Thesis (Ph. D.)--University of Florida, 2004. / Title from title page of source document. Document formatted into pages; contains 145 pages. Includes vita. Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Göteborg : Univ. , 2010.

Translocation of viral integrase into nucleus is a critical precondition of integration during the life cycle of HIV, a causative agent of Acquired Immunodeficiency Syndromes (AIDS). It has been considered as an important target for the drug development to treat AIDS. In order to understand the detailed mechanisms of integrase-host cell protein complex interactions, we cloned HIV-1 integrase-EGFP into pTRE2hyg as visible tag to monitor the translocation process. When transiently transfected this vector into Tet-off ready HeLa cells, the EGFP: integrase is mainly localized in the nucleus. It has been hypothesized that any drugs that can inhibit the translocation process are novel class of drugs for AIDS treatment. More than 30000 synthetic compounds and 80000 natural products were screened by virtual screening. A total of 34 compounds were obtained and screened for their ability to block the nuclear entry of HIV-1 integrase by monitoring the EGFP fluorescence in the cells by high-throughput live cell imaging. Eight synthetic compounds (DW-IN4, DW-IN5, DW-IN6, DW-IN9, DW-IN15, DW-IN16, DW-IN17, DW-IN21) and one natural product (DW-IN719) were found to block integrase translocation significantly. According to our screening result, six compounds (INNB-1, INNB-2, INNB-3, INNB-4, INNB-5, INNB-6) were designed and synthesized. INNB-1 and INNB-2 had significant inhibition on integrase nuclear translocation. DW-IN6, DWIN719, INNB-1, INNB-2, INNB-3 and INNB-4, showed significant inhibition on P24 production in live virus assay. DW-IN6, INNB-1, INNB-2, INNB-3 and INNB-4 showed significant syncitia formation inhibition in live virus assay. Six compounds (KM7, KM8, KM14, KM30, KM37, KM79) from Kunming were screened as integrase nuclear translocation inhibitors. Using similar cell imaging techniques, we have cloned the GFP-tagged chemokine receptor CXCR4 using the lentivirus transfection system. CXCR4 receptor is a critical co-receptor in CD4 positive lymphocytes mediating the fusion of HIV into the CD4 positive cells. CXCR4-GFP was over-expressed in 293T cells and the results showed that GFP:CXCR4 receptor is expressed at the plasma membrane of the cells. These cells have been used to monitor the blockage of CXCR4 receptor internalization for drug development. Four compounds (KX128, KX166, KX171, KX180) from Kunming showed CXCR4 internalization blockage in imaging assay. The interaction of these compounds with CXCR4 was predicted by molecular docking. KX128 showed significant HIV inhibition in live virus assays. / Gu, Wangang. / Advisers: Pang Chui Shaw; David Chi Cheong Wan. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 165-179). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (Ph.D.). / Written for the Dept. of Medicine, Division of Experimental Medicine. Title from title page of PDF (viewed 2009/06/09). Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 122-140).

Chemerin is a chemoattractant adipokine that regulates adipogenesis and may induce insulin resistance. Chemerin serum concentrations are elevated in obese, insulin-resistant, and inflammatory states in vivo. Here we investigate the role of omental (OM) and subcutaneous (SC) adipose tissue chemerin and CMKLR1 messenger RNA (mRNA) expression in human obesity. In addition, we test the hypothesis that changes in chemerin serum concentrations are primarily associated with reduced body fat mass in the context of 3 weight loss intervention studies. Chemerin serum concentration was measured in 740 individuals in a cross-sectional (n = 629) study including a subgroup (n = 161) for which OM and SC chemerin mRNA expression has been analyzed as well as in 3 interventions including 12 weeks of exercise (n = 60), 6 months of calorie-restricted diet (n = 19) studies, and 12 months after bariatric surgery (n = 32). Chemerin mRNA is significantly higher expressed in adipose tissue of patients with type 2 diabetes mellitus and correlates with circulating chemerin, body mass index (BMI), percentage body fat, C-reactive protein, homeostasis model assessment of insulin resistance, and glucose infusion rate in euglycemic-hyperinsulinemic clamps. CMKLR1 mRNA expression was not significantly different between the 2 fat depots. Obesity surgery–induced weight loss causes a significant reduction on both OM and SC chemerin expression. All interventions led to significantly reduced chemerin serum concentrations. Decreased chemerin serum concentrations significantly correlate with improved glucose infusion rate and reduced C-reactive protein levels independently of changes in BMI. Insulin resistance and inflammation are BMI-independent predictors of elevated chemerin serum concentrations. Reduced chemerin expression and serum concentration may contribute to improved insulin sensitivity and subclinical inflammation beyond significant weight loss.

Tanto a invasão local como o comprometimento de linfonodos cervicais tem grande impacto na sobrevida de pacientes portadores de carcinomas epidermóides de cabeça e pescoço. Em nosso trabalho nós primeiramente determinamos a expressão dos receptores de quimiocinas de CXCR1 a CXCR5, além de CCR7 e CX3CR1 pelo método do ensaio de proteção à ribonuclease (RPA) em 98 fragmentos de tumores primários, 91 fragmentos de mucosas adjacentes e 26 linfonodos comprometidos e correlacionamos estes dados com parâmetros anátomo-patológicos e sobrevida. CXCL12 ligante do receptor CXCR4 e CCL19 e CCL21 ambos ligantes de CCR7 foram determinados em 38 fragmentos de tumores, 33 mucosas adjacentes e 25 linfonodos comprometidos pela técnica de real-time PCR. Os tumores primários apresentam expressão aumentada do mRNA de CXCR1 (P=0.013), CXCR3 (P=0.008) e CXCR4 (P=0.025). Não observamos correlações entre status linfonodal ou tamanho de tumor. Os linfonodos comprometidos expressam mais mRNA dos receptores de quimiocinas CXCR4, CXCR5, CCR7 e CX3CR1 (todos com P<0.0001) em comparação aos tumores comprometidos. Observamos um aumento de sobrevida (P=0.048) e uma tendência a aumento de sobrevida livre de doença (P=0.074) nos pacientes negativos para a expressão de CX3CR1 (n=17) em comparação aos pacientes positivos (n=21) somente no subgrupo de pacientes portadores de carcinomas da cavidade oral. O mesmo foi observado com os pacientes CCR7 negativos também no subgrupo de pacientes portadores de carcinomas da cavidade oral, tanto em sobrevida global (P=0.024) como para sobrevida livre de doença (P=0.049). Em relação aos ligantes de quimiocinas observamos um aumento do mRNA de CCL21 em linfonodos comprometidos em relação aos tumores primários (P=0.059). Concluímos que a interação quimiotática entre CCR7 e de seu ligante CCL21, poderia ser um mecanismo de atração de células tumorais para os linfonodos em tumores de cavidade oral, além disso a negatividade da expressão do mRNA de CCR7 e CX3CR1 são candidatos marcadores de uma melhor sobrevida em carcinomas epidermóides de cavidade oral. / Local invasion and lymph nodal spread impact in the outcome of Head and Neck squamous cell carcinoma (HNSCC) patients (pts). We determined CXCR1-5, CCR7 and CX3CR1 mRNA expression by means of RNAse protection assay in 98 HNSCC primary tumors and 91 adjacent mucosa and 26 metastatic lymph nodes, correlating this data with outcome. CXCL12 and CCL19/CCL21, ligands for CXCR4 and CCR7, were determined in 38 tumor fragments, 33 adjacent mucosas and 25 de metastatic lymph nodes, by means of Quantitative Real-Time PCR. Tumors presented higher CXCR1 (P=0.013), CXCR3 (P=0.008) and CXCR4 mRNA (P=0.025) expression as compared to mucosa. No correlations are observed neither lymph nodal status nor tumor size impacted on chemokine receptor expression. Metastatic lymph nodes expressed more CXCR4, CXCR5, CCR7 and CX3CR1 (P<0.0001) as compared to matched tumors. We found a longer overall survival (OS) (P=0.048) and a trend toward longer disease free survival (DFS) (P=0.074) in CX3CR1 negative (n=17) as compared to positive pts (n=21) only in oral subgroup. The same occurred for CCR7 negative oral SCC, in terms of OS (P=0.024) and DFS (P=0.049). We conclude that, of the chemokine receptors here studied, CCR7 and CX3CR1 mRNA expression seems to better reflect outcome in oral subsite only. In addition, CCL21, a CCR7 ligand mRNAs is more expressed in metastatic lymph nodes than tumors (P=0.059). Further studies are warranted to confirm these results.