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Proteomics of Thyroid Carcinoma: Detection of Potential Biomarkers of Aggressive and Non-aggressive SubtypesKashat, Lawrence 27 November 2013 (has links)
In search of thyroid carcinoma biomarkers, proteins secreted by thyroid cancer cell lines, papillary-derived TPC-1 and anaplastic-derived CAL62, were analyzed using liquid chromatography-tandem mass spectrometry. Of forty six high-confidence identifications, six proteins were considered for verification in thyroid cancer patients’ tissues and blood. The localization of two proteins, nucleolin and prothymosin-alpha (PTMA), was confirmed in TPC-1 and CAL62 by confocal microscopy and immunohistochemically in xenografts of TPC-1 cells and human thyroid carcinomas. Increased nuclear and cytoplasmic expression of PTMA was observed in anaplastic carcinomas compared to normal thyroid tissues, papillary and poorly differentiated carcinomas. Importantly, six proteins were detected in thyroid cancer patients’ sera, warranting future analysis to confirm their potential as blood-based thyroid cancer markers. Herein we demonstrate the ability of secretome analysis of thyroid cancer cell lines to identify proteins that may be studied for application in management of thyroid carcinomas upon future validation.
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The Requirement for Oxygen in the Maturation and Secretion of Soluble urokinase Plasminogen Activator Receptor (uPAR)Rumantir, Ryan Allister 10 December 2013 (has links)
TTumor hypoxia (poor oxygenation) adversely affects patient prognosis by promoting therapeutic resistance and an aggressive tumor phenotype. We aimed to understand how urokinase plasminogen activator receptor (uPAR), a cysteine-rich protein implicated in the malignant phenotype and poor patient prognosis, matures in hypoxia. We hypothesized that secretion of uPAR during hypoxia is conferred by a superior ability to form disulfide bonds without oxygen. A model and assay was established to monitor the oxygen-dependency of suPAR (a soluble secreted isoform of uPAR) folding and secretion. We found that suPAR maturation involves disulfide formation and N-linked glycosylation in normoxia. In anoxia, suPAR disulfide formation was impaired, but suPAR was nevertheless secreted. We propose that suPAR has low dependency on disulfide formation for efficient secretion in comparison to other disulfide-containing proteins. Mechanisms supporting protein expression during hypoxia may potentially be targeted to mitigate the adverse effects of tumor hypoxia and ultimately improve cancer therapy.
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Study of two putative prostate cancer tumor markersShun, Kitty. January 2006 (has links)
The following thesis is based on my study of two candidate prostate cancer tumor markers, namely telomerase and CD9. Accordingly, the thesis will be divided in two main chapters describing the results obtained for each protein. Although these proteins are de-regulated in prostate cancer cells, little is known about their regulation and function in prostate cells. For example, telomerase is generally inactive in normal cells and reactivated in cancer cells and CD9 is a transmembrane protein that is lost as prostate cancer progresses. In chapter 2, I will show that introduction of normal human chromosomes into mouse melanoma cells can shut down its telomerase activity by inhibiting hTERT transcription and that the gene encoding this regulator is likely located on human chromosome 17p11.1. Additionally, following further characterization of CD9 partners in chapter 3, we will learn more about the likely mechanism by which CD9 induces mitotic catastrophe when over-expressed in prostate cancer cells.
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The use of rat glutathione S-transferase A3 for hematopoietic chemoprotection from nitrogen mustards in cancer therapy /Létourneau, Sylvain. January 1999 (has links)
The effectiveness of anti-cancer chemotherapy is limited by acute dose limiting toxicities, principally myelosuppression. The introduction of drug resistance genes into hematopoietic cells may increase the bone marrow (BM) tolerance to chemotherapy and may permit safer dose escalation, and thus increase clinical efficacy. Conferring chemoprotection to nitrogen mustards would be clinically relevant because of their broad spectrum of anti-tumor activity and their predominant, dose-limiting hematotoxicity. The glutathione S-transferase (GST) alpha isoenzymes, particularly the rat GSTA3, have been implicated in resistance to nitrogen mustards. To determine if retrovirus-mediated gene transfer of the rat GSTA3 (previously called GST-Yc) could be used to confer resistance to nitrogen mustards, we studied the expression of rat GSTA3 and the sensitivity to nitrogen mustards in mouse NIH 3T3 fibroblasts following either transfection or transduction of GSTA3 with a Moloney-based retrovirus vector (N2Yc). Populations of GSTA3-transduced cells and single cell-derived clones demonstrated increased glutathione (GSH) peroxidase activity (associated with the A3 subunit) and moderate in vitro resistance to chlorambucil and mechlorethamine. To address the feasibility of using rat GSTA3 gene transfer to confer chemoprotection to the hematopoietic system, we then transduced human leukemia K-562 cells and primary murine hematopoietic progenitor cells with the N2Yc retrovirus vector, Similarly to N2Yc-expressing fibroblasts, K-562 cells and clonogenic primary murine hematopoietic cells transduced with the N2Yc retrovirus vector demonstrated increased GSH peroxidase activity and moderate in vitro resistance to melphalan, chlorambucil and mechlorethamine. We next explored the possibility of conferring chemoprotection against nitrogen mustards in vivo following transplantation of mice with GSTA3-transduced BM cells. Unfortunately, we did not observed chemoprotection from chlorambucil in
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The catecholamine extraneuronal uptake, transporter is associated with the increased sensitivity of gliomas to sarcosinamide chloroethylnitrosourea /Marcantonio, Daniela. January 1997 (has links)
SarCNU, a novel chloroethylnitrosourea analogue, is transported by the extraneuronal uptake2 transporter (uptake2). SK-MG-1 human glioma cells are sensitive to SarCNU cytotoxicity and express uptake 2 whereas SKI-1 glioma cells have no detectable transporter, and are relatively resistant. To clone uptake2, we detected differences in RNA expression utilizing differential display. With differential display, we detected a novel sequence expressed in SK-MG-1 cells but not in SKI-1 cells, having 62% homology to an expressed sequence tag clone from human brain, and could be a partial sequence of uptake2. In the treatment of SF-295 glioma xenografts in athymic mice, SarCNU had superior activity than 1,3-bis-(2-chloroethyl)-1-nitrosourea. This suggested that SF-295 cells express uptake2. We determined if expression of uptake2 in the established SF-295 cell line correlated with the enhanced activity of SarCNU in vivo. Transport of [3H]SarCNU was not decreased by inhibitors of uptake2 in the SF-295 cell line and its steady state accumulation was similar to that of SKI-1. The increased stability of SarCNU versus BCNU may account for its enhanced activity in vivo or the expression of uptake2 in vivo may differ from its expression in vitro.
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Malignancy in systemic lupus erythematosusBernatsky, Sasha. January 2001 (has links)
Objectives. (1) To estimate cancer incidence in systemic lupus erythematosus (SLE) as compared to the general population. (2) To estimate the sensitivity and specificity of methods of cancer ascertainment. (3) To determine the prevalence of malignancy risk factors in SLE. Methods. (1) We determined the incidence of malignancy in the Montreal General Hospital (MGH) lupus cohort, through linkage with the Quebec tumor registry. Standardized incidence ratios (SIRS) were generated, using Quebec population rates. In addition, a meta-analysis was performed by pooling data from eight cohort studies of malignancy in SLE. (2) We administered a postal survey to cohort members to determine risk factors for cancer and self-report of cancer occurrence. For dead or lost-to-follow-up patients, data was abstracted from charts. We calculated the sensitivity and specificity of self-report and chart review for cancer ascertainment, compared to registry linkage results. (3) Using the data collected on self-report and chart review, we compared risk factor prevalence within the MGH cohort to that of the Quebec population. Results. (1) Observed cancers in our cohort were greater than what would be expected; for all cancers, the SIR was 1.8 (95% Confidence Interval 1.2--2.6). The meta-analysis SIR (for all malignancies) was 1.67 (1.42--1.94). Postal survey and chart review methods demonstrated high specificity. Sensitivity was imperfect, but did not greatly effect estimation of the SIR estimate. (2) Our lupus cohort had a distinct profile of risk factors for malignancy compared to the general population; differences included more prevalent nulliparity, obesity, and use of hormone replacement therapy. Conclusions. The risk of malignancy in SLE patients is increased. Risk factor profiles could influence the incidence of certain malignancies in SLE.
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Characterization of a Mouse Model of Soft Tissue Sarcoma: Intraoperative Molecular Imaging and miRNA Regulation of MetastasisMito, Jeffrey January 2013 (has links)
<p>Soft Tissue Sarcomas are a rare group of mesenchymal tumors with over 50 recognized subtypes. These tumors are a diverse group of malignancies that primarily arise from the connective tissue, fat and muscle. In the United States, there are estimated to be approximately 11,000 new diagnoses a year with an annual mortality rate approaching 40%. Unfortunately, with such a diversity of subtypes of soft tissue sarcoma, and the relative scarcity of patient samples, there is a need for animal models that faithfully recapitulate the biology of these tumors. Such animal models would be useful for dissecting the underlying biology of soft tissue sarcomas and to evaluate novel therapies. One such model is the LSL-KrasG12D; p53Flox/Flox mouse model of soft tissue sarcoma. These tumors are generated in a spatial and temporally restricted fashion and closely mimic the natural history of human soft tissue sarcomas, including a predilection to develop lung metastases. Here I will characterize this model of soft tissue sarcoma by: 1) performing cross species genomic comparisons to show that the LSL-KrasG12D; p53Flox/Flox mouse model of soft tissue sarcoma most closely resembles Undifferentiated Pleomorphic Sarcoma , 2) utilizing this mouse model to identify cathepsin proteases as molecular markers of soft tissue sarcoma. I will then use cathepsin activated imaging probes for intraoperative molecular imaging to identify microscopic residual cancer in real time. Finally, 3) I identify a novel mechanism through which MAPK signaling regulates miRNA biogenesis and the development of distant metastases in the LSL-KrasG12D; p53Flox/Flox mouse model of soft tissue sarcoma.</p> / Dissertation
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Copy Number Analysis of CancerMayrhofer, Markus January 2015 (has links)
By accurately describing cancer genomes, we may link genomic mutations to phenotypic effects and eventually treat cancer patients based on the molecular cause of their disease, rather than generalizing treatment based on cell morphology or tissue of origin. Alteration of DNA copy number is a driving mutational process in the formation and progression of cancer. Deletions and amplifications of specific chromosomal regions are important for cancer diagnosis and prognosis, and copy number analysis has become standard practice for many clinicians and researchers. In this thesis we describe the development of two computational methods, TAPS and Patchwork, for analysis of genome-wide absolute allele-specific copy number per cell in tumour samples. TAPS is used with SNP microarray data and Patchwork with whole genome sequencing data. Both are suitable for unknown average ploidy of the tumour cells, are robust to admixture of genetically normal cells, and may be used to detect genetic heterogeneity in the tumour cell population. We also present two studies where TAPS was used to find copy number alterations associated with risk of recurrence after surgery, in ovarian cancer and colon cancer. We discuss the potential of such prognostic markers and the use of allele-specific copy number analysis in research and diagnostics.
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Promoting couple support in cancerBrennan, James Hugh January 1999 (has links)
No description available.
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A morphometric assessment of pre-neoplastic and neoplastic conditions in the gastrointestinal systemHamilton, Peter William January 1989 (has links)
No description available.
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