Publications by authors named "Seung Tae Lee"

275 Publications

Expanding the Non-Invasive Diagnosis of Acute Rejection in Kidney Transplants Through Detection of Donor-Derived DNA in Urine: Proof-of-Concept Study.

Ann Lab Med 2021 Sep;41(5):469-478

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

Background: Approximately 10%-20% of kidney transplant (KT) recipients suffer from acute rejection (AR); thus, sensitive and accurate monitoring of allograft status is recommended. We evaluated the clinical utility of donor-derived DNA (dd-DNA) detection in the urine of KT recipients as a non-invasive means for diagnosing AR.

Methods: Urine samples serially collected from 39 KT recipients were tested for 39 single-nucleotide variant loci selected according to technical criteria (i.e., high minor allele frequency and low analytical error) using next-generation sequencing. The fraction of dd-DNA was calculated and normalized by the urine creatinine (UCr) level (%dd-DNA/UCr). The diagnostic performance of %dd-DNA/UCr for AR was assessed by ROC curve analysis.

Results: There was an increasing trend of %dd-DNA/UCr in the AR group before subsequent graft injury, which occurred before (median of 52 days) histological rejection. The serum creatinine (SCr) level differed significantly between the AR and non-AR groups at two and four months of follow-up, whereas %dd-DNA/UCr differed between the groups at six months of follow-up. The combination of %dd-DNA/UCr, SCr, and spot urine protein (UPtn)/UCr showed high discriminating power, with an area under the ROC curve of 0.93 (95% confidence interval: 0.81-1.00) and a high negative predictive value of 100.0%.

Conclusions: Although the dd-DNA-based test cannot eliminate the need for biopsy, the high negative predictive value of this marker could increase the prebiopsy probability of detecting treatable injury to make biopsy an even more effective diagnostic tool.
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http://dx.doi.org/10.3343/alm.2021.41.5.469DOI Listing
September 2021

DYNC2H1 variants cause Leber congenital amaurosis without syndromic features.

Clin Genet 2021 Mar 23. Epub 2021 Mar 23.

Institute of Vision Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.1111/cge.13958DOI Listing
March 2021

Glucose in a maturation medium with reduced NaCl improves oocyte maturation and embryonic development after somatic cell nuclear transfer and fertilization in pigs.

Zygote 2021 Mar 3:1-8. Epub 2021 Mar 3.

College of Veterinary Medicine, Kangwon National University, Chuncheon24341, Korea.

This study was conducted to examine whether glucose in maturation medium containing reduced NaCl could improve oocyte maturation and embryonic development in pigs. The base medium was bovine serum albumin-free porcine zygote medium (PZM)-3 containing 10% (v/v) pig follicular fluid (FPZM) or 0.1% (w/v) polyvinyl alcohol (PPZM). Using each medium, the effects of NaCl concentrations (108 and 61.6 mM) and 5.56 mM glucose supplementation (designated as PZM108N, PZM108G, PZM61N, and PZM61G, respectively) were examined using a 2 × 2 factorial arrangement. When oocytes were matured in FPZM, glucose supplementation improved nuclear maturation compared with no supplementation, regardless of the NaCl concentrations. FPZM61G showed a higher blastocyst formation compared with FPZM108N and FPZM108G after parthenogenesis (PA). Blastocyst formations of somatic cell nuclear transfer (SCNT) embryos derived from FPZM61N and FPZM61G were higher compared with those of oocytes from FPZM108N. When oocytes were matured in PPZM, glucose added to PPZM108 and PPZM61 increased nuclear maturation compared with no supplementation. However, glucose added to PPZM108 did not alter embryonic development after PA. Additionally, oocytes matured in PPZM61G showed a higher blastocyst formation compared with those from PPZM61N. In SCNT, blastocyst formation was not influenced by glucose supplementation of PPZM108, but was increased by maturation in glucose-supplemented PPZM61. In embryonic development of in vitro fertilization (IVF), oocytes matured in medium with reduced NaCl and glucose showed significantly higher blastocyst formation compared with those matured in PPZM108G. Our results demonstrated that glucose in maturation medium containing 61.6 mM NaCl increased oocyte maturation and embryonic development after PA, SCNT, and IVF.
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http://dx.doi.org/10.1017/S0967199420000891DOI Listing
March 2021

In vitro growth culture in a medium with reduced sodium chloride improves maturation and developmental competence of pig oocytes derived from small antral follicles.

Theriogenology 2021 Apr 24;165:37-43. Epub 2021 Feb 24.

Laboratory of Theriogenology, College of Veterinary Medicine, Kangwon National University, Chuncheon, Gangwon, 24341, South Korea; Institute of Veterinary Science, Kangwon National University, Chuncheon, Gangwon, 24341, South Korea. Electronic address:

The objective of this study was to evaluate the effects of reducing the sodium chloride content in in vitro growth (IVG) medium to 61.6 mM on in vitro maturation (IVM) and embryonic development of pig oocytes derived from small antral follicles (SAF) less than 3 mm in diameter. SAF oocytes were cultured for 2 days to induce IVG in alpha-minimal essential medium with 108 mM NaCl (αMEM-108) or porcine zygote medium (PZM) containing 61.6 mM (PZM-61.6) or 108 mM (PZM-108) NaCl. These media were further supplemented with 1 mM dibutyryl cyclic adenosine monophosphate (dbcAMP) and 10% (v/v) fetal bovine serum. After IVG culture, oocytes were matured for 44 h in our standard IVM medium. The IVG culture in PZM-61.6 significantly increased nuclear maturation (88.0 ± 2.2%) of SAF oocytes compared to that in PZM-108 (77.3 ± 3.9%) or αMEM-108 (75.9 ± 3.8%). After parthenogenesis (PA), the proportions of blastocysts, based on the number of metaphase II (MII) oocytes, induced for PA were not different among IVG oocytes cultured in PZM-61.6 (50.2 ± 3.0%), PZM-108 (46.8 ± 2.9%), or αMEM-108 (45.6 ± 2.9%). The IVM oocytes derived from IVG in PZM-61.6 showed increased perivitelline space (PVS) (12.1 ± 0.6 μm) and intra-oocyte glutathione (GSH) content (1.19 ± 0.04 pixels/oocyte) compared to PVS (8.0 ± 0.5 and 7.4 ± 0.4 μm) and GSH (1.03 ± 0.04 and 1.00 ± 0.04 pixels/oocyte) of oocytes derived from PZM-108 and αMEM-108, respectively. The IVG culture in PZM-61.6 stimulated meiotic resumption after IVG and faster nuclear progression after IVM than that in αMEM-108. After somatic cell nuclear transfer (SCNT), the blastocyst formation of SAF oocytes grown in PZM-61.6 (17.8 ± 3.3%) was higher than that of oocytes grown in PZM-108 (7.5 ± 2.7%) but not different from that of oocytes in αMEM-108 (11.4 ± 3.4%). Regardless of the different osmotic pressures, nuclear maturation was significantly increased by IVG culture in PZM with reduced NaCl (86.8 ± 2.3 and 84.9 ± 4.2% in PZM-61.6 and PZM-61.6 with sorbitol, respectively) than in PZM-108 (70.5 ± 3.4%). Blastocyst formation was not affected by the differences in NaCl content and osmotic pressure of the IVG medium, whereas the mean number of cells in blastocysts was significantly higher following IVG culture in PZM-61.6 than in the other groups. In conclusion, the results demonstrate that, following SCNT in pigs, IVG culture of SAF oocytes in a medium with a reduced NaCl concentration stimulates oocyte maturation and improves subsequent embryonic development.
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http://dx.doi.org/10.1016/j.theriogenology.2020.12.018DOI Listing
April 2021

A Phase 1b Study to Evaluate the Safety and Efficacy of Durvalumab in Combination With Tremelimumab or Danvatirsen in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Clin Lymphoma Myeloma Leuk 2020 Dec 17. Epub 2020 Dec 17.

Division of Hematology & Oncology, MUSC Health Hollings Cancer Center, Charleston, SC.

Background: Despite recent advances, outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) remain poor. Immune checkpoint inhibitors have shown limited efficacy in this setting, but combinations with novel agents may enhance benefit. Combination therapy with durvalumab, an anti-programmed death ligand 1 (PD-L1) antibody, and danvatirsen (AZD9150; an antisense oligonucleotide inhibiting signal transducer and activator of transcription 3 [STAT3]) or tremelimumab (an anti-cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] antibody) may augment endogenous antitumor activity.

Patients And Methods: In this phase 1b dose escalation and dose expansion study, we evaluated durvalumab 20 mg/kg every 4 weeks plus either tremelimumab 1 mg/kg every 4 weeks or danvatirsen 2 or 3 mg/kg (administered on days 1, 3, 5, 8, 15, and 22, then every week). Treatment continued until disease progression. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity.

Results: As of April 4, 2019, 32 patients were enrolled and treated, receiving a median of 2 prior lines of systemic therapy. Treatment-related adverse events occurred in 21 patients (65.6%), most commonly alanine aminotransferase/aspartate aminotransferase increased (grade 1-3), anemia (grade 1-3), and fatigue (grade 1). The overall objective response rate was 6.3%, with 2 partial responses. Median time to response was 11.0 weeks (range, 7.7-14.3 weeks). Median progression-free survival was 7.4 weeks (range, 0.1-31.4 weeks), and median overall survival was 28.0 weeks (range, 1.9-115.4 weeks).

Conclusion: The primary endpoint was met, with durvalumab plus tremelimumab/danvatirsen generally well tolerated in patients with relapsed/refractory DLBCL; however, antitumor activity was limited.
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http://dx.doi.org/10.1016/j.clml.2020.12.012DOI Listing
December 2020

Chimerism Assay Using Single Nucleotide Polymorphisms Adjacent and in Linkage-Disequilibrium Enables Sensitive Disease Relapse Monitoring after Hematopoietic Stem-Cell Transplantation.

Clin Chem 2021 Feb 14. Epub 2021 Feb 14.

Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, South Korea.

Background: Short tandem repeat (STR)-based chimerism analysis has been widely used for chimerism monitoring after hematopoietic stem-cell transplantation (HSCT), but technical artifacts can be problematic. We designed a chimerism assay using single nucleotide polymorphisms (SNPs) adjacent and in linkage-disequilibrium (CASAL), which doubly checked for SNP pairs, and thus could reduce background errors and increase analytical sensitivity.

Methods: CASAL targeted 84 SNP pairs within 10 bp distance and in perfect linkage-disequilibrium. Using undiluted and serially diluted samples, baseline error rates, and linearity was calculated. Clinical performance of CASAL was evaluated in comparison with a conventional STR assay, using 191 posttransplant samples from 42 patients with HSCT.

Results: CASAL had ∼10 times lower baseline error rates compared to that of ordinary next-generation sequencing. Limit of detection and quantification of CASAL were estimated to be 0.09 and 0.39%, respectively, with a linear range of 0.1-100%. CASAL correlated well with STR assay (r2 = 0.99) and the higher sensitivity enabled detection of low-level recipient chimerism and earlier prediction of relapse.

Conclusions: CASAL is a simple, analytically sensitive and accurate assay that can be used in clinical samples after HSCT with a higher performance compared to that of traditional assays. It should also be useful in other forensic and archeological testing.
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http://dx.doi.org/10.1093/clinchem/hvab010DOI Listing
February 2021

Low CtBP2 expression is associated with a stem cell-like signature and adverse clinical outcome in childhood B-cell lymphoblastic leukemia.

Leukemia 2021 Feb 12. Epub 2021 Feb 12.

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.

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http://dx.doi.org/10.1038/s41375-021-01151-2DOI Listing
February 2021

In vitro maturation on ovarian granulosa cells encapsulated in agarose matrix improves developmental competence of porcine oocytes.

Theriogenology 2021 Apr 21;164:42-50. Epub 2021 Jan 21.

Institute of Veterinary Science, Kangwon National University, Chuncheon, 24341, South Korea; College of Veterinary Medicine, Kangwon National University, Chuncheon, 24341, South Korea. Electronic address:

In vivo, mammalian oocytes are surrounded by granulosa cells (GCs) that exist in a three-dimensional (3D) microenvironment with soft stiffness. The GCs play an important role for the in vivo growth and development of oocytes, through bidirectional communication between oocytes and GCs. To mimic the cellular microenvironment of a 3D organized follicle, this study designed a co-culture system using porcine ovarian GCs (pGCs) encapsulated in agarose matrix for in vitro maturation (IVM) of pig oocytes. We report the effects of our newly designed co-culture system on IVM and development of pig oocytes. Immature cumulus-oocyte-complexes (COCs) were matured on a 1% (w/v) agarose matrix encapsulated without or with pGCs. The number of pGCs within the agarose matrix was optimized by analyzing the in vitro development of parthenogenetic embryos. Moreover, the role of the ovarian stromal pGCs as feeder cells was assessed by analyzing the PA embryonic development. Subsequently, the effect of pGCs encapsulated in a 3D agarose matrix was evaluated for the developmental competence of pig oocytes by analyzing blastocyst formation after parthenogenetic activation (PA), intra-oocyte GSH and ROS contents, expression levels of BMP15 and BAX, TUNEL (terminal deoxynucleotidyl transferase-mediated d-UTP nick end-labeling) assay, protein expression levels of BMP15, and intra-oocyte ATP levels. The optimized number of pGCs (5 × 10 cells/well) in a 3D agarose matrix led to a significantly higher blastocyst formation, increased BMP15 gene and protein expression, and intra-oocyte ATP levels; moreover, it induced significantly lower intra-oocyte ROS contents, pro-apoptotic BAX gene expression, and apoptotic index, compared to control. Our results demonstrate that application of pGCs as feeder cells encapsulated in the agarose matrix for IVM effectively increases the developmental competence of porcine oocytes.
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http://dx.doi.org/10.1016/j.theriogenology.2021.01.008DOI Listing
April 2021

Eif2b3 mutants recapitulate phenotypes of Vanishing White Matter Disease and validate novel disease alleles in zebrafish.

Hum Mol Genet 2021 Jan 30. Epub 2021 Jan 30.

Department of Biology, Chungnam National University, Daejeon, Korea.

Leukodystrophy with Vanishing White Matter (VWM), also called Childhood Ataxia with Central Nervous System Hypomyelination (CACH), is caused by mutations in the subunits of the eukaryotic translation initiation factor, EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5. However, little is known regarding the underlying pathogenetic mechanisms, and there is no curative treatment for VWM. In this study, we established the first EIF2B3 animal model for VWM disease in vertebrates by CRISPR mutagenesis of the highly conserved zebrafish ortholog eif2b3. Using CRISPR, we generated two mutant alleles in zebrafish eif2b3, 10- and 16-bp deletions, respectively. The eif2b3 mutants showed defects in myelin development and glial cell differentiation, and increased expression of genes in the induced stress response pathway. Interestingly, we also found ectopic angiogenesis and increased VEGF expression. Ectopic angiogenesis in the eif2b3 mutants was reduced by administration of VEGF receptor inhibitor SU5416. Using the eif2b3 mutant zebrafish model together with in silico protein modeling analysis, we demonstrated the pathogenicity of 18 reported mutations in EIF2B3, as well as of a novel variant identified in a 19-month-old female patient: c.503 T > C (p.Leu168Pro). In summary, our zebrafish mutant model of eif2b3 provides novel insights into VWM pathogenesis and offers rapid functional analysis of human EIF2B3 gene variants.
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http://dx.doi.org/10.1093/hmg/ddab033DOI Listing
January 2021

Genetic Analysis and Clinical Characteristics of Hereditary Pheochromocytoma and Paraganglioma Syndrome in Korean Population.

Endocrinol Metab (Seoul) 2020 12 23;35(4):858-872. Epub 2020 Dec 23.

Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea.

Background: Pheochromocytoma and paragangliomas (PPGL) are hereditary in approximately 30% to 40% cases. With the advancement of genetic analysis techniques, including next-generation sequencing (NGS), there were attempts to classify PPGL into molecular clusters. With NGS being applied to clinical settings recently, we aimed to review the results of genetic analysis, including NGS, and investigate the association with clinical characteristics in Korean PPGL patients.

Methods: We reviewed the medical records of PPGL patients who visited Severance hospital from 2006 to 2019. We documented the clinical phenotype of those who underwent targeted NGS or had known germline mutations of related genes.

Results: Among 57 PPGL patients, we found 28 pathogenic germline mutations of susceptibility genes. Before the targeted NGS was implemented, only obvious syndromic feature lead to the Sanger sequencing for the specific genes. Therefore, for the exact prevalence, only patients after the year 2017, when targeted NGS was added, were included (n=43). The positive germline mutations were found in 14 patients; thus, the incidence rate is 32.6%. Patients with germline mutations had a higher likelihood of family history. There were significant differences in the type of PPGLs, percentage of family history, metastasis rate, presence of other tumors, and biochemical profile among three molecular clusters: pseudohypoxic tricarboxylic acid cycle-related, pseudohypoxic von Hippel-Lindau (VHL)/endothelial PAS domain-containing protein 1-related, and kinase-signaling group. Germline mutations were identified in seven PPGL-related genes (SDHB, RET, VHL, NF1, MAX, SDHA, and SDHD).

Conclusion: We report the expected prevalence of germline mutations in Korean PPGL patients. NGS is a useful and accessible tool for genetic analysis in patients with PPGLs, and further research on molecular classification is needed for precise management.
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http://dx.doi.org/10.3803/EnM.2020.683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803615PMC
December 2020

Providing Ancillary Care in Clinical Research: A Case of Diffuse Large B-Cell Lymphoma during a Malaria Vaccine Trial in Equatorial Guinea.

Am J Trop Med Hyg 2020 Nov 23. Epub 2020 Nov 23.

Sanaria, Inc., Rockville, Maryland.

Providing medical care for participants in clinical trials in resource-limited settings can be challenging and costly. Evaluation and treatment of a young man who developed cervical lymphadenopathy during a malaria vaccine trial in Equatorial Guinea required concerted efforts of a multinational, multidisciplinary team. Once a diagnosis of diffuse large B-cell lymphoma was made, the patient was taken to India to receive immunochemotherapy. This case demonstrates how high-quality medical care was provided for a serious illness that occurred during a trial that was conducted in a setting in which positron emission tomography for diagnostic staging, an oncologist for supervision of treatment, and an optimal therapeutic intervention were not available. Clinical researchers should anticipate the occurrence of medical conditions among study subjects, clearly delineate the extent to which health care will be provided, and set aside funds commensurate with those commitments.
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http://dx.doi.org/10.4269/ajtmh.20-1178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866340PMC
November 2020

Fusobacterium nucleatum in biopsied tissues from colorectal cancer patients and alcohol consumption in Korea.

Sci Rep 2020 11 16;10(1):19915. Epub 2020 Nov 16.

Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.

The roles of individual bacteria and their relationship in the development of colorectal cancer (CRC) remain unclear. We aimed to determine the prevalence of CRC-associated bacteria using quantitative real-time PCR (qPCR) or 16S rRNA analysis and the statistical correlations of patient demographics and clinical characteristics comprising alcohol consumption with CRC-associated bacteria. We determined the prevalence of five CRC-associated bacterial species in 38 CRC patients (39 samples) and 21 normal individuals using qPCR, and the relative abundance of bacterial taxa in the gut microbiome was assessed using 16S rRNA analysis. Fusobacterium nucleatum was the only bacterium that was significantly (P < 0.0001) more prevalent in the cancer tissue (82.1%) than in the normal tissue (0%) by qPCR. 16S rRNA analysis showed a significant correlation between six operational taxonomic units (OTUs), namely, the genera Fusobacterium, Peptostreptococcus, Collinsella, Prevotella, Parvimonas, and Gemella, in patients with CRC. An integrated analysis using 16S rRNA data and epidemiological characteristics showed that alcohol consumption was significantly correlated with the abundance of Fusobacterium OTUs. The correlation of alcohol consumption with the abundance of Fusobacterium OTUs in cancer tissue discovered using 16S rRNA analysis suggests a possible link between alcohol metabolism and subsequent tumorigenesis caused by F. nucleatum.
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http://dx.doi.org/10.1038/s41598-020-76467-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669878PMC
November 2020

Investigation of Age-Related Changes in the Skin Microbiota of Korean Women.

Microorganisms 2020 Oct 14;8(10). Epub 2020 Oct 14.

KustoGen Inc., Chuncheon 24341, Korea.

The microbiota of human skin is influenced by host and environmental factors. To determine if chronological age influences the composition of the skin microbiota on the forehead and hands, 73 Korean women were sorted into one of three age groups: (1) 10-29 years ( = 24), (2) 30-49 years ( = 21), and (3) 50-79 years ( = 28). From the 73 women, 146 skin samples (two skin sites per person) were collected. 16S rRNA gene amplicon sequencing was then conducted to analyze the skin microbiota. The overall microbial distribution varied on the forehead but was similar on the hands across the three age groups. In addition, the composition of the skin microbiota differed between the forehead and hands. Commensal microbiota, such as Streptococcus, Staphylococcus, Cutibacterium, and Corynebacterium, which contribute to maintaining skin health via dominant occupation, were affected by increasing age on forehead and hand skin. Alpha diversity indices increased significantly with age on forehead skin. This study indicates that older people may be more susceptible to pathogenic invasions due to an imbalanced skin microbiota resulting from age-related changes. The results of our study may help develop new strategies to rebalance skin microbiota shifted during aging.
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http://dx.doi.org/10.3390/microorganisms8101581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602415PMC
October 2020

Whole exome sequencing identifies mutational signatures of vitreoretinal lymphoma.

Haematologica 2020 09 1;105(9):e458-460. Epub 2020 Sep 1.

Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine.

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http://dx.doi.org/10.3324/haematol.2019.233783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556491PMC
September 2020

Changes in DNA methylation after 6-week exercise training in colorectal cancer survivors: A preliminary study.

Asia Pac J Clin Oncol 2020 Oct 13. Epub 2020 Oct 13.

Exercise Medicine Center for Diabetes and Cancer Patients, Institute of Convergence of Science (ICONS), Yonsei University, Seoul, South Korea.

Aim: Behavioral interventions such as exercise may induce epigenetic changes. Only few studies investigated the effects of exercise on epigenetic alterations in colorectal cancer survivors. The aim of this study was to explore the changes of genome-wide DNA methylation after 6-week exercise training in colorectal cancer survivors.

Methods: This preliminary study used a subset of data from a randomized controlled trial in 15 colorectal cancer survivors. Participants were randomized either to the 6-week exercise group or control group. The exercise intervention consisted of a weekly, group-based, supervised resistance exercise program and a home-based same resistance exercise plus walking six times per week. Blood samples were collected at baseline and after the intervention and data from eight subjects were analyzed for genome-wide DNA methylation on 865,918 CpG sites.

Results: Compared to the control group, the exercise group shows notable methylation changes in 756 CpG sites (22.7-25.2%). Gene ontology and disease annotation analysis showed that the genes targeting 81 CpG sites in promoter region with significant group-difference were linked in biological process such as immune response and transcription and related to metabolic and immune diseases. Also, hypermethylation on genes related to disease prevention seemed to be inhibited in the exercise group compared to the control group, indicating a likelihood of transcriptional activity of these genes.

Conclusion: We found a preliminary evidence of the positive effects of exercise intervention on epigenetic markers in colorectal cancer survivors. Larger scale randomized controlled trials are warranted to further investigate our findings.
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http://dx.doi.org/10.1111/ajco.13482DOI Listing
October 2020

Localization of integrin heterodimer αβ on the surface of uterine endometrial stromal and epithelial cells in mice.

Anim Cells Syst (Seoul) 2020 Aug 5;24(4):228-232. Epub 2020 Aug 5.

Department of Animal Life Science, Kangwon National University, Chuncheon, Korea.

Previously, we reported that endometrial stromal (ES) and endometrial epithelial (EE) cells did not attach to tenascin C, indicating the absence of active integrin αβ on the surface of mouse ES and EE cells. However, that study used recombinant tenascin C without fibronectin (FN) type III repeats interacting with integrin heterodimers. Therefore, we re-evaluated the presence of integrin αβ actively functioning on the surface of mouse ES and EE cells using full-length native tenascin C with FN type III repeats. The functionality of integrin αβ was confirmed using attachment and antibody inhibition assays. Both mouse ES and EE cells showed significantly increased adhesion to native tenascin C, and functional blocking of integrin αβ significantly inhibited adhesion to native tenascin C. These results demonstrate that the integrin α and β subunits function as active heterodimers on the plasma membrane of mouse ES and EE cells, respectively.
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http://dx.doi.org/10.1080/19768354.2020.1804446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473287PMC
August 2020

Corrigendum to 'Targeted gene panel sequencing in early infantile onset developmental and epileptic encephalopathy' [Brain Dev. 42(6) (2020) 438-448].

Brain Dev 2021 Jan 29;43(1):179. Epub 2020 Sep 29.

Divison of Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Epilepsy Research Institute, Seoul, South Korea. Electronic address:

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http://dx.doi.org/10.1016/j.braindev.2020.09.006DOI Listing
January 2021

The phenotype and treatment of SCN2A-related developmental and epileptic encephalopathy.

Epileptic Disord 2020 Oct;22(5):563-570

Division of Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.

Aims: We aimed to delineate the phenotypic spectrum of SCN2A-related developmental and epileptic encephalopathy (DEE) and determine the effectiveness of various treatment modalities, including sodium channel blockers and the ketogenic diet.

Methods: Eleven patients with SCN2A-related DEE were included in the study. The characteristics of SCN2A mutations, electroclinical features, clinical course, and response to treatment modalities were analysed.

Results: The 11 patients were aged between 0.4 and 9.7 years. The onset of seizures ranged from neonate (six patients) to infant (four patients), to childhood (one patient). Epilepsy presented as Ohtahara syndrome, West syndrome, epilepsy of infancy with migrating focal seizures (EIMFS), and focal epilepsy in neonatal- to infantile-onset patients. The only childhood-onset patient in our study presented with focal epilepsy with autism. Neonatal-to infantile-onset patients had drug-resistant epilepsy (9/10), however, sodium channel blockers were effective in all treated patients (9/9). The ketogenic diet (6/8) and high-dose steroid treatment (4/5) were also effective. The seizures in the childhood-onset patient worsened during treatment with sodium channel blockers. All mutations in neonatal- to infantile-onset patients were missense mutations, whereas the mutation in the childhood-onset patient was a truncation mutation.

Conclusions: These results support earlier observations regarding the epilepsy syndromes and response to antiepileptic drugs in patients with SCN2A-related DEE.
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http://dx.doi.org/10.1684/epd.2020.1199DOI Listing
October 2020

Serial Detection of L265P Mutation in the Aqueous Humor of a Patient with Vitreoretinal Lymphoma for Disease Monitoring.

Ocul Immunol Inflamm 2020 Sep 23:1-5. Epub 2020 Sep 23.

Department of Ophthalmology, Institute of Vision Research, Severance Hospital, Yonsei University College of Medicine , Seoul, Republic of Korea.

Purpose: To report a case of a patient whose mutation disappeared from the aqueous humor following treatment with intravitreal methotrexate.

Methods: A retrospective review of clinical, histopathological and imaging records.

Results: A 49-year-old woman presented with bilateral primary vitreoretinal lymphoma confirmed by molecular and next-generation sequencing studies on vitreous biopsy samples. Initially, the L265P mutation was detected in aqueous samples of both eyes. Serial testing for L265P mutations performed on aqueous samples collected at the time of the weekly intravitreal methotrexate injections showed the mutation ceased to be detected after four weekly injections in the non-vitrectomized right eye and after two weekly injections in the vitrectomized left eye. Clinical improvement accompanied the negativization of the mutation in both eyes.

Conclusion: We present a case that demonstrates the possible utilization of serial testing for the L265P mutation as a tool for monitoring disease course in vitreoretinal lymphoma.
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http://dx.doi.org/10.1080/09273948.2020.1802488DOI Listing
September 2020

Analytical validation of the droplet digital PCR assay for diagnosis of spinal muscular atrophy.

Clin Chim Acta 2020 Nov 19;510:787-789. Epub 2020 Sep 19.

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

Background: Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by homozygote loss of exon 7 on the survival motor neuron 1 (SMN1) gene. The severity of the SMA phenotype is influenced by copies of SMN2, a gene that is highly homologous with SMN1.

Methods: We validated analytical performance of droplet digital polymerase chain reaction (ddPCR) for detection of copy number variation of SMN1 and SMN2 genes for diagnosis of SMA using clinical samples. For accuracy performance evaluation, ddPCR results were compared with those of multiplex ligation-dependent probe amplification (MLPA) as a reference standard. Copy numbers of SMN1/SMN2 exon 7 from 200 clinical samples were concordant between ddPCR and MLPA.

Results: For all samples, the copy number of SMN1/SMN2 exon 7 was concordant between MLPA and ddPCR. The ddPCR also showed acceptable degrees of repeatability and total imprecision.

Conclusion: Therefore, ddPCR is expected to be useful for SMA diagnosis and to predict phenotypic severity of SMA patients by determining the copy number of SMN2 in clinical laboratories.
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http://dx.doi.org/10.1016/j.cca.2020.09.024DOI Listing
November 2020

Clinical characteristics of KCNQ2 encephalopathy.

Brain Dev 2021 Feb 8;43(2):244-250. Epub 2020 Sep 8.

Division of Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Purpose: KCNQ2 mutations are associated with benign familial neonatal epilepsy (BFNE) or developmental and epileptic encephalopathy (DEE). In this study, we aimed to delineate the phenotype of KCNQ2 encephalopathy and evaluate the treatment response.

Methods: Thirteen patients of KCNQ2 encephalopathy were included in the study. Characteristics of KCNQ2 mutations, electroclinical features, clinical course, and response to the treatment were analyzed.

Results: Age range of the thirteen patients was between 3 months and 20.9 years. The onset of seizures in 11 patients ranged from 1 to 3 days of age, while in the other two patients it was 7 and 40 days, respectively. Most common initial seizure types were tonic seizures. Initial EEGs were suppression burst pattern in seven patients and slow and disorganized background with multifocal epileptiform discharges in six patients. Initial epilepsy syndrome was Ohtahara syndrome in seven patients, neonatal focal seizure in five patients, and focal epilepsy beyond neonatal period in one patient. Sodium channel blockers including oxcarbazepine (OXC) (n = 3), lamotrigine (LTG) (n = 3), phenytoin (PHT) (n = 2), topiramate (TPM) (n = 2), and zonisamide (ZNS) (n = 1) were tried and found effective in eleven patients. Ultimately, 12 of 13 patients became seizure-free. However, developmental outcomes were poor.

Conclusions: Sodium channel blockers are effective in seizure control in these patients with KCNQ2 encephalopathy. Early recognition of KCNQ2 encephalopathy and early use of sodium channel blockers might be helpful in seizure control.
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http://dx.doi.org/10.1016/j.braindev.2020.08.015DOI Listing
February 2021

Prevalence and clinical implications of germline predisposition gene mutations in patients with acute myeloid leukemia.

Sci Rep 2020 08 31;10(1):14297. Epub 2020 Aug 31.

Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-ro, Gangnam-gu, Seoul, 06351, Korea.

Acute myeloid leukemia (AML) is one of the most common types of leukemia. With the recent advances in sequencing technology and the growing body of knowledge on the genetics of AML, there is increasing concern about cancer predisposing germline mutations as well as somatic mutations. As familial cases sharing germline mutations are constantly reported, germline predisposition gene mutations in patients with AML are gaining attention. We performed genomic sequencing of Korean patients diagnosed with AML to identify the prevalence and characteristics of germline predisposition mutations. Among 180 patients, germline predisposition mutations were identified in 13 patients (13/180, 7.2%, eight adults and five children). Germline mutations of BLM, BRCA1, BRCA2, CTC1, DDX41, ERCC4, ERCC6, FANCI, FANCM, PALB2, and SBDS were identified. Most of the mutations are in genes involved in DNA repair and genomic stability maintenance. Patients harboring germline mutations tended to have earlier onset of AML (p = 0.005), however, the presence of germline mutations did not showed significant association with other clinical characteristics or treatment outcome. Since each mutation was rare, further study with a larger number of cases would be needed to establish the effect of the mutations.
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http://dx.doi.org/10.1038/s41598-020-71386-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459095PMC
August 2020

Screening of Integrin Heterodimers Expressed Functionally on the Undifferentiated Spermatogonial Stem Cells in the Outbred ICR Mice.

Int J Stem Cells 2020 Nov;13(3):353-363

Department of Animal Life Science, Kangwon National University, Chuncheon, Korea.

Background And Objectives: Outbred mice are widely used in toxicology, pharmacology, and fundamental biomedical research. However, there have been no reports of culture systems for spermatogonial stem cells (SSCs) derived from these mice.

Methods: As a step towards constructing a non-cellular niche supporting the maintenance of outbred mouse SSC self-renewal, we systematically investigated the types of integrin heterodimers that are expressed transcriptionally, translationally, and functionally in SSCs derived from Imprinting Control Region (ICR) mice.

Results: Among the genes encoding 25 integrin subunits, integrin , , , , , and , and integrin and had significantly higher transcriptional levels than the other subunits. Furthermore, at the translational level, integrin , , , , , and were localized on the surface of SSCs, but integrin and not. Moreover, significantly stronger translational expression than integrin and was observed in integrin , , , and . SSCs showed significantly increased adhesion to fibronectin, laminin, tenascin C and vitronectin, and functional blocking of integrin , , or significantly inhibited adhesion to these molecules.

Conclusions: We confirmed that integrin , , and actively function on the surface of undifferentiated SSCs derived from outbred ICR mice.
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http://dx.doi.org/10.15283/ijsc20061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691863PMC
November 2020

Real-world data on the survival outcome of patients with newly diagnosed Waldenström macroglobulinemia.

Korean J Intern Med 2020 Aug 14. Epub 2020 Aug 14.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background/aims: Waldenström macroglobulinemia (WM) is a rare lymphoproliferative disorder that usually follows an indolent clinical course. However, some patients show an aggressive clinical course leading to death. We explored the risk factors predicting poor prognosis in WM patients.

Methods: We retrospectively analyzed 47 patients diagnosed with WM between 2000 and 2018 to explore risk factors predicting poor prognosis using various clinical and laboratory parameters and risk models including the International Prognostic Staging System for WM (IPSS-WM).

Results: Over a median follow-up duration of 80.4 months, 29 patients died. The main causes of death were disease progression, organ failure related to amyloidosis, and infection. The median overall survival (OS) was 55.1 months, and 14 patients, including three with amyloidosis, died within 2 years. Serum β2-microglobulin level higher than 4 mg/dL was significantly associated with poor OS. Accordingly, the IPSS-WM showed a significant association with poor prognosis compared with other risk models, and the low-risk group had better OS than intermediate- and high-risk groups. In the retrospective analysis using the results of targeted sequencing in two cases representing good and bad prognosis, different patterns of mutation profiles were observed, including mutations of MYD88, TP53, ARID1A, and JAK2 in a refractory case.

Conclusions: Serum β2-microglobulin could be a single biomarker strongly predictive of poor survival of WM patients, and the low-risk group of the IPSS-WM risk model including serum β2-microglobulin has better prognostic value than other risk models. Mutation analysis also might provide additional information to predict high-risk patients.
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http://dx.doi.org/10.3904/kjim.2019.367DOI Listing
August 2020

Genetic heterogeneity and prognostic impact of recurrent ANK2 and TP53 mutations in mantle cell lymphoma: a multi-centre cohort study.

Sci Rep 2020 08 7;10(1):13359. Epub 2020 Aug 7.

Division of Haematology-Oncology, Department of Internal Medicine, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, 49267, Busan, South Korea.

The molecular features of mantle cell lymphoma (MCL), including its increased incidence, and complex therapies have not been investigated in detail, particularly in East Asian populations. In this study, we performed targeted panel sequencing (TPS) and whole-exome sequencing (WES) to investigate the genetic alterations in Korean MCL patients. We obtained a total of 53 samples from MCL patients from five Korean university hospitals between 2009 and 2016. We identified the recurrently mutated genes such as SYNE1, ATM, KMT2D, CARD11, ANK2, KMT2C, and TP53, which included some known drivers of MCL. The mutational profiles of our cohort indicated genetic heterogeneity. The significantly enriched pathways were mainly involved in gene expression, cell cycle, and programmed cell death. Multivariate analysis revealed that ANK2 mutations impacted the unfavourable overall survival (hazard ratio [HR] 3.126; P = 0.032). Furthermore, TP53 mutations were related to worse progression-free survival (HR 7.813; P = 0.043). Among the recurrently mutated genes with more than 15.0% frequency, discrepancies were found in only 5 genes from 4 patients, suggesting comparability of the TPS to WES in practical laboratory settings. We provide the unbiased genetic landscape that might contribute to MCL pathogenesis and recurrent genes conferring unfavourable outcomes.
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http://dx.doi.org/10.1038/s41598-020-70310-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414214PMC
August 2020

In vitro maturation on an agarose matrix improves the developmental competence of porcine oocytes.

Theriogenology 2020 Nov 22;157:7-17. Epub 2020 Jul 22.

College of Veterinary Medicine, Kangwon National University, Chuncheon, 24341, Republic of Korea; Institute of Veterinary Science, Kangwon National University, Chuncheon, 24341, Republic of Korea. Electronic address:

Oocytes in vivo generally mature in ovarian follicles that are soft, whereas oocytes that mature in vitro are on the hard surface of culture dishes. Embryonic ontogeny through organogenesis has greater ability in in vivo matured oocytes than it does in in vitro matured oocytes, indicating the importance of a soft culture matrix. In this study, we report the effect of using an agarose matrix as a culture substrate on the development of pig oocytes derived from medium antral follicles. The cumulus-oocyte complexes (COCs) retrieved from medium antral follicles were matured on noncoated (control) culture dishes or dishes coated with 1% and 2% (w/v) agarose matrices. Subsequently, the effect of the soft culture matrix on the developmental competence of porcine oocytes was assessed by analyzing cumulus expansion, blastocyst formation after parthenogenetic activation (PA), gene expression levels (ACTN4, BMP15, BAX, HIF1A, PFKP and VEGFA), TUNEL indices, BMP15 protein expression levels, cortical granule (CG) distribution, and intraoocyte ATP levels. In vitro maturation (IVM) of pig COCs using a 1% (w/v) agarose matrix resulted in significantly higher blastocyst formation, cumulus expansion, gene expression of BMP15, HIF1A and VEGFA, protein expression of BMP15, and intraoocyte ATP levels, and there was significantly reduced expression of a pro-apoptotic gene and ACTN4 gene and a reduction in TUNEL indices. These results demonstrate that the developmental competence of porcine oocytes can be effectively improved through IVM on a soft culture matrix made of agarose over what is observed using hard culture dishes.
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http://dx.doi.org/10.1016/j.theriogenology.2020.07.016DOI Listing
November 2020

SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization.

Hum Mol Genet 2020 Nov;29(18):2989-3002

The University of Leicester Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behaviour, University of Leicester - RKCSB, PO Box 65, Leicester LE2 7LX, UK.

Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development with lack of a foveal pit and no cone photoreceptor outer segment lengthening. Loss of foveal specialization features such as outer segment lengthening implies reduced foveal cone density, which contributes to reduced visual acuity. Unlike other disorders (such as albinism or PAX6 mutations) which exhibit a spectrum of foveal hypoplasia, SLC38A8 mutations have arrest of retinal development at an earlier stage resulting in a more under-developed retina and severe phenotype.
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http://dx.doi.org/10.1093/hmg/ddaa166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645707PMC
November 2020

Reanalysis of Genomic Sequencing Results in a Clinical Laboratory: Advantages and Limitations.

Front Neurol 2020 30;11:612. Epub 2020 Jun 30.

Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, South Korea.

Genetic diagnosis of patients with neurodevelopmental disorders is imperative and a standard clinical practice. Considering the continuous accumulation of data on disease-causing variants, reanalysis of previously established sequencing data is important. Periodic reanalysis of variants with uncertain significance has become mandatory in clinical laboratories. Therefore, to confirm the utility of the reanalysis of targeted gene panel data in clinical laboratories, we re-evaluated the data of two groups of patients who had undergone targeted gene panel testing for neurodevelopmental disorders ( = 116) and epileptic encephalopathy ( = 384). This reanalysis was based on a reannotation process reflecting updated databases. Six (5.2%) and seven (1.8%) new pathogenic or likely pathogenic variants were identified in these two groups, respectively, attributable to the updated guidelines and reports from unrelated patients. Although relatively low, considerable increase in the diagnostic yield was confirmed. We suggest that reanalysis of genetic variants, mainly using changes in databases and updated interpretations, should be implemented as a routine practice in clinical laboratories.
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http://dx.doi.org/10.3389/fneur.2020.00612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338758PMC
June 2020

Screening of integrins localized on the surface of human epidermal melanocytes.

In Vitro Cell Dev Biol Anim 2020 Jun 23;56(6):435-443. Epub 2020 Jun 23.

Department of Animal Life Science, Kangwon National University, Chuncheon, 24341, South Korea.

In vivo, melanocytes occupy three-dimensional (3D) space. Nevertheless, most experiments involving melanocytes are performed in a two-dimensional microenvironment, resulting in difficulty obtaining accurate results. Therefore, it is necessary to construct an artificial in vivo-like 3D microenvironment. Here, as a step towards engineering a precisely defined acellular 3D microenvironment supporting the maintenance of human epidermal melanocytes (HEMs), we examined the types of integrin heterodimers that are expressed transcriptionally, translationally, and functionally in HEMs. Real-time PCR and fluorescent immunoassay analyses were used to elucidate the expression of integrin α and β subunit genes at the transcriptional and translational levels, respectively. The functionality of the presumed integrin heterodimers was confirmed using attachment and antibody-inhibition assays. Among the genes encoding 12 integrin subunits (α, α, α, α, α, α, α, α, β, β, β, and β) showing significantly higher transcription levels, proteins translated from the integrin α, α, α, β, β, and β subunit genes were detected on the surface of HEMs. These HEMs showed significantly increased adhesion to collagen I, fibronectin, laminin, and vitronectin, and functional blockade of the integrin α subunits significantly inhibited adhesion to collagen I, fibronectin, and laminin. In addition, there was no significant inhibition of the adhesion to fibronectin or vitronectin in HEMs with functional blockade of the integrin α, α, or α subunits. These results indicate that the active integrin αβ heterodimer and the inactive integrin α, α, α, β, and β subunits are all localized on the surface of HEMs.
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http://dx.doi.org/10.1007/s11626-020-00471-4DOI Listing
June 2020

Generation of embryonic stem cells derived from the inner cell mass of blastocysts of outbred ICR mice.

Anim Cells Syst (Seoul) 2020 16;24(2):91-98. Epub 2020 Apr 16.

Department of Animal Life Science, Kangwon National University, Chuncheon, Korea.

Embryonic stem cells (ESCs) derived from outbred mice which share several genetic characteristics similar to humans have been requested for developing stem cell-based bioengineering techniques directly applicable to humans. Here, we report the generation of ESCs derived from the inner cell mass of blastocysts retrieved from 9-week-old female outbred ICR mice mated with 9-week-old male outbred ICR mice (ESCs). Similar to those from 129/Ola mouse blastocysts (ESCs), the established ESCs showed inherent characteristics of ESCs except for partial and weak protein expression and activity of alkaline phosphatase. Moreover, ESCs were not originated from embryonic germ cells or pluripotent cells that may co-exist in outbred ICR strain-derived mouse embryonic fibroblasts (MEFs) used for deriving colonies from inner cell mass of outbred ICR mouse blastocysts. Furthermore, instead of outbred MEFs, hybrid MEFs as feeder cells could sufficiently support maintenance of ESC self-renewal. Additionally, ESC-specific characteristics (self-renewal, pluripotency, and chromosomal normality) were observed in ESCs cultured for 40th subpassages (164 days) on MEFs without any alterations. These results confirmed the successful establishment of ESCs derived from outbred ICR mice, and indicated that self-renewal and pluripotency of the established ESCs could be maintained on MEFs in culture.
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http://dx.doi.org/10.1080/19768354.2020.1752306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241472PMC
April 2020