Biomedical subjects

Sek Won Kong

Publications and source records attributed to Sek Won Kong.

10 recordsLinked to original sources

PubMed2025

Genetic Landscape of Opsoclonus-Myoclonus-Ataxia Syndrome in Children.

BACKGROUND: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare neurological disorder, with involuntary rapid saccadic conjugate eye movements as one of characteristics, primarily affecting the cerebellum. While the exact pathogenesis remains unclear, genetic and autoimmune factors have been suggested to contribute to its development. METHODS: We enrolled patients diagnosed with OMAS before the age of 18 years at a pediatric neuroimmunology clinic in Boston, United States, using the 2004 Genoa Criteria. Whole genome sequencing was conducted for the patients and their biological parents in all cases, with one case including an unaffected twin sibling. RESULTS: De novo germline variants (DNVs) in probands were identified and validated and analyses of structural variants, recessive variants in neuroimmune-associated genes, and high-resolution human leukocyte antigen (HLA) typing were performed. Our study included 42 patients, 23 of whom had neuroblastoma. We found 12 confirmed DNVs in protein-coding regions in nine patients (29.0% of 31 from 30 trios and 1 quartet). Ten patients (23.8% of 42) had rare homozygous or compound heterozygous variants known to alter protein function, affecting 11 genes. Notably, the major histocompatibility complex, class II, DR beta 1 (HLA-DRB1) ∗01 allele was observed in 27 out of 84 (32.1%) alleles in the patients, significantly higher than that in the general population (chi-square test, P < 0.0001). In one case, a potential genetic modifier of OMAS with severe cerebellar atrophy was identified, associated with a protein-truncating DNV in the CACNA2D2 gene. CONCLUSIONS: This first genome sequencing study reveals potential genetic contributors to OMAS, implicating polygenic predisposition-with HLA-DRB1∗01 as a possible factor-combined with nongenetic risk factors like neuroblastoma.

Humans↗

PubMed2025

Pre-clinical safety and efficacy of human induced pluripotent stem cell-derived products for autologous cell therapy in Parkinson's disease.

Human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic cells (mDACs) represent a promising source for autologous cell therapy in Parkinson's disease (PD), but standardized regulatory criteria are essential for clinical translation. In this pre-clinical study, we generated multiple clinical-grade hiPSC lines from freshly biopsied fibroblasts of four sporadic PD patients using episomal reprogramming and differentiated them into mDACs using a refined 21-day protocol. Rigorous evaluations included whole-genome/exome sequencing, RNA sequencing, and in vivo studies, including a 39-week Good Laboratory Practice-compliant mouse safety study. While mDACs from all lines met safety criteria, mDACs from one patient failed to improve rodent behavioral outcomes, underscoring inter-individual variability. Importantly, in vitro assessments did not reliably predict in vivo efficacy, identifying dopaminergic fiber density as a key efficacy criterion. These findings support comprehensive quality control guidelines for autologous cell therapy and pave the way for a clinical trial with eight sporadic PD patients, scheduled to commence in 2025.

Humans↗

PubMed2006

Gata4 is required for maintenance of postnatal cardiac function and protection from pressure overload-induced heart failure.

An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiomyocytes, the transcription factor Gata4 is required for agonist-induced hypertrophy. We hypothesized that, in the intact organism, Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed up-regulation of genes associated with apoptosis and fibrosis, including members of the TGF-beta pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure.

Animals↗

PubMed2006

Development of heart valves requires Gata4 expression in endothelial-derived cells.

Cardiac malformations due to aberrant development of the atrioventricular (AV) valves are among the most common forms of congenital heart disease. At localized swellings of extracellular matrix known as the endocardial cushions, the endothelial lining of the heart undergoes an epithelial to mesenchymal transition (EMT) to form the mesenchymal progenitors of the AV valves. Further growth and differentiation of these mesenchymal precursors results in the formation of portions of the atrial and ventricular septae, and the generation of thin, pliable valves. Gata4, which encodes a zinc finger transcription factor, is expressed in the endothelium and mesenchyme of the AV valves. Using a Tie2-Cre transgene, we selectively inactivated Gata4 within endothelial-derived cells. Mutant endothelium failed to undergo EMT, resulting in hypocellular cushions. Mutant cushions had decreased levels of Erbb3, an EGF-family receptor essential for EMT in the atrioventricular cushions. In Gata4 mutant embryos, Erbb3 downregulation was associated with impaired activation of Erk, which is also required for EMT. Expression of a Gata4 mutant protein defective in interaction with Friend of Gata (FOG) cofactors rescued the EMT defect, but resulted in a decreased proliferation of mesenchyme and hypoplastic cushions that failed to septate the ventricular inlet. We demonstrate two novel functions of Gata4 in development of the AV valves. First, Gata4 functions as an upstream regulator of an Erbb3-Erk pathway necessary for EMT, and second, Gata4 acts to promote cushion mesenchyme growth and remodeling.

Animals↗

PubMed2006

A multivariate approach for integrating genome-wide expression data and biological knowledge.

MOTIVATION: Several statistical methods that combine analysis of differential gene expression with biological knowledge databases have been proposed for a more rapid interpretation of expression data. However, most such methods are based on a series of univariate statistical tests and do not properly account for the complex structure of gene interactions. RESULTS: We present a simple yet effective multivariate statistical procedure for assessing the correlation between a subspace defined by a group of genes and a binary phenotype. A subspace is deemed significant if the samples corresponding to different phenotypes are well separated in that subspace. The separation is measured using Hotelling's T(2) statistic, which captures the covariance structure of the subspace. When the dimension of the subspace is larger than that of the sample space, we project the original data to a smaller orthonormal subspace. We use this method to search through functional pathway subspaces defined by Reactome, KEGG, BioCarta and Gene Ontology. To demonstrate its performance, we apply this method to the data from two published studies, and visualize the results in the principal component space.

Algorithms↗

PubMed2005

Discovering statistically significant pathways in expression profiling studies.

Accurate and rapid identification of perturbed pathways through the analysis of genome-wide expression profiles facilitates the generation of biological hypotheses. We propose a statistical framework for determining whether a specified group of genes for a pathway has a coordinated association with a phenotype of interest. Several issues on proper hypothesis-testing procedures are clarified. In particular, it is shown that the differences in the correlation structure of each set of genes can lead to a biased comparison among gene sets unless a normalization procedure is applied. We propose statistical tests for two important but different aspects of association for each group of genes. This approach has more statistical power than currently available methods and can result in the discovery of statistically significant pathways that are not detected by other methods. This method is applied to data sets involving diabetes, inflammatory myopathies, and Alzheimer's disease, using gene sets we compiled from various public databases. In the case of inflammatory myopathies, we have correctly identified the known cytotoxic T lymphocyte-mediated autoimmunity in inclusion body myositis. Furthermore, we predicted the presence of dendritic cells in inclusion body myositis and of an IFN-alpha/beta response in dermatomyositis, neither of which was previously described. These predictions have been subsequently corroborated by immunohistochemistry.

Algorithms↗

PubMed2005

CrossChip: a system supporting comparative analysis of different generations of Affymetrix arrays.

SUMMARY: To increase compatibility between different generations of Affymetrix GeneChip arrays, we propose a method of filtering probes based on their sequences. Our method is implemented as a web-based service for downloading necessary materials for converting the raw data files (*.CEL) for comparative analysis. The user can specify the appropriate level of filtering by setting the criteria for the minimum overlap length between probe sequences and the minimum number of usable probe pairs per probe set. Our website supports a within-species comparison for human and mouse GeneChip arrays. AVAILABILITY: http://www.crosschip.org

Algorithms↗

PubMed2004

Genetic expression profiles during physiological and pathological cardiac hypertrophy and heart failure in rats.

Cardiac hypertrophy is a complex and nonhomogenous response to various stimuli. In this study, we used high-density oligonucleotide microarray to examine gene expression profiles during physiological hypertrophy, pathological hypertrophy, and heart failure in Dahl salt-sensitive rats. There were changes in 404/3,160 and 874/3,160 genes between physiological and pathological hypertrophy and the transition from hypertrophy to heart failure, respectively. There were increases in stress response genes (e.g., heat shock proteins) and inflammation-related genes (e.g., pancreatitis-associated protein and arachidonate 12-lipoxygenase) in pathological processes but not in physiological hypertrophy. Furthermore, atrial natriuretic factor and brain natriuretic protein showed distinctive changes that are very specific to different conditions. In addition, we used a resampling-based gene score-calculating method to define significantly altered gene clusters, based on Gene Ontology classification. It revealed significant alterations in genes involved in the apoptosis pathway during pathological hypertrophy, suggesting that the apoptosis pathway may play a role during the transition to heart failure. In addition, there were significant changes in glucose/insulin signaling, protein biosynthesis, and epidermal growth factor signaling during physiological hypertrophy but not during pathological hypertrophy.

Animals↗

PubMed2004

Combining gene expression data from different generations of oligonucleotide arrays.

BACKGROUND: One of the important challenges in microarray analysis is to take full advantage of previously accumulated data, both from one's own laboratory and from public repositories. Through a comparative analysis on a variety of datasets, a more comprehensive view of the underlying mechanism or structure can be obtained. However, as we discover in this work, continual changes in genomic sequence annotations and probe design criteria make it difficult to compare gene expression data even from different generations of the same microarray platform. RESULTS: We first describe the extent of discordance between the results derived from two generations of Affymetrix oligonucleotide arrays, as revealed in cluster analysis and in identification of differentially expressed genes. We then propose a method for increasing comparability. The dataset we use consists of a set of 14 human muscle biopsy samples from patients with inflammatory myopathies that were hybridized on both HG-U95Av2 and HG-U133A human arrays. We find that the use of the probe set matching table for comparative analysis provided by Affymetrix produces better results than matching by UniGene or LocusLink identifiers but still remains inadequate. Rescaling of expression values for each gene across samples and data filtering by expression values enhance comparability but only for few specific analyses. As a generic method for improving comparability, we select a subset of probes with overlapping sequence segments in the two array types and recalculate expression values based only on the selected probes. We show that this filtering of probes significantly improves the comparability while retaining a sufficient number of probe sets for further analysis. CONCLUSIONS: Compatibility between high-density oligonucleotide arrays is significantly affected by probe-level sequence information. With a careful filtering of the probes based on their sequence overlaps, data from different generations of microarrays can be combined more effectively.

Biopsy↗

PubMed2003

Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate.

Alterations in brain high-energy phosphate metabolism, determined by in vivo magnetic resonance spectroscopy (MRS), have been reported in subjects with a number of brain disorders including major depression, schizophrenia, and substance abuse. It is not clear to what extent these changes can be modified by pharmacological or nutritional means. To address this possibility, we evaluated changes in brain chemistry that were associated with oral creatine (Cr) administration. We hypothesized that oral Cr supplementation, by increasing brain creatine and high-energy phosphate stored in phosphocreatine, would result in an increase in the creatine resonance, as measured using proton 1H-MRS, and a decrease in the beta-nucleoside triphosphate (NTP) peak and an increase in the phosphocreatine (PCr) peak, as measured by phosphorus 31P-MRS, in brain of healthy human subjects. Fifteen healthy male subjects (age=22.9+/-2.2; body mass index=22.9+/-1.7), who were without any axis I disorders or physical or neurological illness, were recruited. Ten subjects took creatine-monohydrate, 0.3 g/kg/day for the first 7 days and 0.03 g/kg/day for the next 7 days (creatine group). Five comparison subjects took equivalent amounts of sucrose as placebo (placebo group). Both 1H- and 31P-MRS scans were acquired at baseline, as well as at day 7 and day 14 of oral supplementation. 1H-MRS: Water suppressed localized spectra were acquired using a single-voxel (1.5 cm x 2 cm x 2 cm) proton MRS PRESS sequence in the left frontal lobe. 31P-MRS: Phosphorus spectral data were recorded from a 5-cm-thick axial brain slice using a short-TE slice selective spin-echo pulse sequence. The creatine group had significantly increased brain creatine levels (8.1% and 9.3%, in creatine/N-acetyl aspartate and creatine/choline ratios, respectively) compared to the placebo group over the 2-week period. The creatine group had significantly decreased beta-NTP levels (7.8%) and marginally increased PCr (3.4%) over the same period. In addition, the brain inorganic phosphate level increased over the same period in the creatine group (9.8%). The current study is the first multinuclear (1H and 31P) MRS study to evaluate changes in brain high-energy phosphate metabolism following oral creatine supplementation in healthy human subjects. These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders, including major depression, schizophrenia, cocaine and opiate abuse, where alterations in brain high-energy phosphate metabolism have been reported.

Administration, Oral↗