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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
811

Role of cysteine proteinases in IGF-1R turnover, invasion and metastasis

Navab, Roya. January 1999 (has links)
Clinical cancer treatment has focused on the use of cytotoxic agents and/or radiation therapy that target both tumor and normal cells. Consequently, current cancer treatments with chemotherapeutic agents are subject to limitations associated with high toxicity and resistance. The cysteine proteinases cathepsin B and L have been linked to the invasive steps during the metastatic process and could therefore provide new targets for drug development. / The present work describes our results with a murine Lewis lung carcinoma model which consists of two cell lines, H-59 and M-27, with different patterns of metastasis in vivo. Using this model, we found that the cysteine proteinase inhibitor, E-64, significantly inhibited the invasive/metastatic properties of the liver colonising cell line, H-59 both in vitro and in vivo. Because IGF-1R was identified as a critical mediator of matrix metalloproteinase-2 (MMP-2) synthesis, invasion and metastasis in H-59 cells, the possibility that the cysteine proteinases interfered with receptor for type 1 insulin-like growth factor (IGF-1R) turnover thereby reducing invasion was subsequently investigated. / To elucidate more specifically the role of cysteine proteinases in the process of liver metastasis, cathepsin L expression was inhibited in the H-59 cells by transfection with a plasmid vector expressing a 300 by cathepsin L cDNA fragment in the antisense orientation. To further investigate the link between IGF-1R expression levels and invasion in these cells, MMP-2 production and activity were investigated. In cathepsin L antisense transfected H-59 cells reduced MMP-2 levels and activity as compared to controls were observed. Together our results suggest that the cysteine proteinases, cathepsin L in particular may regulate the metastatic potential through a role in IGF-1R turnover. The present results provide evidence that metastatic carcinomas which utilize cysteine proteinases for invasion could potentially be responsive to antimetastatic treatment with cysteine proteinase inhibitors. (Abstract shortened by UMI.)
812

Role of the retinoblastoma tumour suppressor family in transformation, differentiation, and cell cycle

Corbeil, Hugues B. January 1996 (has links)
The retinoblastoma tumour suppressor family plays an important role in the regulation of cellular growth in the cell cycle, growth arrest, and differentiation. The RB family includes pRB, p107, and p130 which interact primarily with two sets of transcription factor families, E2F and DP, resulting in the inactivation of E2F/DP transcriptional activity. The RB family members are targets for DNA tumour viral oncogene products such adenovirus E1A proteins which interact with all members, and displace E2F/DP heterodimers, resulting in the activation of E2F-dependent transcription. The binding of pRB was found to be absolutely required for EIA-mediated transformation, however, there is no correlation between E2F activation and transforming efficiency because some E1A mutants which failed to interact with pRB induced E2F at high levels presumably due to interaction with p107 and p130. These results suggest that pRB regulates E2F activity differently from p107 and p130. Analysis of mutants in conserved region 2 (CR2) of the E1A protein, including the (D)LXCXE conserved motif showed that the integrity of these conserved residues is important for interactions with both pRB and p130, but no single site mutation diminished binding of p107. Thus interactions with multiple members of the RB family appeared to be required for full activation of E2F and stable cell transformation by E1A proteins. / In undifferentiated cells such as C2C12 and P19 mouse cells, E2F is primarily complexed with p107/cyclinA/E/Cdk2. It was show that formation of pRB/E2F complexes is specifically induced during cell differentiation. In addition, p130/E2F complexes are also generated. We identified a novel slowly-migrating p130/E2F complex which is present not only in terminally differentiated cells, but also in growth-arrested cells. This complex is found in high amounts in Go/G1 phases, it disappears near the G1/S transition, and reappears in mitosis. Analysis of the content of these complexes showed that they contain cellular protein(s) which interact with p130 in a fashion similar to the CR2 region of E1A. Characterization of the novel E2F complex by antibody supershift assays revealed the presence of a known RB-binding protein, RBP1 which seems to be part of large family of cellular proteins interacting with p130 and which may be involved in the represssion of basal promoter activity of E2F regulated genes.
813

Production and characterization of a monoclonal antibody to a highly metastatic and organ-selective variant of the Lewis lung carcinoma

Shestowsky, William S. January 1988 (has links)
No description available.
814

Evaluation of prostate secretory protein (PSP-94) as a novel therapeutic agent for blocking prostate cancer progression and hypercalcemia of malignancy

Shukeir, Nicholas January 2002 (has links)
Human prostate cancer is one of the most common malignancies affecting men. It is associated with a high degree of mortality and morbidity due to the development of non-skeletal and skeletal metastases. A common complication in patients suffering from prostate cancer is the development of hypercalcemia of malignancy. While determination of PSA and PSP-94 levels can serve as diagnostic/prognostic markers, PSP-94 can also serve as a therapeutic agent. The efficacy of PSP-94 to block tumor progression and hypercalcemia of malignancy was tested in our syngeneic in vivo rat model of prostate cancer. Rat prostate cancer Mat Ly Lu cells were transfected with full length cDNA encoding PTHrP [Mat Ly Lu-PTHrP] which is known to be the main factor responsible for hypercalcemia of malignancy. Mat Ly Lu-PTHrP cells were inoculated subcutaneously into the right flank or via intracardiac injection into the left ventricle of male Copenhagen rats. Animals were treated with different doses of PSP-94. Tumor volume, time of hind-limb paralysis, plasma calcium and plasma and tumoral PTHrP levels were determined. PSP-94 caused a significant delay in the development of hind-limb paralysis, reduction in tumor volume, plasma calcium levels, plasma and tumoral PTHrP levels as compared to control animals receiving vehicle alone. These effects were due to the induction of tumor cell apoptosis. In conclusion, our studies illustrate the ability of PSP-94 to block prostate cancer growth and skeletal metastases.
815

Estrogen-related receptor [alpha] (ERR[alpha]), estrogen receptor [alpha] (ERA[alpha]) and erbB-E (Neu) crosstalk in a mouse model of human breast cancer

Chahrour, Ghada January 2003 (has links)
Estrogen (17-beta estradiol) and its receptor (ERalpha) have important physiological roles and are well implicated in human breast cancer, but less is known about the function of estrogen-related orphan nuclear receptor alpha (ERRalpha). The close kinship between ERalpha and ERRalpha and the existing, but yet to be fully characterized, interplay between ERalpha and erbB2 (Neu) protooncogene signaling pathways, suggest that ERRalpha may also play a significant role in breast cancer. Thus, the focus of the current study was to determine the extent of ERRalpha cross talk with ERalpha, its physiological role, as well as its possible implication in erbB2-driven mammary tumorigenesis. Using a well characterized erbB2 mouse model of human breast cancer where tumorigenesis occurs following a long latency period, we generated ERRalpha deficient mice (ERRalphaKO) expressing an activated erbB2 oncogene.
816

Waiting time for radiation therapy in non-metastatic, surgically-treated breast cancer patients in Quebec

Fortin, Bernard, 1970- January 2003 (has links)
The purpose of this study was to determine among surgically treated non-metastatic breast cancer patients in the province of Quebec the distribution of the time between surgery and post-operative radiation therapy (RT) as well as secular trends and other factors influencing waiting time. Using administrative records, I identified between 1992 and 1998 29,105 episodes of breast cancer and 17,704 of these contained an indication of receiving RT Hierarchical linear regression models were used to identify predictors of waiting time. / The number of cases of breast cancer increased by 5.5% per year while the number of those receiving RT increased by 9%. Median post-surgery waiting time was 75 days in 1992 and by 1998 it had increased by 63% (95% Confidence Interval (CI) 35%--97%) among patients not requiring chemotherapy. In patients receiving chemotherapy, post-chemotherapy waiting time increased from 21 to 30 days (35% increase between 1998 and 1992 (95% CI -3%--88%)). In addition to a significant variability of waiting time according to radiation therapy centre, predictors of shorter waiting times were earlier year of treatment, localised cancer stage, breast conserving surgery, early consultation with a radiation oncologist, being operated in a centre with a radiation therapy facility, living close to a radiation therapy facility, and living in a higher socio-economic area. / In conclusion, waiting time to start of radiation therapy after localised breast cancer increased substantially in Quebec from 1992 to 1998. Possible explanations include increased demand, insufficient resources and changes in the indications for breast conserving surgery and RT.
817

Oligonucleotide microarray analysis of chromosome-X gene expression in human epithelial ovarian cancer cell lines

Benoit, Marie-Helene January 2004 (has links)
Microarray expression analysis was applied as an approach for identifying cancer-related genes on chromosome-X (CHR-X) in epithelial ovarian cancer (EOC). The Hu6800 and U133A GeneChipsRTM were used to evaluate the expression of 446 CHR-X genes in an in vitro EOC model system comprising 4 EOC cell lines and 12 primary cultures of normal ovary surface epithelia. Fifty-one new candidate CHR-X genes were identified in addition to 49 genes previously implicated in cancer. Many genes map to regions with frequent genetic aberrations in EOC tumours, or interact with the known EOC tumour suppressors BRCA1 and BRCA2. Candidate genes described in this study may provide novel markers for histopathological subtypes, or the tumourigenic potential of EOC tumours. The X-inactive-specific-transcript (XIST) was absent in two highly tumourigenic EOC cell lines, TOV21G and TOV112D. XIST mRNA is important for the stability of X-chromosome-inactivation (XCI), as its absence destabilizes the silencing of genes on the inactive-X. Aberrant bi-allelic expression of FHL1, a gene subjected to XCI was detected in the cell line TOV21G but not in the cell line TOV112D. Genotyping assays using polymorphic microsattelite markers suggested that TOV21G has retained heterozygosity of CHR-X. The majority of alleles tested for TOV112D were consistent with loss of heterozygosity of CHR-X. Taken together these findings are consistent with two proposed mechanisms mediating XIST loss-of-expression in cancer: (1) Duplication of the active-X followed by loss of the inactive-X (TOV112D); or (2) Reactivation of the previously inactive-X (TOV21G).
818

A computer vision approach to classification of circulating tumor cells

Hopkins, David 01 August 2013 (has links)
<p> Current research into the detection and characterization of circulating tumor cells (CTCs) in the bloodstream can be used to assess the threat to a potential cancer victim. We have determined specific goals to further the understanding of these cells. 1) Full automation of an algorithm to overcome the current methods challenges of being labor-intensive and time-consuming, 2) Detection of single CTC cells amongst several million white blood cells given digital imagery of a panel of blood, and 3) Objective classification of white blood cells, CTCs, and potential sub-types. </p><p> We demonstrate in this paper the developed theory, code and implementation necessary for addressing these goals using mathematics and computer vision techniques. These include: 1) Formation of a completely data-driven methodology, and 2) Use of Bag of Features computer vision technique coupled with custom-built pixel-centric feature descriptors, 3) Use of clustering techniques such as <i> K</i>-means and Hierarchical clustering as a robust classification method to glean insights into cell characteristics. </p><p> To objectively determine the adequacy of our approach, we test our algorithm against three benchmarks: sensitivity/specificity in classification, nontrivial event detection, and rotational invariance. The algorithm performed well with the first two, and we provide possible modifications to improve performance on the third. The results of the sensitivity and specificity benchmark are important. The unfiltered data we used to test our algorithm were images of blood panels containing 44,914 WBCs and 39 CTCs. The algorithm classified 67.5 percent of CTCs into an outlier cluster containing only 300 cells. A simple modification brought the classification rate up to 80 percent of total CTCs. This modification brings the cluster count to only 400 cells. This is a significant reduction in cells a pathologist would sort through as it is only .9 percent of the total data.</p>
819

The roles of the E26 transcription family member, SAM pointed domain-containing ETS transcription factor (SPDEF), in early stage prostate cancer and the development of castration recurrent disease

Haller, Andrew Clayton 14 August 2013 (has links)
<p> One of the greatest problems in prostate cancer management today is accurate identification of patients who require treatment for aggressive disease versus those with indolent disease who are suitable for observational strategies. Histological appearance of the tumor, called Gleason score in the prostate cancer field, is the most predictive measure currently used. However, recent studies in multiple tumor types have shown that histological appearance does not always reflect the underlying molecular phenotype of the lesion. Therefore, in prostate cancer specifically, assessment of a molecular marker of androgen receptor driven epithelial differentiation may have clinical predicative capabilities. SAM pointed domain-containing Ets transcription factor (SPDEF) is a potential AR target gene that has shown to be necessary and sufficient for epithelial cell differentiation in many tissues. Although generally associated with good prognosis, SPDEF's role in cancer in unclear. This study demonstrates, through retrospective immunohistochemical analysis, the utility of SPDEF as a predictive biomarker for patients that have an extended benefit from androgen deprivation therapy (ADT). Furthermore, dual roles of SPDEF to inhibit the initiation and supporting the progression of castrate recurrent disease through novel androgen receptor expression regulation in castrate conditions are shown. In ADT na&iuml;ve patients, SPDEF did not associate with metastatic disease or an induction of epithelial to mesenchymal transition. However, aggressive tumors tended to be larger, have greater SPDEF variability, and lack vimentin expression; a phenotype that could be explained by a partial EMT. In conclusion, SPDEF may be clinically useful to assess the epithelial phenotype of tumors, and could have utility identifying patients that will respond well to androgen deprivation therapy.</p>
820

Tumor cell adhesion stabilization: Regulation and relationship to organ-specific metastasis

Smith, Thomas W. January 1996 (has links)
Tumor cell arrest and the formation of stable adhesive interactions between tumor cells and endothelial cells or underlying matrix in the microvasculature are crucial steps in the metastatic process. A sensitive hydrodynamic adhesion assay was used to investigate the regulation of melanoma cell adhesion stabilization to the extracellular matrix protein fibronectin, and also to study the relationship between tumor cell adhesion stabilization and organ-specific blood borne metastasis. Modulators of intracellular signals were used to determine the role of the signaling pathways in regulation of adhesion stabilization. Modulators of intracellular (Ca$\sp{2+}$) were found to inhibit stabilization, but extracellular Ca$\sp{2+}$ was not required. Inhibitors of calmodulin, protein kinase C, tyrosine kinases, and the actin cytoskeleton also inhibited adhesion stabilization. Phorbol esters, cAMP modulators, and G protein inhibitors had no effect on adhesion stabilization. Most of the drug treatments that inhibited adhesion stabilization also had significant effects on the actin cytoskeleton organization of the melanoma cells. These results suggest a role for intracellular (Ca$\sp{2+}$), calmodulin, protein kinase C, and tyrosine kinases in the regulation of melanoma cell adhesion stabilization. Adhesion stabilization of metastatic murine RAW117 large-cell lymphoma cells to the extracellular matrix proteins fibronectin and vitronectin, several RGD containing peptides, and microvascular endothelial cells from the liver or lung was also investigated. The highly liver metastatic RAW117-H10 subline showed faster adhesion stabilization to fibronectin, vitronectin, and RGD peptides than did the poorly metastatic RAW117-P cells or the lung- and liver-metastatic RAW117-L17 cells. The adhesion stabilization of the RAW117-H10 cells to the extracellular matrix proteins and RGD peptides was inhibited by anti-$\beta\sb3$ integrin monoclonal antibodies and RGD peptides. In contrast, the RAW117-L17 subline had the shortest stabilization time to unstimulated microvascular endothelial cells of the lung and hepatic sinusoids, followed by RAW117-H10 cells and RAW117-P cells. RGD peptides and monoclonal antibodies against the Mac-1 and $\beta\sb3$ integrins did not inhibit adhesion stabilization of RAW117-H10 cells to endothelial cells. These results suggest that different metastatic variants of large-cell lymphoma cells use different mechanisms to adhere in the microcirculation.

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