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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.
691

Effects of Thromboxane Synthetase Inhibition on Maternal-Fetal Homeostasis in Gravid Ewes With Ovine Pregnancy-Induced Hypertension

Keith, James C., Miller, Kevin, Eggleston, Maurice K., Kutruff, Julie, Howerton, Todd, Konczal, Christin, McDaniels, Cathy 01 January 1989 (has links)
Simultaneous maternal indirect blood pressure measurements, electronic fetal heart rate monitoring, and ultrasonographic biophysical profile testing were used to assess maternal-fetal homeostasis in gravid ewes during gestational days 127 to 134 (term 146), during a 72-hour fast, and during treatment with thromboxane synthetase inhibitors CGS13080 and CGS12970. Seventy-five percent of the ewes (12 of 16) developed clinical signs of ovine pregnancy-induced hypertension, including maternal hypertension and fetal depression. In three untreated hypertensive ewes, pregnancy was terminated by spontaneous premature delivery, and one maternal death occurred after an eclamptic seizure. All nine ewes treated with one of the two thromboxane synthetase inhibitors responded to therapy with decreases in blood pressure and resolution of fetal depression. These nine ewes completed gestation, and were delivered at term. These data indicate that therapy with thromboxane synthetase inhibitors in this animal model of preeclampsia results in profoundly beneficial effects and suggest that further studies of thromboxane synthetase inhibitors are warranted in preeclampsia.
692

Understanding Aromatase: A Mechanistic Basis for Drug Interactions and New Inhibitors

Lu, Wenjie 16 March 2012 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Aromatase is the cytochrome P450 enzyme that converts androgens to estrogens. Aromatase is the target of the aromatase inhibitor class of drugs widely used to treat estrogen-mediated conditions including breast cancer. Little is known about the role of this enzyme in drug metabolism or in drug interactions. Since this lack of knowledge has been an impediment to optimal therapy, it is important to understand these roles of aromatase. Therefore, a comprehensive series of studies was carried out to characterize its ability to metabolize drugs and its susceptibility to inhibition by xenobiotics. The overall objective of this work was to better understand the interactions of small molecules with aromatase and to use this new knowledge to predict aromatase-mediated drug interactions and anticipate novel molecular structures that interact with the enzyme. Aromatase was shown to be a drug metabolizing enzyme able to metabolize methadone both in vitro (Km of 314 μM) and in vivo (22% of methadone clearance). A number of novel aromatase inhibitors that employ diverse kinetic mechanisms were identified. These include a potent competitive inhibitor: norendoxifen (Ki of 35 nM), two non-competitive inhibitors: endoxifen (Ki of 4.0 μM) and N-desmethyl-tamoxifen (Ki of 15.9 μM), a mechanism-based inhibitor: methadone (KI of 40.6 ± 2.8 μM; kinact of 0.061 ± 0.001 min-1), and a stereoselective inhibitor: naringenin (IC50s of 2.8 μM for (R)-enatiomer and 1.4 μM for (S)-enatiomer). Through investigation of the structure-potency relationships so discovered, a series of new biochemical structures to be exploited as aromatase inhibitors were identified. These studies have identified new roles for aromatase as a catalyst for methadone metabolism and as a mediator of the effects of tamoxifen by demonstrating that a number of its metabolites can act as aromatase inhibitors. This work also provides a new mechanistic framework for the design of novel aromatase inhibitors that can be used in breast cancer. Overall, the data suggest ways to more consistently treat breast cancer with current medications, to better anticipate drug interactions, and therefore to improve the quality of life of patients in ways that minimize side effects, while optimizing therapeutic benefits, in each person treated.
693

Kvantitativní analýza inhibitorů tyrozinkinázy metodou kapalinové chromatografie s hmotnostní detekcí / Quantitative analysis of tyrosine kinase inhibitors employing liquid chromatography with mass spectrometry detection

Maier, Jan January 2021 (has links)
The submitted thesis is devoted to the quantitative analysis of tyrosine kinase inhibitors, specifically imatinib and nilotinib, by liquid chromatography-mass spectrometry method. The main purpose of developing this new method of analysis at the Department of Clinical Biochemistry and Diagnostics at the University Hospital in Hradec Králové was measuring and monitoring serum or plasma concentration levels of these drugs in patients with chronic myeloid leukemia, less often in patients with gastrointestinal stromal tumour. The main task during the elaboration of the thesis was to fully optimize and validate the method. Previously, this method for the analysis of tyrosine kinase inhibitors was routinely performed here by high-performance liquid chromatography with spectrophotometric (UV) detection. As part of the modernization of laboratory technology, they started to use high-performance liquid chromatography with mass spectrometry at the workplace. The analytes with their internal standards were obtained by a liquid-liquid extraction process. Then, samples were separated on a C18 reverse phase column using isocratic elution. Subsequently, both analytes were detected by a triple quadrupole tandem mass spectrometer with ESI ion source in a positive mode. As a part of the method validation was to...
694

Targeting Neutrophils to Improve Protection by Sublingual Vaccines

Rowe, John Christopher 04 October 2021 (has links)
No description available.
695

Using the Medication Cabinet to Predict Fall Risk In Elderly Adults

Lopez, Jessica 01 January 2017 (has links)
Background: In the United States, 30-60% of older adults fall each year; 10-20% of these falls result in injury, hospitalization, or even death. Better prevention of falls in this population may be facilitated by broader identification of risk factors. The use of statins has emerged as a potential risk factor, but the data provide conflicted results. Purpose: To examine the relationship between statin use and falls among community-dwelling older adults. Methods: We evaluated the patient registry of a Level 1 trauma center. All patients aged > 50 years who were admitted for falls in 2015 were included (n=615). Many of these patients had been previously admitted for falls and many were later readmitted for falls. We analyzed predictors of both prior admission and readmission with linear regressions. Independent variables were self-reported balance problems, diagnosis of dementia, and the use of statins. Results: On average, patients admitted for falls were 79.9 + 9.3 years old and 28% (n=173) were taking statins. Our collection of predictors explained 14.2% of the variance in the number of prior admissions (p<0.001). In this model, the use of statins significantly predicted the number of previous fall-related admissions (95% CI: 0.07–0.50, p=0.010). This same model maintained its significance when predicting admissions for future falls (p<0.001) and the use of statins continued to predict a greater number of readmissions (95% CI: 0.04–0.36, p=0.015). Conclusion: More than 25% of all Americans age > 40 years are taking cholesterol-lowering medication; 93% of those medications are statins. Although evidence is conflicted, these data support the finding that statin therapy increases the risk of falls in older adults. Incorporating exercise training as a prophylactic measure: enhancing lipid profiles and decreasing the need for statins while also improving balance, coordination, and mobility, may reduce fall-related injuries.
696

In Vitro Assessment of Novel Compounds as Potential Pan-Coronavirus Therapeutics in SARS-CoV-2 and In Vitro Assessment of a Pan-Flavivirus Compound in Zika Virus

Berger, Julia January 2022 (has links)
Through the SARS-CoV-2 pandemic, it has become clear that the development of antivirals is essential for the health and wellbeing of the population. In this study, novel active site protease inhibitors against SARS-CoV-2 were tested for their inhibitory activity against the viral 3-Chymotrypsin like protease through the means of FRET based enzymatic assays. Additionally, Compound 104 targeting the NS2B-NS3 protease was tested against Zika virus through yield reduction assays as a means to assess whether these assays are suitable for the assessment of peptide hybrid compounds in Zika virus.Novel compounds against SARS-CoV-2 were screened and five of the selected six active compounds were found to inhibit the viral protease at a half-maximal inhibitory concentration (IC50) of below 0.075 µM.In Zika virus, the yield reduction assay was assessed and it was found that under the conditions tested, this assay is not suitable for the assessment of peptide hybrid compounds in Zika virus.The active novel compounds against SARS-CoV-2 should be taken for further assessment in cell based assays as the next step of development. Compound 104 should be assessed under different experimental conditions to identify whether different conditions can make this assay suitable for the intended use.
697

Ticagrelor-Induced Diarrhea in a Patient With Acute Coronary Syndrome Requiring Percutaneous Coronary Artery Intervention

Alomari, Mohammad, Bratton, Hunter, Musmar, Ahmad, Al Momani, Laith A., Young, Mark 12 January 2019 (has links)
The P2Y inhibitor, ticagrelor, has been shown to prevent thrombotic events and hence, improve morbidity and mortality in patients with acute coronary syndrome following coronary artery stent placement. Despite many clinical benefits, ticagrelor has been associated with several adverse effects, including dyspnea, easy bruising, and gastrointestinal bleeding. We report the case of a 67-year-old patient with an acute coronary artery syndrome requiring percutaneous coronary artery intervention with stenting who developed ticagrelor-induced diarrhea. The patient's ticagrelor medication was replaced with clopidogrel, and his diarrhea completely resolved within one week with no complications observed at his one-month follow-up visit. Clinicians should be aware of this adverse effect of ticagrelor so as to guide them toward possible underlying etiologies and appropriate workup of chronic diarrhea.
698

Evaluating Corrosion Control Alternatives For A Reverse Osmosis, Nanofiltration And Anion-exchange Blended Water Supply

Wilder, Rebecca J 01 January 2012 (has links)
The research reported herein describes the study activities performed by University of Central Florida (UCF) on behalf of the Town of Jupiter Water Utilities (Town). The Town recently changed its water treatment operations from a combination of reverse osmosis (RO), lime softening (LS) and anion-exchange (IX) to a combination of RO, IX and nanofiltration (NF). Although this treatment change provided enhanced water to the surrounding community in terms of better contaminant removal and reduced DBP formation potential, integration of the NF process altered finished water quality parameters including pH, alkalinity and hardness. There was concern that these changes could result in secondary impacts related to accelerated corrosion of distribution system components and subsequent regulatory compliance. In addition, replacement of the LS process altered the in-plant blending operations by creating an unstable intermediate blend composed of RO and IX waters. There were concerns that this intermediate blend was affecting the integrity of in-plant hydraulic conveyance components. UCF developed a corrosion monitoring study to assess the potential impacts related to internal corrosion, water quality and regulatory compliance after integrating NF into the existing water supply. The intended purpose was to further highlight the complexities of corrosion, describe a unique approach to corrosion monitoring as well as offer various recommendations for corrosion control in a system that relies on a blended water supply. Research was conducted in three phases to address the in-plant and distribution system corrosion issues separately and identify appropriate corrosion control treatment alternatives. The three test phases included: a baseline conditions assessment to iv compare corrosion of the intermediate RO-IX blend with the finished water blend (ROIX-NF); an in-plant corrosion control evaluation; and a distribution system corrosion control evaluation. A test apparatus was constructed and operated at the Town’s facilities to monitor corrosion activity of mild steel, copper and lead solder metal components. The test apparatus consisted of looped PVC pipe segments housed with electrochemical probes and metal coupons to monitor corrosion rates of the metallic components. Electrochemical probes containing metal electrodes were used to obtain instantaneous corrosion rates by means of the Linear Polarization Resistance (LPR) technique while the metal coupons were gravimetrically evaluated for weight loss. The electrochemical probes permitted daily monitoring of each metal’s corrosion rates while metal coupons were analyzed at the conclusion of testing and used for comparison. Different test waters flowed through the corrosion rack according to each test phase and relative corrosion rates were compared to evaluate corrosion control techniques. Study findings indicated that the intermediate blend was more corrosive, in general, then the final blend; however, research also indicated that the final blend of water was increasing lead and copper concentrations within the distribution system. An orthophosphate corrosion inhibitor was evaluated for in-plant corrosion control. The inhibitor’s performance was assessed by comparing mild steel corrosion rates with and without the chemical. In addition, secondary impacts related to introduction of the chemical were evaluated by pre-corroding the metallic components prior to the introduction of the inhibitor. Results indicated that the inhibitor marginally decreased corrosion rates and increased the turbidity of the water supply. Based on these v observations, it was concluded that the inhibitor was not a viable solution for in-plant corrosion control. To resolve in-plant corrosion issues, recommendations were made for modification of in-plant blending operations to eliminate the corrosive intermediate blend from the process allowing the RO, IX and NF treated waters to be blended in a common location. The effectiveness of a poly/ortho blended phosphate chemical inhibitor was evaluated for reducing lead and copper corrosion to resolve distribution corrosion issues. A 50/50 poly/ortho blend was selected because of its analogous use in similar municipal water facilities. Metallic corrosion rates, particularly lead and copper, were compared with and without the inhibitor to assess the performance of the chemical. Like the previous test phase, the metallic components were pre-corroded prior to the chemical’s introduction to determine if secondary impacts could result from its presence. Results indicated that lead and copper corrosion rates were lower in the presence of the inhibitor, and secondary impacts related to increased turbidity were not observed for this chemical. Based on these results, it was recommended that a poly/ortho blended phosphate be used to decrease lead and copper corrosion within the Town’s distribution system.
699

Impact Of Corrosion Inhibitor Blended Orthophosphate On Water Quality In Water Distribution Systems

Alshehri, Abdulrahman 01 January 2008 (has links)
The impact of blended orthophosphate (BOP) inhibitor addition on the corrosion of iron, copper, and lead in drinking water distribution systems was studied under changing water quality environment. Release of iron, copper, and lead were monitored at varying inhibitor doses and changing blends of source waters (groundwater, surface water, and desalinated water). Solid corrosion products on pipe surfaces under BOP treatment were evaluated with surface characterization techniques. Performance of the BOP inhibitor was compared to other corrosion control strategies. Iron scales for iron and galvanized steel coupons incubated in different blended waters in the presence of BOP inhibitor were analyzed by X-ray Photoelectron Spectroscopy (XPS) for surface composition. Identified iron corrosion products were ferric oxide (Fe2O3), magnetite (Fe3O4), and hydrated ferric oxide (FeOOH), in addition to ferric phosphate (FePO4) on coupons exposed to BOP inhibitor. Variations of water quality did not significantly affect the distribution of solid iron forms on surface films. Thermodynamic modeling indicated siderite (FeCO3) was the controlling solid phase of iron release. XPS indicated addition of BOP inhibitor produced a solid phosphate film in the iron scale which could inhibit iron release. Impact of BOP, orthophosphate, and pH adjustment on iron release in a distribution system was examined. Iron release was sensitive to water quality variations (alkalinity and chloride) associated with source and blends of finished water. Finished waters with high alkalinity content (between 149 and 164 mg/L as CaCO3) consistently mitigated iron release regardless of inhibitor use. Dissolved iron constituted about 10% of total iron release. Empirical models were developed that related water quality, inhibitor type and dose to iron release. The BOP inhibitor minimized total iron release followed closely by increasing pH (between 7.9 and 8.1), while orthophosphate dose did not affect iron release. Temperature (ranged from 21.2 to 25.3) had limited influence on iron release with BOP treatment. Monitoring copper release showed that dissolved copper was the dominant form in the effluent, at about 88%. BOP inhibitor doses of 0.5 to 2.0 mg/L proved beneficial in controlling copper concentrations to an average of below 0.5 mg/L. Control of copper release improved with increasing BOP dose, despite changes in alkalinity. Elevation of pH by 0.3 unit beyond pHs (between 7.9 and 8.1) resulted in noticeable decrease in copper concentrations of about 30%, but was more sensitive to higher alkalinity (146 to 151 mg/L as CaCO3) than BOP treatment. Developed empirical models confirmed the importance of BOP inhibitor dose, pH increase, and alkalinity content on copper release. Statistical comparison of the corrosion control strategies proved the advantage of BOP inhibitor, at all doses, over pH elevation in controlling copper release. The BOP inhibitor mitigated lead release below action level, and consistently outperformed pH elevation, in all water quality conditions. XPS analysis identified lead dioxide (PbO2), lead oxide (PbO), cerussite (PbCO3), and hydrocerussite (Pb3(CO3)2(OH)2) as the corrosion products in the scale of lead/tin coupons exposed to BOP inhibitor. XPS and Scanning Electron Microscopy (SEM) analysis suggested cerussite or hydrocerussite is the controlling solid phase of lead release. Thermodynamic models for cerussite and hydrocerussite grossly over predicted actual concentrations. Solubility and equilibrium relationships suggested the possibility of a lead orthophosphate solid that would describe the effectiveness of BOP inhibitor, although no lead-phosphate solid was detected by surface analysis. BOP inhibitor appeared to have mitigated lead release by forming a surface film between lead scale and the bulk water.
700

Examination of 14-3-3 Interactors Identifies a Novel Mechanism of Regulation for the Ubiquitin Binding Kinase TNK1 That Can Be Targeted to Block Tumor Growth

Egbert, Christina Marie 09 August 2022 (has links) (PDF)
Decades of research have begun to identify oncogenic mut-drivers that are responsible for driving a large percentage of cancers. These high frequency mut-drivers have therapeutics in the clinic for patient treatment. However, there is another group of low frequency mut-drivers that fail to rise above the noise of the high frequently drivers. These low frequency drivers represent a group of genes with untapped potential for new targeted therapies. However, identifying these drivers can be difficult. This study focuses on identifying new functional phosphorylations using the phospho-docking protein 14-3-3. The family of 14-3-3 proteins have been linked to many oncogenic pathways due to the diversity in their client protein interactions. One critical problem in studying 14-3-3 interactors is uncovering the docking site on the phospho-binding partner. Our work indicates that intrinsic disorder and unbiased mass spectrometry identification rate of a given phosphorylation are important for improving the selection of a 14-3-3 docking site. Using a machine learning model, we developed a tool that combines current available 14-3-3 prediction data and our observations about disorder and phosphorylation observation to predict 14-3-3 binding sites. Our publicly available tool "14-3-3-site-finder" produces a rank order list of potential 14-3-3 docking sites that could help overcome the time-consuming process of identifying the correct site. In our efforts of identifying functional phosphorylations with 14-3-3, we have observed that 14-3-3 interacts with a non-receptor tyrosine kinase, TNK1. TNK1 is a poorly characterized kinase that has essentially nothing known about its substrates, function or regulation. TNK1 has been implicated in both tumor suppressor and oncogenic roles. Particularly, a Hodgkin Lymphoma cell line is dependent on a truncated form of TNK1 for growth. Our work uncovers the first mechanism of regulation for this kinase. We found that MARK kinase phosphorylates TNK1 within the proline rich domain allowing 14-3-3 to dock on this phosphorylation. 14-3-3 binding restrains TNK1 in the cytosol and holds TNK1 in an inactive state. Upon the release of 14-3-3, TNK1 moves to a membrane fraction where it is active. One unique feature of TNK1 is that it has a c-terminal ubiquitin association domain (UBA). In vitro ubiquitin pulldowns indicate that the TNK1 UBA has no preference for linkage type or length of ubiquitin. Further, biolayer interferometry indicates that the UBA binds ubiquitin tightly. Mutation of residues within the ubiquitin:TNK1 interface prevent ubiquitin binding and decrease TNK1 activity, preventing downstream oncogenic signaling, suggesting a UBA-centric mechanism of regulation for TNK1. Finally, we developed a small molecule inhibitor, TP-5801, that selectively targets TNK1. TP-5801 prevents downstream TNK1 phosphorylation of STAT3. Further, TP-5801 prolonged the life of mice injected with TNK1 driven Ba/F3 cells. Taken together, our data reveal the first mechanism of kinase regulation for TNK1 involving 14-3-3 binding and ubiquitin association as well as the development of a TNK1 specific therapeutic

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