Publications by authors named "Hyung-Jun Kim"

251 Publications

How Cerebral Vessel Tortuosity Affects Development and Recurrence of Aneurysm: Outer Curvature versus Bifurcation Type.

J Stroke 2021 May 31;23(2):213-222. Epub 2021 May 31.

Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background And Purpose: Previous studies have assessed the relationship between cerebral vessel tortuosity and intracranial aneurysm (IA) based on two-dimensional brain image analysis. We evaluated the relationship between cerebral vessel tortuosity and IA according to the hemodynamic location using three-dimensional (3D) analysis and studied the effect of tortuosity on the recurrence of treated IA.

Methods: We collected clinical and imaging data from patients with IA and disease-free controls. IAs were categorized into outer curvature and bifurcation types. Computerized analysis of the images provided information on the length of the arterial segment and tortuosity of the cerebral arteries in 3D space.

Results: Data from 95 patients with IA and 95 controls were analyzed. Regarding parent vessel tortuosity index (TI; P<0.01), average TI (P<0.01), basilar artery (BA; P=0.02), left posterior cerebral artery (P=0.03), both vertebral arteries (VAs; P<0.01), and right internal carotid artery (P<0.01), there was a significant difference only in the outer curvature type compared with the control group. The outer curvature type was analyzed, and the occurrence of an IA was associated with increased TI of the parent vessel, average, BA, right middle cerebral artery, and both VAs in the logistic regression analysis. However, in all aneurysm cases, recanalization of the treated aneurysm was inversely associated with increased TI of the parent vessels.

Conclusions: TIs of intracranial arteries are associated with the occurrence of IA, especially in the outer curvature type. IAs with a high TI in the parent vessel showed good outcomes with endovascular treatment.
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http://dx.doi.org/10.5853/jos.2020.04399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189854PMC
May 2021

Toxicity of pathogenic ataxin-2 in Drosophila shows dependence on a pure CAG repeat sequence.

Hum Mol Genet 2021 Jun 2. Epub 2021 Jun 2.

Department of Biology, University of Pennsylvania, Philadelphia, PA USA.

Spinocerebellar ataxia type 2 is a polyglutamine (polyQ) disease associated with an expanded polyQ domain within the protein product of the ATXN2 gene. Interestingly, polyQ repeat expansions in ATXN2 are also associated with amyotrophic lateral sclerosis (ALS) and parkinsonism depending upon the length of the polyQ repeat expansion. The sequence encoding the polyQ repeat also varies with disease presentation: a pure CAG repeat is associated with SCA2, whereas the CAG repeat in ALS and parkinsonism is typically interrupted with the glutamine encoding CAA codon. Here we asked if the purity of the CAG sequence encoding the polyQ repeat in ATXN2 could impact the toxicity of the ataxin-2 protein in vivo in Drosophila. We found that ataxin-2 encoded by a pure CAG repeat conferred toxicity in the retina and nervous system, whereas ataxin-2 encoded by a CAA-interrupted repeat or CAA-only repeat failed to confer toxicity, despite expression of the protein at similar levels. Furthermore, the CAG-encoded ataxin-2 protein aggregated in the fly eye, while ataxin-2 encoded by either a CAA/G or CAA repeat remained diffuse. The toxicity of the CAG-encoded ataxin-2 protein was also sensitive to the translation factor eIF4H, a known modifier of the toxic GGGGCC repeat in flies. These data indicate that ataxin-2 encoded by a pure CAG vs interrupted CAA/G polyQ repeat domain is associated with differential toxicity, indicating that mechanisms associated with the purity of the sequence of the polyQ domain contribute to disease.
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http://dx.doi.org/10.1093/hmg/ddab148DOI Listing
June 2021

Folate metabolizing gene polymorphisms and genetic vulnerability to preterm birth in Korean women.

Genes Genomics 2021 May 24. Epub 2021 May 24.

Department of Biological Sciences, College of Natural Science, Dankook University, Cheonan, Korea.

Background: The folate metabolism that converts homocysteine to methionine is closely related to the accumulation of homocysteine. Increased homocysteine levels lead to an impaired antithrombotic function of the vascular endothelium and uterine-placental circulation, resulting in abnormal pregnancy outcomes. Previous studies have reported that gene polymorphisms in folate metabolism are associated with the development of preterm birth (PTB) in various populations.

Objective: we performed a case-control study to evaluate the association between five polymorphisms in folate metabolic genes (MTHFR, MTR, MTRR, TCN2) and PTB.

Methods: In this study, a total of 254 subjects were analyzed (111 patients with PTB and 143 women at ≥ 38 weeks of gestation). Genotype and allele frequency differences between patients and control groups and the Hardy-Weinberg equilibrium were assessed using a Chi-square test. For evaluation indicators, odds ratios (ORs) of 95% confidence intervals (CI) were estimated. In addition, we analyzed the combined genotype frequencies of SNPs of folate-metabolizing genes to measure gene-gene interactions for PTB.

Results: Our results showed that the MTR rs1805087 GG (p = 0.031), and TCN2 rs1801198 CG genotype (OR 0.53, 95% CI 0.288-0.980, p = 0.042) were significantly associated with PTB. The MTHFR rs4846049 AA showed a marginal trend toward significance (OR 0.15, 95% CI 0.018-1.205, p = 0.041). In particular, the combined genotypes, including MTHFR rs1537514 CC-MTRR rs1801394 GG, MTHFR rs1537514 CC-TCN2 rs1801198 CG, and MTR rs1805087 AA-TCN2 rs1801198 CG, have significant interactions with PTB (OR 0.49, 95% CI 0.248-0.992, p < 0.05).

Conclusion: The polymorphisms of folate metabolic genes may have a genetic association with the development of PTB in Korean women. A larger sample set and functional studies are required to further elucidate our findings.
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http://dx.doi.org/10.1007/s13258-021-01082-3DOI Listing
May 2021

Comparisons of Efficacy and Safety between Triple (Inhaled Corticosteroid/Long-Acting Muscarinic Antagonist/Long-Acting Beta-Agonist) Therapies in Chronic Obstructive Pulmonary Disease: Systematic Review and Bayesian Network Meta-Analysis.

Respiration 2021 May 10:1-13. Epub 2021 May 10.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Jongno-Gu, Seoul, Republic of Korea.

Background: Various combinations of inhaled corticosteroid (ICS), long-acting muscarinic antagonist (LAMA), and long-acting beta-agonist (LABA) have been used as triple therapy for stable chronic obstructive pulmonary disease (COPD).

Objective: Our study was conducted to answer whether there were significant differences among various combinations in efficacy, for reducing exacerbation or mortality, and in safety, for increasing cardiovascular events or pneumonia.

Method: We searched parallel-group randomized controlled trials (RCTs) comparing ICS/LAMA/LABA with other inhaled drugs in patients with stable COPD for at least 12 weeks in PubMed, EMBASE, the Cochrane Library, and clinical trial registries from inception to December 31, 2019. We conducted a network meta-analysis with Bayesian statistics using a random-effects model with heterogeneous variance structure (PROSPERO, CRD42019126757).

Results: Nine different combinations of ICS/LAMA/LABA were identified in 21 RCTs containing 29,892 patients with moderate to very severe COPD. We could not find any significant evidence suggesting a better treatment for reducing total exacerbations or all-cause mortality among ICS/LAMA/LABA combinations. There were also no significant differences in moderate to severe exacerbation, COPD-related mortality, or cardiovascular disease-related mortality among ICS/LAMA/LABA combinations, and the risk of major adverse cardiovascular events was not different. A significantly lower risk of pneumonia was found in fluticasone propionate (FP)/glycopyrrolate/salmeterol (SAL) than FP/tiotropium/SAL {median odds ratio [OR] (95% credible interval [CrI]) = 0 [0-0.72]} and FP/umeclidinium/SAL {median OR (95% Crl) = 0 [0-0.97]}.

Conclusion: There were no significant differences in clinical outcomes, including acute exacerbation and all-cause mortality among various ICS/LAMA/LABA combinations in patients with moderate to very severe COPD.
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http://dx.doi.org/10.1159/000515133DOI Listing
May 2021

Peroxiredoxin 5 is involved in cancer cell invasion and tumor growth of oral squamous cell carcinoma.

Oral Dis 2021 May 9. Epub 2021 May 9.

Department of Dental Hygiene, College of Health Science, Eulji University, Republic of Korea.

Objectives: Peroxiredoxins (Prxs) are antioxidant enzymes that can coordinate cell signal transduction via reactive species scavenging or by acting as redox sensors. The mechanism by which Prxs promote cancer invasion and progression is not yet fully understood. This study aims to elucidate the precise mechanism through which Prx type 5 (Prx5) promotes cancer invasion and tumor growth.

Materials And Methods: We analyzed the Prx5 expression in oral squamous cell carcinoma (OSCC) by using microarray analysis for gene expression profiling. To identify Prx5 function in cancer, lentiviral short hairpin RNA was used for Prx5 depletion, and invasion assay and mouse xenograft were performed.

Results: In microarray data obtained from OSCC patients, Prx5 showed higher expression at the tumor margin (TM) compared to the tumor center (TC) of the collective invasion. The depletion of Prx5 in OSCC cells (Prx5 ) led to decreased invasion activity. In orthotopic xenograft models, Prx5 cells harbored delimited tumorigenicity compared to wild-type cells as well as the suppression of lymph node metastasis. Prx5 cells showed growth retardation and increased cellular reactive oxygen species (ROS) levels. The growth retardation of Prx5 cells resulted in G1 phase arrest.

Conclusions: This study provides evidence that Prx5 removes excess ROS, especially in the TM, contributing to cancer invasion and tumor progression.
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http://dx.doi.org/10.1111/odi.13910DOI Listing
May 2021

A systematic review and meta-analysis of regional risk factors for critical outcomes of COVID-19 during early phase of the pandemic.

Sci Rep 2021 05 7;11(1):9784. Epub 2021 May 7.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

The mortality rates of COVID-19 vary across the globe. While some risk factors for poor prognosis of the disease are known, regional differences are suspected. We reviewed the risk factors for critical outcomes of COVID-19 according to the location of the infected patients, from various literature databases from January 1 through June 8, 2020. Candidate variables to predict the outcome included patient demographics, underlying medical conditions, symptoms, and laboratory findings. The risk factors in the overall population included sex, age, and all inspected underlying medical conditions. Symptoms of dyspnea, anorexia, dizziness, fatigue, and certain laboratory findings were also indicators of the critical outcome. Underlying respiratory disease was associated higher risk of the critical outcome in studies from Asia and Europe, but not North America. Underlying hepatic disease was associated with a higher risk of the critical outcome from Europe, but not from Asia and North America. Symptoms of vomiting, anorexia, dizziness, and fatigue were significantly associated with the critical outcome in studies from Asia, but not from Europe and North America. Hemoglobin and platelet count affected patients differently in Asia compared to those in Europe and North America. Such regional discrepancies should be considered when treating patients with COVID-19.
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http://dx.doi.org/10.1038/s41598-021-89182-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105319PMC
May 2021

Enhancing Thermocatalytic Activities by Upshifting the d-Band Center of Exsolved Co-Ni-Fe Ternary Alloy Nanoparticles for the Dry Reforming of Methane.

Angew Chem Int Ed Engl 2021 May 7. Epub 2021 May 7.

School of Energy and Chemical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.

Dry reforming of methane (DRM) is a feasible solution to address the reduction of greenhouse gases stipulated by the Paris Climate Agreement, given that it adds value by converting trivial gases, CO and CH , simultaneously into useful syngas. However, the conventional Ni catalyst undergoes deactivation due to carbon coking and particle agglomeration. Here we demonstrate a highly efficient and durable DRM catalyst: exsolved Co-Ni-Fe ternary alloy nanoparticles on the layered perovskite PrBaMn Co Ni O produced by topotactic exsolution. This method readily allows the generation of a larger number of exsolved nanoparticles with enhanced catalytic activity above that of Ni monometallic and Co-Ni bimetallic particles. The enhancement is achieved by the upshift of the d-band center of Co-Ni-Fe relative to those of Co-Ni and Ni, meaning easier charge donation to the adsorbate. Furthermore, the exsolved catalyst shows exceptional stability, with continuous DRM operation for about 350 hours.
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http://dx.doi.org/10.1002/anie.202101335DOI Listing
May 2021

Reply: Effect of Cyclic Compressive Forces on New Bone Formation during the Distraction Period in Mandibular Distraction Osteogenesis Using a Microactuator-Generated Distractor.

Plast Reconstr Surg 2021 Jun;147(6):1073e-1074e

Division of Anatomy and Developmental Biology, Department of Oral Biology, Human Identification Research Institute, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.

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http://dx.doi.org/10.1097/PRS.0000000000007948DOI Listing
June 2021

Primary malignant mucosal melanoma of the maxillofacial area.

J Korean Assoc Oral Maxillofac Surg 2021 Apr;47(2):76-81

Department of Oral and Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul, Korea.

Objectives: We aimed to collect and report data from all patients who have been diagnosed with mucosal malignant melanoma to obtain the epidemiology and principles of current treatments.

Materials And Methods: Between January 2008 and December 2018, 20 patients underwent surgery or follow-up observations at Yonsei University Dental Hospital. The patients' clinical information was reviewed retrospectively.

Results: Seventeen of 20 patients had undergone definitive surgery, while only 6 patients received adjuvant radiotherapy or systemic therapy. Eight of 20 patients, including those that had recurrent lesions, were provided immunotherapy. The 3-year survival for all stages was 50%, with a local recurrence rate of 75% and a metastasis rate of 65%.

Conclusion: The overall survival of patients receiving surgical treatment was longer than that of patients who did not undergo surgical resection. Eight of 20 patients received immunotherapy as the first-line regimen at our clinic, and those patients exhibited longer overall survival compared to patients in reported keynote studies.
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http://dx.doi.org/10.5125/jkaoms.2021.47.2.76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084745PMC
April 2021

Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation.

Cells 2021 Mar 18;10(3). Epub 2021 Mar 18.

Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 41944, Korea.

Transactive response DNA-binding protein 43 (TDP-43) is a ubiquitously expressed DNA/RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 has been implicated in numerous aspects of the mRNA life cycle, as well as in cell toxicity and neuroinflammation. In this study, we used the toxicity of the TDP-43 expression in as an assay to identify genetic interactions. Specifically, we transformed human cDNAs of wild-type or disease-associated mutants ( and ) en masse into 4653 homozygous diploid yeast deletion mutants and then used next-generation sequencing readouts of growth to identify yeast toxicity modifiers. Genetic interaction analysis provided a global view of TDP-43 pathways, some of which are known to be involved in cellular metabolic processes. Selected putative loci with the potential of genetic interactions with were assessed for associations with neurotoxicity and inflammatory activation of astrocytes. The pharmacological inhibition of succinate dehydrogenase flavoprotein subunit A (SDHA) and voltage-dependent anion-selective channel 3 (VDAC3) suppressed TDP-43-induced expression of proinflammatory cytokines in astrocytes, indicating the critical roles played by SDHA and VDAC3 in TDP-43 pathways during inflammatory activation of astrocytes and neuroinflammation. Thus, the findings of our genetic interaction screen provide a global landscape of TDP-43 pathways and may help improve our understanding of the roles of glia and neuroinflammation in ALS and FTD pathogenesis.
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http://dx.doi.org/10.3390/cells10030676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003223PMC
March 2021

C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent nuclear accumulation of Staufen in neurons.

Hum Mol Genet 2021 Jun;30(12):1084-1100

Department of Brain & Cognitive Sciences, DGIST, Daegu 42988, Republic of Korea.

RNA-binding proteins (RBPs) play essential roles in diverse cellular processes through post-transcriptional regulation of RNAs. The subcellular localization of RBPs is thus under tight control, the breakdown of which is associated with aberrant cytoplasmic accumulation of nuclear RBPs such as TDP-43 and FUS, well-known pathological markers for amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). Here, we report in Drosophila model for ALS/FTD that nuclear accumulation of a cytoplasmic RBP Staufen may be a new pathological feature. We found that in Drosophila C4da neurons expressing PR36, one of the arginine-rich dipeptide repeat proteins (DPRs), Staufen accumulated in the nucleus in Importin- and RNA-dependent manner. Notably, expressing Staufen with exogenous NLS-but not with mutated endogenous NLS-potentiated PR-induced dendritic defect, suggesting that nuclear-accumulated Staufen can enhance PR toxicity. PR36 expression increased Fibrillarin staining in the nucleolus, which was enhanced by heterozygous mutation of stau (stau+/-), a gene that codes Staufen. Furthermore, knockdown of fib, which codes Fibrillarin, exacerbated retinal degeneration mediated by PR toxicity, suggesting that increased amount of Fibrillarin by stau+/- is protective. stau+/- also reduced the amount of PR-induced nuclear-accumulated Staufen and mitigated retinal degeneration and rescued viability of flies expressing PR36. Taken together, our data show that nuclear accumulation of Staufen in neurons may be an important pathological feature contributing to the pathogenesis of ALS/FTD.
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http://dx.doi.org/10.1093/hmg/ddab089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188407PMC
June 2021

Postoperative Concurrent Chemoradiotherapy Radiotherapy Alone for Advanced Oral Cavity Cancer in the Era of Modern Radiation Techniques.

Front Oncol 2021 12;11:619372. Epub 2021 Mar 12.

Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

Background/purpose: Surgery followed by postoperative radiotherapy (RT) has been considered the standard treatment for oral cavity squamous cell carcinoma (OCSCC) of advanced stages or with adverse prognostic factors. In this study, we compared the outcomes in patients with OCSCC who received postoperative concurrent chemoradiotherapy (CCRT) or postoperative RT alone using modern RT techniques.

Methods: A total of 275 patients with OCSCC treated between 2002 and 2018 were retrospectively analyzed. Adverse prognostic factor was defined as extranodal extension (ENE), microscopically involved surgical margin, involvement of ≥2 lymph nodes, perineural disease, and/or lymphovascular invasion (LVI). In total, 148 patients (54%) received CCRT and 127 patients (46%) received RT alone. More patients in the CCRT group had N3 disease and stage IVB disease (46.6% 10.2%, <0.001), ENE (56.1% 15.7%, <0.001), LVI (28.4% 13.4%, =0.033).

Results: With a median follow-up of 40 (range, 5-203) months, there were no significant differences in the 5-year overall survival (OS) and PFS between treatment groups. In the subgroup analysis according to high risk, the concurrent use of chemotherapy showed significantly improved OS in patients with ENE (HR 0.39, =0.003).

Conclusion: Our retrospective study showed that postoperative CCRT group had comparable survival outcomes to those in the RT alone group for advanced OCSCC in the era of modern RT techniques and indicated that concurrent chemotherapy should be administered to patients with ENE. Prospective randomized studies for confirmation are needed.
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http://dx.doi.org/10.3389/fonc.2021.619372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994509PMC
March 2021

Prediction of patients requiring intensive care for COVID-19: development and validation of an integer-based score using data from Centers for Disease Control and Prevention of South Korea.

J Intensive Care 2021 Jan 29;9(1):16. Epub 2021 Jan 29.

The Armed Forces Medical Command, Ministry of National Defense, 81, Saemaeul-ro 177, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea.

Background: Unavailability or saturation of the intensive care unit may be associated with the fatality of COVID-19. Prioritizing the patients for hospitalization and intensive care may be critical for reducing the fatality of COVID-19. This study aimed to develop and validate a new integer-based scoring system for predicting patients with COVID-19 requiring intensive care, using only the predictors available upon triage.

Methods: This is a retrospective study using cohort data from the Korean Centers for Disease Control and Prevention that included all admitted patients with COVID-19 between January 19 and June 3, 2020, in South Korea. The primary outcome was patients requiring intensive care defined as actual admission to the intensive care unit; at any time use of an extracorporeal life support device, mechanical ventilation, or vasopressors; and death. Patients admitted until March 20 were included for the training dataset to develop the prediction models and externally validated for the patients admitted afterward. Two logistic regression models were developed with different predictors and the predictive performance was compared: one with patient-provided variables and the other with added radiologic and laboratory variables. An integer-based scoring system was developed based on the developed logistic regression model.

Results: A total of 5193 patients were considered, with 4663 patients included after excluding patients with age under 18 or insufficient data. For the training dataset, 3238 patients were included. Of the included patients, 444 (9.5%) patients required intensive care. The model developed with only the clinical variables showed an area under the curve of 0.884 for the validation set. The performance did not differ when radiologic and laboratory variables were added. Seven variables were selected for developing an integer-based scoring system: age, sex, initial body temperature, dyspnea, hemoptysis, history of chronic kidney disease, and activities of daily living. The area under the curve of the scoring system was 0.880.

Conclusions: An integer-based scoring system was developed for predicting patients with COVID-19 requiring intensive care, with high performance. This system may aid decision support for prioritizing the patient for hospitalization and intensive care, particularly in a situation with limited medical resources.
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http://dx.doi.org/10.1186/s40560-021-00527-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844778PMC
January 2021

Handheld Near-Infrared Fluorescence Imaging Device Using Modified Action Cameras for Peri-Operative Guidance of Microvascular Flap Surgery.

J Clin Med 2021 Jan 21;10(3). Epub 2021 Jan 21.

Department of Oral & Maxillofacial Surgery, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.

Indocyanine green near-infrared fluorescence (ICG-NIRF) imaging has recently come into use as a novel method in peri-operative microvascular flap assessment. However, a majority of the many commercial devices launched for clinical use lack mobility, portability, and cost-efficiency and are thus unsuitable for intra-oral applications. This study introduces a cost-effective, customized, handheld NIRF device following principles of ICG-NIRF imaging. Moreover, the novel characteristics of our prototype, considered in conjunction with a literature review highlighting the significance of fluorescence devices in microvascular surgery, point to a new generation of devices for use in microvascular flap surgery.
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http://dx.doi.org/10.3390/jcm10030410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865367PMC
January 2021

In Vivo Study for Clinical Application of Dental Stem Cell Therapy Incorporated with Dental Titanium Implants.

Materials (Basel) 2021 Jan 14;14(2). Epub 2021 Jan 14.

BK21 Plus Project, Oral Science Research Center, Department of Prosthodontics, Yonsei University College of Dentistry, Seoul 03722, Korea.

The aim of this study was to investigate the behavior of dental-derived human mesenchymal stem cells (d-hMSCs) in response to differently surface-treated implants and to evaluate the effect of d-hMSCs on local osteogenesis around an implant in vivo. d-hMSCs derived from alveolar bone were established and cultured on machined, sandblasted and acid-etched (SLA)-treated titanium discs with and without osteogenic induction medium. Their morphological and osteogenic potential was assessed by scanning electron microscopy (SEM) and real-time polymerase chain reaction (RT-PCR) via mixing of 5 × 10 of d-hMSCs with 1 mL of Metrigel and 20 μL of gel-cell mixture, which was dispensed into the defect followed by the placement of customized mini-implants (machined, SLA-treated implants) in New Zealand white rabbits. Following healing periods of 2 weeks and 12 weeks, the obtained samples in each group were analyzed radiographically, histomorphometrically and immunohistochemically. The quantitative change in osteogenic differentiation of d-hMSCs was identified according to the type of surface treatment. Radiographic analysis revealed that an increase in new bone formation was statistically significant in the d-hMSCs group. Histomorphometric analysis was in accordance with radiographic analysis, showing the significantly increased new bone formation in the d-hMSCs group regardless of time of sacrifice. Human nuclei A was identified near the area where d-hMSCs were implanted but the level of expression was found to be decreased as time passed. Within the limitations of the present study, in this animal model, the transplantation of d-hMSCs enhanced the new bone formation around an implant and the survival and function of the stem cells was experimentally proven up to 12 weeks post-sacrifice.
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http://dx.doi.org/10.3390/ma14020381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829878PMC
January 2021

Impact of long-term exposure to ambient air pollution on the incidence of chronic obstructive pulmonary disease: A systematic review and meta-analysis.

Environ Res 2021 03 6;194:110703. Epub 2021 Jan 6.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, South Korea. Electronic address:

Background: It is well known that air pollution causes respiratory morbidity and mortality by inducing airway inflammation. However, whether long-term exposure to air pollution is associated with increased incidence of chronic obstructive pulmonary disease (COPD) is controversial.

Methods: We conducted a systematic review and meta-analysis with a random-effects model to calculate the pooled risk estimates of COPD development per 10 μg/m increase in individual air pollutants. PubMed, Embase, and Cochrane Library were searched from the date of their inception to August 2019 to identify long-term (at least three years of observation) prospective longitudinal studies that reported the risk of COPD development due to exposure to air pollutants. The air pollutants studied included particulate matter (PM and PM) and nitrogen dioxide (NO).

Results: Of the 436 studies identified, seven met our eligibility criteria. Among the seven studies, six, three, and five had data on PM, PM, and NO, respectively. The meta-analysis results showed that a 10 μg/m increase in PM is associated with increased incidence of COPD (pooled HR 1.18, 95% CI 1.13-1.23). We also noted that a 10 μg/m increase in NO is marginally associated with increased incidence of COPD (pooled HR 1.07, 95% CI 1.00-1.16). PM seems to have no significant impact on the incidence of COPD (pooled HR 0.95, 95% CI 0.83-1.08), although the number of studies was too small. Meta-regression analysis found no significant effect modifiers.

Conclusions: Long-term exposure to PM and NO can be associated with increased incidence of COPD.
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http://dx.doi.org/10.1016/j.envres.2020.110703DOI Listing
March 2021

The complete mitochondrial genome of a marbled eelpout (Perciformes: Zoarcidae).

Mitochondrial DNA B Resour 2019 Nov 13;4(2):4043-4044. Epub 2019 Nov 13.

National Marine Biodiversity Institute of Korea, Seocheon, Republic of Korea.

In this study, the complete mitochondrial genome of the marbled eelpout, Taranetz & Andriashev, 1937 was sequenced using the primer walking method. The mitogenome was 16,569 bp in length and encoded with 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and one Non-Coding Region. The overall nucleotide composition of is 25.5%, 25.3%, 18.7%, and 30.5% for A, T, G, and C, respectively. Phylogenetic analysis using the ML method showed that was clustered into one branch with and .
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http://dx.doi.org/10.1080/23802359.2019.1688698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707741PMC
November 2019

Role of the Variant in Vascular Outcomes in Patients With Intracranial Atherosclerosis.

J Am Heart Assoc 2021 01 25;10(1):e017660. Epub 2020 Dec 25.

Department of Neurology School of Medicine Samsung Medical CenterSungkyunkwan University Seoul South Korea.

Background The ( gene) variant R4810K is a susceptibility allele not only for Moyamoya disease (MMD) but also for intracranial atherosclerosis (ICAS) in East Asian populations. We hypothesized that this variant would affect the distribution of ICAS and recurrence of cerebrovascular events. Methods and Results We conducted a prospective study of patients with ICAS and MMD using high-resolution magnetic resonance imaging and R4810K genotyping. Patients were included in the ICAS group when relevant plaques existed on high-resolution magnetic resonance imagingand in the MMD group when they carried the variant and high-resolution magnetic resonance imaging showed no plaques but characteristic features of MMD. We compared clinical and neuroimaging features of patients with ICAS-+ with patients with ICAS-- and of patients with MMD. Of 477 patients, 238 patients were in the ICAS group and 239 were in the MMD group. Among patients with ICAS, 79 patients (33.2%) were in the ICAS-+ group and 159 (66.8%) in the ICAS-- group. Tandem lesions were significantly more common in the ICAS- group than in the ICAS-- group (40.3% versus 72.2%, <0.001), and their distributions were similar between the ICAS- and MMD groups. The presence of the R4810K variant (hazard ratio [HR], 3.203; 95% CI, 1.149-9.459; =0.026) and tandem lesions (≥3) (HR, 8.315; 95% CI, 1.930-39.607; =0.005) were independently associated with recurrent cerebrovascular events. Conclusions Patients with ICAS carrying the R4810K variant showed clinical and imaging features distinct from patients with ICAS without the variant, suggesting that the R4810K variant plays a role in intracranial atherosclerosis in East Asian patients.
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http://dx.doi.org/10.1161/JAHA.120.017660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955464PMC
January 2021

Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3.

Elife 2020 12 11;9. Epub 2020 Dec 11.

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

Cytoplasmic accumulation of TDP-43 in motor neurons is the most prominent pathological feature in amyotrophic lateral sclerosis (ALS). A feedback cycle between nucleocytoplasmic transport (NCT) defect and TDP-43 aggregation was shown to contribute to accumulation of TDP-43 in the cytoplasm. However, little is known about cellular factors that can control the activity of NCT, thereby affecting TDP-43 accumulation in the cytoplasm. Here, we identified via FRAP and optogenetics cytosolic calcium as a key cellular factor controlling NCT of TDP-43. Dynamic and reversible changes in TDP-43 localization were observed in sensory neurons during development. Genetic and immunohistochemical analyses identified the cytosolic calcium-Calpain-A-Importin α3 pathway as a regulatory mechanism underlying NCT of TDP-43. In ALS fly models, upregulation of the pathway activity by increasing cytosolic calcium reduced cytoplasmic accumulation of TDP-43 and mitigated behavioral defects. Together, these results suggest the calcium-Calpain-A-Importin α3 pathway as a potential therapeutic target of ALS.
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http://dx.doi.org/10.7554/eLife.60132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748415PMC
December 2020

Non-inferiority study of the efficacy of two hyaluronic acid products in post-extraction sockets of impacted third molars.

Maxillofac Plast Reconstr Surg 2020 Dec 9;42(1):40. Epub 2020 Dec 9.

Department of Oral & Maxillofacial Surgery, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Background: Hyaluronic acid (HA) is well known to exert an anti-inflammatory effect during oral wound healing and is commonly applied after tooth extraction. However, no double-blind randomized controlled study comparing two hyaluronate mouthwash products has been conducted so far. The aim of this study was to comparatively analyze the efficacy of Mucobarrier® and Aloclair® in terms of clinical symptoms.

Results: A total of 112 patients were randomly assigned to assess the degree of discomfort, pain reduction, redness, burning sensation, and swelling between two groups on the day of surgery and 7 days later in a double blind test, with a total 56 Aloclair patients and 56 Mucobarrier patients. There was no statistically significant difference in the overall discomfort, degree of pain reduction, redness, burning sensation, and swelling between the Mucobarrier and Aloclair groups.

Conclusion: The local application of hyaluronic acid mouth wash after wisdom tooth extraction is beneficial in reducing overall discomfort and pain reduction, and the clinical utility of Mucobarrier® is no different from Aloclair®.

Trial Registration: Institutional Review Board of Yonsei University College of Dentistry, 2-2018-0036. Registered 10 September 2018-prospectively registered, https://eirb.yuhs.ac/.
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http://dx.doi.org/10.1186/s40902-020-00287-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726083PMC
December 2020

The Role of HDAC6 in TDP-43-Induced Neurotoxicity and UPS Impairment.

Front Cell Dev Biol 2020 17;8:581942. Epub 2020 Nov 17.

Dementia Research Group, Korea Brain Research Institute, Daegu, South Korea.

Transactive response DNA-binding protein 43 (TDP-43)-induced neurotoxicity is currently well recognized as a contributor to the pathology of amyotrophic lateral sclerosis (ALS), and the deposition of TDP-43 has been linked to other neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Recent studies also suggest that TDP-43-induced neurotoxicity is associated with ubiquitin-proteasome system (UPS) impairment. Histone deacetylase 6 (HDAC6) is a well-known cytosolic deacetylase enzyme that suppresses the toxicity of UPS impairment. However, the role of HDAC6 in TDP-43-induced neurodegeneration is largely unknown. In this study, we found that HDAC6 overexpression decreased the levels of insoluble and cytosolic TDP-43 protein in TDP-43-overexpressing N2a cells. In addition, TDP-43 overexpression upregulated HDAC6 protein and mRNA levels, and knockdown of elevated the total protein level of TDP-43. We further found that HDAC6 modulates TDP-43-induced UPS impairment via the autophagy-lysosome pathway (ALP). We also showed that TDP-43 promoted a short lifespan in flies and that the accumulation of ubiquitin aggregates and climbing defects were significantly rescued by overexpression of HDAC6 in flies. Taken together, these findings suggest that HDAC6 overexpression can mitigate neuronal toxicity caused by TDP-43-induced UPS impairment, which may represent a novel therapeutic approach for ALS.
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http://dx.doi.org/10.3389/fcell.2020.581942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705063PMC
November 2020

The Role of Glial Mitochondria in α-Synuclein Toxicity.

Front Cell Dev Biol 2020 11;8:548283. Epub 2020 Nov 11.

Dementia Research Group, Korea Brain Research Institute, Daegu, South Korea.

The abnormal accumulation of alpha-synuclein (α-syn) aggregates in neurons and glial cells is widely known to be associated with many neurodegenerative diseases, including Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and Multiple system atrophy (MSA). Mitochondrial dysfunction in neurons and glia is known as a key feature of α-syn toxicity. Studies aimed at understanding α-syn-induced toxicity and its role in neurodegenerative diseases have primarily focused on neurons. However, a growing body of evidence demonstrates that glial cells such as microglia and astrocytes have been implicated in the initial pathogenesis and the progression of α-Synucleinopathy. Glial cells are important for supporting neuronal survival, synaptic functions, and local immunity. Furthermore, recent studies highlight the role of mitochondrial metabolism in the normal function of glial cells. In this work, we review the complex relationship between glial mitochondria and α-syn-mediated neurodegeneration, which may provide novel insights into the roles of glial cells in α-syn-associated neurodegenerative diseases.
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http://dx.doi.org/10.3389/fcell.2020.548283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686475PMC
November 2020

New-onset nontuberculous mycobacterial pulmonary disease in bronchiectasis: tracking the clinical and radiographic changes.

BMC Pulm Med 2020 Nov 10;20(1):293. Epub 2020 Nov 10.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 110-744, South Korea.

Background: The close association between bronchiectasis and nontuberculous mycobacterial pulmonary disease (NTM-PD) is well-known. However, the clinical impact of subsequent new-onset NTM-PD in bronchiectasis patients has not been elucidated. The aim of this study is to investigate the clinical courses and radiographic changes of patients with bronchiectasis in whom NTM-PD subsequently developed.

Methods: A total of 221 patients with bronchiectasis who had participated in a non-NTM bronchiectasis cohort between July 1st 2011 and August 31st 2019 at Seoul National University Hospital were included in this study. The data of patients in whom NTM-PD developed during this observation period were analyzed; specifically, changes in the Bronchiectasis Severity Index (BSI) and lesions on computerized tomography (CT) scan of the chest arising during the observation period.

Results: During the observation period, NTM was isolated from 35 patients. A total of 31 patients (14.0%) satisfied the diagnostic criteria of NTM-PD. The median time from enrollment in the cohort to the development of subsequent NTM-PD was 37 months (Interquartile range [IQR], 18-78 months). Mycobacterium avium complex was the most common pathogen (80.6%). Twelve patients underwent antibiotic treatment for NTM-PD with a median interval of 20 months (IQR, 13-30) from the time of NTM-PD diagnosis. When NTM-PD developed, the severity and extent of bronchiectasis, cellular bronchiolitis, and the extent of nodules worsened on CT scans, while BSI did not change.

Conclusions: NTM-PD can develop in previously negative bronchiectasis patients. It is associated with worsening radiographic lesions. Active screening of non-NTM bronchiectasis patients for new-onset NTM infection should be considered, especially if radiographic findings worsen. The BSI is not a reliable predictor of new-onset NTM-PD.

Trial Registration: This study was performed at Seoul National University Hospital ( NCT01616745 ).
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http://dx.doi.org/10.1186/s12890-020-01331-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653824PMC
November 2020

An Easy-to-Use Machine Learning Model to Predict the Prognosis of Patients With COVID-19: Retrospective Cohort Study.

J Med Internet Res 2020 11 9;22(11):e24225. Epub 2020 Nov 9.

The Armed Forces Medical Command, Seongnam, Republic of Korea.

Background: Prioritizing patients in need of intensive care is necessary to reduce the mortality rate during the COVID-19 pandemic. Although several scoring methods have been introduced, many require laboratory or radiographic findings that are not always easily available.

Objective: The purpose of this study was to develop a machine learning model that predicts the need for intensive care for patients with COVID-19 using easily obtainable characteristics-baseline demographics, comorbidities, and symptoms.

Methods: A retrospective study was performed using a nationwide cohort in South Korea. Patients admitted to 100 hospitals from January 25, 2020, to June 3, 2020, were included. Patient information was collected retrospectively by the attending physicians in each hospital and uploaded to an online case report form. Variables that could be easily provided were extracted. The variables were age, sex, smoking history, body temperature, comorbidities, activities of daily living, and symptoms. The primary outcome was the need for intensive care, defined as admission to the intensive care unit, use of extracorporeal life support, mechanical ventilation, vasopressors, or death within 30 days of hospitalization. Patients admitted until March 20, 2020, were included in the derivation group to develop prediction models using an automated machine learning technique. The models were externally validated in patients admitted after March 21, 2020. The machine learning model with the best discrimination performance was selected and compared against the CURB-65 (confusion, urea, respiratory rate, blood pressure, and 65 years of age or older) score using the area under the receiver operating characteristic curve (AUC).

Results: A total of 4787 patients were included in the analysis, of which 3294 were assigned to the derivation group and 1493 to the validation group. Among the 4787 patients, 460 (9.6%) patients needed intensive care. Of the 55 machine learning models developed, the XGBoost model revealed the highest discrimination performance. The AUC of the XGBoost model was 0.897 (95% CI 0.877-0.917) for the derivation group and 0.885 (95% CI 0.855-0.915) for the validation group. Both the AUCs were superior to those of CURB-65, which were 0.836 (95% CI 0.825-0.847) and 0.843 (95% CI 0.829-0.857), respectively.

Conclusions: We developed a machine learning model comprising simple patient-provided characteristics, which can efficiently predict the need for intensive care among patients with COVID-19.
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http://dx.doi.org/10.2196/24225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655730PMC
November 2020

NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases.

J Cell Biol 2020 12;219(12)

Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea.

Dendrite pathology is frequently observed in various neurodegenerative diseases (NDs). Although previous studies identified several pathogenic mediators of dendrite defects that act through loss of function in NDs, the underlying pathogenic mechanisms remain largely unexplored. Here, our search for additional pathogenic contributors to dendrite defects in NDs identifies Relish/NF-κB as a novel gain-of-toxicity-based mediator of dendrite defects in animal models for polyglutamine (polyQ) diseases and amyotrophic lateral sclerosis (ALS). In a Drosophila model for polyQ diseases, polyQ-induced dendrite defects require Dredd/Caspase-8-mediated endoproteolytic cleavage of Relish to generate the N-terminal fragment, Rel68, and subsequent Charon-mediated nuclear localization of Rel68. Rel68 alone induced neuronal toxicity causing dendrite and behavioral defects, and we identify two novel transcriptional targets, Tup and Pros, that mediate Rel68-induced neuronal toxicity. Finally, we show that Rel68-induced toxicity also contributes to dendrite and behavioral defects in a Drosophila model for ALS. Collectively, our data propose disinhibition of latent toxicity of Relish/NF-κB as a novel pathogenic mechanism underlying dendrite pathology in NDs.
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http://dx.doi.org/10.1083/jcb.202004107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588142PMC
December 2020

A Patient Self-Checkup App for COVID-19: Development and Usage Pattern Analysis.

J Med Internet Res 2020 11 6;22(11):e19665. Epub 2020 Nov 6.

Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea.

Background: Clear guidelines for a patient with suspected COVID-19 infection are unavailable. Many countries rely on assessments through a national hotline or telecommunications, but this only adds to the burden of an already overwhelmed health care system. In this study, we developed an algorithm and a web application to help patients get screened.

Objective: This study aims to aid the general public by developing a web-based application that helps patients decide when to seek medical care during a novel disease outbreak.

Methods: The algorithm was developed via consultations with 6 physicians who directly screened, diagnosed, and/or treated patients with COVID-19. The algorithm mainly focused on when to test a patient in order to allocate limited resources more efficiently. The application was designed to be mobile-friendly and deployed on the web. We collected the application usage pattern data from March 1 to March 27, 2020. We evaluated the association between the usage pattern and the numbers of COVID-19 confirmed, screened, and mortality cases by access location and digital literacy by age group.

Results: The algorithm used epidemiological factors, presence of fever, and other symptoms. In total, 83,460 users accessed the application 105,508 times. Despite the lack of advertisement, almost half of the users accessed the application from outside of Korea. Even though the digital literacy of the 60+ years age group is half of that of individuals in their 50s, the number of users in both groups was similar for our application.

Conclusions: We developed an expert-opinion-based algorithm and web-based application for screening patients. This innovation can be helpful in circumstances where information on a novel disease is insufficient and may facilitate efficient medical resource allocation.
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http://dx.doi.org/10.2196/19665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652594PMC
November 2020

The overexpression of TDP-43 in astrocytes causes neurodegeneration via a PTP1B-mediated inflammatory response.

J Neuroinflammation 2020 Oct 14;17(1):299. Epub 2020 Oct 14.

Dementia Research Group, Korea Brain Research Institute (KBRI), Daegu, 41062, South Korea.

Background: Cytoplasmic inclusions of transactive response DNA binding protein of 43 kDa (TDP-43) in neurons and astrocytes are a feature of some neurodegenerative diseases, such as frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). However, the role of TDP-43 in astrocyte pathology remains largely unknown.

Methods: To investigate whether TDP-43 overexpression in primary astrocytes could induce inflammation, we transfected primary astrocytes with plasmids encoding Gfp or TDP-43-Gfp. The inflammatory response and upregulation of PTP1B in transfected cells were examined using quantitative RT-PCR and immunoblot analysis. Neurotoxicity was analysed in a transwell coculture system of primary cortical neurons with astrocytes and cultured neurons treated with astrocyte-conditioned medium (ACM). We also examined the lifespan, performed climbing assays and analysed immunohistochemical data in pan-glial TDP-43-expressing flies in the presence or absence of a Ptp61f RNAi transgene.

Results: PTP1B inhibition suppressed TDP-43-induced secretion of inflammatory cytokines (interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α)) in primary astrocytes. Using a neuron-astrocyte coculture system and astrocyte-conditioned media treatment, we demonstrated that PTP1B inhibition attenuated neuronal death and mitochondrial dysfunction caused by overexpression of TDP-43 in astrocytes. In addition, neuromuscular junction (NMJ) defects, a shortened lifespan, inflammation and climbing defects caused by pan-glial overexpression of TDP-43 were significantly rescued by downregulation of ptp61f (the Drosophila homologue of PTP1B) in flies.

Conclusions: These results indicate that PTP1B inhibition mitigates the neuronal toxicity caused by TDP-43-induced inflammation in mammalian astrocytes and Drosophila glial cells.
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http://dx.doi.org/10.1186/s12974-020-01963-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556969PMC
October 2020

The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies.

Exp Mol Med 2020 10 13;52(10):1652-1662. Epub 2020 Oct 13.

Dementia Research Group, Korea Brain Research Institute (KBRI), Daegu, 41062, South Korea.

TAR DNA-binding protein 43 (TDP-43) is a highly conserved nuclear RNA/DNA-binding protein involved in the regulation of RNA processing. The accumulation of TDP-43 aggregates in the central nervous system is a common feature of many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Accumulating evidence suggests that prion-like spreading of aberrant protein aggregates composed of tau, amyloid-β, and α-synuclein is involved in the progression of neurodegenerative diseases such as AD and PD. Similar to those of prion-like proteins, pathological aggregates of TDP-43 can be transferred from cell-to-cell in a seed-dependent and self-templating manner. Here, we review clinical and experimental studies supporting the prion-like spreading of misfolded TDP-43 and discuss the molecular mechanisms underlying the propagation of these pathological aggregated proteins. The idea that misfolded TDP-43 spreads in a prion-like manner between cells may guide novel therapeutic strategies for TDP-43-associated neurodegenerative diseases.
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http://dx.doi.org/10.1038/s12276-020-00513-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080625PMC
October 2020

COVID-19 Outcome Prediction and Monitoring Solution for Military Hospitals in South Korea: Development and Evaluation of an Application.

J Med Internet Res 2020 11 4;22(11):e22131. Epub 2020 Nov 4.

Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea.

Background: COVID-19 has officially been declared as a pandemic, and the spread of the virus is placing sustained demands on public health systems. There are speculations that the COVID-19 mortality differences between regions are due to the disparities in the availability of medical resources. Therefore, the selection of patients for diagnosis and treatment is essential in this situation. Military personnel are especially at risk for infectious diseases; thus, patient selection with an evidence-based prognostic model is critical for them.

Objective: This study aims to assess the usability of a novel platform used in the military hospitals in Korea to gather data and deploy patient selection solutions for COVID-19.

Methods: The platform's structure was developed to provide users with prediction results and to use the data to enhance the prediction models. Two applications were developed: a patient's application and a physician's application. The primary outcome was requiring an oxygen supplement. The outcome prediction model was developed with patients from four centers. A Cox proportional hazards model was developed. The outcome of the model for the patient's application was the length of time from the date of hospitalization to the date of the first oxygen supplement use. The demographic characteristics, past history, patient symptoms, social history, and body temperature were considered as risk factors. A usability study with the Post-Study System Usability Questionnaire (PSSUQ) was conducted on the physician's application on 50 physicians.

Results: The patient's application and physician's application were deployed on the web for wider availability. A total of 246 patients from four centers were used to develop the outcome prediction model. A small percentage (n=18, 7.32%) of the patients needed professional care. The variables included in the developed prediction model were age; body temperature; predisease physical status; history of cardiovascular disease; hypertension; visit to a region with an outbreak; and symptoms of chills, feverishness, dyspnea, and lethargy. The overall C statistic was 0.963 (95% CI 0.936-0.99), and the time-dependent area under the receiver operating characteristic curve ranged from 0.976 at day 3 to 0.979 at day 9. The usability of the physician's application was good, with an overall average of the responses to the PSSUQ being 2.2 (SD 1.1).

Conclusions: The platform introduced in this study enables evidence-based patient selection in an effortless and timely manner, which is critical in the military. With a well-designed user experience and an accurate prediction model, this platform may help save lives and contain the spread of the novel virus, COVID-19.
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http://dx.doi.org/10.2196/22131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644266PMC
November 2020

Immunopathogenesis of ANCA-Associated Vasculitis.

Int J Mol Sci 2020 Oct 3;21(19). Epub 2020 Oct 3.

Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, 08830 Barcelona, Spain.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis.
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http://dx.doi.org/10.3390/ijms21197319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584042PMC
October 2020