Dissertation (LL.M.)--University of Helsinki, April 2005. / Title from PDF title page (viewed May 18, 2006). Includes bibliographical references.

Thesis (D. Ed.)--University of Pretoria, 2006. / Includes bibliographical references. Available on the Internet via the World Wide Web.

Thesis (Th. M.)--Talbot School of Theology, Biola University, 1987. / Includes bibliographical references (leaves 154-175).

Thesis (PH.D.) -- Syracuse University, 2006 / "Publication number AAT 3240438."

Lung cancer is a leading cause of cancer in the United States and accounts for more deaths than prostate, breast, and colorectal cancers combined. Genetic variation has been known to play a role in lung cancer survival and risk. Furthermore, a racial disparity exists in lung cancer risk and survival such that African American males have increased risk and greater mortality compared to other U.S. racial/ethnic groups. This dissertation sought to expand our present understanding of the role of genetics in lung cancer survival and risk in African Americans. In a population of African Americans and whites from the Southern Community Cohort Study (SCCS), we examined the association between global African ancestry and overall survival and found no significant association. Stage and treatment, however, were strong predictors of overall survival. Since both stage and treatment are highly dependent on external social factors such as access to healthcare and willingness to seek treatment, we conclude that the observed racial disparity in lung cancer survival is strongly driven social determinants. We next examined genetic variants associated with lung cancer survival in the SCCS African Americans. We identified rs1878022 to be significantly associated with lung cancer survival, though in opposing direction to a previous study in whites. We also identified a region on chromosome 6p21.33 as suggestive of association with lung cancer survival. Finally, we sought to identify cross-cancer pleiotropic associations of lung cancer risk in African Americans by examining variant regions previously associated with cancer risk. We confirmed previous associations between chromosomes 15q25 and 5p15 and lung cancer risk. We also identified a peak on chromosome 16q22.2 significantly associated with increased lung cancer risk. Cumulatively these findings deepen our understanding of the role of genetics in both lung cancer risk and survival, particularly in African Americans. Future studies in African Americans are necessary to confirm these genetic associations.

Uterine fibroids, benign tumors of the uterus, are the most common female pelvic tumor. Fibroids are highly heterogeneous, with some women developing a single small fibroid while other women develop multiple and/or large fibroids. In addition, racial disparities in fibroid size and number support that fibroid characteristics have a genetic component. For example, African American (AA) women have more numerous and larger fibroids than European American (EA) women. Furthermore, AAs are two times more likely than EAs to receive surgical treatments for fibroids such as a hysterectomy. Unfortunately, most research on fibroids to date has not evaluated risk factors for specific fibroid characteristics. The purpose of this thesis is to provide a deeper understanding on both epidemiology and genetic risk factors of fibroid characteristics, fibroid number (single vs. multiple), volume of largest fibroid, and largest dimension of all fibroid measurements. After identifying epidemiologic risk factors for fibroid characteristics, this study identified several novel genetic loci associating with either fibroid size or number by methods of genome-wide association studies (GWAS) and admixture mapping studies. Lastly, this study estimated heritability of fibroids and fibroid size.

No description available.

Understanding the genetic and environmental factors contributing to blood pressure is an important step in elucidating the causes of hypertension, a disease of high blood pressure. African Americans experience the highest burden of hypertension in the United States, however little is known about the genetic factors contributing to blood pressure in African Americans, despite a high estimated heritability. Furthermore, current large scale studies of genetic variants contributing to blood pressure in African Americans do not include socioeconomic status (SES) information, in spite of a strong association between SES and blood pressure. To examine the potential interactions between SES and genetic variants contributing to blood pressure, a hospital-based population with electronic health records was used. Prior to conducting genetic analysis, several algorithms were developed to extract SES information from electronic health records (EHR). These algorithms extracted occupation, retirement, education level, unemployment, homelessness, Medicaid, and uninsured status with high accuracy. With the extracted education information, interactions between genetic variants contributing to blood pressure in African Americans and education were examined. No statistically significant interactions were observed. Some novel statistically significant and suggestive associations between genetic variants and blood pressure were observed. One suggestive interaction between a genetic variant and education level affecting blood pressure was detected. These results indicate that exploring interactions between SES data extracted from EHRs and genetic variants is possible on a large scale.

Magister Scientiae (Medical Bioscience) - MSc(MBS) / Human Coronavirus NL-63 is a respiratory virus with a high incidence rate, causing mild respiratory infections in children under the age of 18. The outbreak of Sever Acute Respiratory Syndrome (SARS) in 2003 sparked increased interest into the field of coronavirology and respiratory diseases subsequently led to the discovery of this novel Human Coronavirus (HCoV) by a group of scientists in Holland. The membrane protein (M) of NL-63 has been shown to interact with the nucleocapsid, spike and envelope proteins of the virus when expressed ex vivo. In contrast, the envelope protein (E) is shown to exhibit ion channel activity, interacts with the membrane protein during the formation of viral-like particles. The functions of the open reading frame 3 (ORF3) proteins remains a mystery. Research does, however, indicate that this protein is needed for in vivo infectivity and pathogenesis. Bioinformatic analysis indicates that both the ORF3 and M proteins posses at least 3 C-terminal transmembrane regions. To further characterize the biological activity of these three proteins in clinical and laboratory samples, sensitive and specific antibodies are required. Thus, the antigenic regions of ORF3, M and the entire E gene were amplified by PCR and ligated into a bacterial expression vector for expression and subsequent generation of antibodies in a mouse system. The identities of the cloned genes were confirmed by sequencing before being expressed in an in vitro bacterial system. Western Blots were used to identify the expression of the 41kDa, 42kDa and 34kDa GST-tagged viral proteins which were consistent with the bioinformatically predicted protein species. Verified fusion proteins were expressed in large quantities, quantified and concentrated for in vivo antibody production. Inoculation of 9 healthy, female Balb/C mice with the purified fusion proteins yielded high titers of polyclonal antibodies. Western Blotting was once again used to validate the production of the antibodies before their specificity was quantitatively measured using a modified competition ELISA. / South Africa

Includes bibliographical references (leaves 62-84). / Axon regeneration failure in the adult mammalian central nervous system is partly due to inhibitory molecules associated with myelin. The Nogo receptor plays a role in this process through an extraordinary degree of cross reactivity with three structurally unrelated myelin-associated inhibitory ligands namely; Nogo-A, myelin associated glycoprotein and oligodendrocyte myelin glycoprotein. The major aim of the study was to investigate the expression pattern of Nogo receptor and one of its ligands, Nogo-A in the mammalian nervous system, and also investigate whether Nogo receptor is located in neuronal lipid rafts by linking it to flotillins, known lipid raft markers. We therefore generated a rabbit polyclonal Nogo receptor antibody from the leucine rich repeat number 9 domain of Nogo receptor polypeptide chain. Together with a commercially available polyclonal antibody specific for Nogo receptor, and in conjunction with double labelling immunofluorescence methods on crysections and cell cultures, Nogo receptor immunoreactivity was also observed in brain, spinal cord, and dorsal ganglia. In cellular populations, it was confined to neuronal cell bodies and their processes. Nogo receptor was localised on the surface of extending dorsal root ganglion intact axons and growth cones in live staining experiments. Nogo-A, an important axon growth inhibitory molecule and member of the reticulon family protein, was widely distributed in the mammalian brain, spinal cord, and dorsal root ganglia. Intense Nogo-A immunoreactivity was dete cted in oligodendrocyte cell bodies and their myelin sheaths in nerve fibre tracts of the central nervous system. Furthermore, numerous populations of neurons in the brain and spinal cord expressed Nogo-A to a variable extent in their cell bodies and neurites, suggesting additional, as-yet-unknown, functions of this protein. In cell culture, cytoplasmic staining with anti-Nogo-A antibody was observed after fixation oligodendrocytes and neurones, but intracellular structures that presumably represent endoplasmic reticulum were also strongly labelled in fibroblasts. These results confirm results obtained by other researchers with different set of antibodies. However, they also raise the question of the mechanism and circumstances under which the Nogo receptor interacts with Nogo-A, as this protein appears to be confined to the cytoplasm and can therefore not be expected to bind Nogo receptor on the axon surface. To investigate whether Nogo receptor is localised in neuronal lipid rafts, commercial and local antibodies specific for Nogo receptor, in conjunction with flotillin (a known lipid raft-associated protein) were used in double-immunofluorescence, co-immunoprecipitation and western blotting experiments. Results revealed substantial immunofluorescent colocalisation of Nogo receptor and flotillin in membranes of axons and PC-12 cells. Further more, extraction Nogo receptor antigen from rat brain using receptor bound protein-A sepharose beads, followed by probing with anti-flotillin antibody, established the link between lipid rafts and Nogo receptor.