Dissertationen zum Thema „STAT inhibitors“
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Etter, Jonathan Parker. „Development of Inhibitors in the IL-6/GP130/JAK/STAT Pathway as Therapeutic Agents“. The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1376525461.
Der volle Inhalt der QuelleGhafoory, Shima. „Development of a screening assay for inhibitors of inflammation useful against pancreatic cancer“. Thesis, Mälardalen University, Mälardalen University, School of Sustainable Development of Society and Technology, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-7797.
Der volle Inhalt der QuellePancreatic cancer is the fourth most lethal cancer and ranks as the eighth most commonly diagnosed cancer worldwide. This is due to its rapid proliferation, strong metastatic potential and its delayed detection. One major risk factor for developing pancreatic cancer is the aggressive inflammatory disease chronic pancreatitis. Chronic inflammation frequently precedes the development of certain pancreatic cancers.
Inflammation is a protective and necessary process by which the body can alert the immune system of the existence of a wound or infection and mount an immune response to remove the harmful stimuli and start wound healing. The cross-talking of cells of the immune system and infected cells happens through cytokines, soluble proteins that activate and recruit other immune cells to increase the system’s response to the pathogen. Failure to resolve the injury can result in persistent cytokine production that in turn allows a cell that is damaged or altered to survive when in normal conditions it would be killed. Inflammation is thought to create a microenvironment that facilitates the initiation and/or growth of pancreatic cancer cells.
Cytokines use two important kinases for their signaling: Janus Kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs). The JAKs are activated upon the binding of cytokines to their corresponding receptors. When activated, the JAKs activate STATs through tyrosine phosphorylation. The STATs transduce signals to the nucleus of the cells to induce expression of critical genes essential in normal physiological cellular events such as differentiation, proliferation, cell survival, apoptosis and angiogenesis. STAT3 (a member of the STAT family) is constitutively activated in some pancreatic cancers, promoting cell cycle progression, cellular transformations and preventing apoptosis. Therefore, STAT3 is a promising target for cancer treatment. Novel therapies that inhibit STAT3 activity in cancers are urgently needed. Natural products are a very good resource for the discovery of new drugs against pancreatic cancer.
Covering more than 70% of the Earths surface, The Ocean is an excellent source of bioactive natural products. Harbor Branch Oceanographic Institute’s Center for Marine Biomedical and Biotechnology Research (HBOI-CMBBR) situated in Florida, aims to find new marine natural products useful in disease prevention and drug therapy. Their current focus is to look for novel treatments for preventing both the formation of new pancreatic tumors and the metastasis of existing tumors.
The hypothesis of this degree project was that novel inhibitors of STAT3 useful in the treatment of pancreatitis and/or pancreatic cancer could be found from marine-natural products. The first specific aim of this degree project was to set up an assay to identify bioactive marine natural products as inhibitors of inflammation. Furthermore the assay was validated using a commercially available inhibitor of inflammation (Cucurbitacin I). The last aim was to further validate the assay by screening pure compounds and peak library material from the HBOI marine specimen collection.
At the end of the experimentation time, the assay still was not set-up as there were difficulties in proper cell culture techniques and the cell line did not respond as advertised. While the results were not as expected, the work performed resulted in familiarization with research laboratory practices and increased laboratory skills. Moreover, the results from the assays point to future directions to accomplish this project.
Development of a screening assay for inhibitors of inflammation useful against pancreatic cancer
Berrabah, Sofia. „Etude de nouvelles cibles thérapeutiques dans les lymphomes compliquant la maladie cœliaque“. Electronic Thesis or Diss., Université Paris Cité, 2021. http://www.theses.fr/2021UNIP5201.
Der volle Inhalt der QuelleRefractory coeliac disease type II (RCDII), also called intraepithelial lymphoma, is a rare but severe complication of coeliac disease characterized by the clonal expansion of a small subset of innate intraepithelial lymphocytes (IEL), present in the normal human and murine intestine. Our lab has shown that this population displays shared features between T and natural killer (NK) cells. These so-called iCD3+ innate IEL are mainly characterized by intracellular expression of CD3, which is not detected at the cell surface, expression of NK receptors as well as DNA rearrangement of T cell receptor genes. Our lab has also shown that iCD3+ innate IEL originate from bone marrow precursors through coordinated NOTCH1 and interleukin (IL)-15 signals. During lymphomagenesis, iCD3+ innate IEL of most RCDII patients were shown to have acquired somatic gain-of-function mutations in JAK1 and/or STAT3 that confer increased sensitivity to interleukin-15, a cytokine overexpressed in the intestine of coeliac patients, thereby promoting their clonal expansion. Thus, our hypothesis is that JAK1/STAT3 mutations play a key role in initiating lymphomagenesis associated to coeliac disease in an IL-15-rich environment and that they could represent an attractive therapeutic target.The first objective of my thesis was to study the interest of JAK/STAT inhibitors for RCDII treatment. First, we have tested in vitro different JAK/STAT inhibitors on IL-15-dependent RCDII or normal IEL-T cell lines. We have shown that these inhibitors decrease the proliferation and phosphorylation of STAT3 and increase cellular apoptosis in both RCDII and normal T cell lines. Secondly, we have established a xenograft model based on the injection of cells derived from biopsy or blood from one RCDII patient into immunodeficient mice overexpressing the human IL-15 transgene in their gut epithelium (Rag-/-Gc-/- IL-15TgE; IRGC) to test the efficacy of JAK/STAT inhibitors in vivo. Treatment of xenografted mice with ruxolitinib, a potent inhibitor of JAK1/JAK2 decreased the frequency, number and cytotoxic potential of human tumoral cells and allowed clinical restoration. These preliminary results are encouraging but need to be confirmed. The second objective of my thesis was to test whether the Stat3 pD661V mutation is sufficient to induce the intraepithelial lymphoma in an IL-15-rich context in IRGC mice. We have successfully generated murine iCD3+ innate IEL in vitro, resembling their human counterparts from common lymphoid precursors by combining NOTCH and IL-15 signals. We then transduced CLP with a retroviral vector containing wild-type or mutated Stat3 pD661V. The transduced cells were injected into IRGC mice that subsequently were followed-up during a period of 8 weeks. In vitro generated iCD3+ innate IEL preferentially homed to the intestine. However, no development of intraepithelial lymphoma was observed suggesting that the Stat3 pD661V variant alone is not sufficient to induce the intraepithelial lymphoma. These preliminary results need to be reproduced and confirmed. The murine model used to test the role of STAT3 will now be used to evaluate the respective contribution of canonical mutations in JAK1 and STAT3 and of other recurrent mutations identified in RCDII
Gomes, Guilherme Wataru. „Expressão gênica dos transportadores de membrana ABCB1,ABCG2, SLC22A1 e SLCO1A2 em linhagens celulares tratadas com inibidor comercial da via JAK-STAT“. Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-16032016-095918/.
Der volle Inhalt der QuelleBACKGROUND: JAK-STAT pathway signaling disregulation is a hallmark of myeloproliferative neoplasms (MPN), hematopoietic stem cell clonal diseases, among which is myelofibrosis (MF). Several JAK inhibitors have been developed for MF treatment and are found in different stages of clinical development. Because the recent development of these compounds, the role of drug transporters in their pharmacokinetics is poorly understood. These proteins perform celular influx and effux of endogenous substrates and xenobiotics, and changes in the expression of these drugs transporters may affect the response to these drugs. AIM: To evaluate the effect of a JAK-STAT pathway commercial inhibitor in gene expression of drug transporters ABCB1, ABCG2, SLC22A1 and SLCO1A2 in HepG2, Caco-2 and HEL92.1.7 cells. METHODS: Hepatocellular carcinoma cell line HepG2, colorectal adenocarcinoma cell line Caco-2 and human erythroleukemia homozygous JAK2V617F cell line HEL92.1.7 were grown and treated with the JAK-STAT pathway inhibitor JAK Inhibitor I. In order to determine the optimal concentration for treatment with the inhibitor, cells were treated with several concentrations of JAK inhibitor by 24 hours, and cell viability and DNA fragmentation tests were performed. Once the treatment conditions were standardized, total RNA were obtained from the cells, and cDNA was synthesized in order to evaluate the mRNA expression of ABCB1, ABCG2, SLC22A1 and SLCO1A2 genes, performed by real time PCR. We also evaluate the expression of drug efflux transporters ABCB1 and ABCG2 by flow cytometry, using primary antibodies directed to these proteins. RESULTS: In HepG2 cells, it was observed an increase in ABCB1 mRNA expression in cells treated with 4,00 µM of JAK inhibitor, when compared with controls (cells exposed only to the vehicle) (P=0.041). There was no change in ABCB2 and SLC22A1 mRNA expression with the treatment with JAK inhibitor in this cell line (P>0.05); SLCO1A2 mRNA was not detected in this cell line. In Caco-2 cells, ABCB1, ABCG2, SLC22A1 and SLCO1A2 mRNA expression did not change with treatment with the JAK inhibitor at the concentrations used (0.25 µM to 1.00 µM) by 24 hours (P>0.05). In HEL92.1.7 cells, it was not observed differences in ABCB1, ABCG2 and SLC22A1 mRNA expression with the treatment with 1 µM of JAK inhibitor by 24 hours when compared with controls (P>0.05); in this cell line, SLCO1A2 mRNA was not detected. Protein expression of ABCB1 and ABCG2 drug transporters has not changed with treatment with the JAK inhibitor under the conditions used in the three cell lines studied. CONCLUSIONS: Only HepG2 cells presented an increase in mRNA expression of drug efflux transporter ABCB1 in presence of high levels of JAK inhibitor, suggesting that JAK inhibitors could modulate this transporter gene expression in liver. Treatment with JAK-STAT pathway inhibitor was not associated with changes in ABCB1 and ABCG2 protein expression in all cell lines studied.
Khatchaturyan, Levon [Verfasser], Udo [Akademischer Betreuer] Markert, Uta-Christina [Akademischer Betreuer] Hipler und Ulrike [Akademischer Betreuer] Kämmerer. „Die Rolle von PIAS (Protein Inhibitors of Activated STATs) in der Regulation von STAT (Signal Transducer and Activator of Transcription) : vermittelten Funktionen trophoblastärer Zellen / Levon Khachaturyan. Gutachter: Udo Markert ; Uta-Christina Hipler ; Ulrike Kämmerer“. Jena : Thüringer Universitäts- und Landesbibliothek Jena, 2012. http://d-nb.info/1020402113/34.
Der volle Inhalt der QuelleAubert-Jürgens, Ana. „STAT3 inhibitors for cancer treatment“. [S.l.] : [s.n.], 2005. http://elib.tu-darmstadt.de/diss/000563.
Der volle Inhalt der QuelleHill, Jacqueline M. „Transition state analogues as inhibitors of metallo-proteases“. Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260112.
Der volle Inhalt der QuelleFisher, Michael I. „Transition state analogue inhibitors of the aspartyl proteases“. Thesis, University of Huddersfield, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363233.
Der volle Inhalt der QuelleBhasin, Deepak. „Small Molecule Inhibitors asAnticancer Agents“. The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1305826098.
Der volle Inhalt der QuelleHaque, Mohammad Rashedul. „Novel STAT3 small-molecule inhibitors as potential anticancer agents“. Thesis, University of London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.535504.
Der volle Inhalt der QuelleSingh, Danny Ravinder. „Phosphorus containing transition state analogue inhibitors of the aspartyl proteases“. Thesis, University of Huddersfield, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368303.
Der volle Inhalt der QuelleChamberlain, Christopher Daniel. „Development and validation of assays used to evaluate STAT3 inhibitors“. Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/development-and-validation-of-assays-used-to-evaluate-stat3-inhibitors(007f8426-c173-4802-955e-181bf9aec424).html.
Der volle Inhalt der QuelleEkegren, Jenny. „Design and Synthesis of Novel HIV-1 Protease Inhibitors Comprising a Tertiary Alcohol in the Transition-State Mimic“. Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6737.
Der volle Inhalt der QuelleSmith, Cressida Sally. „Design and synthesis of novel transition state isostere inhibitors of MurD“. Thesis, University of Leeds, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418195.
Der volle Inhalt der QuelleWang, Xiaodong. „Design, Syntheses, and Bioactivities of Conformationally Locked Pin1 Ground State Inhibitors“. Diss., Virginia Tech, 2005. http://hdl.handle.net/10919/26625.
Der volle Inhalt der QuellePh. D.
Cao, Yu. „The synthesis of organo-phosphorus transition-state analogue inhibitors of dihydroorotase“. Master's thesis, Canberra, ACT : The Australian National University, 1994. http://hdl.handle.net/1885/141358.
Der volle Inhalt der QuelleXu, Guoyan. „Pin1 Inhibitors: Towards Understanding the Enzymatic Mechanism“. Diss., Virginia Tech, 2010. http://hdl.handle.net/10919/37823.
Der volle Inhalt der QuellePh. D.
Wang, Xinning [Verfasser]. „Tetrazole-containing STAT5 Inhibitors Derived from Furazan-based Phosphate Mimetics / Xinning Wang“. Berlin : Freie Universität Berlin, 2020. http://d-nb.info/121464130X/34.
Der volle Inhalt der QuelleMasciocchi, D. „DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF POTENTIAL STAT3 INHIBITORS AS ANTICANCER AGENTS“. Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/170266.
Der volle Inhalt der QuelleMisale, Antonio. „Synthesis of angucycline-based small molecules as potential STAT3 : STAT3 protein-protein interaction inhibitors for cancer therapy“. Thesis, University of London, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555844.
Der volle Inhalt der QuelleMiller, David James. „Phosphinic acids as inhibitors of D-Ala-D-Ala adding enzyme“. Thesis, University of Southampton, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242865.
Der volle Inhalt der QuelleStephan-Queffeulou, Emilie. „Sélection de peptides inhibiteurs de l'activité des protéines STAT5“. Compiègne, 2011. http://www.theses.fr/2011COMP1928.
Der volle Inhalt der QuelleConstitutive activation of STAT5 proteins has been demonstrated in numerous cases of malignant hemopathies and solid tumors. This phenomenon results in enhanced transcription of proliferative and anti-apoptotic genes, contributing to cancer development. Consequently, STAT5 proteins are attractive targets for innovative anticancer therapy. Developing STAT5 direct inhibitors is all the more important that current treatment against leukemias are few specific and cause secondary effects. This project aims at selecting STAT5 inhibiting molecules from a peptide library expressed on bacteriophage surface (phage display technology). First, recombinant STAT5B protein was produced, purified and used as a target during affinity-based selection. After a two-step selection, two peptides (PepA and PepM) were identified. The affinity of the two soluble peptides was measured by Biacore (Surface Plasmon Resonance technology) : PepM shows an nanomolar affinity towards STAT5B recombinant protein. This peptide interacts also with active STAT5 protein as demonstrated by pull down experiments. Finally, PepM effects on different cell lines were studied. This peptide penetrates in cells and preliminary results show that PepM diminishes STAT5 dependent cell viability
Hajiw, Martha. „Étude des conditions de dissociation des hydrates de gaz en présence de gaz acides“. Thesis, Paris, ENMP, 2014. http://www.theses.fr/2014ENMP0042/document.
Der volle Inhalt der QuelleThe twentieth century has seen an important increase of the fossil energy demand, representing today 80% of world energy consumption. To meet the request, oil and gas companies are interested in new gas fields. 40% of these reserves are acid and sour gases, i.e. the percentage of carbon dioxide and hydrogen sulphide is significant, sometimes over 20% of CO2 or H2S. Natural gas production with high content of acid gases can be a challenge, due to their corrosiveness potential in pipelines in the presence of water and H2S toxicity. On another hand, as a result of world's dependence on fossil energies, the release of carbon into atmosphere is increasing and leads to climate changes. Carbon Capture and Storage (CCS) is one of the most promising ways to reduce CO2 emissions in the atmosphere. Whether in natural gas or carbon dioxide transport, water may be present. During production, transportation and processing, changes in temperature and pressure can lead to water condensation (cause of corrosion, and consequently a possible pipeline rupture), ice and/or gas hydrates formation. Hydrates are a serious flow assurance problem and may block pipelines. To avoid hydrates formation, chemical inhibitors are used. Therefore accurate knowledge of mixtures phase equilibria are important for safe operation of pipelines and production/processing facilities
Gonzalez, Palmén Lorena. „Homotrimeric dUTPases : Principles of Catalysis and Inhibitor Design“. Doctoral thesis, Högskolan i Kalmar, Naturvetenskapliga institutionen, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-6119.
Der volle Inhalt der QuelleAl-Lami, Naeemah. „Synthesis of nitrogen-containing bicyclic sesquiterpenes as potential transition state inhibitors of aristolochene synthase“. Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/53674/.
Der volle Inhalt der QuelleMaughan, Michael A. T. „Cyclic imine sugars : towards the synthesis of transition-state mimics as potential glycosyltransferase inhibitors“. Thesis, Durham University, 2003. http://etheses.dur.ac.uk/3694/.
Der volle Inhalt der QuelleSwedberg, Joakim Erik. „Rational design of serine protease inhibitors“. Thesis, Queensland University of Technology, 2011. https://eprints.qut.edu.au/48131/1/Joakim_Swedberg_Thesis.pdf.
Der volle Inhalt der QuelleMautsa, Nicodemus. „Structural and functional characterisation of the protein inhibitor of activated STAT3 (PIAS3)“. Thesis, Rhodes University, 2011. http://hdl.handle.net/10962/d1004050.
Der volle Inhalt der QuelleZiegler, Inna. „Posttranslationale Modifikationen der IL-6-Typ-Zytokin-Rezeptoren gp130 und LIFR und ihr Einfluss auf die Assoziation mit Detergenz-resistenten Membranmikrodomänen (DRM)“. [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:100-opus-3124.
Der volle Inhalt der QuelleFrase, Hilary. „TOWARDS DEVELOPING SPECIFIC INHIBITORS OF THE ATP-DEPENDENT LON PROTEASE“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1175637588.
Der volle Inhalt der QuelleYu, Wenying. „Computational, Synthetic, Biochemical and Biological Studies and Characterization on STAT3 Inhibitors for Potential Anticancer Therapy“. The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1373328058.
Der volle Inhalt der QuelleCsatary, Erika Elizabeth. „Asymmetric Multicomponent Aza-Diels-Alder Reaction for Construction of Multicyclic Heterocycles and Development of XZH-5 Derivatives as Inhibitors of Signal Transducer and Activator of Transcription 3 (STAT3)“. Miami University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=miami1435110305.
Der volle Inhalt der QuelleAltundas, Abdullah Bilal. „Synthesis of XZH-5 Derivatives as Inhibitors of Signal Transducer and Activator of Transcription 3 (STAT3) and Synthesis of π-Extended Tetraphenylporphyrins“. Miami University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=miami1473201129.
Der volle Inhalt der QuelleSchust, Jochen. „Neue Ansätze zur Identifizierung niedermolekularer Inhibitoren der STAT3-Aktivierung und -Homodimerisierung“. [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=982197438.
Der volle Inhalt der QuelleGoodall, Scott. „Probing the structure of acetylcholinesterase inhibitors in their binding site using solid state nuclear magnetic resonance“. Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270619.
Der volle Inhalt der QuelleDAKA, PHILIAS. „ENAMINE-METAL LEWIS ACID BIFUNCTIONAL CATALYSTS FOR ASYMMETRIC ALDOL REACTIONS. DESIGN AND SYNTHESIS OF STAT3 INHIBITORS“. Miami University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=miami1374852476.
Der volle Inhalt der QuelleCouto, Jason. „Biologic Activity of the Novel Small Molecule STAT3 Inhibitor Against Canine Osteosarcoma Cell Lines“. The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1373986927.
Der volle Inhalt der QuelleFeng, You. „Kinetic Mechanism and Inhibitory Study of Protein Arginine Methyltransferase 1“. Digital Archive @ GSU, 2012. http://digitalarchive.gsu.edu/chemistry_diss/68.
Der volle Inhalt der QuelleWong, Ee Lin [Verfasser]. „The transcription factor STAT5 catalyzes Mannich ligation reactions yielding inhibitors of leukemic cell proliferation / Ee Lin Wong“. Berlin : Freie Universität Berlin, 2019. http://d-nb.info/1201346711/34.
Der volle Inhalt der QuelleTorikoshi, Kazuo. „Protein inhibitor of activated STAT, PIASy regulates α-smooth muscle actin expression by interacting with E12 in mesangial cells“. Kyoto University, 2013. http://hdl.handle.net/2433/174820.
Der volle Inhalt der QuelleTurner, Kimberly Ann. „Deliberate Memory in Three-Year-Old Children: Interrelations among Task Approaches, Working Memory, and Inhibitory Control“. NCSU, 2008. http://www.lib.ncsu.edu/theses/available/etd-03242008-181800/.
Der volle Inhalt der QuelleYounis, Usir, und Usir Younis. „Inhalational Delivery of a JAK3 Inhibitor for the Novel Treatment of Asthma and the Investigation of Pharmaceutical Salts in HFA Propellant Systems“. Diss., The University of Arizona, 2018. http://hdl.handle.net/10150/626756.
Der volle Inhalt der QuelleCamerino, Eugene. „Trifluoromethyl ketones: Potential insecticides towards Anopheles gambiae“. Thesis, Virginia Tech, 2013. http://hdl.handle.net/10919/54015.
Der volle Inhalt der QuelleFocus was directed towards synthesis of oximes, oxime ethers, and hydrazones as potential prodrugs to prevent immediate hydration and reach the central nervous system. The synthesis of various oximes, oxime ethers, and hydrazones has been shown to give cimpounds toxic to Anopheles gambiae within 3- to 4- fold of the toxicity of propoxur. However, thus far we have not been able to link the toxicity of these compounds to a cholinergic mechanism. Pre-incubation studies suggest that significant hydrolysis of these compounds to TFKs does not occur or 22 h at pH 7.7 or 5.5.
Future work will be directed towards TFKs that have better pharmacokinetic properties. Work will also be directed at synthesis of oxime and hydrazone TFK isosteres to determine the mechanism of action of these compounds.
Master of Science
Júnior, Paulo de Sousa Carvalho. „Pharmaceutical salts of the antidepressants Paroxetine and Fluoxetine, selective serotonin reuptake inhibitors: crystal engineering, solid-state characterization and thermodynamic aspects“. Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-27012017-084846/.
Der volle Inhalt der QuelleO desenvolvimento de novas formas sólidas de ingredientes farmacêuticos ativos (API) é relevante tanto numa perspectiva fundamental como industrial. Para tal, a Engenharia de cristais tem desempenhado um papel importante nas ciências farmacêuticas. Dentre as estratégias, a formação de sais é a abordagem mais importante e implementada. Os sais de APIs são capazes de modular e ajustar a solubilidade e a estabilidade, a fim de proporcionar uso prático. Nesta tese, são reportados sais de dois fármacos Inibidores Seletivos de Recaptação de Serotonina, consolidados no tratamento da depressão e distúrbios de ansiedade, a Paroxetina (PRX) e a Fluoxetina (FLX). Brometo de Paroxetina hemiidratado ((PRXBr)0.5H2O), Nitrato de Paroxetina hidratado (PRXNO3H2O) e polimorfos de Nitrato de Fluoxetina (FLXNO3), síntese e protocolos de cristalização foram cuidadosamente delineados, com base na sistematização de dados estruturais e supramoleculares das moléculas e seus análogos, depositados no Cambridge Structural Database. Todos os sais foram caracterizados por Difração de Raios-X por Monocristal, Calorimetria Explanatória Diferencial (DSC), Análise termogravimétrica (TGA), Termomicroscopia, Espectroscopia vibracional na região do infravermelho (IR) e solubilidade. Considerando que a hidratação/desidratação induz mudanças de fases que comprometem a eficiência do API, a caracterização do (PRXBr)0.5H2O auxiliou no entendimento do processo de desidratação reversível que ocorre para esse fármaco. Estas mudanças de fase resultam também em implicações sobre a compreensão do processo de desidratação do sal isoestrutural de cloreto de PRX hemiidratado. Além disso, por meio da elucidação estrutural do (PRXNO3)H2O, foi possível analisar a diversidade conformacional e supramolecular da PRX. Quanto à FLX, verificou-se que sua quiralidade está relacionada com seu polimorfismo. Um racemato e uma estrutura não centrossimétrica com dois enatiômeros independentes na unidade assimétrica foram obtidos para o FLXNO3. A comparação destas estruturas permitiu mostrar a existência de arranjos supramoleculares racêmicos, constituídos por diferentes orientações de enatiômeros. A rara ocorrência de sistemas racêmicos em grupos espaciais não-centrossimétricos tornou este evento um caso notável. A partir das propriedades físico-químicas, os polimorfos puderam ser monotropicamente relacionados. Os resultados desta tese trazem importantes contribuições científicas para diversidade de formas sólidas e também define novas formulações sólidas para utilização como antidepressivos.
Wooldridge, Lydia Katherine. „Supplementing Bovine Embryo Culture Media to Improve the Production and Quality of In Vitro Produced Bovine Embryos“. Diss., Virginia Tech, 2020. http://hdl.handle.net/10919/105143.
Der volle Inhalt der QuelleDoctor of Philosophy
Bovine embryos have been produced in vitro for the purpose of being transferred to recipient cattle to produce a calf since the 1980s. This practice allows cattle breeders to increase the number of offspring from their best females each year, and also allows for more rapid progress in generational genetic improvement. However, only approximately 10% of bovine oocytes survive and produce a calf. This poor efficiency of bovine in vitro embryo production negatively impacts the procedure's widespread use. A significant portion of these embryo losses are likely a result of inadequate in vitro culture conditions, particularly of the embryo culture media, the fluid in which embryos are grown. This media is often called "synthetic oviduct fluid," or SOF, because it is designed to mimic the fluid present in the cow's oviduct, where the embryo would normally reside. However, SOF is much simpler in nature than actual cow oviduct fluid, and this leads to reduced embryonic survival of in vitro produced embryos. Unfortunately, we know very little of what molecules control and promote bovine embryo development. Therefore, one major goal of bovine embryo research is to identify these factors and add them to SOF. The goal of this work was to examine the ability of three molecules, interleukin-6 (IL6), leukemia inhibitory factor (LIF), and zinc sulfate, to increase the number and quality of blastocysts produced through in vitro culture techniques. Additionally, I tested the replacement of SOF with a complex cell culture media, known as TeSR. This medium is more complex than SOF, and therefore should better promote embryo development. This work revealed that IL6, but not LIF, improves in vitro produced (IVP) bovine blastocyst quality. Unfortunately, neither IL6 nor LIF affected the percentage of embryos which survived to the blastocyst stage. However, IL6, but not LIF, increased the number of cells in the inner cell mass (ICM) of the blastocysts. ICM cells are the portion of the embryo which will produce the future calf. IVP bovine embryos are known to have fewer cells than normal, in vivo derived, blastocysts, and this issue is believed to cause some embryonic death after embryo transfer. Therefore, treatment with IL6 may increase the percentage of embryos which will survive after transfer and produce a calf. We also found the addition of zinc sulfate to SOF to benefit embryo quality. None of the concentrations of zinc significantly improved the percentage of embryos which survived to the blastocyst stage, but 2 µM zinc did increase ICM cell number. Like IL6, this may improve embryo survival after transfer. The use of the TeSR media as a replacement for SOF had some benefits. Unfortunately, this media is unusable for producing embryos for transfer to recipients, as we discovered early embryos could not survive in the media. However, blastocyst-stage embryos thrived in it, and could be cultured in vitro for a longer period of time as a result. Therefore, this media will be a useful tool for studying bovine embryo development in vitro, however it is unlikely to benefit calf production. In summary, this work provides evidence that zinc sulfate and IL6 are beneficial additions to SOF. However, future work is needed to determine if embryos produced with these factors are more able to produce a calf. Additionally, we discovered that TeSR is a superior extended blastocyst culture medium.
Dimberg, Lina. „Apoptosis Regulation in Multiple Myeloma“. Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7099.
Der volle Inhalt der QuelleSANTORO, Marco. „THE ANTINEOPLASTIC ROLE OF STAT5 INHIBITION IN BCRABL1-POSITIVE CELLS EXPOSED TO PIMOZIDE ALONE AND IN COMBINATION WITH DASATINIB AND PONATINIB“. Doctoral thesis, Università degli Studi di Palermo, 2021. http://hdl.handle.net/10447/514733.
Der volle Inhalt der QuelleBall, Sarah Lynnette. „Small molecule inhibitors, LLL12 and celecoxib, effectively inhibit STAT3 phosphorylation, decrease cellular viability and induce apoptosis in medulloblastoma and glioblastoma cell lines“. The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1298906960.
Der volle Inhalt der QuelleAlbrengues, Jean. „Rôle de la cytokine Leukemia Inhibitory Factor (LIF) dans l'activation et le maintien des fibroblastes pro-invasifs lors de la carcinogénèse“. Thesis, Nice, 2014. http://www.theses.fr/2014NICE4107/document.
Der volle Inhalt der QuelleSignaling crosstalk between tumor cells and fibroblasts confers proinvasive properties to the tumor microenvironment. We identify LIF as a tumor promoter that mediates proinvasive activation of stromal fibroblasts independent of alpha-smooth muscle actin expression. We demonstrate that a pulse of transforming growth factor β (TGF-β) establishes stable proinvasive fibroblast activation by inducing LIF production in both fibroblasts and tumor cells. In fibroblasts, LIF mediates TGF-β-dependent actomyosin contractility and extracellular matrix remodeling, which results in collective carcinoma cell invasion. Indeed, pharmacological inhibition of JAK activity by counteracts fibroblast-dependent carcinoma cell invasion in vitro and in vivo. We next unveil that LIF initiates an epigenetic switch leading to the constitutive activation of JAK1/STAT3 signaling, which results in sustained pro-invasive activity of fibroblasts. The process is mediated by p300-histone acetyltransferase acetylation of STAT3, and DNA methyltransferase DNMT3b, which induce the hypermethylation of SHP1 phosphatase promoter and results in constitutive phosphorylation of JAK1. Sustained JAK1/STAT3 signaling is maintained by DNMT1. Accordingly, carcinomas display strong LIF upregulation, which correlates with dense collagen fiber organization, cancer cell collective invasion, and poor clinical outcome. Moreover, we show that STAT3 acetylation and phosphorylation are inversely correlated with SHP1 expression in tumors stroma. Combined inhibition of DNMT activities and JAK signaling results in long-term reversion of CAF-associated pro-invasive activity and restoration of the wild-type fibroblast phenotype
Wu, Gengshu. „Lipoprotein lipase : mechanism for adaptation of activity to the nutritional state“. Doctoral thesis, Umeå : Umeå univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-175.
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