Publications by authors named "Young-Sun Lee"

190 Publications

Label-free quantitative proteomic analysis of serum extracellular vesicles differentiating patients of alcoholic and nonalcoholic fatty liver diseases.

J Proteomics 2021 Jun 2;245:104278. Epub 2021 Jun 2.

Department of Chemistry, Chungnam National University, Daejeon, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Republic of Korea. Electronic address:

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are typically asymptomatic and slow-progressing but potentially fatal diseases that are common causes of liver cirrhosis and related complications. Exosomes are nano-sized extracellular vesicles that have been linked to various intercellular communication processes and can carry biological materials reflecting the state and severity of disease. In this study, shotgun proteomic analysis of the protein expression profiles of extracellular vesicles, including exosomes and microvesicles, enriched from human serum samples of 24 patients diagnosed with various fatty liver diseases was performed using liquid chromatography tandem mass spectrometry (LC-MS/MS) followed by protein identification and label-free quantification using the MaxQuant platform. A total of 329 proteins, including 190 previously reported exosome-specific proteins, were identified from four types of liver disease, where significant differences in protein expression were found in apolipoproteins, immunoglobulins, and other previously reported markers of liver disease. Principal component analysis of 61 proteins identified from MaxQuant analysis of the LC-MS/MS data provided a confident differentiation between ALD and NAFLD. SIGNIFICANCE: The current investigation revealed the difference among various types of liver disease using LC-MS/MS of exosomes enriched from human serum samples of 24 patients where the most significantly up-regulation proteins were alpha-2-macroglobulin for alcoholic hepatitis and apolipoprotein C3 for nonalcoholic fatty liver disease.
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http://dx.doi.org/10.1016/j.jprot.2021.104278DOI Listing
June 2021

Benefits and Risks of Antiviral Treatment during Pregnancy in Patients with Chronic Hepatitis B.

J Clin Med 2021 May 26;10(11). Epub 2021 May 26.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Korea.

Hepatitis B virus (HBV) is a main cause of chronic liver disease worldwide and can lead to severe liver diseases. The World Health Organization has planned to eliminate viral hepatitis, including hepatitis caused by HBV and hepatitis C virus, by 2030. As mother-to-child transmission (MTCT) of HBV is a main cause of chronic HBV infection, MTCT prevention is the main target to reduce the risk of chronic HBV infection and eliminate the disease. Recent clinical trials and meta-analyses found that antiviral therapy could prevent MTCT effectively in mothers with ≥200,000 IU/mL of HBV DNA, in combination with serial vaccination and hepatitis B immune globulin administration in infants. Despite the preventive role of antivirals for MTCT of HBV, there are several concerns regarding antiviral therapy with respect to the safety of the mother and fetus during pregnancy. This review summarizes the benefits and risks of antiviral treatment during pregnancy in women with chronic HBV infection.
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http://dx.doi.org/10.3390/jcm10112320DOI Listing
May 2021

Anti-Inflammatory Effects of Dimethyl Fumarate in Microglia via an Autophagy Dependent Pathway.

Front Pharmacol 2021 7;12:612981. Epub 2021 May 7.

Department of Medical Science, College of Medicine, Catholic Kwandong University, Gangneung, Korea.

Dimethyl fumarate (DMF), which has been approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis, is considered to exert anti-inflammatory and antioxidant effects. Microglia maintain homeostasis in the central nervous system and play a key role in neuroinflammation, while autophagy controls numerous fundamental biological processes, including pathogen removal, cytokine production, and clearance of toxic aggregates. However, the role of DMF in autophagy induction and the relationship of this effect with its anti-inflammatory functions in microglia are not well known. In the present study, we investigated whether DMF inhibited neuroinflammation and induced autophagy in microglia. First, we confirmed the anti-neuroinflammatory effect of DMF in mice with streptozotocin-induced diabetic neuropathy. Next, we used models including microglial cell lines and primary microglial cells to examine the anti-inflammatory and neuroprotective effects of DMF. We found that DMF significantly inhibited nitric oxide and proinflammatory cytokine production in lipopolysaccharide-stimulated microglia and induced the switch of microglia to the M2 state. In addition, DMF treatment increased the expression levels of autophagy markers including microtubule-associated protein light chain 3 (LC3) and autophagy-related protein 7 (ATG7) and the formation of LC3 puncta in microglia. The anti-inflammatory effect of DMF in microglia was significantly reduced by pretreatment with autophagy inhibitors. These data suggest that DMF leads to the induction of autophagy in microglia and that its anti-inflammatory effects are partially mediated through an autophagy-dependent pathway.
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http://dx.doi.org/10.3389/fphar.2021.612981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137969PMC
May 2021

Early Normalization of Alanine Aminotransferase during Antiviral Therapy Reduces Risk of Hepatocellular Carcinoma in HBV Patients.

J Clin Med 2021 Apr 23;10(9). Epub 2021 Apr 23.

Department of Internal Medicine, Korea University College of Medicine, Seoul 08308, Korea.

Potent antiviral agents effectively reduce liver-related events in patients with chronic hepatitis B. This study aimed to determine whether alanine aminotransferase normalization using potent antiviral agents was related to hepatocellular carcinoma development. From 2007 to 2017, we included 610 patients with chronic hepatitis B who received entecavir or tenofovir disoproxil fumarate. The patients were divided into the alanine aminotransferase normalization group (Gr.1) and non-normalization group (Gr.2) within a year of potent antiviral treatment. Liver-related events included hepatic encephalopathy, variceal bleeding, and ascites. The mortality rate and hepatocellular carcinoma incidence were investigated for each group. The patients who showed ALT normalization at 1 year of treatment were 397 (65.1%) of 610. During a median follow-up period of 86 months, 65 (10.7%) patients developed hepatocellular carcinoma. The cumulative incidence of hepatocellular carcinoma was significantly lower in Gr.1 than in Gr.2 ( < 0.001). Risk factors for alanine aminotransferase non-normalization were body mass index, cholesterol, and liver cirrhosis at baseline. Male sex, age, platelet level, alcohol use, presence of cirrhosis at baseline, and non-normalization after 1 year of treatment were independent risk factors for hepatocellular carcinoma. Alanine aminotransferase normalization within 1 year of initiating antiviral agents reduces the risk of hepatocellular carcinoma development.
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http://dx.doi.org/10.3390/jcm10091840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123072PMC
April 2021

Associations of Circulating Levels of Sphingosine 1-Phosphate with the Trabecular Bone Score and Bone Mineral Density in Postmenopausal Women.

J Clin Densitom 2021 Mar 6. Epub 2021 Mar 6.

Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea. Electronic address:

Despite the potential roles of sphingosine 1-phosphate (S1P) as a biomarker of osteoporotic fracture (OF), independent of bone mineral density (BMD) and clinical risk factors (CRFs), its association with bone microarchitecture, a key determinant of bone quality, have not been studied yet. We here investigated the association of S1P with the trabecular bone score (TBS), an index of the bone microarchitecture. The plasma S1P concentrations, TBS, and BMD were measured in the 339 postmenopausal women. The S1P level was inversely correlated with the TBS (γ=-0.096, p=0.049) and BMD at the femur neck (FN-BMD: γ=-0.122, p=0.025) and tended to be inversely correlated the BMD at the total hip (TH-BMD: γ=-0.096, p=0.079), but not at the lumbar spine (LS-BMD). After adjusting for fracture risk assessment tool probabilities of major OF from CRFs, the S1P level was inversely associated with the TBS (β=-0.096, p=0.049) and FN-BMD (β=-0.118, p=0.025) and tended to be inversely associated with the TH-BMD (β=-0.092, p=0.083). Compared with subjects in the lowest S1P tertile, those in the highest S1P tertile had a significantly lower TBS (p=0.032) and BMD at femur (p=0.004-0.036). These findings indicated that a high S1P level in postmenopausal women was inversely associated with the both bone mass and microarchitecture, reflecting the compromised bone strength.
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http://dx.doi.org/10.1016/j.jocd.2021.03.005DOI Listing
March 2021

Hevin-calcyon interaction promotes synaptic reorganization after brain injury.

Cell Death Differ 2021 Mar 22. Epub 2021 Mar 22.

Brain Science & Engineering Institute, Kyungpook National University, Daegu, Republic of Korea.

Hevin, also known as SPARC-like protein 1 (SPARCL1 or SC1), is a synaptogenic protein secreted by astrocytes and modulates the formation of glutamatergic synapses in the developing brain by interacting with synaptic adhesion proteins, such as neurexin and neuroligin. Here, we identified the neuron-specific vesicular protein calcyon as a novel interaction partner of hevin and demonstrated that this interaction played a pivotal role in synaptic reorganization after an injury in the mature brain. Astrocytic hevin was upregulated post-injury in a photothrombotic stroke model. Hevin was fragmented by MMP3 induced during the acute stage of brain injury, and this process was associated with severe gliosis. At the late stage, the functional hevin level was restored as MMP3 expression decreased. The C-terminus of hevin interacted with the N-terminus of calcyon. By using RNAi and binding competitor peptides in an ischemic brain injury model, we showed that this interaction was crucial in synaptic and functional recoveries in the sensory-motor cortex, based on histological and electrophysiological analyses. Regulated expression of hevin and calcyon and interaction between them were confirmed in a mouse model of traumatic brain injury and patients with chronic traumatic encephalopathy. Our study provides direct evidence for the causal relationship between the hevin-calcyon interaction and synaptic reorganization after brain injury. This neuron-glia interaction can be exploited to modulate synaptic reorganization under various neurological conditions.
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http://dx.doi.org/10.1038/s41418-021-00772-5DOI Listing
March 2021

Primary prophylaxis of gastric variceal bleeding: endoscopic obturation, radiologic intervention, or observation?

Hepatol Int 2021 Mar 11. Epub 2021 Mar 11.

Department of Internal Medicine, Korea University College of Medicine, Korea University Ansan Hospital, 123, Jeokgeum-ro, Danwon-gu, Ansan, Gyeonggi-do, 15355, Korea.

Background: No single effective method has yet been established for the primary prophylaxis of bleeding from gastric varices (GV).

Methods: We retrospectively analyzed liver cirrhosis patients with GV who had undergone either endoscopic variceal obturation (EVO) or balloon-occluded retrograde transvenous obliteration (BRTO) as prophylactic treatments, comparing them with those who were observed without any procedural intervention. The endpoints were GV bleeding rate and complete eradication rate.

Results: 72 patients in EVO, 41 patients in BRTO, and 97 patients in the clinical observation groups were enrolled. No difference was observed in baseline characteristics. As the primary endpoint, 14 (19.4%) patients in the EVO group and 3 (7.3%) in the BRTO group bled from GV after prophylactic treatment, and 34 (35.1%) patients bled in the observation group during the median follow-up of 35 months (p = 0.001). Patients who received EVO or BRTO developed less bleeding from GV than those who received observation only, with no difference between EVO and BRTO (EVO vs. observation, p = 0.038; BRTO vs. observation, p = 0.001; EVO vs. BRTO, p = 0.089). As secondary endpoints, GV disappeared completely in 33 patients (45.8%) in the EVO group and 31 patients (75.6%) in the BRTO group (p = 0.003). By multivariate analysis, complete eradication of GV was the sole determinant for predicting GV bleeding.

Conclusions: EVO and BRTO are effective and safe primary prophylactic treatments for preventing bleeding from GV. In particular, BRTO is better than EVO in complete eradication of GV.
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http://dx.doi.org/10.1007/s12072-021-10154-1DOI Listing
March 2021

Effects of Parents' Mealtime Conversation Techniques for Preschool Children With Hearing Loss Who Use Listening and Spoken Language.

J Speech Lang Hear Res 2021 03 23;64(3):979-992. Epub 2021 Feb 23.

Department of Human Development, Teachers College, Columbia University, New York, NY.

Purpose This mixed-methods study aimed to examine the conversation techniques used by parents of young children with hearing loss (HL) during dinnertime at home. Parents' usage rates of open- and closed-ended language elicitation, reformulation, imitation, directives, and explicit vocabulary instruction were examined in relation to children's receptive vocabulary and basic-concepts skills. Method Twenty-minute dinnertime segments were extracted from naturalistic, daylong recordings of 37 preschoolers with HL who used listening and spoken language. The segments were hand-coded for parents' use of conversation techniques. Children's receptive vocabulary and basic concepts were assessed using standardized measures. Results Parents' use of conversation techniques varied widely, with closed-ended elicitation and directives used most frequently during dinner. Explicit vocabulary instruction was correlated with general receptive vocabulary and basic-concepts skills. Thematic analysis of the conversations revealed common themes, including concrete topics and sibling speakers. In addition, parents who used many techniques often introduced abstract conversation topics; electronic media was present in all conversations with few techniques. Conclusions Parents of preschoolers with HL may benefit from specific coaching to elicit language and introduce new vocabulary during home routines. These techniques may help develop their children's receptive language.
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http://dx.doi.org/10.1044/2020_JSLHR-20-00420DOI Listing
March 2021

Serum milk fat globule-EGF factor 8 protein as a potential biomarker for metabolic syndrome.

Clin Mol Hepatol 2021 Feb 15. Epub 2021 Feb 15.

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

Background/aims: Useful biomarkers for metabolic syndrome have been insufficient. We investigated the performance of serum milk fat globule-EGF factor-8 (MFG-E8), the key mediator of inflammatory pathway, in diagnosis of metabolic syndrome.

Methods: Subjects aged between 30 and 64 years were prospectively enrolled in the Seoul Metabolic Syndrome cohort. Serum MFG-E8 levels were measured at baseline.

Results: A total of 556 subjects were included, comprising 279 women (50.2%) and 277 men (49.8%). Metabolic syndrome was diagnosed in 236 subjects (42.4%), and the mean MFG-E8 level of subjects with metabolic syndrome was significantly higher than that of subjects without metabolic syndrome (P <0.001). MFG-E8 level was significantly correlated with all metabolic syndrome components and pulse wave velocity (all P <0.05). Subjects were categorized into two groups according to the best MFG-E8 cut-off value as follows: group 1, MFG-E8 level <4,745.1 pg/mL (n=401, 72.1%); and group 2, MFG-E8 level ≥4,745.1 (n=155, 27.9%). At baseline, metabolic syndrome in group 2 was significantly more prevalent than in group 1 (63.9% vs. 34.2%, P <0.001). During median follow-up of 17 months, metabolic syndrome developed in 122 (38.1%) subjects among 320 subjects without it at baseline. The incidence of metabolic syndrome in group 2 was significantly higher than that in group 1 (55.4% vs. 34.5%, P=0.003). On multivariate analysis, MFG-E8 level ≥4745.1 pg/mL was an independent predictor for diagnosis and development of metabolic syndrome after adjusting other factors (all P <0.05).

Conclusions: Serum MFG-E8 level is a potent biomarker for the screening and prediction of metabolic syndrome.
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http://dx.doi.org/10.3350/cmh.2020.0351DOI Listing
February 2021

Betacellulin-Induced α-Cell Proliferation Is Mediated by ErbB3 and ErbB4, and May Contribute to β-Cell Regeneration.

Front Cell Dev Biol 2020 21;8:605110. Epub 2021 Jan 21.

Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.

Betacellulin (BTC), an epidermal growth factor family, is known to promote β-cell regeneration. Recently, pancreatic α-cells have been highlighted as a source of new β-cells. We investigated the effect of BTC on α-cells. Insulin+glucagon+ double stained bihormonal cell levels and pancreatic and duodenal homeobox-1 expression were increased in mice treated with recombinant adenovirus-expressing BTC (rAd-BTC) and β-cell-ablated islet cells treated with BTC. In the islets of rAd-BTC-treated mice, both BrdU+glucagon+ and BrdU+insulin+ cell levels were significantly increased, with BrdU+glucagon+ cells showing the greater increase. Treatment of αTC1-9 cells with BTC significantly increased proliferation and cyclin D2 expression. BTC induced phosphorylation of ErbB receptors in αTC1-9 cells. The proliferative effect of BTC was mediated by ErbB-3 or ErbB-4 receptor kinase. BTC increased phosphorylation of ERK1/2, AKT, and mTOR and PC1/3 expression and GLP-1 production in α-cells, but BTC-induced proliferation was not changed by the GLP-1 receptor antagonist, exendin-9. We suggest that BTC has a direct role in α-cell proliferation via interaction with ErbB-3 and ErbB-4 receptors, and these increased α-cells might be a source of new β-cells.
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http://dx.doi.org/10.3389/fcell.2020.605110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859283PMC
January 2021

ANO1 regulates the maintenance of stemness in glioblastoma stem cells by stabilizing EGFRvIII.

Oncogene 2021 Feb 15;40(8):1490-1502. Epub 2021 Jan 15.

Radiation Therapeutics Development Team, Division of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.

Glioblastoma multiforme (GBM) or glioblastoma is the most deadly malignant brain tumor in adults. GBM is difficult to treat mainly due to the presence of glioblastoma stem cells (GSCs). Epidermal growth factor receptor variant III (EGFRvIII) has been linked to stemness and malignancy of GSCs; however, the regulatory mechanism of EGFRvIII is largely unknown. Here, we demonstrated that Anoctamin-1 (ANO1), a Ca-activated Cl channel, interacts with EGFRvIII, increases its protein stability, and supports the maintenance of stemness and tumor progression in GSCs. Specifically, shRNA-mediated knockdown and pharmacological inhibition of ANO1 suppressed the self-renewal, invasion activities, and expression of EGFRvIII and related stem cell factors, including NOTCH1, nestin, and SOX2 in GSCs. Conversely, ANO1 overexpression enhanced the above phenomena. Mechanistically, ANO1 protected EGFRvIII from proteasomal degradation by directly binding to it. ANO1 knockdown significantly increased survival in mice and strongly suppressed local invasion of GSCs in an in vivo intracranial mouse model. Collectively, these results suggest that ANO1 plays a crucial role in the maintenance of stemness and invasiveness of GSCs by regulating the expression of EGFRvIII and related signaling molecules, and can be considered a promising therapeutic target for GBM treatment.
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http://dx.doi.org/10.1038/s41388-020-01612-5DOI Listing
February 2021

Comparing hemostatic resuscitation management of intraoperative massive bleeding with traumatic massive bleeding: a computer simulation.

Anesth Pain Med (Seoul) 2020 Oct 7;15(4):459-465. Epub 2020 Oct 7.

Department of Anesthesiology and Pain Medicine, Hanyang University College of Medicine, Seoul, Korea.

Background: Appropriate blood component transfusion might differ between intraoperative massive bleeding and traumatic massive bleeding in the emergency department because trauma patients initially bleed undiluted blood and replacement typically lags behind blood loss. We compared these two blood loss scenarios, intraoperative and traumatic, using a computer simulation.

Methods: We modified the multi-compartment dynamic model developed by Hirshberg and implemented it using STELLA 9.0. In this model, blood pressure changes as blood volume fluctuates as bleeding rate and transcapillary refill rate are controlled by blood pressure. Using this simulation, we compared the intraoperative bleeding scenario with the traumatic bleeding scenario. In both scenarios, patients started to bleed at a rate of 50 ml/min. In the intraoperative bleeding scenario, fluid was administered to maintain isovolemic status; however, in the traumatic bleeding scenario, no fluid was supplied for up to 30 min and no blood was supplied for up to 50 min. Each unit of packed red blood cells (PRBC) was given when the hematocrit decreased to 27%, fresh frozen plasma (FFP) was transfused when plasma was diluted to 30%, and platelet concentrate (PC) was transfused when platelet count became 50,000/ml.

Results: In both scenarios, the appropriate ratio of PRBC:FFP was 1:0.47 before PC transfusion, and the ratio of PRBC:FFP:platelets was 1:0.35:0.39 after initiation of PC transfusion.

Conclusion: The ratio of transfused blood component did not differ between the intraoperative bleeding and traumatic bleeding scenarios.
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http://dx.doi.org/10.17085/apm.20042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724118PMC
October 2020

Sirtuin 1-dependent regulation of high mobility box 1 in hypoxia-reoxygenated brain microvascular endothelial cells: roles in neuronal amyloidogenesis.

Cell Death Dis 2020 12 14;11(12):1072. Epub 2020 Dec 14.

Department of Pharmacology, College of Medicine, Inha University, Incheon, 22212, Republic of Korea.

Hypoxia-reperfusion injury is one of the major risk factors for neurodegeneration. However, it is unclear whether ischaemic damage in brain microvascular endothelial cells plays roles in neurodegeneration, particularly in the amyloidogenic changes contributing to the development of Alzheimer's disease (AD) pathologies. Therefore, we investigated the roles of hypoxia-reoxygenation (H/R)-induced release of high mobility group box protein 1 (HMGB1), a risk molecule for AD pathogenesis in the ischaemic damaged brain, from human brain microvascular endothelial cells (HBMVECs) in neuronal amyloid-beta (Aβ) production. H/R increased nuclear-cytosolic translocation and secretion of HMGB1 in HBMVECs, along with increased permeability and HMGB1-dependent p-c-Jun activation. In addition, H/R increased the expression of Sirtuin 1 (Sirt1), coincident with an increase of intracellular Sirt1-HMGB1 binding in HBMVECs. H/R increased the acetylation of HMGB1 and extracellular secretion, which was significantly inhibited by Sirt1 overexpression. Furthermore, Sirt1 contributed to autophagy-mediated endogenous HMGB1 degradation. More importantly, treatment of neuronal cells with conditioned medium from H/R-stimulated HBMVECs (H/R-CM) activated their amyloidogenic pathways. The neuronal amyloidogenic changes (i.e. increased levels of extracellular Aβ40 and Aβ42) by H/R-CM from HBMVECs were further increased by Sirt1 inhibition, which was significantly suppressed by neutralization of the HMGB1 in H/R-CM. Collectively, our results suggest that HMGB1 derived from H/R-stimulated HBMVECs contributes to amyloidogenic pathways in neurons playing roles in the pathogenesis of AD, which are regulated by endothelial Sirt1.
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http://dx.doi.org/10.1038/s41419-020-03293-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736319PMC
December 2020

Direct Bilirubin Is More Valuable than Total Bilirubin for Predicting Prognosis in Patients with Liver Cirrhosis.

Gut Liver 2020 Dec 9. Epub 2020 Dec 9.

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

Background/aims: Most prognostic prediction models for patients with liver cirrhosis include serum total bilirubin (TB) level as a component. This study investigated prognostic performance of serum direct bilirubin (DB) and developed new DB level-based prediction models for cirrhosis.

Methods: A total of 983 hospitalized patients with liver cirrhosis were included. DB-Model for End-Stage Liver Disease (MELD) score was calculated using MELD score formula, with serum DB level replacing TB level.

Results: Mean age of study population was 56.1 years. Alcoholic liver disease was the most frequent underlying condition (471 patients, 47.9%). Within 6 months, 144 patients (14.6%) died or received liver transplantation due to severe liver dysfunction. The area under the receiver operating characteristic curve (AUROC) for prediction of 6-month mortality with DB level was significantly higher than that with TB level (p<0.001). The AUROC of DB-MELD score for prediction of 6-month mortality was significantly higher than that of MELD score (p<0.001). Patients were randomly divided into training (n=492) and validation (n=491) cohorts. A new prognostic prediction model, "Direct Bilirubin, INR, and Creatinine" (DiBIC) score, was developed based on the most significant predictors of 6-month mortality. In training set, AUROC of DiBIC score for prediction of 6-month mortality was 0.892, which was significantly higher than that of the MELD score (0.875, p=0.017), but not different from that of DB-MELD score (0.886, p=0.272). Similar results were observed in validation set.

Conclusions: New prognostic models, DB-MELD and DiBIC scores, have good prognostic performance in liver cirrhosis patients, outperforming other currently available models.
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http://dx.doi.org/10.5009/gnl20171DOI Listing
December 2020

A Case of Vanishing Bile Duct Syndrome after Drug-Induced Liver Injury Caused by Pelubiprofen.

Yonsei Med J 2020 Dec;61(12):1060-1063

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

Vanishing bile duct syndrome (VBDS) is a rare disease characterized by ductopenia and cholestasis, and is linked to immunological damage to the bile duct system. VBDS can be triggered by infection, ischemia, autoimmune diseases, adverse drug reactions, and humoral factors associated with malignancy. A few cases of VBDS associated with nonsteroidal anti-inflammatory drug-related drug-induced liver injury (DILI) have been reported. Here, we report a case of a 29-year-old patient who developed DILI that progressed to VBDS after the administration of pelubiprofen.
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http://dx.doi.org/10.3349/ymj.2020.61.12.1060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700876PMC
December 2020

Ginsenoside F2 attenuates chronic-binge ethanol-induced liver injury by increasing regulatory T cells and decreasing Th17 cells.

J Ginseng Res 2020 Nov 10;44(6):815-822. Epub 2020 Apr 10.

Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

Background: Recently, beneficial roles of ginsenoside F2 (GF2), a minor constituent of , have been demonstrated in diverse inflammatory diseases. However, its roles in alcoholic liver inflammation and injury have not been clearly understood. Here, we investigated the underlying mechanism by which GF2 ameliorated alcoholic liver injury.

Methods: To induce alcoholic liver injury, C57BL/6J wild type (WT) or interleukin (IL)-10 knockout (KO) mice were orally administered with ethanol (3 g/kg) or ethanol-containing GF2 (50 mg/kg) for 2 wk. Liver injury and infiltration of macrophages and neutrophils were evaluated by serum biochemistry and immunohistochemistry, respectively. The changes of hepatic immune cells were assessed by flow cytometry and polymerase chain reaction analysis. differentiation of naïve T cells was performed.

Results: GF2 treatment significantly attenuated alcoholic liver injury, in which infiltrations of inflammatory macrophages and neutrophils were decreased. Moreover, the frequencies of Foxp3 regulatory T cells (Tregs) increased but IL-17-producing T (Th17) cells decreased in GF2-treated mice compared to controls. Furthermore, the mRNA expression of IL-10 and Foxp3 was significantly increased, whereas IL-17 mRNA expression was suppressed in GF2-treated mice. However, these beneficial roles of GF2 were not observed in GF2-treated IL-10 KO mice, suggesting a critical role of IL-10. Similarly, GF2 treatment suppressed differentiation of naïve T cells into Th17 cells by inhibiting RORγt expression and stimulating Foxp3 expression.

Conclusion: The present study suggests that GF2 treatment attenuates alcoholic liver injury by increasing IL-10 expression and Tregs and decreasing IL-17 expression and Th17 cells.
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http://dx.doi.org/10.1016/j.jgr.2020.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655498PMC
November 2020

Effect of urea cream on sorafenib-associated hand-foot skin reaction in patients with hepatocellular carcinoma: A multicenter, randomised, double-blind controlled study.

Eur J Cancer 2020 11 8;140:19-27. Epub 2020 Oct 8.

Department of Internal Medicine, Dongnam Institute of Radiological & Medical Sciences, South Korea.

Background: Hand-foot skin reaction (HFSR) is the most common adverse event during sorafenib treatment in patients with hepatocellular carcinoma (HCC). In the present study, we aimed to investigate the role of urea cream in the prevention of HFSR or amelioration of HFSR severity.

Patients And Methods: Patients with HCC were treated with either placebo cream or urea cream for 12 weeks concomitantly with sorafenib treatment. HFSR development, the Hand-Foot Skin Reaction and Quality of Life (HF-QoL) questionnaire score, and adverse events were assessed at 2, 4, 8 and 12 weeks.

Results: Of the 288 patients, 247 patients, with 117 patients in the placebo control group and 130 patients in the urea cream group, were analysed. The urea cream group showed a trend towards a lower cumulative incidence of any-grade HFSR (log-rank, P = 0.247) and severe HFSR of grade II or higher (log-rank, P = 0.394) without statistical significance. In the incidence by time point, the incidence of severe HFSR of grade II or higher was significantly lower in the urea cream group than in the placebo control group at 2 weeks (13.8% versus 23.9%, P = 0.042). The urea cream group showed a significantly better HF-QoL questionnaire score than the placebo control group (11.8 versus 19.7, P = 0.014) at 12 weeks.

Conclusions: Treatment with urea cream showed a lower incidence of severe sorafenib-induced HFSR at 2 weeks and reduced the tendency of HFSR development in HCC patients. Therefore, treatment with urea cream may be considered for prophylaxis or improvement of HFSR grade in HCC patients treated with sorafenib.

Trial Registration: ClinicalTrials.gov (NCT03212625).
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http://dx.doi.org/10.1016/j.ejca.2020.09.012DOI Listing
November 2020

Anti-glioma effects of 2-aminothiophene-3-carboxamide derivatives, ANO1 channel blockers.

Eur J Med Chem 2020 Dec 8;208:112688. Epub 2020 Aug 8.

KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea; Chemical Kinomics Research Center, Korea Institute of Science and Technology, 5 Hwarangro 14-gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. Electronic address:

Anoctamin1 (ANO1), a calcium-activated chloride ion channel (CaCC), is associated with various physiological functions including cancer progression and metastasis/invasion. ANO1 has been considered as a promising target for cancer therapeutics as ANO1 is over-expressed in a variety of cancers including glioblastoma (GBM) and inhibition of ANO1 has been reported to suppress cell proliferation, migration and invasion in GBM. GBM is one of the most common and aggressive cancers with poor prognosis with median survival for 15 months. Lack of effective treatment options against GBM emphasizes urgent necessity of effective GBM therapeutics. In an effort to discover potent and selective ANO1 inhibitors capable of inhibiting GBM cells, we have designed and synthesized a series of new 2-aminothiophene-3-carboxamide derivatives and performed SAR studies using both fluorescent cellular membrane potential assay and whole-cell patch-clamp recording. We observed that among these substances, 9c and 10q strongly suppress ANO1 channel activities and possess remarkable selectivity over ANO2. Unique structural feature of 10q, a cyclopentane-fused thiophene-3-carboxamide derivative, is the presence of benzoylthiourea functionality which dramatically contributes to activity. Both 9c and 10q suppress more strongly proliferation of GBM cells than four reference compounds including 3, Ani-9 and are also capable of inhibiting much more strongly colony formation than reference compounds in both 2D colony formation assay and 3D soft agar assay using U251 glioma cells. In addition, 9c and 10q suppress far more strongly migration/invasion of GBM cells than reference compounds. We, for the first time, found that the combination of ANO1 inhibitor (9c or 3) and temozolomide (TMZ) brings about remarkable synergistic effects in suppressing proliferation of GBM cells. Our study may provide an insight into designing selective and potent ANO1 inhibitors aiming at GBM treatment.
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http://dx.doi.org/10.1016/j.ejmech.2020.112688DOI Listing
December 2020

Change in the Recurrence Pattern and Predictors over Time after Complete Cure of Hepatocellular Carcinoma.

Gut Liver 2021 May;15(3):420-429

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

Background/aims: We investigated changes in recurrence rates and significant recurrence predictors over time after complete cure of hepatocellular carcinoma (HCC).

Methods: A total of 1,491 patients with first-time diagnosis of Barcelona Clinic Liver Cancer stage A HCC, completely cured by treatment between 2007 and 2016, were recruited from two Korean tertiary institutes.

Results: The mean age of the population (1,144 men and 347 women) was 58.6 years. Of the total population, 914 patients (61.3%) had liver cirrhosis. Nine-hundred and forty-one (63.1%) and 550 (36.9%) patients were treated with surgical resection and radiofrequency ablation (RFA), respectively. One-year cumulative incidences of HCC recurrence were 14.3%, 9.9%, and 5.1% from the time of treatment, 3 years after treatment, and 5 years after treatment, respectively. Upon multivariate analysis, multiple tumors, maximal tumor size ≥3 cm, and high Model for End-Stage Liver Disease scores were independently associated with increased HCC recurrence risk from the time of treatment and 1 and 2 years after curative treatment (all p<0.05, except for maximal tumor size ≥3 cm for recurrence 2 years after treatment). Meanwhile, liver cirrhosis and RFA were independently associated with the increased HCC recurrence risk for almost all time points (liver cirrhosis: all p<0.05; RFA: all p<0.005 except for recurrence from 5 years after treatment).

Conclusions: The recurrence rate of HCC after curative treatment gradually decreased over time. Two years after treatment, when tumor-related factors lose their prognostic implications, may be used as a cutoff to define the boundary between early and late recurrence of HCC.
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http://dx.doi.org/10.5009/gnl20101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129665PMC
May 2021

Prognosis predictability of serum and urine renal markers in patients with decompensated cirrhosis: A multicentre prospective study.

Liver Int 2020 12;40(12):3083-3092

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

Background And Aims: This prospective observational study aimed to evaluate the best serum and urine markers to assess predictability for the prognosis of patients with decompensated cirrhosis.

Methods: Serum creatinine and cystatin C (CysC), and urinary N-acetyl-beta-D glucosaminidase (uNAG) and neutrophil gelatinase-associated lipocalin (uNGAL) levels were measured from hospitalized patients with decompensated cirrhosis.

Results: In total, 328 patients (mean age, 57.2 ± 12.0 years; 237 men) with decompensated cirrhosis were included. Alcoholic liver disease was the most frequent underlying liver disease (68.0%). Acute kidney injury (AKI) was concomitantly present in 41 patients (12.5%) at baseline. INR, serum creatinine and CysC levels, and uNAG and uNGAL levels were significantly higher in patients with AKI. During hospitalization, AKI had progressed in 37 patients (11.3%). In 287 patients without AKI, the incidence of AKI at 3, 6, 9 and 12 months was 15.4%, 22.2%, 28.6% and 32.5% respectively. On multivariate analysis, serum CysC and uNAG levels were independent predictors of AKI, and their optimal cut-off values were 1.055 mg/L and 23.1 U/g urinary Cr respectively. When patients were classified into three groups with these cut-off values of serum CysC and uNAG levels (group 1, both low; group 2, one of two high; and group 3, both high), progression of AKI during hospitalization (P = .001), incidence of AKI in patients without AKI at baseline (P = .001) and mortality rate (P < .001) differed significantly according to serum CysC and uNAG levels.

Conclusion: Serum CysC and uNAG levels are useful prognostic markers for renal outcomes and mortality in patients with decompensated cirrhosis.
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http://dx.doi.org/10.1111/liv.14631DOI Listing
December 2020

Real-world systemic sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Korea.

Invest New Drugs 2021 Feb 4;39(1):260-268. Epub 2020 Aug 4.

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

Background/Aims Regorafenib has been approved as a second-line systemic therapy for hepatocellular carcinoma (HCC) patients after the phase III RESORCE trial. This study analyzed real-world data to assess the clinical effectiveness and safety of regorafenib compared to the RESORCE trial. Methods This multicenter cohort study included HCC patients treated with regorafenib after sorafenib (n = 133). We evaluated the time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety in patients receiving regorafenib along with the predictors of prognosis. Results The median age was 60 years and 81.2% patients were men. Hepatitis B virus infection (68.4%) was the commonest etiology. Most patients were classified as Child-Pugh A (98.5%) and had extrahepatic metastasis (84%) and vascular invasion (45.1%). This study demonstrated similar characteristics apart from more frequent hepatitis B etiology and more vascular or extrahepatic involvement compared with the RESORCE trial. An objective response rate of 12.5% was obtained for response assessment (n = 112); the disease control rate was 34.8%. Thirty-eight patients died during follow-up. With regorafenib, the median OS, PFS, and TTP were 10.0, 2.7, and 2.6 months, respectively. In the exploratory analysis after sorafenib administration, the median OS was 25.8 months. The rate of response and survival were comparable to those in the RESORCE trial. Child-Pugh score > 5, alpha-fetoprotein > 400 ng/ml, and TTP for sorafenib ≥ median were independently associated with OS. Conclusions This real-word regorafenib study showed comparable effectiveness and safety to the RESORCE trial. Regorafenib improves the prognosis of patients with prolonged TTP during previous sorafenib therapy.
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http://dx.doi.org/10.1007/s10637-020-00977-4DOI Listing
February 2021

BAX-dependent mitochondrial pathway mediates the crosstalk between ferroptosis and apoptosis.

Apoptosis 2020 10;25(9-10):625-631

Department of Surgery, School of Medicine, University of Pittsburgh, 5117 Centre Ave, Pittsburgh, PA, 15213, USA.

Ferroptosis is considered a distinctive form of cell death compared to other types of death such as apoptosis. It is known to result from iron-dependent accumulation of lipid peroxides rather than caspase activation. However, we reported recently that ferroptosis interplays with apoptosis. In this study, we investigated a possible mechanism of this interplay between ferroptosis and apoptosis. Results from our studies reveal that combined treatment of the ferroptotic agent erastin and the apoptotic agent TRAIL effectively disrupted mitochondrial membrane potential (ΔΨm) and subsequently promoted caspase activation. The alterations of mitochondrial membrane potential are probably due to an increase in oligomerization of BAX and its accumulation at the mitochondria during treatment with erastin and TRAIL. Interestingly, the combined treatment-promoted apoptosis was effectively inhibited in BAX-deficient HCT116 cells, but not BAK-deficient cells. These results indicate that the BAX-associated mitochondria-dependent pathway plays a pivotal role in erastin-enhanced TRAIL-induced apoptosis.
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http://dx.doi.org/10.1007/s10495-020-01627-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529973PMC
October 2020

High Circulating Sphingosine 1-Phosphate is a Risk Factor for Osteoporotic Fracture Independent of Fracture Risk Assessment Tool.

Calcif Tissue Int 2020 10 27;107(4):362-370. Epub 2020 Jul 27.

Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.

Circulating sphingosine 1-phosphate (S1P) levels may be a biomarker for osteoporotic fracture (OF). This study assessed whether the addition of S1P levels to the fracture risk assessment tool (FRAX) could improve predictability of OF risk. Plasma S1P concentrations and FRAX variables were measured in 81 subjects with and 341 subjects without OF. S1P levels were higher in subjects with than those without OF (3.11 ± 0.13 μmol/L vs. 2.65 ± 0.61 μmol/L, P = 0.001). Higher S1P levels were associated with a higher likelihood of OF (odds ratio [OR] = 1.33, 95% confidence interval [CI] = 1.05-1.68), even after adjusting for FRAX probabilities. Compared with the lowest S1P tertile, subjects in the middle (OR = 3.37, 95% CI = 1.58-7.22) and highest (OR = 3.65, 95% CI = 1.66-8.03) S1P tertiles had higher rates of OF after adjustment. The addition of S1P levels to FRAX probabilities improved the area under the receiver-operating characteristics curve (AUC) for OF, from 0.708 to 0.769 (P = 0.013), as well as enhancing category-free net reclassification improvement (NRI = 0.504, 95% CI = 0.271-0.737, P < 0.001) and integrated discrimination improvement (IDI = 0.044, 95% CI = 0.022-0.065, P < 0.001). Adding S1P levels to FRAX probabilities especially in 222 subjects with osteopenia having a FRAX probability of 3.66-20.0% markedly improved the AUC for OF from 0.630 to 0.741 (P = 0.012), as well as significantly enhancing category-free NRI (0.571, 95% CI = 0.221-0.922, P = 0.001) and IDI (0.060, 95% CI = 0.023-0.097, P = 0.002). S1P is a consistent and significant risk factor of OF independent of FRAX, especially in subjects with osteopenia and low FRAX probability.
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http://dx.doi.org/10.1007/s00223-020-00731-1DOI Listing
October 2020

Tenofovir-based combination therapy or monotherapy for multidrug-resistant chronic hepatitis B: Long-term data from a multicenter cohort study.

J Viral Hepat 2020 12 20;27(12):1306-1318. Epub 2020 Aug 20.

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

The treatment of multidrug-resistant (MDR) chronic hepatitis B (CHB) is challenging. Herein, we report a multicenter prospective cohort study for the evaluation of tenofovir disoproxil fumarate (TDF)-based therapy for MDR CHB in a real-life setting. The inclusion criteria comprised patients with resistance to more than two nucleos(t)ide analogue (NA) classes and hepatitis B virus (HBV) DNA level of ≥200 IU/mL. The primary end-point was virologic response (VR), defined as undetectable HBV DNA (<20 IU/mL) after 60 months. A total of 236 patients met the inclusion criteria. The mean HBV DNA level was 4.16 ± 1.44 log IU/mL; 26.7% of patients had liver cirrhosis. Before the initiation of TDF, 33.5%, 44.9% and 21.6% of patients had mutations resistant to L-NA + adefovir, L-NA + entecavir (ETV) and L-NA + adefovir + ETV, respectively. A total of 184 patients received TDF-based combination therapy [TDF + ETV (n = 178) or TDF + L-NA (n = 6)], and 52 patients received TDF monotherapy. In the entire cohort, the VR rates were 77.2%, 89.9% and 92.2% at 12, 36 and 60 months, respectively. The VR rates were not significantly different between the combination therapy and the monotherapy group after 12 (76.2% vs 80.4%, P = .533), 36 (89.8% vs 90.3%, P = 1.000) or 60 (92.9% vs 87.5%, P = .499) months. Also, there was no significant difference in the cumulative VR rates for 5 years between the treatment groups (P = .910). Newly developed antiviral resistance was not observed. TDF-based therapy was effective for the treatment of MDR CHB. The efficacy of TDF monotherapy was not different from that of the TDF-based combination therapy.
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http://dx.doi.org/10.1111/jvh.13363DOI Listing
December 2020

Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice.

Aging Cell 2020 08 21;19(8):e13195. Epub 2020 Jul 21.

Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Republic of Korea.

Mitochondrial dysfunction is associated with aging-mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 (GDF15) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of GDF15 to the aging process are poorly understood in mammals. In this study, we identified a link between mitochondrial stress-induced GDF15 production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of GDF15 as well as pro-inflammatory cytokines in elderly subjects. Circulating levels of cell-free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of GDF15. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression. Mendelian randomization links reduced GDF15 expression in human blood to increased body weight and inflammation. GDF15 deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20-month-old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15-deficient mice. Although GDF15 is not required for Th17 cell differentiation and IL-17 production in Th17 cells, GDF15 contributes to regulatory T-cell-mediated suppression of conventional T-cell activation and inflammatory cytokines. Taken together, these data reveal that GDF15 is indispensable for attenuating aging-mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice.
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http://dx.doi.org/10.1111/acel.13195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431835PMC
August 2020

Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer.

Cancer Cell 2020 08 16;38(2):279-296.e9. Epub 2020 Jul 16.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20185, USA. Electronic address:

Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.
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http://dx.doi.org/10.1016/j.ccell.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472556PMC
August 2020

Management of liver diseases during the pandemic of coronavirus disease-19.

Clin Mol Hepatol 2020 07 23;26(3):243-250. Epub 2020 Jun 23.

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

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http://dx.doi.org/10.3350/cmh.2020.0111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364349PMC
July 2020

Differential Impact of Serum 25-Hydroxyvitamin D3 Levels on the Prognosis of Patients with Liver Cirrhosis According to MELD and Child-Pugh Scores.

J Korean Med Sci 2020 May 18;35(19):e129. Epub 2020 May 18.

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

Background: Prognosis of patients with diverse chronic diseases is reportedly associated with 25-hydroxyvitamin D levels. In this study, we investigated the potential role of 25-hydroxyvitamin D3 (25[OH]D3) levels in improving the predictive power of conventional prognostic models for patients with liver cirrhosis.

Methods: We investigated clinical findings, including serum 25(OH)D3 levels at admission, of 155 patients with cirrhosis who were followed up for a median of 16.9 months.

Results: Median 25(OH)D3 levels were significantly different among patients exhibiting Child-Pugh grades A, B, and C. Mortality, including urgent transplantation, was significantly associated with 25(OH)D3 levels in univariate analysis. Severe vitamin-D deficiency (serum 25[OH]D3 level < 5.0 ng/mL) was significantly related to increased mortality, even after adjusting for Child-Pugh and Model for End-stage Liver Disease (MELD) scores. In particular, the presence of severe vitamin D deficiency clearly defined a subgroup with significantly poorer survival among patients with Child-Pugh scores of 5-10 or MELD scores ≤ 20. A new combination model of MELD score and severe vitamin D deficiency showed significantly more accurate predictive power for short- and long-term mortality than MELD scores alone. Additionally, serum 25(OH)D3 levels and new model scores were significantly associated with the development of spontaneous bacterial peritonitis, overt encephalopathy, and acute kidney injury.

Conclusion: Serum 25(OH)D3 level is an independent prognostic factor for patients with liver cirrhosis and has a differential impact on disease outcomes according to MELD and Child-Pugh scores.
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http://dx.doi.org/10.3346/jkms.2020.35.e129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234861PMC
May 2020

Suppression of CaMKIIβ Inhibits ANO1-Mediated Glioblastoma Progression.

Cells 2020 04 26;9(5). Epub 2020 Apr 26.

School of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul 02841, Korea.

ANO1, a Ca-activated chloride channel, is highly expressed in glioblastoma cells and its surface expression is involved in their migration and invasion. However, the regulation of ANO1 surface expression in glioblastoma cells is largely unknown. In this study, we found that Ca/Calmodulin-dependent protein kinase II (CaMKII) β specifically enhances the surface expression and channel activity of ANO1 in U251 glioblastoma cells. When KN-93, a CaMKII inhibitor, was used to treat U251 cells, the surface expression and channel activity of ANO1 were significantly reduced. Only CaMKIIβ, among the four CaMKII isoforms, increased the surface expression and channel activity of ANO1 in a heterologous expression system. Additionally, gene silencing of CaMKIIβ suppressed the surface expression and channel activity of ANO1 in U251 cells. Moreover, gene silencing of CaMKIIβ or ANO1 prominently reduced the migration and invasion of U251 and U87 MG glioblastoma cells. We thus conclude that CaMKIIβ plays a specific role in the surface expression of ANO1 and in the ANO1-mediated tumorigenic properties of glioblastoma cells, such as migration and invasion.
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http://dx.doi.org/10.3390/cells9051079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290681PMC
April 2020

Phthalates and non-phthalate plasticizers in sediment from Korean coastal waters: Occurrence, spatial distribution, and ecological risks.

Mar Pollut Bull 2020 May 2;154:111119. Epub 2020 Apr 2.

Department of Marine Science and Convergence Engineering, College of Science and Convergence Technology, Hanyang University, Ansan 15588, Republic of Korea. Electronic address:

Due to regulations on phthalates, non-phthalate plasticizers (NPPs) are now used as an alternative. Limited studies have been conducted on the occurrence and distribution of NPPs. In this study, sediment samples were collected from 50 locations along the Korean coast to assess the occurrence, distribution, sources, and ecological risks of phthalates and NPPs. Phthalates and NPPs were detected in all sediments, indicating ubiquitous contamination of the coastal environment. Di(2-ethylhexyl)phthalate (DEHP) and di(2-ethylhexyl)terephthalate (DEHT) were dominant, suggesting that DEHT could be an emerging contaminant of concern. The highest concentrations of phthalates and NPPs were found in sediment samples from harbors, implying they are contaminated hotspots. Sedimentary organic carbon was a major factor governing the distribution of phthalates and NPPs. Significant correlations were observed among phthalates and NPPs, suggesting similar sources and geochemical behavior. DEHP concentration exceeded threshold values, indicating potential health risks to benthic organisms in sediments.
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http://dx.doi.org/10.1016/j.marpolbul.2020.111119DOI Listing
May 2020