No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

In this thesis I examined molecular mechanisms involved in acute and chronic liver injury, and also studied basic pathways mediating tumour promotion. Acute hepatic failure secondary to paracetamol poisoning is associated with high mortality. C-jun (NH2) terminal kinase (JNK) is a member of the mitogen activated protein kinase family and is a key intracellular signaling molecule involved in the control of cell fate. Paracetamol induced hepatic JNK activation in both human and murine paracetamol hepatotoxicity, and in a murine model preceded the onset of hepatocyte death. JNK inhibition in vivo (using two JNK inhibitors with different mechanisms of action) markedly reduced mortality in murine paracetamol hepatotoxicity. In addition, delayed administration of JNK inhibitor was more effective than N-acetylcysteine following paracetamol poisoning in mice. JNK inhibition was not protective in acute carbon tetrachloride or anti-Fas antibody mediated hepatic injury, suggesting specificity for the role of JNK in paracetamol hepatotoxicity. Furthermore, disruption of the JNK1 or JNK2 genes did not protect against paracetamol-induced hepatic damage. Pharmacological JNK inhibition had no effect on paracetamol metabolism, but markedly inhibited hepatic TNF-alpha production following paracetamol poisoning. These data demonstrate a central role for JNK in the pathogenesis of paracetamol induced liver failure, thereby identifying JNK as an important therapeutic target in the treatment of paracetamol hepatotoxicity. Liver fibrosis with loss of tissue architecture and subsequent hepatic failure represents a massive healthcare burden worldwide. Expression of Galectin-3 (a beta-galactoside binding animal lectin) is upregulated in established human fibrotic liver disease, during the development of experimental liver fibrosis and is temporally and spatially related to the induction and resolution of experimental hepatic fibrosis. Disruption of the gene encoding Galectin-3 blocks transdifferentiation of precursors to myofibroblasts in vitro and in vivo, markedly attenuating hepatic scarring in a murine model of liver fibrosis. Inhibition of Galectin-3 expression by siRNA in primary murine and human hepatic stellate cells significantly reduced myofibroblast activation and procollagen(I) expression. The reduction in hepatic fibrosis observed in the Galectin-3-/- mouse occurred despite equivalent liver injury and inflammation, and similar tissue expression of TGF-beta. TGF-beta failed to transactivate Galectin-3-/- hepatic stellate cells, in contrast with wild type hepatic stellate cells. However TGF-beta stimulated signaling via Smad-2 and 3 was equivalent in both Galectin-3-/- and wild type hepatic stellate cells indicating that Galectin-3 is required for TGF-beta mediated myofibroblast activation and matrix production. This supports a novel and important mechanistic role for Galectin-3 in the regulation of myofibroblast activation and consequent liver fibrosis. Finally, in vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation following hepatic injury and may therefore provide a novel therapeutic approach to the prevention and treatment of liver fibrosis. CD98hc (a ligand for Galectin-3) constitutively and specifically associates with beta1 integrins and is highly expressed on the surface of human tumour cells irrespective of the tissue of origin. CD98hc promotes both anchorage- and serum-independent growth. Using chimeras of CD98hc and the type II membrane protein CD69 demonstrated that the transmembrane domain of CD98hc is necessary and sufficient for integrin association in cells. Furthermore, CD98hc/β1 integrin association is required for focal adhesion kinase-dependent phosphoinositol 3-hydroxykinase activation and cellular transformation. Amino acids 82-87 in the putative cytoplasmic/transmembrane region appear to be critical for the oncogenic potential of CD98hc and provide a novel mechanism for tumour promotion by integrins.

With the corporatization of healthcare, combined with rapid advances in medical technology, frontline health care workers, especially nurses, are facing an increase in daily ethical dilemmas, with potential increases in moral distress. The contributing factors and negative effects of moral distress are well researched, in particular as they impact nurses in specialty areas. However, understanding how nurses navigate moral distress, specifically in general medical and surgical units, is not as well understood. The purpose of this study was to understand and articulate the processes that nurses carry out when navigating moral distress, by exploring their interactions with the health care environment. Using grounded theory methodology, a substantive theory was developed to explain the process. The participants in this study were all registered nurses from an acute care academic hospital, who worked on non-specialty medical and/or surgical units. Data collection consisted of audio-recorded face-to-face interviews that were transcribed post interview. All the events and situations that resulted in the experience of moral distress were primarily rooted in organizational structures, which often blindsided the nurses in this study, and led to a sense of feeling ill-equipped and unsupported to respond in the moment. Furthermore, the participants expressed their inability to be agents of change due to the established organizational expectations. The basic social process for navigating moral distress was “Just getting through the shift”. This theory is comprised of the categories of Experiencing Moral Distress, Making Sense of the Situation, and Finding the Way. In working through these processes, the participants engaged in navigating moral distress. Making sense of the situation was an ongoing process that nurses engaged in whereby they sought out knowledge in various ways, such as exploring internal resources, and building relationships with their peers, their patients, and patients’ families. Throughout this iterative process of making sense of the situation, the nurses were then able to find their way. Participants discussed positive outcomes such as reflecting and learning from the experience. However, despite this response, there was a feeling of powerlessness to make a difference. Therefore, they focused on providing the best care they could and getting on with their shift without experiencing closure. / Graduate