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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
781

The effect of acute gout on inflammatory markers in hyperuricemic patients

Kopke, Amy 23 May 2012 (has links)
Introduction: Gout is a painful form of acute inflammatory arthritis associated with elevated uric acid crystal deposition especially in the joints, but also in tendons and the kidney. Between 1 and 2% of Western populations are affected and in severe cases, gout sufferers can be completely incapacitated. Despite the number of gout sufferers, the high number of risk factors and high incidence of adverse drug reactions using the standard treatment regimens, little research involving gout has been done within the highly diverse multiracial and multicultural population of South Africa. Hypothesis: This study was a hypothesis generating observational study to assess whether serum levels of pro-inflammatory cytokines and acute phase protein levels could be used as markers of the gout status of a patient. Method: Thirty gout patients were enrolled onto the study and attended two visits. At the screening visit; medical history, vital signs and demographic details were collected from intercritical gout patients. At both visits, patients completed visual analogue scales; namely: subject’s assessment of pain and subject’s assessment of disease activity. A doctor completed the physician’s assessment of disease activity at both of the visits. At the end visit, patients experiencing an acute gout attack were asked to list various foods and beverages that triggered said attacks. Patients were requested to return for their second visit as soon as they experienced a gout attack, however, those patients that did not experience a gout attack were asked to return to the clinic to complete the follow up visit four months after their baseline visit. Uric acid, IL-1β, TNF-α and CRP were measured for each patient at both visits. Results: Many of the patients displayed risk factors for metabolic syndrome. The mean subject’s assessment of pain score increased from 31mm at the screening visit to 40mm at the end visit (p=0.1947; n=26), while the mean subject’s assessment of disease activity score and the mean physician’s assessment of disease activity increased from 30mm to 37mm (p=0.3196; n=26) and 23mm to 35 mm (p=0.0937; n=26) respectively. Uric acid levels decreased from 1.053mmol/L to 0.871mmol/L between visits (p=0.0926; n=25) while CRP concentrations increased significantly from 10.2mg/L to 26.6mg/L (p=0.0278, n=24). IL-1β concentrations remained similar (12.17pg/ml to 12.54pg/ml) while TNF-α concentrations decreased from 12.63pg/ml to 3.54pg/ml, however neither of these were statistically significant differences. Upon stratifying results into active and non-active patients, both IL-1β and TNF-α concentrations decreased between non-active and active patients, while CRP and urate concentrations increased. However, none of these differences were statistically significant. Conclusion: The visual analogue scales all showed an increase between the screening and final visits, although this was not statistically significant. Uric acid concentrations decreased between visits, however this increase was once again not statistically significant. There appears to be no association between inflammatory markers and the level of gout activity, although this needs to be tested in a larger sample population. Results in South African patients have confirmed results from previous studies where gout patients are at a higher risk of metabolic syndrome than the normal population. Copyright / Dissertation (MSc)--University of Pretoria, 2011. / Pharmacology / unrestricted
782

Percutaneous sensitization is limited by in situ inhibition of cutaneous dendritic cell migration via skin-resident regulatory T cells / 経皮感作は皮膚制御性T細胞による樹状細胞遊走の阻害を介して制限されている

Hanakawa, Sho 25 November 2019 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第22122号 / 医科博第107号 / 新制||医科||7(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 生田 宏一, 教授 濵﨑 洋子, 教授 杉田 昌彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
783

Maternal Glucocorticoids Make the Fetal Membrane Thinner: Involvement of Amniotic Macrophages / 母体グルココルチコイド投与は羊膜マクロファージの関与により卵膜を脆弱化させる

Kiyokawa, Hikaru 23 March 2020 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22322号 / 医博第4563号 / 新制||医||1041(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 椛島 健治, 教授 安達 泰治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
784

Frequent mutations converging into NFKBIZ signalling in ulcerative colitis / 潰瘍性大腸炎におけるNFKBIZシグナル経路変異

Kakiuchi, Nobuyuki 23 March 2020 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22364号 / 医博第4605号 / 新制||医||1043(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 濵﨑 洋子, 教授 松田 文彦, 教授 遊佐 宏介 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
785

The Role of 14-3-3ζ in IL-17A Signaling

Peter, Cara 06 September 2019 (has links)
No description available.
786

Interleukin-2 Receptor Alpha Nuclear Localization Impacts Vascular Smooth Muscle Cell Function and Phenotype

Dinh, Kristie Nhi 01 September 2021 (has links)
No description available.
787

Regulation and Function of IL-36γ in Genital HSV-2 Infection and Disease Pathogenesis

January 2019 (has links)
abstract: An estimated 267 million women worldwide are HSV-2 seropositive, including roughly 20% of reproductive-aged American women. HSV-2 is a neurotropic virus that establishes a persistent, life-long infection that increases risk for STI acquisition in individuals. The vaginal epithelium represents a critical first line of defense against infection, and during acute infection, underlying immune mechanisms in the epithelium may be critical to protect against disease pathogenesis. The recently identified pro-inflammatory cytokine IL-36gamma has been shown to be expressed at mucosal epithelia, including the female reproductive tract (FRT) and may be an important factor in host defense. Although IL-36gamma has been shown to be induced in the FRT after exposure to microbial products, the contributions of IL-36gamma to host defense mechanisms in response to this clinically relevant STI pathogen are not well understood. This dissertation describes the regulation of IL-36gamma in the FRT and explores its contribution to the host response against genital HSV-2 infection. To test the hypothesis that IL-36gamma is a key regulator of mucosal inflammation and immunity in the FRT, hormonal regulation of IL-36gamma in the FRT was investigated using estrogen- and progesterone-conditioned mice. From this preliminary study, it was shown that progesterone dampens IL36G expression relative to estrogen and may potentially increase susceptibility to infection. Next, the impact of IL-36gamma treatment on HSV-2 infection and replication in human 3-D vaginal epithelial cells was explored. In parallel, the impact of intravaginal IL-36gamma delivery on HSV-2 disease pathogenesis was evaluated using a lethal murine challenge model. IL-36gamma pre-treatment significantly limited HSV-2 replication in vitro and in vivo and was associated with transient neutrophil infiltration that corresponded with decreased disease severity and increased survival in mice. Last, the requirement for IL-36gamma in host defense was investigated utilizing IL-36gamma-/- mice in a lethal HSV-2 murine challenge model. Following infection, IL-36gamma-/- mice exhibited significantly impaired neutrophil recruitment, decreased overall survival time, and significantly increased viral neuroinvasion relative to wild type mice. Collectively, these data indicate that IL-36gamma is a crucial regulator of HSV-2-induced neutrophil infiltration and appears to function in a previously uncharacterized manner to limit viral neuroinvasion in genital HSV-2 disease pathogenesis. / Dissertation/Thesis / Doctoral Dissertation Molecular and Cellular Biology 2019
788

Cannabinoids Induce Immunoglobulin Class Switching to IgE in B Lymphocytes

Agudelo, Marisela 18 May 2009 (has links)
Cannabinoid treatment increases Th2 activity and previous reports showed B cells express the highest level of CB2 mRNA relative to other immune cells suggesting that cannabinoids play a critical role in B cell activation and maturation. To examine the direct effect of cannabinoids on B cell antibody class switching, mouse splenic B cells were purified by negative selection and cultured with IL4 and anti-CD40 in the presence or absence of the nonselective cannabinoid agonist, CP55940, or the CB1 selective agonist, methanandamide, or the CB2 selective agonist, JW015. The cultures were then analyzed at different times by flow cytometry for expression of B cell surface markers, such as CD19, CD138, CD40, MHCII, CD23, CD80, CD45R, immunoglobulins produced such as IgM, IgE, IgD, and IgG1, and Toll-like receptors such as TLR 2 and 4. Cells treated with CP55940 showed an increase in surface expression of IgE by day 5 in culture; methanandamide had no effect. CP55940 also induced an increase in secreted IgE in culture supernatants analyzed by ELISA. In addition, CB2 receptors were increased on B cells following stimulation with IL-4 and anti-CD40 and the class switching effect of CP55940 was attenuated by the CB2 antagonist, SR144528. We also observed that cannabinoid treatment of B cells modulates cell functions other than antibody class switching such as surface marker and TLR expression. CP55940 caused a significant increase in surface expression of TLR 4, but had no effect on other markers. Additional experiments with cannabinoid receptor selective agonists and antagonists suggested both CB1 and CB2 receptors were involved in the TLR effect. Receptor involvement and Gi coupling was supported by our findings that cannabinoids inhibit intracellular cAMP levels in forskolin stimulated B cells, and increasing intracellular cAMP with forskolin suppressed IgE antibody class switching in activated B cell cultures. These results suggest cannabinoids negatively regulate cAMP in B cells resulting in increased IgE. In conclusion, cannabinoids can directly affect the function of B cells by inducing antibody class switching to IgE and TLR4 expression through mechanisms involving CB1 and CB2 receptors suggesting the endocannabinoid system may be an important regulator of humoral immunity and the allergic response.
789

Role of Oncogenic Protein Kinase C-iota in Melanoma Progression; A Study Based on Atypical Protein Kinase-C Inhibitors

Ratnayake, Wishrawana Sarathi Bandara 28 March 2019 (has links)
Irrespective of plentiful efforts to enhance primary prevention and early detection, the number of melanoma cases in the United States has increased steadily over the past 30 years, thus greatly affecting public health and the economy. We have investigated the effects of five novel aPKC inhibitors; 2-acetyl-1,3-cyclopentanedione (ACPD), 3,4-Diaminonaphthalene-2,7-disulfonic acid (DNDA), [4-(5-amino-4-carbamoylimidazol-1-yl)-2,3-dihydroxycyclopentyl] methyl dihydrogen phosphate (ICA-1T) along with its nucleoside analog 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat) on cell proliferation, apoptosis, migration and invasion of two malignant melanoma cell lines compared to normal melanocyte cell lines. Molecular docking data suggested that both ACPD and DNDA specifically bind to protein kinase C-zeta (PKC-ζ) and PKC-iota (PKC-ι) while both ICA-1 compounds specifically bind to PKC-ι, and ζ-Stat showed a high affinity towards PKC-ζ. Kinase activity assays were carried out to confirm these observations. Results suggest that PKC-ι is involved in melanoma malignancy than PKC-ζ. Both isoforms promote the activation of nuclear factor (NF)-κB and protein kinase B (AKT) thereby supporting survival and progression. In addition, we demonstrated that PKC-ι induced the metastasis of melanoma cells by activating Vimentin, and PKC-ι inhibition downregulated epithilial-mesencymal transition (EMT), while inducing apoptosis. Of note, PKC-ἱ specific inhibitors downregulated the expression of both PKC-ι and phosphorylated PKC-ι, suggesting that PKC-ι plays a role in regulating its own expression in melanoma. We also report the underlaying mechanisms of the transcriptional regulation of PKC-ι (PRKCI gene) expression in melanoma. c-Jun, interferon-stimulated gene factor 3 (ISGF3), paired box gene 3 (PAX3), early growth response protein 1 (EGR1) and forkhead box protein O1 (FOXO1), which bind on or near the promoter sequence of the PRKCI gene, were analyzed for their role in PKC-ι regulation in SK-MEL-2 and MeWo cell lines. We silenced selected transcription factors using siRNA, and the results revealed that the silencing of c-Jun and FOXO1 significantly altered the expression of PRKCI. The levels of both phosphorylated and total PKC-ι increased upon FOXO1 silencing and decreased upon c-Jun silencing, suggesting that c-Jun acts as an upregulator, while FOXO1 acts as a downregulator of PRKCI expression. We also used a multiplex ELISA to analyze multiple pathways other than NF-κB that were affected by treatment with PKC-ι inhibitor. The silencing of NF-κB p65 and PKC-ι by siRNA suggested that the regulation of PKC-ι expression was strongly associated with FOXO1. In addition, we observed a significant decrease in the mRNA levels of both interleukin (IL)-6 and IL-8, with a significant increase in the levels of IL-17E and intercellular adhesion molecule 1 (ICAM-1) upon the knockdown of expression of PKC-ι in both cell lines. This suggested that PKC-ι expression was affected by these cytokines in an autocrine manner. Overall, the findings of this study suggest that PKC-ι inhibition suppresses its own expression, diminishing oncogenic signaling, while upregulating anti-tumor signaling, thus rendering it an effective novel biomarker for use in the design of novel targeted therapeutics for melanoma.
790

The Development of Targeted Cytokine-based Gene Therapies for Treating Prostate Cancer Bone Metastases

Janelle Weslyn Salameh (9759410) 11 December 2020 (has links)
Prostate cancer (PCa) bone metastases have been reported in ~90% of patients with advanced disease. Bone metastases disrupt tissue homeostasis and weaken the skeleton, resulting in an increased risk of bone fractures and morbidity. Specifically, PCa cells disrupt the crosstalk between critical cells within the tumor/bone microenvironment (osteoblasts, osteoclasts, and immune cells), and utilize this effector-rich environment for cancer survival and growth. Therefore, a key therapeutic objective in malignant skeletal disease management is to eliminate tumors while restoring bone homeostasis. Current treatments include palliative radiotherapy, chemotherapy, or anti-RANK treatments, all of which have considerable side effects such as osteonecrosis of the jaw or enhanced tumor invasion. There remains a critical gap in therapies than can reduce tumor burden and simultaneously restore bone homeostasis. To address this gap, our work explores emerging gene therapy approaches for treating skeletal malignancies by utilizing multifunctional cytokine-based agents that can simultaneously combat tumor growth and promote bone regeneration.<div><br></div><div>We hypothesize that rationally designed cytokine-based gene therapies that can be secreted from skeletal muscle and targeted to the bone/tumor microenvironment, could effectively reduce tumor growth and restore bone cell homeostasis. To test this hypothesis, we adopted two strategies: 1) a second-generation targeted IL-27 cytokine, and 2) a de novodesign of a cytokine-like therapeutic agent (Propeptide) that includes anti-tumorigenic and pro-osteogenic domains. Both strategies share modules with overlapping therapeutic functions, rendering them complementary in their therapeutic application. In this work, we examined the proof of principle for propeptide gene therapy in muscle cells (in vitro models) and assessed the therapeutic efficacy of our cytokine-based biologics in reducing prostate tumor growth and rebalancing bone cell proliferation and differentiation. Our studies resulted in a propeptide construct representative of a cytokine structure comprised of a bundle of helices that we were able to express in cells. Additionally, our work demonstrated the targeting and anti-tumor efficacy of our therapeutic cytokines in cancer and bone cell models. Ultimately, this will provide the framework for innovative peptide and cytokine-based therapeutics that target and treat both the tumor metastases and bone. This approach will facilitate improvement of morbidity and quality of life of prostate cancer patients with bone metastases and could be applicable to other diseases with bone/tumor pathologies. <br><div><br></div></div>

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