Publications by authors named "Ji-Hye Choi"

73 Publications

In response to the "Letter to the editor regarding 'Can gait kinetic data predict femoral bone mineral density in elderly men and women aged 50 years and older?' by wooyoung et al."

J Biomech 2021 10 4;127:110719. Epub 2021 Sep 4.

Department of Orthopedic Surgery, Seoul National University Bundang Hospital, Republic of Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jbiomech.2021.110719DOI Listing
October 2021

Extracts Improve Scopolamine-Induced Cognitive Impairment via Activation of the Cholinergic System and Anti-Neuroinflammation in Mice.

Nutrients 2021 Aug 23;13(8). Epub 2021 Aug 23.

National Institute of Agricultural Sciences, Rural Development Administration, Wanju 55365, Jeonbuk, Korea.

(AH) is a medicinal food that has been used in Southeast Asia for various physiological activities. The objective of this study was to investigate the activation of the cholinergic system and the anti-neuroinflammation effects of AH on scopolamine-induced memory impairment in mice. Scopolamine (1 mg/kg body weight, i.p.) impaired the performance of the mice on the Y-maze test, passive avoidance test, and water maze test. However, the number of error actions was reduced in the AH groups supplemented with leaf and root extracts from AH. AH treatment improved working memory and avoidance times against electronic shock, increased step-through latency, and reduced the time to reach the escape zone in the water maze test. AH significantly improved the cholinergic system by decreasing acetylcholinesterase activity, and increasing acetylcholine concentration. The serum inflammatory cytokines (IL-1β, IL-6, and IFN-γ) increased by scopolamine treatment were regulated by the administration of AH extracts. Overexpression of NF-κB signaling and cytokines in liver tissue due to scopolamine were controlled by administration of AH extracts. AH also significantly decreased Aβ and caspase-3 expression but increased NeuN and ChAT. The results suggest that AH extracts improve cognitive effects, and the root extracts are more effective in relieving the scopolamine-induced memory impairment. They have neuroprotective effects and reduce the development of neuroinflammation.
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http://dx.doi.org/10.3390/nu13082890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400157PMC
August 2021

TPRG1-AS1 induces RBM24 expression and inhibits liver cancer progression by sponging miR-4691-5p and miR-3659.

Liver Int 2021 Nov 8;41(11):2788-2800. Epub 2021 Aug 8.

Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.

Background & Aims: Noncoding RNAs (ncRNAs) play critical roles in hepatocellular carcinoma (HCC) progression. Here, by performing RNA-sequencing (RNA-Seq) profiling, we sought to identify novel ncRNAs that potentially drive the heterogeneous progression of liver cancers.

Methods: RNA-Seq profiles were obtained from 68 HCC specimens and 10 samples of adjacent non-tumour liver tissues. The functional significance of the potential driver ncRNAs was evaluated by cell experiments.

Results: TPRG1-AS1 was identified as a potential driver noncoding RNA that promotes heterogeneous liver cancer progression. TPRG1-AS1 induced tumour suppressor RNA-binding motif protein 24 (RBM24), suppressing tumour growth by activating apoptotic tumour cell death. In addition, we report that TPRG1-AS1 acts as a competing endogenous RNA (ceRNA) for RBM24, sponging miR-4691-5p and miR-3659 to interfere with their binding to RBM24.

Conclusions: We suggest that TPRG1-AS1 is a novel ceRNA sponging miR-4691-5p and miR-3659, resulting in RBM24 expression and suppression of liver cancer growth. Our results provide new insights into the functions of ncRNAs in heterogeneous HCC progression.
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http://dx.doi.org/10.1111/liv.15026DOI Listing
November 2021

USO1 isoforms differentially promote liver cancer progression by dysregulating the ER-Golgi network.

Carcinogenesis 2021 Oct;42(9):1208-1220

Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.

Alternative splicing of RNA transcripts plays an important role in cancer development and progression. Recent advances in RNA-seq technology have made it possible to identify alternately spliced events in various types of cancer; however, research on hepatocellular carcinoma (HCC) is still limited. Here, by performing RNA-seq profiling of HCC transcripts at isoform level, we identified tumor-specific and molecular subtype-dependent expression of the USO1 isoforms, which we designated as a normal form USO1-N (XM_001290049) and a tumor form USO1-T (NM_003715). The expression of USO1-T, but not USO1-N, was associated with worse prognostic outcomes of HCC patients. We confirmed that the expression of USO1-T promoted an aggressive phenotype of HCC, both in vitro and in vivo. In addition, structural modeling analyses revealed that USO1-T lacks an ARM10 loop encoded by exon 15, which may weaken the dimerization of USO1 and its tethering to GM130. We demonstrated that USO1-T ensured unstacking of the Golgi and accelerated the vesicles trafficking from endoplasmic reticulum (ER) to Golgi and plasma membrane in multiple liver cancer cells. ERK and GRASP65 were found to be involved in the USO1-T-mediated Golgi dysfunction. Conclusively, we provide new mechanophysical insights into the USO1 isoforms that differentially regulate the ER-Golgi network, promoting the heterogeneous HCC progression.
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http://dx.doi.org/10.1093/carcin/bgab067DOI Listing
October 2021

Intrasubject Radiographic Progression of Hallux Valgus Deformity in Patients With and Without Metatarsus Adductus: Bilateral Asymmetric Hallux Valgus Deformity.

J Foot Ankle Surg 2021 Jun 11. Epub 2021 Jun 11.

Department of Mechanical Engineering, Korea Advanced Institute of Science and Technology, Daejon, Korea. Electronic address:

This study was to analyze intrasubject radiographic progression of the hallux valgus deformity by comparing the mildly and severely affected sides in patients with bilateral asymmetric hallux valgus in the whole group as well as the metatarsus adductus and the nonmetatarsus adductus subgroups. A total of 186 patients with bilateral asymmetrical hallux valgus deformity with a difference of 5° or greater in the hallux valgus angle were included, and 11 radiographic measurements were analyzed. The radiographic differences between the mildly and severely affected sides were compared. Correlation between the changes in the hallux valgus angle and those in other measurements was analyzed, and multiple regression analyses were performed. The anteroposterior talo-second metatarsal angle showed no significant difference between the mildly and severely affected sides. Changes in the intermetatarsal angle and sesamoid rotation angle were significantly associated with the progression of hallux valgus angle in the whole group as well as the nonmetatarsus adductus subgroup. Change in the intermetatarsal angle (p = .006) was the significant factor associated with the progression of hallux valgus angle in the metatarsus adductus subgroup. The anteroposterior talo-second metatarsal angle might be useful in evaluating the overall foot shape in the hallux valgus deformity. Progression of the hallux valgus deformity might be pathophysiologically different between those with and without metatarsus adductus.
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http://dx.doi.org/10.1053/j.jfas.2020.05.025DOI Listing
June 2021

Relationship between ankle varus moment during gait and radiographic measurements in patients with medial ankle osteoarthritis.

PLoS One 2021 24;16(6):e0253570. Epub 2021 Jun 24.

Department of Orthopaedic Surgery, Seoul National University Bundang Hospital, Seongnam-si, South Korea.

Background: Kinetic data obtained during gait can be used to clarify the biomechanical pathogenesis of osteoarthritis of the lower extremity. This study aimed to investigate the difference in ankle varus moment between the varus angulation and medial translation types of medial ankle osteoarthritis, and to identify the radiographic measurements associated with ankle varus moment.

Methods: Twenty-four consecutive patients [mean age 65.8 (SD) 8.0 years; 9 men and 15 women] with medial ankle osteoarthritis were included. Fourteen and 10 patients had the varus angulation (tibiotalar tilt angle≥3 degrees) and medial translation (tibiotalar tilt angle<3 degrees) types, respectively. All patients underwent three-dimensional gait analysis, and the maximum varus moment of the ankle was recorded. Radiographic measurement included tibial plafond inclination, tibiotalar tilt angle, talar dome inclination, and lateral talo-first metatarsal angle. Comparison between the two types of medial ankle osteoarthritis and the relationship between the maximum ankle varus moment and radiographic measurements were analyzed.

Results: The mean tibial plafond inclination, tibiotalar tilt angle, talar dome inclination, lateral talo-first metatarsal angle, and maximum ankle varus moment were 6.4 degrees (SD 3.3 degrees), 5.0 degrees (SD 4.6 degrees), 11.4 degrees (SD 5.2 degrees), -6.5 degrees (SD 11.7 degrees), and 0.185 (SD 0.082) Nm/kg, respectively. The varus angulation type showed a greater maximum ankle varus moment than the medial translation type (p = .005). The lateral talo-first metatarsal angle was significantly associated with the maximum ankle varus moment (p = .041) in the multiple regression analysis.

Conclusion: The varus angulation type of medial ankle osteoarthritis is considered to be more imbalanced biomechanically than the medial displacement type. The lateral talo-first metatarsal angle, being significantly associated with the ankle varus moment, should be considered for correction during motion-preserving surgeries for medial ankle osteoarthritis to restore the biomechanical balance of the ankle.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253570PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224910PMC
June 2021

Consistency and Reliability of Ankle Stress Radiography in Patients With Chronic Lateral Ankle Instability.

Orthop J Sports Med 2021 May 18;9(5):23259671211004099. Epub 2021 May 18.

Department of Orthopaedic Surgery, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea.

Background: Ankle stress radiographs are important tools for evaluating chronic lateral ankle instability. The consistency of a patient's ankle condition as it affects the reliability of ankle stress radiographs has never been evaluated.

Purpose: To investigate the consistency and reliability of ankle stress radiographs in patients with chronic lateral ankle instability without an ankle injury during the study period.

Study Design: Cohort study (diagnosis); Level of evidence, 3.

Methods: Included were patients with chronic lateral ankle instability who underwent 2 repeated ankle stress radiographs between January 2014 and July 2019; those with an ankle injury during the study period were excluded. The tibiotalar tilt angle on varus stress radiographs and anterior translation of the talus on anterior drawer stress radiographs were measured at initial presentation and final follow-up examination. Interobserver reliability and consistency of ankle stress radiographs were analyzed using the intraclass correlation coefficient (ICC).

Results: A total of 45 patients (mean ± standard deviation age, 36.4 ± 13.4 years; 18 men and 27 women; follow-up duration, 9.1 ± 3.2 months) were included. The mean ± standard deviation tibiotalar tilt angle and anterior talar translation at initial presentation were 10.8° ± 5.2° and 6.9 ± 2.7 mm, respectively. The interobserver reliabilities of the tibiotalar tilt angle and anterior talar translation were excellent (ICC = 0.926 [95% CI, 0.874-0.959] and 0.911 [95% CI, 0.766-0.961], respectively). The consistency between the initial and final radiographs was good for tibiotalar tilt angle (ICC = 0.763 [95% CI, 0.607-0.862]) and poor for anterior talar translation (ICC = 0.456 [95% CI, 0.187-0.660]).

Conclusion: Although the interobserver reliability of the radiographic measurements was excellent, the consistency of the ankle stress radiographs was not as acceptable. Surgeons need to be cautious when deciding whether to operate on a patient with chronic lateral ankle instability based on a single ankle stress radiograph.
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http://dx.doi.org/10.1177/23259671211004099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135217PMC
May 2021

Can gait kinetic data predict femoral bone mineral density in elderly men and women aged 50 years and older?

J Biomech 2021 06 12;123:110520. Epub 2021 May 12.

Department of Orthopedic Surgery, Seoul National University Bundang Hospital, South Korea. Electronic address:

This retrospective study was conducted to investigate the correlation between kinetic gait parameters and femoral bone mineral density (BMD) in elderly subjects aged 50 years and older that could walk independently. Four hundred and twenty-six subjects (158 men and 258 women; mean age 68.7 years, standard deviation (SD) 7.9 years) were included in the study. BMDs (g/cm) of the femoral neck, trochanter, shaft, and total proximal femur were collected. Kinetic data including maximum hip power and hip power-time integral was obtained from a three-dimensional gait analysis with self-selected walking speed. Correlation between BMDs of proximal femur and gait kinetic data was analyzed. Multiple regression analysis was also performed to identify factors significantly associated with BMD. Correlation between BMD and hip kinetic data was not prominent in elderly men. In women, BMD was significantly correlated with hip kinetic data. Hip power-time integral showed greater correlation with BMD than maximum hip power during gait in elderly women. Age (p < 0.001), weight (p = 0.007) and hip power-time integral (p = 0.008) were significant factors associated with femoral neck BMD, and these factors explained 25.4% of femoral neck BMD. In conclusion, the association between the mechanical load and BMD in the different sexes provokes future research into these issues. The effects of various types of exercises on BMD should be investigated more precisely using a gait analysis tool.
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http://dx.doi.org/10.1016/j.jbiomech.2021.110520DOI Listing
June 2021

MLH1 single-nucleotide variant in circulating tumor DNA predicts overall survival of patients with hepatocellular carcinoma.

Sci Rep 2020 10 20;10(1):17862. Epub 2020 Oct 20.

Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea.

Liquid biopsy can provide a strong basis for precision medicine. We aimed to identify novel single-nucleotide variants (SNVs) in circulating tumor DNA (ctDNA) in patients with hepatocellular carcinoma (HCC). Deep sequencing of plasma-derived ctDNA from 59 patients with HCC was performed using a panel of 2924 SNVs in 69 genes. In 55.9% of the patients, at least one somatic mutation was detected. Among 25 SNVs in 12 genes, four frequently observed SNVs, MLH1 (13%), STK11 (13%), PTEN (9%), and CTNNB1 (4%), were validated using droplet digital polymerase chain reaction with ctDNA from 62 patients with HCC. Three candidate SNVs were detected in 35.5% of the patients, with a frequency of 19% for MLH1 chr3:37025749T>A, 11% for STK11 chr19:1223126C>G, and 8% for PTEN chr10:87864461C>G. The MLH1 and STK11 SNVs were also confirmed in HCC tissues. The presence of the MLH1 SNV, in combination with an increased ctDNA level, predicted poor overall survival among 107 patients. MLH1 chr3:37025749T>A SNV detection in ctDNA is feasible, and thus, ctDNA can be used to detect somatic mutations in HCC. Furthermore, the presence or absence of the MLH1 SNV in ctDNA, combined with the ctDNA level, can predict the prognosis of patients with HCC.
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http://dx.doi.org/10.1038/s41598-020-74494-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576198PMC
October 2020

PCAF-Mediated Histone Acetylation Promotes Replication Fork Degradation by MRE11 and EXO1 in BRCA-Deficient Cells.

Mol Cell 2020 10 22;80(2):327-344.e8. Epub 2020 Sep 22.

Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA; Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address:

Stabilization of stalled replication forks is a prominent mechanism of PARP (Poly(ADP-ribose) Polymerase) inhibitor (PARPi) resistance in BRCA-deficient tumors. Epigenetic mechanisms of replication fork stability are emerging but remain poorly understood. Here, we report the histone acetyltransferase PCAF (p300/CBP-associated) as a fork-associated protein that promotes fork degradation in BRCA-deficient cells by acetylating H4K8 at stalled replication forks, which recruits MRE11 and EXO1. A H4K8ac binding domain within MRE11/EXO1 is required for their recruitment to stalled forks. Low PCAF levels, which we identify in a subset of BRCA2-deficient tumors, stabilize stalled forks, resulting in PARPi resistance in BRCA-deficient cells. Furthermore, PCAF activity is tightly regulated by ATR (ataxia telangiectasia and Rad3-related), which phosphorylates PCAF on serine 264 (S264) to limit its association and activity at stalled forks. Our results reveal PCAF and histone acetylation as critical regulators of fork stability and PARPi responses in BRCA-deficient cells, which provides key insights into targeting BRCA-deficient tumors and identifying epigenetic modulators of chemotherapeutic responses.
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http://dx.doi.org/10.1016/j.molcel.2020.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572766PMC
October 2020

Transcriptomic analysis of the effect of (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl) prop-2-en-1-one (DPP23) on reactive oxygen species generation in MIA PaCa-2 pancreatic cancer cells.

Genes Genomics 2020 11 19;42(11):1267-1279. Epub 2020 Sep 19.

Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul, 05029, Republic of Korea.

Background: Reactive oxygen species (ROS) generation specifically in cancer cells may be a promising strategy for their selective killing. The synthetic chalcone derivative (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP23) exerts antitumor activity through ROS-mediated apoptosis in cancer cells but not in healthy cells. However, the mechanism underlying ROS generation by DPP23 remains unknown.

Objective: The current study aims to identify possible DPP23 target genes responsible for ROS generation through the mining of microarray data stored in NCBI's Gene Expression Omnibus (GEO).

Methods: A comprehensive expression profile of genes modulated by DPP23 was examined by gene ontology analysis. DPP23-modulated genes in Mia-PaCa2 pancreatic cells were validated by reverse transcription-PCR.

Results: Multiple genes were up and downregulated by DPP23 treatment in MiaPaCa2 pancreatic cancer cells. Genes with absolute fold-change (FC) of > 2 were selected as the cut-off criteria and grouped into 10 clusters to analyze expression patterns systematically. We observed that genes with increased expression at 6 h were significantly affected by ROS increase, unfolded protein response, and cell death. Expression of 13 genes involved in glutathione metabolism, including CHAC1, GCLC, G6PD, GSTO2, GSTA5, GSTM2, GSR, GPX3/6/8, GGT1, PGD, ATF4, and NAT8B, are modulated by DPP23. Of these, CHAC1 was most highly upregulated upon DPP23 treatment.

Conclusion: DPP23 alters global gene expression associated with multiple cellular responses, including oxidative stress and apoptosis. We found that DPP23 may induce GSH depletion through modulation of gene expression, which is especially involved in glutathione metabolism. Of these, CHAC1 emerged as the most prominent candidate for DPP23 as it was the most responsive to DPP23 treatment.
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http://dx.doi.org/10.1007/s13258-020-00994-wDOI Listing
November 2020

Posterior Tibial Tendon Integrity Can Be Screened With Plain Anteroposterior Foot Radiography.

Orthopedics 2020 Nov 3;43(6):e503-e507. Epub 2020 Sep 3.

Posterior tibial tendon integrity is an important consideration when treating adult-acquired flatfoot caused by posterior tibial tendon dysfunction. The condition of this tendon traditionally has been evaluated with ultrasonography or magnetic resonance imaging, but recent advances in radiography have increased the resolution of radiographic soft tissue images. The authors examined whether the posterior tibial tendon could be screened with anteroposterior foot radiographs, based on interobserver agreement and accuracy. The authors retrospectively evaluated consecutive patients who underwent weight-bearing foot radiography and ultrasonography based on suspicion of posterior tibial tendinopathy. The integrity of the posterior tibial tendon was evaluated by 2 orthopedic surgeons with foot radiographs and scored as normal or abnormal. The authors evaluated interobserver agreement and compared the findings of ultrasonography and radiography to evaluate diagnostic accuracy. The study included 21 patients with a mean age of 51.5±15.7 years. Ultrasonography showed that 4 patients had normal tendon integrity, 6 patients had tenosynovitis and no tendinopathy, 8 patients had tendinopathy and tendon continuity, and 3 patients had loss of tendon continuity. The surgeons provided consistent radiographic findings for 81.0% of patients (17 of 21). On the basis of the ultrasonographic findings, the surgeons' accuracy was 76.2% (16 of 21) and 61.9% (13 of 21). The results indicate that weight-bearing anteroposterior foot radiography can be used to evaluate posterior tibial tendon integrity, which may allow orthopedic surgeons to predict the prognosis of patients with posterior tibial tendon dysfunction, determine the extent of surgical treatment, and evaluate tendon integrity postoperatively. [Orthopedics. 2020;43(6):e503-e507.].
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http://dx.doi.org/10.3928/01477447-20200827-04DOI Listing
November 2020

scTyper: a comprehensive pipeline for the cell typing analysis of single-cell RNA-seq data.

BMC Bioinformatics 2020 Aug 4;21(1):342. Epub 2020 Aug 4.

Department of Physiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, 16499, Republic of Korea.

Background: Recent advances in single-cell RNA sequencing (scRNA-seq) technology have enabled the identification of individual cell types, such as epithelial cells, immune cells, and fibroblasts, in tissue samples containing complex cell populations. Cell typing is one of the key challenges in scRNA-seq data analysis that is usually achieved by estimating the expression of cell marker genes. However, there is no standard practice for cell typing, often resulting in variable and inaccurate outcomes.

Results: We have developed a comprehensive and user-friendly R-based scRNA-seq analysis and cell typing package, scTyper. scTyper also provides a database of cell type markers, scTyper.db, which contains 213 cell marker sets collected from literature. These marker sets include but are not limited to markers for malignant cells, cancer-associated fibroblasts, and tumor-infiltrating T cells. Additionally, scTyper provides three customized methods for estimating cell-type marker expression, including nearest template prediction (NTP), gene set enrichment analysis (GSEA), and average expression values. DNA copy number inference method (inferCNV) has been implemented with an improved modification that can be used for malignant cell typing. The package also supports the data preprocessing pipelines by Cell Ranger from 10X Genomics and the Seurat package. A summary reporting system is also implemented, which may facilitate users to perform reproducible analyses.

Conclusions: scTyper provides a comprehensive and user-friendly analysis pipeline for cell typing of scRNA-seq data with a curated cell marker database, scTyper.db.
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http://dx.doi.org/10.1186/s12859-020-03700-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430822PMC
August 2020

Aggravation of Ankle Varus Incongruency Following Total Knee Replacement Correcting ≥10° of Genu Varum Deformity: A Radiographic Assessment.

J Arthroplasty 2020 11 17;35(11):3305-3310. Epub 2020 Jun 17.

Department of Orthopedic Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea.

Background: This study aimed to investigate the change in ankle varus incongruencies following total knee replacement (TKR) in patients with preoperative genu varum deformity of ≥10°.

Methods: The study cohort was composed of patients who underwent TKR in a single institution for knee osteoarthritis with preoperative genu varum deformity of ≥10° and concomitant varus ankle incongruencies. Eight radiographic measurements were evaluated preoperatively and postoperatively: mechanical tibiofemoral angle, mechanical lateral distal femoral angle, medial proximal tibial angle, lateral distal tibial angle, tibial plafond inclination, talar inclination, tibiotalar tilt angle (TTTA), and tibia-mechanical axis angle. Of these, TTTA represented the quantitative degree of ankle joint incongruency.

Results: A total of 110 patients (male = 2; female = 108) were included in the analysis. The mean patient age was 68.9 (standard deviation [SD] 7.2) years at the time of TKR. All radiographic measurements showed significant changes postoperatively, representing the appropriate correction of genu varum deformity and restoration of the mechanical axis. Nineteen patients (17.3%) showed postoperative decrease in TTTA, 2 (1.8%) remained the same, and 89 (80.9%) showed increase. Overall, mean preoperative and postoperative TTTA were 3.3° (SD 2.2°) and 4.7° (SD 2.9°), respectively (P < .001), representing the aggravation of varus ankle incongruencies.

Conclusion: Varus ankle incongruencies showed aggravation following TKR despite correction of genu varum deformity and restoration of the mechanical axis. This could be an important cause of postoperative increase or development of ankle pain following TKR. Therefore, patients with preoperative varus ankle incongruencies need to be warned of possible aggravation of ankle symptoms and be evaluated before TKR.

Level Of Evidence: Prognostic level III.
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http://dx.doi.org/10.1016/j.arth.2020.06.027DOI Listing
November 2020

Developing and Evaluating an Educational Program for Respiratory Infection Prevention among Rural Elderly Residents in South Korea.

Int J Environ Res Public Health 2020 04 28;17(9). Epub 2020 Apr 28.

School of Nursing, Research Institute of Nursing Science, Hallym University, Gangwon-do 24252, Chuncheon-si, Korea.

Based on social cognitive theory (SCT), an educational program was developed to prevent rural elderly residents from respiratory infections in South Korea. The effectiveness of the program was investigated in terms of knowledge, attitudes, and practices about respiratory infection prevention, as well as social capital. A pretest-posttest nonequivalent control group quasi-experimental design was used to test the short-term effect of this program. In addition, 1- and 6-month follow-up surveys were administered to evaluate the long-term effects. A total of 69 subjects (37 in the experimental group and 32 in the control group) participated in the experiment. The results showed that knowledge about respiratory infection prevention, respiratory infection prevention practices, and social capital were enhanced among the elderly residents who participated in the educational program. The educational effects differed significantly across time periods (pretest, posttest, 1- and 6-month follow up) in all the above variables. In particular, the program remained effective 1 month after the intervention, but a reinforcement session extended the program's effects up to 6 months later. This educational program would be used as an effective intervention to help rural elderly residents prevent respiratory infections.
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http://dx.doi.org/10.3390/ijerph17093057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246853PMC
April 2020

Transcription factor EGR-1 transactivates the MMP1 gene promoter in response to TNFα in HaCaT keratinocytes.

BMB Rep 2020 Jun;53(6):323-328

Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University, Seoul 05029; Cancer and Metabolism Institute, Konkuk University, Seoul 05029, Korea.

Matrix metalloproteinase 1 (MMP-1), a calcium-dependent zinccontaining collagenase, is involved in the initial degradation of native fibrillar collagen. Tissue necrosis factor-alpha (TNFα) is a pro-inflammatory cytokine that is rapidly produced by dermal fibroblasts, monocytes/macrophages, and keratinocytes and regulates inflammation and damaged-tissue remodeling. MMP-1 is induced by TNFα and plays a critical role in tissue remodeling and skin aging processes. However, the regulation of the MMP1 gene by TNFα is not fully understood. We aimed to find additional cis-acting elements involved in the regulation of TNFα-induced MMP1 gene transcription in addition to the nuclear factor-kappa B (NF-κB) and activator protein 1 (AP1) sites. Assessments of the 5'-regulatory region of the MMP1 gene, using a series of deletion constructs, revealed the requirement of the early growth response protein 1 (EGR-1)-binding sequence (EBS) in the proximal region for proper transcription by TNFα. Ectopic expression of EGR-1, a zinc-finger transcription factor that binds to G-C rich sequences, stimulated MMP1 promoter activity. The silencing of EGR-1 by RNA interference reduced TNFα-induced MMP-1 expression. EGR-1 directly binds to the proximal region and transactivates the MMP1 gene promoter. Mutation of the EBS within the MMP1 promoter abolished EGR-1-mediated MMP-1 promoter activation. These data suggest that EGR-1 is required for TNFα-induced MMP1 transcriptional activation. In addition, we found that all three MAPKs, ERK1/2, JNK, and p38 kinase, mediate TNFα-induced MMP-1 expression via EGR-1 upregulation. These results suggest that EGR-1 may represent a good target for the development of pharmaceutical agents to reduce inflammation-induced MMP-1 expression. [BMB Reports 2020; 53(6): 323-328].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330807PMC
June 2020

A retrospective single-center study comparing clinical outcomes of 3-dimensional and 2-dimensional laparoscopic cholecystectomy in acute cholecystitis.

Ann Hepatobiliary Pancreat Surg 2019 Nov 29;23(4):339-343. Epub 2019 Nov 29.

Department of Surgery, National Medical Center, Seoul, Korea.

Backgrounds/aims: Laparoscopic cholecystectomy (LC) has become widely used and preferred standard treatment for gallbladder (GB) disease in many countries. In this study, we aimed to compare the overall clinical outcomes of 3-dimensional (3D) LC system with those of the 2D LC method.

Methods: We retrospectively analyzed patients who underwent LC for acute cholecystitis between January 2010 and March 2019 at the National Medical Center in Korea. We entered them into 3D LC (group A) and 2D LC (group B) groups. We used Olympus CLV-190 laparoscopic device with dual lenses, capable of displaying both 3D and 2D images. Postoperative variables considered for evaluating between-group differences in clinical outcomes included diet resumption period after surgery, postoperative hospital length-of-stay, outpatient department follow-up period, surgical time, and postoperative surgery-related complications (blood loss and open conversion).

Results: We analyzed 278 acute cholecystitis patients (Group A, n=116; Group B, n=162). Compared to group B, group A had a significantly reduced surgical time and postoperative hospital stay. Although underlying diseases and abdominal surgical history were more prevalent in the 3D LC group, no significant between-group differences in blood loss and open conversion rate were observed.

Conclusions: The 3D imaging system offered many advantages over 2D LC, including reduced surgical time and shorter postoperative hospital stay; therefore, it has significance in reducing hospital costs.
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http://dx.doi.org/10.14701/ahbps.2019.23.4.339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893058PMC
November 2019

Dynamics of Genomic, Epigenomic, and Transcriptomic Aberrations during Stepwise Hepatocarcinogenesis.

Cancer Res 2019 Nov 10;79(21):5500-5512. Epub 2019 Sep 10.

Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.

Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multilayered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., , and ) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells. Transcriptome analysis revealed that HGDNs expressed endoplasmic reticulum (ER) stress-related genes, while eHCC started to express oncogenes. Furthermore, integrative analysis indicated that expression of the serine peptidase inhibitor, Kazal type 1 (SPINK1), played a pivotal role in eHCC development. Significant demethylation of SPINK1 was observed in eHCC compared to HGDN. The study also demonstrated that ER stress may induce SPINK1 demethylation and expression in liver cancer cells. In conclusion, these results reveal the dynamics of multiomic aberrations during malignant conversion of liver cancer, thus providing novel pathobiological insights into hepatocarcinogenesis. SIGNIFICANCE: Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0991DOI Listing
November 2019

Stool-Based miR-92a and miR-144* as Noninvasive Biomarkers for Colorectal Cancer Screening.

Oncology 2019 19;97(3):173-179. Epub 2019 Jun 19.

Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Objectives: Current noninvasive screening tests for colorectal cancer (CRC) have insufficient sensitivity. MicroRNA (miRNA) levels in stool have potential as markers for noninvasive screening of CRC. We evaluated the diagnostic value of stool miRNA levels and determined the optimal miRNA subtypes for detecting CRC.

Methods: Stool samples were collected from 29 patients with CRC and 29 healthy controls. The stool levels of miR-21, miR-92a, miR-200c, miR-144*, miR-135a, miR-135b, miR-106a, and miR-17-3p were determined by real-time quantitative reverse transcription polymerase chain reaction. The sensitivity and specificity of the miRNAs for CRC were determined by receiver operating characteristics analysis.

Results: Among the eight tested miRNAs, the mean stool levels of miR-21, miR-92a, miR-144*, and miR-17-3p differed significantly between the CRC group and the control group (p =0.014, 0.001, <0.001, and 0.008, respectively). The sensitivities and specificities of miR-21, miR-92, miR-144*, and miR-17-3p were 79.3 and 48.3%, 89.7 and 51.7%, 78.6 and 66.7%, and 67.9 and 70.8%, respectively. In a multivariate analysis, miR-92a and miR-144* were significantly associated with the presence of CRC (p = 0.03 and 0.011, respectively).

Conclusions: The stool levels of miR-92a and miR-144* showed good sensitivity and fair specificity for detection of CRC, and thus may be useful as noninvasive biomarkers for this disease.
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http://dx.doi.org/10.1159/000500639DOI Listing
September 2019

EPHB6 mutation induces cell adhesion-mediated paclitaxel resistance via EPHA2 and CDH11 expression.

Exp Mol Med 2019 06 3;51(6):1-12. Epub 2019 Jun 3.

Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.

Mutations affect gene functions related to cancer behavior, including cell growth, metastasis, and drug responses. Genome-wide profiling of cancer mutations and drug responses has identified actionable targets that can be utilized for the management of cancer patients. Here, the recapitulation of pharmacogenomic data revealed that the mutation of EPHB6 is associated with paclitaxel resistance in cancer cells. Experimental data confirmed that the EPHB6 mutation induces paclitaxel resistance in various cancer types, including lung, skin, and liver cancers. EPHB6 mutation-induced paclitaxel resistance was mediated by an interaction with EPHA2, which promotes c-Jun N-terminal kinase (JNK)-mediated cadherin 11 (CDH11) expression. We demonstrated that EPHB6-mutated cells acquire cell adhesion-mediated drug resistance (CAM-DR) in association with CDH11 expression and RhoA/focal adhesion kinase (FAK) activation. Targeted inhibition of EPHA2 or CDH11 reversed the acquired paclitaxel resistance, suggesting its potential clinical utility. The present results suggest that the EPHB6 mutation and its downstream EPHA2/JNK/CDH11/RhoA/FAK signaling axis are novel diagnostic and therapeutic targets for overcoming paclitaxel resistance in cancer patients.
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http://dx.doi.org/10.1038/s12276-019-0261-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547695PMC
June 2019

Buforin-1 blocks neuronal SNARE-mediated membrane fusion by inhibiting SNARE complex assembly.

Biochem Biophys Res Commun 2019 06 23;514(1):105-111. Epub 2019 Apr 23.

School of Life Sciences, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju, 61005, South Korea; Pilot Plant, Anygen, Gwangju Technopark, 333 Cheomdankwagi-ro, Buk-gu, Gwangju, 61008, South Korea. Electronic address:

Assembly of neuronal SNARE protein complexes is essential for fusion of synaptic vesicles with the presynaptic plasma membrane, which releases neurotransmitters into the synaptic cleft and mediates neurotransmission. However, despite the potential of pharmacological regulation of this process for the treatment of various neurological disorders, only a few reagents, including botulinum neurotoxins, are currently available. Here, we report that buforin-1, an antimicrobial peptide from the Asian toad Bufo gargarizans, inhibits neuronal SNARE complex assembly, resulting in neuronal SNARE-mediated membrane fusion in vitro via its direct association with neuronal t-SNAREs syntaxin-1 and SNAP-25. Consistently, buforin-1 significantly inhibited neuronal-SNARE-mediated exocytosis in PC-12 cells. Thus, buforin-1 has potential for the treatment of neurological disorders caused by dysregulated neurotransmission.
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http://dx.doi.org/10.1016/j.bbrc.2019.04.124DOI Listing
June 2019

Comparison of high and low molecular weight chitosan as in-vitro boosting agent for photodynamic therapy against Helicobacter pylori using methylene blue and endoscopic light.

Photodiagnosis Photodyn Ther 2019 Jun 2;26:111-115. Epub 2019 Mar 2.

Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Electronic address:

Background: We reported in a previous study that photodynamic therapy (PDT) of Helicobacter pylori(H. pylori) could potentiate bactericidal effect by adding chitosan. As a next step, we compared the bactericidal effects of low molecular weight (LMW) combined with Photodynamic Therapy to high molecular weight (HMW) chitosan.

Method: To perform PDT to kill H. pylori, we used endoscopic light as light source, methylene blue (MB) as a photosensitizer and chitosan (310-375, 50-190 kDa). We evaluated bacterial removal rate and its membrane damage by ethidium bromide monoazide PCR method (EMA q-PCR). 8-oxo-2'-dexoyguanosine by ELISA was measured for oxidative stress.

Results: At a chitosan concentration of ≤0.05%, the killing effect did not differ between the two molecular weights, and 100% bacterial removal rate was observed at a light energy ≥ 6.23 mJ/cm powers under 0.02% MB. After 15 min irradiation, LMW chitosan with high concentration of MB (0.004%) showed highest killing effects, which were consistent with the results of EMA q-PCR but not with the level of 8-OHdG. Bactericidal effects of LMW chitosan plus PDT using 0.002 and 0.004% MB for 15 min irradiation were significantly higher than those using HMW chitosan plus PDT.

Conclusion: We found that PDT using methylene blue with LMW chitosan to kill H. pylori exerted greater bactericidal effects through bacterial membrane damage than PDT with HMW chitosan. These results suggest that it would be better to choose LMW chitosan to enhance the effect of PDT for clinical application, even at a very low concentration of PS.
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http://dx.doi.org/10.1016/j.pdpdt.2019.03.005DOI Listing
June 2019

SEQprocess: a modularized and customizable pipeline framework for NGS processing in R package.

BMC Bioinformatics 2019 Feb 20;20(1):90. Epub 2019 Feb 20.

Department of Physiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon, 16499, Republic of Korea.

Backgrounds: Next-Generation Sequencing (NGS) is now widely used in biomedical research for various applications. Processing of NGS data requires multiple programs and customization of the processing pipelines according to the data platforms. However, rapid progress of the NGS applications and processing methods urgently require prompt update of the pipelines. Recent clinical applications of NGS technology such as cell-free DNA, cancer panel, or exosomal RNA sequencing data also require appropriate customization of the processing pipelines. Here, we developed SEQprocess, a highly extendable framework that can provide standard as well as customized pipelines for NGS data processing.

Results: SEQprocess was implemented in an R package with fully modularized steps for data processing that can be easily customized. Currently, six pre-customized pipelines are provided that can be easily executed by non-experts such as biomedical scientists, including the National Cancer Institute's (NCI) Genomic Data Commons (GDC) pipelines as well as the popularly used pipelines for variant calling (e.g., GATK) and estimation of allele frequency, RNA abundance (e.g., TopHat2/Cufflink), or DNA copy numbers (e.g., Sequenza). In addition, optimized pipelines for the clinical sequencing from cell-free DNA or miR-Seq are also provided. The processed data were transformed into R package-compatible data type 'ExpressionSet' or 'SummarizedExperiment', which could facilitate subsequent data analysis within R environment. Finally, an automated report summarizing the processing steps are also provided to ensure reproducibility of the NGS data analysis.

Conclusion: SEQprocess provides a highly extendable and R compatible framework that can manage customized and reproducible pipelines for handling multiple legacy NGS processing tools.
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http://dx.doi.org/10.1186/s12859-019-2676-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383233PMC
February 2019

Does unicompartmental knee arthroplasty have worse outcomes in spontaneous osteonecrosis of the knee than in medial compartment osteoarthritis? A systematic review and meta-analysis.

Arch Orthop Trauma Surg 2019 Mar 24;139(3):393-403. Epub 2019 Jan 24.

Department of Orthopaedic Surgery, Seoul National University College of Medicine, SMG-SNU Boramae Medical Center, 20, Boramae-ro 5-gil, Dongjak-gu, Seoul, 07061, South Korea.

Introduction: The role of unicompartmental knee arthroplasty (UKA) in spontaneous osteonecrosis of the knee (SONK) remains controversial, even though SONK involves only one compartment of the knee joint. We aimed to compare the survival rate and clinical outcomes of UKA in SONK and medial compartment osteoarthritis (MOA) via a meta-analysis of previous studies.

Materials And Methods: MEDLINE, Embase, and Cochrane Library were searched up to January 2018 with keywords related to SONK and knee arthroplasty. Studies were selected with predetermined inclusion criteria: (1) medial UKA as the primary procedure, (2) reporting implant survival or clinical outcomes of osteonecrosis and osteoarthritis, and (3) follow-up period > 1 year. Quality assessment was performed using the risk of bias assessment tool for non-randomized studies. A random-effects model was used to estimate the pooled relative risk (RR) and standardized mean difference.

Results: The incidence of UKA revision for any reason was significantly higher in SONK than in MOA group (pooled RR = 1.83, p = 0.009). However, the risk of revision due to aseptic loosening was not significantly different between the groups. Moreover, when stratified by the study quality, high-quality studies showed similar risk of overall revision in SONK and MOA (p = 0.71). Subgroup analysis revealed no significant difference in failure between SONK and MOA after cemented mobile and fixed bearing UKA. Results of uncemented UKA were reported only in one study, which showed higher failure of SONK compared to MOA. Clinical outcomes after UKA were similar between SONK and MOA (p = 0.66).

Conclusions: Cemented UKA has similar survival and clinical outcomes in SONK and MOA. Prospective studies designed specifically to compare the UKA outcomes in SONK and MOA are necessary.
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http://dx.doi.org/10.1007/s00402-019-03125-7DOI Listing
March 2019

The EGR1-STAT3 Transcription Factor Axis Regulates α-Melanocyte-Stimulating Hormone-Induced Tyrosinase Gene Transcription in Melanocytes.

J Invest Dermatol 2019 07 14;139(7):1616-1619. Epub 2019 Jan 14.

Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul, Republic of Korea; Cancer and Metabolism Institute, Konkuk University, Seoul, Republic of Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2018.12.020DOI Listing
July 2019

Identification of novel susceptibility loci associated with hepatitis B surface antigen seroclearance in chronic hepatitis B.

PLoS One 2018 5;13(7):e0199094. Epub 2018 Jul 5.

Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.

Background/aims: The seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is regarded as a functional cure of chronic hepatitis B (CHB) although it occurs rarely. Recently, several genome-wide association studies (GWASs) revealed various genetic alterations related to the clinical course of HBV infection. However, all of these studies focused on the progression of HBV infection to chronicity and had limited application because of the heterogeneity of HBV genotypes. In the present study, we aimed to determine susceptibility genetic markers for seroclearance of HBsAg in CHB patients with a homogenous viral genotype.

Methods: One hundred patients with CHB who had experienced HBsAg seroclearance before 60 years of age and another 100 with CHB showing high serum levels of HBsAg even after 60 years of age were enrolled. Extreme-phenotype GWAS was conducted using blood samples of participants.

Results: We identified three single nucleotide polymorphisms, rs7944135 (P = 4.17 × 10-6, odds ratio [OR] = 4.16, 95% confidence interval [CI] = 2.27-7.63) at 11q12.1, rs171941 (P = 3.52×10-6, OR = 3.69, 95% CI = 2.13-6.42) at 5q14.1, and rs6462008 (P = 3.40×10-6, OR = 0.34, 95% CI = 0.22-0.54) at 7p15.2 as novel susceptibility loci associated with HBsAg seroclearance in patients with CHB. The flanking genes at these loci including MPEG1, DTX4, MTX3, and HOXA13 were suggested to have functional significance. In addition, through functional analysis, CXCL13 was also presumed to be related.

Conclusions: To the best of our knowledge, this study is the first GWAS regarding the seroclearance of HBsAg in CHB patients. We identify new susceptibility loci for cure of CHB, providing new insights into its pathophysiology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199094PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033413PMC
December 2018

Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer.

Oncogene 2018 08 3;37(32):4443-4454. Epub 2018 May 3.

Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.

Gene mutations play critical roles during cancer development and progression, and therefore represent targets for precision medicine. Here we recapitulated the pharmacogenomic data to delineate novel candidates for actionable mutations and therapeutic target drugs. As a proof-of-concept, we demonstrated that the loss-of-function of SULF2 by mutation (N491K) or inhibition enhanced sorafenib sensitivity in liver cancer cells and in vivo mouse models. This effect was mediated by deregulation of EGFR signaling and downstream expression of LCN2. We also report that the liver cancer patients non-responding to sorafenib treatment exhibit higher expression of SULF2 and LCN2. In conclusion, we suggest that SULF2 plays a key role in sorafenib susceptibility and resistance in liver cancer via deregulation of LCN2. Diagnostic or therapeutic targeting of SULF2 (e.g., OKN-007) and/or LCN2 can be a novel precision strategy for sorafenib treatment in cancer patients.
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http://dx.doi.org/10.1038/s41388-018-0291-3DOI Listing
August 2018

Agerarin inhibits α-MSH-induced TYR gene transcription via STAT3 suppression independent of CREB-MITF pathway.

J Dermatol Sci 2018 Jul 30;91(1):107-110. Epub 2018 Mar 30.

Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul, Republic of Korea; Cancer and Metabolism Institute, Konkuk University, Seoul, Republic of Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jdermsci.2018.03.014DOI Listing
July 2018

Identification of genomic aberrations associated with lymph node metastasis in diffuse-type gastric cancer.

Exp Mol Med 2018 04 6;50(4):1-11. Epub 2018 Apr 6.

Department of Pathology, Ajou University School of Medicine, Suwon, Republic of Korea.

Diffuse-type gastric cancer (DGC) is a GC subtype with heterogeneous clinical outcomes. Lymph node metastasis of DGC heralds a dismal progression, which hampers the curative treatment of patients. However, the genomic heterogeneity of DGC remains unknown. To identify genomic variations associated with lymph node metastasis in DGC, we performed whole exome sequencing on 23 cases of DGC and paired non-tumor tissues and compared the mutation profiles according to the presence (N3, n = 13) or absence (N0, n = 10) of regional lymph node metastasis. Overall, we identified 185 recurrently mutated genes in DGC, which included a significant novel mutation at CMTM2, as well as previously known mutations at CDH1, RHOA, and TP53. Noticeably, CMTM2 expression could predict the prognostic outcomes of DGC but not intestinal-type GC (IGC), indicating pivotal roles of CMTM2 in DGC progression. In addition, we identified a recurrent loss of heterozygosity (LOH) of DNA copy numbers at the 3p12-pcen locus in DGC. A comparison of N0 and N3 tumors showed that N3 tumors exhibited more frequent DNA copy number aberrations, including copy-neutral LOH and mutations of CpTpT trinucleotides, than N0 tumors (P = 0.2 × 10). In conclusion, DGCs have distinct profiles of somatic mutations and DNA copy numbers according to the status of lymph node metastasis, and this might be helpful in delineating the pathobiology of DGC.
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http://dx.doi.org/10.1038/s12276-017-0009-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938030PMC
April 2018

Keratin 19 Expression in Hepatocellular Carcinoma Is Regulated by Fibroblast-Derived HGF via a MET-ERK1/2-AP1 and SP1 Axis.

Cancer Res 2018 04 23;78(7):1619-1631. Epub 2018 Jan 23.

Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.

Keratin (KRT) 19 is a poor prognostic marker for hepatocellular carcinoma (HCC); however, regulatory mechanisms underlying its expression remain unclear. We have previously reported the presence of fibrous tumor stroma in KRT19-positive HCC, suggesting that cross-talk between cancer-associated fibroblasts (CAF) and tumor epithelial cells could regulate KRT19 expression. This was investigated in this study using an model of paracrine interaction between HCC cell lines (HepG2, SNU423) and hepatic stellate cells (HSC), a major source of hepatic myofibroblasts. HSCs upregulated transcription and translation of KRT19 in HCC cells via paracrine interactions. Mechanistically, hepatocyte growth factor (HGF) from HSCs activated c-MET and the MEK-ERK1/2 pathway, which upregulated KRT19 expression in HCC cells. Furthermore, AP1 (JUN/FOSL1) and SP1, downstream transcriptional activators of ERK1/2, activated KRT19 expression in HCC cells. In clinical specimens of human HCC ( = 339), HGF and KRT19 protein expression correlated with CAF levels. In addition, HGF or MET protein expression was associated with FOSL1 and KRT19 expression and was found to be a poor prognostic factor. Analysis of data from The Cancer Genome Atlas also revealed KRT19 expression was closely associated with CAF and MET-mediated signaling activities. These results provide insights into the molecular background of KRT19-positive HCC that display an aggressive phenotype. These findings reveal KRT19 expression in hepatocellular carcinoma is regulated by cross-talk between cancer-associated fibroblasts and HCC cells, illuminating new therapeutic targets for this aggressive disease. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0988DOI Listing
April 2018
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