Publications by authors named "Jung Min Kim"

243 Publications

Perinatal outcomes and factors affecting the survival rate of fetuses with twin-to-twin transfusion syndrome treated with fetoscopic laser coagulation: a single-center seven-year experience.

J Matern Fetal Neonatal Med 2021 Apr 20:1-12. Epub 2021 Apr 20.

Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, Seoul, Republic of Korea.

Objectives: This single-center study aimed to assess the perinatal outcomes and its associated factors in fetuses with twin-to-twin transfusion syndrome (TTTS) treated by fetoscopic laser coagulation (FLC).

Methods: In this retrospective study, we included fetuses prenatally diagnosed with TTTS at Asan Medical Center, Seoul, Korea, between October 2011 and December 2018. All patients with TTTS stage II or higher and those with stage I TTTS coupled with symptomatic polyhydramnios or cardiac dysfunction were eligible for FLC.

Results: A total of 172 cases of monochorionic diamniotic twins and one case of dichorionic triamniotic triplets were prenatally diagnosed with TTTS and treated with FLC. The median gestational ages (GAs) at diagnosis and FLC were 20.3 and 20.5 weeks, respectively. The median GA of survivors at delivery was 32.5 weeks. The overall at least one twin- and double-survival rates within 28 days after birth were 82.1% and 55.5%, respectively. The GAs at diagnosis and FLC, Quintero stage, inter-twin weight discordance, associated selective intrauterine growth restriction (sIUGR), procedure time, volume of amnioreduction, preterm prelabor rupture of membranes (PPROM) within one week after FLC, intraoperative intrauterine bleeding, and chorioamnionitis were significant predictive factors of perinatal death. Associated sIUGR, absent end-diastolic flow of umbilical artery, and abnormal cord insertion were significantly associated with donor demise , whereas lower GA at diagnosis and FLC, smaller twins at FLC, pulsatile umbilical vein, and presence of mitral regurgitation were significantly associated with recipient demise . Since the application of the Solomon technique, the survival rate has improved from 75.4% to 88.8%. The FLC before 17 weeks was associated with PPROM within one week after FLC and lower survival rate, whereas that after 24 weeks was associated with twin anemia-polycythemia sequence and higher survival rate. We reached a survival rate of 82% for at least one survival with only 12 procedures.

Conclusions: FLC is an effective treatment for TTTS. The learning curve reached the acceptable target faster than in previous studies. Several prenatal parameters are identified as predictive factors of fetal survival in TTTS treated with FLC.
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http://dx.doi.org/10.1080/14767058.2021.1888286DOI Listing
April 2021

Microbiome analysis reveals that Ralstonia is responsible for decreased renal function in patients with ulcerative colitis.

Clin Transl Med 2021 Mar;11(3):e322

Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea.

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http://dx.doi.org/10.1002/ctm2.322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933010PMC
March 2021

Detecting Genetic Mobility Using a Transposon-Based Marker System in Gamma-Ray Irradiated Soybean Mutants.

Plants (Basel) 2021 Feb 15;10(2). Epub 2021 Feb 15.

Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Korea.

Transposable elements (TEs)-major components of eukaryotic genomes-have the ability to change location within a genome. Because of their mobility, TEs are important for genome diversification and evolution. Here, a simple rapid method, using the consensus terminal inverted repeat sequences of PONG, miniature inverted-repeat transposable element (MITE)-Tourist (M-t) and MITE-Stowaway (M-s) as target region amplification polymorphism (TE-TRAP) markers, was employed to investigate the mobility of TEs in a gamma-irradiated soybean mutant pool. Among the different TE-TRAP primer combinations, the average polymorphism level and polymorphism information content value were 57.98% and 0.14, respectively. Only the PONG sequence separated the mutant population into three major groups. The inter-mutant population variance, determined using the PONG marker (3.151 and 29%) was greater than that of the M-t (2.209 and 20%) and M-s (2.766 and 18%) markers, whereas the reverse was true for the intra-mutant population variations, with M-t and M-s values, being 15.151 (82%) and 8.895 (80%), respectively, compared with the PONG marker (7.646 and 71%). Thus, the MITE markers revealed more dynamic and active mobility levels than the PONG marker in gamma-ray irradiated soybean mutant lines. The TE-TRAP technique associated with sensitive MITEs is useful for investigating genetic diversity and TE mobilization, providing tools for mutant selection in soybean mutation breeding.
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http://dx.doi.org/10.3390/plants10020373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919005PMC
February 2021

The clinical importance of multifocality on tumor recurrence in papillary thyroid carcinoma.

Authors:
Jung Min Kim

Gland Surg 2021 Jan;10(1):273-278

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

Background: Although the origin of the multifocality of papillary thyroid carcinoma (PTC) is unclear, it is not unusual and has not been considered as an independent prognostic factor from several tumor staging systems. This study aims to evaluate whether the presence of multifocality is associated with PTC recurrence.

Methods: We reviewed retrospectively detailed histological reports of PTC patients who underwent thyroidectomy from January 2000 through December 2010 at a single institution. We assessed the relationship between multifocality and other possible prognostic factors using binary logistic regression analysis. We compared recurrence by the Kaplan-Meier method (the log-rank test). We analyzed a prognostic factor for recurrence using Cox's proportional hazard model (the stepwise forward method).

Results: We enrolled a total of 434 PTC patients (380 women and 54 men; mean age, 48 years). The median follow-up period was 10.2 years. Of all PTC patients enrolled, 135 patients (31%) had multifocal PTC. There was a significant association between multifocality and cervical lymph node (CLN) metastasis (P=0.01). Multivariate analyses showed a significant association between multifocality and CLN metastasis (P<0.001). Multifocal PTC patients had higher CLN metastasis and tumor recurrence than those with single PTC. There was a significant association between multifocality and tumor recurrence (P=0.03 by log-rank test), but it disappeared in multivariate analysis.

Conclusions: Multifocality of PTC might be related to CLN metastasis and tumor recurrence.
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http://dx.doi.org/10.21037/gs-20-603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882335PMC
January 2021

Multifunctional Microparticles with Stimulation and Sensing Capabilities for Facile NK Cell Activity Assay.

ACS Sens 2021 03 19;6(3):693-697. Epub 2021 Feb 19.

Research Institute of Advanced Materials (RIAM), Seoul National University, Seoul, 08826, South Korea.

Natural killer (NK) cells are a subset of innate lymphoid cells playing an important role in immune surveillance and early defense against infection and cancer. They recognize and directly kill infected or transformed cells. At the same time, they produce various cytokines and chemokines to regulate other immune cells. NK cell activity can be a useful marker for health screenings because impaired NK cell functions may indicate a more susceptible environment for infection or tumor development. Currently, most NK cell activity assays are focused on measuring either cytokine secretion, in particular, interferon γ (IFN-γ), or cytotoxicity against target cells such as K562, thus only providing partial information on NK cell activity. In order to develop a comprehensive test for measuring NK cell function, cytotoxicity and cytokine secretion ability should be measured simultaneously. In addition, current NK cell assays are performed by stimulating NK cells with cocktails of cytokines, antibody-coated beads, or live target cells. In this study, we developed multifunctional microparticles for NK cell activity assay (MNAs) that allow simultaneous stimulation and sensing various NK cell activities, including cytokine secretion and cytotoxicity. The surfaces of MNAs are decorated with multiple functional biomolecules, including antibodies that stimulate NK cells by engaging NK cell activating receptors, antibodies that can capture cytokines secreted by NK cells, and a peptide sensor that reacts with granzyme B, a key molecule released by NK cells for cytotoxicity. The performances of MNAs are assessed using flow cytometry and live cell imaging. NK cell activity is measured by simply mixing MNAs with NK cells and performing flow cytometry, and the results are comparable to those measured by standard NK cell activity assays.
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http://dx.doi.org/10.1021/acssensors.0c02138DOI Listing
March 2021

Deep-learning system for real-time differentiation between Crohn's disease, intestinal Behçet's disease, and intestinal tuberculosis.

J Gastroenterol Hepatol 2021 Feb 7. Epub 2021 Feb 7.

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

Background And Aim: Pattern analysis of big data can provide a superior direction for the clinical differentiation of diseases with similar endoscopic findings. This study aimed to develop a deep-learning algorithm that performs differential diagnosis between intestinal Behçet's disease (BD), Crohn's disease (CD), and intestinal tuberculosis (ITB) using colonoscopy images.

Methods: The typical pattern for each disease was defined as a typical image. We implemented a convolutional neural network (CNN) using Pytorch and visualized a deep-learning model through Gradient-weighted Class Activation Mapping. The performance of the algorithm was evaluated using the area under the receiver operating characteristic curve (AUROC).

Results: A total of 6617 colonoscopy images of 211 CD, 299 intestinal BD, and 217 ITB patients were used. The accuracy of the algorithm for discriminating the three diseases (all-images: 65.15% vs typical images: 72.01%, P = 0.024) and discriminating between intestinal BD and CD (all-images: 78.15% vs typical images: 85.62%, P = 0.010) was significantly different between all-images and typical images. The CNN clearly differentiated colonoscopy images of the diseases (AUROC from 0.7846 to 0.8586). Algorithmic prediction AUROC for typical images ranged from 0.8211 to 0.9360.

Conclusion: This study found that a deep-learning model can discriminate between colonoscopy images of intestinal BD, CD, and ITB. In particular, the algorithm demonstrated superior discrimination ability for typical images. This approach presents a beneficial method for the differential diagnosis of the diseases.
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http://dx.doi.org/10.1111/jgh.15433DOI Listing
February 2021

Harnessing NK cells for cancer immunotherapy: immune checkpoint receptors and chimeric antigen receptors.

BMB Rep 2021 Jan;54(1):44-58

Department of Biomedical Sciences and Stem Cell Immunomodulation Research Center (SCIRC), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; Department of Microbiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

Natural killer (NK) cells, key antitumor effectors of the innate immune system, are endowed with the unique ability to spontaneously eliminate cells undergoing a neoplastic transformation. Given their broad reactivity against diverse types of cancer and close association with cancer prognosis, NK cells have gained considerable attention as a promising therapeutic target for cancer immunotherapy. NK cell-based therapies have demonstrated favorable clinical efficacies in several hematological malignancies but limited success in solid tumors, thus highlighting the need to develop new therapeutic strategies to restore and optimize anti-tumor activity while preventing tumor immune escape. The current therapeutic modalities yielding encouraging results in clinical trials include the blockade of immune checkpoint receptors to overcome the immune-evasion mechanism used by tumors and the incorporation of tumor-directed chimeric antigen receptors to enhance NK cell anti-tumor specificity and activity. These observations, together with recent advances in the understanding of NK cell activation within the tumor microenvironment, will facilitate the optimal design of NK cell-based therapy against a broad range of cancers and, more desirably, refractory cancers. [BMB Reports 2021; 54(1): 44-58].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851441PMC
January 2021

Assessment of NK Cell Activity Based on NK Cell-Specific Receptor Synergy in Peripheral Blood Mononuclear Cells and Whole Blood.

Int J Mol Sci 2020 Oct 30;21(21). Epub 2020 Oct 30.

Asan Medical Center, Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea.

Natural killer (NK) cells are cytotoxic innate lymphocytes endowed with a unique ability to kill a broad spectrum of cancer and virus-infected cells. Given their key contribution to diverse diseases, the measurement of NK cell activity (NKA) has been used to estimate disease prognosis or the effect of therapeutic treatment. Currently, NKA assays are primarily based on cumbersome procedures related to careful labeling and handling of target cells and/or NK cells, and they require a rapid isolation of peripheral blood mononuclear cells (PBMCs) which often necessitates a large amount of blood. Here, we developed an ELISA-based whole blood (WB) NKA assay involving engineered target cells (P815-ULBP1+CD48) providing defined and synergistic stimulation for NK cells via NKG2D and 2B4. WB collected from healthy donors (HDs) and patients with multiple myeloma (MM) was stimulated with P815-ULBP1+CD48 cells combined with IL-2. Thereafter, it utilized the serum concentrations of granzyme B and IFN-γ originating in NK cells as independent and complementary indicators of NKA. This WB NKA assay demonstrated that MM patients exhibit a significantly lower NKA than HDs following stimulation with P815-ULBP1+CD48 cells and had a good correlation with the commonly used flow cytometry-based PBMC NKA assay. Moreover, the use of P815-ULBP1+CD48 cells in relation to assessing the levels of NKG2D and 2B4 receptors on NK cells facilitated the mechanistic study and led to the identification of TGF-β1 as a potential mediator of compromised NKA in MM. Thus, our proposed WB NKA assay facilitates the reliable measurement of NKA and holds promise for further development as both a clinical and research tool.
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http://dx.doi.org/10.3390/ijms21218112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662667PMC
October 2020

Facile Synthesis of Poly(ethylene oxide)-Based Self-Healable Dynamic Triblock Copolymer Hydrogels.

Biomacromolecules 2020 12 16;21(12):4913-4922. Epub 2020 Oct 16.

Department of Chemistry, Yonsei University, Seoul 03722, Republic of Korea.

Stimuli-responsive smart hydrogels have garnered considerable interest for their potential in biomedical applications. While widely utilized, little is known about the rheological and mechanical properties of the hydrogels with respect to the type of cross-linker in a systematic manner. In this study, we present a facile synthetic route toward ABA triblock copolymer hydrogels based on poly(ethylene oxide) (PEO). Two classes of hydrogels were prepared by employing the functional allyl glycidyl ether (AGE) monomer during the polymerization followed by the subsequent post-polymerization modification of prepared PAGE--PEO--PAGE via respective hydrogenation or thiol-ene reaction: (1) chemically cross-linked hydrogels responsive to redox stimuli and (2) physically cross-linked hydrogels responsive to temperature. A series of dynamic mechanical analyses revealed the relaxation dynamics of the associative A block. Most interestingly, the redox-responsive hydrogels demonstrated a highly tunable nature by introducing reducing and oxidizing agents, which provided the self-healing property and injectability. Together with superior biocompatibility, these smart hydrogels offer the prospect of advancing biomedical applications.
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http://dx.doi.org/10.1021/acs.biomac.0c01140DOI Listing
December 2020

Identification of the determinant of tomato yellow leaf curl Kanchanaburi virus infectivity in tomato.

Virus Res 2021 01 13;291:198192. Epub 2020 Oct 13.

Department of Agriculture, Forestry and Bioresources, Research Institute of Agriculture and Life Sciences, Plant Genomics and Breeding Institute, College of Agriculture and Life Sciences, Seoul National University, Seoul, 08826, Republic of Korea. Electronic address:

Geminiviruses cause devastating diseases in solanaceous crops, with the bipartite begomoviruses tomato yellow leaf curl Kanchanaburi virus (TYLCKaV) and pepper yellow leaf curl Thailand virus (PYLCThV) major threats in Southeast Asia. To determine the molecular mechanism of geminivirus infection, we constructed infectious clones of TYLCKaV and PYLCThV. Both constructs infected Nicotiana benthamiana, but only TYLCKaV could infect Solanum lycopersicum 'A39'. A genome-swapping of TYLCKaV with PYLCThV revealed the TYLCKaV-B genome segment as the determinant of TYLCKaV infectivity in tomato. We constructed five geminivirus clones with chimeric TYLCKaV-B and PYLCThV-B genome segments to narrow down the region determining TYLCKaV infectivity in tomato. Only chimeric clones carrying the TYLCKaV intergenic region (IR) showed infectivity in S. lycopersicum 'A39', indicating that the IR of TYLCKaV-B is essential for TYLCKaV infectivity in tomato. Our results provide a foundation for elucidating the molecular mechanism of geminivirus infection in plants.
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http://dx.doi.org/10.1016/j.virusres.2020.198192DOI Listing
January 2021

Development of CT Effective Dose Conversion Factors from Clinical CT Examinations in the Republic of Korea.

Diagnostics (Basel) 2020 Sep 21;10(9). Epub 2020 Sep 21.

School of Health and Environmental Science, Korea University, Seoul 02841, Korea.

The aim of this study was to determine the conversion factors for the effective dose (ED) per dose length product (DLP) for various computed tomography (CT) protocols based on the 2007 recommendations of the International Commission on Radiological Protection (ICRP). CT dose data from 369 CT scanners and 13,625 patients were collected through a nationwide survey. Data from 3793 patients with a difference in height within 5% of computational human phantoms were selected to calculate ED and DLP. The anatomical CT scan ranges for 11 scan protocols (adult-10, pediatric-1) were determined by experts, and scan lengths were obtained by matching scan ranges to computational phantoms. ED and DLP were calculated using the NCICT program. For each CT protocol, ED/DLP conversion factors were calculated from ED and DLP. Estimated ED conversion factors were 0.00172, 0.00751, 0.00858, 0.01843, 0.01103, 0.02532, 0.01794, 0.02811, 0.02815, 0.02175, 0.00626, 0.00458, 0.00308, and 0.00233 mSv∙mGy∙cm for the adult brain, intra-cranial angiography, C-spine, L-spine, neck, chest, abdomen and pelvis, coronary angiography, calcium scoring, aortography, and CT examinations of pediatric brain of <2 years, 4-6 years, 9-11 years, and 13-15 years, respectively. We determined ED conversion factors for 11 CT protocols using CT data obtained from a nationwide survey in Korea and Monte Carlo-based dose calculations.
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http://dx.doi.org/10.3390/diagnostics10090727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554984PMC
September 2020

Comparative Analysis of Volatile Compounds of Gamma-Irradiated Mutants of Rose ().

Plants (Basel) 2020 Sep 17;9(9). Epub 2020 Sep 17.

Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeollabuk-do 56212, Korea.

Roses are one of the most important floricultural crops, and their essential oils have long been used for cosmetics and aromatherapy. We investigated the volatile compound compositions of 12 flower-color mutant variants and their original cultivars. Twelve rose mutant genotypes were developed by treatment with 70 Gy of Co gamma irradiation of six commercial rose cultivars. Essential oils from the flowers of the 18 genotypes were analyzed by gas chromatography-mass spectrometry. Seventy-seven volatile compounds were detected, which were categorized into six classes: Aliphatic hydrocarbons, aliphatic alcohols, aliphatic ester, aromatic compounds, terpene alcohols, and others. Aliphatic (hydrocarbons, alcohols, and esters) compounds were abundant categories in all rose flowers. The CR-S2 mutant had the highest terpene alcohols and oil content. Three (CR-S1, CR-S3, and CR-S4) mutant genotypes showed higher ester contents than their original cultivar. Nonacosane, 2-methylhexacosane, and 2-methyltricosane were major volatile compounds among all genotypes. Hierarchical cluster analysis (HCA) of the rose genotypes gave four groups according to grouping among the 77 volatile compounds. In addition, the principal component analysis (PCA) model was successfully applied to distinguish most attractive rose lines. These findings will be useful for the selection of rose genotypes with improved volatile compounds.
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http://dx.doi.org/10.3390/plants9091221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569881PMC
September 2020

Nanocomposites-based targeted oral drug delivery systems with infliximab in a murine colitis model.

J Nanobiotechnology 2020 Sep 15;18(1):133. Epub 2020 Sep 15.

Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Background: Infliximab (IFX), a TNF-α blocking chimeric monoclonal antibody, induces clinical response and mucosal healing in patients with inflammatory bowel disease (IBD). However, systemic administration of this agent causes unwanted side effects. Oral delivery of antibody therapeutics might be an effective treatment strategy for IBD compared to intravenous administration.

Results: All three carriers had a high encapsulation efficiency, narrow size distribution, and minimal systemic exposure. There was a higher interaction between nanocomposite carriers and monocytes compared to lymphocytes in the PBMC of IBD patients. Orally administered nanocomposite carriers targeted to inflamed colitis minimized systemic exposure. All IFX delivery formulations with nanocomposite carriers had a significantly less colitis-induced body weight loss, colon shortening and histomorphological score, compared to the DSS-treated group. AC-IFX-L and EAC-IFX-L groups showed significantly higher improvement of the disease activity index, compared to the DSS-treated group. In addition, AC-IFX-L and EAC-IFX-L alleviated pro-inflammatory cytokine expressions (Tnfa, Il1b, and Il17).

Conclusion: We present orally administered antibody delivery systems which improved efficacy in murine colitis while reducing systemic exposure. These oral delivery systems suggest a promising therapeutic approach for treating IBD.
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http://dx.doi.org/10.1186/s12951-020-00693-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493402PMC
September 2020

Phenolic Compounds in Extracts of (Cranberry Hibiscus) and Their Antioxidant and Antibacterial Properties.

Molecules 2020 Sep 12;25(18). Epub 2020 Sep 12.

Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongup 56212, Korea.

Hibiscus species are rich in phenolic compounds and have been traditionally used for improving human health through their bioactive activities. The present study investigated the phenolic compounds of leaf extracts from 18 different accessions and evaluated their biofunctional properties, focusing on antioxidant and antibacterial activity. The most abundant phenolic compound in was caffeic acid, with levels ranging from 14.95 to 42.93 mg/100 g. The antioxidant activity measured by the ABTS assay allowed the accessions to be classified into two groups: a high activity group with red leaf varieties (74.71-84.02%) and a relatively low activity group with green leaf varieties (57.47-65.94%). The antioxidant activity was significantly correlated with TAC (0.933), Dp3-Sam (0.932), Dp3-Glu (0.924), and Cy3-Sam (0.913) contents ( < 0.001). The phenolic extracts exhibited antibacterial activity against two bacteria, with zones of inhibition between 12.00 and 13.67 mm (), and 10.67 and 13.33 mm (). All accessions exhibited a basal antibacterial activity level (12 mm) against the Gram-positive , with PI500758 and PI500764 exhibiting increased antibacterial activity (13.67 mm), but they exhibited a more dynamic antibacterial activity level against the Gram-negative .
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http://dx.doi.org/10.3390/molecules25184190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571108PMC
September 2020

Osteoblast-Osteoclast Communication and Bone Homeostasis.

Cells 2020 09 10;9(9). Epub 2020 Sep 10.

Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Bone remodeling is tightly regulated by a cross-talk between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoblasts and osteoclasts communicate with each other to regulate cellular behavior, survival and differentiation through direct cell-to-cell contact or through secretory proteins. A direct interaction between osteoblasts and osteoclasts allows bidirectional transduction of activation signals through EFNB2-EPHB4, FASL-FAS or SEMA3A-NRP1, regulating differentiation and survival of osteoblasts or osteoclasts. Alternatively, osteoblasts produce a range of different secretory molecules, including M-CSF, RANKL/OPG, WNT5A, and WNT16, that promote or suppress osteoclast differentiation and development. Osteoclasts also influence osteoblast formation and differentiation through secretion of soluble factors, including S1P, SEMA4D, CTHRC1 and C3. Here we review the current knowledge regarding membrane bound- and soluble factors governing cross-talk between osteoblasts and osteoclasts.
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http://dx.doi.org/10.3390/cells9092073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564526PMC
September 2020

Conductive Hearing Loss Aggravates Memory Decline in Alzheimer Model Mice.

Front Neurosci 2020 13;14:843. Epub 2020 Aug 13.

Department of Otorhinolaryngology, Boramae Medical Center, Seoul Metropolitan Government-Seoul National University, Seoul, South Korea.

The study of cognitive impairment associated with hearing loss has recently garnered considerable interest. Epidemiological data have demonstrated that hearing loss is a risk factor for cognitive decline as a result of aging. However, no previous study has examined the effect of hearing loss in patients with cognitive problems such as Alzheimer's disease. Therefore, we investigated the effect of conductive hearing loss in an Alzheimer's mouse model. Positron emission tomography (PET) and magnetic resonance imaging (MRI) were used to evaluate changes in glucose metabolism and gray matter concentrations in the 5xFAD Alzheimer's Disease (AD) transgenic mouse model with and without conductive hearing loss (HL). Conductive hearing loss was induced using chronic perforation of the tympanic membrane. Behavioral data from the Y-maze and passive avoidance tests revealed greater memory deficits in the AD with HL (AD-HL) group than in the AD group. Following induction of hearing loss, lower cerebral glucose metabolism in the frontal association cortex was observed in the AD-HL group than in the AD group. Although lower glucose metabolism in the hippocampus and cerebellum was found in the AD-HL group than in the AD group at 3 months, the gray matter concentrations in these regions were not significantly different between the groups. Furthermore, the gray matter concentrations in the simple lobule, cingulate/retrosplenial cortex, substantia nigra, retrosigmoid nucleus, medial geniculate nucleus, and anterior pretectal nucleus at 7 months were significantly lower in the AD-HL group than in the AD group. Taken together, these results indicate that even partial hearing loss can aggravate memory impairment in Alzheimer's disease.
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http://dx.doi.org/10.3389/fnins.2020.00843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438902PMC
August 2020

The effect of parental depression on the problem behaviour and academic performance of children with asthma.

Nurs Open 2020 09 17;7(5):1597-1605. Epub 2020 Jun 17.

Department of Nursing Gangneung-wonju National University Gangneung Korea.

Aim: This study attempts to determine the factors affecting problem behaviour and academic performance of children with asthma.

Design: This is a cross-sectional study used actor and partner interdependence model.

Methods: Data of 236 children and their parents from the 10th Panel Study on Korean Children were used, and analysis was performed using SPSS 20.0 and AMOS 20.0. We have received panel data from the Korea Institute of Child Care and Education on April 10th, 2019.

Results: Parental depression had actor and partner effects on marital conflict, and marital conflict perceived by the father had actor and partner effects on parent-child interactions, while marital conflict perceived by the mother had only actor effect on parent-child interactions. Parent-child interaction perceived by both fathers and mothers was found to affect the problem behaviour of children. The problem behaviour of children affects academic performance.
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http://dx.doi.org/10.1002/nop2.542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424461PMC
September 2020

The role of the α-tubulin acetyltransferase αTAT1 in the DNA damage response.

J Cell Sci 2020 09 4;133(17). Epub 2020 Sep 4.

Department of Pharmacology, Chonnam National University Medical School, Jellanamdo, 58128, Republic of Korea

Lysine 40 acetylation of α-tubulin (Ac-α-tubulin), catalyzed by the acetyltransferase αTAT1, marks stabilized microtubules. Recently, there is growing evidence to suggest crosstalk between the DNA damage response (DDR) and microtubule organization; we therefore investigated whether αTAT1 is involved in the DDR. Following treatment with DNA-damaging agents, increased levels of Ac-α-tubulin were detected. We also observed significant induction of Ac-α-tubulin after depletion of DNA repair proteins, suggesting that αTAT1 is positively regulated in response to DNA damage. Intriguingly, αTAT1 depletion decreased DNA damage-induced replication protein A (RPA) phosphorylation and foci formation. Moreover, DNA damage-induced cell cycle arrest was significantly delayed in αTAT1-depleted cells, indicating defective checkpoint activation. The checkpoint defects seen upon αTAT1 deficiency were restored by expression of wild-type αTAT1, but not by αTAT1-D157N (a catalytically inactive αTAT1), indicating that the role of αTAT1 in the DDR is dependent on enzymatic activity. Furthermore, αTAT1-depleted direct repeat GFP (DR-GFP) U2OS cells had a significant decrease in the frequency of homologous recombination repair. Collectively, our results suggest that αTAT1 may play an essential role in DNA damage checkpoints and DNA repair through its acetyltransferase activity.
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http://dx.doi.org/10.1242/jcs.246702DOI Listing
September 2020

Characterization of Gene Isoforms Related to Cellulose and Lignin Biosynthesis in Kenaf ( L.) Mutant.

Plants (Basel) 2020 May 14;9(5). Epub 2020 May 14.

Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 56212, Korea.

Kenaf is a source of fiber and a bioenergy crop that is considered to be a third world crop. Recently, a new kenaf cultivar, "Jangdae," was developed by gamma irradiation. It exhibited distinguishable characteristics such as higher biomass, higher seed yield, and earlier flowering than the wild type. We sequenced and analyzed the transcriptome of apical leaf and stem using Pacific Biosciences single-molecule long-read isoform sequencing platform. De novo assembly yielded 26,822 full-length transcripts with a total length of 59 Mbp. Sequence similarity against protein sequence allowed the functional annotation of 11,370 unigenes. Among them, 10,100 unigenes were assigned gene ontology terms, the majority of which were associated with the metabolic and cellular process. The Kyoto encyclopedia of genes and genomes (KEGG) analysis mapped 8875 of the annotated unigenes to 149 metabolic pathways. We also identified the majority of putative genes involved in cellulose and lignin-biosynthesis. We further evaluated the expression pattern in eight gene families involved in lignin-biosynthesis at different growth stages. In this study, appropriate biotechnological approaches using the information obtained for these putative genes will help to modify the desirable content traits in mutants. The transcriptome data can be used as a reference dataset and provide a resource for molecular genetic studies in kenaf.
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http://dx.doi.org/10.3390/plants9050631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285769PMC
May 2020

Bone-Targeting AAV-Mediated Gene Silencing in Osteoclasts for Osteoporosis Therapy.

Mol Ther Methods Clin Dev 2020 Jun 18;17:922-935. Epub 2020 Apr 18.

Division of Rheumatology, University of Massachusetts Medical School, Worcester, MA, USA.

Improper activity of bone-resorbing osteoclasts results in low bone density and deterioration of bone structure, which increase the risk of fractures. Anti-resorptive therapies targeting osteoclasts have proven effective in preserving bone mass, but these therapeutic agents lead to defective new bone formation and numerous potential side effects. In this study, we demonstrate that recombinant adeno-associated virus, serotype 9 (rAAV9) can deliver to osteoclasts an artificial microRNA (amiR) that silences expression of key osteoclast regulators, RANK (receptor activator for nuclear factor κB) and cathepsin K (rAAV9., rAAV9.), to prevent bone loss in osteoporosis. As rAAV9 is highly effective for the transduction of osteoclasts, systemic administration of rAAV9 carrying or results in a significant increase of bone mass in mice. Furthermore, the bone-targeting peptide motif (Asp) or (AspSerSer) was grafted onto the AAV9-VP2 capsid protein, resulting in significant reduction of transgene expression in non-bone peripheral organs. Finally, systemic delivery of bone-targeting rAAV9. counteracts bone loss and improves bone mechanical properties in mouse models of postmenopausal and senile osteoporosis. Collectively, inhibition of osteoclast-mediated bone resorption via bone-targeting rAAV9-mediated silencing of is a promising gene therapy that can preserve bone formation and mitigate osteoporosis, while limiting adverse off-target effects.
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http://dx.doi.org/10.1016/j.omtm.2020.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210389PMC
June 2020

A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation.

Nat Commun 2020 05 8;11(1):2289. Epub 2020 May 8.

Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.

The osteoblast differentiation capacity of skeletal stem cells (SSCs) must be tightly regulated, as inadequate bone formation results in low bone mass and skeletal fragility, and over-exuberant osteogenesis results in heterotopic ossification (HO) of soft tissues. RUNX2 is essential for tuning this balance, but the mechanisms of posttranslational control of RUNX2 remain to be fully elucidated. Here, we identify that a CK2/HAUSP pathway is a key regulator of RUNX2 stability, as Casein kinase 2 (CK2) phosphorylates RUNX2, recruiting the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP), which stabilizes RUNX2 by diverting it away from ubiquitin-dependent proteasomal degradation. This pathway is important for both the commitment of SSCs to osteoprogenitors and their subsequent maturation. This CK2/HAUSP/RUNX2 pathway is also necessary for HO, as its inhibition blocked HO in multiple models. Collectively, active deubiquitination of RUNX2 is required for bone formation and this CK2/HAUSP deubiquitination pathway offers therapeutic opportunities for disorders of inappropriate mineralization.
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http://dx.doi.org/10.1038/s41467-020-16038-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210266PMC
May 2020

Survival Benefit for Metformin Through Better Tumor Response by Neoadjuvant Concurrent Chemoradiotherapy in Rectal Cancer.

Dis Colon Rectum 2020 06;63(6):758-768

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

Background: Metformin may reduce cancer risk and mortality and improve radiotherapy responses in several malignancies.

Objective: This study aimed to compare tumor responses and prognoses of metformin and nonmetformin groups of diabetic patients receiving neoadjuvant concurrent chemoradiotherapy for rectal cancer.

Design: This is a retrospective study.

Setting: This study was conducted at a single institution in the Republic of Korea.

Patients: Between January 2000 and November 2017, 104 patients with rectal cancer who were taking diabetes medication and treated with neoadjuvant concurrent chemoradiotherapy followed by radical surgery were reviewed. Patients were divided into those taking (n = 62) and not taking metformin (n = 42). Tumor responses, survival, and other outcomes were analyzed.

Main Outcome Measures: Tumor response, rectal cancer-specific survival, and disease-free survival rates were measured.

Results: Tumor regression grade (p = 0.002), pathological complete response (p = 0.037), and N downstaging (p < 0.001) after neoadjuvant concurrent chemoradiotherapy were significantly higher in the metformin group than in the nonmetformin group. In analysis of cancer-specific mortality, metformin use, differentiation (well, moderate vs poor), pathological Union for International Cancer Control stage (3 vs 1-2), ypN stage (1-2 vs 0), and N downstaging (HR, 0.256 (95% CI, 0.082-0.794), p = 0.018; HR, 0.147 (95% CI, 0.031-0.697), p = 0.016; HR, 3.693 (95% CI, 1.283-10.635), p = 0.015; HR, 3.181 (95% CI, 1.155-8.759), p = 0.025, and HR, 0.175 (95% CI, 0.040-0.769), p = 0.021) were significant factors related to mortality in diabetic patients with rectal cancer. In addition, in the multivariate analysis of cancer recurrence, the interaction between metformin use and lymph node downstaging was a significant predictive factor (HR, 0.222 (95% CI, 0.077-0.639); p = 0.005).

Limitations: This was a small retrospective study conducted at a single institution.

Conclusions: Metformin use was associated with better tumor responses and cancer-specific survival, as well as a lower risk of cancer recurrence, in patients with diabetes mellitus who had lymph node downstaging after neoadjuvant concurrent chemoradiotherapy in rectal cancer. See Video Abstract at http://links.lww.com/DCR/B185. BENEFICIO EN SUPERVIVENCIA CON METFORMINA A TRAVÉS DE UNA MEJOR RESPUESTA TUMORAL CON QUIMIORRADIOTERAPIA CONCURRENTE NEOADYUVANTE EN CÁNCER RECTAL: La metformina puede reducir el riesgo de cáncer y la mortalidad y mejorar las respuestas a la radioterapia en varios tumores malignos.Comparar las respuestas tumorales y los pronósticos de los grupos con metformina y sin metformina de pacientes diabéticos que reciben quimiorradioterapia concurrente neoadyuvante para cáncer de recto.Estudio retrospectivo.Institución única en la República de Corea.Se revisaron 104 pacientes entre enero de 2000 y noviembre de 2017, con cáncer rectal que tomaban medicamentos para diabetes y que fueron tratados con quimiorradioterapia concurrente neoadyuvante seguida de cirugía radical. Los pacientes se dividieron en aquellos que tomaban (n = 62) y los que no tomaban metformina (n = 42). Se analizaron las respuestas tumorales, la supervivencia y otros resultados.Se midieron las tasas de la respuesta tumoral, la supervivencia específica de cáncer rectal y de la supervivencia libre de enfermedad.El grado de regresión tumoral (p = 0.002), la remisión patológica completa (p = 0.037) y la reducción de la etapa N (p < 0.001) después de la quimiorradioterapia concurrente neoadyuvante fueron significativamente mayores en el grupo de metformina que en el grupo sin metformina. En el análisis de la mortalidad específica por cáncer, el uso de metformina, la diferenciación (bien, moderada vs pobre), el estadio patológico UICC (3 vs 1-2), el estadio ypN (1-2 vs 0) y la disminución de la etapa N (hazard ratios [intervalos de confianza 95%]: 0.256 [0.082-0.794], p = 0.018; 0.147 [0.031-0.697], p = 0.016; 3.693 [1.283-10.635], p = 0.015; 3.181 [1.155-8.759], p = 0.025 y 0.175 [0.040-0.769], p = 0.021, respectivamente) fueron factores significativos relacionados con la mortalidad en pacientes diabéticos con cáncer rectal. Adicionalmente, en el análisis multivariado de la recurrencia del cáncer, la interacción entre el uso de metformina y la disminución de la etapa ganglionar (N) fue un factor predictivo significativo (hazard ratios [intervalos de confianza del 95%]: 0.222 [0.077-0.639]; p = 0.005).Este fue un estudio retrospectivo pequeño realizado en un solo instituto.El uso de metformina se asoció con mejores respuestas tumorales y supervivencia específica de cáncer, así como un menor riesgo de recurrencia del cáncer, en pacientes con disminución de la etapa ganglionar (N) después de quimiorradioterapia concurrente neoadyuvante en pacientes con cáncer rectal y diabetes. Consulte Video Resumen en http://links.lww.com/DCR/B185. (Traducción-Dr. Jorge Silva Velazco).
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http://dx.doi.org/10.1097/DCR.0000000000001624DOI Listing
June 2020

Common and different alterations of bone marrow mesenchymal stromal cells in myelodysplastic syndrome and multiple myeloma.

Cell Prolif 2020 May 5;53(5):e12819. Epub 2020 May 5.

Catholic Genetic Laboratory Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Objective: The objective of this study was to explore characteristics of bone marrow mesenchymal stromal cells (BM-MSCs) derived from patients with myelodysplastic syndrome (MDS) and multiple myeloma (MM).

Methods: BM-MSCs were recovered from 17 of MDS patients, 23 of MM patients and 9 healthy donors and were passaged until proliferation stopped. General characteristics and gene expression profiles of MSCs were analysed. In vitro, ex vivo coculture, immunohistochemistry and knockdown experiments were performed to verify gene expression changes.

Results: BM-MSCs failed to culture in 35.0% of patients and 50.0% of recovered BM-MSCs stopped to proliferate before passage 6. MDS- and MM-MSCs shared characteristics including decreased osteogenesis, increased angiogenesis and senescence-associated molecular pathways. In vitro and ex vivo experiments showed disease-specific changes such as neurogenic tendency in MDS-MSCs and cardiomyogenic tendency in MM-MSCs. Although the age of normal control was younger than patients and telomere length was shorter in patient's BM-MSCs, they were not different according to disease category nor degree of proliferation. Specifically, poorly proliferation BM-MSCs showed CDKN2A overexpression and CXCL12 downregulation. Immunohistochemistry of BM biopsy demonstrated that CDKN2A was intensely accumulation in perivascular BM-MSCs failed to culture. Interestingly, patient's BM-MSCs revealed improved proliferation activity after CDKN2A knockdown.

Conclusion: These results collectively indicate that MDS-MSCs and MM-MSCs have common and different alterations at various degrees. Hence, it is necessary to evaluate their alteration status using representative markers such as CDKN2A expression.
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http://dx.doi.org/10.1111/cpr.12819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260074PMC
May 2020

Culture and children's reasoning about preferences and gender norms.

J Exp Child Psychol 2020 08 25;196:104861. Epub 2020 Apr 25.

Graduate School of Education, University of California, Berkeley, Berkeley, CA 94720, USA.

To examine how children and young adults in two cultures think about gender norms, participants evaluated preferences that were inconsistent with gender norms. Participants (N = 200) included 53 children aged 5 years, 49 children aged 7 years, and 49 children aged 9 years, and 49 young adults from Korea and the United States. Both Koreans and Americans reasoned about violations of gender norms primarily as matters of personal choice in both public and private, with some conventional concerns in public settings. In both cultures, participants rejected the idea that an authority could have jurisdiction over gender-norm-related choices, and both groups suggested that being unable to express those preferences in public has a negative impact on individuals.
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http://dx.doi.org/10.1016/j.jecp.2020.104861DOI Listing
August 2020

Pathogenesis and clinical perspectives of extraintestinal manifestations in inflammatory bowel diseases.

Intest Res 2020 Jul 18;18(3):249-264. Epub 2020 Apr 18.

Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.

A considerable number of patients with inflammatory bowel disease (IBD) experience extraintestinal manifestations (EIMs), which can present either before or after IBD diagnosis. Unraveling the pathogenic pathways of EIMs in IBD is challenging because of the lack of reliable criteria for diagnosis and difficulty in distinguishing EIMs from external pathologies caused by drugs or other etiologies. Optimizing treatment can also be difficult. Early diagnosis and management of EIM revolve around multidisciplinary teams, and they should have the resources necessary to make and implement appropriate decisions. In addition, specialists of the affected organs should be trained in IBD treatment. Furthermore, patient awareness regarding the extraintestinal symptoms of IBD is of paramount importance for improving patient understanding of disease and health outcomes. Herein, we review the pathogenesis and clinical perspectives of EIMs in IBD.
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http://dx.doi.org/10.5217/ir.2019.00128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385581PMC
July 2020

Low-field H NMR spectroscopy: Factors impacting signal-to-noise ratio and experimental time in the context of mixed microstructure polyisoprenes.

Magn Reson Chem 2020 Dec 7;58(12):1168-1176. Epub 2020 Apr 7.

Department of Chemical Engineering, Auburn University, Auburn, Alabama, USA.

Low-cost, high-accuracy characterization of polymeric materials is critical for satisfying societal demand for high-quality materials with ultra-specific requirements. Low-field nuclear magnetic resonance (NMR) spectroscopy presents an opportunity to replace costlier or destructive methods while utilizing nondeuterated solvents. Many factors play key roles in the ability of low-field NMR spectroscopy to accurately analyze polymer systems. Sample characteristics such as polymer concentration, composition, and molecular weight all directly affect the capability of low-field spectrometers to accurately determine polymer microstructure compositions. In addition to inherent sample properties affecting instrumental accuracy, many choices concerning instrumental parameters (including number of scans, relaxation delay, spectral width, and points per scan) must be made that impact the quality of the resulting NMR spectra. In this work, we benchmark the capability of a 60-MHz low-field NMR spectrometer for analyzing polymer materials using mixed microstructure polyisoprenes as a model polymer system of interest. The aforementioned critical sample and instrumental variables are varied, and we report on the ability to quantitatively characterize polyisoprene microstructure to within 1-2% of a higher field NMR spectrometer (400 MHz). We anticipate our findings to be generally applicable to other low-field spectrometers of similar field strength and other polymer systems.
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http://dx.doi.org/10.1002/mrc.5022DOI Listing
December 2020

MiR-4435 is an UQCRB-related circulating miRNA in human colorectal cancer.

Sci Rep 2020 02 18;10(1):2833. Epub 2020 Feb 18.

Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.

Ubiquinol-cytochrome c reductase (UQCRB), a subunit of the mitochondrial complex III, is highly expressed in tissues from colorectal cancer patients. Since UQCRB is highly expressed in colorectal cancer, we investigated miRNAs from mutant UQCRB-expressing cell lines to identify new miRNA biomarkers. After sequencing miRNAs in the mutant UQCRB-expressing cell lines, miR-4435 was selected as a potential biomarker candidate from the six up-regulated miRNAs. The expression level of miR-4435 in the mutant UQCRB-expressing cell lines and colon cancer was increased. Notably, the expression level of miR-4435 was increased in exosomes isolated from cell culture medium, suggesting that miR-4435 is closely related to colon cancer and that large amounts of miR-4435 may be secreted outside of the cells through exosomes. Additionally, exosomes extracted from the serum samples of colorectal cancer patients showed increased miR-4435 levels depending on the cancer progression stage. Moreover, analyses of a miRNA database and mRNA-sequencing data of the mutant UQCRB-expressing cell lines revealed that TIMP3, a tumor suppressor, could be a target of miR-4435. Additionally, the expression of miR-4435 was suppressed by UQCRB inhibitor treatment whereas TIMP3 was up-regulated. Upregulation of TIMP3 decreased proliferation of the mutant UQCRB-expressing cell lines and a colorectal cancer cell line. TIMP3 was also upregulated in response to miR-4435 inhibitor and UQCRB inhibitor treatments. Furthermore, these findings suggest that miR-4435 is related to an oncogenic function in UQCRB related disease, CRC, and that effects migration and invasion on mutant UQCRB-expressing cell lines and colorectal cancer cell. In conclusion, our results identified miR-4435 as a potential circulating miRNA biomarker of colorectal cancer associated with UQCRB.
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http://dx.doi.org/10.1038/s41598-020-59610-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029028PMC
February 2020

Validity and reliability of a Korean version of the breast cancer survivors resilience scale.

Jpn J Nurs Sci 2020 Jul 17;17(3):e12331. Epub 2020 Feb 17.

College of Nursing Science, Kyung Hee University, Seoul, South Korea.

Aim: To examine the resilience of breast cancer patients by investigating the validity and reliability of a Korean version of the breast cancer survivors resilience scale (BCRS) and to provide basic data for developing interventions that can be used by healthcare professionals to enhance the resilience of breast cancer patients.

Methods: Data were obtained from 280 breast cancer survivors receiving treatment at the outpatient clinic of Kosin University Hospital located in Busan City, Korea, and the collected data were used to confirm content validity, construct validity, criterion validity, and internal consistency reliability.

Results: The Korean version of the BCRS comprised two subdomains and a total of 16 items, and the internal consistency reliability estimated by Cronbach's alpha was .87~.89.

Conclusion: This study found that the Korean version BCRS has high validity and reliability. In future studies, it will be necessary to conduct research that identifies the resilience levels of patients with breast cancer, using the Korean version BCRS, and seeks interventions in agreement with the results.
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http://dx.doi.org/10.1111/jjns.12331DOI Listing
July 2020

Rapid detection of deformed wing virus in honeybee using ultra-rapid qPCR and a DNA-chip.

J Vet Sci 2020 Jan;21(1):e4

Department of Life Science, College of Fusion Science, Kyonggi University, Suwon 16227, Korea.

Fast and accurate detection of viral RNA pathogens is important in apiculture. A polymerase chain reaction (PCR)-based detection method has been developed, which is simple, specific, and sensitive. In this study, we rapidly (in 1 min) synthesized cDNA from the RNA of deformed wing virus (DWV)-infected bees (), and then, within 10 min, amplified the target cDNA by ultra-rapid qPCR. The PCR products were hybridized to a DNA-chip for confirmation of target gene specificity. The results of this study suggest that our method might be a useful tool for detecting DWV, as well as for the diagnosis of RNA virus-mediated diseases on-site.
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http://dx.doi.org/10.4142/jvs.2020.21.e4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000893PMC
January 2020

Glucosylceramide synthase regulates adipo-osteogenic differentiation through synergistic activation of PPARγ with GlcCer.

FASEB J 2020 01 29;34(1):1270-1287. Epub 2019 Nov 29.

School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.

Dysregulation of the adipo-osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and osteoporosis. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation; however, the detailed underlying mechanisms are largely unknown. Here, we demonstrate that glucosylceramide (GlcCer) and its synthase, glucosylceramide synthase (GCS), are key determinants of MSC differentiation into adipocytes or osteoblasts. GCS expression was increased during adipogenesis and decreased during osteogenesis. Targeting GCS using RNA interference or a chemical inhibitor enhanced osteogenesis and inhibited adipogenesis by controlling the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ). Treatment with GlcCer sufficiently rescued adipogenesis and inhibited osteogenesis in GCS knockdown MSCs. Mechanistically, GlcCer interacted directly with PPARγ through A/B domain and synergistically enhanced rosiglitazone-induced PPARγ activation without changing PPARγ expression, thereby treatment with exogenous GlcCer increased adipogenesis and inhibited osteogenesis. Animal studies demonstrated that inhibiting GCS reduced adipocyte formation in white adipose tissues under normal chow diet and high-fat diet feeding and accelerated bone repair in a calvarial defect model. Taken together, our findings identify a novel lipid metabolic regulator for the control of MSC differentiation and may have important therapeutic implications.
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http://dx.doi.org/10.1096/fj.201901437RDOI Listing
January 2020