a unique dual specificity serine/threonine kinase containing two N-terminal LIM domains in tandem, a PDZ domain and a C-terminal catalytic domain. LIMK1 is involved in modulation of actin cytoskeleton through inactivating phosphorylation of the ADF (actin depolymerization factor) family protein cofilin. Recent studies have shown that LIMK1 is upregulated in breast and prostate cancer cells and tissues, promotes metastasis in animals and induces acquisition of an invasive phenotype when ectopically expressed in benign prostate epithelial (BPH) cells. Furthermore, overexpression of LIMK1 was associated with altered sub cellular localization of the membrane type 1 matrix metalloprotease (MT1-MMP). Matrix metalloproteases (MMPs) are a family of zinc dependant proteolytic enzymes that hydrolyze extra cellular matrix and cell surface molecules. A number of MMPs including MMP-2, MMP-9 and their activator MT1-MMP are over expressed in a variety of cancers including prostate cancer. The abundant expression of these enzymes contributes to changes in the tumor microenvironment, which facilitate degradation of the surrounding collagen matrix and migration of cells through the matrix defects. In this study, we show that MMPs are involved in LIMK1 induced invasion of otherwise non-invasive BPH cells. We also show that (a) the kinase activity of LIMK is not essential for the invasive behavior of the cells and (b) the absence of LIM domains significantly retards cell invasion. We have established transfected sub lines of BPH cells stably expressing 1) constitutively active LIMK1 (BPHLCA), 2) kinase dead LIMK1 (BPHLKD) and 3) only the kinase domain of LIMK1 (BPHLK) for our study. In vitro invasion assays revealed that LIMK1 induced invasion was inhibited by the MMP specific inhibitor, GM6001, and that cells expressing kinase-dead LIMK1 were equally invasive. Furthermore, BPH cells expressing LIMK1 mutants expressed higher amounts of MMP-2 and MMP-9. Substrate zymography revealed increased concentration of secreted MMP-2 and MMP-9 in the media of BPHLCA and BPHLK cells respectively compared to BPHV (vector control) cells. Quantitative RT-PCR also showed a ~10 fold increase in the steady state concentration of MMP-2 in BPHLCA cells compared to the control BPHLV cells. Expression of active LIMK1 stimulated cell-surface expression of MT1-MMP in BPHLCA cells as determined by flow cytometry. A modest increase in expression of MT1-MMP was noted in BPHLKD cells compared to BPHLK and BPHV cells. Immunoflourescence analysis indicated differential localization of MT1-MMP and LIMK1 in BPH cells expressing different mutants of LIMK1. Co-localization of LIMK1 and MT1-MMP in the plasma membrane and in the perinuclear region was also evident in these cells. Furthermore, here we provide evidence that suggests a functional role for phosphorylated (activated) LIMK1/2 (p-LIMK1/2) during mitosis through its association with γ-tubulin. Immunoflourescence analysis showed distinct co-localization of γ -tubulin and p-LIMK1/2 in the centrosomes during mitosis from early prophase to the beginning of telophase. No association was seen in the interphase or in late telophase. Phospho-LIMK1/2 was co-precipitated in immunoprecipitates of γ -tubulin using an anti- γ -tubulin antibody suggesting a physical association between these proteins in a complex. This finding reveals a novel role of LIMK1 in the mitotic process. In summary, our data suggests that MMPs are involved in LIMK1 induced invasion of prostate epithelial cells, and that this effect is mediated through altered expression and activation of specific MMPs. Furthermore, LIMK1 induced invasion is dependant on the presence of LIM domains more than the kinase activity. Finally, we show that phosphorylated LIMK1 and LIMK2 are involved in the mitotic process in a stage specific manner through its association with the centrosomal protein γ -tubulin. Because LIMK1 promotes invasion in vitro, regulates expression of MMPs, and is involved in mitotic processes, it is an attractive drug target for prostate cancer therapy.
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Date Issued: 2007
Identifier: CFE0001812, ucf:47361
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0001812

Title: BLOODLINES.
Creator: toner, Pamela, Bartkevicius, Jocelyn, University of Central Florida
Abstract / Description: "Bloodlines" is a collection of personal essays that focus on the process of remembering, imagining, and reflecting on the past through the lens of a perpetually shifting present. They consider situations ranging from mental and physical illnesses, from cancer to alcohol addiction, to career changes, to the often dysfunctional and displaced family ties that distance and adulthood have not severed. In "Searching," I write the narrative of the ongoing search for my birthmother, and how the...
Show more"Bloodlines" is a collection of personal essays that focus on the process of remembering, imagining, and reflecting on the past through the lens of a perpetually shifting present. They consider situations ranging from mental and physical illnesses, from cancer to alcohol addiction, to career changes, to the often dysfunctional and displaced family ties that distance and adulthood have not severed. In "Searching," I write the narrative of the ongoing search for my birthmother, and how the search complicates the relationship with my adoptive mother, who always feared she'd lose me. Similarly, "Of Flesh and Blood" recounts and negotiates how hereditary and environmental factors have shaped my identity. Loss and betrayal are weaved throughout "Flight Patterns" when I trace the links between relationships among my family and my pets. In "Signs and Stars" and "Seeing Stars," I search for ways of dealing with my cancer diagnosis and alcoholism, weaving through my past as I fight for recovery. By exploring the subjective nature of memory and circumstance through sensory, expositional, structural, and even written documentation, I have attempted to capture what is, for me, the tenuous hold on intertwined moments in time by creating a palimpsest of perspectives.
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Date Issued: 2006
Identifier: CFE0001053, ucf:46819
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0001053

Title: USE OF CERIUM OXIDE NANOPARTICLES FOR PROTECTION AGAINSTRADIATION-INDUCED CELL DEATH.
Creator: Colon, Jimmie, Kolattukudy, Pappachan, University of Central Florida
Abstract / Description: The ability of engineered cerium oxide nanoparticles to confer radioprotection was examined. Rat astrocytes were treated with cerium oxide nanoparticles to a final concentration of 10 nanomolar, irradiated with a single 10 Gy dose of ionizing radiation and cell death was evaluated by propidium iodine uptake at 24 and 48 hours after radiation insult. Treatment of rat astrocytes with nanoceria resulted in an approximate 3-fold decrease in radiation induced death. These results suggest that the...
Show moreThe ability of engineered cerium oxide nanoparticles to confer radioprotection was examined. Rat astrocytes were treated with cerium oxide nanoparticles to a final concentration of 10 nanomolar, irradiated with a single 10 Gy dose of ionizing radiation and cell death was evaluated by propidium iodine uptake at 24 and 48 hours after radiation insult. Treatment of rat astrocytes with nanoceria resulted in an approximate 3-fold decrease in radiation induced death. These results suggest that the nanoceria are conferring protection from radiation induced cell death. Further experiments with human cells were conducted. Human normal and tumor cells (MCF-7 and CRL8798) were treated with the same dosage of cerium oxide nanoparticles, irradiated and evaluated for cell survival. Treatment of normal cells (MCF-7) conferred nearly 99% protection from radiation-induced cell death while the same concentration of nanoceria showed almost no protection in tumor cells (CRL8798). TUNEL analysis results of similarly treated cells demonstrated that nanoceria reduced radiation-induced cell death by 3-fold in normal breast cells but not in MCF-7 tumor cell lines when cultured under the same conditions. We concluded that cerium oxide nanoparticles confer radioprotection in a normal human breast line (CRL 8798) but not in a human breast tumor line (MCF-7). It is hoped that the outcome of this study will guide future endeavors toward a better elucidation of the molecular pathways involved in the protection of cells with nanoceria against radiation-induced cell death, as well as the minimization of the bystander effect in radiation therapy.
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Date Issued: 2006
Identifier: CFE0001048, ucf:46823
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0001048

Title: THE EFFECT OF K562-IL21-2 PLASMA MEMBRANE PARTICLES ON THE PROLIFERATION OF NATURAL KILLER CELLS TO FIGHT CANCER.
Creator: Prophete, Michelle, Copik, Alicja, University of Central Florida
Abstract / Description: Immunotherapy has emerged as a current and future paradigm of cancer treatment, which utilizes the body's immune system to eradicate cancer. Natural Killer (NK) cells as part of the innate immune system have immense potential in their anti-tumor cytotoxic activities and host cell surveillance properties. NK cells comprise approximately five to fifteen percent of peripheral blood lymphocytes and can be proliferated in vitro using recently developed methods with co-cultures with feeder cells ...
Show moreImmunotherapy has emerged as a current and future paradigm of cancer treatment, which utilizes the body's immune system to eradicate cancer. Natural Killer (NK) cells as part of the innate immune system have immense potential in their anti-tumor cytotoxic activities and host cell surveillance properties. NK cells comprise approximately five to fifteen percent of peripheral blood lymphocytes and can be proliferated in vitro using recently developed methods with co-cultures with feeder cells (derived from engineered tumor cells) or plasma membrane (PM) particles, produced from the fore mentioned feeder cells, in combination with soluble cytokines. For efficient growth and maintenance of these NK cells, Interleukin-2 (IL-2) is utilized. IL-2 in solution, through receptor mediated signaling, stimulates proliferation of T-cells and NK cells. NK cells have lower responsiveness to IL-2 and consequently require a larger systemic dose to stimulate them as opposed to competing cell populations that have higher expression of receptors for IL-2, such as T-cells, which can have the effect of lower effective stimulation of NK cell growth. Such difference in the stimulatory capability of IL-2 toward NK cells and the short circulation lifetime of soluble IL-2 require higher dosages of soluble IL-2 for effective in vivo NK cell proliferation for therapeutic application against cancer, but is toxic. Therefore establishing another form of IL-2 delivery that improves its specific targeting to NK cells would be beneficial and may be crucial for novel therapeutic improvement. The Copik Laboratory has made an IL-2 fusion protein construct having a membrane anchor for expression of membrane-bound IL-2 on K562-41bbl-21 cells (K562-IL21). K562-IL21 cells are selectively recognized by NK cells and stimulate their proliferation and cytotoxicity. Hence, a K562-IL21 membrane-bound IL-2 form should be targeted to NK cells with IL-2 delivery. K562-IL21-2 cells were then used to prepare PM21-2 particles which have the potential to provide NK cell targeted, long-lived form of IL-2 for use as an injectable drug for in vivo adjuvant stimulation of NK cells. The presence of IL-2 on the in the PM21-2 particle product was verified by Western blot, and ELISA. Particle preparations from the modified K562 cells should possess characteristics that allow them to possibly replace soluble IL-2 and more specifically increase the numbers or anti-tumor activity of NK cell populations. The effect of PM21-2 particles was studied in in vitro culture based experiments, which tested the effectiveness the PM21-2 particles to induce selective NK cells expansion as compared to PM21 particles in the presence or absence of soluble IL-2.
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Date Issued: 2017
Identifier: CFH2000353, ucf:45918
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH2000353

Title: INTENSIVE CARE IN ONCOLOGY: ADMISSION AND OUTCOMES IN ADULT PATIENTS WITH CANCER.
Creator: John, Surya, Loerzel, Victoria, University of Central Florida
Abstract / Description: Background: Historically, patients with cancer have been perceived as poor candidates for ICU admission. General ICU admission criteria lists cancer patients as low priority in ICU admission depriving them of the care they rightfully deserve. The purpose of this literary synthesis was to examine ICU admission criteria, risk factors, and outcomes of ICU admission in relation to hematological and solid tumor cancers and discuss ways that practitioners and nurses can educate patients with cancer...
Show moreBackground: Historically, patients with cancer have been perceived as poor candidates for ICU admission. General ICU admission criteria lists cancer patients as low priority in ICU admission depriving them of the care they rightfully deserve. The purpose of this literary synthesis was to examine ICU admission criteria, risk factors, and outcomes of ICU admission in relation to hematological and solid tumor cancers and discuss ways that practitioners and nurses can educate patients with cancer and their families on appropriateness of ICU care. Methods: A total of 768 articles were found in a literature search including all literature from 2005 to 2016 from all countries using the databases CINAHL Plus, MEDLINE, PsycINFO, and Academic Search Premier. These were further narrowed down based on relevancy by topic or reading abstracts. A total of 13 articles utilizing the inclusion and exclusion criteria of the literature search were included in the final literature synthesis. Results: In addition to general ICU admission criteria several other criteria and scores can be helpful in admitting patients with cancer to the ICU including cancer specific criteria, mortality predictor tools, performance status, and ICU trials. Mortality predictors, in combination with other patient characteristics, demonstrated effectiveness to predict outcomes in patients with cancer. Survival rates in hematological and solid tumor cancers have improved from the past, and lower prognostic scores can predict who will have better outcomes. Conclusion: Cancer specific criteria, mortality predictor tools, performance status, and ICU trials in addition to general ICU criteria should be used for admission of cancer patients into ICU. Practitioners and nurses should become familiar with the newest outcomes in patients with cancer to make collaborative informed decisions about ICU admission.
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Date Issued: 2016
Identifier: CFH2000093, ucf:45522
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH2000093

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