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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.
711

Preclinical and clinical characterization of lung cancers with Exon 19 insertion

Shaffer, William Wood Lee 08 March 2024 (has links)
The epidermal growth factor receptor (EGFR)-K745_E746insIPVAIK and others with rare PVAI amino-acid insertions are exon 19 insertion mutations (<1% of all EGFR mutations), which, at the structural modeling level, resemble EGFR tyrosine kinase inhibitor (TKI)-sensitizing mutants. An important unmet clinical need is the characterization of therapeutic windows of rare exon 19 PVAI amino-acid insertions to available EGFR TKIs. A limited number of preclinical and clinical reports have studied the response of these mutants to all classes of approved EGFR TKIs. We used models of EGFR-K745_E746insIPVAIK and more typical EGFR mutations (exon 19 deletion, L858R, L861Q, G719S, A763_Y764insFQEA, other exon 20 insertion mutations) to probe representative 1st (erlotinib), 2nd (afatinib), 3rd generation (osimertinib), and EGFR exon 20 active (mobocertinib) TKIs. We used human lung-cancer derived cell lines and transduced Ba/F3 cells to measure the treatment efficacy. We also compiled outcomes of EGFR exon 19 insertion mutated lung cancers−from our institution plus the literature−treated with EGFR TKIs. Cells driven by EGFR-K745_E746insIPVAIK had sensitivity to all classes of EGFR TKIs when compared to cells driven by EGFR-wild type in proliferation assays and at the protein level. However, the therapeutic window (calculated in preclinical models as the logarithm of the 50% inhibitory concentration of EGFR mutation compared to wild-type EGFR) of EGFR-K745_E746insIPVAIK driven cells was most akin to those of cells driven by EGFR-L861Q, EGFR-G719S and EGFR- A763_Y764insFQEA than the more sensitive patterns seen with cells driven by an EGFR exon 19 deletion or EGFR-L858R. The majority of patients with lung cancers harboring EGFR- K745_E746insIPVAIK and other mutations with rare PVAI amino-acid insertions responded to clinically available EGFR TKIs (including icotinib, gefitinib, erlotinib, afatinib and osimertinib), with heterogeneous periods of progression-free survival. This is the largest preclinical/clinical report to highlight that EGFR- K745_E746insIPVAIK and other mutations with rare exon 19 PVAI amino-acid insertions are sensitive to clinically available TKIs; in a pattern that mostly resembles the outcomes of models with EGFR-L861Q, EGFR-G719S and EGFR-A763_Y764insFQEA mutations. These findings are consistent with the proposed mechanism of activation of mutant EGFR by alteration of the proposed hydrophobic core. These data may help with the off-label selection of EGFR TKIs and clinical expectations of outcomes when targeted therapy is deployed for these rare EGFR mutated lung cancers. / 2026-03-08T00:00:00Z
712

Overview of Direct Thrombin Inhibitors for use in Staphylococcus Aereus Infections

Risler, Joseph C 01 January 2019 (has links)
The pathogenicity and intractable nature of the microorganism Staphylococcus aureus (SA) has been long documented and highlighted by many health care agencies, with emphasis on its ability to exploit the human coagulation system to deadly effect. Two drugs from a class of inhibitors known as Direct Thrombin Inhibitors (DTI) have been shown to have a substantial effect on the enzyme secreted by SA known as Staphylocoagulase (SC), but up until now the application of this potential treatment has been limited. This paper strives to supply an overview of these clinical studies and propose a novel protocol for testing DTI's on SA in an in vitro setting. Three DTIs have been identified, including two already tested in clinical trials, and computational molecular docking simulations have been applied to elucidate the mechanisms of action for the inhibition. An additional DTI has been developed using these mechanisms as principles and shows promise for future development. After conducting this preliminary protocol, it has been found that running a minimum inhibitory concentration test across several tubes with varying degrees of these DTIs demonstrated varying levels of coagulation consistent with the findings of clinical research papers. It is fair to conclude, then, that after development or discovery of new coagulase inhibitors, they can be quickly and accurately tested against existent DTIs to gauge their efficacy.
713

Elevated Clearance of Immune Checkpoint Inhibitors in Animal Models of Cancer Cachexia

Vu, Trang Thu January 2022 (has links)
No description available.
714

Binding of the Nonnucleoside Reverse Transcriptase Inhibitor Efavirenz to HIV-1 Reverse Transcriptase Monomers and Dimers

Braz, Valerie Ann January 2010 (has links)
No description available.
715

Mechanisms of β- lactamase Inhibition and Heterotropic Allosteric Regulation of an Engineered β- lactamase-MBP Fusion Protein

Ke, Wei January 2011 (has links)
No description available.
716

Modulation of Folate Receptor Beta for Drug Targeting in Acute Myelogenous Leukemia

Qi, Huiling January 2005 (has links)
No description available.
717

Na/K-ATPase Signaling: from Bench to Bedside

Li, Zhichuan 18 December 2008 (has links)
No description available.
718

Uncovering the complexity of muscular dystrophy pathology through disease signaling

Wissing, Erin R. 17 October 2014 (has links)
No description available.
719

Signaling Pathways Associated with Gefitinib Resistance in Glioblastoma Multiforme (GBM)

Aljohani, Hashim M., B.S. 10 October 2014 (has links)
No description available.
720

Hyaluronan Rafts on Airway Epithelial Cells

Amineh , Abbadi 11 August 2014 (has links)
No description available.

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