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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.
1

Étude de la régulation de l'expression de la TACE par la cytokine TNF[alpha] et l'hypoxie via les facteurs de transcriptions HIF-1 et NF-[kappa]B

Charbonneau, Martine January 2005 (has links)
La polyarthrite rhumatoïde (PR) est une maladie auto-immunitaire touchant environ 1% de la population mondiale. Elle représente l'une des formes d'arthrite les plus sévères parmi plus de cent formes diagnostiquées à ce jour. Malheureusement, l'étiologie de cette maladie n'est pas encore connue et il n'existe aucun traitement curatif. Cette pathologie dégénérative est caractérisée par l'inflammation et l'hypertrophie de la membrane synoviale causant des dommages irréversibles à plusieurs articulations tels que la destruction du cartilage et l'érosion des os. Plusieurs molécules participent au développement de cette affection, notamment des facteurs de croissance, des métalloprotéinases ainsi que des cytokines. De celles-ci, le TNF[alpha] est l'une des plus importantes. En effet, il a été démontré que cette cytokine pro-inflammatoire puissante est essentielle dans la pathogenèse de la PR. Pour ce faire, le TNF[alpha] transmembranaire doit être clivé par la TACE pour générer sa forme soluble et active. Donc, la TACE, via son action protéolytique sur le TNF[alpha], est impliquée dans la progression de la PR. De plus, il a été démontré que cette protéase transmembranaire est induite au niveau des articulations arthritiques et que l'inhibition de cette enzyme diminue les symptômes chez les rats atteints d'arthrite. Ceci en fait donc une cible thérapeutique intéressante, d'où l'importance de comprendre sa régulation et son mode d'action. Afin d'étudier la régulation de la TACE en conditions inflammatoires, nous avons choisi deux agents importants dans le développement de la PR. On sait depuis longtemps que l'hypoxie, soit le manque d'oxygène, est une condition souvent présente au niveau des articulations arthritiques et que ces dernières sont caractérisées par des concentrations élevées de TNF[alpha]. Nous avons donc testé l'influence de ces deux stimuli sur la modulation de l'ARN messager de la TACE chez les deux principaux types cellulaires composant la membrane synoviale, soit les macrophages (synoviocytes de type A) et les synoviocytes de type B. Nous avons démontré, par RT-PCR, que l'hypoxie et le TNF[alpha] induisent l'accumulation de l'ARN messager de la TACE et que ces inductions sont dépendantes de la synthèse de l'ARN. De plus, nous avons établi que ces inductions au niveau de l'ARN messager corrèlent avec l'accumulation de la protéine TACE et l'augmentation de son activité protéolytique chez les synoviocytes de type B stimulés par le TNF[alpha] et en condition hypoxique. Nous avons ensuite cloné le promoteur de la TACE dans le vecteur d'expression pGL2 dans le but d'effectuer des essais luciférase afin d'étudier les mécanismes transcriptionnels régissant la régulation de la TACE. Nous avons démontré, grâce à cette technique, que l'hypoxie augmente l'activité du promoteur de la TACE via l'induction de la liaison du facteur de transcription HIF-1 à deux sites HRE contenus dans ce promoteur. D'un autre côté, même si l'induction régie par le TNF[alpha] requiert en partie la présence du HIF-1, elle est principalement dépendante du facteur de transcription NF-[kappa]B. Finalement, nous avons vérifié l'effet de l'anti-inflammatoire dexaméthasone, souvent utilisé pour traiter la PR, au niveau de la régulation de la TACE et nous avons découvert que ce glucocorticoïde a un effet inhibiteur sur l'activité du promoteur de la TACE. Ces résultats indiquent que l'hypoxie et le TNF[alpha], deux conditions présentes chez les articulations arthritiques, sont impliqués dans la régulation à la hausse de la TACE et, par conséquent, augmentent la disponibilité du TNF[alpha] soluble, une cytokine pro-inflammatoire importante dans l'amplification de la réponse inflammatoire.
2

α-Secretase processing of the Alzheimer amyloid-β precursor protein and its homolog APLP2

Jacobsen, Kristin January 2013 (has links)
The amyloid-β precursor protein (APP) has been widely studied due to its role in Alzheimer´s disease (AD). When APP is sequentially cleaved by β- and γ-secretase, amyloid-β (Aβ) is formed. Aβ is prone to aggregate and is toxic to neurons. However, the main processing pathway for APP involves initial cleavage at the α-site, within the Aβ region, instead generating a neuroprotective soluble fragment, sAPPα. APP is a member of a protein family, also including the proteins APLP1 and APLP2, which are processed in a similar way as APP. In addition, K/O studies in mice have shown that the three proteins have overlapping functions where APLP2 play a key physiological role. The aim of this thesis was to study mechanisms underlying the α-secretase processing of APP and APLP2. We have used the human neuroblastoma cell-line SH-SY5Y as a model system and stimulated α-secretase processing with insulin-like growth factor-1 (IGF-1) or retinoic acid (RA). Our results show that the stimulated α-site cleavage of APP and APLP2 is regulated by different signaling pathways and that the cleavage is mediated by different enzymes. APP was shown to be cleaved by ADAM10 in a PI3K-dependent manner, whereas APLP2 was cleaved by TACE in a PKC-dependent manner. We further show that protein levels and maturation of ADAM10 and TACE is increased in response to RA, mediated by a PI3K- or PKC-dependent signaling pathway, respectively. Another focus of our research has been O-GlcNAcylation, a dynamic post-translational modification regulated by the enzymes O-GlcNAc transferase and O-GlcNAcase (OGA). We show that decreased OGA activity stimulates sAPPα secretion, without affecting APLP2 processing. We further show that ADAM10 is O-GlcNAcylated. Lastly, we show that APP can be manipulated to be cleaved in a similar way as APLP2 during IGF-1 stimulation by substituting the E1 domain in APP with the E1 domain in APLP2. Together our results show distinct α-site processing mechanisms of APP and APLP2. / <p>At the time of the doctoral defence the following papers were unpublished and had a status as follows: Paper 4: Manuscript; Paper 5: Manuscript.</p>
3

STUDIES ON THE ROLE OF ACID SPHINGOMYELINASE AND CERAMIDE IN THE REGULATION OF TACE ACTIVITY AND TNFα SECRETION BY MACROPHAGES

Rozenova, Krasimira 01 January 2009 (has links)
Acid Sphingomyelinase (ASMase) activity has been proposed to mediate LPS signaling in various cell types. This study shows that in macrophages, ASMase is a negative regulator of LPS-induced TNFα secretion. ASMasedeficient (asm-/-) mice and isolated peritoneal macrophages produce several fold more TNFα than their wild-type (asm+/+) counterparts when stimulated with LPS. The mechanism for these differences however is not transcriptional but post-translational. The TNFα converting enzyme (TACE) catalyzes the maturation of the 26kD precursor (proTNFα) to the active 17kD form (sTNFα). In mouse peritoneal macrophages, the activity of TACE rather than the rate of TNFα mRNA synthesis was the rate-limiting factor regulating TNFα production. Substantial portion of the translated proTNFα was not processed to sTNFα; instead it was rapidly internalized and degraded in the lysosomes. TACE activity was 2 to 3 fold higher in asm-/- macrophages as compared to asm+/+ macrophages and was suppressed when cells were treated with exogenous ceramide and SMase. In asm-/- but not in asm+/+macrophages, indirect immunofluorescence experiments revealed distinct TNFα-positive structures in close vicinity of the plasma membrane. Asm-/- cells also had higher number of EEA1-positive early endosomes. Co-localization experiments that involved inhibitors of TACE and/or lysosomal proteolysis suggest that in asm-/-cells a significant portion of proTNFα is sequestered within the early endosomes, and instead of undergoing lysosomal proteolysis it is recycled to the plasma membrane and processed to sTNFα.
4

Examination of the Informed Consent Process as Experienced by Patients Who Underwent a De Novo Transjugular Intrahepatic Portosystemic Shunt, Chemoembolization or Radioembolization Procedure

Hughes-Gay, Marsha A. 08 1900 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / The purpose of this study is to examine the informed consent (IC) procedure as it was experienced by patients who had undergone a de novo transjugular intrahepatic portosystemic shunt (TIPS), chemoembolization (TACE), or radioembolization (TARE) procedure in an Interventional Radiology (IR) Department. The three main study aims and a fourth exploratory aim are as follows: (1) Describe how patients who underwent a de novo TIPS, TACE, or TARE procedure in an IR Department described the IC procedure; (2) Describe what information patients who underwent a de novo TIPS, TACE, or TARE procedure in an IR Department recalled being told during the IC procedure; (3) Describe the satisfaction of patients who underwent a de novo TIPS, TACE, or TARE procedure in an IR Department with the IC procedure; and (4) Explore how the IC experiences of patients who underwent a de novo TIPS, TACE, or TARE procedure in an IR Department differed according to their levels of health literacy. Using a qualitative descriptive design, participants were recruited from an IR department that performed these procedures. A total of 14 participants were interviewed about their IC experiences and the Newest Vital Sign (NVS) Health Literacy assessment was administered. The participants described the IC procedure by discussing the staff they encountered, their feelings during the visit, the support persons who accompanied them, and the decisions they made about the procedure. The participants recalled being told about how their procedure would be performed, the care they would need, and the benefits and risks of the procedure. Most were satisfied with the information received during the IC procedure and found the information consistent with how they experienced the procedure. A few participants would have liked more visual materials, addition details about the procedure, simpler language, or more explanation of the medical terminology. No apparent differences in the IC experience could be attributed to health literacy. These findings suggest that persons’ experiences during the IC process are multi-faceted and affected by their emotions and concerns and the nature of their encounters with their healthcare providers.
5

Lokoregionäre Therapie kolorektaler Lebermetastasen im Rattenmodell: Immunhistochemische Differenzierung von DNA und Hypoxie induzierten Schäden nach Applikation von Embolisatpartikeln / Hepatic arterial infusion in a rat model of colorectal liver metastases: Immunohistochemical differentiation between DNA and hypoxia induced damages caused by embolization particles and irinotecan

Nowack, Hannah Sophie 01 December 1100 (has links)
No description available.
6

The DNA methyltransferase inhibitor, guadecitabine, targets tumor-induced myelopoiesis and recovers T cell activity to slow tumor growth

Elkovich, Andrea J 01 January 2019 (has links)
Myeloid Derived Suppressor Cells (MDSC) represent a significant hurdle to cancer immunotherapy because they dampen anti-tumor cytotoxic T cell responses. Previous studies have reported on the myelo-depletive effects of certain chemotherapies. Using guadecitabine, a next-generation DNA methyltransferase inhibitor (DNMTi), we observed significantly reduced tumor burden in the 4T1 murine mammary carcinoma model. Guadecitabine treatment prevents excessive tumor-induced myeloid proliferation and systemic accumulation, and skews remaining MDSCs toward a beneficial antigen-presenting phenotype. Together, this alters the splenic environment to improve T cell activation and interferon-gamma (IFNg) production. Additionally, guadecitabine enhances the therapeutic effect of adoptively transferred antigen-experienced lymphocytes to diminish tumor growth and improve overall survival. Based on these findings, the immune-modulatory effects of guadecitabine can help rescue the anti-tumor immune response and could contribute to the overall effectiveness of current cancer immunotherapies. Allergies and asthma are common ailments that are on the rise around the world. Mast cells play a direct role in the signs and symptoms characteristic in allergic patients. The family of A Disintegrin And Metalloproteinases (ADAMs) are involved in regulating many cellular processes by cleaving surface receptors, ligands, and signaling molecules. We sought to determine the role of ADAM17 in mast cell activity. In studies using ADAM17-deficient mast cells, percent degranulation and cytokines released by IgE-mediated activation were significantly reduced. Interestingly, ionomycin-activation was unchanged, suggesting ADAM17 may be involved in IgE-mediated mast cell activation upstream of calcium release. Additionally, ADAM17MC-/- mice showed protection from IgE-, but not histamine-, mediated passive systemic anaphylaxis (PSA). The underlying mechanism behind the reduced degranulation occurs through signaling deficiencies downstream of Lyn phosphorylation. Together, the data suggest that ADAM17 is required for proper mast cell signaling through its interaction with the Src family kinase, Lyn.
7

Implication des disintégrines dans le clivage physiologique de la protéine prion : régulation par les récepteurs muscariniques et les protéines kinases

Alfa Cisse, Moustapha 21 March 2007 (has links) (PDF)
Les encéphalopathies spongiformes transmissibles (EST) constituent de graves maladies neurodégéneratives atypiques, affectant aussi bien l'homme que l'animal. Ces maladies ont une origine infectieuse, génétique ou sporadique. On distingue chez l'homme la maladie de Creutzfeldt-Jakob, le syndrome de Gerstmann-Sträussler-Sheinker, le nouveau variant de la maladie de Creutzfeldt-Jakob dû à l'ingestion d'aliments contaminés, et les formes iatrogènes, qui surviennent le plus souvent à la suite d'une contamination contractée lors d'interventions chirurgicales. Les maladies à prions animales les plus courantes sont l'encéphalopathie spongiforme bovine et la tremblante du mouton. Le facteur commun à toutes ces maladies est la protéine prion ou PrP, présente de façon ubiquitaire dans l'organisme et de manière prépondérante dans le cerveau. La PrP existe sous deux états conformationnels qui ont la même séquence en acides aminés, mais qui possèdent des propriétés physicochimiques différentes. La forme anormale du prion appelée "scrapie" ou "PrPsc " est partiellement résistante aux protéases et plus riche en feuillets b que la PrPc, ce qui lui confère une susceptibilité exacerbée à l'agrégation. L'hypothèse de "la protéine seule" proposée par Prusiner prédit que le titre infectieux serait composé uniquement de la PrPsc, capable de se répliquer de manière autocatalytique en se servant de la PrPc endogène comme matrice de conversion. Les mécanismes moléculaires régissant ce processus sont encore mal connus. Cependant ce phénomène de conversion apparaît comme l'évènement central contrôlant l'infection et sa propagation vers le système nerveux central. Ces processus nécessitent la présence de la PrPc endogène, puisqu'il a été montré que des souris invalidées pour la protéine prion résistent à l'infection et sont viables. Ces observations ouvrent de nouvelles perspectives en terme d'approches thérapeutiques théoriquement envisageables dans le domaine des EST. La PrPc, après une étape de maturation, subit un clivage physiologique à la membrane plasmique en position 111/112 qui conduit à la formation d'un fragment sécrété appelé N1. Des travaux effectués dans notre laboratoire ont montré que ce clivage est constitutif et régulé par la PKC et nécessite l'activité des disintégrines ADAM10 et ADAM17, respectivement. Mon travail de thèse à consisté à étudier ce clivage en identifiant les isoformes de la PKC impliquées, et à démontrer sa régulation par les récepteurs muscariniques.
8

FRMD8 is a novel regulator of iRhom-dependent ADAM17 activity

Künzel, Ulrike January 2017 (has links)
A disintegrin and metalloprotease (ADAM) 17 cleaves and releases membrane-tethered pro-forms of several signalling molecules from the plasma membrane, including the inflammatory cytokine tumour necrosis factor alpha (TNFα) and ligands of the epidermal growth factor receptor (EGFR). Due to the important functions of its substrates, ADAM17 activity has to be tightly controlled, and its misregulation has implications for inflammation and cancer. The multi-pass membrane proteins iRhom1 and iRhom2 are members of the conserved rhomboid-like superfamily and control ADAM17 activity by several mechanisms throughout the secretory pathway. First, iRhoms facilitate trafficking of the catalytically inactive proenzyme form of ADAM17 from the endoplasmic reticulum (ER) to the Golgi apparatus, where the inhibitory pro-domain of ADAM17 is removed. Subsequently, iRhoms exert a different form of control of ADAM17 at the plasma membrane, this time on stimulus-induced ADAM17 activity, its substrate specificity, and its stability. iRhoms ultimately regulate the release of ADAM17 substrates, and are consequently key players in TNF&alpha; and EGFR signalling. However, it remains unclear how iRhom function itself is regulated posttranslationally, and whether iRhoms require co-factors to exert their roles as ADAM17 regulators. The goal of my project was to shed light into these questions by identifying new iRhom interaction partners. I developed a mass spectrometry-based screen to identify new binding partners of human iRhoms using co-immunoprecipitation. The top hit of the screen was the poorly characterised FERM domain-containing protein 8 (FRMD8), which binds to both iRhom1 and iRhom2. FRMD8 was found to play a crucial role in the iRhom/ADAM17 pathway because FRMD8 knockdown and knockout in HEK293T cells significantly reduced the levels of mature ADAM17 and the release of ADAM17 substrates. The closely related metalloprotease ADAM10 was not affected by the loss of FRMD8, implying that FRMD8 is not a general regulator of ADAM metalloproteases. Interaction studies revealed that FRMD8 binds to the cytosolic N-terminus of iRhom2 throughout the entire secretory pathway. FRMD8 loss does not affect the ER-to-Golgi trafficking of iRhom2 but plays a role in stabilising iRhom2 at the plasma membrane by preventing the lysosomal degradation of both iRhom2 and mature ADAM17. Using human induced pluripotent stem cell (hiPSC)-derived macrophages, I showed that FRMD8 regulates mature ADAM17 levels and the ADAM17-dependent release of TNF&alpha; in human macrophages. Studies in FRMD8 knockout (KO) mice confirmed the reduced mature ADAM17 levels in all mouse tissues tested, further supporting the conclusion that FRMD8 is a novel regulator of the iRhom/ADAM17 pathway with physiological relevance in mammals. Finally, I showed that the interaction of FRMD8 and iRhom, which are both conserved from Drosophila to human, is also conserved. Furthermore, loss of the FRMD8 orthologue in flies, Bili, leads to motility defects and shows similarity to the loss of iRhom in flies. These results suggest that FRMD8 is a novel regulator of iRhom function in mammals and Drosophila.
9

The Effect of Exercise Training and/or Diet-Induced Weight Loss Intervention on TNFα Converting Enzyme (TACE) in Older Adults

Chalke, Arushi Milind 20 July 2021 (has links)
No description available.
10

Risk Factors for Extended Hospital Stay in Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma

Lin, Jau-Nan 29 June 2011 (has links)
Hepatocellular carcinoma (HCC) is the second most common cancer in Taiwan and transcatheter arterial chemoembolization (TACE) is now the mainstay of treatment for noncurative HCC. Due to increasing medical costs yearly and financial problem of the Bureau of National Health Insurance, it is important to reduce medical resource utilization including hospital stay and medical costs. The aim is to figure out the risk factors of extended hospital stay, and increased in-hospital medical costs in hepatocellular carcinoma patients receiving transcatheter arterial chemoembolization. The result of this study should be available for further improvement of medical care quality in the limited medical resource. From January 2008 to January 2010, 162 patients (121 male and 41 female) with histologically proven hepatocellular carcinoma underwent TACE only (131 pts) or TACE followed by catheter placement for hepatic artery infusion chemotherapy (HAIC) (31pts) at district teaching hospital. The extended hospital stay (EHS) and extended post-procedure stay (EPS) are defined as stay larger than their median values (11 & 7 days respectively). Clinical demographic, disease factors, tumor factors, procedure (TACE)-related factors and complications are used to identify the univariate factors related to EHS and EPS statistically. To find out predictors of EHS, EPS and increased in-hospital medical costs, multiple linear regression analyses are used. The risk factors for EPS are procedure-related, including complications and procedure methods ( TACE + HAIC related to TACE only) (R2=.367, p<.001), while those for EHS are complications, encephalopathy, procedure methods, Child-Pugh classification C (related to classification A) and age (R2=.490, p<.001). The predictors for increased in-hospital medical costs include procedure methods, AJCC stage IV, T4 stage, hepatoencephalopathy and complications (R2=0.615, p<.001). Taking total hospital stay into consideration, the most important risk factor related to increased medical cost is total hosptial stay itself. The most powerful risk factor for EPS, EHS is procedure-related complication. The different procedure methods also affect hospital stay and medical costs. In order to reduce medical resource utilization, we should avoid post-procedure complication and pay attention to cirrhotic degree as well as American Joint Committee of Cancer (AJCC) tumor stage system. The result of this study can provide some ideas to adjust medical expense polices for the Bureau of National Health Insurance and to control medical cost for the hospitals.

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