Current Search: Pancreatic Cancer (x)
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- Title
- Fabrication of Polyelectrolyte Nanoparticles Through Hydrophobic Interaction.
- Creator
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Catarata, Ruginn Porce, Zhai, Lei, Kang, Ellen, Huo, Qun, University of Central Florida
- Abstract / Description
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Anticancer drugs like gemcitabine (GEM) are used to treat cancers such as, pancreatic ductal adenocarcinoma (PDAC). However, the use of free gemcitabine yields challenges including cytotoxicity to healthy cells and poor circulation time. By encapsulating GEM in nanoparticles these challenges can be overcome. In this study poly(acrylic acid) (PAA)-GEM nanoparticles are fabricated by coupling GEM onto PAA. The particle formation is driven by the hydrophobic interaction of GEM, which collects in...
Show moreAnticancer drugs like gemcitabine (GEM) are used to treat cancers such as, pancreatic ductal adenocarcinoma (PDAC). However, the use of free gemcitabine yields challenges including cytotoxicity to healthy cells and poor circulation time. By encapsulating GEM in nanoparticles these challenges can be overcome. In this study poly(acrylic acid) (PAA)-GEM nanoparticles are fabricated by coupling GEM onto PAA. The particle formation is driven by the hydrophobic interaction of GEM, which collects in the core of the nanoparticle, forming a PAA shell. The nanoparticles were optimized by studying the PAA/GEM ratio and pH during fabrication. Characteristics of the nanoparticles including size, morphology and surface charge were investigated using dynamic light scattering (DLS), transmission electron microscopy (TEM) and zeta potential measurements. Conditions such as ionic stability and pH stability were optimized to achieve high drug loading efficiency. Cell uptake and cytotoxicity studies were used to determine the efficiency of the nanoparticles as drug delivery vehicle.
Show less - Date Issued
- 2019
- Identifier
- CFE0007791, ucf:52364
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0007791
- Title
- TESTING MICE AT RISK OF PANCREATIC CANCER FOR ALTERED PROTEIN PATHWAYS FOUND IN DIABETES.
- Creator
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Cheung, Henley, Altomare, Deborah A., University of Central Florida
- Abstract / Description
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Pancreatic cancer is nearly asymptomatic, which can result in extensive grow and even metastasis to other organs before detection. When diagnosed at a late stage, the survival rate is 3%. Early detection is therefore the key to treating pancreatic cancer. Diabetes was identified as a risk factor for the development of pancreatic cancer, but the mechanism remains unknown. In this project, the objective was to delineate a link between diabetes and pancreatic cancer by examining their shared...
Show morePancreatic cancer is nearly asymptomatic, which can result in extensive grow and even metastasis to other organs before detection. When diagnosed at a late stage, the survival rate is 3%. Early detection is therefore the key to treating pancreatic cancer. Diabetes was identified as a risk factor for the development of pancreatic cancer, but the mechanism remains unknown. In this project, the objective was to delineate a link between diabetes and pancreatic cancer by examining their shared protein signaling pathways. In a previous study, hyper-activation of AKT1 resulted in a pre-diabetic phenotype and also increased upregulation of downstream phosphorylated mTOR and phosphorylated p70S6 kinase. More recently, mice with mutations that hyper-activated AKT1 and KRAS showed a significantly higher blood glucose level compared to littermate matched wild-type, mutant AKT1, or mutant KRAS mice. Interestingly, mice with a combination of mutations that hyper-activated AKT1 and KRAS also showed faster development of pancreatic cancer compared to these other groups of littermate mice. Toward determining a molecular basis for the crosstalk between AKT1 and KRAS, pancreas and liver tissues were collected from all four groups of mice including wild-type, mutant AKT1, mutant KRAS, and mice with dual AKT1/KRAS hyper-activation. One strategy was to examine expression and/or phosphorylation of downstream protein signaling crosstalk by analysis of p70S6K using Western Blots. Erk 1/2 proteins were also tested as downstream proteins of KRAS to provide a molecular view of the individual and cooperative roles of AKT1 and KRAS in the mouse models. A potential feedback mechanism to affect insulin receptor signaling in the pancreas was examined using enzyme-linked immunosorbent assays (ELISA). A significant decrease in insulin receptor phosphorylation, possibly contributing to insulin resistance, was found when mice had mutant hyper-activated KRAS. Contrary to the original expectations, mice with combined mutations of AKT1 and KRAS may contribute to the accentuated diabetic phenotype by targeting two different points in the AKT and KRAS protein signaling pathways. The information can help understand the relationship between glucose metabolism, diabetes, and pancreatic cancer development. By thoroughly studying the interactions between targets in the AKT1/KRAS signaling pathways, key molecular events that induce metabolic changes and potentially early biomarkers may lead to an improved understanding of risk and/or detection of pancreatic cancer.
Show less - Date Issued
- 2017
- Identifier
- CFH2000273, ucf:45895
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH2000273
- Title
- POLYAMINE TRANSPORT INHIBITOR EFFECTS ON PANCREATIC CANCER PROLIFERATION CELLS IN VIVO.
- Creator
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Hogan, Frederick, Altomare, Deborah, University of Central Florida
- Abstract / Description
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Pancreatic cancer is a serious disease, one in which the survival rate over five years is less than 6%. (1) Often, malignant tumors will exhibit uncontrolled proliferation and it is postulated that they have high metabolic needs. One of the areas of interest in cancer metabolism is the unique need for large amounts of polyamines in order to sustain this uncontrolled proliferation. Polyamines are organic compounds that all cells need for proliferation and differentiation. (2) Cells obtain...
Show morePancreatic cancer is a serious disease, one in which the survival rate over five years is less than 6%. (1) Often, malignant tumors will exhibit uncontrolled proliferation and it is postulated that they have high metabolic needs. One of the areas of interest in cancer metabolism is the unique need for large amounts of polyamines in order to sustain this uncontrolled proliferation. Polyamines are organic compounds that all cells need for proliferation and differentiation. (2) Cells obtain polyamines by manufacture of them directly or obtain them from the environment through their transport across the cell membrane. When cancer cells have limited access to polyamines they enter apoptosis, or controlled cell death. In animal models of cancer, cellular apoptosis can be tracked by measuring tumor weights as well as histological methods. It is known that difluromethylornithine (DFMO), a polyamine synthesis inhibitor, has shown some success in reducing tumor weights. (3) Cells deprived of the ability to manufacture polyamines will resort to transporting existing polyamines from the environment for their use. (3) It is believed that a polyamine transport inhibitor (PTI) can be designed and used in conjunction with DFMO to completely deprive cancer cells of polyamines and increase rates of apoptosis in tumor cells. Through this study the interaction of DFMO with newly identified PTI will be analyzed. A mouse model with tumor cells in the pancreas will give a picture of how cancer cells react to DFMO / PTI in vivo. The findings allow us to postulate how targeted compounds interact with protein signaling pathways that may be important for regulating response to inhibitors of polyamine synthesis and/or transport.
Show less - Date Issued
- 2015
- Identifier
- CFH0004749, ucf:45395
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFH0004749
- Title
- Diabetes Phenotypes in Transgenic Pancreatic Cancer Mouse Models.
- Creator
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Albury, Toya, Altomare, Deborah, Zhao, Jihe, Masternak, Michal, Khaled, Annette, University of Central Florida
- Abstract / Description
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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.
Show less - Date Issued
- 2015
- Identifier
- CFE0006245, ucf:51081
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0006245
- Title
- The development of motuporamine derivatives and an investigation into their biological properties.
- Creator
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Skruber, Kristen, Phanstiel, Otto, Teter, Kenneth, Vonkalm, Laurence, University of Central Florida
- Abstract / Description
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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.
Show less - Date Issued
- 2016
- Identifier
- CFE0006505, ucf:51390
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0006505
- Title
- Learning Algorithms for Fat Quantification and Tumor Characterization.
- Creator
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Hussein, Sarfaraz, Bagci, Ulas, Shah, Mubarak, Heinrich, Mark, Pensky, Marianna, University of Central Florida
- Abstract / Description
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Obesity is one of the most prevalent health conditions. About 30% of the world's and over 70% of the United States' adult populations are either overweight or obese, causing an increased risk for cardiovascular diseases, diabetes, and certain types of cancer. Among all cancers, lung cancer is the leading cause of death, whereas pancreatic cancer has the poorest prognosis among all major cancers. Early diagnosis of these cancers can save lives. This dissertation contributes towards the...
Show moreObesity is one of the most prevalent health conditions. About 30% of the world's and over 70% of the United States' adult populations are either overweight or obese, causing an increased risk for cardiovascular diseases, diabetes, and certain types of cancer. Among all cancers, lung cancer is the leading cause of death, whereas pancreatic cancer has the poorest prognosis among all major cancers. Early diagnosis of these cancers can save lives. This dissertation contributes towards the development of computer-aided diagnosis tools in order to aid clinicians in establishing the quantitative relationship between obesity and cancers. With respect to obesity and metabolism, in the first part of the dissertation, we specifically focus on the segmentation and quantification of white and brown adipose tissue. For cancer diagnosis, we perform analysis on two important cases: lung cancer and Intraductal Papillary Mucinous Neoplasm (IPMN), a precursor to pancreatic cancer. This dissertation proposes an automatic body region detection method trained with only a single example. Then a new fat quantification approach is proposed which is based on geometric and appearance characteristics. For the segmentation of brown fat, a PET-guided CT co-segmentation method is presented. With different variants of Convolutional Neural Networks (CNN), supervised learning strategies are proposed for the automatic diagnosis of lung nodules and IPMN. In order to address the unavailability of a large number of labeled examples required for training, unsupervised learning approaches for cancer diagnosis without explicit labeling are proposed. We evaluate our proposed approaches (both supervised and unsupervised) on two different tumor diagnosis challenges: lung and pancreas with 1018 CT and 171 MRI scans respectively. The proposed segmentation, quantification and diagnosis approaches explore the important adiposity-cancer association and help pave the way towards improved diagnostic decision making in routine clinical practice.
Show less - Date Issued
- 2018
- Identifier
- CFE0007196, ucf:52288
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0007196
- Title
- Cerium Oxide Nanoparticles Sensitize Pancreatic Cancer Cells to Radiation by Promoting Acidic pH, ROS, and JNK Dependent Apoptosis.
- Creator
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Wason, Melissa, Zhao, Jihe, Self, William, Altomare, Deborah, Baker, Cheryl, University of Central Florida
- Abstract / Description
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Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. In this report we determined whether and how cerium oxide nanoparticles (CONPs) sensitize pancreatic cancer cells to RT. CONP pretreatment enhanced radiation-induced reactive oxygen species (ROS) production preferentially in acidic cell-free solutions as well as acidic human pancreatic cancer cells. In acidic environments, CONPs favor the scavenging of superoxide radical over the hydroxyl...
Show moreSide effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. In this report we determined whether and how cerium oxide nanoparticles (CONPs) sensitize pancreatic cancer cells to RT. CONP pretreatment enhanced radiation-induced reactive oxygen species (ROS) production preferentially in acidic cell-free solutions as well as acidic human pancreatic cancer cells. In acidic environments, CONPs favor the scavenging of superoxide radical over the hydroxyl peroxide resulting in accumulation of the latter whereas in neutral pH CONPs scavenge both. CONP treatment prior to RT markedly potentiated the cancer cell apoptosis both in culture and in tumors and the inhibition of the pancreatic tumor growth without harming the normal tissues or host mice. Mechanistically, CONPs were not able to significantly impact RT-induced DNA damage in cancer cells, thereby ruling out sensitization through increased mitotic catastrophe. However, JNK activation, which is known to be a key driver of RT-induced apoptosis, was significantly upregulated by co-treatment with CONPs and RT in pancreatic cancer cells in vitro and human pancreatic tumors in nude mice in vivo compared to CONPs or RT treatment alone. Further, CONP-driven increase in RT-induced JNK activation was associated with marked increases in Caspase 3/7 activation, indicative of apoptosis. We have shown CONPs increase ROS production in cancer cells; ROS has been shown to drive the oxidation of thioredoxin (TRX) 1 which results in the activation of Apoptosis Signaling Kinase (ASK) 1. The dramatic increase in ASK1 activation following the co-treatment of pancreatic cancer cells with CONPs followed by RT in vitro suggests that increased the c-Jun terminal kinase (JNK) activation is the result of increased TRX1 oxidation. The ability of CONPs to sensitize pancreatic cancer cells to RT was mitigated when the TRX1 oxidation was prevented by mutagenesis of a cysteine residue, or the JNK activation was blocked by an inhibitor,. Additionally, angiogenesis in pancreatic tumors treated with CONPs and RT was significantly reduced compared to other treatment options. Taken together, these data demonstrate an important role and mechanisms for CONPs in specifically killing cancer cells and provide novel insight into the utilization of CONPs as a radiosensitizer and therapeutic agent for pancreatic cancer.
Show less - Date Issued
- 2013
- Identifier
- CFE0005116, ucf:50725
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0005116