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Function of the cell surface receptor component integrin beta1 in human tumour cellsSchooley, Allana M January 2008 (has links)
The work presented herein examines the potential impact of extracellular matrix (ECM) protein-integrin receptor interactions on tumour cell chemotherapeutic sensitivity, proliferation and anchorage-independent growth. First, a screen was performed to assess the impact of ECM proteins on the survival of various tumour cell lines treated with different chemotherapeutic agents, however no significant modulation by ECM was detected. To more specifically understand potential influences of ECM on tumour cell phenotypes, a siRNA approach targeting integrin beta1, an important ECM receptor component, was employed. Integrin beta1 depletion studies conducted in paired cisplatin sensitive and resistant ovarian cancer cells did not support a role for ECM-integrin receptor binding in drug sensitivity. Similarly, reduction of integrin beta1 protein using the siRNA approach did not impact the adhesion or adherent growth of the cancer cell lines studied. However, integrin beta1 was shown to be necessary for the anchorage-independent growth of all tumour cell lines tested in soft agarose colony formation assays. The importance of integrin beta1 for anchorage-independent growth of PC3 cells was further confirmed using both neutralizing antibodies to the receptor subunit and a signaling-impaired splice variant of integrin beta1. Depletion of the integrin ligand, fibronectin, from the tumour cell culture medium similarly reduced soft agarose colony formation, suggesting that ligation of beta1 integrins is necessary for anchorage-independence. Co-immunoprecipitation studies revealed the formation of a de novo interaction between beta catenin and integrin beta1 when tumour cells were transitioned to grow anchorage-independently. These findings suggest a model whereby ligation of the beta1 integrin-containing receptors by soluble fibronectin drives the anchorage-independent growth of tumor cells through a beta catenin signaling pathway.
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Translational Reprogramming by eIF4E in Tamoxifen-Resistant ER+ Breast CancerGeter, Phillip A. 18 April 2018 (has links)
<p> The majority of breast cancers express the estrogen receptor (ER+) and are treated with anti-estrogen therapies, particularly the inhibitor tamoxifen. However, many women treated with tamoxifen develop resistance, leading to metastatic disease, which is responsible for the majority of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen sensitive and resistant breast cancer cells, a patient derived tamoxifen-resistant xenograft model, and genome-wide transcription and translation studies, we show that tamoxifen resistance is mediated by selective mRNA translational reprogramming. Tamoxifen resistant translation is mediated by increased expression of translation factor eIF4E, increased mTOR activity to promote eIF4E availability, and increased MNK activity to promote eIF4E Ser209 phosphorylation. Tamoxifen re-sensitization is restored only by reducing eIF4E expression or mTOR activity and blocking MNK1-directed eIF4E phosphorylation. Of the translationally upregulated mRNAs specific to tamoxifen resistant cells, we show that Runx2, which encodes a regulator of ER signaling that antagonizes estrogen responses and promotes breast cancer metastasis, significantly increases tamoxifen resistance and restores sensitivity when silenced. Moreover, tamoxifen resistant but not sensitive patient ER+ breast cancer specimens demonstrate strongly increased levels of mTOR and MNK activity and eIF4E protein. eIF4E levels, availability and phosphorylation therefore promote tamoxifen resistance in ER+ breast cancer through translatome reprogramming.</p><p>
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Mitochondrial Priming and Anti-Apoptotic Dependencies in Aging and Diseased Bone MarrowHogdal, Leah Justine 02 November 2015 (has links)
This thesis explores two questions; how aging of the hematopoietic stem cell (HSC) may contribute to the increase in hematological malignancies with age and secondly, how hematological malignancies can be better treated when they arise. At the intersection of both of these questions is the mitochondrial apoptotic pathway and the tool, BH3 profiling, which measures the mitochondrial priming and anti-apoptotic dependencies within normal and malignant cells. Mitochondrial priming and anti-apoptotic dependencies are measured by assessing the sensitivity of cellular mitochondria to standardized amounts of BH3 peptides derived from the BH3 domains of pro-apoptotic proteins.
In our first study, we use BH3 profiling to identify anti-apoptotic dependencies to direct treatment of the anti-apoptotic BCL-2 inhibitor ABT-199 in acute myeloid leukemia (AML). We found that AML blasts are often dependent on the pro-survival protein BCL-2 and the mitochondrial dependence on BCL-2 measured by BH3 profiling correlated with cellular sensitivity to ABT-199. These pre-clinical results showed that ABT-199 was functioning on-target at the mitochondria and that BH3 profiling could be used to identify patients who would be most sensitive to BCL-2 inhibition. Importantly, these results directly led to a Phase II clinical trial of ABT-199 in relapsed/refractory AML patients and BH3 profiling was integrated into the study to test its efficacy as a predictive biomarker. In the clinical trial, we showed that BH3 profiling correlated well with clinical response.
Secondly, in our studies of aging in the HSC compartment, we used BH3 profiling to explore how mitochondrial priming is altered during normal hematopoietic differentiation and during differentiation of HSCs isolated from young and old mice. We found that HSCs are less primed than more differentiated progenitor cells and that old HSCs are even less primed than young HSCs which correlates with decreased sensitivity to apoptotic stimuli of old HSCs. These studies expand upon the biological understanding of functional defects of aged HSCs, and showed for the first time in a clinical setting that BH3 profiling may be used successfully to direct treatment of BH3 mimetics in the clinic. / Medical Sciences
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Characterizing Tumor Hypoxia and Anoikis Resistance in Human Osteosarcoma| Addressing Critical Aspects of Disease ProgressionScholten II, Donald Jay 15 July 2017 (has links)
<p> Osteosarcoma (OS) is the most common type of solid bone cancer, mainly arising in children and young adults, and remains the second leading cause of cancer-related death in this age group. Chemotherapy resistance underlying latent recurrence and metastasis represent major contributors to poor outcome for many cancer patients especially those with OS. Tumor hypoxia is an essential element intrinsic to most solid tumor microenvironments and is associated with resistance to therapy and a malignant phenotype, while metastatic dissemination is dependent on a cells ability to resist anoikis, i.e., programmed cell death in the absence of attachment to an extracellular matrix. We sought to better characterize hypoxia and anoikis resistance in human OS using established and novel patient-derived OS cells and OS animal models with the long-term goal of identifying and validating targetable signaling pathways. We show that hypoxia-inducible factors (HIFs), canonical proteins associated with the hypoxic response, are present and can be induced in human OS cells. We demonstrate that the Wnt/β-catenin signaling pathway, a key pathway in OS pathogenesis, is down-regulated in response to hypoxia in OS cells, and that this appears to result from both HIF-dependent and HIF-independent mechanisms. Hypoxia promotes resistance of human OS cells to standard chemotherapy, which is mitigated by treatment with Wnt/β-catenin signaling inhibitors. Using an anchorage-independent growth model, we show that anoikis-resistant OS subpopulations have altered growth rates, increased resistance to standard chemotherapies, and display distinct changes in gene expression and DNA methylation. Finally, we validate the use of two FDA-approved epigenetic therapies predicted by expression profiling in both inhibiting anchorage-independent growth and sensitizing anoikis-resistant OS cells to chemotherapy. In summary, despite the heterogeneity of human OS, our work suggests that unique and effectively targetable signaling pathways underlie the phenotypic consequences in response to hypoxia and anoikis resistance.</p><p>
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Influence of Dual Process Decision-Making Theory in Patients Diagnosed With CancerQuinonez, Bonnie 29 November 2017 (has links)
<p> Each year millions of people face the medical decision-making cycle that comes with a diagnosis of cancer. For patients and their families, this can be a rollercoaster of confusion and fear. Researchers have indicated that the complexity of the decision-making process is underrepresented in the current approach of informed decision-making. The purpose of this study was to add to scientifically-validated research expanding the identification of factors that influence decision-making for individuals diagnosed with cancer. Fuzzy trace theory (FTT) is the dual process memory theory used as the framework for this study. Qualitative data were collected using semistructured interviews with 10 participants. The sampling strategy included purposeful sampling and snowball or chain sampling. The audio-recorded interviews were transcribed and analyzed. Software tools were used to aid in the creation of word mapping and clusters and a naming structure emerged. A comprehensive thematic analysis was completed. Participants detailed experiences with family and social dynamics, psychological or emotional stress, external influencing factors to the decision-making process, and experiences with cancer advertising. This research can create positive social change through the advancement of scientifically-validated research to support patients during the decision-making process.</p><p>
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The descriptive epidemiology of cancer and its treatment in older peopleRivers, Helen L. January 2001 (has links)
No description available.
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Une étude phénoménologique expérientielle du cancer: Théorie, méthode et praxisCaron-Bourbonnais, Diane January 1989 (has links)
Abstract not available.
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An examination of chemo fog: Cognitive decline in early-stage breast cancer patients treated with adjuvant chemotherapyStewart, Angela January 2007 (has links)
Abstract not available.
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Investigating acute effects of oncolytic virus infection of tumoursBreitbach, Caroline January 2009 (has links)
Oncolytic viruses (OVs) are selected or designed to eliminate malignancies by direct infection and lysis of cancer cells. In contrast to this concept of direct tumour lysis by viral infection, a significant portion of the in vivo tumour killing activity of two OVs, vesicular stomatitis virus (VSV) and vaccinia virus is caused by indirect killing of uninfected tumour cells. Limited virus infection rapidly triggers a loss of tumour perfusion within the tumour core. Tumour cells within the tumour rim remain viable and are associated with intact vasculature. Transcript profiling of tumours demonstrates a pro-inflammatory gene signature with significant induction of neutrophil chemo-attractants. Depletion of neutrophils in animals prior to VSV administration eliminates uninfected tumour cell apoptosis and permits more extensive replication and spreading of the virus throughout the tumour. Tumour targeted inflammation triggers extensive intravascular coagulation which is responsible for the loss of perfusion as inhibition of coagulation results in maintenance of tumour perfusion in the context of VSV therapy. Interestingly, the remaining viable tumour rim does not expand in tumours implanted into immune competent mice. Conversely, a massive expansion of the viable tumour rim ensues following treatment of tumour bearing nude mice that possess a defective adaptive T cell response. These results suggest that outgrowth of viable tumour cells from the tumour rim following OV therapy is inhibited by an adaptive immune response triggered to target tumour cells. Taken all together, these results indicate that targeted recruitment of neutrophils triggers coagulation within infected tumour beds and enhances the killing of malignant cells. Activation of inflammatory cells may be used for enhancing the effectiveness of oncolytic virus therapeutics as well as other anticancer agents that may similarly trigger inflammation. Understanding mechanism and consequences of inflammation dependent tumour cell death is important as loss of tumour perfusion has now also been measured in patients treated with vaccinia virus.
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Microtechnologies for mimicking tumor-imposed transport limitations and developing targeted cancer therapiesToley, Bhushan J 01 January 2012 (has links)
Intravenously delivered cancer drugs face transport limitations at the tumor site and cannot reach all parts of tumors at therapeutically effective concentrations. Transport limitations also prevent oxygen from distributing evenly in tumors resulting in hypoxia, which plays a critical role in cancer progression. In this dissertation, I present the development of micro-devices that mimic transport limitations of drugs and nutrients on three dimensional tumor tissues, enable visualization and quantification of the ensuing gradients, and enable simple analysis and mathematical modeling of obtained data. To measure the independent effects of oxygen gradients on tumor tissues, an oxygen delivery device that used microelectrodes to generate oxygen directly underneath three-dimensional tumor cylindroids was developed. Supplying oxygen for 60 hours eliminated the necrotic region typically found in the center of cylindroids. Dead cells were observed moving away from the location of oxygen delivery. These measurements show that oxygen gradients are an important determinant of cell viability and rearrangement. Another micro-device was developed to mimic the delivery and systemic clearance of therapeutic agents. This microfluidic device consisted of cuboidal tumor tissue subjected to continuous medium perfusion along one face. The device was used to measure the spatiotemporal dynamics of the accumulation of therapeutic bacteria in tumors. Suspensions of Salmonella typhimurium and Escherichia coli strains were delivered to tumor tissues for 1 hour. Bacterial motility strongly correlated (R2 = 99.3%) with the extent of tissue accumulation. Based on spatio-temporal profiles and a mathematical model of motility and growth, bacterial dispersion was found to be necessary for deep penetration into tissue. These results show that motility is critical for effective distribution of bacteria in tumors. The microfluidic device was further used to mimic the delivery and clearance of equal concentrations of doxorubicin and liposome-encapsulated doxorubicin (Doxil). A pharmacokinetic/pharmacodynamic model incorporating mechanisms of tissue-level diffusion and binding was developed and experimental data was fit to this model. Doxorubicin was found to have the optimal diffusivity and binding for maximizing therapeutic effect. Doxil was severely limited by low intratumor drug release. These results show that in-vitro models mimicking tissue-level transport limitations more accurately predict the therapeutic response of drugs.
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