Background: Breast cancer is the commonest female cancer. DNA double-strand breaks (DSBs) associated proteins such as BRCA1 have been shown to be involved in tumourigenesis of breast tissue. One of the key regulators of DSBs, the RING Finger Protein 168 (RNF168), controls DNA damage responses (including the manipulation of homologous recombinant and non-homologous end-joining repair) which are responsible for correction of errors that occur during DSBs in order to maintain genomic stability. The nature of this protein suggests that RNF168 may play an important role in development of breast cancer. Material and methods: This study investigated the relationship of RNF168 expression in breast cancer by immunohistochemistry staining of 118 breast cancer samples in tissue microarray. The nuclear stain and cytoplasmic stain of the sections were assessed. Nuclear localization score was obtained and correlated with clinico-pathological features of the patients. Results: Immunohistological staining of RNF168 was successful in 99 cases of the tested breast cancer specimens. The expression of RNF168 was found to be significantly correlated with the occurrence of breast cancer metastasis (p=0.032). Strong expression of the protein was also found to be significantly associated with poorer breast cancer prognosis (p=0.033). In addition, correlation analysis also showed marginal correlation between nuclear localization of RNF168 with the age of patients at their first disease diagnosis (p=0.061). Conclusion: RNF168 might play a critical role in promoting breast cancer metastasis during the advanced stage of breast cancer, which results in poor disease prognosis. Detailed mechanism involved in metastasis promotion remained to be revealed in further study. / published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / Surgery / Master / Master of Surgery

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Viral hepatitis infection represents a significant epidemiological and economic burden on society. Following infection, some patients mount a blunted immune response to the virus, which ultimately can result in chronic infection. FGL2, a member of the fibrinogen-related protein superfamily, has been implicated in vitro in suppressing both innate and adaptive immune responses. In a murine model of acute viral hepatitis caused by Lymphocytic Choriomeningitis Virus strain WE, we demonstrate that FGL2 expressed by reticuloendothelial cells limits viral spread. When expressed by Treg cells FGL2 binds to FCγRIIB and prevents DC maturation and suppresses virus-specific T and B cell responses. We provide compelling evidence to suggest that hepatitis viruses utilize the FGL2-FCγRIIB pathway to evade immune detection. Inhibition of this pathway restores effective cellular and humoral antiviral immune responses towards hepatitis viruses.

Viral hepatitis infection represents a significant epidemiological and economic burden on society. Following infection, some patients mount a blunted immune response to the virus, which ultimately can result in chronic infection. FGL2, a member of the fibrinogen-related protein superfamily, has been implicated in vitro in suppressing both innate and adaptive immune responses. In a murine model of acute viral hepatitis caused by Lymphocytic Choriomeningitis Virus strain WE, we demonstrate that FGL2 expressed by reticuloendothelial cells limits viral spread. When expressed by Treg cells FGL2 binds to FCγRIIB and prevents DC maturation and suppresses virus-specific T and B cell responses. We provide compelling evidence to suggest that hepatitis viruses utilize the FGL2-FCγRIIB pathway to evade immune detection. Inhibition of this pathway restores effective cellular and humoral antiviral immune responses towards hepatitis viruses.

Streptococcus pneumoniae can be found in the normal flora of the throat and upper respiratory tract of humans. However, it can commonly become pathogenic causing diseases such as pneumonia and meningitis. S. pneumoniae is unique in that a large percentage of its genome encodes for proteins involved in carbohydrate metabolism. A number of these pathways are essential for full virulence of the bacterium, including a putative fucose utilization pathway. There are two strain-dependent varieties of fucose operons in S. pneumoniae. The type 1 operon consists of a putative extracellular galactosidase (Sp4GH98), intra-cellular fucosidase (GH95A), PTS relay system (EIIA, EIIB, EIIC, EIID), fucose mutarotase (FcsU), fucose isomerase (FcsI), fuculose kinase (FcsK), and fuculose 1-phosphate aldolase (FcsA). Alternatively, the type 2 operon consists of a putative extracellular galactosidase (Sp3GH98), intra-cellular fucosidase (GH29), two intra-cellular galactosidases (GH36A and B), ABC transporter system, and fucose processing enzymes (FcsI, FcsK, and FcsA). The objective of this research is to characterize individual components from both fucose operons ultimately to generate both pneumococcal fucose utilization pathways. Specific focus on the extracellular GH98 enzymes provided evidence that these fucose pathways are initiated by the depolymerization of specific histo-blood group antigens presented on host cells. It is then proposed that the products liberated from the complex carbohydrate degradation are transported into the bacterium for further cleavage by intracellular GH enzymes releasing fucose for processing. This process is critical for S. pneumoniae virulence and may be involved in bacterial internalization by host cells suggesting a novel role for this pathway in pneumococcal pathogenesis. / Graduate

No description available.

Mode of access: World Wide Web. / Thesis (Ph. D.)--University of Hawaii at Manoa, 2005. / Includes bibliographical references (leaves 158-166). / Electronic reproduction. / Also available by subscription via World Wide Web / xiii, 166 leaves, bound col. ill. 29 cm. +

Thesis (M.S.)--University of Hawaii at Manoa, 2007. / Includes bibliographical references (leaves 57-63). / xii, 63 leaves, bound col. ill. 29 cm