Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 4 uppsatser.

The bonding in a series of ligand-bridged metal dimer complexes has been characterized by He(I) and He(II) photoelectron spectroscopy and approximate molecular orbital calculations. Bridging ligands such as carbonyl, nitrosyl, methylene and pyrazolyl in the complexes [CpFe(NO)]₂, [Cp*Fe(NO)]₂, [CpRu(NO)]₂, [Cp*Co(CO)]₂, [CpFe(CO)₂]₂, [Cp*Fe(CO)₂]₂, [CpFe(CO)]₂-μCO-μCH₂, [Cp*Fe(CO)]₂-μCO-μCH₂, [CpFe(NO)]₂- μCh₂, [CpRu(NO)]₂-μCH₂, [CpCo(CO)]₂-μCH₂, [CpRh(CO)]₂-μCH₂, [Ir(pyrazolyl)(CO)₂]₂, [Ir(3-methylpyrazolyl)(CO)₂]₂ and [Ir(3,5-dimethylpyrazolyl)(CO)₂]₂ are investigated and their effects upon metal-metal interactions are surveyed. Due to the presence of two d⁷ or d⁸ late metal atoms per molecule, these complexes display many overlapping ionization bands in a narrow valence ionization region. Attention has been given to modelling the photoelectron single ionization with asymmetric and symmetric Gaussians. The overlapping ionizations are successfully represented in terms of the model bandshapes. Thermodynamic relationships between bond dissociation and photoelectron ionization energies are also investigated. With relationships of this type, trends in bond energies may be correlated with ionization energies. Ligand inductive and bonding effects as well as small changes in molecular geometry cause shifts in the metal-based ionizations, which aid chemical understanding and interpretation of the molecular orbital picture. By comparing a series of related metal dimers, the assignment of related ionizations in the photoelectron spectra becomes apparent. Changes in ligand π accepting ability and changes in metal and formal oxidation states are also probed. Addition information is provided by vibrational fine structure in Cp₂Os, [CpFe(NO)]₂, and [Cp*Co(CO)]₂ and spin-orbit splitting in Cp₂Os. The metal-ligand backbonding combinations are found to be the most stable interactions and are responsible for the stability of the metal dimers. Metal-metal interactions are found to be relatively unimportant. Ligands with stronger π accepting abilities allow for more stabilized supported metal dimer complexes.

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Indiana University-Purdue University Indianapolis (IUPUI) / An investigation of the lipid metabolism pathway in the yeast Yarrowia lipolytica was conducted. Yarrowia is an oleaginous ascomycete that is capable of growing on many different substrates, which derives its name from its high efficiency of growth on lipids. Once the exogenous lipids are converted into free fatty acids and internalized by the yeast, the primary mode of degradation is through β-oxidation mediated by the peroxisomal oxidases, or POX genes. These enzymes catalyze the formation of a trans double bond, producing the trans-2-enoyl product. Our study looked at the comparison of the Y. lipolytica prototrophic strain against a knockout of the Pox2 gene on the uptake, incorporation, and degradation of relevant fatty acids. To construct this gene knockout, a novel gene deletion method using a combination of Cre recombinase and the AHAS* gene was synthesized, developed, and tested successfully. This knockout system allows for serial deletion of genes with the use of only one resistance marker, with excision of the marker after selection.

Indiana University-Purdue University Indianapolis (IUPUI) / Immunostimulatory cytokines can enhance anti-tumor immunity and are part of the therapeutic armamentarium for cancer treatment. We previously reported that chemotherapy-treated lymphoma patients acquire a deficiency of Signal Transducer and Activator of Transcription 4 (STAT4), which results in defective IFNy production during clinical immunotherapy. With the goal of further improvement in cytokine-based immunotherapy, we examined the effects of a soybean peptide called lunasin that exhibits immunostimulatory effects on natural killer cells (NKCs). Peripheral blood mononucleated cells (PBMCs) from healthy donors and chemotherapy-treated lymphoma patients were stimulated with or without lunasin in the presence of IL-12 or IL-2. NK activation was evaluated, and its tumoricidal activity was assessed using in vitro and in vivo tumor models. Chromatin immunoprecipitation (ChIP) assay was performed to evaluate the histone modification of gene loci that are regulated by lunasin and cytokine. Adding lunasin to IL-12- or IL-2-cultuted NK cells demonstrated synergistic effects in the induction of IFNG and genes involved in cytotoxicity. The combination of lunasin and cytokines (IL-12 plus IL-2) was capable of restoring IFNy production by NK cells from post-transplant lymphoma patients. In addition, NK cells stimulated with lunasin plus cytokines have higher tumoricidal activity than those stimulated with cytokines alone using in vitro tumor models. The underlying mechanism responsible for the effects of lunasin on NK cells is likely due to epigenetic modulation at target gene loci. Lunasin represents a different class of immune modulating agent that may augment the therapeutic responses mediated by cytokine-based immunotherapy.

Indiana University-Purdue University Indianapolis (IUPUI) / All platinum (Pt)-based chemotherapeutics exert their efficacy primarily via the formation of DNA adducts which interfere with DNA replication, transcription and cell division and ultimately induce cell death. Repair and tolerance of Pt-DNA lesions by nucleotide excision repair and homologous recombination (HR) can substantially reduce the effectiveness of the Pt therapy. Inhibition of these repair pathways, therefore, holds the potential to sensitize cancer cells to Pt treatment and increase clinical efficacy. Replication Protein A (RPA) plays essential roles in both NER and HR, along with its role in DNA replication and DNA damage checkpoint activation. Each of these functions requires RPA binding to single-stranded DNA (ssDNA). We synthesized structural analogs of our previously reported RPA inhibitor TDRL-505, determined the structure activity relationships and evaluated their efficacy in tissue culture models of epithelial ovarian cancer (EOC) and non-small cell lung cancer (NSCLC). These data led us to the identification of TDRL-551, which exhibited a greater than 2-fold increase in in vitro and cellular activity. TDRL-551 showed synergy with Pt in tissue culture models of EOC and in vivo efficacy, as a single agent and in combination with platinum, in a NSCLC xenograft model. These data demonstrate the utility of RPA inhibition in EOC and NSCLC and the potential in developing novel anticancer therapeutics that target RPA-DNA interactions.