Doctor of Philosophy

dissertationLung cancer causes more than 1 million deaths in every year worldwide, and is the leading cause of cancer-related death in the United States. Targeting epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) harboring activating mutations in EGFR is an effective treatment but is eventually limited by drug-resistance. This has led to a pressing need to identify alternative treatments or additional targets for resistant tumors. I found abundant activation of cyclooxygenase-2 (COX-2) signal in mutant EGFR NSCLC, suggesting that it might play tumorigenic roles in these tumors. Targeting COX-2 in mutant EGFR lung cancer cells and transgenic mouse models of mutant EGFR lung cancer reduced tumor cell growth, and was more effective in combination with EGFR inhibition. I found that COX-2 signaling regulates interleukin-6 (IL-6) transcription leading to signal transducer and activator of transcription 3 (STAT3) activation. These findings demonstrate that COX-2 modulates the IL-6/STAT3 signaling axis in mutant EGFR NSCLC and targeting COX-2 in combination with EGFR inhibition could be an effective strategy to treat mutant EGFR NSCLC. Since COX-2 inhibition is a promising chemopreventive agent in other cancers; therefore, I next hypothesized that targeting COX-2 might be a viable strategy to prevent tumor formation. Using transgenic mouse models, I found that targeting COX-2 prior to tumor development delayed tumor formation, which suggests that COX-2 inhibition could be a potential strategy to delay or prevent development of mutant EGFR NSCLC. iv In further efforts to identify other targets in mutant EGFR lung cancer, I found evidence of abundant activation of protein kinase C δ (PKCδ). This kinase normally functions as a tumor-suppressor, but it also is considered as a tumor-promoter in some contexts. I found reduced growth of mutant EGFR human lung cancer cells under PKCδ depletion. I also discovered that PKCδ promotes IL-6/STAT3 signal in mutant EGFR NSCLC, suggesting that PKCδ is a tumor-promoter in mutant EGFR NSCLC. Collectively, my data indicate that PKCδ is a potential target to treat mutant EGFR NSCLC. In this dissertation, I identified COX-2 and PKCδ as novel targets for treating mutant EGFR NSCLC and defined their oncogenic roles in mutant EGFR NSCLC by regulating the critical oncogenic signal, IL-6/STAT3

Full-length genomic analysis of korean porcine sapelovirus strains.

Porcine sapelovirus (PSV), a species of the genus Sapelovirus within the family Picornaviridae, is associated with diarrhea, pneumonia, severe neurological disorders, and reproductive failure in pigs. However, the structural features of the complete PSV genome remain largely unknown. To analyze the structural features of PSV genomes, the full-length nucleotide sequences of three Korean PSV strains were determined and analyzed using bioinformatic techniques in comparison with other known PSV strains. The Korean PSV genomes ranged from 7,542 to 7,566 nucleotides excluding the 3' poly(A) tail, and showed the typical picornavirus genome organization; 5'untranslated region (UTR)-L-VP4-VP2-VP3-VP1-2A-2B-2C-3A-3B-3C-3D-3'UTR. Three distinct cis-active RNA elements, the internal ribosome entry site (IRES) in the 5'UTR, a cis-replication element (CRE) in the 2C coding region and 3'UTR were identified and their structures were predicted. Interestingly, the structural features of the CRE and 3'UTR were different between PSV strains. The availability of these first complete genome sequences for PSV strains will facilitate future investigations of the molecular pathogenesis and evolutionary characteristics of PSV

Electrical characteristics of metal-insulator-semiconductor Schottky diodes using a photowashing treatment in AlzGa1-xAs/InGaAs (X=0.75) pseudimorphic high electron mobility transistors

MIS Schottky diodes on Al0.75Ga0.25As/In0.2Ga0.8As PHEMTs were produced using both photowashing and H2O2 treatments. The Schottky contact on the GaAs layer with photowashing and H2O2 treatments showed enhancements of the SBH of about 0.11 and 0.05 eV, respectively. However, on the undoped AlGaAs layer, no further improvement in SBH was observed. After the photowashing treatment, the Ga oxide (Ga2O3) was dominantly created. In the mean time, two types of As oxide (As2O3,As5O2) were mainly produced by the H2O2 treatment, which are distributed uniformly on the GaAs surface. The thickness of the oxide layer formed by both treatments was nearly the same. Applying a representative model, formation of Ga oxide after the photowashing treatment effectively enhanced the SBH.open4

The seroprevalence of Japanese encephalitis virus in goats raised in Korea

Japanese encephalitis virus (JEV) causes a mosquito-borne viral zoonosis that is becoming increasingly important to public health in east and south Asia. Although JEV is primarily associated with reproductive failure in swine, JEV infection can cause fever and headache in humans and is associated with aseptic meningitis and encephalitis. The exact mode of transmission, including host range and possible source of viral amplification within livestock, is still not completely clear. This study consisted of a serological survey of JEV infection in goats. A total of 804 goat serum samples were collected from 144 farms in Korea between May 2005 and May 2006. The incidence of positive cases was 12.1% (97 out of 804 goats). The seroprevalence of JEV infection in the 144 farms screened was 31.3% (45/144), indicating that JEV infection is frequent in goat farms in Korea. In addition, three districts of Korea (mainly in the southern region) had a higher seroprevalence of JEV compared to other areas. The results suggest that goats could be monitored epidemiologically as a sentinel animal for JEV transmission in Korea

In Vitro inhibitory activity of Alpinia katsumadai extracts against influenza virus infection and hemagglutination

<p>Abstract</p> <p>Background</p> <p><it>Alpinia katsumadai </it>(AK) extracts and fractions were tested for <it>in vitro </it>antiviral activities against influenza virus type A, specially human A/PR/8/34 (H1N1) and avian A/Chicken/Korea/MS96/96 (H9N2), by means of time-of-addition experiments; pre-treatment, simultaneous treatment, and post treatment.</p> <p>Results</p> <p>In pre-treatment assay, the AK extracts and AK fractions did not show significant antiviral activity. During the simultaneous treatment assay, one AK extract and five AK fractions designated as AK-1 to AK-3, AK-5, AK-10, and AK-11 showed complete inhibition of virus infectivity against A/PR/8/34 (H1N1) and A/Chicken/Korea/MS96/96 (H9N2). The 50% effective inhibitory concentrations (EC₅₀) of these one AK extracts and five AK fractions with exception of the AK-9 were from 0.8 ± 1.4 to 16.4 ± 4.5 <it>μ</it>g/mL against A/PR/8/34 (H1N1). The two AK extracts and three AK fractions had EC₅₀values ranging from <0.39 ± 0.4 to 2.3 ± 3.6 <it>μ</it>g/mL against A/Chicken/Korea/MS96/96 (H9N2). By the hemagglutination inhibition (HI) assay, the two AK extracts and five AK fractions completely inhibited viral adsorption onto chicken RBCs at less than 100 <it>μ</it>g/mL against both A/PR/8/34 (H1N1) and A/Chicken/Korea/MS96/96 (H9N2). Interestingly, only AK-3 was found with inhibition for both viral attachment and viral replication after showing extended antiviral activity during the post treatment assay and quantitative real-time PCR.</p> <p>Conclusions</p> <p>These results suggest that AK extracts and fractions had strong anti-influenza virus activity that can inhibit viral attachment and/or viral replication, and may be used as viral prophylaxis.</p

Crystal structure of Helicobacter pylori MinE, a cell division topological specificity factor

In Gram-negative bacteria, proper placement of the FtsZ ring, mediated by nucleoid occlusion and the activities of the dynamic oscillating Min proteins MinC, MinD and MinE, is required for correct positioning of the cell division septum. MinE is a topological specificity factor that counters the activity of MinCD division inhibitor at the mid-cell division site. Its structure consists of an anti-MinCD domain and a topology specificity domain (TSD). Previous NMR analysis of truncated Escherichia coli MinE showed that the TSD domain contains a long α-helix and two anti-parallel β-strands, which mediate formation of a homodimeric α/β structure. Here we report the crystal structure of full-length Helicobacter pylori MinE and redefine its TSD based on that structure. The N-terminal region of the TSD (residues 19–26), previously defined as part of the anti-MinCD domain, forms a β-strand (βA) and participates in TSD folding. In addition, H. pylori MinE forms a dimer through the interaction of anti-parallel βA-strands. Moreover, we observed serial dimer–dimer interactions within the crystal packing, resulting in the formation of a multimeric structure. We therefore redefine the functional domain of MinE and propose that a multimeric filamentous structure is formed through anti-parallel β-strand interactions

Prognostic Factors and Clinical Outcomes of High-Dose Chemotherapy followed by Autologous Stem Cell Transplantation in Patients with Peripheral T Cell Lymphoma, Unspecified: Complete Remission at Transplantation and the Prognostic Index of Peripheral T Cell Lymphoma Are the Major Factors Predictive of Outcome

AbstractHigh-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) offers a rescue option for T cell lymphoma patients with poor prognosis. However, the effectiveness of HDT/ASCT in patients with various peripheral T cell subtypes, optimal transplant timing, and the prognostic factors that predict better outcomes, have not been identified. We retrospectively investigated the clinical outcomes and prognostic factors for HDT/ASCT in 64 Korean patients with peripheral T cell lymphoma, unspecified (PTCL-U) between March 1995 and February 2007. The median age at transplantation was 44 years (range: 15-63 years). According to the age-adjusted International Prognostic Index (a-IPI) and the prognostic index of PTCL (PIT), 8 patients (12.5%) were in the high-risk group and 16 (26.6%) had the 2-3 PIT factors, respectively. After a median follow-up of 29.7 months, the 3-year overall survival (OS) and progression-free survival (PFS) rates were 53.0% ± 7.5% and 44.3% ± 7.0%, respectively. Univariate analysis showed that poor performance status, high lactate dehydrogenase (LDH) levels, high a-IPI score, high PIT classes, failure to achieve complete response (CR) at transplantation, and nonfrontline transplantation were associated with poor OS. Multivariate analysis showed that failure to achieve CR at transplantation (hazard ratio [HR] 2.23; 95% confidence interval [CI] 1.78-7.93) and 2-3 PIT factors (HR 3.76; 95% CI 1.02-5.42) were independent prognostic factors for OS. Failure to achieve CR at transplantation and high PIT are negative predictable factors for survival following HDT/ASCT in patients with PTCL-U

An innovative strategy for standardized, structured, and interoperable results in ophthalmic examinations

Background Although ophthalmic devices have made remarkable progress and are widely used, most lack standardization of both image review and results reporting systems, making interoperability unachievable. We developed and validated new software for extracting, transforming, and storing information from report images produced by ophthalmic examination devices to generate standardized, structured, and interoperable information to assist ophthalmologists in eye clinics. Results We selected report images derived from optical coherence tomography (OCT). The new software consists of three parts: (1) The Area Explorer, which determines whether the designated area in the configuration file contains numeric values or tomographic images; (2) The Value Reader, which converts images to text according to ophthalmic measurements; and (3) The Finding Classifier, which classifies pathologic findings from tomographic images included in the report. After assessment of Value Reader accuracy by human experts, all report images were converted and stored in a database. We applied the Value Reader, which achieved 99.67% accuracy, to a total of 433,175 OCT report images acquired in a single tertiary hospital from 07/04/2006 to 08/31/2019. The Finding Classifier provided pathologic findings (e.g., macular edema and subretinal fluid) and disease activity. Patient longitudinal data could be easily reviewed to document changes in measurements over time. The final results were loaded into a common data model (CDM), and the cropped tomographic images were loaded into the Picture Archive Communication System. Conclusions The newly developed software extracts valuable information from OCT images and may be extended to other types of report image files produced by medical devices. Furthermore, powerful databases such as the CDM may be implemented or augmented by adding the information captured through our program.This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant No.HI19C0373). The publication cost of this article was funded by KHIDI and it had no role in the design or conduct of this researc