Doctoral Recitals

Recital presented at the UNT College of Music Recital Hall in partial fulfillment of the Doctor of Musical Arts (DMA) degree

Liquid biopsy in lung cancer: Clinical applications of circulating biomarkers (CTCs and ctDNA)

Lung cancer is by far the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Recent advances in the understanding of the biology of tumors and in highly sensitive detection technologies for molecular analysis offer targeted therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. However, our understanding of an individual patient's lung cancer is often limited by tumor accessibility because of the high risk and invasive nature of current tissue biopsy procedures. Liquid biopsy, the analysis of circulating biomarkers from peripheral blood, such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), offers a new source of cancer-derived materials that may reflect the status of the disease better and thereby contribute to more personalized treatment. In this review, we examined the clinical significance and uniqueness of CTCs and ctDNA from NSCLC patients, isolation and detection methods developed to analyze each type of circulating biomarker, and examples of clinical studies of potential applications for early diagnosis, prognosis, treatment monitoring, and prediction of resistance to therapy. We also discuss challenges that remain to be addressed before such tools are implemented for routine use in clinical settings

TCF/β-catenin plays an important role in HCCR-1 oncogene expression

<p>Abstract</p> <p>Background</p> <p>Oncogene <it>HCCR-1 </it>functions as a negative regulator of the p53 and contributes to tumorigenesis of various human tissues. However, it is unknown how <it>HCCR-1 </it>contributes to the cellular and biochemical mechanisms of human tumorigenesis.</p> <p>Results</p> <p>In this study, we showed how the expression of <it>HCCR-1 </it>is modulated. The luciferase activity assay indicated that the <it>HCCR-1 </it>5'-flanking region at positions -166 to +30 plays an important role in <it>HCCR-1 </it>promoter activity. Computational analysis of this region identified two consensus sequences for the T-cell factor (TCF) located at -26 to -4 (Tcf1) and -136 to -114 (Tcf2). Mutation at the Tcf1 site led to a dramatic decrease in promoter activity. Mobility shift assays (EMSA) revealed that nuclear proteins bind to the Tcf1 site, but not to the Tcf2 site. LiCl, Wnt signal activator by GSK-3β inhibition, significantly increased reporter activities in wild-type Tcf1-containing constructs, but were without effect in mutant Tcf1-containing constructs in HEK/293 cells. In addition, endogenous <it>HCCR-1 </it>expression was also increased by treatment with GSK-3β inhibitor, LiCl or AR-A014418 in HEK/293 and K562 cells. Finally, we also observed that the transcription factor, TCF, and its cofactor, β-catenin, bound to the Tcf1 site.</p> <p>Conclusion</p> <p>These findings suggest that the Tcf1 site on the <it>HCCR-1 </it>promoter is a major element regulating <it>HCCR-1 </it>expression and abnormal stimulation of this site may induce various human cancers.</p

Polyclonal gammopathy related to renal bleeding in a peritoneal dialysis patient

Polyclonal gammopathy represents the diffuse activation of B cells and is usually related to inflammation or immune-related diseases. However, the mechanisms leading to polyclonal gammopathy are essentially speculative. Generally, infectious, inflammatory, or various other reactive processes may be indicated by the presence of a broad-based peak or band in the gamma region on serum protein electrophoresis results. A 15-year-old girl, who had been receiving peritoneal dialysis, presented with polyclonal gammopathy and massive gross hematuria. Renal artery embolization was performed, after which the continuous bleeding subsided and albumin-globulin dissociation resolved. This is a rare case of polyclonal gammopathy related to renal bleeding

Human AP endonuclease suppresses DNA mismatch repair activity leading to microsatellite instability

The multifunctional mammalian apurinic/apyrimidinic (AP) endonuclease (APE) participates in the repair of AP sites in the cellular DNA as well as participating in the redox regulation of the transcription factor function. The function of APE is considered as the rate-limiting step in DNA base excision repair. Paradoxically, an unbalanced increase in APE protein leads to genetic instability. Therefore, we investigated the mechanisms of genetic instability that are induced by APE. Here, we report that the overexpression of APE protein disrupts the repair of DNA mismatches, which results in microsatellite instability (MSI). We found that expression of APE protein led to the suppression of the repair of DNA mismatches in the normal human fibroblast cells. Western blot analysis revealed that hMSH6 protein was markedly reduced in the APE-expressing cells. Moreover, the addition of purified Mutα (MSH2 and MSH6 complex) to the extracts from the APE-expressing cells led to the restoration of mismatch repair (MMR) activity. By performing MMR activity assay and MSI analysis, we found that the co-expression of hMSH6 and APE exhibited the microsatellite stability, whereas the expression of APE alone generated the MSI-high phenotype. The APE-mediated decrease in MMR activity described here demonstrates the presence of a new and highly effective APE-mediated mechanism for MSI

A lab-on-a-disc platform enables serial monitoring of individual CTCs associated with tumor progression during EGFR-targeted therapy for patients with NSCLC

Rationale: Unlike traditional biopsy, liquid biopsy, which is a largely non-invasive diagnostic and monitoring tool, can be performed more frequently to better track tumors and mutations over time and to validate the efficiency of a cancer treatment. Circulating tumor cells (CTCs) are considered promising liquid biopsy biomarkers; however, their use in clinical settings is limited by high costs and a low throughput of standard platforms for CTC enumeration and analysis. In this study, we used a label-free, high-throughput method for CTC isolation directly from whole blood of patients using a standalone, clinical setting-friendly platform. Methods: A CTC-based liquid biopsy approach was used to examine the efficacy of therapy and emergent drug resistance via longitudinal monitoring of CTC counts, DNA mutations, and single-cell-level gene expression in a prospective cohort of 40 patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Results: The change ratio of the CTC counts was associated with tumor response, detected by CT scan, while the baseline CTC counts did not show association with progression-free survival or overall survival. We achieved a 100% concordance rate for the detection of EGFR mutation, including emergence of T790M, between tumor tissue and CTCs. More importantly, our data revealed the importance of the analysis of the epithelial/mesenchymal signature of individual pretreatment CTCs to predict drug responsiveness in patients. Conclusion: The fluid-assisted separation technology disc platform enables serial monitoring of CTC counts, DNA mutations, as well as unbiased molecular characterization of individual CTCs associated with tumor progression during targeted therapy

Increase of Orexin A in the Peripheral Blood of Adolescents with Internet Gaming Disorder

BACKGROUND AND AIMS: Overindulgence in Internet gaming, which is related to rapid development of the online game industry, can cause a psychiatric disorder known as Internet gaming disorder (IGD). The number of adolescents with IGD is on the rise in countries with developed Internet technologies, such as South Korea. Therefore, it is important to develop biomarkers to detect patients at high risk of IGD. This study investigated expression levels of proteins in the blood of adolescents to provide insight into the development of biomarkers. METHODS: We collected blood samples from 73 subjects [40 healthy adolescents (Internet gaming control, IGC) and 33 adolescents with IGD] between 13:00 and 15:00. We analyzed the expression levels of orexin A, oxytocin, cortisol, melatonin, BDNF, sICAM-1, RANTES, and NCAM using multiplex assay kits. RESULTS: Orexin A was significantly (p = .016) elevated in the IGD group and the expression levels of melatonin tended to be higher (p = .055) in the IGD group. On the other hand, increased Internet gaming time in the IGD group was negatively correlated (p = .041) with expression of BDNF. On the contrary, sICAM-1 associated with inflammation exhibited the tendency of the positive correlation (p = .073) with Internet gaming time in the IGD group. DISCUSSION AND CONCLUSIONS: We identified elevation of orexin A in the peripheral blood of adolescents with IGD and a negative correlation between Internet gaming time and BDNF in adolescents with IGD. Our results provide useful information to understand the pathophysiology of IGD in adolescents

Implant-supported orbital prosthesis: a technical innovation of silicone fabrication

Background Silicone-based facial prostheses have traditionally been considered difficult to make and require time-consuming fabrication due to their basic liquid characteristics. Methods and results A detailed procedure for creating an ideal silicone orbital prosthesis was developed, including dental implant-supported retention, three-dimensional (3D) orbital scanning with symmetric volume and size measurement based on matching the opposite side, master mold fabrication for convenient pouring of the liquid silicone elastomer, and easy and comfortable management of the prosthesis by the patient. Conclusion A silicone orbital prosthesis could be more easily and conveniently produced using updated surgical skills and modern 3D technology. The combination of 3D scanning with digital reconstruction and an innovative fabrication protocol using a reproducible major mold and multiple prototypes fitting resulted in an accuracy personalized facial prosthesis with accessible cost and short production period

Predictors and patterns of problematic Internet game use using a decision tree model

Background and aims Problematic Internet game use is an important social issue that increases social expenditures for both individuals and nations. This study identified predictors and patterns of problematic Internet game use. Methods Data were collected from online surveys between November 26 and December 26, 2014. We identified 3,881 Internet game users from a total of 5,003 respondents. A total of 511 participants were assigned to the problematic Internet game user group according to the Diagnostic and Statistical Manual of Mental Disorders Internet gaming disorder criteria. From the remaining 3,370 participants, we used propensity score matching to develop a normal comparison group of 511 participants. In all, 1,022 participants were analyzed using the chi-square automatic interaction detector (CHAID) algorithm. Results According to the CHAID algorithm, six important predictors were found: gaming costs (50%), average weekday gaming time (23%), offline Internet gaming community meeting attendance (13%), average weekend and holiday gaming time (7%), marital status (4%), and self-perceptions of addiction to Internet game use (3%). In addition, three patterns out of six classification rules were explored: cost-consuming, socializing, and solitary gamers. Conclusion This study provides direction for future work on the screening of problematic Internet game use in adults

Seven-dimensional considerations of Einstein's connection. I. The recurrence relations of the first kind in n

Einstein's connection in a generalized Riemannian manifold Xn has been investigated by many authors for lower-dimensional cases n=2,…,6. In a series of papers, we obtain a surveyable tensorial representation of 7-dimensional Einstein's connection in terms of unified field tensor, with main emphasis on the derivation of powerful and useful recurrence relations which hold in X7. In this paper, we give a brief survey of Einstein's unified field theory and derive the recurrence relations of the first kind which hold in a general Xn. All considerations in this paper are restricted to the first and second classes only since the case of the third class, the simplest case, was already studied by many authors