2012 UMKC Dissertations - Access Restricted to UMKC
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Item Organoisocyanates: the conformational stability determination by infrared, raman and microwave spectroscopy and ab initio calculation(University of Missouri-Kansas City, 2012) Zhou, Xiao Hua; Durig, James R.Conformational stability studies have been carried out for several quasilinear organoisocyanates and organoisothiocyanates. The infrared and Raman spectra in the gaseous, liquid and solid phases have been recorded as well as the variable temperature infrared spectra of the sample compound dissolved in rare gas solution. The complete vibrational assignments have been proposed for all the energetically stable conformations. Microwave spectra for several of the ring molecules have been investigated from 10,000 to 21,000 MHz with transitions for the most stable conformer assigned. For methylisocyanate, the barrier to internal rotation and linearity has been determined to be 46 cm-1 and 975 cm-1, respectively. For the Ethylisocyanate, the cis conformation is determined to be more stable than the trans form by 100 ± 4 cm-1. dimethylsilylisocyanate was determined to have an essentially linear SiNCO moiety. The spectral analyses of Isopropylisothiocyanate indicated one stable conformer (trans) in the annealed solid but in the fluid phases most of the molecules have energies above the barriers of the two predicted bound vibrational states i.e., trans and gauche forms. For dimethylsilylisocyanate, the low wavenumber Raman spectrum of the gas with a significant number of Q-branches for the SiNC(O) bend is consistent with an essentially linear SiNCO moiety. For cyclopropylisocyanate, the enthalpy difference has been determined to be 77 ± 8 cm-1 with the trans form more stable than the cis conformer with 59 ± 2% of the trans form present at ambient temperature. For cyclobutylisocyanate, an enthalpy difference of 131 ± 13 cm-1 was obtained with the equatorial-trans conformer the more stable form. For cyclohexylisocyanate, an enthalpy difference of 397 40 cm-1 was obtained from seven conformer pairs with the equatorial-trans form more stable than the axial-trans conformer. To support the analysis of the vibrational assignment, ab initio and hybrid density functional theory calculations have been carried out. For each molecule, a completed vibrational analysis and potential energy distributions have been proposed. The adjusted r0 structural parameters have been determined for all molecules.Item Evaluation of therapeutic effect of IKK epsilon SiRNA on breast cancer cells and development of a peptide-based SiRNA delivery system(University of Missouri--Kansas City, 2012) Qin, Bin; Cheng, Kun (Professor)The objective of this dissertation is to develop siRNA-based cancer therapeutics. In chapters 1 and 2, we introduced the mechanism, challenge and promise of RNAi-based therapy, as well as various siRNA delivery systems. In Chapter 3, we examined the therapeutic potential of IKKε siRNA on human breast cancer cells. Eight siRNAs targeting different regions of the IKKε mRNA were designed, and the silencing effect was screened by quantitative real time RT-PCR. Silencing of IKKε in human breast cancer cells resulted in decrease of focus formation potential and clonogenicity as well as in vitro cell migration/invasion capabilities. Moreover, knockdown of IKKε suppressed cell proliferation. Cell cycle assay showed that the anti-proliferation effect of IKKε siRNA was mediated by arresting cells in G0/G1 phase, which was caused by downregulation of cyclin D1. Furthermore, we demonstrated that silencing of IKKε inhibited the NF-κB basal activity and the Bcl-2 expression. Significant apoptosis was not observed in breast cancer cells upon the silencing of IKKε. In chapter 4, cholesterol was conjugated to a series of peptides composed of lysine and histidine residues. Our results indicate that the amphiphilic cholesteryl peptides can self-assemble to form a micelle-like structure in aqueous solutions. Formation of the micelle structure significantly promotes siRNA condensation capability of the peptides. The cholesteryl peptides can form stable complex with siRNA and effectively protect siRNA from enzymatic degradation in rat serum. Furthermore, the cholesteryl peptides can efficiently transfect siRNA into different cancer cells and mediate potent gene silencing effect, whereas peptides without cholesterol modification fail to deliver siRNA into the cells. In addition, one of the cholesteryl peptide Chol-H3K2s displayed comparable cellular uptake and gene silencing effect but less cytotoxicity compared with bPEI and lipofectamine-2000. In chapter 5, we introduced folic acid and a disulfide linker into the Chol-H3K2s. The reducible cholesteryl peptides efficiently condense siRNA, and the resultant complexes can release siRNA under reductive condition. PEGylation of the reducible cholesteryl peptide significantly decreased nonspecific cellular uptake. Conjugation of folic acid via a PEG spacer resulted in high cellular uptake and gene silencing effect. In Chapter 6, we identified a prostate cancer specific peptide using a phage display library and evaluate its potential application in targeted drug delivery. One phage clone with a high binding affinity to LNCaP cells was identified. Cell phage ELISA and immunostaining demonstrated high specificity of this phage to LNCaP cells. The fluorescein labeled KYL peptide exhibited higher binding to LNCaP cells in comparison to other cells. The fusion peptide composed of the KYL peptide and the proapoptotic peptide induced cell death in LNCaP cells, but not in PC-3 cells. The KYL peptide-protamine conjugate also efficiently delivered a fluorescein labeled siRNA into LNCaP cells.Item The governance-performance relationship: examining the impact of nonprofit governance on financial performance in medium-sized nonprofit organizations(University of Missouri--Kansas City, 2012) Andersson, Fredrik O.; Renz, David O. (David Owen)As the nonprofit sector has grown rapidly in size and significance in recent decades, the role and impact of governance of nonprofit organizations have become increasingly important and popular topics among nonprofit scholars and practitioners. Extensive research and practice in nonprofit governance are based on the premise that a well-performing governance function coincides with effective and high-performing organizations, yet the empirical assessment and knowledge about the mechanisms that links governance to performance are still limited. This dissertation focuses on how nonprofit governance, and the boards entrusted to fulfill this critical function, impacts nonprofit organizational performance by examining how three critical governance elements - board composition, funding strategy, and planning and evaluation practices - affect the financial performance in 152 mediumsized nonprofit agencies.Item Improved delivery of molecularly targeted agents upon modulation of multidrug resistance efflux proteins at mouse blood brain barrier(University of Missouri--Kansas City, 2012) Minocha, Mukul; Mitra, Ashim K., 1954-Recurrent brain tumors are one of the most lethal forms of solid tumors with poor prognosis. Molecularly targeted therapy, inhibiting the tyrosine kinase domain of epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptors (VEGFR) is at the forefront of current clinical practice for management of highly vascularized brain tumors. However, current molecularly targeted agents used in clinical trials so far have shown limited clinical benefit to block tumor progression. It has now been well established that P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are the two major efflux proteins that restrict the entry of xenobiotics across BBB. Overexpression of these efflux pumps in brain tumors at the BBB further compromises brain penetration of anti-tumor agents. The broad objective of this dissertation project is to study the role of efflux on brain penetration of selected small molecule tyrosine kinase inhibitors; pazopanib and vandetanib. In vitro and in vivo results showed that the entry across the BBB for these drugs is limited via active efflux. This could be a plausible mechanism for inefficacy seen for these drugs in clinical trials when used as monotherapy. As a secondary aim of this investigation we wanted to develop a viable strategy to overcome efflux at the BBB by coadministering clinically relevant efflux modulators which could also impart a synergistic pharmacological effect in the treatment regimen. Erlotinib, canertinib, everolimus and temsirolimus were screened as potential modulators of P-gp and Bcrp1 activity. The fact that these drugs inhibit a different class of receptor population than pazopanib and vandetanib, offer a dual advantage for synergistic pharmacological effect in addition to the primary role of efflux modulation. Our results demonstrate that co-administration of selected clinically relevant efflux modulators can significantly enhance brain partitioning of pazopanib and vandetanib in mice and hence warrant further pre-clinical and clinical investigation.Item The impact of instrumental music programs on student achievement in an urban-suburban fringe school district(University of Missouri--Kansas City, 2012-06-18) Moore, Amanda-Fay; Thompson, Sue Carol, 1946-The purpose of this study is to examine if students that participate in instrumental music programs have higher academic achievement as measured by ACT composite test score than students who do not participate in instrumental music programs in a mid-western urban-suburban fringe district. This study examined the ACT composite scores of those who participate in instrumental music and those who do not participate in instrumental music of the entire graduating 2010-2011 senior class in all three high schools of the participating district. Data revealed that 12th grade students having had instrumental music participation during their high school years scored significantly higher with an average ACT composite score of 23.39 as compared to students not having instrumental music participation with an average ACT composite score of 19.68. Research on music implementation is crucial for all educators due to the increased accountability for student achievement. Educators must explore alternatives to utilize when striving for academic achievement. The results of this proposed quantitative study may increase awareness of how music influences student achievement, particularly with administration whose decisions affect the curriculum.