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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.
101

Novel strategies towards engineering therapeutic enzymes with reduced immunogenicity for cancer therapy

Cantor, Jason Robert 14 February 2012 (has links)
Heterologous enzymes have been investigated for a variety of therapeutic applications, including the treatment of a number of cancers that are sensitive to the systemic depletion of specific amino acids. One such example is acute lymphoblastic leukemia (ALL) for which enzyme-mediated L-Asparagine (L-Asn) depletion by the Escherichia coli L-Asparaginase II (EcAII) has been proven critical for treatment. However, the repeated or prolonged therapeutic administration of such enzymes is restricted by their immunogenicity, which frequently results in the generation of anti-enzyme antibodies that may in turn mediate a variety of adverse hypersensitivity reactions and neutralization of the enzymes themselves. Thus, while the therapeutic efficacy of asparaginase is well established, a significant number of patients still develop adverse immune responses to the enzyme. Here, we have developed and explored novel strategies towards engineering an asparaginase with reduced immunogenicity for ALL therapy. First, we identified and investigated human enzymes that putatively shared functional similarity to asparaginase with the long-term aim of engineering such enzymes to acquire biochemical and pharmacological properties requisite for eventual therapeutic application. In one study, we described the bacterial expression and characterization of the human asparaginase-like protein 1 (hASRGL1). We presented evidence that hASRGL1 exhibited an activity profile consistent with enzymes previously designated as [Beta]-aspartyl peptidases, which had only been previously identified in plants and bacteria. Similar to non-mammalian [Beta]-aspartyl peptidases, hASRGL1 was revealed to be an N-terminal nucleophile (Ntn) hydrolase whereby Thr168 serves as the essential Ntn for both intramolecular processing and catalysis. In a second study, we described the optimized bacterial expression and biochemical characterization of the human N-terminal asparagine amidohydrolase 1 (hNTAN1). We demonstrated that hNTAN1 catalysis is dependent upon direct involvement of a thiol group, and subsequently identified Cys75 as an essential residue that may act as the catalytic nucleophile. Further, we presented the first description of hNTAN1 kinetics, secondary structure composition, and thermal stability. Second, we devised and validated a novel therapeutic deimmunization approach by combinatorial T-cell epitope removal using neutral drift. We showed that combinatorial saturation mutagenesis coupled with a robust neutral drift screen enabled the isolation of engineered EcAII variants that contained multiple amino acid substitutions yet exhibited catalytic efficiencies nearly indistinguishable to that of the parent enzyme. Three regions of EcAII were computationally identified as putative T-cell epitopes and then subjected to saturation mutagenesis at 4 positions (per region) believed to be critical for MHC-II binding. The resulting libraries were then sequentially subjected to a neutral drift FACS screen in order to isolate EcAII mutants that retained wild-type function. Pools of neutral drift variants were then computationally evaluated for MHC-II binding and those that displayed scores indicative of compromised binding were purified and biochemically characterized. Finally, T-cell activation assays and antibody titers in HLA-transgenic mice were used to evaluate T-cell epitope removal and immunogenicity, respectively. Ultimately, we revealed that mice immunized with an EcAII neutral variant containing 8 amino acid substitutions -- 3 of which were non-phylogenetically conserved -- within computationally predicted T-cell epitopes, displayed a significant 10-fold reduction in serum anti-EcAII IgG titer relative to mice similarly immunized with the parent enzyme. / text
102

Enzymatic treatment of pharmaceuticals and personal care products (PPCPs) in municipal wastewater

Sharkey, Margaret E 29 October 2013 (has links)
Conventional wastewater treatment plants do not effectively remove pharmaceuticals and personal care products (PPCPs). As a result, PPCPs enter the environment via treated wastewater discharge. Enzymatic treatment, using the laccasemediator system, is a novel biochemical process that has been shown to effectively treat some PPCPs. This study investigates the efficacy of the laccase-mediator system to treat PPCPs using a process that can be easily implemented at an existing wastewater treatment plant. Enzymatic treatment will be most beneficial after primary sedimentation and before conventional biological treatment, where unoxidized PPCPs and byproducts could have the opportunity for further degradation in biological treatment. In this work, two enzymatic treatment configurations were studied. A step-wise optimization process was used that alternately varied treatment conditions: pH, enzyme activity, mediator concentration, and reactor detention time. In the optimization process of each configuration, successful oxybenzone removal (~90%) was achieved in municipal primary effluent. In a direct comparison of treatment configurations, both resulted in vi similar percent removals of oxybenzone. Therefore, the configuration with the simpler operation and reactor design was chosen for further study. During the optimization process, several noteworthy conclusions were made that might have full-scale enzymatic treatment implications. Specifically, successful oxybenzone removal occurred at unadjusted pH and without aeration, but increased biological oxygen demand of the wastewater increased the required mediator concentration. While the first finding would decrease enzymatic treatment costs, the latter would increase the costs associated with the mediator. Thus, an alternative mediator source, specifically one high in phenolic compounds, is desired. The use of wine, as a surrogate of winery wastewater, was in investigated and proved ineffective. Further investigation of alternative mediator sources is required. Treatment of another PPCP, sulfamethoxazole, was less efficient (65% removal) than that of oxybenzone, but nevertheless, the substantial removal might indicate that other PPCPs can be treated with the laccase-mediator system. The most promising result of this work was the simultaneous treatment of multiple PPCPs, oxybenzone and sulfamethoxazole. Simultaneous treatment proved to be as effective as when each PPCP was treated individually. / text
103

THE REGULATION OF THE PYRUVATE DEHYDROGENASE MULTIENZYME COMPLEX BY CALCIUM AND MAGNESIUM IN HEART MITOCHONDRIAL SYSTEMS

Schuster, Sheldon Mark, 1947- January 1974 (has links)
No description available.
104

Development of rapid toxicity tests using enzyme inhibition as sulethal biomarker

Burbank, Susan Elizabeth 05 1900 (has links)
No description available.
105

An investigation of chymotrypsin A[gamma]inhibition with peptide aldehydes and related analogs ; II Inhibition of elastase by tetrapeptide chloromethyl ketones

Whitley, Ronald Jay 12 1900 (has links)
No description available.
106

I Inhibition of elastase by peptide chloromethyl ketones II Modification of chymotrypsin by an aryl cyanate reagent

Tuhy, Peter Mirko 05 1900 (has links)
No description available.
107

Kinetic study of inhibitors of carboxyl-terminal amidating enzymes

Shi, Jing 08 1900 (has links)
No description available.
108

New reactive substrates and potent inhibitors of serine proteases

Harper, Jeffrey Wade 05 1900 (has links)
No description available.
109

Characterization and modification of fluorogenic substrate coated particles for use as enzyme probes

Olsen, Greta A. 08 1900 (has links)
No description available.
110

Tyrosine hydroxylase inhibition : and L-ascorbic acid 2-phosphate uptake by chromaffin cells and influenece of treatment of cyclosporine a and cyclosporine G on lymphoctye responsiveness and adjuvant arthritis in rats

Chang, Kai Yuan 08 1900 (has links)
No description available.

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