Publications by authors named "Tae Sung Kim"

424 Publications

The Wound Healing Peptide, AES16-2M, Ameliorates Atopic Dermatitis In Vivo.

Molecules 2021 Feb 22;26(4). Epub 2021 Feb 22.

Korea University Kine Sciences Research Institute, Kine Sciences, 525, Seolleung-ro, Gangnam-gu, Seoul 06149, Korea.

Peptide materials have recently been considered for use in various industrial fields. Because of their efficacy, safety, and low cost, therapeutic peptides are studied for various diseases, including atopic dermatitis (AD). AD is a common inflammatory skin disease impairing the patient's quality of life. Various therapies, such as treatments with corticosteroids, calcineurin inhibitors, and antibody drugs, have been applied, but numerous side effects have been reported, including skin atrophy, burning, and infection. In the case of antibody drugs, immunogenicity against the drugs can be a problem. To overcome these side effects, small peptides are considered therapeutic agents. We previously identified the small wound healing peptide AES16-2M with a sequence of REGRT, and examined its effects on AD in this study. Interestingly, the administration of AES16-2M downregulated the AD disease score, ear thickness, serum IgE, and thymic stromal lymphopoietin (TSLP) in AD mice. The thickness of the epidermal layer was also improved by AES16-2M treatment. In addition, quantities of IL-4-, IL-13-, and IL-17-producing CD4 T cells from peripheral lymph nodes and spleens were reduced by injection of AES16-2M. Furthermore, the expression of TSLP was significantly reduced in AES16-2M-treated human keratinocytes. Therefore, these results suggest that AES16-2M can be a novel candidate for AD treatment.
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http://dx.doi.org/10.3390/molecules26041168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926726PMC
February 2021

NUT Midline Carcinoma of the Lung: Computed Tomography Findings in 10 Patients.

J Comput Assist Tomogr 2021 Mar-Apr 01;45(2):330-336

Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Objective: The aim of the study was to evaluate computed tomography (CT) findings of pulmonary NUT midline carcinoma.

Methods: We assessed clinical and CT features of pulmonary NUT carcinoma in 10 consecutive patients (M:F, 7:3; mean, 39 years).

Results: The primary tumors (size range, 15-65 mm) manifested as either a peripheral tumor (5/10) or a central tumor (5/10). All tumors showed relatively low-attenuation at contrast-enhanced CT (mean net enhancement, 26 HU). Associated CT findings were metastatic hilar or mediastinal lymphadenopathy (8/10), ipsilateral pleural seeding with malignant pleural effusion (2/10), and distant metastasis (2/10). Five patients with low tumor-node-metastasis stages after optimal treatment showed no evidence of disease (50%) for 6 to 35 months.

Conclusions: Pulmonary NUT carcinoma presented as a peripheral or a central lung mass showing mild degree of contrast enhancement, frequent metastatic regional lymphadenopathy, affecting relatively young adults. Although known to be highly aggressive, an early diagnosis in low TNM stages can lead to a favorable prognosis.
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http://dx.doi.org/10.1097/RCT.0000000000001133DOI Listing
April 2021

Factors Affecting Central Node Metastasis and Metastatic Lymph Node Ratio in Papillary Thyroid Cancer.

Otolaryngol Head Neck Surg 2021 Feb 9:194599821991465. Epub 2021 Feb 9.

Department of Otorhinolaryngology-Head and Neck Surgery, National Cancer Center, Goyang, Republic of Korea.

Objective: Despite the growing evidence that metastatic lymph node ratio (MLNR) is a valuable predictor for the prognosis of papillary thyroid carcinoma, it has not yet been fully determined which factors give the ratio predictive value independent of the number of metastatic lymph nodes (MLNs).

Study Design: Retrospective cohort study.

Setting: A comprehensive cancer center.

Methods: Recurrence and clinicopathologic factors were analyzed in 2409 patients with papillary thyroid carcinoma who underwent total thyroidectomy and central node dissection.

Results: Cutoff values of MLNs ≥2 and MLNR ≥28.2% increased the recurrence risk (hazard ratio [95% CI], 9.97 [4.73-21.0] and 11.4 [5.53-23.3], respectively). Younger age, male sex, multifocality, tumor size, lymphatic and vascular invasion, and gross extrathyroidal extension positively correlated with MLN and MLNR (all < .05). Meanwhile, lymphocytic thyroiditis negatively correlated with MLNR in female patients ( < .001), by increasing total lymph node yields as compared with papillary thyroid carcinoma without lymphocytic thyroiditis. In multivariate analysis, younger age, tumor size, and lymphatic invasion remained significant in male and female patients for MLN and MLNR; lymphocytic thyroiditis was also significantly correlated with MLNR in female patients.

Conclusion: Our study demonstrates that MLN and MLNR are independently observed prognostic markers for tumor recurrence. However, lymphocytic thyroiditis in female patients seems to have lower MLNR by increasing total lymph node yields. In light of their association, a different cutoff for MLNR needs to be applied according to the presence or absence of underlying lymphocytic thyroiditis in the use of MLNR for predicting the recurrence.

Level Of Evidence: 4.
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http://dx.doi.org/10.1177/0194599821991465DOI Listing
February 2021

Response evaluation after immunotherapy in NSCLC: Early response assessment using FDG PET/CT.

Medicine (Baltimore) 2020 Dec;99(51):e23815

Center for Lung Cancer.

Abstract: The present study aimed to evaluate the role of early F-18 2-deoxy-2-[fluorine-18] fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT) in non-small cell lung cancer patients undergoing immune checkpoint inhibitor (ICI) treatment.Twenty-four non-small cell lung cancer patients who received nivolumab or pembrolizumab and underwent FDG PET/CT as an interim analysis after 2 or 3 cycles of ICI treatment were retrospectively enrolled. Tumor response was assessed using the PET Response Criteria in Solid Tumors 1.0 (PERCIST) and the European Organization for Research and Treatment of Cancer (EORTC) criteria after 2 or 3 cycles of ICI treatment (SCAN-1) and after an additional 2 cycles of ICI treatment (SCAN-2). The best overall response was determined by FDG PET/CT or chest CT at ≥ 3 months after therapy initiation, and the clinical benefit was investigated. progression-free survival was investigated, and its correlation with clinicopathologic and metabolic parameters was examined using a Cox multivariate proportional hazards model.In the interim analysis, 4 patients achieved a complete metabolic response (CMR), 1 patient exhibited a partial metabolic response (PMR), and 14 patients had Progressive metabolic disease (PMD) according to the PERCIST and EORTC criteria. Four patients showed stable metabolic disease (SMD) according to the PERCIST criteria, and 2 patients showed different responses (i.e., PMR) according to the EORTC criteria. Patients with a CMR or PMR at SCAN-1 had a clinical benefit. Among the 4 patients with SMD at SCAN-1, only 1 experienced a clinical benefit regardless of the percent change in the peak standardized uptake value. Two patients with discordant response assessments between the PERCIST and EORTC criteria showed conflicting clinical benefits. Among the 14 patients with PMD, none experienced any clinical benefit. Only metabolic parameters were significant factors for predicting progression in the multivariate analysis (peak standardized uptake value and metabolic tumor volume, HRs of 1.18 and 1.00, respectively).Based on early F-18 FDG PET/CT after ICI treatment, metabolic parameters could predict post-treatment progression. Responses after ICI treatment were correctly assessed in patients with a CMR, a PMR, and PMD, but patients with SMD required a meticulous follow-up because of varying clinical benefits.
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http://dx.doi.org/10.1097/MD.0000000000023815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748304PMC
December 2020

Randomized phase II study of platinum-based chemotherapy plus controlled diet with or without metformin in patients with advanced non-small cell lung cancer.

Lung Cancer 2021 01 19;151:8-15. Epub 2020 Nov 19.

Center for Lung Cancer, National Cancer Center Korea, Goyang, Republic of Korea. Electronic address:

Objectives: Accumulating evidence indicates anti-diabetic drug metformin has anti-cancer effect by controlling cancer metabolism. We evaluated whether addition of metformin to chemotherapy improved survival of lung cancer patients.

Materials And Methods: This randomized phase II study enrolled 164 patients with chemo-native, EGFR-ALK wild-type, stage IIIB/IV non-small-cell lung cancer (NSCLC). Patients were randomized to receive chemotherapy either with metformin (1000 mg twice daily) or alone every 3 weeks for six cycles. The patients received gemcitabine (1000 mg/m) on days 1 and 8 and carboplatin (5 area under the curve) on day 1. Exploratory studies included serum metabolic panels, positron-emission tomography (PET) imaging, and genetic mutation tests for metabolism-related genes.

Results: Metformin group showed no significant difference in the risk of progression and death compared to control group (progression: hazard ratio [HR] = 1.01 [95% confidence interval (CI) = 0.72 - 1.42], P = 0.935; death: HR = 0.95 [95% CI = 0.67-1.34], P = 0.757). Squamous cell carcinoma (SqCC) had significantly higher fluorodeoxyglucose (FDG) uptake on baseline PET image than non-SqCC NSCLC (P = 0.004). In the SqCC with high FDG uptake, the addition of metformin significantly decreased the risk of progression and death (progression: HR = 0.31 [95% CI = 0.12-0.78], P = 0.013; death: HR = 0.42 [95% CI = 0.18-0.94], P = 0.035). The HDL-cholesterol level was significantly increased after the treatment in metformin group compared to control group (P = 0.011). The metformin group showed no survival benefit in the patients with hyperinsulinemia or patients whose insulin level was decreased after treatment.

Conclusions: Addition of metformin to chemotherapy provided no survival benefit in unselected NSCLC patients. However, it significantly improved the survival of the selected patients with SqCC showing high FDG uptake. It suggests metformin shows the synergistic anti-tumor effect in the tumor which are highly dependent on glucose metabolism.
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http://dx.doi.org/10.1016/j.lungcan.2020.11.011DOI Listing
January 2021

Phase separation of the Cep63•Cep152 complex underlies the formation of dynamic supramolecular self-assemblies at human centrosomes.

Cell Cycle 2020 Dec 18;19(24):3437-3457. Epub 2020 Nov 18.

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA.

The centrosome is a unique membraneless organelle that plays a pivotal role in the orderly progression of the cell cycle in animal cells. It has been shown that two pericentriolar scaffold proteins, Cep63 and Cep152, generate a heterotetrameric complex to self-assemble into a higher-order cylindrical architecture around a centriole. However, the mechanisms underlying how they reach their threshold concentrations in the vast intracellular space and generate a self-assembled architecture remain mysterious. Here we demonstrate that, like liquid-like assemblies, Cep63 and Cep152 cooperatively generate amorphous aggregates capable of undergoing dynamic turnover and inter-aggregate fusion and a significant level of internal rearrangemefnt within a condensate . Consistently, 1,6-hexanediol, a liquid-liquid phase separation disruptor, greatly diminished the ability of endogenous Cep63 and Cep152 to localize to centrosomes. Interestingly, a purified Cep63•Cep152 complex generated either a cylindrical structure or a vesicle-like hollow sphere in a spatially controlled manner. It also formed condensate-like solid spheres in the presence of a macromolecular crowder. At the molecular level, two hydrophobic motifs, one each from Cep63 and Cep152, were required for generating phase-separating condensates and a high molecular-weight assembly. Thus, we propose that the self-assembly of the Cep63•Cep152 complex is triggered by an intrinsic property of the complex undergoing density transition through the hydrophobic-motif-mediated phase separation. PCM, pericentriolar material; LLPS, liquid-liquid phase separation; MW, molecular-weight; CLEM, correlative light and electron microscopy; WT, wild-type; CMV, cytomegalovirus; FRAP, fluorescence recovery after photobleaching; FITC, fluorescein isothiocyanate; PCR, polymerase chain reaction; 3D-SIM, three-dimensional structured illumination microscopy; DMEM, Dulbecco's Modified Eagle Medium; PEI Max, Polyethylenimine Max; PBS, phosphate-buffered saline; RT, room temperature; DAPI, 4', 6-diamidino-2-phenylindole; AOTF, acousto-optic tunable filter; LB, Luria broth; OD, optical density; IPTG, isopropyl β-D-1-thiogalactopyranoside; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
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http://dx.doi.org/10.1080/15384101.2020.1843777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781590PMC
December 2020

Threonyl-tRNA Synthetase Promotes T Helper Type 1 Cell Responses by Inducing Dendritic Cell Maturation and IL-12 Production an NF-κB Pathway.

Front Immunol 2020 14;11:571959. Epub 2020 Oct 14.

Department of Life Science, College of Life Science and Biotechnology, Korea University, Seoul, South Korea.

Threonyl-tRNA synthetase (TRS) is an aminoacyl-tRNA synthetase that catalyzes the aminoacylation of tRNA by transferring threonine. In addition to an essential role in translation, TRS was extracellularly detected in autoimmune diseases and also exhibited pro-angiogenetic activity. TRS is reported to be secreted into the extracellular space when vascular endothelial cells encounter tumor necrosis factor-α. As T helper (Th) type 1 response and IFN-γ levels are associated with autoimmunity and angiogenesis, in this study, we investigated the effects of TRS on dendritic cell (DC) activation and CD4 T cell polarization. TRS-treated DCs exhibited up-regulated expression of activation-related cell-surface molecules, including CD40, CD80, CD86, and MHC class II. Treatment of DCs with TRS resulted in a significant increase of IL-12 production. TRS triggered nuclear translocation of the NF-κB p65 subunit along with the degradation of IκB proteins and the phosphorylation of MAPKs in DCs. Additionally, MAPK inhibitors markedly recovered the degradation of IκB proteins and the increased IL-12 production in TRS-treated DCs, suggesting the involvement of MAPKs as the upstream regulators of NF-κB in TRS-induced DC maturation and activation. Importantly, TRS-stimulated DCs significantly increased the populations of IFN-γCD4 T cells, and the levels of IFN-γ when co-cultured with CD4 T cells. The addition of a neutralizing anti-IL-12 mAb to the cell cultures of TRS-treated DCs and CD4 T cells resulted in decreased IFN-γ production, indicating that TRS-stimulated DCs may enhance the Th1 response through DC-derived IL-12. Injection of OT-II mice with OVA-pulsed, TRS-treated DCs also enhanced Ag-specific Th1 responses . Importantly, injection with TRS-treated DC exhibited increased populations of IFN-γ-CD4 and -CD8 T cells as well as secretion level of IFN-γ, resulting in viral clearance and increased survival periods in mice infected with influenza A virus (IAV), as the Th1 response is associated with the enhanced cellular immunity, including anti-viral activity. Taken together, these results indicate that TRS promotes the maturation and activation of DCs, DC-mediated Th1 responses, and anti-viral effect on IAV infection.
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http://dx.doi.org/10.3389/fimmu.2020.571959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592646PMC
October 2020

Glycolytic phenotypes in an evaluation of ovarian carcinoma based on carcinogenesis and BRCA mutation.

Eur J Radiol 2020 Dec 2;133:109391. Epub 2020 Nov 2.

Center for Uterine and Ovarian Cancer, Hospital, National Cancer Center, Republic of Korea; Division of Gynecologic Oncology, Obstetrics and Gynecology, National Cancer Center, Republic of Korea.

Backgrounds: Recently, a dualistic carcinogenesis model of ovarian cancer has emerged. We aimed to investigate differences in the glycolytic phenotypes of type I and type II ovarian carcinoma on the basis of FDG uptake and in the pathological features according to tumour grade and histology.

Materials And Methods: In total, 386 epithelial ovarian carcinoma patients underwent debulking surgery, and the histopathological results of the patients were retrospectively reviewed from 2003 to 2017. Among these patients, 170 patients had histopathological data that were available due to primary cytoreductive surgery and could be analysed regarding FDG avidity in type I and type II ovarian cancer. The FDG uptake of the tumour (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were analysed according to the tumour grade, histology and type of ovarian carcinogenesis (type I and II) and prognosis.

Results: Among the 386 patients, there was a significant difference in SUVmax among ovarian cancer subtypes. There was a significant increase in SUVmax as the tumour grade increased (8.08 ± 0.63, 10.5 ± 0.40, and 12.7 ± 0.38 for grades I, II and III, respectively, Kruskal-Wallis test, p < 0.0001). Among the 90 type I and 80 type II ovarian carcinoma patients, there was a significant difference in SUVmax (type I and II, 9.47 ± 0.54 and 12.97 ± 0.70, respectively, Mann-Whitney test, p = 0.0003). However, no significant change in SUVmax was observed between BRCA-positive and BRCA-negative patients (N = 80, 13.8 ± 5.78 and 12.4 ± 6.30, Student's t-test, p = 0.3075). Among clinicopathologic and metabolic parameters, type of ovarian cancer, MTV and CA125 were significant factors in the prediction of recurrence.

Conclusions: The glycolytic phenotype was related to tumour grade and histological subtype, with significant differences between type I and II ovarian cancer. SUVmax of the ovarian cancer would be considered in the differentiation of type I and II ovarian cancer.
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http://dx.doi.org/10.1016/j.ejrad.2020.109391DOI Listing
December 2020

Erythroid differentiation regulator 1 promotes wound healing by inducing the production of C‑C motif chemokine ligand 2 via the activation of MAP kinases in vitro and in vivo.

Int J Mol Med 2020 Dec 19;46(6):2185-2193. Epub 2020 Oct 19.

Department of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.

The erythroid differentiation regulator 1 (Erdr1) protein has been studied for its role in various inflammatory skin diseases, including skin cancer, actinic keratosis and psoriasis. However, the therapeutic effects of Erdr1 on wound repair and its underlying mechanisms remain unknown. The present study aimed to investigate the effects of Erdr1 on wound healing in vitro and in vivo. The results demonstrated that treatment with recombinant Erdr1 enhanced wound healing in vivo and in vitro. In addition, Erdr1 increased the proliferation and migration of human dermal fibroblasts (HDFs). Notably, Erdr1 significantly induced the production of the chemoattractant C‑C motif chemokine ligand 2 (CCL2) and recruited immune cells involved in wound healing. Treatment with recombinant Erdr1 induced the activation of the ERK1/1, p38 and JNK1/2 mitogen‑activated protein (MAP) kinases. Treatment with specific inhibitors for MAP kinase inhibitors markedly suppressed cell proliferation and migration, and inhibited the production of CCL2 in HDFs. Furthermore, the inhibition of CCL2 with a neutralizing antibody significantly suppressed the recombinant Erdr1‑induced proliferation and migration of HDFs. The wound healing activity of Erdr1 was comparable to that of epidermal growth factor. Taken together, these results demonstrated that Erdr1 promoted the proliferation and migration of HDFs and exhibited potent wound healing properties mediated by CCL2. Therefore, the results of the present study suggested that Erdr1 may be a potential therapeutic target for promoting wound healing.
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http://dx.doi.org/10.3892/ijmm.2020.4762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595652PMC
December 2020

Recent Survey of Effective Doses of F-18 FDG Torso PET/CT in Korea and the Current Recommendations for CT Protocols of PET/CT.

Nucl Med Mol Imaging 2020 Oct 20;54(5):224-232. Epub 2020 Jul 20.

Department of Nuclear Medicine, National Cancer Center, Goyang-si, South Korea.

Purpose: This study aimed to construct a database of the effective doses (ED) from F-18 fluorodeoxyglucose (FDG) torso positron emission tomography/computed tomography (PET/CT) in Korea to provide data that supports the reduction of the CT dose of PET/CT and optimization of PET/CT protocols in Korea.

Methods: We investigated data of ED and CT parameters of FDG PET/CT. The data were analyzed by body weight groups.

Results: A total of 31 hospitals participated in the survey (99 adults). The mean total EDs (± SD) were 8.77 ± 2.76, 10.93 ± 3.14, and 12.57 ± 3.79 mSv for the 55-, 70-, and 85-kg groups, respectively. The FDG EDs were 4.80 ± 0.98, 6.05 ± 1.15, and 6.89 ± 1.52 mSv, and the CT EDs were 4.00 ± 2.12, 4.88 ± 2.51, and 5.68 ± 2.89 mSv, respectively. Of the enrolled hospitals, 54.5% used ultra-low-dose CT protocols, and their CT ED was significantly lower than low-dose CT group in all groups (2.9 ± 1.0, 3.2 ± 1.1, and 3.3 ± 1.0 mSv vs. 6.6 ± 1.6, 7.2 ± 2.1, and 7.9 ± 2.2 mSv, all  < 0.001, respectively). In the ultra-low-dose CT group, the CT ED with the iterative reconstruction was significantly lower than that of CT without iterative reconstruction in the 55-kg group (2.4 ± 0.9 vs. 3.3 ± 0.9,  = 0.04).

Conclusions: These results and current recommendations can be helpful for optimizing PET/CT diagnostic reference level (DRL) and reducing unnecessary PET/CT radiation exposure.
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http://dx.doi.org/10.1007/s13139-020-00654-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560676PMC
October 2020

Phenotypic Discovery of an Antivirulence Agent against via Modulation of Quorum-Sensing Regulator SmcR.

ACS Infect Dis 2020 11 21;6(11):3076-3082. Epub 2020 Oct 21.

CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul 08826, Korea.

An antivirulence agent against named quoromycin (QM) was discovered by a phenotype-based elastase inhibitor screening. Using the fluorescence difference in two-dimensional gel electrophoresis (FITGE) approach, SmcR, a quorum-sensing master regulator and homologue of LuxR, was identified as the target protein of QM. We confirmed that the direct binding of QM to SmcR inhibits the quorum-sensing signaling pathway by controlling the DNA-binding affinity of SmcR and thus effectively alleviates the virulence of and . QM can be regarded as a novel antivirulence agent for the treatment of infection.
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http://dx.doi.org/10.1021/acsinfecdis.0c00587DOI Listing
November 2020

Satellite radar observation of large surface collapses induced by the 2017 North Korea nuclear test.

Sci Rep 2020 Oct 20;10(1):17833. Epub 2020 Oct 20.

Earthquake Research Centre, Korea Institute of Geoscience and Mineral Resources, Seoul, Korea.

The artificial earthquake of mb 6.1 related to the North Korea's sixth nuclear test occured at Mt. Mantap, North Korea on September 3, 2017. It was reported that a large and complex surface deformation was caused by the event. The surface deformation was composed of expansion of explosions, collapse, compaction and landslides. Since the precise vertical deformation measurement is very important to estimate the stability of the nuclear test facility, we retrieved a precise 3D surface deformation field and then decomposed the vertical deformation pattern from the 3D deformation. The measured maximum deformation was about - 491, - 343 and 166 cm with the measurement uncertainty of about 3.3, 4.1 and 2.7 cm in the east, north and up directions, respectively. The maximum horizontal deformation was approximately 515 cm. The horizontal deformation clearly showed a radial pattern because it was mainly caused by the explosions and landslides, while the vertical deformation displayed a rugged pattern because it was affected by the explosions, compaction and collapse. The collapse may seem to occur along the underground tunnels and at the test site's epicenter as well. Moreover, the severe collapse was observed westside from the epicenter of the sixth nuclear test, and it has a depth of about 68.6 cm on the area of 0.3765 km. On the basis of our results including the shapes, locations and volume changes of the large collapse, evidently a new vital piece of information was obtained so that it could be used to interprete the sixth nuclear test more accurately.
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http://dx.doi.org/10.1038/s41598-020-74957-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575570PMC
October 2020

CT features and disease spread patterns in ROS1-rearranged lung adenocarcinomas: comparison with those of EGFR-mutant or ALK-rearranged lung adenocarcinomas.

Sci Rep 2020 10 1;10(1):16251. Epub 2020 Oct 1.

Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.

The purpose of this study was to investigate the differences in CT characteristics and disease spread patterns between ROS1-rearranged adenocarcinomas and epidermal growth factor receptor (EGFR)-mutant or anaplastic lymphoma kinase (ALK)-rearranged adenocarcinomas. Patients with stage IIIb/IV adenocarcinoma with ROS1 rearrangement, EGFR mutations, or ALK rearrangement were retrospectively identified. Two radiologists evaluated CT features and disease spread patterns. A multivariable logistic regression model was applied to determine the clinical and CT characteristics that can discriminate between ROS1-rearranged and EGFR-mutant or ALK-rearranged adenocarcinomas. A cohort of 169 patients was identified (ROS1 = 23, EGFR = 120, and ALK = 26). Compared to EGFR-mutant adenocarcinomas, ROS1-rearranged adenocarcinomas were less likely to have air-bronchogram (p = 0.011) and pleural retraction (p = 0.048) and more likely to have pleural effusion (p = 0.025), pericardial metastases (p < 0.001), intrathoracic and extrathoracic nodal metastases (p = 0.047 and 0.023, respectively), and brain metastases (p = 0.017). Following multivariable analysis, age (OR = 1.06; 95% CI: 1.01, 1.12; p = 0.024), pericardial metastases (OR = 10.50; 95% CI: 2.10, 52.60; p = 0.005), and nodal metastases (OR = 8.55; 95% CI: 1.14, 62.52; p = 0.037) were found to be more common in ROS1-rearranged tumors than in non-ROS1-rearranged tumors. ROS1-rearranged adenocarcinomas appeared as solid tumors and were associated with young age, pericardial metastases and advanced nodal metastases relative to tumors with EGFR mutations or ALK rearrangement.
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http://dx.doi.org/10.1038/s41598-020-73533-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529803PMC
October 2020

TRAF6-mediated ubiquitination of MST1/STK4 attenuates the TLR4-NF-κB signaling pathway in macrophages.

Cell Mol Life Sci 2021 Mar 25;78(5):2315-2328. Epub 2020 Sep 25.

Department of Life Sciences, Korea University, Seoul, 02841, Korea.

Pattern-recognition receptors including Toll-like receptors (TLRs) recognize invading pathogens and trigger an immune response in mammals. Here we show that mammalian ste20-like kinase 1/serine/threonine kinase 4 (MST1/STK4) functions as a negative regulator of lipopolysaccharide (LPS)-induced activation of the TLR4-NF-κB signaling pathway associated with inflammation. Myeloid-specific genetic ablation of MST1/STK4 increased the susceptibility of mice to LPS-induced septic shock. Ablation of MST1/STK4 also enhanced NF-κB activation triggered by LPS in bone marrow-derived macrophages (BMDMs), leading to increased production of proinflammatory cytokines by these cells. Furthermore, MST1/STK4 inhibited TRAF6 autoubiquitination as well as TRAF6-mediated downstream signaling induced by LPS. In addition, we found that TRAF6 mediates the LPS-induced activation of MST1/STK4 by catalyzing its ubiquitination, resulting in negative feedback regulation by MST1/STK4 of the LPS-induced pathway leading to cytokine production in macrophages. Together, our findings suggest that MST1/STK4 functions as a negative modulator of the LPS-induced NF-κB signaling pathway during macrophage activation.
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http://dx.doi.org/10.1007/s00018-020-03650-4DOI Listing
March 2021

KSNM/KSID/KOSHIC Guidance for Nuclear Medicine Department Against the Coronavirus Disease 2019 (COVID-19) Pandemic.

Nucl Med Mol Imaging 2020 Aug 11;54(4):163-167. Epub 2020 Aug 11.

Korean Society of Nuclear Medicine Quality Control Committee, Bucheon, Republic of Korea.

The dramatic spread of Coronavirus Disease 2019 (COVID-19) has profound impacts on every continent and life. Due to human-to-human transmission of COVID-19, nuclear medicine staffs also cannot escape the risk of infection from workplaces. Every staff in the nuclear medicine department must prepare for and respond to COVID-19 pandemic which tailored to the characteristics of our profession. This article provided the guidance prepared by the Korean Society of Nuclear Medicine (KSNM) in cooperation with the Korean Society of Infectious Disease (KSID) and Korean Society for Healthcare-Associated Infection Control and Prevention (KOSHIC) in managing the COVID-19 pandemic for the nuclear medicine department. We hope that this guidance will support every practice in nuclear medicine during this chaotic period.
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http://dx.doi.org/10.1007/s13139-020-00660-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417777PMC
August 2020

Me-too validation study for in vitro skin irritation test with a reconstructed human epidermis model, KeraSkin™ for OECD test guideline 439.

Regul Toxicol Pharmacol 2020 Nov 5;117:104725. Epub 2020 Aug 5.

College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea. Electronic address:

We conducted a me-too validation study to confirm the reproducibility, reliability, and predictive capacity of KeraSkin™ skin irritation test (SIT) as a me-too method of OECD TG 439. With 20 reference chemicals, within-laboratory reproducibility (WLR) of KeraSkin™ SIT in the decision of irritant or non-irritant was 100%, 100%, and 95% while between-laboratory reproducibility (BLR) was 100%, which met the criteria of performance standard (PS, WLR≥90%, BLR≥80%). WLR and BLR were further confirmed with intra-class correlation (ICC, coefficients >0.950). WLR and BLR in raw data (viability) were also shown with a scatter plot and Bland-Altman plot. Comparison with existing VRMs with Bland-Altman plot, ICC and kappa statistics confirmed the compatibility of KeraSkin™ SIT with OECD TG 439. The predictive capacity of KeraSkin™ SIT was estimated with 20 reference chemicals (the sensitivity of 98.9%, the specificity of 70%, and the accuracy of 84.4%) and additional 46 chemicals (for 66 chemicals [20 + 46 chemicals, the sensitivity, specificity and accuracy: 95.2%, 82.2% and 86.4%]). The receiver operating characteristic (ROC) analysis suggested a potential improvement of the predictive capacity, especially sensitivity, when changing cut-off (50% → 60-75%). Collectively, the me-too validation study demonstrated that KeraSkin™ SIT can be a new me-too method for OECD TG 439.
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http://dx.doi.org/10.1016/j.yrtph.2020.104725DOI Listing
November 2020

Rationally designed redirection of natural killer cells anchoring a cytotoxic ligand for pancreatic cancer treatment.

J Control Release 2020 10 16;326:310-323. Epub 2020 Jul 16.

Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seongbuk-Gu, Seoul 02792, South Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

The emergence of T-cell engineering with chimeric antigen receptors (CARs) has led to attractive therapeutics; however, autologous CAR-T cells are associated with poor clinical outcomes in solid tumors because of low safety and efficacy. Therefore, the aim of our study was to develop a CAR therapy with enhanced cytotoxicity against solid cancer using allogeneic NK cells. In this study, we engineered "off-the-shelf" NK cells to redirect them towards pancreatic ductal adenocarcinoma (PDAC) by improving their target-specific cytotoxic potential. By integrated bioinformatic and clinicopathological analyses, folate receptor alpha (FRα) and death receptor 4 (DR4) were significantly highly expressed in patient-derived tumor cells. The combined expression of FRα and DR4/5 was associated with inferior clinical outcomes, therefore indicating their use as potential targets for biomolecular treatment. Thus, FRα and DR4 expression pattern can be a strong prognostic factor as promising therapeutic targets for the treatment of PDAC. For effective PDAC treatment, allogeneic CAR-NK cells were reprogrammed to carry an apoptosis-inducing ligand and to redirect them towards FRα and initiate DR4/5-mediated cancer-selective cell death in FRα- and DR4/5-positive tumors. As a result, the redirected cytotoxic ligand-loaded NK cells led to a significantly enhanced tumor-selective apoptosis. Accordingly, use of allogeneic CAR-NK cells that respond to FRα and DR4/5 double-positive cancers might improve clinical outcomes based on personal genome profiles. Thus, therapeutic modalities based on allogeneic NK cells can potentially be used to treat large numbers of patients with optimally selective cytotoxicity.
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http://dx.doi.org/10.1016/j.jconrel.2020.07.016DOI Listing
October 2020

Understanding the Differentiation, Expansion, Recruitment and Suppressive Activities of Myeloid-Derived Suppressor Cells in Cancers.

Int J Mol Sci 2020 May 20;21(10). Epub 2020 May 20.

Centre for Virus and Vaccine Research, School of Science and Technology, Sunway University, Bandar Sunway, Kuala Lumpur, Selangor 47500, Malaysia.

There has been a great interest in myeloid-derived suppressor cells (MDSCs) due to their biological functions in tumor-mediated immune escape by suppressing antitumor immune responses. These cells arise from altered myelopoiesis in response to the tumor-derived factors. The most recognized function of MDSCs is suppressing anti-tumor immune responses by impairing T cell functions, and these cells are the most important players in cancer dissemination and metastasis. Therefore, understanding the factors and the mechanism of MDSC differentiation, expansion, and recruitment into the tumor microenvironment can lead to its control. However, most of the studies only defined MDSCs with no further characterization of granulocytic and monocytic subsets. In this review, we discuss the mechanisms by which specific MDSC subsets contribute to cancers. A better understanding of MDSC subset development and the specific molecular mechanism is needed to identify treatment targets. The understanding of the specific molecular mechanisms responsible for MDSC accumulation would enable more precise therapeutic targeting of these cells.
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http://dx.doi.org/10.3390/ijms21103599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279333PMC
May 2020

Ribosomal protein S3 is a novel negative regulator of non-homologous end joining repair of DNA double-strand breaks.

FASEB J 2020 06 16;34(6):8102-8113. Epub 2020 Apr 16.

Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul, Republic of Korea.

DNA double-strand breaks (DSBs) are one of the most serious types of DNA damage. However, multiple repair pathways are present in cells to ensure rapid and appropriate repair of DSBs. Pathway selection depends on several factors including cell type, cell cycle phase, and damage severity. Ribosomal protein S3 (rpS3), a component of the 40S small ribosomal subunit, is a multi-functional protein primarily involved in protein synthesis. rpS3 is also involved in the mediation of various extra-ribosomal pathways, including DNA damage processing and the stress response. Here, we report that rpS3 is a novel negative regulator of non-homologous end joining (NHEJ)-mediated repair of DSBs. We found that rpS3 interacts with the Ku heterodimers of the DNA-dependent protein kinase (DNA-PK) complex and slows down NHEJ ligation reactions, ultimately triggering p53-dependent cell death following treatment with high-dose ionizing radiation. After DSB formation, DNA-PK phosphorylates rpS3, which consequently reduces the binding of rpS3 to the Ku complex. We hypothesized that rpS3 may play a role in DSB repair by repressing NHEJ, while inducing other repair pathways, and by initiating DSB-induced cell death in response to severe DNA damage.
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http://dx.doi.org/10.1096/fj.201903245RDOI Listing
June 2020

Phase I and pharmacokinetic study of the vascular-disrupting agent CKD-516 (NOV120401) in patients with refractory solid tumors.

Pharmacol Res Perspect 2020 04;8(2):e00568

National Cancer Center Hospital, Goyang-si, Gyeonggi-do, Republic of Korea.

We report a phase I pharmacological study of an oral formulation of CKD-516, a vascular-disrupting agent, in patients with refractory solid tumors. Twenty-seven patients (16 in the dose-escalation cohort and 11 in the expansion cohort) received a single daily dose (5-25 mg) of CKD-516 five days per week. Nausea (67%) and diarrhea (63%) were the most common treatment-related adverse events. The recommended phase II dose of oral CKD-516 was 20 mg/d (15 mg/d with a body surface area (BSA) <1.65 m ). Notably, S-516 half-lives in patients receiving 15-20 mg CKD-516/d significantly differed between patients with and without splenomegaly that is suggestive of portal hypertension associated with liver cirrhosis (6.1 vs 4.6 hours, respectively). Of 11 patients without splenomegaly who completed at least one cycle of a daily CKD-516 dose of either 15 or 20 mg, only one patient (9.1%) suffered from any dose-limiting toxicity. We conclude that a daily oral dose of 15 or 20 mg CKD-516 five days per week could be tolerable in patients without liver cirrhosis.
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http://dx.doi.org/10.1002/prp2.568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066534PMC
April 2020

Requirement of the Cep57-Cep63 Interaction for Proper Cep152 Recruitment and Centriole Duplication.

Mol Cell Biol 2020 04 28;40(10). Epub 2020 Apr 28.

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

Cep57 has been characterized as a component of a pericentriolar complex containing Cep63 and Cep152. Interestingly, Cep63 and Cep152 self-assemble into a pericentriolar cylindrical architecture, and this event is critical for the orderly recruitment of Plk4, a key regulator of centriole duplication. However, the way in which Cep57 interacts with the Cep63-Cep152 complex and contributes to the structure and function of Cep63-Cep152 self-assembly remains unknown. We demonstrate that Cep57 interacts with Cep63 through N-terminal motifs and associates with Cep152 via Cep63. Three-dimensional structured illumination microscopy (3D-SIM) analyses suggested that the Cep57-Cep63-Cep152 complex is concentrically arranged around a centriole in a Cep57-in and Cep152-out manner. Cep57 mutant cells defective in Cep63 binding exhibited improper Cep63 and Cep152 localization and impaired Sas6 recruitment for procentriole assembly, proving the significance of the Cep57-Cep63 interaction. Intriguingly, Cep63 fused to a microtubule (MT)-binding domain of Cep57 functioned in concert with Cep152 to assemble around stabilized MTs Thus, Cep57 plays a key role in architecting the Cep63-Cep152 assembly around centriolar MTs and promoting centriole biogenesis. This study may offer a platform to investigate how the organization and function of the pericentriolar architecture are altered by disease-associated mutations found in the Cep57-Cep63-Cep152 complex.
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http://dx.doi.org/10.1128/MCB.00535-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189096PMC
April 2020

Analysis of complete chloroplast genome sequence of Korean landrace .

3 Biotech 2020 Jan 6;10(1):29. Epub 2020 Jan 6.

1Department of Plant Bioscience, College of Natural Resources and Life Science, Pusan National University, Miryang, 50463 Republic of Korea.

The complete chloroplast genome sequence of Korean acc smg222 was analyzed. Based on a comparison with Chinese , losses of nine subunits (A, B, C, D, E, F, H, J, and K), three protein-coding genes ( 1-like, 15, and 68), six transfer RNAs, and one conserved open reading frame ( 42). In addition, 219 InDels (insertion or deletion) and 171 simple sequence repeats were observed. Twenty-Five of which InDel markers have been evaluated, that useful for distinguishing Korean and Chinese associations based on the polymorphisms of chloroplast genomes between Korean acc smg222 and Chinese and evaluation of genetic diversity. Finally, the phylogenetic relationships of the 39 Korean and 22 Chinese species was constructed based on the five InDel markers of them and obtained high support, indicating that our data may be useful in resolving relationships in this genus. The information about chloroplast DNA structure and gene variants of acc. smg222 chloroplast genome will provide sufficient phylogenetic information for resolving evolutionary relationships. The molecular markers developed in here will contribute to further research of species and conservation of endemic species.
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http://dx.doi.org/10.1007/s13205-019-2020-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944737PMC
January 2020

The Novel Synthetic Peptide AESIS-1 Exerts a Preventive Effect on Collagen-Induced Arthritis Mouse Model via STAT3 Suppression.

Int J Mol Sci 2020 Jan 7;21(2). Epub 2020 Jan 7.

Institute of Convergence Science, Korea University, Anam-ro 145, Seongbuk-ku, Seoul 02841, Korea.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is associated with systemic inflammation and results in the destruction of joints and cartilage. The pathogenesis of RA involves a complex inflammatory process resulting from the action of various proinflammatory cytokines and, therefore, many novel therapeutic agents to block cytokines or cytokine-mediated signaling have been developed. Here, we tested the preventive effects of a small peptide, AESIS-1, in a mouse model of collagen-induced arthritis (CIA) with the aim of identifying a novel safe and effective biological for treating RA. This novel peptide significantly suppressed the induction and development of CIA, resulting in the suppression of synovial inflammation and cartilage degradation in vivo. Moreover, AESIS-1 regulated JAK/STAT3-mediated gene expression in vitro. In particular, the gene with the most significant change in expression was (), which was enhanced 8-fold. Expression of the STAT3-specific inhibitor, , was obviously enhanced dose-dependently by AESIS-1 at both the mRNA and protein levels, resulting in a significant reduction of STAT3 phosphorylation in splenocytes from severe CIA mice. This indicated that AESIS-1 regulated STAT3 activity by upregulation of SOCS3 expression. Furthermore, IL-17 expression and the frequency of Th17 cells were considerably decreased by AESIS-1 in vivo and in vitro. Collectively, our data suggest that the novel synthetic peptide AESIS-1 could be an effective therapeutic for treating RA via the downregulation of STAT3 signaling.
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http://dx.doi.org/10.3390/ijms21020378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013888PMC
January 2020

Comparative Analysis of Lung Perfusion Scan and SPECT/CT for the Evaluation of Functional Lung Capacity.

Nucl Med Mol Imaging 2019 Dec 11;53(6):406-413. Epub 2019 Nov 11.

1Department of Nuclear Medicine, National Cancer Center, Goyang, Republic of Korea.

Purpose: This study aimed to compare lung perfusion scan with single photon emission computed tomography/computed tomography (SPECT/CT) for the evaluation of lung function and to elucidate the most appropriate modality for the prediction of postoperative lung function in patients with lung cancer.

Methods: A total of 181 patients underwent Tc-99m macroaggregated albumin lung perfusion scan and SPECT/CT to examine the ratio of diseased lung and diseased lobe. Forty-one patients with lung cancer underwent both preoperative and postoperative pulmonary function tests within 1 month to predict postoperative pulmonary function. Predicted postoperative forced expiratory volume in 1 s (ppoFEV) was calculated by the % radioactivity of lung perfusion scan and SPECT, and the % volume of the residual lung, assessed on CT.

Results: The ratios of diseased lung as seen on lung perfusion scan and SPECT showed significant correlation, but neither modality correlated with CT. The ratios of the diseased lung and diseased lobe based on CT were higher than the ratios based on either perfusion scan or SPECT, because CT overestimated the function of the diseased area. The lobar ratio of both upper lobes was lower based on the perfusion scan than on SPECT but was higher for both lower lobes. Actual postoperative FEV showed significant correlation with ppoFEV based on lung perfusion SPECT and perfusion scan.

Conclusions: We suggest SPECT/CT as the primary modality of choice for the assessment of the ratio of diseased lung area. Both perfusion scan and SPECT/CT can be used for the prediction of postoperative lung function.
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http://dx.doi.org/10.1007/s13139-019-00617-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898701PMC
December 2019

IL-33 changes CD25 Tregs to Th17 cells through a dendritic cell-mediated pathway.

Immunol Lett 2020 02 18;218:5-10. Epub 2019 Dec 18.

Division of Life Science, College of Life Science and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea. Electronic address:

Interleukin (IL)-33 is an alarmin factor that is highly secreted in a variety of autoimmune diseases, induces maturation of dendritic cells (DCs) and differentiation of T helper 17 (Th17) cells. As the balance between Th17 cells and regulatory T cells (Tregs) is important to maintain immune homeostasis, in this study, we investigated the effects of IL-33 on Treg cell response. We observed that direct treatment with IL-33 had no effect on Treg differentiation, whereas IL-33-matured DCs (IL33-matDCs) inhibited the differentiation of CD4 T cells to Tregs by decreasing the expression of Foxp3. Furthermore, co-culture with IL-33-matDCs changed stable Tregs (CD25CD4 Tregs) to IL-17-producing cells, whereas IL-33-matDCs had little effects on unstable Tregs (CD25CD4 Tregs). The stable Tregs were demonstrated to express high levels of IL-6 receptors. Blocking of IL-6 secreted from IL-33-matDCs suppressed the conversion of Tregs to Th17 cells, indicating the greater propensity to convert stable Tregs to Th17 cells is due to IL-6 signaling. Taken together, these results demonstrate that IL-33 inhibits Treg differentiation and the conversion of stable Tregs to Th17 cells via DCs.
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http://dx.doi.org/10.1016/j.imlet.2019.12.003DOI Listing
February 2020

Correction to: Clinical outcomes in patients with diffuse large B cell lymphoma with a partial response to first-line R-CHOP chemotherapy: prognostic value of secondary International Prognostic Index scores and Deauville scores.

Ann Hematol 2020 01;99(1):213

Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, 50-1 Yonsei-ro, Seoul, Seodaemun-gu, 03722, South Korea.

An additional affiliation for the first author was not indicated. Hyewon Lee is also affiliated with: Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, South Korea.
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http://dx.doi.org/10.1007/s00277-019-03868-8DOI Listing
January 2020

Compensatory Mutations in GI and ZTL May Modulate Temperature Compensation in the Circadian Clock.

Plant Physiol 2020 02 18;182(2):1130-1141. Epub 2019 Nov 18.

Department of Molecular Genetics, The Ohio State University, Columbus, Ohio 43210

Circadian systems share the three properties of entrainment, free-running period, and temperature compensation (TC). TC ensures nearly the same period over a broad range of physiologically relevant temperatures; however, the mechanisms behind TC remain poorly understood. Here, we identify single point mutations in two key elements of the Arabidopsis circadian clock, GIGANTEA (GI) and ZEITLUPE (ZTL), which likely act as compensatory substitutions to establish a remarkably constant free-running period over a wide range of temperatures. Using near-isogenic lines generated from the introgression of the Cape Verde Islands (Cvi) alleles of GI and ZTL into the Landsberg (L) background, we show how longer periods in the Cvi background at higher temperatures correlate with a difference in strength of the GI/ZTL interaction. Pairwise interaction testing of all GI/ZTL allelic combinations shows similar affinities for isogenic alleles at 22°C, but very poor interaction between GI (Cvi) and ZTL (Cvi) at higher temperature. In vivo, this would result in lower ZTL levels at high temperatures leading to longer periods in the Cvi background. Mismatched allelic combinations result in extremely strong or weak GI/ZTL interactions, indicating how the corresponding natural variants likely became fixed through epistatic selection. Additionally, molecular characterization of GI (Cvi) reveals a novel functional motif that can modulate the GI/ZTL interaction as well as nucleocytoplasmic partitioning. Taken together, these results identify a plausible temperature-dependent molecular mechanism, which contributes to the robustness of TC through natural variation in GI and ZTL alleles found on the Cape Verde Islands.
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http://dx.doi.org/10.1104/pp.19.01120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997678PMC
February 2020

Two tiered approaches combining alternative test methods and minimizing the use of reconstructed human cornea-like epithelium tests for the evaluation of eye irritation potency of test chemicals.

Toxicol In Vitro 2020 Mar 22;63:104675. Epub 2019 Oct 22.

Toxicological Screening & Testing Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju-si, Republic of Korea. Electronic address:

In order to overcome the limitations of single in vitro eye irritation tests, Integrated Approaches to Testing Assessment strategies have been suggested for evaluating eye irritation. This study developed two tiered approaches combining alternative test methods. They were designed in consideration of the solubility property of test chemicals and to use the RhCE tests at final steps. The tiered approach A is composed of the STE, BCOP, HET-CAM or RhCE tests, whereas the tiered approach B is designed to perform simultaneously two in vitro test methods at the first stage and the RhCE test at the final stage. The predictive capacity of the two tiered approaches was estimated using 47 chemicals. The accuracy, sensitivity, and specificity value of the tiered approach A were 95.7% (45/47), 100% (34/34), and 84.6% (11/13), respectively, whereas those of the tiered approach B were 95.7% (45/47), 97.1% (33/34), and 92.3% (12/13), respectively. The approach A and B were considered to be available methods for distinguishing test chemicals of Category 1 (all 73.3%) and No Category (84.6% and 92.3%), respectively. Especially, the approach B was considered as an efficient method as the Bottom-Up approach, because it predicted correctly test chemicals classified as No Category.
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http://dx.doi.org/10.1016/j.tiv.2019.104675DOI Listing
March 2020

NLRP3 negatively regulates Treg differentiation through Kpna2-mediated nuclear translocation.

J Biol Chem 2019 11 9;294(47):17951-17961. Epub 2019 Oct 9.

Division of Life Science, College of Life Science and Biotechnology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea

Naïve CD4 T cells in the periphery differentiate into regulatory T cells (Tregs) in which Foxp3 is expressed for their suppressive function. NLRP3, a pro-inflammatory molecule, is known to be involved in inflammasome activation associated with several diseases. Recently, the expression of NLRP3 in CD4 T cells, as well as in myeloid cells, has been described; however, a role of T cell-intrinsic NLRP3 in Treg differentiation remains unknown. Here, we report that NLRP3 impeded the expression of Foxp3 independent of inflammasome activation in Tregs. NLRP3-deficient mice elevate Treg generation in various organs in the pathway. NLRP3 deficiency increased the amount and suppressive activity of Treg populations, whereas NLRP3 overexpression reduced Foxp3 expression and Treg abundance. Importantly, NLRP3 interacted with Kpna2 and translocated to the nucleus from the cytoplasm under Treg-polarizing conditions. Taken together, our results identify a novel role for NLRP3 as a new negative regulator of Treg differentiation, mediated via its interaction with Kpna2 for nuclear translocation.
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http://dx.doi.org/10.1074/jbc.RA119.010545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879348PMC
November 2019

Catalytic Hydroboration of Aldehydes, Ketones, and Alkenes Using Potassium Carbonate: A Small Key to Big Transformation.

ACS Omega 2019 Oct 20;4(14):15893-15903. Epub 2019 Sep 20.

Department of Chemistry, Kangwon National University, Chuncheon 24341, Republic of Korea.

An efficient transition-metal-free protocol for the hydroboration of aldehydes and ketones (reduction) was developed. The hydroboration of a wide range of aldehydes and ketones with pinacolborane (HBpin) under the KCO catalyst has been studied. The reaction system is practical and reliable and proceeds under extremely mild and operationally simple conditions. No prior preparation of the complex metal catalyst was required, and hydroboration occurred stoichiometrically. Further, the chemoselective reduction of aldehydes over ketones was carried out. Moreover, we demonstrated the use of KCO as an efficient catalyst for the hydroboration of alkenes. The operational simplicity, inexpensive and transition-metal-free catalyst, and the applicability to gram-scale synthesis strengthen its potential applications for hydroboration (reduction) at an industrial scale.
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http://dx.doi.org/10.1021/acsomega.9b01877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776975PMC
October 2019