The complexity of melanoma is pronounced at many levels, whereby both environmental influences and genetic predisposition are involved and interact. Embedded within this complexity is heterogeneity, a defining characteristic of this malignancy. The rearrangement of genomic material on chromosomes 1p, 6q, 9p or 10q, 11q and 17q has been frequently reported during the development and progression of cutaneous malignant melanoma (CMM), suggesting several putative tumour suppressor genes and oncogenes in these regions. The genomic complexity of chromosome 9p21 in melanoma development is well documented. This region encodes a potent cyclin-dependent kinase inhibitor CDKN2/INK4A/p16 as a tumour suppressor gene (TSG) that is frequently inactivated in melanomas. Functional evidence suggested the presence of additional TSG loci in the 9p21-22 chromosome region (Parris et al., 1999). In pursuit of identifying novel TSG(s), our previous group’s collaborative research provided experimental evidence that suggests IFNA1 as a candidate TSG for melanoma development. Therefore, the aim of this work was to provide a further functional validation of such tumour-suppressive activity in CMM. Firstly, I have successfully subcloned IFNA1 cDNA into pcDNA3 expression vector and established a panel of stably IFNA1-expressing clones. Subsequently, I have assessed their tumourigenicity in soft agar by measuring the colony-forming ability of each transfected clone. Expression analyses of IFNA1, at both post-transcriptional and translational levels, were also carried out. I have also demonstrated a strong correlation between anchorage-independent growth in soft agar and IFNA1 expression in qRT-PCR. The antiproliferative and pro-apoptotic effects of IFNα have been widely documented, however, the precise mechanisms that trigger and potentiate this behaviour are not completely known. Based on previous findings, I have investigated whether IFNA1 exerts its antitumoural activity through apoptosis. I was able to demonstrate a moderate relationship between anchorage-independent growth in soft agar and the apoptotic levels in the transfected clones. Although unpersuasive and inconclusive, the results seemed encouraging since this study was carried out using only the highly tumourigenic malignant melanoma UACC903 cell line.

Les mécanismes impliqués dans l’activation de foyers ectopiques dans les veines thoraciques, source de fibrillation auriculaire (FA) chez l’Homme, sont encore méconnus. Nous avons montré que la noradrénaline peut induire une activité automatique sur la veine pulmonaire (VP) mais pas sur l’oreillette gauche (OG) chez le Rat. Au cours de cette étude, nous avons montré : 1) un potentiel de membrane de repos dépolarisé dans la VP et la veine cave supérieure (VCS) par rapport à l’OG ainsi que la présence d’une activité automatique en salves sur la VP ; 2) une dépolarisation due à la stimulation des récepteurs α1-adrénergiques (α1-AR) plus importante sur la VP que sur les deux autres tissus qui induit une inexcitabilité de la VP et la VCS ; 3) la présence d’une activité déclenchée favorisée par la stimulation des β1-AR sur la VCS ; 4) une diminution liée à l’âge de l’incidence de l’activité automatique catécholaminergique et des réponses à la stimulation des α1-AR sur la VP ainsi que la présence d’une activité déclenchée sous stimulation des α1-AR sur la VP chez les animaux âgés. Nous avons donc pu mettre en évidence des différences fonctionnelles entre le myocarde des veines thoraciques et le tissu atrial. Cependant, la relation entre l’activité automatique observée sur la VP du Rat et la FA reste encore à établir. / The mechanisms involved in the activation of ectopic foci within the thoracic veins, cause of atrial fibrillation (AF) in man, are still unknown. We shown that norepinephrine (NE) can induce an automatic activity in pulmonary vein (PV) but not in left atrium (LA) of the Rat. In this study, we shown: 1) a depolarised resting membrane potential in PV and superior vena cava (SVC) compared with LA and the occurence of an automatic activity in repetitive bursts in PV; 2) a depolarisation due to α1-adrenergic receptors (α1-AR) stimulation more pronounced in PV than the other two tissues, which induce an inexcitability of the PV and the SVC; 3) the occurence of a triggered activity facilitated by the simulation of β1-AR in SVC; 4) a decrease with age of the incidence of the catecholaminergic automatic activity and responses to the stimulation of α1-AR in PV and the occurence of a triggered activity under stimulation of α1-adrenergic in PV of old animals. Therefore, we have shown some functionnal differences between the myocardium of thoracic veins and atrial tissu. Nevertheless, the relationship between automatic activity observed in Rat PV and AF remains to establish.

No description available.

No description available.

No description available.

Thesis (Ph. D.)--University of Nevada, Reno, 2005. / Includes bibliographical references. Online version available on the World Wide Web.

Tierärztl. Hochsch., Diss., 2004--Hannover.

Purpose/Aims: The American Thoracic Society (ATS) published recommendations for alpha-1 antitrypsin deficiency (AATD) testing in 2003. This descriptive project evaluates the outcomes of ATS AATD guideline use in the setting of the pulmonary function testing (PFT) lab.The specific aims met by this descriptive project describe the prevalence of AATD cases and carriers in the sample, examine to what degree the established clinical guideline promoted accurate patient selection for the alpha-1 test in the sample, and aimed to determine whether alpha-1 antitrypsin blood levels are reduced in current smokers compared to former or never smokers.Background: Alpha-1 antitrypsin prevents lung tissue breakdown by attenuating excess elastase released from neutrophils during the inflammatory response. Smoking impairs alpha-1 antitrypsin protection at the site of lung inflammation promoting emphysema development. In the case of genetic mutation, protective alpha-1 antitrypsin levels are reduced, causing emphysema even in non-smokers. Significantly reduced protective levels of alpha-1 antitrypsin increase the odds for morbidity and early mortality from emphysema. The literature provides support for targeted testing in the population most affected.Sample/Methods: The sample population included adults 21 through 79 years completing pulmonary function testing over 18 months in a metropolitan pulmonary medicine practice and was retrospectively reviewed.Of the 521 in the sample, 190 were tested for AATD, and 24 were found to carry an abnormal genotype. However, using Table 11 from the ATS CPG failed to provide structured, consistent guidance in selecting patients for AATD testing. Still, the prevalence of the abnormal genotypes MS, MZ, SZ, and ZZ was increased in this pulmonary population compared to the published estimated prevalence for the general population.A structured decision-tree, developed from the original guideline for diagnostic testing, may provide superior guidance for AATD test patient selection in this setting. Increased case finding by targeted testing of patients in the setting of the pulmonary function lab can serve to integrate this clinical practice guideline in a consistent streamlined fashion.In this sample, no difference between AAT blood levels among ever, never, and current tobacco smokers was detected. A more powerful sample is needed.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted. Includes bibliographical references.