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PRINCIPAL FACULTY

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Multi-targeted therapy resistance via drug-induced secretome fucosylation
Multi-targeted therapy resistance via drug-induced secretome fucosylation
Multi-targeted therapy resistance via drug-induced secretome fucosylation

Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post- translational cancer hallmark and the consequences thereof remain elusive. Here we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In cancer cell cultures, xenograft mouse models, and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes identified fucosylation of the antioxidant PON1 as a critical component of the therapy-induced secretome (TIS). N-glycosylation of TIS and target core fucosylation of PON1 are mediated by the fucose salvage-FUT8-SLC35C1 axis with PON3 directly modulating GDP-Fuc transfer on PON1 scaffolds. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Global and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. We defined the resistance-associated transcription factors (TFs) and genes modulated by the N-glycosylated TIS via a focused and transcriptome-wide analyses. These genes characterize the oxidative stress, inflammatory niche, and unfolded protein response as important factors for this modulation. Our findings demonstrate...

2023.03.31 | 논문
Elife | 2023 | 12 | 1
Rex: R-linked EXcel add-in for statistical analysis of medical and bioinformatics data
Rex: R-linked EXcel add-in for statistical analysis of medical and bioinformatics data
Rex: R-linked EXcel add-in for statistical analysis of medical and bioinformatics data

Background Microsoft Excel has substantial functionalities for data management and analyses, and has been the most popular software in this field. However, in spite of Excel’s user-friendly interface and functionality for data management, it provides very few functions for in-depth statistical analyses, which has limited its wider application for this purpose. Objective Here, we introduce Rex, an Excel add-in software implementing the powerful analytical and graphical functions of R within Excel. Methods Rex was implemented using three types of programming software: R, JavaScript, and Microsoft VB.Net. Results Rex provides a graphical user interface (GUI) through Excel, and statistical analysis can be conducted by pointing and clicking the menu without programming R. Rex covers a wide range of analyses from basic statistics to advanced analysis, including structural equation modeling, complex sampling design, and machine learning models, making it possible for researchers not skilled in using a command-line interface to conduct in-depth statistical analyses. Most Rex modules are available in a free version for non-commercial use, and it can be used for educational and public purposes. Conclusion In this article, we introduce the framework and features of Rex with illustrative examples of its implementation.

2023.03.31 | 논문
Genes & Genomics | 2023 | 45 | 1
Heritability of cognitive abilities and regional brain structures in middle-aged to elderly East Asians
Heritability of cognitive abilities and regional brain structures in middle-aged to elderly East Asians
Heritability of cognitive abilities and regional brain structures in middle-aged to elderly East Asians

This study examined the single-nucleotide polymorphism heritability and genetic correlations of cognitive abilities and brain structural measures (regional subcortical volume and cortical thickness) in middle-aged and elderly East Asians (Korean) from the Gwangju Alzheimer’s and Related Dementias cohort study. Significant heritability was found in memory function, caudate volume, thickness of the entorhinal cortices, pars opercularis, superior frontal gyri, and transverse temporal gyri. There were 3 significant genetic correlations between (i) the caudate volume and the thickness of the entorhinal cortices, (ii) the thickness of the superior frontal gyri and pars opercularis, and (iii) the thickness of the superior frontal and transverse temporal gyri. This is the first study to describe the heritability and genetic correlations of cognitive and neuroanatomical traits in middle-aged to elderly East Asians. Our results support the previous findings showing that genetic factors play a substantial role in the cognitive and neuroanatomical traits in middle to advanced age. Moreover, by demonstrating shared genetic effects on different brain regions, it gives us a genetic insight into understanding cognitive and brain changes with age, such as aging-related cognitive decline, cortical atrophy, and neural compensation.

2023.03.31 | 논문
Cerebral Cortex | 2023 | 1 | 1
Genome-Wide Association Study of Airway Wall Thickening in a Korean Chronic Obstructive Pulmonary Disease Cohort
Genome-Wide Association Study of Airway Wall Thickening in a Korean Chronic Obstructive Pulmonary Disease Cohort
Genome-Wide Association Study of Airway Wall Thickening in a Korean Chronic Obstructive Pulmonary Disease Cohort

Airway wall thickening (AWT) plays an important pathophysiological role in airway diseases such as chronic obstructive pulmonary disease (COPD). There are only a few studies on the genetic components contributing to AWT in the Korean population. This study aimed to identify AWT-related single-nucleotide polymorphisms (SNPs) using a genome-wide association study (GWAS). We performed GWAS for AWT using the CODA and KUCOPD cohorts. Thereafter, a meta-analysis was performed. Airway wall thickness was measured using automatic segmentation software. The AWT at an internal perimeter of 10 mm (AWT-Pi10) was calculated by the square root of the theoretical airway wall area using the full-width-half-maximum method. We identified a significant SNP (rs11648772, p = 1.41 × 10−8) located in LINC02127, near SALL1. This gene is involved in the inhibition of epithelial–mesenchymal transition in glial cells, and it affects bronchial wall depression in COPD patients. Additionally, we identified other SNPs (rs11970854, p = 1.92 × 10−6; rs16920168, p = 5.29 × 10−6) involved in airway inflammation and proliferation and found that AWT is influenced by these genetic variants. Our study helps identify the genetic cause of COPD in an Asian population and provides a potential basis for treatment.

2023.03.31 | 논문
Genes | 2022 | 13 | 7
Functions and dysfunctions of oligodendrocytes in neurodegenerative diseases
Functions and dysfunctions of oligodendrocytes in neurodegenerative diseases
Functions and dysfunctions of oligodendrocytes in neurodegenerative diseases

Neurodegenerative diseases (NDDs) are characterized by the progressive loss of selectively vulnerable populations of neurons, which is responsible for the clinical symptoms. Although degeneration of neurons is a prominent feature that undoubtedly contributes to and defines NDD pathology, it is now clear that neuronal cell death is by no means mediated solely by cell-autonomous mechanisms. Oligodendrocytes (OLs), the myelinating cells of the central nervous system (CNS), enable rapid transmission of electrical signals and provide metabolic and trophic support to neurons. Recent evidence suggests that OLs and their progenitor population play a role in the onset and progression of NDDs. In this review, we discuss emerging evidence suggesting a role of OL lineage cells in the pathogenesis of age-related NDDs. We start with multiple system atrophy, an NDD with a well-known oligodendroglial pathology, and then discuss Alzheimer’s disease (AD) and Parkinson’s disease (PD), NDDs which have been thought of as neuronal origins. Understanding the functions and dysfunctions of OLs might lead to the advent of disease-modifying strategies against NDDs.

2023.03.31 | 논문
Frontiers in Cellular Neuroscience | 2022 | 16 | 1
Serum protein profiling of lung, pancreatic, and colorectal cancers reveals alcohol consumption-mediated disruptions in early-s
Serum protein profiling of lung, pancreatic, and colorectal cancers reveals alcohol consumption-mediated disruptions in early-s
Serum protein profiling of lung, pancreatic, and colorectal cancers reveals alcohol consumption-mediated disruptions in early-s

While the link between serum proteins and cancer has been studied in an effort to enable early-stage cancer detection, factors that might perturb this link has been poorly understood. To ask this question, we performed serum protein profiling on a prospective cohort of 601 individuals with or without lung, pancreatic, or colorectal cancers and identified ten distinct serum protein signatures with distinct link to the patient metadata. Importantly, we discovered that a positive history of alcohol consumption is a major factor that diminishes the sensitivity of serum protein-mediated liquid biopsy in early-stage malignancies, resulting in a 44% decline in the sensitivity of detecting American Joint Committee on Cancer (AJCC) stage I malignancies. Our data provide evidence that patient lifestyle can affect the sensitivity of liquid biopsy and suggest the potential need for abstinence from alcohol before measurement during serum protein-based cancer screening.

2023.03.31 | 논문
Heliyon | 2022 | 8 | 12

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