Publications by authors named "Byung-Gyu Kim"

106 Publications

Novel therapies emerging in oncology to target the TGF-β pathway.

J Hematol Oncol 2021 Apr 6;14(1):55. Epub 2021 Apr 6.

Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

The TGF-β signaling pathway governs key cellular processes under physiologic conditions and is deregulated in many pathologies, including cancer. TGF-β is a multifunctional cytokine that acts in a cell- and context-dependent manner as a tumor promoter or tumor suppressor. As a tumor promoter, the TGF-β pathway enhances cell proliferation, migratory invasion, metastatic spread within the tumor microenvironment and suppresses immunosurveillance. Collectively, the pleiotropic nature of TGF-β signaling contributes to drug resistance, tumor escape and undermines clinical response to therapy. Based upon a wealth of preclinical studies, the TGF-β pathway has been pharmacologically targeted using small molecule inhibitors, TGF-β-directed chimeric monoclonal antibodies, ligand traps, antisense oligonucleotides and vaccines that have been now evaluated in clinical trials. Here, we have assessed the safety and efficacy of TGF-β pathway antagonists from multiple drug classes that have been evaluated in completed and ongoing trials. We highlight Vactosertib, a highly potent small molecule TGF-β type 1 receptor kinase inhibitor that is well-tolerated with an acceptable safety profile that has shown efficacy against multiple types of cancer. The TGF-β ligand traps Bintrafusp alfa (a bifunctional conjugate that binds TGF-β and PD-L1), AVID200 (a computationally designed trap of TGF-β receptor ectodomains fused to an Fc domain) and Luspatercept (a recombinant fusion that links the activin receptor IIb to IgG) offer new ways to fight difficult-to-treat cancers. While TGF-β pathway antagonists are rapidly emerging as highly promising, safe and effective anticancer agents, significant challenges remain. Minimizing the unintentional inhibition of tumor-suppressing activity and inflammatory effects with the desired restraint on tumor-promoting activities has impeded the clinical development of TGF-β pathway antagonists. A better understanding of the mechanistic details of the TGF-β pathway should lead to more effective TGF-β antagonists and uncover biomarkers that better stratify patient selection, improve patient responses and further the clinical development of TGF-β antagonists.
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http://dx.doi.org/10.1186/s13045-021-01053-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022551PMC
April 2021

Extracellular vesicles derived from macrophages display glycyl-tRNA synthetase 1 and exhibit anti-cancer activity.

J Extracell Vesicles 2020 Nov 1;10(1):e12029. Epub 2020 Dec 1.

Institute for Artificial Intelligence and Biomedical Research Medicinal Bioconvergence Research Center College of Pharmacy & College of Medicine Gangnam Severance Hospital Yonsei University Incheon Korea.

Glycyl-tRNA synthetase 1 (GARS1), a cytosolic enzyme secreted from macrophages, promotes apoptosis in cancer cells. However, the mechanism underlying GARS1 secretion has not been elucidated. Here, we report that GARS1 is secreted through unique extracellular vesicles (EVs) with a hydrodynamic diameter of 20-58 nm (mean diameter: 36.9 nm) and a buoyant density of 1.13-1.17 g/ml. GARS1 was anchored to the surface of these EVs through palmitoylated C390 residue. Proteomic analysis identified 164 proteins that were uniquely enriched in the GARS1-containing EVs (GARS1-EVs). Among the identified factors, insulin-like growth factor II receptor, and vimentin also contributed to the anti-cancer activity of GARS1-EVs. This study identified the unique secretory vesicles containing GARS1 and various intracellular factors that are involved in the immunological defence response against tumorigenesis.
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http://dx.doi.org/10.1002/jev2.12029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890555PMC
November 2020

Residual-Based Graph Convolutional Network for Emotion Recognition in Conversation for Smart Internet of Things.

Big Data 2021 Mar 2. Epub 2021 Mar 2.

Department of IT Engineering, Sookmyung Women's University, Seoul, Republic of Korea.

Recently, emotion recognition in conversation (ERC) has become more crucial in the development of diverse internet of things devices, especially closely connected with users. The majority of deep learning-based methods for ERC combine the multilayer, bidirectional, recurrent feature extractor and the attention module to extract sequential features. In addition to this, the latest model utilizes speaker information and the relationship between utterances through the graph network. However, before the input is fed into the bidirectional recurrent module, detailed intrautterance features should be obtained without variation of characteristics. In this article, we propose a residual-based graph convolution network (RGCN) and a new loss function. Our RGCN contains the residual network (ResNet)-based, intrautterance feature extractor and the GCN-based, interutterance feature extractor to fully exploit the intra-inter informative features. In the intrautterance feature extractor based on ResNet, the elaborate context feature for each independent utterance can be produced. Then, the condensed feature can be obtained through an additional GCN-based, interutterance feature extractor with the neighboring associated features for a conversation. The proposed loss function reflects the edge weight to improve effectiveness. Experimental results demonstrate that the proposed method achieves superior performance compared with state-of-the-art methods.
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http://dx.doi.org/10.1089/big.2020.0274DOI Listing
March 2021

Loss of p27Kip1 leads to expansion of CD4+ effector memory T cells and accelerates colitis-associated colon cancer in mice with a T cell lineage restricted deletion of Smad4.

Oncoimmunology 2020 12 3;9(1):1847832. Epub 2020 Dec 3.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.

The cyclin-dependent kinase inhibitor p27 is a tumor suppressor whose intrinsic activity in cancer cells correlates with tumor aggressiveness, invasiveness, and impaired tumor cell differentiation. Here we explore whether p27 indirectly influences tumor progression by restricting expansion and survival of effector memory T cell (T) populations in a preclinical model of spontaneous colitis-associated colorectal cancer (CAC). We show mRNA and protein expression of p27 to be significantly decreased in the colons of mice with a T cell-restricted deletion of the TGF-β intermediate, SMAD4 (Smad4). Loss of p27 expression in T cells correlates with the onset of spontaneous CAC in Smad4 mice by 8 months of age. This phenotype is greatly accelerated by the introduction of a germline deletion of (the gene encoding p27) in Smad4 mice (Smad4/p27 DKO). DKO mice display colon carcinoma by 3 months of age and increased mortality compared to Smad4. Importantly, the phenotype in DKO mice is associated with a significant increase in the frequency of effector CD4 T cells expressing abundant IFN-γ and with a concomitant decrease in Foxp3 regulatory T cells, both in the intestinal mucosa and in the periphery. In addition, induction of inflammatory mediators (IFN-γ, TNF-γ, IL-6, IL-1β, iNOS) and activation of Stat1, Stat3, and IκB is also observed in the colon as early as 1-2 months of age. Our data suggest that genomic alterations known to influence p27 abundance in gastrointestinal cancers may indirectly promote epithelial malignancy by augmenting the production of inflammatory mediators from a spontaneously expanding pool of T cells.
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http://dx.doi.org/10.1080/2162402X.2020.1847832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722707PMC
December 2020

O-GlcNAcylation regulates dopamine neuron function, survival and degeneration in Parkinson disease.

Brain 2020 12;143(12):3699-3716

School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.

The dopamine system in the midbrain is essential for volitional movement, action selection, and reward-related learning. Despite its versatile roles, it contains only a small set of neurons in the brainstem. These dopamine neurons are especially susceptible to Parkinson's disease and prematurely degenerate in the course of disease progression, while the discovery of new therapeutic interventions has been disappointingly unsuccessful. Here, we show that O-GlcNAcylation, an essential post-translational modification in various types of cells, is critical for the physiological function and survival of dopamine neurons. Bidirectional modulation of O-GlcNAcylation importantly regulates dopamine neurons at the molecular, synaptic, cellular, and behavioural levels. Remarkably, genetic and pharmacological upregulation of O-GlcNAcylation mitigates neurodegeneration, synaptic impairments, and motor deficits in an animal model of Parkinson's disease. These findings provide insights into the functional importance of O-GlcNAcylation in the dopamine system, which may be utilized to protect dopamine neurons against Parkinson's disease pathology.
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http://dx.doi.org/10.1093/brain/awaa320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805798PMC
December 2020

Common plasma protein marker LCAT in aggressive human breast cancer and canine mammary tumor.

BMB Rep 2020 Dec;53(12):664-669

Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul 08826; The Canine Cancer Research Center, Seoul National University, Seoul 08826, Korea.

Breast cancer is one of the most frequently diagnosed cancers. Although biomarkers are continuously being discovered, few specific markers, rather than classification markers, representing the aggressiveness and invasiveness of breast cancer are known. In this study, we used samples from canine mammary tumors in a comparative approach. We subjected 36 fractions of both canine normal and mammary tumor plasmas to highperformance quantitative proteomics analysis. Among the identified proteins, LCAT was selectively expressed in mixed tumor samples. With further MRM and Western blot validation, we discovered that the LCAT protein is an indicator of aggressive mammary tumors, an advanced stage of cancer, possibly highly metastatic. Interestingly, we also found that LCAT is overexpressed in high-grade and lymph-node-positive breast cancer in silico data. We also demonstrated that LCAT is highly expressed in the sera of advanced-stage human breast cancers within the same classification. In conclusion, we identified a possible common plasma protein biomarker, LCAT, that is highly expressed in aggressive human breast cancer and canine mammary tumor. [BMB Reports 2020; 53(12): 664-669].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781914PMC
December 2020

Exploring the Role of a Novel Peptide from Larvae in Ameliorating Lipid Metabolism in Obesity.

Int J Mol Sci 2020 Nov 12;21(22). Epub 2020 Nov 12.

Department of Food Science and Nutrition, Dong-A University, Busan 49315, Korea.

The aim of this study was to identify an anti-obesity peptide from and investigate the lipid metabolic mechanism. Enzymatically hydrolyzed larvae were further separated using tangential flow filtration and consecutive chromatographic processes. Finally, an anti-obesity peptide that showed the highest inhibitory effect on lipid accumulation was obtained, and the sequence was Glu-Ile-Ala-Gln-Asp-Phe-Lys-Thr-Asp-Leu (EIA10). EIA10 decreased lipid aggregation in vitro and significantly reduced the accumulation of body weight gain, liver weight, and adipose tissue weight in high-fat-fed mice. Compared with the control group, the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL), insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in the high-fat diet (HFD) group increased significantly, and the content of high-density lipoprotein cholesterol (HDL) in the serum decreased significantly. On the contrary, the levels of TC, TG, and insulin in the EIA10 group decreased significantly, and the HDL content increased significantly compared with the HFD group. Additionally, EIA10 dramatically decreased mRNA and protein levels of transcription factors involved in lipid adipogenesis. Taken together, our results suggest that EIA10 could be a promising agent for the treatment and prevention of obesity.
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http://dx.doi.org/10.3390/ijms21228537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698306PMC
November 2020

PDK2 Deficiency Prevents Ovariectomy-Induced Bone Loss in Mice by Regulating the RANKL-NFATc1 Pathway During Osteoclastogenesis.

J Bone Miner Res 2021 Mar 28;36(3):553-566. Epub 2020 Nov 28.

Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Republic of Korea.

Estrogen deficiency leads to osteoporosis as a result of an imbalance in bone remodeling due to greater bone resorption. Estrogen deficiency increases the osteoclastic resorption of bone, and many of the FDA-approved therapies for osteoporosis are antiresorptive drugs that mainly act by reducing osteoclast activity. The mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) is a critical regulator of aerobic glycolysis that exerts its effects by phosphorylating the pyruvate dehydrogenase complex (PDC), which is responsible for oxidative phosphorylation. In the present study, we found that during osteoclast differentiation, PDK2 expression increased more than that of the other PDK isoenzymes. Bone loss was delayed and the number of osteoclasts was lower in ovariectomized (OVX) Pdk2 mice than in OVX wild-type mice. The differentiation of osteoclasts was suppressed in Pdk2 bone marrow-derived monocyte/macrophage lineage cells, which was associated with lower phosphorylation of cAMP response element-binding protein (CREB) and c-FOS, and a consequent reduction in NFATc1 transcription. Administration of AZD7545, a specific inhibitor of PDK2, prevented the OVX-induced bone loss and reduced the phosphorylation of CREB and c-FOS, and the protein expression of NFATc1, in osteoclasts. Collectively, these results indicate that the inhibition of PDK2 prevents osteoporosis in estrogen-deficient mice by reducing aberrant osteoclast activation, probably via inhibition of the RANKL-CREB-cFOS-NFATc1 pathway. These findings imply that PDK2 inhibitors might be repurposed for the therapy of estrogen deficiency-induced osteoporosis. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4202DOI Listing
March 2021

Ewing sarcoma protein promotes dissociation of poly(ADP-ribose) polymerase 1 from chromatin.

EMBO Rep 2020 11 1;21(11):e48676. Epub 2020 Oct 1.

Center for Genomic Integrity, Institute for Basic Science, Ulsan, Korea.

Poly(ADP-ribose) polymerase 1 (PARP1) facilitates DNA damage response (DDR). While the Ewing's sarcoma breakpoint region 1 (EWS) protein fused to FLI1 triggers sarcoma formation, the physiological function of EWS is largely unknown. Here, we investigate the physiological role of EWS in regulating PARP1. We show that EWS is required for PARP1 dissociation from damaged DNA. Abnormal PARP1 accumulation caused by EWS inactivation leads to excessive Poly(ADP-Ribosy)lation (PARylation) and triggers cell death in both in vitro and in vivo models. Consistent with previous work, the arginine-glycine-glycine (RGG) domain of EWS is essential for PAR chain interaction and PARP1 dissociation from damaged DNA. Ews and Parp1 double mutant mice do not show improved survival, but supplementation with nicotinamide mononucleotides extends Ews-mutant pups' survival, which might be due to compensatory activation of other PARP proteins. Consistently, PARP1 accumulates on chromatin in Ewing's sarcoma cells expressing an EWS fusion protein that cannot interact with PARP1, and tissues derived from Ewing's sarcoma patients show increased PARylation. Taken together, our data reveal that EWS is important for removing PARP1 from damaged chromatin.
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http://dx.doi.org/10.15252/embr.201948676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645264PMC
November 2020

Response by Kim et al. to Letter regarding article, "Prominent Thebesian veins, a rare congenital coronary anomaly presenting as acute myocardial ischemia".

J Cardiol Cases 2020 Sep 30;22(3):147-148. Epub 2020 Jun 30.

Division of Cardiology, Department of Internal Medicine, Inje University College of Medicine, Sanggye Paik Hospital, Seoul, Republic of Korea.

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http://dx.doi.org/10.1016/j.jccase.2020.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452171PMC
September 2020

Early surgical intervention for unusually located cardiac fibroelastomas.

Yeungnam Univ J Med 2020 Oct 5;37(4):345-348. Epub 2020 Aug 5.

Department of Pathology, Inje University Sanggye Paik Hospital, Inje University School of Medicine, Seoul, Korea.

Papillary fibroelastomas are the second most common primary cardiac tumor in adults. Over 80% of fibroelastomas occur on the cardiac valves, usually on the left side of the heart, while the remaining lesions are typically scattered throughout the atria and ventricles. Although the optimal timing for surgery is controversial and depends on tumor size and location, prompt surgical resection is warranted in patients at high risk of embolism. A tumor on the cardiac valve can be removed using the slicing excision technique without leaflet injury. Here we present two cases of papillary fibroelastomas occurring on the ventricular surface of the aortic valve and in the right ventricle.
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http://dx.doi.org/10.12701/yujm.2020.00556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606954PMC
October 2020

O-GlcNAcylation of Mef2c regulates myoblast differentiation.

Biochem Biophys Res Commun 2020 08 18;529(3):692-698. Epub 2020 Jul 18.

Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Glycosylation Network Research Center, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Interdisciplinary Program of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. Electronic address:

Unlike other types of glycosylation, O-GlcNAcylation is a single glycosylation which occurs exclusively in the nucleus and cytosol. O-GlcNAcylation underlie metabolic diseases, including diabetes and obesity. Furthermore, O-GlcNAcylation affects different oncogenic processes such as osteoblast differentiation, adipogenesis and hematopoiesis. Emerging evidence suggests that skeletal muscle differentiation is also regulated by O-GlcNAcylation, but the detailed molecular mechanism has not been fully elucidated. In this study, we showed that hyper-O-GlcNAcylation reduced the expression of myogenin, a transcription factor critical for terminal muscle development, in C2C12 myoblasts differentiation by O-GlcNAcylation on Thr9 of myocyte-specific enhancer factor 2c. Furthermore, we showed that O-GlcNAcylation on Mef2c inhibited its DNA binding affinity to myogenin promoter. Taken together, we demonstrated that hyper-O-GlcNAcylation attenuates skeletal muscle differentiation by increased O-GlcNAcylation on Mef2c, which downregulates its DNA binding affinity.
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http://dx.doi.org/10.1016/j.bbrc.2020.06.031DOI Listing
August 2020

ATAD5 restricts R-loop formation through PCNA unloading and RNA helicase maintenance at the replication fork.

Nucleic Acids Res 2020 07;48(13):7218-7238

Center for Genomic Integrity, Institute for Basic Science, Ulsan, Korea.

R-loops are formed when replicative forks collide with the transcriptional machinery and can cause genomic instability. However, it is unclear how R-loops are regulated at transcription-replication conflict (TRC) sites and how replisome proteins are regulated to prevent R-loop formation or mediate R-loop tolerance. Here, we report that ATAD5, a PCNA unloader, plays dual functions to reduce R-loops both under normal and replication stress conditions. ATAD5 interacts with RNA helicases such as DDX1, DDX5, DDX21 and DHX9 and increases the abundance of these helicases at replication forks to facilitate R-loop resolution. Depletion of ATAD5 or ATAD5-interacting RNA helicases consistently increases R-loops during the S phase and reduces the replication rate, both of which are enhanced by replication stress. In addition to R-loop resolution, ATAD5 prevents the generation of new R-loops behind the replication forks by unloading PCNA which, otherwise, accumulates and persists on DNA, causing a collision with the transcription machinery. Depletion of ATAD5 reduces transcription rates due to PCNA accumulation. Consistent with the role of ATAD5 and RNA helicases in maintaining genomic integrity by regulating R-loops, the corresponding genes were mutated or downregulated in several human tumors.
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http://dx.doi.org/10.1093/nar/gkaa501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367208PMC
July 2020

Non-steroidal anti-inflammatory drug-induced enteropathy as a major risk factor for small bowel bleeding: a retrospective study.

BMC Gastroenterol 2020 Jun 8;20(1):178. Epub 2020 Jun 8.

Department of Internal Medicine, Kosin University College of Medicine, Kosin University Gospel Hospital, Busan, South Korea.

Background: Small bowel (SB) bleeding accounts for 5% of all gastrointestinal (GI) bleeding cases and 80% of obscure GI bleeding cases. Although angioectasia is the common etiology of SB bleeding, nonsteroidal anti-inflammatory drug (NSAID)-induced SB lesions are also reported as a major cause in studies from Eastern countries. Herein, we assessed the frequency of occurrence of NSAID-induced SB lesions in Korean patients with obscure GI bleeding.

Methods: We retrospectively analyzed medical records of all consecutive patients aged ≥18 years who underwent capsule endoscopy from March 2018 to February 2019 at Ulsan University Hospital and Kosin University Gospel Hospital.

Results: Of the 83 subjects (all Korean; mean age ± standard deviation: 59 ± 18 years; age range: 18-84 years; men: n = 52; women: n = 31), 55 (66.2%) had stool with clear blood and 28 (33.8%) had normal stool with iron deficiency anemia. The detection rate of SB bleeding and lesions using capsule endoscopy was 72.3% (60 of 83 patients). A significantly higher frequency (40 of 51) of ulcerative/erosive lesions than other causes was observed in patients with inactive bleeding but visible SB lesions. As a result, NSAID-induced enteropathy accounted for 30.1% of 83 patients with obscure GI bleeding (25 of the all 60 SB bleeding cases).

Conclusions: Contrary to what is reported for patients in Western countries, this study in Korean patients showed an improved diagnostic yield of capsule endoscopy for obscure GI bleeding and that NSAID-induced enteropathy was the most common etiology of SB bleeding. Aggressive small intestine examination is required for patients with unexplained GI bleeding.
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http://dx.doi.org/10.1186/s12876-020-01329-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282042PMC
June 2020

Prominent Thebesian veins, a rare congenital coronary anomaly presenting as acute myocardial ischemia.

J Cardiol Cases 2020 Apr 5;21(4):127-129. Epub 2019 Dec 5.

Division of Cardiology, Department of Internal Medicine, Inje University College of Medicine, Seoul Paik Hospital, Seoul, Republic of Korea.

Persistent Thebesian veins with the appearance of multiple coronary artery microfistulas are a rare finding and little is known about their physiologic and clinical features. In addition, few reports have demonstrated the perfusion status of patients with Thebesian veins. We report a 75-year-old woman referred for non-ST-elevation myocardial infarction due to prominent Thebesian veins who displayed a perfusion defect in cardiac magnetic resonance imaging. < This case emphasizes that non-obstructive coronary arterial anomaly can lead to myocardial ischemia with angina symptoms and cardiac enzyme rise. Moreover, it provided the typical angiographic appearance of Thebesian vein network and image of myocardial perfusion defect induced by coronary steal.>.
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http://dx.doi.org/10.1016/j.jccase.2019.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125364PMC
April 2020

Deep Joint Spatiotemporal Network (DJSTN) for Efficient Facial Expression Recognition.

Sensors (Basel) 2020 Mar 30;20(7). Epub 2020 Mar 30.

Department of IT Engineering, Sookmyung Women's University, 100 Chungpa-ro 47 gil, Yongsna-gu, Seoul 04310, Korea.

Understanding a person's feelings is a very important process for the affective computing. People express their emotions in various ways. Among them, facial expression is the most effective way to present human emotional status. We propose efficient deep joint spatiotemporal features for facial expression recognition based on the deep appearance and geometric neural networks. We apply three-dimensional (3D) convolution to extract spatial and temporal features at the same time. For the geometric network, 23 dominant facial landmarks are selected to express the movement of facial muscle through the analysis of energy distribution of whole facial landmarks.We combine these features by the designed joint fusion classifier to complement each other. From the experimental results, we verify the recognition accuracy of 99.21%, 87.88%, and 91.83% for CK+, MMI, and FERA datasets, respectively. Through the comparative analysis, we show that the proposed scheme is able to improve the recognition accuracy by 4% at least.
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http://dx.doi.org/10.3390/s20071936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180996PMC
March 2020

PCNA Unloading Is Negatively Regulated by BET Proteins.

Cell Rep 2019 12;29(13):4632-4645.e5

Center for Genomic Integrity, Institute for Basic Science, Ulsan 44919, Republic of Korea. Electronic address:

Proliferating cell nuclear antigen (PCNA) is a DNA clamp essential for DNA replication. During DNA synthesis, PCNA is continuously loaded onto and unloaded from DNA. PCNA recruits various proteins to nascent DNA to facilitate chromosome duplication. Therefore, timely PCNA unloading is crucial for high-fidelity DNA replication. The ATAD5-RFC-like complex (ATAD5-RLC) unloads PCNA from replicated DNA. It is unclear how ATAD5-RLC activity is regulated to prevent premature PCNA unloading. Here, we find that BRD4, an acetyl-histone-binding chromatin reader, inhibits the PCNA-unloading activity of ATAD5-RLC. The BRD4 ET domain interacts with a region upstream of the ATAD5 PCNA-unloading domain. BRD4-ATAD5 binds to acetyl-histones in nascent chromatin. BRD4 release from chromatin correlates with PCNA unloading. Disruption of the interaction between BRD4 and acetyl-histones or between BRD4 and ATAD5 reduces the PCNA amount on chromatin. In contrast, the overexpression of BRD4 increases the amount of chromatin-bound PCNA. Thus, acetyl-histone-bound BRD4 fine-tunes PCNA unloading from nascent DNA.
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http://dx.doi.org/10.1016/j.celrep.2019.11.114DOI Listing
December 2019

Clinical significance of postoperative atrial arrhythmias in patients who underwent lung transplantation.

Korean J Intern Med 2020 07 25;35(4):897-905. Epub 2019 Nov 25.

Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Background/aims: Atrial arrhythmia (AA) occasionally occurs after lung transplantation (LT); however, risk factors for AA and their impact on clinical outcomes are inconsistent. We aimed to investigate the incidence, predisposing factors, and clinical outcomes of AA after LT.

Methods: We retrospectively evaluated 153 consecutive patients who underwent LT between January 2010 and August 2016. An AA episode was defined as a documented atrial fibrillation (AF), atrial flutter, or atrial tachycardia on 12-lead electrocardiography or episodes lasting ≥ 30 seconds on telemetry monitoring.

Results: The mean follow-up time was 22.0 ± 19.1 months. Postoperative AA occurred in 46 patients (30.1%) after LT. Patients with postoperative AA were older, had larger body surface area, and had an increased incidence of paroxysmal AF prior to transplantation, idiopathic pulmonary fibrosis, and postoperative tracheostomy than patients without AA. Preoperative right atrial pressure (RAP) (odds ratio [OR], 1.19; p = 0.005) and longer periods of mechanical ventilation (OR, 1.03; p = 0.008) were found to be independent risk factors for AA after surgery. Development of AA was a significant predictor of long-term overall mortality (hazard ratio, 2.75; p = 0.017).

Conclusion: Patients with elevated preoperative RAP and long-term ventilator care had a higher risk of AA after LT. Further, AA after LT was associated with poor long-term survival.
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http://dx.doi.org/10.3904/kjim.2018.326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373957PMC
July 2020

Successful percutaneous coronary intervention with extracorporeal membrane oxygenation support after right coronary artery dissection in an eisenmenger syndrome patient.

Acute Crit Care 2020 Feb 6;35(1):46-50. Epub 2018 Nov 6.

Division of Cardiology, Department of Internal Medicine, Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea.

The presentation of coronary artery disease in a patient with Eisenmenger syndrome (ES) is relatively rare. Cardiogenic shock due to coronary artery dissection during percutaneous coronary intervention (PCI) can be more critical in these patients. Here, we report a case of successful PCI under mechanical circulation support in a patient with ES who experienced potentially fatal right coronary artery dissection. This case emphasizes that use of extracorporeal membrane oxygenation (ECMO) can lead to successful management of critical complication during PCI, and that the immediate decision to apply of ECMO is important in ES patients who face impending cardiogenic shock with acute heart failure.
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http://dx.doi.org/10.4266/acc.2017.00024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056956PMC
February 2020

Simple Method To Characterize the Ciliary Proteome of Multiciliated Cells.

J Proteome Res 2020 01 18;19(1):391-400. Epub 2019 Nov 18.

Center for Genomic Integrity , Institute for Basic Science , Ulsan 44919 , Republic of Korea.

Motile cilia of multiciliated epithelial cells have important roles in animal development and cell homeostasis. Although several studies have identified and reported proteins localized in this complex organelle and the related immotile primary cilia from various cell types, it is still challenging to isolate high quantities of ciliary proteins for proteomic analysis. In this study, African clawed frog () embryos, which have many multiciliated cells in the epidermis, were treated with a simple ionic buffer to identify 1009 proteins conserved across vertebrates; these proteins were putatively localized in motile cilia. Using two ciliary proteome databases, we confirmed that previously validated cilia-associated proteins are highly enriched in our ciliary proteome. Proteins localized at the transition zone and Ellis-van Creveld zone, which are distinct regions at the base of cilia, near the junction with the apical cell surface, were isolated using our method. Among the newly identified ciliary proteins, we report that KRT17 may have an unrecognized function in motile cilia. Hence, the method developed in this study would be useful for understanding the ciliary proteome.
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http://dx.doi.org/10.1021/acs.jproteome.9b00589DOI Listing
January 2020

Relation of Preprocedural Hemoglobin Level to Outcomes After Percutaneous Coronary Intervention.

Am J Cardiol 2019 11 9;124(9):1319-1326. Epub 2019 Aug 9.

Division of Cardiology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. Electronic address:

Adverse effects have been reported in patients with preprocedural anemia after percutaneous coronary intervention (PCI), but data regarding the relation between elevated hemoglobin (Hb) level and post-PCI prognosis remain limited. This study assessed the impact of elevated Hb on major adverse cardiac and cerebrovascular event (MACCE) at 12 months, a composite of all-cause mortality, nonfatal myocardial infarction, and ischemic stroke after PCI. We pooled patient-level data from four Korean multicenter drug-eluting stent registries from 2010 to 2016. In total, 5,107 patients were divided into 5 categories according to the baseline Hb level (<10, 10 to 12.9, 13 to 14.9, 15 to 16.9 and ≥17 g/dl). Patients with higher Hb levels were significantly younger, predominantly male, current smokers with higher body mass index, and more frequent dyslipidemia. Hypertension, diabetes, chronic kidney disease, and cerebrovascular accident were more prevalent in lower Hb groups. Categorically, a U-shaped curvilinear relation was observed between baseline Hb and clinical outcomes showing significantly higher MACCE rate in <10g/dl (hazard ratio [HR], 4.62 [2.81 to 7.68]) and ≥17 g/dl (HR, 4.06 [1.57 to 10.5]) groups compared with the reference group (13 to 14.9 g/dl), especially in men. In nonanemic patients (Hb ≥13 g/dl), adjusted HRs of MACCE, mortality, and stroke were significantly higher in ≥17 g/dl group than in the reference group. Furthermore, ≥17 g/dl was an independent predictor for MACCE and all-cause mortality after PCI. In conclusion, not only low Hb but also elevated Hb of ≥17 g/dl was significantly associated with higher MACCE rates and all-cause mortality after PCI. An appropriate treatment strategy for patients with high Hb level should be identified through future studies.
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http://dx.doi.org/10.1016/j.amjcard.2019.07.056DOI Listing
November 2019

Relationship between the ST-Segment Resolution and Microvascular Dysfunction in Patients Who Underwent Primary Percutaneous Coronary Intervention.

Cardiol Res Pract 2019 1;2019:8695065. Epub 2019 Aug 1.

Division of Cardiology, Department of Internal Medicine, Inje University College of Medicine, Sanggye Paik Hospital, Seoul, Republic of Korea.

Objectives: Incomplete ST-segment elevation resolution (STR) occasionally occurs despite successful revascularization of epicardial coronary artery after primary percutaneous coronary intervention (PPCI). The aim of this study was to evaluate the relationship between the degree of STR and the severity of microvascular dysfunction.

Methods: A total of 73 consecutive patients with ST-segment elevation myocardial infarction (STEMI) who underwent successful PPCI were evaluated. Serial 12-lead electrocardiography was performed at baseline and at 90 minutes after PPCI. Microvascular dysfunction was assessed by index of microvascular resistance (IMR) immediately after PPCI.

Results: Patients were classified into 2 groups: 50 patients with complete STR (STR ≥50%) and 23 patients with incomplete STR (STR <50%). The incomplete STR group had a higher IMR value and lower left ventricular ejection fraction (LVEF), compared with the complete STR group. The degree of STR was significantly correlated with IMR ( = -0.416, =0.002) and LVEF ( = 0.300, =0.011). These correlations were only observed in patients with left anterior descending artery (LAD) infarction but not observed in patients with non-LAD infarction. A cutoff IMR value was 27.3 for predicting incomplete STR after PPCI.

Conclusion: Incomplete STR after PPCI in patients with STEMI reflects the presence of microvascular and left ventricular dysfunction, especially in patients with LAD infarction.
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http://dx.doi.org/10.1155/2019/8695065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701325PMC
August 2019

CTCF cooperates with CtIP to drive homologous recombination repair of double-strand breaks.

Nucleic Acids Res 2019 09;47(17):9160-9179

Department of Life Sciences and Cellulomics Institute Ajou University, Suwon 16499, Korea.

The pleiotropic CCCTC-binding factor (CTCF) plays a role in homologous recombination (HR) repair of DNA double-strand breaks (DSBs). However, the precise mechanistic role of CTCF in HR remains largely unclear. Here, we show that CTCF engages in DNA end resection, which is the initial, crucial step in HR, through its interactions with MRE11 and CtIP. Depletion of CTCF profoundly impairs HR and attenuates CtIP recruitment at DSBs. CTCF physically interacts with MRE11 and CtIP and promotes CtIP recruitment to sites of DNA damage. Subsequently, CTCF facilitates DNA end resection to allow HR, in conjunction with MRE11-CtIP. Notably, the zinc finger domain of CTCF binds to both MRE11 and CtIP and enables proficient CtIP recruitment, DNA end resection and HR. The N-terminus of CTCF is able to bind to only MRE11 and its C-terminus is incapable of binding to MRE11 and CtIP, thereby resulting in compromised CtIP recruitment, DSB resection and HR. Overall, this suggests an important function of CTCF in DNA end resection through the recruitment of CtIP at DSBs. Collectively, our findings identify a critical role of CTCF at the first control point in selecting the HR repair pathway.
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http://dx.doi.org/10.1093/nar/gkz639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753481PMC
September 2019

Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype.

Front Immunol 2019 7;10:944. Epub 2019 May 7.

BK21 Plus KNU Biomedical Convergence Programs, Department of Biomedical Science, Kyungpook National University, Daegu, South Korea.

Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.
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http://dx.doi.org/10.3389/fimmu.2019.00944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514528PMC
September 2020

Simultaneous left and right ventricular apical thrombi after occlusion of the wrapped left anterior descending artery.

J Cardiol Cases 2019 May 13;19(5):153-156. Epub 2019 Feb 13.

Department of Internal Medicine, Inje University College of Medicine, Seoul Paik Hospital, Seoul, Republic of Korea.

Left ventricular (LV) thrombus formation is a well-known complication of acute myocardial infarction (AMI) and is reported to occur in 5-8% of patients who have anterior or apical myocardial infarction. However, right ventricular (RV) thrombus has not previously been reported after AMI. We describe a 54-year-old woman who presented with an ST-elevation myocardial infarction due to occlusion of the distal left anterior descending artery, which wrapped around the apex and led to simultaneous LV and RV apical thrombi. < This case emphasizes the following: (1) in patients who have a long left anterior descending artery (LAD) that wraps around the apex, even distal LAD occlusion can cause a large infarct area including the apex, inferior wall, and right ventricular apex, as well as serious complications such as cardiac arrest and left ventricular and right ventricular (RV) thrombus. (2) Cardiac magnetic resonance imaging is useful for detecting apical thrombus especially in the RV.>.
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http://dx.doi.org/10.1016/j.jccase.2018.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495048PMC
May 2019

Transcatheter aortic valve replacement in a patient with anomalous origin of the left coronary artery.

J Cardiol Cases 2019 Apr 10;19(4):133-135. Epub 2019 Feb 10.

Division of Cardiology, Department of Internal Medicine, Inje University College of Medicine, Seoul Paik Hospital, Seoul, South Korea.

Transcatheter aortic valve replacement (TAVR) is widely performed in patients with severe aortic stenosis (AS), having a high surgical risk. However, reports of TAVR performed in patients with anomalous coronary arteries are rare. In existing literature, several complications including coronary obstruction are reported. In this study, we report a 77-year-old female patient with severe AS and anomalous origin of the left coronary artery from the right coronary sinus, who successfully underwent TAVR. < During transcatheter aortic valve replacement in patients with anomalous coronary arteries, special attention might be given to the topographical location of the coronary artery from the aortic root and the implanted valve for preventing a coronary obstruction.>.
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http://dx.doi.org/10.1016/j.jccase.2018.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451060PMC
April 2019

Impact of lenalidomide on collected hematopoietic myeloid and erythroid progenitors: peripheral stem cell collection may not be affected.

Leuk Lymphoma 2019 09 7;60(9):2199-2206. Epub 2019 Mar 7.

Stem Cell Transplant Program University Hospitals Seidman Cancer Center Case Comprehensive Cancer Center and Case Western Reserve University , Cleveland , OH , USA.

Lenalidomide (LEN) is commonly used as part of induction therapy in transplant-eligible patients with multiple myeloma. However, LEN use is associated with increased chance of peripheral blood stem cell (PBSC) collection failure. This has led to early collection in patients receiving induction with LEN-containing regimens, and the use of mobilization agents such as plerixafor. Despite potential significant clinical implications, the impact of LEN on autograft composition is unclear. We examined the effect of LEN exposure on hematopoietic progenitors in collected grafts of 94 patients who underwent autologous stem cell transplantation (HSCT) at our institution. LEN exposure resulted in lower myeloid and erythroid progenitors in collected grafts, but this effect was not seen in patients who received plerixafor-based mobilization. Exposure to LEN did not affect PBSC collection, possibly due to high plerixafor use in our cohort (70%). LEN changes the composition of PBSC grafts; the clinical implication of this finding is unknown.
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http://dx.doi.org/10.1080/10428194.2019.1573367DOI Listing
September 2019

The E3 ubiquitin ligase TRIM25 regulates adipocyte differentiation via proteasome-mediated degradation of PPARγ.

Exp Mol Med 2018 10 15;50(10):1-11. Epub 2018 Oct 15.

Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 689-798, Korea.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor that regulates adipocyte differentiation and glucose homeostasis. The transcriptional activity of PPARγ is regulated not only by ligands but also by post-translational modifications (PTMs). In this study, we demonstrate that a novel E3 ligase of PPARγ, tripartite motif-containing 25 (TRIM25), directly induced the ubiquitination of PPARγ, leading to its proteasome-dependent degradation. During adipocyte differentiation, both TRIM25 mRNA and protein expression significantly decreased and negatively correlated with the expression of PPARγ. The stable expression of TRIM25 reduced PPARγ protein levels and suppressed adipocyte differentiation in 3T3-L1 cells. In contrast, the specific knockdown of TRIM25 increased PPARγ protein levels and stimulated adipocyte differentiation. Furthermore, TRIM25-knockout mouse embryonic fibroblasts (MEFs) exhibited an increased adipocyte differentiation capability compared with wild-type MEFs. Taken together, these data indicate that TRIM25 is a novel E3 ubiquitin ligase of PPARγ and that TRIM25 is a novel target for PPARγ-associated metabolic diseases.
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http://dx.doi.org/10.1038/s12276-018-0162-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189217PMC
October 2018

The chromatin remodeler RSF1 controls centromeric histone modifications to coordinate chromosome segregation.

Nat Commun 2018 09 21;9(1):3848. Epub 2018 Sep 21.

Department of Biochemistry, Ajou University School of Medicine, Suwon, 16499, Korea.

Chromatin remodelers regulate the nucleosome barrier during transcription, DNA replication, and DNA repair. The chromatin remodeler RSF1 is enriched at mitotic centromeres, but the functional consequences of this enrichment are not completely understood. Shugoshin (Sgo1) protects centromeric cohesion during mitosis and requires BuB1-dependent histone H2A phosphorylation (H2A-pT120) for localization. Loss of Sgo1 at centromeres causes chromosome missegregation. Here, we show that RSF1 regulates Sgo1 localization to centromeres through coordinating a crosstalk between histone acetylation and phosphorylation. RSF1 interacts with and recruits HDAC1 to centromeres, where it counteracts TIP60-mediated acetylation of H2A at K118. This deacetylation is required for the accumulation of H2A-pT120 and Sgo1 deposition, as H2A-K118 acetylation suppresses H2A-T120 phosphorylation by Bub1. Centromeric tethering of HDAC1 prevents premature chromatid separation in RSF1 knockout cells. Our results indicate that RSF1 regulates the dynamics of H2A histone modifications at mitotic centromeres and contributes to the maintenance of chromosome stability.
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http://dx.doi.org/10.1038/s41467-018-06377-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155007PMC
September 2018

Association between body mass index and clinical outcomes after new-generation drug-eluting stent implantation: Korean multi-center registry data.

Atherosclerosis 2018 10 31;277:155-162. Epub 2018 Aug 31.

Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea.

Background And Aims: It is unclear whether the obesity paradox is still apparent in the new-generation drug-eluting stent (DES) era. Therefore, we assessed the impact of body mass index (BMI) on clinical outcome after percutaneous coronary intervention (PCI) with new-generation DESs.

Methods: A total of 5264 consecutive patients from 4 new-generation DES registries were divided into 4 categories according to BMI: 1) underweight (BMI<18.5 kg/m, n = 130), 2) normal weight (18.5 ≤ BMI <25 kg/m, n = 2943), 3) overweight (25 ≤ BMI<30 kg/m, n = 1932), and 4) obese (BMI≥30 kg/m, n = 259). The primary endpoint was the occurrence of major adverse cardiac and cerebrovascular event (MACCE) at 12 months, including all-cause mortality, nonfatal myocardial infarction, stroke, and target-vessel revascularization.

Results: The 12-month MACCE rates decreased according to increasing BMI categories. (underweight, 13.1%; normal, 6.0%; overweight, 4.8%; obese, 4.2%; p < 0.001). After adjustment for other confounders, the underweight group had significantly higher MACCE rates than the normal-weight (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.33-0.99; p = 0.049), overweight (HR, 0.49; 95% CI, 0.27-0.88; p = 0.017), and obese (HR, 0.41; 95% CI, 0.18-0.98; p = 0.044) groups. These differences were mainly driven by all-cause mortality and target-vessel revascularization. When BMI was treated as a continuous variable, BMI per 1 kg/m was also an independent predictor for MACCE (HR, 0.95; 95% CI, 0.91-0.99; p = 0.008) and a MACE increase began below a BMI of 24 kg/m.

Conclusions: Lower BMI was significantly associated with higher rates of MACCE and all-cause mortality after PCI. The obesity paradox is manifested in Korean patients in the new-generation DES era.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.08.047DOI Listing
October 2018