Publications by authors named "Do Young Kim"

691 Publications

Apremilast for oral ulcers associated with active Behçet's syndrome over 68 weeks: long-term results from a phase 3 randomised clinical trial.

Clin Exp Rheumatol 2021 Sep-Oct;39 Suppl 132(5):80-87. Epub 2021 Oct 6.

Division of Rheumatology, New York University School of Medicine, NY, USA.

Objectives: This study assessed the efficacy and safety of apremilast for the oral ulcers associated with Behçet's syndrome (BS) up to 64 weeks.

Methods: The phase 3, double-blind, placebo-controlled RELIEF study randomised adult patients with active BS to placebo or apremilast 30 mg twice daily for 12 weeks, followed by an extension phase with all patients receiving apremilast through Week 64 and 4-week post-treatment follow-up (upon treatment discontinuation). The primary endpoint was area under the curve for the number of oral ulcers over 12 weeks (AUCWk0-12), reflecting the number of oral ulcers over time and accounting for their recurring-remitting course. Oral ulcer number, complete and partial responses, pain and disease activity and quality of life (QoL) were also assessed throughout the study.

Results: A total of 207 participants were randomised and received at least one dose of study medication; 178 entered the extension phase and 143 completed Week 64. AUCWk0-12 was significantly lower with apremilast versus placebo (p<0.0001), and oral ulcers number, pain, complete/partial responses, disease activity and QoL with apremilast versus placebo showed improvements at Week 12, which were maintained through Week 64. The most common adverse events were diarrhoea, nausea, headache and upper respiratory tract infection; no new safety concerns were observed with longer-term apremilast exposure.

Conclusions: In patients with oral ulcers associated with BS, apremilast was efficacious and benefits were sustained up to 64 weeks with continued treatment. Apremilast was well tolerated, and safety was consistent with its known safety profile.
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October 2021

Association of atrial fibrillation and various cancer subtypes.

J Arrhythm 2021 Oct 17;37(5):1205-1214. Epub 2021 Jul 17.

Department of Cardiology St. Mary Medical Center Langhorne PA USA.

Background: Studies have shown that the incidence of atrial fibrillation (AF) in cancer is most likely due to the presence of inflammatory markers. The purpose of our study is to determine the association of AF with different cancer subtypes and its impact on in-hospital outcomes.

Methods: Data were obtained from the National Inpatient Sample database between 2005 and 2015. Patients with various cancers and AF were studied. ICD-9-CM codes were utilized to verify variables. Patients were divided into three age groups: Group 1 (age < 65 years), Group 2 (age 65-80 years), and Group 3 (age > 80 years). Statistical analysis was performed using Pearson chi-square and binary logistic regression analysis to determine the association of individual cancers with AF.

Results: The prevalence of AF was 14.6% among total study patients (n = 46 030 380). After adjusting for confounding variables through multivariate regression analysis, AF showed significant association in Group 1 with lung cancer (odds ratio, OR = 1.92), multiple myeloma (OR = 1.59), non-Hodgkin lymphoma (OR = 1.55), respiratory cancer (OR = 1.55), prostate cancer (OR = 1.20), leukemia (OR = 1.12), and Hodgkin's lymphoma (OR = 1.03). In Group 2, the association of AF with multiple myeloma (1.21), lung cancer (OR = 1.15), Hodgkin lymphoma (OR = 1.15), non-Hodgkin lymphoma (OR = 1.12), respiratory cancer (OR = 1.08), prostate cancer (OR = 1.06), leukemia (OR = 1.14), and colon cancer (OR = 1.01) were significant. In Group 3, AF showed significant association with non-Hodgkin lymphoma (OR = 1.06), prostate (OR = 1.03), leukemia (OR = 1.03), Hodgkin's lymphoma (OR = 1.02), multiple myeloma (OR = 1.01), colon cancer (OR = 1.01), and breast cancer (OR = 1.01). The highest mortality was found in lung cancer in age <80 and prostate cancer in age >80.

Conclusion: In patients age <80 years, AF has significant association with lung cancer and multiple myeloma, whereas in patients age >80 years, it has significant association with non-Hodgkin lymphoma and prostate cancer. In patients age <80 years, increased mortality was seen in AF with lung cancer and in patients age >80 years, increased mortality was seen in those with AF and prostate cancer.

Twitter Abstract: In age <80, lung cancer and multiple myeloma have a strong association with AF while thyroid and pancreatic cancers have no association with AF at any age. In age greater than 80, NHL and prostate cancer have a significant association with AF.
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http://dx.doi.org/10.1002/joa3.12589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485786PMC
October 2021

Korean Red Ginseng Ameliorates Fatigue via Modulation of 5-HT and Corticosterone in a Sleep-Deprived Mouse Model.

Nutrients 2021 Sep 6;13(9). Epub 2021 Sep 6.

Institute of Bioscience & Integrative Medicine, Daejeon Oriental Hospital of Daejeon University, 75, Daedeok-daero 176, Seo-gu, Daejeon 35235, Korea.

Central fatigue, which is neuromuscular dysfunction associated with neurochemical alterations, is an important clinical issue related to pathologic fatigue. This study aimed to investigate the anti-central fatigue effect of Korean red ginseng (KRG) and its underlying mechanism. Male BALB/c mice (8 weeks old) were subjected to periodic sleep deprivation (SD) for 6 cycles (forced wakefulness for 2 days + 1 normal day per cycle). Simultaneously, the mice were administered KRG (0, 100, 200, or 400 mg/kg) or ascorbic acid (100 mg/kg). After all cycles, the rotarod and grip strength tests were performed, and then the changes regarding stress- and neurotransmitter-related parameters in serum and brain tissue were evaluated. Six cycles of SD notably deteriorated exercise performance in both the rotarod and grip strength tests, while KRG administration significantly ameliorated these alterations. KRG also significantly attenuated the SD-induced depletion of serum corticosterone. The levels of main neurotransmitters related to the sleep/wake cycle were markedly altered (serotonin was overproduced while dopamine levels were decreased) by SD, and KRG significantly attenuated these alterations through relevant molecules including brain-derived neurotropic factor and serotonin transporter. This study demonstrated the anti-fatigue effects of KRG in an SD mouse model, indicating the clinical relevance of KRG.
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http://dx.doi.org/10.3390/nu13093121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469198PMC
September 2021

Liver Stiffness-Based Risk Prediction Model for Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease.

Cancers (Basel) 2021 Sep 11;13(18). Epub 2021 Sep 11.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.

Non-alcoholic fatty liver disease (NAFLD) is associated with an increased hepatocellular carcinoma (HCC) risk. We established and validated a liver stiffness (LS)-based risk prediction model for HCC development in patients with NAFLD. A total of 2666 and 467 patients with NAFLD were recruited in the training and validation cohorts, respectively. NAFLD was defined as controlled attenuated parameter ≥238 dB/m by transient elastography. Over a median of 64.6 months, HCC developed in 22 (0.8%) subjects in the training cohort. Subjects who developed HCC were older and had higher prevalence of diabetes and cirrhosis, lower platelet count, and higher AST levels compared to those who did not develop HCC (all < 0.05). In multivariate analysis, age ≥60 years (hazard ratio (HR) = 9.1), platelet count <150 × 10/μL (HR = 3.7), and LS ≥9.3 kPa (HR = 13.8) were independent predictors (all < 0.05) that were used to develop a risk prediction model for HCC development, together with AST ≥34 IU/L. AUCs for predicting HCC development at 2, 3, and 5 years were 0.948, 0.947, and 0.939, respectively. This model was validated in the validation cohort (AUC 0.777, 0.781, and 0.784 at 2, 3, and 5 years, respectively). The new risk prediction model for NAFLD-related HCC development showed acceptable performance in the training and validation cohorts.
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http://dx.doi.org/10.3390/cancers13184567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472221PMC
September 2021

Cross-protective efficacy of inactivated whole influenza vaccines against Korean Y280 and Y439 lineage H9N2 viruses in mice.

Vaccine 2021 Oct 21;39(42):6213-6220. Epub 2021 Sep 21.

Animal and Plant Quarantine Agency, Gimcheon, Republic of Korea. Electronic address:

Since June 2020, the Y280 lineage H9N2 virus, which is distinct from the previously endemic Y439 lineage, has been circulating in poultry in Korea. In this study, we developed two whole inactivated vaccines, rgHS314 and vac564, against the Y280 and Y439 lineages, respectively, and evaluated their immunogenicity and protective efficacy against homologous or heterologous viral challenge in mice. Serum neutralizing antibody titers in the rgHS314-vaccinated group were higher (68 ± 8.4 10log) than in the vac564-vaccinated group (18 ± 8.4 10log). In homologous challenge, rgHS314 conferred 100% protection, with no severe clinical signs, no body weight loss, and no viral replication in any tissues tested except the nasal turbinate. Viral replication in the lungs at 1, 3, 5, and 7 days post-infection (dpi) was significantly lower than in the sham group (p < 0.01). By contrast, all mice in the sham group were dead by 8 dpi with severe clinical signs and weight loss. Likewise, vac564 conferred 100% protection with no weight loss and with significantly lower viral replication in the lung than in the sham group at 3 dpi (p < 0.01). However, both vaccines showed partial protection in heterologous challenge. Our results suggest that both the rgHS314 and vac564 vaccines could be candidate vaccines for further evaluation in humans.
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http://dx.doi.org/10.1016/j.vaccine.2021.09.028DOI Listing
October 2021

History and future of hepatitis B virus control in South Korea.

Authors:
Do Young Kim

Clin Mol Hepatol 2021 Oct 23;27(4):620-622. Epub 2021 Sep 23.

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

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http://dx.doi.org/10.3350/cmh.2021.0277DOI Listing
October 2021

Development of a recombinant H9N2 influenza vaccine candidate against the Y280 lineage field virus and its protective efficacy.

Vaccine 2021 Oct 14;39(42):6201-6205. Epub 2021 Sep 14.

Animal and Plant Quarantine Agency, 177 Hyeoksin 8-ro, Gimcheon-si, Gyeongsangbuk-do 39660, Republic of Korea. Electronic address:

Since June 2020, a new H9N2 virus of the Y280 lineage has been epidemic in Korea. Initially, a Korean commercial vaccine against the Y280 and Y439 lineages of H9N2 was evaluated for use in SPF chickens. A single vaccination did not protect chickens against virus of the Y280 lineage, with no significant reduction in virus shedding and a 37.5% inhibition in virus recovery rate in cecal tonsil. rgHS314 was selected as a vaccine candidate, showing immunogenicity in SPF chickens, and was highly productive in eggs. Moreover, rgHS314 protected with high levels of protective immunity and significantly reduced virus shedding, with 100% and 83.3% inhibition of virus recovery in the cecal tonsil against homologous and heterologous challenge viruses, respectively. Taken together, these data suggest that a single vaccination with this recombinant vaccine candidate could elicit cross-reactive immune responses capable of protecting chickens against H9N2 viruses of the Y439 and Y280 lineages.
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http://dx.doi.org/10.1016/j.vaccine.2021.08.089DOI Listing
October 2021

Distinctive Roles of Two Acinetobactin Isomers in Challenging Host Nutritional Immunity.

mBio 2021 Sep 14:e0224821. Epub 2021 Sep 14.

Department of Chemistry, Korea University, Seoul, Republic of Korea.

The human pathogen Acinetobacter baumannii produces and utilizes acinetobactin for iron assimilation. Although two isomeric structures of acinetobactin, one featuring an oxazoline (Oxa) and the other with an isoxazolidinone (Isox) at the core, have been identified, their differential roles as virulence factors for successful infection have yet to be established. This study provides direct evidence that Oxa supplies iron more efficiently than Isox, primarily owing to its specific recognition by the cognate outer membrane receptor, BauA. The other components in the acinetobactin uptake machinery appear not to discriminate these isomers. Interestingly, Oxa was found to form a stable iron complex that is resistant to release of the chelated iron upon competition by Isox, despite their comparable apparent affinities to Fe(III). In addition, both Oxa and Isox were found to be competent iron chelators successfully scavenging iron from host metal sequestering proteins responsible for nutritional immunity. These observations collectively led us to propose a new model for acinetobactin-based iron assimilation at infection sites. Namely, Oxa is the principal siderophore mediating the core Fe(III) supply chain for A. baumannii, whereas Isox plays a minor role in the iron delivery and, alternatively, functions as an auxiliary iron collector that channels the iron pool toward Oxa. The unique siderophore utilization mechanism proposed here represents an intriguing strategy for pathogen adaptation under the various nutritional stresses encountered at infection sites. Acinetobacter baumannii has acquired antibiotic resistance at an alarming rate, and it is becoming a serious threat to society, particularly due to the paucity of effective treatment options. Acinetobactin is a siderophore of Acinetobacter baumannii, responsible for active iron supply, and it serves as a key virulence factor to counter host nutritional immunity during infection. While two acinetobactin isomers were identified, their distinctive roles for successful infection of Acinetobacter baumannii remained unsettled. This study clearly identified the isomer containing an oxazoline core as the principal siderophore based on comparative analysis of the specificity of the acinetobactin uptake machinery, the stability of the corresponding iron complexes, and the iron scavenging activity against the host iron sequestering proteins. Our findings are anticipated to stimulate efforts to discover a potent antivirulence agent against Acinetobacter baumannii that exploits the acinetobactin-based iron assimilation mechanism.
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http://dx.doi.org/10.1128/mBio.02248-21DOI Listing
September 2021

Episodic Detectable Viremia Does Not Affect Prognosis in Untreated Compensated Cirrhosis With Serum Hepatitis B Virus DNA <2,000 IU/mL.

Am J Gastroenterol 2021 Sep 10. Epub 2021 Sep 10.

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

Introduction: The necessity of antiviral therapy (AVT) for hepatitis B virus (HBV)-infected compensated cirrhosis with low-level viremia (LLV) is controversial. Herein, we evaluated its natural history.

Methods: From 3 tertiary hospitals, we enrolled untreated patients with compensated cirrhosis with persistent serum HBV-DNA levels <2,000 IU/mL; LLV was defined as having at least 1 detectable serum HBV-DNA (20-2,000 IU/mL) episode, whereas maintained virological response (MVR) was defined as having persistently undetectable serum HBV-DNA (<20 IU/mL). When serum HBV-DNA was ≥2,000 IU/mL during follow-up, AVT was administered according to guidelines. Study end points were development of cirrhotic complication event (CCE) or hepatocellular carcinoma (HCC).

Results: Among 567 patients analyzed, cumulative HCC risk at 3, 5, and 7 years was comparable between LLV (n = 391) vs MVR (n = 176) groups (5.7%, 10.7%, and 17.3% vs 7.2%, 15.5%, and 19.4%, respectively [P = 0.390]). CCE risk was also comparable between 2 groups (7.5%, 12.8%, and 13.7% vs 7.8%, 12.3%, and 14.6%, respectively [P = 0.880]). By multivariate analysis, LLV (vs MVR) was not associated with HCC or CCE risks, with adjusted hazard ratios of 1.422 (95% confidence interval [CI] 0.694-2.913; P = 0.336) and 1.816 (95% CI: 0.843-3.911; P = 0.128), respectively. Inverse probability of treatment weighting analysis yielded comparable outcomes between 2 groups, regarding HCC and CCE risks with hazard ratios of 0.903 (95% CI: 0.528-1.546; P = 0.711) and 1.192 (95% CI: 0.675-2.105; P = 0.545), respectively.

Discussion: Episodic LLV among untreated patients with compensated cirrhosis does not increase the risk of disease progression compared with MVR status. Thus, the benefits of AVT for episodic LLV should be re-evaluated.
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http://dx.doi.org/10.14309/ajg.0000000000001497DOI Listing
September 2021

Lung and lymph node metastases from hepatocellular carcinoma: Comparison of pathological aspects.

Liver Int 2021 Sep 7. Epub 2021 Sep 7.

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

Background & Aims: Extrahepatic metastasis from hepatocellular carcinoma (HCC) is a catastrophic event, yet organ-specific pathological characteristics of metastatic HCC remain unclear. We aimed to characterize the pathological aspects of HCC metastases to various organs.

Methods: We collected intrahepatic HCC (cohort 1, n = 322) and extrahepatic metastatic HCC (cohort 2, n = 130) samples. Clinicopathological evaluation and immunostaining for K19, CD34, αSMA, fibroblast-associated protein (FAP), CAIX, VEGF, PD-L1, CD3, CD8, Foxp3, CD163 and epithelial-mesenchymal transition (EMT)-related markers were performed.

Results: Independent factors for extrahepatic metastasis included BCLC stage B-C, microvascular invasion (MVI), vessels encapsulating tumour clusters (VETC)-HCC, K19 and FAP expression, and CD163+ macrophage infiltration (cohort 1, P < .05 for all). Lung metastases (n = 63) had the highest proportion of VETC-HCC and macrotrabecular-massive (MTM)-HCC. Lymph node metastases (n = 19) showed significantly high rates of EMT-high features, K19 expression, fibrous tumour stroma with αSMA and FAP expression, high immune cell infiltration, PD-L1 expression (combined positive score), CD3+, CD8+, Foxp3+ T cell and CD163+ macrophage infiltration (adjusted P < .05 for all). In both cohorts, EMT-high HCCs showed higher rates of K19 expression, fibrous tumour stroma, high immune cell infiltration, PD-L1 expression and CD3+ T cell infiltration, whereas EMT-low HCCs were more frequent among VETC-HCCs (P < .05 for all). Overall phenotypic features were not significantly different between paired primary-metastatic HCCs (n = 32).

Conclusions: Metastatic HCCs to various organs showed different pathological features. VETC and MTM subtypes were related to lung metastasis, whereas K19 expression, EMT-high features with fibrous tumour stroma and high immune cell infiltration were related to lymph node metastasis.
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http://dx.doi.org/10.1111/liv.15051DOI Listing
September 2021

Long-term effects of entecavir and tenofovir treatment on the fibrotic burden in patients with chronic hepatitis B.

J Gastroenterol Hepatol 2021 Sep 3. Epub 2021 Sep 3.

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

Background And Aim: Antiviral therapy (AVT) induces fibrosis regression in patients with chronic hepatitis B. We investigated long-term effects of entecavir (ETV) versus tenofovir (TDF) on fibrotic burden.

Methods: Treatment-naïve chronic hepatitis B patients who had begun ETV or TDF were recruited from four tertiary hospitals. The aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4) were used to determine fibrotic burden.

Results: In the entire population (n = 3277), although patients treated with ETV had higher baseline APRI (1.71 vs 1.07, P < 0.001) and FIB-4 (3.60 vs 2.80, P < 0.001) than those treated with TDF, significant fibrosis regression was identified during 6 years of AVT in both ETV (APRI, mean 1.71 → 0.48, P < 0.001; FIB-4, mean 3.60 → 2.21, P < 0.001) and TDF groups (APRI, mean 1.07 → 0.43, P < 0.001; FIB-4, mean 2.80 → 2.19, P < 0.001). In patients without cirrhosis (n = 2366), baseline APRI was significantly higher in ETV group than in TDF group (1.72 vs 0.97, P < 0.001); however, they became similar after 6 months. Similarly, baseline FIB-4 was significantly higher in ETV group than in TDF group (3.25 vs 2.35, P < 0.001), but became similar from 4 to 6 years. In patients with cirrhosis (n = 911), baseline APRI (1.70 vs 1.34, P < 0.001) and FIB-4 (4.62 vs 3.91, P = 0.005) were higher in ETV group than in TDF, however, both parameters became statistically similar from 6 months to 6 years.

Conclusion: Significant regression of APRI and FIB-4 was observed during long-term ETV and TDF treatment. Despite higher baseline fibrotic burden in ETV group, fibrotic burden between the groups eventually converged through significant fibrosis regression after 1 to 4 years of AVT.
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http://dx.doi.org/10.1111/jgh.15678DOI Listing
September 2021

Prevalence and Risk Factors of Cardiovascular Disease in Patients with Chronic Hepatitis B.

Dig Dis Sci 2021 Sep 2. Epub 2021 Sep 2.

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

Background: The association between chronic hepatitis B (CHB) and cardiovascular disease (CVD) remains unclear. We investigated the prevalence and risk factors of CVD in patients with CHB.

Methods: Data from the Korean National Health and Nutrition Examination Surveys 2008-2011 were analyzed. Significant liver fibrosis was defined as the highest nonalcoholic fatty liver disease fibrosis score quartile, highest Forns index quintile, or fibrosis-4 ≥ 2.67. The CVD risk was calculated using the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score from the 2013 ACC/AHA Guidelines.

Results: Among the 506 subjects with CHB, 15 (3.0%) and 150 (29.6%) patients had a CVD history and significant liver fibrosis, respectively. Patients with CVD history were significantly older; showed a significantly higher prevalence of hypertension, metabolic syndrome, and significant liver fibrosis; and had a significantly higher platelet count, lower aspartate and alanine aminotransferase levels, higher triglyceride level, lower high-density lipoprotein level, and higher ASCVD risk than those without (all p < 0.05). In multivariate analysis, higher ASCVD risk (odds ratio [OR] = 1.090) and significant liver fibrosis (OR = 4.341) independently predicted the risk of CVD history (p < 0.05). The prevalence of CVD risk (6.7% vs. 1.4%; OR = 5.014) and high ASCVD risk (> 15%) (34.0% vs. 7.3%; OR = 6.538) was significantly higher in patients with significant liver fibrosis than in those without (all p < 0.05).

Conclusions: Significant liver fibrosis was independently associated with the risk of CVD history in patients with CHB. Prospective studies are needed to validate the longitudinal association between fibrotic burden and CVD development in patients with CHB.
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http://dx.doi.org/10.1007/s10620-021-07157-1DOI Listing
September 2021

Impairment of ULK1 sulfhydration-mediated lipophagy by SREBF1/SREBP-1c in hepatic steatosis.

Autophagy 2021 Aug 30:1-2. Epub 2021 Aug 30.

Department of Animal Science, Chonnam National University, Gwangju, Republic of Korea.

Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the global population. However, its pathogenesis is not completely understood. In our recent study, we have demonstrated that in a high-fat diet-induced liver steatosis model, the activation of SREBF1/SREBP-1c (sterol regulatory element binding transcription factor 1) directly upregulates transcription, which inhibits CTH/CSE (cystathionase (cystathionine gamma-lyase)) expression and its function in hydrogen sulfide (HS) production. Reduced HS production suppresses the sulfhydration of ULK1 (unc-51 like autophagy activating kinase 1), consequently inhibiting autophagic flux and lipid droplet turnover. A single substitution mutation (C951S) in ULK1 or the silencing of CTH impairs ULK1 sulfhydration-mediated lipophagy, thereby promoting hepatic steatosis in mice. Interestingly, the sulfhydration of ULK1 increases its intrinsic kinase activity to modulate autophagy at both initiation and progression stages of autophagic catabolic flux. This study reveals that SREBF1/SREBP-1c contributes to hepatic lipid accumulation through its combined effect of increased lipid synthesis coupled with decreased lipid degradation mediated by autophagic dysregulation.
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http://dx.doi.org/10.1080/15548627.2021.1968608DOI Listing
August 2021

Core Gene Signatures of Atopic Dermatitis Using Public RNA-Sequencing Resources: Comparison of Bulk Approach with Single-Cell Approach.

J Invest Dermatol 2021 Aug 27. Epub 2021 Aug 27.

Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea; Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2021.07.169DOI Listing
August 2021

Novel Anti-Fungal d-Laminaripentaose-Releasing Endo-β-1,3-glucanase with a RICIN-like Domain from HY-13.

Biomolecules 2021 07 22;11(8). Epub 2021 Jul 22.

Department of Biotechnology, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Korea.

Endo-β-1,3-glucanase plays an essential role in the deconstruction of β-1,3-d-glucan polysaccharides through hydrolysis. The gene (1650-bp) encoding a novel, bi-modular glycoside hydrolase family 64 (GH64) endo-β-1,3-glucanase (GluY) with a ricin-type β-trefoil lectin domain (RICIN)-like domain from HY-13 was identified and biocatalytically characterized. The recombinant enzyme (rGluY: 57.5 kDa) displayed the highest degradation activity for laminarin at pH 4.5 and 40 °C, while the polysaccharide was maximally decomposed by its C-terminal truncated mutant enzyme (rGluYΔRICIN: 42.0 kDa) at pH 5.5 and 45 °C. The specific activity (26.0 U/mg) of rGluY for laminarin was 2.6-fold higher than that (9.8 U/mg) of rGluYΔRICIN for the same polysaccharide. Moreover, deleting the C-terminal RICIN domain in the intact enzyme caused a significant decrease (>60%) of its ability to degrade β-1,3-d-glucans such as pachyman and curdlan. Biocatalytic degradation of β-1,3-d-glucans by inverting rGluY yielded predominantly d-laminaripentaose. rGluY exhibited stronger growth inhibition against in a dose-dependent manner than rGluYΔRICIN. The degree of growth inhibition of by rGluY (approximately 1.8 μM) was approximately 80% of the fungal growth. The superior anti-fungal activity of rGluY suggests that it can potentially be exploited as a supplementary agent in the food and pharmaceutical industries.
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http://dx.doi.org/10.3390/biom11081080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394091PMC
July 2021

Effect of tenofovir alafenamide vs. tenofovir disoproxil fumarate on hepatocellular carcinoma risk in chronic hepatitis B.

J Viral Hepat 2021 Nov 4;28(11):1570-1578. Epub 2021 Sep 4.

Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.

It is unclear whether tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) is more effective for preventing hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB). In this study, we compared the effectiveness of these two antiviral agents for preventing HCC. We included treatment-naïve CHB patients undergoing antiviral therapy with TDF only (TDF group) or a TAF-based regimen (TAF group) at three academic teaching hospitals from 2012 to 2019. The TAF group included patients receiving TAF as first-line treatment and patients switching from TDF to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded. Cumulative probabilities of HCC were assessed using Kaplan-Meier methodology. In total, 2,117 patients were included: 1,832 in the TDF group and 285 in the TAF group. The annual HCC incidence was not significantly different between TDF and TAF groups: 1.66 vs. 1.19 per 100 person-years [PY], respectively (multivariate analysis: adjusted hazard ratio [HR] 0.774 [reference: TDF group]; p = .438). Male, liver cirrhosis, hepatitis B e antigen negativity, Fibrosis-4 index>3.25 and low albumin were independently associated with a higher risk of HCC. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results: 1.56 vs. 1.19 per 100 PY, respectively (HR 1.175; p = .708) and 1.66 vs. 1.29 per 100 PY, respectively (HR 0.888; p = .446). The risk of HCC development was not significantly different between TDF and TAF groups of CHB patients. Further studies with a larger sample size and longer follow-up are required to validate our results.
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http://dx.doi.org/10.1111/jvh.13601DOI Listing
November 2021

Impact of tenofovir alafenamide vs. entecavir on hepatocellular carcinoma risk in patients with chronic hepatitis B.

Hepatol Int 2021 Oct 16;15(5):1083-1092. Epub 2021 Aug 16.

Department of Internal Medicine, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu, 41944, Republic of Korea.

Background And Aims: Whether entecavir (ETV) or tenofovir alafenamide (TAF) is better at preventing hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B (CHB) remains unclear. The present study was conducted to explore the ability of these two antivirals to prevent HCC.

Methods: From 2012 to 2019, treatment-naïve CHB patients undergoing ETV or TAF therapy were recruited at three academic teaching hospitals. The TAF group comprised patients starting TAF as first-line antiviral and those switching antivirals from tenofovir disoproxil fumarate to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded from the analysis. Cumulative probabilities of HCC were assessed using the Kaplan-Meier method.

Results: In total, 1810 patients (1525 and 285 in ETV and TAF groups, respectively) were recruited. The annual HCC incidence was statistically not different between the ETV and TAF groups (1.67 vs. 1.19 per 100 person-years, respectively) with an adjusted hazard ratio (HR) of 0.681 (p = 0.255), as determined by multivariate analysis. Male, hypertension, liver cirrhosis, FIB-4 index, and albumin were independent prognostic factors for HCC development. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results, with non-statistically different HCC incidence between the ETV and TAF groups (1.07 vs. 1.19 per 100 person-years (HR = 0.973; p = 0.953) and 1.67 vs. 1.89 per 100 person-years, respectively (HR = 0.949; p = 0.743).

Conclusions: These findings suggest that ETV- and TAF-treated CHB patients have similar risk of developing HCC. Further studies with the larger sample size and longer follow-up are needed to validate these results.
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http://dx.doi.org/10.1007/s12072-021-10234-2DOI Listing
October 2021

No influence of hepatic steatosis on the 3-year outcomes of patients with quiescent chronic hepatitis B.

J Viral Hepat 2021 Nov 16;28(11):1545-1553. Epub 2021 Aug 16.

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

The influence of hepatic steatosis on the natural history of chronic hepatitis B (CHB) virus is unclear. Therefore, we investigated whether concurrent steatosis in patients with CHB influences the probability of hepatitis B surface antigen (HBsAg) loss, fibrosis progression and hepatocellular carcinoma (HCC) development. This study enrolled treatment-naïve patients with virologically (HBV DNA <2,000 IU/ml) and biochemically (alanine aminotransferase level <40 IU/L) quiescent CHB who underwent transient elastography between January 2004 and December 2015 and completed 3 years of follow-up. RESULTS: The mean age of the study population (n = 720) was 52.0 years, and there were more men than women (n = 419, 58.2%). The mean HBV DNA level was 321.6 IU/ml. During the 3-year period, 74 (10.3%) patients achieved HBsAg seroclearance. Lower HBV DNA levels (hazard ratio = 0.995, p < .05) were independently associated with HBsAg seroclearance, while hepatic steatosis was not (p > .05). Fibrosis progressed in 89 (12.4%) patients. Male gender (odds ratio [OR] = 1.720) and higher body mass index (OR = 1.083) were independently associated with an increased probability of fibrosis progression (all p < .05), while higher total cholesterol levels (OR = 0.991) and higher liver stiffness values (OR = 0.862) were independently associated with a decreased probability of fibrosis progression (all p < .05). HCC developed in 46 (6.4%) patients. Male gender (OR = 3.917) and higher AST levels (OR = 1.036) were independently associated with an increased probability of HCC development (p < .05). Hepatic steatosis was not associated with the probability of HBsAg seroclearance, fibrosis progression or HCC development in patients quiescent CHB in our study. Further studies with longer follow-up periods are required to validate our findings.
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http://dx.doi.org/10.1111/jvh.13594DOI Listing
November 2021

Non-thermal atmospheric pressure plasma activates Wnt/β-catenin signaling in dermal papilla cells.

Sci Rep 2021 08 9;11(1):16125. Epub 2021 Aug 9.

Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea.

There is an unmet need for novel, non-pharmacological therapeutics to treat alopecia. Recent studies have shown the potential biological benefits of non-thermal atmospheric pressure plasma (NTAPP), including wound healing, angiogenesis, and the proliferation of stem cells. We hypothesized that NTAPP might have a stimulatory effect on hair growth or regeneration. We designed an NTAPP-generating apparatus which is applicable to in vitro and in vivo experiments. The human dermal papilla (DP) cells, isolated fresh hair follicles, and mouse back skin were exposed with the NTAPP. Biological outcomes were measured using RNA-sequencing, RT-PCR, Western blots, and immunostaining. The NTAPP treatment increased the expression levels of Wnt/β-catenin pathway-related genes (AMER3, CCND1, LEF1, and LRG1) and proteins (β-catenin, p-GSK3β, and cyclin D1) in human DP cells. In contrast, inhibitors of Wnt/β-catenin signaling, endo-IWR1 and IWP2, attenuated the levels of cyclin D1, p-GSK3β, and β-catenin proteins induced by NTAPP. Furthermore, we observed that NTAPP induced the activation of β-catenin in DP cells of hair follicles and the mRNA levels of target genes of the β-catenin signaling pathway (CCND1, LEF1, and TCF4). NTAPP-treated mice exhibited markedly increased anagen induction, hair growth, and the protein levels of β-catenin, p-GSK3β, p-AKT, and cyclin D1. NTAPP stimulates hair growth via activation of the Wnt/β-catenin signaling pathway in DP cells. These findings collectively suggest that NTAPP may be a potentially safe and non-pharmacological therapeutic intervention for alopecia.
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http://dx.doi.org/10.1038/s41598-021-95650-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352944PMC
August 2021

Development and Validation of a Risk Score Model for Predicting the Cardiovascular Outcomes After Breast Cancer Therapy: The CHEMO-RADIAT Score.

J Am Heart Assoc 2021 08 7;10(16):e021931. Epub 2021 Aug 7.

Division of Cardiology Dongtan Sacred Heart HospitalHallym University College of Medicine Hwaseong Republic of Korea.

Background Cardiovascular disease is an important cause of mortality among survivors of breast cancer (BC). We developed a prediction model for major adverse cardiovascular events after BC therapy, which is based on conventional and BC treatment-related cardiovascular risk factors. Methods and Results The cohort of the study consisted of 1256 Asian female patients with BC from 4 medical centers in Korea and was randomized in a 1:1 ratio into the derivation and validation cohorts. The outcome measures comprised cardiovascular mortality, myocardial infarction, congestive heart failure, and transient ischemic attack/stroke. To correct overfitting, a penalized Cox proportional hazards regression was performed with a cross-validation approach. Number of cardiovascular diseases (myocardial infarction, peripheral artery disease, heart failure, and transient ischemic attack/stroke), number of baseline cardiovascular risk factors (hypertension, age ≥60, body mass index ≥30 kg/m, estimated glomerular filtration rate <60 mL/min per 1.73 m, dyslipidemia, and diabetes mellitus), radiation to the left breast, and anthracycline dose per 100 mg/m were included in the risk prediction model. The time-dependent C-indices at 3 and 7 years after BC diagnosis were 0.876 and 0.842, respectively, in the validation cohort. Conclusions A prediction score model, including BC treatment-related risk factors and conventional risk factors, was developed and validated to predict major adverse cardiovascular events in patients with BC. The CHEMO-RADIAT (congestive heart failure, hypertension, elderly, myocardial infarction/peripheral artery occlusive disease, obesity, renal failure, abnormal lipid profile, diabetes mellitus, irradiation of the left breast, anthracycline dose, and transient ischemic attack/stroke) score may provide overall cardiovascular risk stratification in survivors of BC and can assist physicians in multidisciplinary decision-making regarding the BC treatment.
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http://dx.doi.org/10.1161/JAHA.121.021931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475066PMC
August 2021

Substance-P Inhibits Cardiac Microvascular Endothelial Dysfunction Caused by High Glucose-Induced Oxidative Stress.

Antioxidants (Basel) 2021 Jul 5;10(7). Epub 2021 Jul 5.

Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Korea.

Diabetes is characterized by high glucose (HG) levels in the blood circulation, leading to exposure of the vascular endothelium to HG conditions. Hyperglycemia causes oxidative stress via excessive reactive oxygen species (ROS) production in the endothelium, which leads to cellular dysfunction and the development of diabetic vascular diseases. Substance-P (SP) is an endogenous peptide involved in cell proliferation and migration by activating survival-related signaling pathways. In this study, we evaluated the role of SP in cardiac microvascular endothelial cells (CMECs) in HG-induced oxidative stress. CMECs were treated with diverse concentrations of glucose, and then the optimal dose was determined. Treatment of CMECs with HG reduced their viability and induced excessive ROS secretion, inactivation of PI3/Akt signaling, and loss of vasculature-forming ability in vitro. Notably, HG treatment altered the cytokine profile of CMECs. However, SP treatment inhibited the HG-mediated aggravation of CMECs by restoring viability, free radical balance, and paracrine potential. SP-treated CMECs retained the capacity to form compact and long stretching-tube structures. Collectively, our data provide evidence that SP treatment can block endothelial dysfunction in hyperglycemia and suggest the possibility of using SP for treating diabetic complications as an antioxidant.
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http://dx.doi.org/10.3390/antiox10071084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301094PMC
July 2021

Risk stratification using sarcopenia status among subjects with metabolic dysfunction-associated fatty liver disease.

J Cachexia Sarcopenia Muscle 2021 Oct 1;12(5):1168-1178. Epub 2021 Aug 1.

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

Background: Sarcopenia is a significant indicator of the severity of non-alcoholic fatty liver disease. We investigated whether sarcopenia could identify subgroups with different risk of liver fibrosis and atherosclerotic cardiovascular disease (ASCVD) among subjects with metabolic dysfunction-associated fatty liver disease (MAFLD).

Methods: Subjects from the Korea National Health and Nutrition Examination Survey 2008-2011 were selected (n = 8361). Sarcopenia was defined using the sarcopenia index. Hepatic steatosis was defined as a fatty liver index ≥30. Significant liver fibrosis was defined as a fibrosis-4 index (FIB-4) ≥2.67 or the highest quartile of non-alcoholic fatty liver disease fibrosis score (NFS). High probability of ASCVD was defined as ASCVD risk score >10%.

Results: The mean age was 48.5 ± 15.6 years, and 42.6% of subjects were male. The prevalence of MAFLD was 37.3% (n = 3116 of 8361), and the proportion of sarcopenic subjects was 9.9% among those with MAFLD. After adjusting for confounders, the risk of significant liver fibrosis significantly increased from non-sarcopenic subjects with MAFLD [odds ratio (OR) = 1.57 by FIB-4 and 2.13 by NFS] to sarcopenic subjects with MAFLD (OR = 4.51 by FIB-4 and 5.72 by NFS), compared with subjects without MAFLD (all P < 0.001). The risk for high probability of ASCVD significantly increased from non-sarcopenic subjects with MAFLD (OR = 1.47) to sarcopenic subjects with MAFLD (OR = 4.08), compared with subjects without MAFLD (all P < 0.001).

Conclusions: The risks of significant liver fibrosis and ASCVD differed significantly according to sarcopenic status among subjects with MAFLD. An assessment of sarcopenia might be helpful in risk stratification among subjects with MAFLD.
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http://dx.doi.org/10.1002/jcsm.12754DOI Listing
October 2021

CREB mediates the C. elegans dauer polyphenism through direct and cell-autonomous regulation of TGF-β expression.

PLoS Genet 2021 07 14;17(7):e1009678. Epub 2021 Jul 14.

Department of Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea.

Animals can adapt to dynamic environmental conditions by modulating their developmental programs. Understanding the genetic architecture and molecular mechanisms underlying developmental plasticity in response to changing environments is an important and emerging area of research. Here, we show a novel role of cAMP response element binding protein (CREB)-encoding crh-1 gene in developmental polyphenism of C. elegans. Under conditions that promote normal development in wild-type animals, crh-1 mutants inappropriately form transient pre-dauer (L2d) larvae and express the L2d marker gene. L2d formation in crh-1 mutants is specifically induced by the ascaroside pheromone ascr#5 (asc-ωC3; C3), and crh-1 functions autonomously in the ascr#5-sensing ASI neurons to inhibit L2d formation. Moreover, we find that CRH-1 directly binds upstream of the daf-7 TGF-β locus and promotes its expression in the ASI neurons. Taken together, these results provide new insight into how animals alter their developmental programs in response to environmental changes.
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http://dx.doi.org/10.1371/journal.pgen.1009678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312985PMC
July 2021

Controlled attenuation parameter value and the risk of hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy.

Hepatol Int 2021 Aug 14;15(4):892-900. Epub 2021 Jul 14.

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

Background: Controlled attenuation parameter (CAP) can evaluate hepatic steatosis in patients with chronic hepatitis B (CHB). However, prognostic implications of CAP value remain unclear. We evaluated the association between CAP and the risk of hepatocellular carcinoma (HCC) in patients with CHB under antiviral therapy and maintained virologic response.

Methods: A total of 1823 CHB patients who were taking nucleos(t)ide analogue and showing suppressed hepatitis B virus replication were analyzed. The primary outcome was incident HCC during follow-up. Patients were grouped into those with and without advanced chronic liver disease (ACLD) (liver stiffness measurement cutoff: 10 kPa), and those with and without hepatic steatosis (CAP cutoff: 222 dB/m).

Results: During 6.4 years of follow-up, 127 patients (7.0%) newly developed HCC. Among patients with ACLD (n = 382), the cumulative HCC incidence rate was lower for those with CAP ≥ 222 (11.0% at 5 years) than those with CAP < 222 (24.0% at 5 years, p = 0.002), and was an independent factor associated with HCC. When CAP value was further stratified, the cumulative HCC incidence rate decreased in dose-dependent manner according to an increase in CAP value (24.0%, 13.9%, 12.8% and 6.0% at 5 years for those with CAP < 222, 222-246, 247-273 and ≥ 274, respectively). Among patients without ACLD (n = 1441), there was no significance difference in HCC risk according to CAP value (HCC incidence rate: 3.3% and 4.0% at 5 years for those with CAP < 222 and CAP ≥ 222, p = 0.20).

Conclusions: Among CHB patients under antiviral therapy showing suppressed HBV replication, low CAP value predicted higher risk for HCC among ACLD patients, indicating that CAP value has a prognostic implication in this population.
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http://dx.doi.org/10.1007/s12072-021-10205-7DOI Listing
August 2021

Cardiovascular Risk Is Elevated in Lean Subjects with Nonalcoholic Fatty Liver Disease.

Gut Liver 2021 Jul 12. Epub 2021 Jul 12.

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

Background/aims: Nonalcoholic fatty liver disease (NAFLD) and obesity are independently associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality in patients with NAFLD. Many NAFLD patients are lean, but their ASCVD risk compared to obese subjects with NAFLD is unclear.

Methods: Data from the 2008 to 2011 Korea National Health and Nutrition Examination Surveys database were analyzed (n=4,786). NAFLD was defined as a comprehensive NAFLD score ≥40 or a liver fat score ≥-0.640. ASCVD risk was evaluated using the American College of Cardiology/ American Heart Association guidelines.

Results: The frequency of subjects without NAFLD, with obese NAFLD, and with lean NAFLD was 62.4% (n=2,987), 26.6% (n=1,274), and 11.0% (n=525), respectively. Subjects with lean NAFLD had a significantly higher ASCVD score and prevalence of a high ASCVD risk (mean 15.6±14.0, 51.6%) than those with obese NAFLD and without NAFLD (mean 11.2±11.4, 39.8%; mean 7.9±10.9, 25.5%; all p<0.001). Subjects with lean NAFLD and significant liver fibrosis showed a significantly higher odds ratio for a high risk for ASCVD than those with obese NAFLD with or without significant liver fibrosis (odds ratio, 2.60 vs 1.93; p=0.023).

Conclusions: Subjects with lean NAFLD had a significantly higher ASCVD score and prevalence of high risk for ASCVD than those with obese NAFLD. Similarly, lean subjects with significant liver fibrosis had a higher probability of ASCVD than obese subjects in the subpopulation with NAFLD.
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http://dx.doi.org/10.5009/gnl210084DOI Listing
July 2021

SREBP-1c impairs ULK1 sulfhydration-mediated autophagic flux to promote hepatic steatosis in high-fat-diet-fed mice.

Mol Cell 2021 09 6;81(18):3820-3832.e7. Epub 2021 Jul 6.

Department of Animal Science, Chonnam National University, Gwangju, Republic of Korea. Electronic address:

A metabolic imbalance between lipid synthesis and degradation can lead to hepatic lipid accumulation, a characteristic of patients with non-alcoholic fatty liver disease (NAFLD). Here, we report that high-fat-diet-induced sterol regulatory element-binding protein (SREBP)-1c, a key transcription factor that regulates lipid biosynthesis, impairs autophagic lipid catabolism via altered HS signaling. SREBP-1c reduced cystathionine gamma-lyase (CSE) via miR-216a, which in turn decreased hepatic HS levels and sulfhydration-dependent activation of Unc-51-like autophagy-activating kinase 1 (ULK1). Furthermore, Cys951Ser mutation of ULK1 decreased autolysosome formation and promoted hepatic lipid accumulation in mice, suggesting that the loss of ULK1 sulfhydration was directly associated with the pathogenesis of NAFLD. Moreover, silencing of CSE in SREBP-1c knockout mice increased liver triglycerides, confirming the connection between CSE, autophagy, and SREBP-1c. Overall, our results uncover a 2-fold mechanism for SREBP-1c-driven hepatic lipid accumulation through reciprocal activation and inhibition of hepatic lipid biosynthesis and degradation, respectively.
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http://dx.doi.org/10.1016/j.molcel.2021.06.003DOI Listing
September 2021

Single dose of multi-clade virus-like particle vaccine protects chickens against clade 2.3.2.1 and clade 2.3.4.4 highly pathogenic avian influenza viruses.

Sci Rep 2021 07 2;11(1):13786. Epub 2021 Jul 2.

Avian influenza Research & Diagnostic Division, Animal and Plant Quarantine Agency, 177 Hyeoksin 8-ro, Gimcheon-si, Gyeongsangbuk-do, 39660, Republic of Korea.

Virus-like particles (VLPs) are recognized as an alternative vaccine platform that provide effective protection against various highly pathogenic avian influenza viruses (HPAIVs). Here, we developed multi-clade VLPs expressing two HAs (a chimera of clade 2.3.2.1c and clade 2.3.4.4c HA) within a single vector. We then compared its protective efficacy with that of a monovalent VLP and evaluated its potency against each homologous strain. Chickens vaccinated with the multi-clade VLP shed less virus and were better protected against challenge than birds receiving monovalent vaccines. Single vaccination with a multi-clade VLP resulted in 100% survival, with no clinical symptoms and high levels of pre-challenge protective immunity (7.6-8.5 log). Moreover, the multi-clade VLP showed high productivity (128-256 HAU) both in the laboratory and on a large scale, making it cheaper than whole inactivated vaccines produced in eggs. However, the PD (protective dose 50%) of the multi-clade VLP against clades 2.3.2.1c and 2.3.4.4c was < 50 PD (28 and 42 PD, respectively), and effective antibody response was maintained for 2-3 months. This multi-clade VLP protects against both clades of HPAI viruses and can be produced in high amounts at low cost. Thus, the vaccine has potential as a pandemic preparedness vaccine.
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http://dx.doi.org/10.1038/s41598-021-93060-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253753PMC
July 2021

Risk assessment of hepatocellular carcinoma and liver-related events using ultrasonography and transient elastography in patients with chronic hepatitis B.

J Viral Hepat 2021 10 23;28(10):1362-1372. Epub 2021 Aug 23.

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

Cirrhosis has prognostic value. We investigated whether the combined use of ultrasonography (US) and transient elastography (TE) to diagnose cirrhosis is beneficial for the risk assessment of hepatocellular carcinoma (HCC) and liver-related events in patients with chronic hepatitis B (CHB). A total of 9300 patients with CHB who underwent US and TE in two institutions between 2006 and 2018 were enrolled. TE value ≥13 kPa was set to indicate cirrhosis. Patients were divided into four groups: US(+)TE(+) (cirrhosis by US and TE), US(+)TE(-) (cirrhosis by US, but not by TE), US(-)TE(+) (cirrhosis by TE, but not by US) and US(-)TE(-) (non-cirrhosis by US and TE).The patients were predominantly male (n = 5474, 58.9%) with a mean age of 47.5 years. The proportions of patients with cirrhosis diagnosed by US and TE were 17.2% (n = 1595) and 13.2% (n = 1225), respectively. The proportion of patients with discordant results in diagnosing cirrhosis by US and TE was 18.7% (n = 1740). During follow-up (median: 60.0 months), HCC and liver-related events developed in 481 (5.2%) and 759 (8.2%) patients, respectively. The cumulative incidence rates of HCC and liver-related events were highest in the US(+)TE(+) group, intermediate-high in the US(-)TE(+) group, intermediate-low in the US(+)TE(-) group and lowest in the US(-)TE(-) group (overall p < .001). Cirrhosis assessed using US and TE was a major predictor of HCC and liver-related event development in patients with CHB. Cirrhosis assessed using TE seemed better in predicting HCC or liver-related events than using US, when cirrhosis diagnosis was discordant by US and TE.
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http://dx.doi.org/10.1111/jvh.13560DOI Listing
October 2021

Clinical Characteristics of Long-Term Survivors After Sorafenib Treatment for Unresectable Hepatocellular Carcinoma: A Korean National Multicenter Retrospective Cohort Study.

J Hepatocell Carcinoma 2021 18;8:613-623. Epub 2021 Jun 18.

Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Background/aim: Sorafenib is the first systemic therapy for the treatment of advanced-stage hepatocellular carcinoma (HCC) and progressive HCC after locoregional therapy. The aim of this study was to evaluate the prognostic factors of long-term survivors after sorafenib treatment.

Methods: This multicenter, retrospective, cohort study included 1,566 unresectable HCC patients who received sorafenib treatment between 2007 and 2014 in nine tertiary centers in Korea. The patients were classified into a long-term survivor group (survival more than two years, n = 257) or a control group (n = 1309). The primary outcomes were the prognostic factors affecting long-term survival. Secondary endpoints included time-to-progression and other safety profiles.

Results: The patients were predominantly men (83.8%) with chronic hepatitis B (77.3%) and Barcelona clinic of liver cancer-stage C (BCLC-C) (78.3%). The median overall survival was 9.0 months. After treatment, eight patients (0.4%) achieved complete response and 139 patients (8.8%) achieved partial response according to the mRECIST criteria. The prognostic factors predicting long-term survival were metformin use (adjusted hazard ratio [aHR] = 3.464; P < 0.001), hand-foot skin reaction (aHR = 1.688; P = 0.003), and concomitant treatment with chemoembolization or radiotherapy (aHR = 2.766; P < 0.001). Poor prognostic factors of long-term survival were a Child-Pugh score of B (HR = 0.422; P < 0.001), the presence of extrahepatic metastasis (HR = 0.639; P = 0.005), main portal vein invasion (HR = 0.502; P = 0.001), and elevated alpha-fetoprotein (>1,000 ng/mL; HR = 0.361; P < 0.001).

Conclusion: This large, multicenter, retrospective study showed an objective response rate of 9.1% and a proportion of long-term survivors of 16.4% in Korean patients. The prognostic factors derived in our study can be used in clinical practice during sorafenib treatment.
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http://dx.doi.org/10.2147/JHC.S304439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219232PMC
June 2021

Inhibition of Transforming Growth Factor Beta and Immune Checkpoints Induces a Distinctively Distributed, Severe Bullous Pemphigoid.

Acta Derm Venereol 2021 06 30;101(6):adv00489. Epub 2021 Jun 30.

Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemoon-Gu, Seoul 120-752, Korea

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http://dx.doi.org/10.2340/00015555-3853DOI Listing
June 2021
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