Global ETD Search

91	Mechanisms of translational regulation in the pancreatic β cell stress response Templin, Andrew Thomas January 2014 (has links) Indiana University-Purdue University Indianapolis (IUPUI) / The islet beta cell is unique in its ability to synthesize and secrete insulin for use in the body. A number of factors including proinflammatory cytokines, free fatty acids, and islet amyloid are known to cause beta cell stress. These factors lead to lipotoxic, inflammatory, and ER stress in the beta cell, contributing to beta cell dysfunction and death, and diabetes. While transcriptional responses to beta cell stress are well appreciated, relatively little is known regarding translational responses in the stressed beta cell. To study translation, I established conditions in vitro with MIN6 cells and mouse islets that mimicked UPR conditions seen in diabetes. Cell extracts were then subjected to polyribosome profiling to monitor changes to mRNA occupancy by ribosomes. Chronic exposure of beta cells to proinflammatory cytokines (IL-1 beta, TNF-alpha, IFN-gamma), or to the saturated free fatty acid palmitate, led to changes in global beta cell translation consistent with attenuation of translation initiation, which is a hallmark of ER stress. In addition to changes in global translation, I observed transcript specific regulation of ribosomal occupancy in beta cells. Similar to other privileged mRNAs (Atf4, Chop), Pdx1 mRNA remained partitioned in actively translating polyribosomes during the UPR, whereas the mRNA encoding a proinsulin processing enzyme (Cpe) partitioned into inactively translating monoribosomes. Bicistronic luciferase reporter analyses revealed that the distal portion of the 5’ untranslated region of mouse Pdx1 (between bp –105 to –280) contained elements that promoted translation under both normal and UPR conditions. In contrast to regulation of translation initiation, deoxyhypusine synthase (DHS) and eukaryotic translation initiation factor 5A (eIF5A) are required for efficient translation elongation of specific stress relevant messages in the beta cell including Nos2. Further, p38 signaling appears to promote translational elongation via DHS in the islet beta cell. Together, these data represent new insights into stress induced translational regulation in the beta cell. Mechanisms of differential mRNA translation in response to beta cell stress may play a key role in maintenance of islet beta cell function in the setting of diabetes. Diabetes, Islet, ER stress, Pdx1 Pancreatic beta cells -- Research Endoplasmic reticulum -- Pathophysiology Stress (Physiology) Cellular signal transduction Islands of Langerhans -- Research Small interfering RNA -- Research Protein folding -- Research Proteins -- Conformation Apoptosis Pancreas -- Growth -- Molecular aspects Transcription factors Cellular control mechanisms
92	Development of nonsymmetrical 1,4-disubstituted anthraquinones that are potently active against cisplatin-resistant ovarian cancer cells Teesdale-Spittle, P.H., Pors, Klaus, Brown, R., Patterson, Laurence H., Plumb, J.A. January 2005 (has links) No / A novel series of 1,4-disubstituted aminoanthraquinones were prepared by ipso-displacement of 1,4-difluoro-5,8-dihydroxyanthraquinones by hydroxylated piperidinyl- or pyrrolidinylalkyl-amino side chains. One aminoanthraquinone (13) was further derivatized to a chloropropyl-amino analogue by treatment with triphenylphosphine-carbon tetrachloride. The compounds were evaluated in the A2780 ovarian cancer cell line and its cisplatin-resistant variants (A2780/ cp70 and A2780/MCP1). The novel anthraquinones were shown to possess up to 5-fold increased potency against the cisplatin-resistant cells compared to the wild-type cells. Growth curve analysis of the hydroxyethylaminoanthraquinone 8 in the osteosarcoma cell line U-2 OS showed that the cell cycle is not frozen, rather there is a late cell cycle arrest consistent with the action of a DNA-damaging topoisomerase II inhibitor. Accumulative apoptotic events, using time lapse photography, indicate that 8 is capable of fully engaging cell cycle arrest pathways in G2 in the absence of early apoptotic commitment. 8 and its chloropropyl analogue 13 retained significant activity against human A2780/cp70 xenografted tumors in mice. Treatment resistance Transition metal Complexes Divalent metal Complexes Platinum II Complexes Malignant tumour Alkylating agent Vertebrata Mammalia Rodentia Cell line Chlorine Organic compounds Animal Ovary Tumour cell Human Alcohol Antineoplastic agent Mechanism of action Antimitotic Intraperitoneal administration Chemotherapy Cytotoxicity In vivo Pyrrolidine derivatives Piperidine derivatives Tricyclic compound Condensed benzenic compound Structure activity relation Diphenols Aromatic amine Ovarian cancer In vitro Chemical synthesis Cisplatin
93	Synthese und biologische Evaluierung von fluorezenzmarkierten Duocarmycin-Analoga / Synthesis and biological evaluation of fluorescence labeled Duocarmycin analogues Behrendt, Frank 25 November 2011 (has links) No description available. 540 Chemie Chemistry ADEPT Tumortherapie Prodrug CC-1065 Duocarmycine DNA Fluoreszenz Live Cell Imaging Zelluläre Aufnahme Wirkmechanismus ADEPT tumor therapy prodrug CC-1065 duocarmycin DNA fluorescence Live Cell Imaging Cellular Uptake mechanism of action 35.26 35.29 35.33 35.59 35.71 35.75 35.52 44.33
94	Synthese, biologische Evaluation und Untersuchung des Wirkmechanismus neuartiger Duocarmycin-Analoga für eine selektive Krebstherapie / Synthesis, Biological Evaluation and Investigation of the Mode of Action of Novel Anti-Tumour Agents for a Selective Cancer Therapy Krewer, Birgit 22 January 2009 (has links) No description available. 540 Chemie Mathematics and Computer Science ADEPT Tumortherapie Prodrug CC-1065 Duocarmycine DNA Massenspektrometrie Chromatographie Circular Dichroismus Wirkmechanismus ADEPT tumor therapy prodrug CC-1065 duocarmycin DNA mass spectrometry chromatography Circular Dichroism mechanism of action 35.26 35.29 35.33 35.59 35.71 35.75 35.52 44.33
95	Biomarkers for Better Understanding of the Pathophysiology and Treatment of Chronic Pain : Investigations of Human Biofluids Lind, Anne-Li January 2017 (has links) Chronic pain affects 20 % of the global population, causes suffering, is difficult to treat, and constitutes a large economic burden for society. So far, the characterization of molecular mechanisms of chronic pain-like behaviors in animal models has not translated into effective treatments. In this thesis, consisting of five studies, pain patient biofluids were analyzed with modern proteomic methods to identify biomarker candidates that can be used to improve our understanding of the pathophysiology chronic pain and lead to more effective treatments. Paper I is a proof of concept study, where a multiplex solid phase-proximity ligation assay (SP-PLA) was applied to cerebrospinal fluid (CSF) for the first time. CSF reference protein levels and four biomarker candidates for ALS were presented. The investigated proteins were not altered by spinal cord stimulation (SCS) treatment for neuropathic pain. In Paper II, patient CSF was explored by dimethyl and label-free mass spectrometric (MS) proteomic methods. Twelve proteins, known for their roles in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity, were identified to be associated with SCS treatment of neuropathic pain. In Paper III, proximity extension assay (PEA) was used to analyze levels of 92 proteins in serum from patients one year after painful disc herniation. Patients with residual pain had significantly higher serum levels of 41 inflammatory proteins. In Paper IV, levels of 55 proteins were analyzed by a 100-plex antibody suspension bead array (ASBA) in CSF samples from two neuropathic pain patient cohorts, one cohort of fibromyalgia patients and two control cohorts. CSF protein profiles consisting of levels of apolipoprotein C1, ectonucleotide pyrophosphatase/phosphodiesterase family member 2, angiotensinogen, prostaglandin-H2 D-isomerase, neurexin-1, superoxide dismutases 1 and 3 were found to be associated with neuropathic pain and fibromyalgia. In Paper V, higher CSF levels of five chemokines and LAPTGF-beta-1were detected in two patient cohorts with neuropathic pain compared with healthy controls. In conclusion, we demonstrate that combining MS proteomic and multiplex antibody-based methods for analysis of patient biofluid samples is a viable approach for discovery of biomarker candidates for the pathophysiology and treatment of chronic pain. Several biomarker candidates possibly reflecting systemic inflammation, lipid metabolism, and neuroinflammation in different pain conditions were identified for further investigation. / Uppsala Berzelii Technology Centre for Neurodiagnostics chronic pain neuropathic pain lumbar radicular pain amyotrophic lateral sclerosis radiculopathy fibromyalgia pathophysiology spinal cord stimulation mechanism of action disc herniation cerebrospinal fluid plasma biomarker human protein chemokines cytokines inflammation neuroinflammation mass spectrometry proximity ligation assay proximity extension assay antibody suspension bead array protein profiling molecular medicine personalized medicine Anesthesiology and Intensive Care Anestesi och intensivvård Clinical Laboratory Medicine Klinisk laboratoriemedicin Biomedical Laboratory Science/Technology Analytical Chemistry Analytisk kemi

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