Thesis (Ph. D.)--University of Wisconsin--Madison, 1995. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 287-330).

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 152-176).

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Made available in DSpace on 2014-06-11T19:24:38Z (GMT). No. of bitstreams: 0 Previous issue date: 2006Bitstream added on 2014-06-13T20:52:13Z : No. of bitstreams: 1 avendanorueda_jc_me_arafo.pdf: 1556515 bytes, checksum: 41f930447d5e928990d3469d3288f326 (MD5) / Universidade Estadual Paulista (UNESP) / O objetivo deste estudo foi o de avaliar a biocompatibilidade e a infiltração no sentido coroa/ápice de um cimento obturador de canais radiculares à base de uretano dimetacrilato denominado Endo-Rez. Foram utilizados 56 canais radiculares de dentes de cães, os quais foram divididos em 4 grupos experimentais: Grupo I, Endo-Rez com restauração coronária (18 raízes); Grupo II, Sealapex com restauração coronária (10 raízes); Grupo III, Endo-Rez sem restauração coronária (18 raízes) e Grupo IV, canais radiculares obturados com Sealapex sem restauração coronária (10 raízes). Os canais radiculares foram instrumentados pela técnica clássica e obturados pela técnica de condensação lateral ativa (Grupo II e IV) e técnica de cone único (Grupo I e III). Decorridos 90 dias, os animais foram mortos e as peças submetidas ao processamento histológico. A avaliação histopatológica mostrou que os grupos I e III que foram obturados com Endo-Rez com e sem restauração coronária respectivamente, apresentaram semelhante infiltrado inflamatório periapical crônico de grau moderado/severo, severo aumento do espaço periodontal apical e ausência de selamento biológico apical. O grupo IV, obturado com Sealapex, aberto ao meio bucal por 90 dias, apresentou características histopatológicas similares aos grupos I e III. O Grupo II, cujos canais radiculares foram obturados com o Sealapex com restauração coronária ocorreu infiltrado inflamatório moderado e espessamento do espaço periodontal apical predominantemente leve, na maioria dos espécimes, exibindo selamento apical biológico em apenas 1 caso, portanto 10% dos espécimes. / The aim of this study was to evaluate in vivo the biocompatibility and coronal leakage of a new urethane metacrylate resin-based sealer, EndoRez. Sixty root canals of dog's teeth were divided into four experimental groups. Group I and III, EndoRez with and without coronal obturation respectively, Group II and IV Sealapex with and without coronal obturation respectively. The teeth were instrumented with a classic technique with Groups II and IV filled by the lateral condensation active technique with gutta percha points, while groups I and III were filled by the single cone technique. After 90 days, the animals were killed and specimens prepared histopathologically. The histopathological evaluation showed in the Groups I and III filled with EndoRez and the Group IV filled with Sealapex, most specimens with severe and moderate chronic inflammatory infiltrate, severe thickness of periodontal ligament and the apical sealing absence, Whereas, in Group II filled with Sealapex, most specimens showed mild and moderate inflammatory infiltrate, less thickness of periodontal ligament, and 30% exhibit biological apical sealing.

South Africa is at present encountering one of the worst Tuberculosis (TB) epidemics in the world, accentuating the need for intervention to eradicate TB. Various studies have established that certain population groups are at risk for increased susceptibility to infection with Mycobacterium tuberculosis (M. tuberculosis). This predominantly occurs in populations, like the native African population groups, who were not exposed to TB until the disease arrived in their country with European settlers, colonialists and missionaries. These population groups consequently lack the natural resistance to infection, which other populations developed through years of exposure to the pathogen. Several susceptibility-associated genetic polymorphisms have been proposed to explain differential susceptibility to TB. HLA class II molecules play a pivotal role in the activation of the host immune response against M. tuberculosis. Consequently numerous HLA class II genes have been found to be associated with TB. Among the most commonly observed associations is that of HLA-DR2 with TB, which has been observed in various population groups. Although this association has been observed to transcend ethnic barriers, inter-population variation has also been established regarding HLA-TB associations. In this study, the possible association of HLA class II polymorphisms, specifically of the HLA-DRB1, DQB1, DRB3, DRB4 and DRB5 loci, with TB susceptibility was investigated in the Venda population of South Africa. This was achieved by conducting both a case-control and family-based association study. The results obtained in this study established a unique association between HLA-DRB1*1302, DQ7 and TB susceptibility. A marginally significant association was also observed with DRB1*1301 and DQ6d and possible TB resistance. The above-mentioned results, which were observed in the case-control group, could not be replicated in the family-based study. It was therefore concluded from the results obtained in this study that employing both a case-control and family-based analysis when undertaking an association study is the most beneficial option. / Prof. Liza Bornman

Immune evasion is an emerging hallmark of cancer. Dysregulation of the major histocompatibility complex class I (MHC-I) is a frequent mechanism of immune evasion utilized by tumor cells and is particularly relevant to the pathogenesis of B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). A better understanding of MHC-I dysregulation in B-cell lymphomas is necessary to identify factors related to the risk, development, and progression of these tumors. In this thesis, we investigate the role of MHC-I dysregulation in DLBCL and cHL through the application of computational approaches to study genomic data. First, we introduce some background information about the normal function of MHC-I in the immune response to cancer and viral infection as well as the phenomenon of MHC-I dysregulation in the context of cancer. We provide an overview of how factors such as germline zygosity of HLA class I (HLA-I) genes and somatic alterations in the genes B2M and HLA-I that encode the protein subunits of MHC-I contribute to the development of DLBCL and cHL. Second, we present a study of the effects of HLA-I allele zygosity on survival in a cohort of 519 DLBCL patients treated with R-CHOP immunochemotherapy stratified by molecular subtype. Homozygosity in HLA-I was associated with a worse overall survival in patients whose tumors were classified in the “EZB” subtype, associated with somatic mutation in the epigenetic regulator EZH2. We find an association between the zygosity of the genes HLA-B and -C specifically and overall survival in EZB-DLBCL. These findings indicate that HLA-I zygosity may be a risk factor for worse clinical prognosis in patients with the EZB subtype of DLBCL. Third, we present a study of the genetic landscape of cHL tumors that are associated with infection with Epstein-Barr virus (EBV). We analyze inherited HLA-I allele types, somatic mutations, copy number changes, and mutational signatures in a cohort of 57 cHL patients (15 EBV-positive). We find that EBV-positive cHL is genetically distinct from EBV-negative cHL and is characterized by lower somatic mutation load and different activities of mutation signatures. Further, we find that cHL tumors are characterized by different patterns of MHC-I dysregulation depending on the EBV infection status. Germline homozygosity in HLA-I was associated with the EBV-positive subtype of cHL, while somatic alterations in HLA-I were associated with the EBV-negative subtype of cHL. These results suggest that inherited HLA-I homozygosity may be a risk factor for the EBV-positive subtype of cHL. Fourth, we expand our study of HLA-I in virus-associated cHL to perform a comparative analysis of virus-positive and virus-negative tumors in nine cancers linked to five viruses. We find that virus-positive tumors occur more frequently in males and show geographical disparities in incidence. Genomic analysis of 1,658 tumors reveals virus-positive tumors exhibit distinct mutation signatures, recurrent mutations in the RNA helicases DDX3X and EIF4A1, and a lower somatic mutation burden compared to virus-negative tumors of the same cancer type. We find that germline homozygosity in HLA-I is a potential risk factor for the development of EBV-positive cHL, but not other common virus-associated solid or hematological malignancies. Finally, we present in the Appendix a study of the genomic characterization of plasmablastic lymphoma (PBL), a rare EBV-associated B-cell lymphoma that occurs in the context of immunodeficiency caused by human immunodeficiency virus (HIV) infection. We find that PBL is characterized by mutations leading to constitutive activation of the JAK-STAT pathway. We additionally identify recurrent mutations in immune-related genes, such as B2M. These findings indicate a potential role for MHC-I and immune dysregulation in the pathogenesis of other B-cell lymphomas.

[Truncated abstract] Sporadic inclusion body myositis (sIBM) is a chronic inflammatory disease that is the most common myopathy in individuals above the age of 50 in the Caucasian population. sIBM is characterised by cytotoxic immune infiltration of skeletal muscle, consisting primarily of CD8+ T-cells and macrophages, as well as a degenerative process, with muscle fibre vacuolation and intracellular filamentous inclusions. The pathogenesis of sIBM is likely to involve a complex interaction between genetic and environmental factors. Whilst the physiological and pathological characteristics of sIBM have been clearly identified, the exact origin and genetic basis of the disease remains unknown. A number of studies show that sIBM is associated with alleles of the major histocompatibility complex (MHC) on chromosome 6p21.3 and specifically with two ancestral haplotypes (AH) in Caucasians – the 8.1AH, defined by HLA-B*0801, HLA-DRB1*0301 and the 35.2AH, defined by HLA-B*3501, HLA-DRB1*0101. Mapping studies subsequently showed that sIBM susceptibility likely originates from a 389kb region of the MHC, spanning from centromeric of PBX2 to telomeric of HLA-DRB1. The central hypothesis of this thesis was that susceptibility to sIBM is conferred by a single allele found within a region defined using the 8.1AH, which is also carried by other haplotypes associated with sIBM. Three patient cohorts from Australia, the U.S.A and Japan were studied. ... Of the 32 alleles genotyped, none were found in all susceptibility haplotypes and one was common, but not unique, to the 8.1AH, 7.2AH and 52.1AH. Five SNPs were also found in two of the three haplotypes, although none were specific to the sIBM susceptibility haplotypes. These data suggest that the 8.1AH is likely to carry an sIBM susceptibility allele independent of the 35.2AH, 7.2AH and 52.1AH. Based on the possible mechanism of action in cellular differentiation and its location within the 8.1AH-defined sIBM susceptibility region reported in 2004, NOTCH4 was a strong candidate for conferring sIBM susceptibility. NOTCH4 coding region polymorphisms were thus investigated in a Caucasian patient cohort to assess any possible role in sIBM susceptibility. While the frequency of some alleles were increased in sIBM patients, the strong linkage disequilibrium throughout the MHC prevented confirmation of any alleles as playing a direct role in sIBM. The 8.1AH-derived sIBM susceptibility region was further refined using recombination mapping. This approach used markers characterised against multiple haplotypes to genotype patients carrying part of the 8.1AH to locate a common, overlapping susceptibility region. Recombination mapping of patients revealed a common overlapping region of the 8.1AH, extending from BTNL2 to HLA-DRB3. The results of the study indicate that 8.1AH-derived susceptibility for sIBM is likely to originate from a 172kb region encompassing HLA-DRA, HLA-DRB3 and part of BTNL2. These genes warrant further investigation in future studies.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.

Thesis (Ph. D.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains xii, 239 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

Thesis (M.Sc.)--Memorial University of Newfoundland, Faculty of Medicine, 1999. / Typescript. Bibliography: leaves 113-124.