Dissertations / Theses on the topic 'Pancreatic cancer'
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Sirivatanauksorn, Vorapan. "Molecular analysis of pancreatic cancer." Thesis, Imperial College London, 1999. http://hdl.handle.net/10044/1/7489.
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Isaksson, Bengt. "Insulin resistance in pancreatic cancer /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-493-3/.
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Shehata, Fady Fouad Amin. "Pancreatic cancer : a developmental quest." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=101742.
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Pancreatic cancer is considered the fifth leading cause of cancer deaths in Canada and one of the most fatal diseases in the world. Its definite underlying cause is still unidentified, and its actual cell of origin remains unclear. Unfortunately, most of the current research on the pancreas is focused on one disease only, namely diabetes with much less consideration for other pancreatic diseases. Diabetes has been extensively studied from a developmental aspect, and continues to attract the interest of numerous researchers. On the contrary, few accomplishments have been done to decode the developmental errors occurring in pancreatic cancer. It is therefore necessary to allocate more research resources to address this disease from a developmental aspect.This study provides a literature review of the pancreas concerning its anatomy and function, transcription factors and signaling pathways controlling its development, and the role of these signaling pathways in pancreatic cancer. The review provides distinct emphasis on three important aspects. First, a review of pancreas development is provided, with a focus on different transcription factors and signaling pathways involved in this process. Second, it addresses how the signaling pathways which play a role in pancreas development are the same signaling pathways that play a role in pancreatic cancer, additional emphasis is placed on describing the genetic alterations occurring in pancreatic cancer. Third, a methodology of approaching pancreatic cancer research from a developmental aspect is presented. Using an example of one gene, Anterior gradient 2 (Agr2), is highly expressed in pancreatic cancer in ductal cells only, and might play a role in ductal cell development of the pancreas. Thus, the main objective of this review is to provide a developmental framework for the analysis of pancreatic cancer.
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Nakao, Akimasa. "Oncological problems in pancreatic cancer surgery." Nagoya University School of Medicine, 2000. http://hdl.handle.net/2237/5352.
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Wang, Lei. "Molecular Probes for Pancreatic Cancer Imaging." PDXScholar, 2016. http://pdxscholar.library.pdx.edu/open_access_etds/3108.
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Pancreatic ductal adenocarcinoma (PDAC) has the poorest five-year survival rate of any cancer. Currently, there are no effective diagnostics or chemotherapeutics. Surgical resection is the only curative therapy. However, most patients experience recurrence due largely to challenges in assessing tumor margin status in the operating room. Molecular probes that selectively highlight pancreatic cancer tissue, having the potential to improve PDAC margin assessment intraoperatively, are urgently needed. In this work, a series of red and near-infrared fluorescent probes is reported. Two were found to distribute to normal pancreas following systemic administration. One selectively accumulates in genetically modified mouse models of PDAC, providing cancer-specific fluorescence. In contrast to the small molecule probes reported previously, it possesses inherent affinity for PDAC cells and tissue, and thus does not require conjugation to targeting agents. Moreover, the probe exhibits intracellular accumulation and enables visualization of four levels of structure including the whole organ, tissue, individual cells and subcellular organelles. It can thus promote new strategies for precision image-guided surgery, pancreatic cancer detection, the monitoring of therapeutic outcomes and basic research.
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Mesenhöller, Maike. "Endogenous photosensitisation of pancreatic cancer cells." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343044.
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Lunardi, Serena. "Tumour-stroma interaction in pancreatic cancer." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:8cb21185-38ab-40ae-8f12-2b52cc61a988.
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Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs). There is accumulating evidence that PSCs influence the malignant phenotype of PDAC. The aim of this study was to analyse the tumour response to radiation treatment in the presence of PSCs and to investigate the cytokine network in the coculture of PSCs and pancreatic cancer cells (PCCs). PSCs were used in coculture with different PCC lines. Clonogenic survival assays of several PCC lines cocultured with PSCs showed decreased radiosensitivity. This effect was abrogated by inhibition of the β1-integrin/FAK signalling pathway. Furthermore, tumour regrowth experiments after irradiation showed that coinjected PSCs were radioprotective for PCCs after single-dose and fractionated irradiation in xenografts. In addition, we examined the expression of 50 proteins in the supernatants of PCCs and PSCs in mono- and coculture conditions. The detected cytokine expression profile of PSCs included many proinflammatory factors. Also, we identified IP-10 as the chemokine with the highest differential upregulation in PSCs by paracrine stimuli from five different PCC lines. Human PDAC with a high stroma component had elevated IP-10 mRNA expression. IP-10 did not stimulate tumour cell growth and migration in our conditions even though several PCCs expressed its cognate receptor CXCR3. Nevertheless, we discovered that in human PDAC samples IP-10 and CXCR3 mRNA levels correlated with the presence of CD3ε, CD4, FoxP3, CTLA4 and CD39 used as surrogate markers for T regulatory cells (Tregs), known to exert an immunosuppressive effect. In conclusion, these data demonstrate that PSCs enhance survival of PCCs to radiation by activating β1-integrin/FAK signalling. Furthermore, the interaction between the tumour stroma in pancreatic cancer may support an immunosuppression by chemoattraction of Tregs following upregulation of IP-10. Further characterisation of the paracrine signalling between PCCs, PSCs and immune cells will improve the understanding of pancreatic cancer biology and could lead to the identification of new targets for multimodal therapy.
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Quinn, Bridget A. "Novel Therapeutic Strategies for Pancreatic Cancer." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/4671.
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Pancreatic cancer is a devastating disease that leaves patients with a very poor prognosis and few therapeutic options. Many of the treatment options available are the same that have been used for almost 2 decades. There is a dire need for both novel treatments for this disease as well as novel strategies of treatment. This body of work will introduce and provide evidence in support of a novel combination therapy for pancreatic cancer treatment, a novel strategy of modifying currently used chemotherapeutics for pancreatic cancer therapy, and a novel transgenic preclinical mouse model of pancreatic cancer. Sabutoclax, an antagonist of the anti-apoptotic Bcl-2 proteins, and Minocycline, a commonly used antibiotic, show potent synergy when used in combination in both pancreatic cancer cells and in multiple immune-deficient and immune-competent mouse models of pancreatic cancer. Sabutoclax alone is capable of inducing cell cycle arrest and apoptosis in cells and its cytotoxicity is enhanced significantly when combined with Minocycline. This combination results in the loss of Stat3 activation both in vitro and in vivo, which is essential for its toxicity. It also inhibits tumor growth and prolongs survival in the KPC transgenic mouse model of pancreatic cancer. Also presented here are studies that demonstrate efficacy in vivo of modified versions of Gemcitabine and Paclitaxel. These drugs are linked to a peptide that shows specificity for the EphA2 receptor, which is overexpressed on the surface of pancreatic cancer cells and only minimally on normal cells. This peptide results in increased cellular uptake of drug, as it is bypassing its normal mechanism of entry. These normal mechanisms are often dysregulated in cancer, leading to decreased uptake and drug resistance. The use of these modified drugs show significantly increased tumor growth inhibition as compared to the parent drug alone. Finally, we provide data on the characterization of a novel transgenic mouse model of pancreatic cancer. This model, the Pan Met View (PMV) mouse, combines the commonly used KPC transgenic mouse model of pancreatic cancer and a mouse that expresses a Luciferase reporter gene under the control of the cancer-specific promoter, CCN1. Our data shows that double transgenic PMV mice can now be used to follow primary tumor and metastasis development in real time by Bioluminescent imaging (BLI) through disease progression and potentially therapy. This strategy will enhance the use of genetically engineered mouse models (GEMMS) to study cancer initiation and progression with potential to non-invasively monitor therapy. These chapters present novel and exciting data that have the potential to open multiple avenues of translational study and result in significant advances in pancreatic cancer therapy.
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Fesinmeyer, Megan Dann. "Pancreatic cancer risk and prevention : association with PPARG gene and policy analysis of tabacco-related pancreatic cancer /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8440.
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Kottabi, Zahra. "Statistical Modeling and Analysis of Breast Cancer and Pancreatic Cancer." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4350.
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The object of the present study is to apply statistical modeling and estimate the mean of optimism of breast cancer patients as function of attribute variables; delay, education and age for each race of breast cancer patients. Moreover, to investigate the nonlinear association between optimism, education, age and delay with respect to each race and both. Furthermore, to develop differential equations that will characterize the behavior of the pancreatic cancer tumor size as a function of time. Having such differential equations, the mean solution of which once plotted will identify the rate of change of tumor size as a function of age. The structures of the differential equations characterize the growth of pancreatic cancer tumor. Once we have developed the differential equations and their solutions, and the object of the present study is to probabilistically evaluate commonly used methods to perform survival analysis of medical patients to validate the quality of the differential system and discuss its usefulness.
In the last study, a comparison of parametric, semi-parametric and nonparametric analysis of probability survival time models. The first part of the evaluation of survival time by applying the statistical tests will guide us to how precede the actual cancer data and second part, identifying the parametric survival time function for each race and both. Moreover, we will evaluate the Kernel density, the popular Kaplan-Meier (KM) and the Cox Proportional Hazard (Cox PH) models by using actual pancreatic cancer data. As expected, the parametric survival analysis when applicable gives the best results followed by the not commonly used nonparametric Kernel density approach for evaluations actual cancer data.
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Li, Causi Eleanor. "The role of CX3CR1 in pancreatic cancer." Thesis, Queen Mary, University of London, 2018. http://qmro.qmul.ac.uk/xmlui/handle/123456789/36210.
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Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer death in Western countries. The PDAC tumour microenvironment (TME) is characterized by a dense stromal reaction, consisting of many cell types including fibroblasts and immune cells. The chemokine receptor, CX3CR1 forms a high-affinity axis with its unique ligand CX3CL1 and is expressed on monocytes, macrophages and T cells. CX3CR1 is also present on pancreatic malignant cells, where it has been associated with metastasis formation. The aim of my project is to investigate the role of CX3CR1 in the progression and development of pancreatic cancer in a genetically engineered mouse model of PDAC, the CX3CR1GFP/GFPLSL-KRASG12D/+LSL-Trp53R172H/+Pdx1-Cre (CKPC) mouse. In these mice, the CX3CR1 protein is not functional but they express GFP. I have found that the absence of CX3CR1 in KPC mice has no effect in their lifespan and response to chemotherapy. Comparison of the immune infiltrate of the tumours revealed that the lack of CX3CR1 causes a significant decrease in T cells and a possible increase in myeloid cells in CKPC mice compared to KPC mice. Expression analysis of several inflammatory cytokines in the TME showed a significant difference in IL-10 between KPC and CKPC mice. There was also a significant increase in levels of, CX3CL1, both locally and in the plasma. Finally, we performed RNA-seq on KPC and CKPC tumours. My analysis revealed 607 differentially-expressed genes, some of which encoded other chemokines or protein regulating the immune system. In particular, I observed the upregulation of Cxcl10 and Cxcl12, and the downregulation of Gata3 and S100a4, which could explain the decrease in T cells in the TME of CKPC mice. In conclusion, although the lack of CX3CR1 modifies the TME in this genetic model of PDAC, these changes do not affect the lifespan or the response to chemotherapy.
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Coe, Peter. "Validation and early qualification of pancreatic fat deposition as an imaging biomarker of pancreatic cancer risk." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/validation-and-early-qualification-of-pancreatic-fat-deposition-as-an-imaging-biomarker-of-pancreatic-cancer-risk(ff38a95b-f135-4bfe-b901-80d79c388974).html.
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Introduction: Pancreatic cancer is the 10th most common cause of cancer in the United Kingdom (UK) yet the 5th most common cause of cancer related death. Although excess adiposity, measured as body mass index (BMI), is a risk factor for the development of pancreatic cancer the increase in relative risk is modest. Animal models suggest that the intra-organ deposition of lipids may be more specific to disease risk than anthropometric measurements. There is therefore a need to develop non-invasive methods to quantify intra-pancreatic fat deposition as a potential biomarker for pancreatic cancer predisposition. Cancer Research UK (CRUK) sets out clear guidelines for biomarker discovery and development. Potential biomarkers must go through a process of discovery and assay development followed by qualification. Methods Three streams of research: (i) Stage-one of the PanORAMA project. Assessment of accuracy through comparison of CS-MR and MRS quantified intra-pancreatic fat with histologically quantified intra-pancreatic fat in 12 patients undergoing pancreatic surgery. (ii) Stage-two of the PanORAMA study. Assessment of precision (reproducibility) and comparison with other anthropometric markers of excess adiposity in healthy volunteers (n=15). Refinement of MRS protocols and repeated assessment of precision in healthy volunteers (n=10). (iii) The Breast Risk Reduction Intermittent Dietary Evaluation 2 (BRRIDE-2) trial. Comparison of the effects of Intermittent Energy Restriction (IER) with Daily Energy Restriction (DER) on intra-pancreatic and intra-hepatic fat stores and metabolic markers of disease risk (n=26). Results (i) CS-MR and MRS had agreement with histological assessment of intra-pancreatic fat, but correlations were only moderate to good (rho 0.672 and 0.781 respectively). (ii) CS-MR, and after refinement, MRS, have clinically acceptable precision. This study tested this principle in intra-pancreatic fat in healthy volunteers with a range of intra-pancreatic fat consistent with the literature on the healthy population. (iii) I found no differences in reduction in intra-hepatic or intra-pancreatic fat when comparing IER with DER. Overall, I found that significant reductions (mean: 6.5%) in both of these ectopic fat stores could be achieved with eight-weeks of dietary intervention. Discussion More recent hypotheses on the link between excess adiposity and cancer have focused on the importance of within organ local ectopic fat as an abnormal micro-environment favouring cancer development and progression. Importantly, this hypothesis explains the specificity of epidemiological associations between excess adiposity and cancer risk. The observations that within a given individual, in the presence of short-term weight reduction, there are differential changes in local within organ fats – hepatic fat and pancreatic fat – support the specificity hypothesis. This thesis has put us in position to scale-up and explore the importance of intra-organ fats using non-invasive imaging techniques.
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Pålsson, Birger. "Tumour marker CA-50 in pancreatic cancer." Lund : Dept. of Surgery, Lund University, 1993. http://catalog.hathitrust.org/api/volumes/oclc/38154714.html.
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Bashir, Kifah, and Yvonne Bengtsson. "Palliative care for pancreatic cancer - patients´ experiences." Thesis, Kristianstad University College, Department of Teacher Education, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:hkr:diva-4609.
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To receive a diagnosis of pancreatic cancer can lead to a tremendous change in a person’s life. Thoughts regarding death may cause a personal crisis which can have negative influences on the patient’s social, mental and spiritual state. Most people with pancreatic cancer are diagnosed in a late stage of the disease. Therefore, palliative care is often one of the options that are offered to patients. Moreover, to be able to provide patients with nursing care and tend to their needs, it is very important to see them as unique individuals. The purpose with the literature review was to illustrate the experiences of palliative nursing care of patients with pancreatic cancer. A systematic literature review of scientific articles was performed. The study showed that patients’ experiences of need for information, patients’ need for time, support and personal relations, patients’ experiences of hope as well as patients’ need for symptom control were of importance in palliative nursing care.
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Ceha, Heleen Margriet. "Molecular and radiotherapeutic features of pancreatic cancer." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2003. http://dare.uva.nl/document/87079.
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Kersting, Stephan, Johanna Roth, and Alfred Bunk. "Transabdominal Contrast-Enhanced Ultrasonography of Pancreatic Cancer." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-136474.
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Since its introduction, contrast-enhanced ultrasonography (CEUS) has significantly extended the value of ultrasonography (US). CEUS can be used to more accurately determine pancreatic lesions compared to conventional US or to characterize lesions already detectable by US. Thus, CEUS can aid in the differential diagnosis of pancreatic tumors. Using US contrast media, it is possible to visually detect microvessels in the majority of pancreatic ductal adenocarcinomas. Thus, the use of quantitatively evaluated transabdominal CEUS can help in the differentiation of patients with mass-forming pancreatitis from patients with pancreatic adenocarcinomas. In neuroendocrine pancreatic tumors, different enhancement patterns can be observed in relation to the tumor mass: larger ones show a rapid early enhancement sometimes combined with necrotic central structures, and smaller ones disclose a capillary-blush enhancement. Pseudocysts, the most widespread cystic lesions of the pancreas, are not vascularized. They do not show any signal in CEUS and remain entirely anechoic in all phases, while true cystic pancreatic tumors usually have vascularized septa and parietal nodules. In summary, CEUS is effective for differentiating solid pancreatic tumors in most cases. CEUS is safe and cost effective and can better discriminate solid from cystic pancreatic lesions, thereby directing further imaging modalitiesDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Alfahad, Mohanad Abdul-Satar Mahmood. "Pro-drug strategies for pancreatic cancer therapy." Thesis, Keele University, 2018. http://eprints.keele.ac.uk/4534/.
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Pancreatic cancer is the fourth main cancer in the western world. Currently the only chemotherapy available clinically is gemcitabine. However, gemcitabine treatment only proves effective in 23.8% of patients. Nano-structures (< 120 nm) are capable of entering the highly permeable blood capillaries which supply the rapidly growing tumours. Once inside the capillaries they accumulate and are retained in the tumour as a result of the poor lymphatic drainage. This allows for a deeper tissue penetration which is otherwise difficult to achieve. Hybrid nanoparticles with an iron oxide core covered by gold shell (HNPs) have shown great potential for anti-cancer therapies. The magnetic iron oxide cores and the surface plasmon resonance (SPR) properties of the gold surface provide the HNPs with the capabilities of diagnostic imaging and drug delivery, making them true theranostic agents. A novel prodrug of gemcitabine has been developed by a regioselective coupling of gemcitabine and lipoic acid, itself a potent antioxidant. Gemcitabine-N-lipoate (GL) was obtained in a one-pot synthesis and the optimum conditions for the reaction were established. GL prodrug loading on to the HNPs surface was confirmed and the release profile of gemcitabine from the GL-HNPs formulation was studied at pH 3.6, 5.6 and 7.4 utilising different temperature conditions (20, 37, 44 °C) using RPMI serum free media under sink conditions. The data showed the stability of the formulation at pH 7.4, 20 °C while the optimum release conditions for gemcitabine from the GL-HNPs formulation were at pH 5.6, 44 °C with the highest release of 41.1% recorded after 24 hrs. III Preliminary in vitro MTT assay together with the drug uptake study show the superior inhibitory effect of the GL-HNPs formulation on the cell viability over gemcitabine after 24 hrs which indicates faster uptake of the formulation, however the overall effect of gemcitabine is greater after 48 hrs which is mainly due to the slow release of gemcitabine from the formulation. The behaviour of the GL-HNPs formulation as a drug delivery system shows a great potential for the system to act as a theranostic tool and to overcome the significant drawbacks associated with gemcitabine.
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Smith, Alena J. "THE ROLE OF PHLPP IN PANCREATIC CANCER." UKnowledge, 2015. http://uknowledge.uky.edu/biochem_etds/24.
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Medicine has come a long way in recent years with reliable treatments for many cancers. Pancreatic ductal adenocarcinoma (PDAC) has very few treatment options available. PDAC has a dismal 5 year survival rate of 4% and a median survival span of 6 months from point of diagnosis; with a high rate of chemotherapy and radiation resistance. A better understanding of the molecular events leading to cancer progression is needed in order to improve the treatment and prognosis of PDAC patients. We begin to elucidate the functional importance of PHLPP on suppressing progression and metastasis of PDAC. PHLPP belongs to a novel family of Ser/Thr protein phosphatases. Our previously published studies have demonstrated that PHLPP plays a tumor suppressor role in colon cancer by negatively regulating Akt and inhibiting cell proliferation. To determine the effect of PHLPP on cell migration and invasion, stable cells were generated to knock down or overexpress PHLPP in PDAC cells. The ability of cells to migrate and invade was examined using Transwell assays. We found that increased PHLPP expression significantly reduced the rate of migration and invasion in PDAC cells whereas knockdown of PHLPP had the opposite effect. To begin to elucidate the molecular mechanism underlying PHLPP-mediated inhibition of migration and invasion in PDAC cells, we discovered that the expression level of β4 Integrin was decreased in PHLPP overexpressing cells and increased in PHLPP knockdown cells. The increased expression of β4 Integrin has been shown to promote PDAC development and metastasis, although the mechanism leading to β4 Integrin upregulation is less clear. Interestingly, we found that the expression of β4 Integrin was highly sensitive to PI3K/Akt/mTOR activity in cells in which inhibition of PI3K/Akt/mTOR signaling significantly decreased the expression of β4 Integrin. Moreover, the quantitative real-time RT-PCR analysis revealed that the mRNA expression of β4 Integrin was not altered by changes in PHLPP expression or PI3K/Akt/mTOR activity, thus suggesting a post-transcriptional mechanism. Taken together, these results identify a tumor suppressor role of PHLPP in PDAC. Mechanistically, PHLPP suppresses PDAC cell migration and invasion by negatively controlling β4 Integrin expression through its ability to inhibit PI3K/Akt/mTOR signaling.
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King, Helen. "The role of PAK4 in pancreatic cancer." Thesis, King's College London (University of London), 2014. http://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-pak4-in-pancreatic-cancer(79fa0eaa-4d90-447f-88d4-c4d55561bad2).html.
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Perone, Jennifer A., Taylor S. Riall, and Kelly Olino. "Palliative Care for Pancreatic and Periampullary Cancer." W B SAUNDERS CO-ELSEVIER INC, 2016. http://hdl.handle.net/10150/622658.
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Most patients with pancreatic cancer will present with metastatic or locally advanced disease. Unfortunately, most patients with localized disease will experience recurrence even after multimodality therapy. As such, pancreatic cancer patients arrive at a common endpoint where decisions pertaining to palliative care come to the forefront. This article summarizes surgical, endoscopic, and other palliative techniques for relief of obstructive jaundice, relief of duodenal or gastric outlet obstruction, and relief of pain due to invasion of the celiac plexus. It also introduces the utility of the palliative care triangle in clarifying a patient's and family's goals to guide decision making.
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Kersting, Stephan, Johanna Roth, and Alfred Bunk. "Transabdominal Contrast-Enhanced Ultrasonography of Pancreatic Cancer." Karger, 2011. https://tud.qucosa.de/id/qucosa%3A27707.
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Since its introduction, contrast-enhanced ultrasonography (CEUS) has significantly extended the value of ultrasonography (US). CEUS can be used to more accurately determine pancreatic lesions compared to conventional US or to characterize lesions already detectable by US. Thus, CEUS can aid in the differential diagnosis of pancreatic tumors. Using US contrast media, it is possible to visually detect microvessels in the majority of pancreatic ductal adenocarcinomas. Thus, the use of quantitatively evaluated transabdominal CEUS can help in the differentiation of patients with mass-forming pancreatitis from patients with pancreatic adenocarcinomas. In neuroendocrine pancreatic tumors, different enhancement patterns can be observed in relation to the tumor mass: larger ones show a rapid early enhancement sometimes combined with necrotic central structures, and smaller ones disclose a capillary-blush enhancement. Pseudocysts, the most widespread cystic lesions of the pancreas, are not vascularized. They do not show any signal in CEUS and remain entirely anechoic in all phases, while true cystic pancreatic tumors usually have vascularized septa and parietal nodules. In summary, CEUS is effective for differentiating solid pancreatic tumors in most cases. CEUS is safe and cost effective and can better discriminate solid from cystic pancreatic lesions, thereby directing further imaging modalities.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Ramos, Delgado Carmen Fernanda. "Exploring PI3K signalling dynamics in pancreatic cancer." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30152.
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Les PI3K sont des enzymes qui phosphorylent le groupe hydroxyl en position 3 des phosphatidylinositols comme le PIP2 ou le PI. Ces lipides sont impliqués dans de nombreux processus cellulaires tels que la croissance, la prolifération, la motilité, l'autophagie et le trafic cellulaire. Chez les mammifères, il y a 8 isoformes de PI3K et elles sont regroupées en trois classes (I, II et III) en fonction de leur structure et spécificité du substrat. Les PI3K de classe I sont les mieux caractérisées et impliquées dans le cancer. Les rôles oncogéniques des PI3K de classe II et III restent méconnus. La voie PI3K/Akt est fréquemment suractivée dans les cancers et est corrélée à un mauvais pronostic, particulièrement dans l'adénocarcinome canalaire pancréatique (PDAC). La mutation oncogénique de Kras est détectée dans plus de 90% des cas de PDAC et induit l'activation des voies effectrices, y compris de la voie PI3K. Le PDAC est l'un des cancers les plus mortels, caractérisé par un diagnostic tardif, une progression rapide et des options thérapeutiques limitées. Des études antérieures de l'équipe ont démontré que la PI3Kalpha, une PI3K de classe I, est cruciale dans les étapes précoces du PDAC. Néanmoins, son rôle dans la progression du PDAC reste inconnu. Ma thèse vise à élucider la dynamique de signalisation des PI3K dans le PDAC. J'ai commencé par caractériser le rôle de la PI3Kalpha dans la progression du PDAC et j'ai déterminé sa pertinence en tant que cible thérapeutique. Enfin, je montre des données préliminaires sur le rôle de Vps34, une PI3K de classe III, dans la physiologie des cellules acineuses et son rôle éventuel dans la cancérogenèse pancréatique. L'inactivation pharmacologique et génétique de PI3Kalpha in vitro démontre que cette PI3K contrôle les paramètres cellulaires qui régulent la progression des cellules tumorales pancréatiques, et ce quelles que soient leurs mutations génétiques. Ces résultats ont été validés in vivo dans le modèle murin appelé KPC. Ainsi, des souris KPC avec des taux élevés de cfDNA (cell free DNA, marqueur d'inflammation) et une tumeur détectée par échographie ont été traitées avec l'inhibiteur spécifique de PI3Kalpha, BYL-719. J'ai également comparé l'inhibition pharmacologique de PI3Kalpha avec l'inactivation génétique de PI3Kalpha dans l'épithélium pancréatique de souris KPC (réalisé avec des souris génétiquement modifiées). L'inhibition de la PI3Kalpha in vivo, diminue le volume tumoral, prolonge la survie et retarde la dissémination métastatique. L'effet anti-métastatique des inhibiteurs de PI3Kalpha a été validé par une injection de cellules cancéreuse pancréatiques dans la veine caudale avec ou sans traitement avec du BYL-719. L'inhibition de la PI3Kalpha a également diminué l'infiltration des macrophages protumoraux, suggérant un rôle dans la réponse immunitaire, facteur connu de progression du PDAC. [...]PI3Ks are enzymes that catalyse the phosphorylation of inositol phospholipids in the 3-position of the inositol ring. These substrates and products are involved in multiple cellular processes such as cell growth, proliferation, cell motility and cellular trafficking. In mammals, there are 8 isoforms of PI3Ks and they are grouped into three classes (class I, II and III) depending on their structure and substrate specificity. Class I PI3Ks are the best characterised and the most commonly implicated in cancer. Current evidence on the oncogenic roles of class II and class III PI3Ks is limited. The PI3K/Akt signalling pathway is frequently hyperactivated in cancers and is usually correlated to a poor prognosis, particularly in pancreatic ductal adenocarcinoma (PDAC). More than 90% of PDAC cases are driven by activating mutations in Kras, which then activate downstream effector-signalling pathways, including the PI3K pathway. PDAC is one of the most lethal cancers, characterised by a late-stage diagnosis, a rapid progression and limited therapeutic options. There is a dire need to find new biomarkers and to design novel therapeutics for PDAC management. Previous studies from the team demonstrated that PI3Kalpha, a class I PI3K, is crucial in the initial stages of PDAC. Nonetheless, its role during PDAC progression remains unknown. My PhD aims to elucidate PI3K signalling dynamics in PDAC. I focused on characterising the role of PI3Kalpha in PDAC progression and on determining its suitability as a therapeutic target. Additionally, I show preliminary data on the role of Vps34, a class III PI3K, in acinar cell physiology and its possible role in pancreatic carcinogenesis. The pharmacological and genetic inactivation of PI3Kalpha in vitro demonstrate that this PI3K isoform regulates parameters that drive pancreatic tumour cell progression regardless of oncogenic mutations. These effects are organ-specific; depending on the organ context, another class I PI3K isoform could drive the cancer progression. These results were then validated in vivo in the KPC mouse model used for preclinical testing of PDAC. KPC mice with high levels of cfDNA and a detected tumour via ultrasound imaging were treated with the PI3Kalpha-specific inhibitor, BYL-719. Likewise, I compared the pharmacological inhibition of PI3Kalpha with the genetic inactivation of PI3Kalpha in the pancreatic epithelium of KPC mice. Targeting PI3Kalpha in vivo, pharmacologically and genetically, decreases tumour volume, increases life expectancy and delays metastatic dissemination. To further support the anti-metastatic effect of PI3Kalpha, a tail vein assay was performed and the mice were also given BYL-719. This last experiment reproduced the previous results obtained with the other mouse models, reinforcing the role of PI3Kalpha in decreasing metastatic dissemination. Besides delaying metastatic dissemination, PI3Kalpha also decreased the infiltration of protumoral macrophages, suggesting a role for this isoform in shaping the immune response. [...]
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Abualainin, Wafa. "Evaluation of UHRF1 expression in pancreatic cancer." Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2003401/.
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The ubiquitin-like with PHD and ring finger domains 1 (UHRF1) is a DNA binding protein, involved in epigenetic regulation. UHRF1 expression varies in different cancers, and its role in pancreatic ductal adenocarcinoma (PDAC) is unknown. PDAC is a devastating disease with an overall 5-year survival rate of less than 5 %. Here we report that UHRF1 is frequently overexpressed in PDAC and negatively regulates Keap1, an important component of the Nrf2-mediated cellular stress response pathway. UHRF1 was expressed in 114 of 132 (86%) pancreatic tumours, was associated with larger tumour size (p= 0.02) and had higher expression in tumours compared to matched preneoplastic (PanIN) lesions (n=9). UHRF1 expression varied at different phases of the cell cycle with a peak level at G2/M. Moreover, siRNA-mediated depletion of UHRF1 was associated with a G2/M phase block and induced apoptosis. UHRF1 protein expression levels varied in different PDAC cell lines and reflected the DNA methylation levels in examined sequences. UHRF1 knockdown reduced global DNA methylation in LINE-1 and Alu-V repetitive elements and tumour suppressor-specific (p16Ink4a and RASSF1) promoter methylation. Combining UHRF1 knockdown with 5-aza-deoxycytidine treatment resulted in restoration of P16 levels compared to controls siRNA samples. KEAP1 expression loss was previously reported in ~70 % of PDAC cases. Here we established that the Keap1 promoter is hypermethylated in pancreatic cancer cells. UHRF1 knockdown was accompanied by a reduction in Keap1 promoter methylation, restoration of KEAP1 protein, loss of NRF2 protein and corresponding loss of NRF2 downstream gene expression. We showed strong evidence that Keap1 expression is regulated by its promoter methylation, as KEAP1 expression was restored following 5-aza-deoxycytidine treatment. In PDAC tumour specimens (n=124), an inverse relationship between UHRF1 and KEAP1 expression was observed (p=0.002). In summary, we have shown a role for UHRF1 in pancreatic cancer growth and promoter methylation. Moreover, we have discovered an important function for UHRF1 in controlling KEAP1 expression and consequently regulating the KEAP1/NRF2 stress response pathway.
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Smeenk, Henri Gerard. "Surgical and adjuvant treatment of pancreatic cancer." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008. http://hdl.handle.net/1765/13713.
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Stack, Christianna Otey Carol A. "The role of palladin in pancreatic cancer." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,2072.
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Thesis (M.S.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Feb. 17, 2009). "... in partial fulfillment of the requirements for the degree of Master of Science in the Department of Cell and Molecular Physiology." Discipline: Cell and Molecular Physiology; Department/School: Medicine.
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Melling, J. "Mechanisms of gemcitabine resistance in pancreatic cancer." Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3012781/.
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Valetti, Sabrina. "Targeted squalenoyl nanomedicines for pancreatic cancer treatment." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA114805/document.
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Le cancer pancréatique représente la cinquième cause de décès par cancer dans les pays occidentaux. Son mauvais pronostic (survie à 5 ans inférieure à 3,5 % des cas) est dû à l’absence de facteurs de risques spécifiques interdisant une prévention efficace, et à un diagnostic tardif qui révèle un cancer agressif chez environ 90% des patients. Actuellement, le seul traitement curatif de ce cancer est la chirurgie, mais celle-ci ne peut être envisagée que dans 10 à 15 % des cas. L’adressage de molécules thérapeutiques vers l’organe, le tissu ou la cellule malade constitue aujourd’hui un défi majeur pour le traitement des maladies humaines notamment infectieuses, cancéreuses ou d’origine génétique. C’est pour ces raisons que le développement de nanotechnologies, en tant que vecteurs de médicaments, a pris un essor considérable au cours des dernières années. Dans ce contexte, le concept de squalènisation repose sur le couplage chimique entre le squalène (SQ), un lipide naturel précurseur de la synthèse du cholestérol, et des principes actifs (notamment des molécules anticancéreuses). Les bioconjugués ainsi formés sont alors capables de s’auto-assembler en solution aqueuse pour former des nanoparticules stables de diamètres compris entre 100 et 300 nm. L’exemple de référence dans ce domaine est la nanoparticule de gemcitabine-squalène (SQdFdC) qui a donné lieu à des résultats spectaculaires in vitro sur des lignées de cellules cancéreuses humaines In vivo, les nanoparticules de gemcitabine-squalène se sont avérées beaucoup plus efficaces que la gemcitabine libre sur des tumeurs solides greffées par voie sous-cutanée ainsi que sur des modèles murins de leucémies agressives métastatiques.Au vu de ces résultats encourageants, le projet de thèse a été développé autour de deux axes de recherche. (I) Dans un premier temps, les nanoparticules de gemcitabine-squalène ont été fonctionnalisées par un peptide capable de reconnaître et de cibler spécifiquement les cellules cancéreuses pancréatiques. (II) Le deuxième axe de recherche a visé l’encapsulation d’un second principe actif au sein des nanoparticules de gemcitabine-squalène afin de développer le concept de nanoparticule « multi-thérapeutique »Pancreatic cancer is a lethal disease with the worst prognosis among all solid tumors. In the last decades, progresses in pancreatic cancer therapy had remained exceedingly slow and disappointing offering minimal benefits in median survival which remains of less than 6 months and the maximum of 5 years in the 6% of patients. One of the major requirements for a successful cancer therapy is its ability to selectively kill cancer cells with minimal damage to healthy tissues. In this context, a great deal of attention focused on advanced nanoscale systems (i.e., nanomedicines) with the aim to overcome the limits associated to the traditional drug delivery modalities. Nanomedicines can indeed enhance drug properties by (i) offering protection from degradation, (ii) enabling controlled release and distribution and increasing bioavailability while reducing undesired side effects.In the current work we aimed to propose novel nanoscale-based strategies to optimize pancreatic cancer treatment taking into account the specific physio-pathology of this tumor. The first approach relied on the design of a targeted nanomedicine able to specifically bind receptors mainly expressed onto pancreatic cancer cells in order to selectively increase drug accumulation in these cells saving healthy ones.In a second approach, by combining two therapeutic agents in the same nanoparticle we constructed a multi-therapeutic drug delivery system capable to increase the therapeutic index of the combined therapy. In particular, taking advantages from the “squalenoylation prodrug approach”, the research activity of this Ph.D. work lead to the to design of (i) a novel peptide-functionalized squalenoyl gemcitabine nanoparticle and (ii) a tyrosine kinase inhibitor-loaded squalenoyl gemcitabine nanoparticle. Obtained nanoparticles were investigated with respect to their physico-chemical properties and in vitro antitumor activity. The efficacy of peptide-functionalized nanoparticles in impairing tumor growth was assessed in vivo on an experimental model of pancreatic cancer
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Lewis, Sylvester. "Dissertation: Sociodemographics and Pancreatic Cancer Survival Rate." ScholarWorks, 2018. https://scholarworks.waldenu.edu/dissertations/5745.
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Pancreatic carcinoma or pancreatic cancer (PaCa) is an insidious disease with a prognosis of 6- to 12-month survival time for a late stage diagnosis. This problem has become crucial given that no study to date had been able to establish a definitive association between independent factors (other than a few diseases) and the survival rate of pancreatic cancer. The purpose of this quantitative, cross-sectional study was to determine whether an association exists between the independent, sociodemographic variables (marital status, age, education, income, and employment) and the outcome variable of survival rate. The social cognitive theory was the framework that provided the blueprint throughout the development of this study and helped guide the analysis of the secondary data, which was procured from the surveillance, epidemiology, and end results program. The sample of 56,166 participants was collected from 2009 to 2013 and Cox proportional hazard was used to analyze the data and arrive at the answers to the research hypotheses. A Cox proportional hazard model was used to analyze whether an association existed between each of the independent variables and the outcome variable. The analysis showed significant association between age, education, income, and employment and survival rate. It was not the same for marital status. These findings could stimulate social change by allowing stakeholders and other policy makers to become aware of the role that sociodemographic factors can play in health care. In addition, a need exists for effective research to be undertaken in the prevention and intervention of this disease. This could then lead to private and public health innovations and procedures to benefit patients with PaCa.
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Emmanouilidi, Aikaterini. "Investigation of Novel Biomarkers for Pancreatic Cancer." Thesis, Curtin University, 2019. http://hdl.handle.net/20.500.11937/78328.
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Pancreatic ductal adenocarcinoma (PDAC) is a disease with dismal prognosis and an 8% chance of survival 5 years post-diagnosis, and is very challenging diagnostically and therapeutically. Exosomes are nanometre-sized vesicles known to mediate cancer spread and chemotherapy resistance. In this study, a comprehensive proteomic and lipidomic analysis of PDAC-derived exosomes has been performed. A specific enrichment of key signalling proteins and lipids with a potential role in PDAC progression has been identified.
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Abozeid, Mohamed. "Imaging and Radio-immunotherapy of pancreatic cancer." Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3422678.
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Background
The aims of this study are imaging and Radio-immunotherapy (RIT) of pancreatic cancer through the development of new target-specific radiopharmaceuticals based on mAb directed to prostate stem cell antigen (PSCA) and Mesothelin antigen, which are heavily overexpressed in this tumor histotype.
Methods
Flow cytometry studies were carried out in order to confirm the ability of both anti-APSCA (APSCA) and anti-mesothelin (AM) mAbs to recognize the specific antigen receptors PSCA and mesothelin on the surface of the malignant cells. Two tumor cell lines were used, the human pancreatic adenocarcinoma T3M4 cell transduced or not to express PSCA receptors (T3M4-PSCA) and the embryonic human kidney 293-cell transduced or not to express mesothelin receptors (293-Meso).
Cytometry studies were done to identify the expression of PSCA and Mesothelin antigen on the cell surface. First, both mAbs conjugated to Alexa 680 using the SAIVI rapid antibody labelling kit, the labelled products was purified and the labelling degree and protein concentration were determined by absorbance. Then, 3x105 cells were stained with 1 µg of Alexa 680-APSCA or Alexa 680-AM mAbs to be analysed using a FACS Calibur flow cytometry.
Optical imaging studies were performed in mice to confirm the ability of both mAbs to identify specifically the antigens in vivo.
Direct labelling of APSCA and AM mAbs was performed by reduction of mAb disulphide bridges with 2-mercaptoehanol (2-ME). Reduced mAbs were radiolabeled by the addition of eluted 99mTc-pertechnetate to mAb, followed by the reducing agent SnCl2. The preparation was incubated at room temperature and gently mixed. Radiochemical purity (RCP) analyses were performed using radio-HPLC and stability was tested after dilution in different solutions at different ratios.
Conjugations of DOTA were done by incubation of p-SCN-Bz-DOTA to APSCA and AM mAbs, then characterization studies of DOTA conjugates were done using size exclusion HPLC. Conjugated mAbs were indirectly radiolabelled with Lutetium-177 177(Lu), incubated at 37oC and labelling efficiency (LE) was evaluated. Stability against dilution and transchelation were also assessed at different time points by size exclusion HPLC and ITLC-SG.
Results and conclusions
AM and APSCA mAbs that efficiently detected pancreatic cancer cells in vitro and in vivo were successfully labeled using direct and indirect methods with 99mTc and 177Lu, respectively. All the resulting compounds were prepared by rapid simple methods and demonstrated high RCP, high in vitro stability and high in vitro binding specificity. Therefore, our results are highly encouraging and open additional opportunities for further in vivo studies to assess such mAbs as novel imaging diagnostic and effective therapeutic tools in pancreatic cancer.Gli obiettivi di questo studio sono l'imaging e la radioimmunoterapia (RIT) del cancro del pancreas attraverso lo sviluppo di nuovi radiofarmaci target-specifici basati su mAb diretti all'antigene della prostata staminale prostatica (PSCA) e all'antigene della mesotelina, che sono fortemente sovraespressi in questo istotipo tumorale . Gli mAb AM e APSCA che hanno rilevato in modo efficiente le cellule di cancro al pancreas in vitro e in vivo sono stati etichettati con successo usando metodi diretti e indiretti con 99mTc e 177Lu, rispettivamente. Tutti i composti risultanti sono stati preparati con metodi semplici rapidi e hanno dimostrato un alto RCP, elevata stabilità in vitro ed elevata specificità di legame in vitro. Pertanto, i nostri risultati sono altamente incoraggianti e aprono ulteriori opportunità per ulteriori studi in vivo per valutare tali mAb come nuovi strumenti diagnostici per immagini e strumenti terapeutici efficaci nel cancro del pancreas.
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Rigg, Anne Sagar. "Gene therapy for human cancer." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341902.
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Alldinger, Ingo, Dag Dittert, Matthias Peiper, Alberto Fusco, Gennaro Chiappetta, Eike Staub, Matthias Löhr, et al. "Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-136495.
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Background: Pancreatic cancer is one of the leading causes of cancer-related death. Using DNA gene expression analysis based on a custom made Affymetrix cancer array, we investigated the expression pattern of both primary and established pancreatic carcinoma cell lines. Methods: We analyzed the gene expression of 5 established pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2 and HPAF II) and 5 primary isolates, 1 of them derived from benign pancreatic duct cells. Results: Out of 1,540 genes which were expressed in at least 3 experiments, we found 122 genes upregulated and 18 downregulated in tumor cell lines compared to benign cells with a fold change > 3. Several of the upregulated genes (like Prefoldin 5, ADAM9 and E-cadherin) have been associated with pancreatic cancer before. The other differentially regulated genes, however, play a so far unknown role in the course of human pancreatic carcinoma. By means of immunohistochemistry we could show that thymosin [β-10 (TMSB10), upregulated in tumor cell lines, is expressed in human pancreatic carcinoma, but not in non-neoplastic pancreatic tissue, suggesting a role for TMSB10 in the carcinogenesis of pancreatic carcinoma. Conclusion: Using gene expression profiling of pancreatic cell lines we were able to identify genes differentially expressed in pancreatic adenocarcinoma, which might contribute to pancreatic cancer developmentDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Alldinger, Ingo, Dag Dittert, Matthias Peiper, Alberto Fusco, Gennaro Chiappetta, Eike Staub, Matthias Löhr, et al. "Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer." Karger, 2005. https://tud.qucosa.de/id/qucosa%3A27709.
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Background: Pancreatic cancer is one of the leading causes of cancer-related death. Using DNA gene expression analysis based on a custom made Affymetrix cancer array, we investigated the expression pattern of both primary and established pancreatic carcinoma cell lines. Methods: We analyzed the gene expression of 5 established pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2 and HPAF II) and 5 primary isolates, 1 of them derived from benign pancreatic duct cells. Results: Out of 1,540 genes which were expressed in at least 3 experiments, we found 122 genes upregulated and 18 downregulated in tumor cell lines compared to benign cells with a fold change > 3. Several of the upregulated genes (like Prefoldin 5, ADAM9 and E-cadherin) have been associated with pancreatic cancer before. The other differentially regulated genes, however, play a so far unknown role in the course of human pancreatic carcinoma. By means of immunohistochemistry we could show that thymosin [β-10 (TMSB10), upregulated in tumor cell lines, is expressed in human pancreatic carcinoma, but not in non-neoplastic pancreatic tissue, suggesting a role for TMSB10 in the carcinogenesis of pancreatic carcinoma. Conclusion: Using gene expression profiling of pancreatic cell lines we were able to identify genes differentially expressed in pancreatic adenocarcinoma, which might contribute to pancreatic cancer development.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Amr, Bassem Ismail Metwaly Ismail. "Aspects of the preoperative pathway in pancreatic head malignancy." Thesis, University of Plymouth, 2018. http://hdl.handle.net/10026.1/12167.
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Malignancy within the pancreatic head can arise from pancreatic duct, distal bile duct, ampulla or duodenum. Since September 2000, surgery for all pancreatic head malignancy (PHM) has been centralised into regional pancreatic centres where assessment of preoperative imaging and subsequent surgery is undertaken. As part of this guidance, surgery must be performed within 62-days of referral. This project will assess four aspects of the pre-operative pathway in PHM: 1) Potential variation in outcome of patients referred from different sites within a Cancer Network 2) Potential variation in outcome associated with different intervals to surgery within the 62 day guideline 3) The ability of interpretation of heterogeneous pre-operative CT scans from different hospitals to determine the resectability of PHM 4) The ability of CT scan to distinguish the different tumour types of PHM Images of a consecutive series of patients were re-reported and compared with final pathology reports. Good agreement was noted in determining the tumour origin of PHM (observed agreement = 0.758, Kappa= 0.6 (0.51-0.68)). In the assessment surgical outcomes, geographical isolation from the regional centre was not associated with delay to surgery. Variation in outcome between referral centres was however noted but this was not associated with travel distance. Although little association was noted between delay to surgery and outcome overall, a paradoxical improvement in survival was noted however for the small group of patients with ampullary tumours who waited longer than the median interval to surgery.
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Sasaki, Naoya. "Alpha-fetoprotein-producing pancreatic cancer cells possess cancer stem cell characteristics." Kyoto University, 2012. http://hdl.handle.net/2433/157414.
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Mège, Diane. "Microparticles in colorectal and pancreatic cancers." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM5038.
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Le cancer colorectal (CRC) est le plus fréquent des cancers digestifs. Cependant, il est moins grave et moins fréquemment associé à une complication thrombo-embolique que le cancer du pancréas (PC). Les microparticules (MPs) sont de petites vésicules produites par bourgeonnement de la membrane cellulaire. Les MPs sont impliquées dans la croissance tumorale, le développement de métastases et l’activité pro-coagulante associée aux cancers. Les objectifs de ces travaux étaient d’identifier et de caractériser les différentes MPs dans le CRC and le PC, afin de décrire une signature microparticulaire, puis d’évaluer leur implication dans la survenue de complications thrombo-emboliques. Nous avons donc rapporté une signature microparticulaire spécifique dans le CRC et le PC par rapport à des pathologies bénignes colorectales et pancréatiques, ainsi que des sujets sains, que nous avons appelé “microparticulosome”. Le microparticulosome se modifie avec l’évolution de la maladie, pour se rapprocher des formes bénignes voire des sujets sains, en cas de rémission du CRC. De plus,il varie en présence ou non d'une complication thrombo-embolique. Nous avons également rapporté le cas d’un cancer du sein diagnostiqué grâce à des taux élevés de MPs exprimant la fibrine. En conclusion, les MPs pourraient constituer de nouveaux bio-marqueurs pertinents en cancérologie, dans le diagnostic, le pronostic de survie et de survenue d’une complication thrombo-embolique. La connaissance des interactions des MPs avec le microenvironnement tumoral permettra de mettre au point des thérapeutiques adaptées et efficaces dans la croissance tumorale et l’extension métastatiqueColorectal cancer (CRC) is the most common gastrointestinal cancer. It is less serious and less frequently associated with thrombo-embolic event than pancreatic cancer (PC). Microparticles (MPs) are small vesicles produced and released by exocytic blebbing of the activated and apoptotic cell membrane from most, if not all, types of cells. They are known to be implicated in the tumor growth, the development of metastases and the cancer-associated procoagulant activity. Our objectives were to identify and to characterize the different concentrations of circulating MPs in CRC and PC, in order to describe a MPs hallmark, and to evaluate their implication in the occurrence of a venous thromboembolism. We have thus reported a specific hallmark of MPs in CRC and PC, comparing to benign colorectal and pancreatic diseases and healthy subjects, so-called the “microparticulosome”. We have observed that microparticulosome changed with the evolution of the disease, and tended to the signature observed for benign diseases or healthy subject in case of CRC remission. We also reported variations in the microparticulosome in case of an occurrence of a thrombo-embolic event.In conclusion, MPs may constitute new pertinent biomarkers in cancers, in the diagnosis, the survival prognostic and the prognostic of the occurrence of thrombo-embolic events. Understanding the interactions of MPs with tumor environment will allow to find efficient treatments against tumor growth and metastases development
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Kadaba, Raghunandan. "Desmoplastic stromal cells modulate tumour cell behaviour in pancreatic cancer." Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8825.
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Pancreatic ductal adenocarcinoma (PDAC) is characterised by an intense desmoplastic stromal response that can comprise 60 to 80% of tumour volume and has been implicated to be a factor in promoting tumour invasiveness and the poor prognosis associated with this cancer type. It is now well established that pancreatic stellate cells, which are vitamin A storing cells found in the periacinar spaces of the stroma in the normal gland, are primarily responsible for this desmoplastic reaction. Studying the interaction between stellate cells and cancer cells could provide for a better understanding of the disease process. During the evolution of PDAC, the stromal proportion increases from 4% in the normal gland to up to 80%. We hypothesised that there is an optimal proportion of stellate cells and cancer cells that modulates tumour behaviour and we attempted to dissect out this probable ‘tipping point’ for stromal composition upon cancer cell behaviour using a well-established in vitro organotypic culture model of pancreatic cancer. The cancer cell-stromal cell interaction led to extra-cellular matrix contraction and stiffening; and an increase in cancer cell number. The stromal stellate cells conferred a pro-survival and pro-invasive effect on cancer cells which was most pronounced at a stellate cell proportion of 0.66-0.83. The expression of key molecules involved in EMT and metastasis such as E-Cadherin and β-catenin showed a reduction and this was found to be most significant again at a stellate cell proportion of 0.66-0.83. Stellate cells altered the genetic profile of cancer cells leading to differential expression of genes involved in key cellular pathways such as cell-cycle and proliferation, cell movement and death, cell-cell signalling, and inflammatory response. qRT-PCR confirmed the differential expression of the top differentially expressed genes and protein validation by immunofluorescence staining using PIGR as a candidate molecule confirmed the experimental findings in human PDAC specimens. This study demonstrates that the progressive accumulation of desmoplastic stromal cells has a tumour progressive (pro-survival, pro-invasive) effect on cancer cells in addition to stiffening (contraction) of the extracellular matrix (maximum effect when the stromal cell proportion is 60-80%). This is mediated through a number of signalling cascades and molecular targets. Dampening this tumour-promoting interaction between cancer and stromal cells by ‘multi-targeting’ agents may allow traditional chemo- and/or radiotherapy to be effective.
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Lo, Maisie K. Y. "Role of transporters in pancreatic cancer drug resistance." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/361.
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Pancreatic cancer (PC) is known to be highly resistant to chemotherapy. Transporters, which regulate the influx and efflux of substrates across the plasma membrane, may play a role in PC drug resistance. ABC transporters are a large family of transmembrane proteins with diverse physiological functions, several of which play major roles in cancer drug resistance. Given that 90% of PC express a mutant K-ras oncogene and that PC are highly hypoxic, I postulated that constitutive K-ras activation and/or hypoxia may correlate with ABC transporter expression, which in turn may promote drug resistance in PC. Using normal and PC cell lines either overexpressing mutant K-ras or subjected to hypoxic treatment, mRNA expression was profiled for 48 ABC transporters. My findings indicate that expression of mutant K-ras and hypoxic treatment, as well as long-term exposure to chemotherapy, may contribute to the development of drug resistance in PC cells in part by inducing the expression of ABC transporters.
Similar to ABC transporters, I investigated whether amino acid transporters would mediate drug resistance in PC. The xc" amino acid transporter (xc") mediates cellular uptake of cystine for the biosynthesis of glutathione, a major detoxifying agent. Because the xc" has been regulates the growth of various cancer cell types, and x," is expressed in the pancreas, I postulated that the xc" may be involved in growth and drug resistance in PC. The xc" transporter is differentially expressed in normal pancreatic tissues and is overexpressed in PC in vivo. UsingPC cell lines, I found that cystine uptake via the N.: was required for growth and survival in response to oxidative stress, and that expression of the xc" correlated with gemcitabine resistance. Accordingly, inhibition of xc" expression via siRNA reduced PC cell proliferation and restored sensitivity to gemcitabine. I also identified the anti-inflammatory drug sulfasalazine as a mixed inhibitor of the x,-, which acts to inhibit cell proliferation via reducing xc" activity and not by reducing NFKB activity. My findings thus indicate that the xc" plays a role in PC growth in part by contributing to glutathione synthesis to promote PC cell proliferation, survival, and drug resistance.
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Bassagañas, i. Puigdemont Sònia. "Regulation and function of silayltransferases in pancreatic cancer." Doctoral thesis, Universitat de Girona, 2014. http://hdl.handle.net/10803/285783.
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Changes in the expression of Lewis-type glycan antigens, especially a predominance of sialyl-Lewis x (SLex) structure, and the glycosyltransferases involved in its synthesis, correlate with pancreatic cancer invasive and metastatic capacities. This Doctoral Thesis has focused on the involvement of sialylated determinants on key stages of pancreatic cancer tumourigenesis, such as cell-extracellular matrix adhesion and cell-cell adhesion, and invasion; and also on the influence of glycosylation on the function of membrane glycoproteins involved in these processes, such as α2β1 integrin and E-cadherin.In addition, this study also describes that pancreatic tumour cells take advantage of the inflammatory environment that accompanies the tumour.It shows that proinflammatory cytokines regulate the cell expression of specific sialyltransferase and fucosyltransferase genes that contribute to the biosynthesis of Lewis-type and sialylated determinants, and thus may contribute to accelerate the tumour progression.S’ha descrit que canvis en l’expressió d’antígens glucídics tipus Lewis, especialment un predomini de l’estructura sialil-Lewis x (SLex), així com de les glicosiltransferases implicades en la seva síntesi, correlacionen amb la seva capacitat invasiva i metastàtica. En aquesta Tesi Doctoral s’ha aprofundit en l’estudi de la implicació dels determinants sialilats en etapes clau del procés tumorogènic del càncer de pàncrees, com són els processos d’adhesió cèl·lula-matriu extracel·lular i cèl·lula-cèl·lula, i la invasió, estudiant també la influència de la glicosilació en la funció de glicoproteïnes de membrana involucrades en aquests processos, com la integrina α2β1 i la E-cadherina. Alhora es posa de manifest que les cèl·lules tumorals de càncer de pàncrees treuen profit de les característiques de l’ambient inflamatori que acompanya el tumor, ja que les citoquines presents en l’estroma regulen l’expressió cel·lular dels gens involucrats en la biosíntesi dels antígens tipus Lewis i sialilats.
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Storey, Rowland Lewis. "NMR-based metabonomic studies of human pancreatic cancer." Thesis, University of Leeds, 2016. http://etheses.whiterose.ac.uk/13491/.
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Pancreatic cancer is one of the most fatal malignancies in the world with an overall 5-year survival rate of less than 5%. Diagnosing pancreatic cancer is not always straightforward. Clinical imaging of the pancreas can be misleading and currently available clinical biomarkers are few and lack sensitivity and specificity. Obtaining tissue or cytology from the pancreaticobiliary system to confirm a diagnosis is clinically invasive and may be inconclusive. Further non-invasive diagnostic biomarkers are clearly required. I describe the feasibility of nuclear magnetic resonance (NMR) spectroscopy as a modality for novel plasma and urine pancreaticobiliary biomarker discovery Plasma and urine samples from 44 patients undergoing pancreatic resection for pancreaticobiliary malignancy along with a benign cohort of 45 patients were acquired. Spectra were obtained on a Varian NMR 500 MHz spectrometer. Unsupervised and supervised multivariate pattern recognition techniques were used for chemometric analysis. Model validation was assessed through permutation and cross validation techniques Plasma metabonomic profiling identified clear separation between malignant and benign pancreaticobiliary disease with an overall sensitivity and specificity of 64.9 and 73.5% respectively. Sensitivity and specificity among non-jaundiced patients rose to 75 and 75.8% respectively. Suppressed metabolites among cancer patients included VLDL, valine and acetate. Up- regulated metabolites included isobutyrate, 3-hydroxybutyrate, lactate, acetoacetate, pyruvate, glucose and taurine. Urinary metabonomic profiling failed to satisfactorily discriminate between benign and malignant disease. Plasma nuclear magnetic resonance metabonomic profiling has significant potential for future pancreaticobiliary biomarker development. Plasma bilirubin is an important confounding factor, which must be accounted for in all future pancreaticobiliry metabonomic studies.
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Segara, Davendra St Vincents Hospital Clinical School UNSW. "Studies of retinoic acid signalling in pancreatic cancer." Awarded by:University of New South Wales. St Vincents Hospital Clinical School, 2006. http://handle.unsw.edu.au/1959.4/26269.
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Pancreatic cancer (PC) is the fourth leading cause of cancer death in Western societies. Despite significant progress in understanding the molecular pathology of PC and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility. Affymetrix Genechipfi oligonucleotide microarrays were used to interrogate mRNA expression of PC and normal pancreas to identify molecular pathways dysregulated in PC. Analysis of these data identified altered expression of numerous components of the S100 Calcium Binding Protein Family, Retinoic Acid signalling pathway and the HOX transcriptional network in PC compared to normal pancreas. These pathways were assessed using immunohistochemistry (IHC) and in-situ hybridisation (ISH) in a cohort of patients with PC. Increased protein expression, of S100A2, S100A6 and S100P was observed in 43%, 60% and 48% of PC respectively. Expression of S100A2 was associated with a poor outcome (p = 0.009), whilst increased expression of S100A6 (p = 0.0008) and S100P (p = 0.0005) were associated with an improved outcome. Additionally, S100A2 expression was identified as an independent marker of outcome in resected tumours. Aberrant expression of retinoic acid signalling components was demonstrated in PC cell lines using semi-quantitative RT-PCR. ISH demonstrated expression of Retinoic Acid Induced 3 (RAI3), an orphan G protein coupled receptor normally expressed in the fetal lung, in 68% of PC, and this co-segregated with an improved overall survival (p = 0.026).Ectopic protein expression of HOXB2, a transcription factor normally expressed in the developing hindbrain and modulated by retinoic acid, was observed in 15% of early PanIN lesions and 38% of PC specimens. Expression of HOXB2 was associated with non-resectable tumours and was an independent predictor of poor survival in resected tumours. Suppression of HOXB2 protein expression using small interfering RNA, resulted in epithelioid trans-differentiation in the Panc-1 PC cell line, however no alteration in proliferation rates were observed compared to controls. This thesis has shown that transcript profiling and tissue validation has identified potential markers of early diagnosis and outcome in PC. Furthermore, pathways and molecules previously thought to be associated with normal human development have been implicated to play a role in the development and progression of PC. Further analyses of these markers will determine any potential role in future diagnostic and therapeutic strategies.
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Warner, Steven Lawrence. "Targeting the Aurora Kinases to Treat Pancreatic Cancer." Diss., Tucson, Arizona : University of Arizona, 2005. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1291%5F1%5Fm.pdf&type=application/pdf.
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Tascilar, Metin. "Clinical significance of molecular markers in pancreatic cancer." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2002. http://dare.uva.nl/document/61858.
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Heijden, Michiel Simon van der. "The Fanconi anemia/BRCA2 pathway in pancreatic cancer." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2005. http://dare.uva.nl/document/79702.
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Hiley, Crispin. "Arming vaccinia virus for pancreatic cancer oncolytic virotherapy." Thesis, Queen Mary, University of London, 2011. http://qmro.qmul.ac.uk/xmlui/handle/123456789/2344.
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Vaccinia virus is a 250-300nm enveloped DNA virus from the poxvirus family and is used as a vector for oncolytic viral gene therapy. No unique cell surface receptor has been identified for Vaccinia virus and the reasons for its tropism for cancer cells are unclear. Pancreatic adenocarcinoma (PDAC) is resistant to conventional chemotherapy and typically contains areas that are profoundly hypoxic. We have investigated the utility of Vaccinia virus as a vector for targeting hypoxic regions in pancreatic adenocarcinoma, as other viral vectors have been found to replicate poorly in hypoxia. We found that cytotoxicity was equivalent in normoxia and hypoxia in some PDAC cell lines but in others cytotoxicity was enhanced in hypoxia. This increase in cytotoxicity was only seen in cell lines where there was hypoxic induction of vascular endothelial growth factor (VEGF). Functional studies using over-expression and knockdown of VEGF in pancreatic cancer cell models showed that VEGF can augment viral transgene expression, cytotoxicity and replication in vitro and in vivo. We found that VEGF facilitates the internalisation of Vaccinia virus. These results show that VEGF is an additional factor involved in the tropism and pathogenesis of Vaccinia virus. We then constructed an oncolytic Vaccinia virus to target hypoxic cancer cells using the HIF-1α oxygen degradation domain, encephalomyocarditis virus internal ribosomal entry site and the VEGF 3‟ un-translated region to regulate luciferase expression in hypoxia. We have shown a dose-, time- and oxygen-dependent effect using this construct and propose this may be adapted to regulate therapeutic genes, or produce a conditionally replicating Vaccinia virus, in hypoxic conditions.
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Kaur, Anuvinder. "Innate immune surveillance in ovarian and pancreatic cancer." Thesis, Brunel University, 2017. http://bura.brunel.ac.uk/handle/2438/15847.
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Activation of innate immune surveillance mechanisms during the development of cancer is well-documented. However, knowledge of how these innate immune proteins, when added exogenously, independent of tumour microenvironment, affect tumour cells is limited. In Chapter 3, the effects of human C1q and its individual globular domains (ghA, ghB and ghC) on an ovarian cancer cell line, SKOV3, have been examined. C1q and globular head modules induced apoptosis in approximately 55% of cells, which involved upregulation of TNF-α and Fas and activation of the caspase cascade. This occurred in parallel to the downregulation of mTOR, RICTOR and RAPTOR survival pathways, which are often over-expressed in the majority of the cancers. Thus, this study provided evidence for another complement-independent role of C1q. The second part of this thesis was to investigate the effect of Human Surfactant Protein-D (SP-D), which is known to modulate secretion of a range of cytokines and chemokines by effector immune cells, such as TNF-a and TGF-β, at mucosal surfaces during infection and inflammation. Our hypothesis was that SP-D can influence these soluble factors as a part of its putative role in the immune surveillance against pancreatic cancer, where the inflammatory tumour microenvironment contributes to the epithelial-to-mesenchymal transition (EMT) invasion and metastases. In this study, a recombinant fragment of human SP-D (rfhSP-D) inhibited TGF-β expression in a range of pancreatic cancer cell lines, thereby reducing their invasive potential by downregulating Smad2/3 expression that may have interrupted signal transduction negatively, which affected the transcription of key mesenchymal genes such as Vimentin, Zeb1 and Snail. Furthermore, prolonged treatment with rfhSP-D induced apoptosis in the pancreatic cancer cell lines via activation of the caspase cascade. Thus, this study added another layer to the well-known protective role of SP-D.
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floyd, stuart. "Data Mining Techniques for Prognosis in Pancreatic Cancer." Digital WPI, 2007. https://digitalcommons.wpi.edu/etd-theses/671.
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This thesis focuses on the use of data mining techniques to investigate the expected survival time of patients with pancreatic cancer. Clinical patient data have been useful in showing overall population trends in patient treatment and outcomes. Models built on patient level data also have the potential to yield insights into the best course of treatment and the long-term outlook for individual patients. Within the medical community, logistic regression has traditionally been chosen for building predictive models in terms of explanatory variables or features. Our research demonstrates that the use of machine learning algorithms for both feature selection and prediction can significantly increase the accuracy of models of patient survival. We have evaluated the use of Artificial Neural Networks, Bayesian Networks, and Support Vector Machines. We have demonstrated (p<0.05) that data mining techniques are capable of improved prognostic predictions of pancreatic cancer patient survival as compared with logistic regression alone.
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Manawadu, Harshi Chathurangi. "Design of a nanoplatform for treating pancreatic cancer." Diss., Kansas State University, 2014. http://hdl.handle.net/2097/17736.
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Doctor of PhilosophyDepartment of Chemistry
Stefan H. Bossmann
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the USA. Asymptomatic early cancer stages and late diagnosis leads to very low survival rates of pancreatic cancers, compared to other cancers. Treatment options for advanced pancreatic cancer are limited to chemotherapy and/or radiation therapy, as surgical removal of the cancerous tissue becomes impossible at later stages. Therefore, there's a critical need for innovative and improved chemotherapeutic treatment of (late) pancreatic cancers. It is mandatory for successful treatment strategies to overcome the drug resistance associated with pancreatic cancers. Nanotechnology based drug formulations have been providing promising alternatives in cancer treatment due to their selective targeting and accumulation in tumor vasculature, which can be used for efficient delivery of chemotherapeutic agents to tumors and metastases. The research of my thesis is following the principle approach to high therapeutic efficacy that has been first described by Dr. Helmut Ringsdorf in 1975. However, I have extended the use of the Ringsdorf model from polymeric to nanoparticle-based drug carriers by exploring an iron / iron oxide nanoparticle based drug delivery system. A series of drug delivery systems have been synthesized by varying the total numbers and the ratio of the tumor homing peptide sequence CGKRK and the chemotherapeutic drug doxorubicin at the surfaces of Fe/Fe₃O₄-nanoparticles. The cytotoxicity of these nanoformulations was tested against murine pancreatic cancer cell lines (Pan02) to assess their therapeutic capabilities for effective treatments of pancreatic cancers. Healthy mouse fibroblast cells (STO) were also tested for comparison, because an effective chemotherapeutic drug has to be selective towards cancer cells. Optimal Experimental Design methodology was applied to identify the nanoformulation with the highest therapeutic activity. A statistical analysis method known as response surface methodology was carried out to evaluate the in-vitro cytotoxicity data, and to determine whether the chosen experimental parameters truly express the optimized conditions of the nanoparticle based drug delivery system. The overall goal was to optimize the therapeutic efficacy in nanoparticle-based pancreatic cancer treatment. Based on the statistical data, the most effective iron/iron oxide nanoparticle-based drug delivery system has been identified. Its Fe/Fe₃O₄ core has a diameter of 20 nm. The surface of this nanoparticle is loaded with the homing sequence CGKRK (139-142 peptide molecules per nanoparticle surface) and the chemotherapeutic agent doxorubicin (156-159 molecules per surface), This nanoplatform is a promising candidate for the nanoparticle-based chemotherapy of pancreatic cancer.
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Butler, J. V. "Factors which influence penetrance in familial pancreatic cancer." Thesis, University of Liverpool, 2016. http://livrepository.liverpool.ac.uk/3000838/.
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Introduction: Pancreatic cancer (PDAC) confers a high mortality rate as it often presents at an advanced stage. Screening could improve early detection and survival. However, the prevalence of the disease and absence of specific screening tools mean that screening of the general population would result in many false positive tests. This may mean unnecessary overtreatment including surgery with considerable morbidity. Current screening techniques have associated risks including exposure to radiation and induction of pancreatitis. It is therefore essential to identify high risk screening populations and improve both specificity and safety of the screening modality. The European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) was established to identify individuals with a genetic predisposition for PDAC to offer secondary screening. Thesis Aims: The aims of this thesis were to identify subpopulations of high risk families who are at the greatest risk of pancreatic cancer in order to undertake targeted screening. Furthermore, to minimise the risks and complications to individuals participating in the EUROPAC secondary screening study for early PDAC. Materials and Methods: Familial Pancreatic Cancer (FPC) was defined as autosomal dominant predisposition for PDAC. Hereditary Pancreatitis (HP) is an autosomal dominant predisposition for pancreatitis associated with an approximately 40% life time risk of PDAC. Families with other recognised cancer syndromes conferring a predisposition to PDAC were also recruited. At recruitment, blood samples for DNA storage and cell lines were obtained for the analysis of potential candidate genes implicated in FPC. Individual and familial demographic, lifestyle and disease related data were collected to facilitate analysis of possible risk factors which could influence penetrance in these high risk groups. On confirmation of a familial predisposition, eligible individuals were invited to participate in the EUROPAC secondary screening study for early pancreatic cancer. The screening protocol comprised blood tests and imaging techniques along with analysis of molecular markers in pancreatic juice. Results: 273 potential FPC kindreds were identified and recruited; 89 had 3 or more affected family members. In FPC, age is a major risk factor but the pattern of age related risk is the same as in the general population. However, this is consistently 100 fold greater in FPC. No evidence was found for earlier age of onset in FPC contrary to other reports. Selection bias based on proband is proposed as an explanation for the apparent differences seen in the literature. Reporting bias could also explain the relationship of smoking and PDAC in FPC kindreds. No further causative mutations were found during the preparation of this thesis but a PALB2 mutation was found in three families (possibly associated with breast cancer). A model for risk was proposed, but in this thesis only secondary screening based on previous estimates is described. The methodology involved Endoscopic Retrograde Cholangiopancreatography (ERCP) and 7 cases of pancreatitis resulted. Consequently, stenting and use of diclofenac was introduced resulting in a significant reduction in ERCP associated pancreatitis (3 of 31 screens). Use of secretin to allow sampling of pancreatic juice from the duodenum was also piloted to further improve safety. This thesis provides data to support risk stratification in FPC and an improved screening modality. A total of 212 HP kindreds were identified. A variable clinical picture and cancer risk was found in the HP families with p.R122H, p.N29I and p.A16V all conferring a significantly increased lifetime risk for the development of pancreatic cancer, in addition to the earlier age of onset of exocrine and endocrine failure. Cancer risk was shown to be increased with smoking and diabetes. Risk of PDAC increases with age equally for HP and the general population but was 28 fold higher in each age group with HP. Conclusion: My thesis has identified specific lifestyle and disease derived risk factors which may influence risk for the development of PDAC in high risk groups. As a direct result of this thesis, amendments made to the screening protocol have improved safety and minimised harm to those individuals undertaking screening for early pancreatic cancer under the auspices of EUROPAC.
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Gray, Sophie. "The role of HOX genes in pancreatic cancer." Thesis, University of Surrey, 2015. http://epubs.surrey.ac.uk/807615/.
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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of solid cancer with 5-year survival rates approaching a dismal 5%. Novel therapeutic targets need to be identified thus aiding and assisting the design of treatments which will improve survival rates that have not changed in the last 30 years. Of particular interest are homeobox (HOX) genes, a set of 39 evolutionarily conserved transcription factors involved in embryonic antero-posterior patterning. Although expressed in development, HOX genes have been found to be re-expressed and indeed dysregulated in several types of cancer including lung, breast, ovarian and renal neoplasia. Limited research has been undertaken on the dysregulation of HOX genes in PDAC. HOX genes can be antagonised using HXR9, a peptide which competitively inhibits the interaction between HOX genes and their co-factor PBX, subsequently preventing HOX genes to fulfill their role of transcription factors. Cancer-specific tumour-modelling is fundamental to drug testing. There are few animal models that recapitulate the unique tumour architecture and molecular signature of PDAC, particularly the desmoplastic reaction characteristic of this malignancy. The chorioallantoic membrane (CAM) assay, an in ovo model that utilises the immunologically naive properties of the developing chick embryo to grow a solid tumour derived from pancreatic cancer cell lines. The CAM model is not widely used in pancreatic cancer research and more work is needed to evaluate it’s efficacy for tumour remodelling and subsequent drug testing. We have found that the CAM model is suitable for drug testing as it recapitulates the architecture and molecular signature of PDAC. In order to establish the CAM model as appropriate for drug testing in this context, we assessed whether the mitogen-activated protein kinases (MAPK) pathway was conserved, due to the high frequency of mutational activation of the KRAS gene in this cancer. Global gene expression was also carried out to determine genetic changes between cells grown in vitro and cells in a tumour microenvironment in the CAM model. Experimental design We investigated whether there is a signature HOX gene profile unique to this disease. We measured HOX gene expression by RT-PCR in four well-described pancreatic cancer cell lines. HOX gene expression was also measured in commercially obtained RNA and snap-frozen pancreatic cancer tissue from surgical resections. The CAM model was set up by grafting 4 pancreatic cancer cell lines and tumour architecture and molecular signature was evaluated by H&E staining and IHC. Gene expression was assessed by microarray analysis to compare global gene expression in cell-lines and CAM tumours and conservation of mitogen-activated protein kinases (MAPK) pathway was addressed by western blotting. HOX gene expression was measured by RT-PCR in both cell lines and CAM tumours. Finally, the efficacy of HRX9 was measured by generating IC50s using MTS and LDH assays. Levels of apoptosis were measured in vitro using Annexin-V-PE assay and in vivo by cleaved-caspase activation, assessed by IHC. Results: We found that HOX gene expression was elevated in tumour samples compared with normal tissue and in particular a significantly higher expression of HOXA13 in PDAC samples compared with normal pancreas. This was confirmed at the protein level by Immunohistochemistry (IHC). We also showed that the CAM model is suitable for drug testing as it recapitulates the architecture and molecular signature of PDAC. Results showed that MAPK pathway was conserved, due to the high frequency of mutational activation of the KRAS gene in this cancer. Cleaved-caspase activation also supports the hypothesis that tumour cells are driven into apoptosis upon HXR9 treatment. Conclusions HOX gene expression is highly dys-regulated in pancreatic cancer and more work is need to individually evaluate HOX genes on interest highlighted in this study. HOX gene expression can be antagonised by using HXR9. Finally, we have demonstrated the potential for HOX gene targeting as a novel therapy for PDAC.