Publications by authors named "Kyung-Min Lee"

243 Publications

IL10RB as a key regulator of COVID-19 host susceptibility and severity.

medRxiv 2021 Jun 2. Epub 2021 Jun 2.

Background: Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes and readily available compounds that reduce COVID-19 host susceptibility is a critical next step.

Methods: We integrate COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX) and perturbargen signatures to identify candidate genes and compounds that reverse the predicted gene expression dysregulation associated with COVID-19 susceptibility. The top candidate gene is validated by testing both its GReX and observed blood transcriptome association with COVID-19 severity, as well as by perturbation to quantify effects on viral load and molecular pathway dysregulation. We validate the drug repositioning analysis by examining whether the top candidate compounds decrease COVID-19 incidence based on epidemiological evidence.

Results: We identify as the top key regulator of COVID-19 host susceptibility. Predicted GReX up-regulation of and higher expression in COVID-19 patient blood is associated with worse COVID-19 outcomes. IL10RB overexpression is associated with increased viral load and activation of immune-related molecular pathways. Azathioprine and retinol are prioritized as candidate compounds to reduce the likelihood of testing positive for COVID-19.

Conclusions: We establish an integrative data-driven approach for gene target prioritization. We identify and validate as a suitable molecular target for modulation of COVID-19 host susceptibility. Finally, we provide evidence for a few readily available medications that would warrant further investigation as drug repositioning candidates.
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http://dx.doi.org/10.1101/2021.05.31.21254851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183086PMC
June 2021

Quantitative Proteomics Reveals Knockdown of CD44 Promotes Proliferation and Migration in Claudin-Low MDA-MB-231 and Hs 578T Breast Cancer Cell Lines.

J Proteome Res 2021 Jun 2. Epub 2021 Jun 2.

Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul 03082, Korea.

CD44 is a transmembrane glycoprotein that can regulate the oncogenic process. This is known to be a marker of the claudin-low subtype of breast cancer, as well as a cancer stem cell marker. However, its functional regulatory roles are poorly understood in claudin-low breast cancer. To gain comprehensive insight into the function of CD44, we performed an in-depth tandem mass tag-based proteomic analysis of two claudin-low breast cancer cell lines (MDA-MB-231 and Hs 578T) transfected with CD44 siRNA. As a result, we observed that 2736 proteins were upregulated and 2172 proteins were downregulated in CD44-knockdown MDA-MB-231 cells. For Hs 578T CD44-knockdown cells, 412 proteins were upregulated and 443 were downregulated. Gene ontology and network analyses demonstrated that the suppression of this marker mediates significant functional alterations related to oncogenic cellular processes, including proliferation, metabolism, adhesion, and gene expression regulation. A functional study confirmed that CD44 knockdown inhibited proliferation by regulating the expression of genes related to cell cycle, translation, and transcription. Moreover, this promoted the expression of multiple cell adhesion-associated proteins and attenuated cancer cell migration. Finally, our proteomic study defines the landscape of the CD44-regulated proteome of claudin-low breast cancer cells, revealing changes that mediate cell proliferation and migration. Our proteomics data set has been deposited to the ProteomeXchange Consortium via the PRIDE repository with the data set identifier PXD015171.
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http://dx.doi.org/10.1021/acs.jproteome.1c00293DOI Listing
June 2021

Cross-Sectional Study of Varicella Zoster Virus Immunity in Healthy Korean Children Assessed by Glycoprotein Enzyme-Linked Immunosorbent Assay and Fluorescent Antibody to Membrane Antigen Test.

Vaccines (Basel) 2021 May 12;9(5). Epub 2021 May 12.

Department of Microbiology, College of Medicine, Yeungnam University, Daegu 42415, Korea.

The prevalence of varicella is especially high among children in the age group of 4-6 years in South Korea, regardless of vaccination. We investigated the immune status of healthy children enrolled in day-care centers and compared pre- and post-vaccination immunity. Antibody titers were measured using a glycoprotein enzyme-linked immunosorbent assay (gpEIA) kit, and the seroconversion rate was assessed using a fluorescent antibody to membrane antigen (FAMA) test. Among 541 vaccinated children, 109 (20.1%) had breakthrough varicella. However, 13 (72.2%) of the 18 unvaccinated children had a history of varicella. The gpEIA geometric mean titers (GMTs) of pre- and 5 weeks post-vaccination in 1-year-old children were 14.7 and 72 mIU/mL, respectively, and the FAMA seroconversion rate was 91.1%. The gpEIA GMTs of 2-, 3-, 4-, 5-, and 6-year-old children were 104.1, 133.8, 223.5, 364.1, and 353.0 mIU/mL, respectively. Even though the gpEIA GMT increased with age, the pattern of gpEIA titer distribution in 4- to 6-year-old vaccinees without varicella history represented both waning immunity and natural boosting immunity. These results suggest that some vaccinees are vulnerable to varicella infection. Therefore, it is necessary to consider a two-dose varicella vaccine regimen in South Korea.
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http://dx.doi.org/10.3390/vaccines9050492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151998PMC
May 2021

Nuclear FGFR1 regulates gene transcription and promotes antiestrogen resistance in ER+ breast cancer.

Clin Cancer Res 2021 May 19. Epub 2021 May 19.

Medicine, UTSW Simmons Cancer Center

Purpose: FGFR1 overexpression has been associated with endocrine resistance in ER+ breast cancer. We found FGFR1 localized in the nucleus of breast cancer cells in primary tumors resistant to estrogen suppression. We investigated a role of nuclear FGFR1 on gene transcription and antiestrogen resistance.

Experimental Design: Tumors from patients treated with letrozole were subjected to Ki67 and FGFR1 IHC. MCF7 cells were transduced with FGFR1(SP-)(NLS) to promote nuclear FGFR1 overexpression. FGFR1 genomic activity in ER+/-amplified breast cancer cells {plus minus} FOXA1 siRNA or {plus minus} the FGFR tyrosine kinase inhibitor (TKI) erdafitinib was examined by ChIP-Seq and RNA-Seq. The nuclear and chromatin-bound FGFR1 interactome was investigated by Mass Spectrometry (MS).

Results: High nuclear FGFR1 expression in ER+ primary tumors positively correlated with post-letrozole Ki67 values. Nuclear FGFR1 overexpression influenced gene transcription and promoted resistance to estrogen suppression and to fulvestrant A gene expression signature induced by nuclear FGFR1 correlated with shorter survival in the METABRIC cohort of patients treated with antiestrogens. ChIP-Seq revealed FGFR1 occupancy at transcription start sites, overlapping with active transcription histone marks. MS analysis of the nuclear FGFR1 interactome identified phosphorylated RNA-Polymerase II and FOXA1, with FOXA1 RNAi impairing FGFR1 recruitment to chromatin. Treatment with erdafitinib did not impair nuclear FGFR1 translocation and genomic activity.

Conclusions: These data suggest nuclear FGFR1 contributes to endocrine resistance by modulating gene transcription in ER+ breast cancer. Nuclear FGFR1 activity was unaffected by FGFR TKIs, thus supporting the development of treatment strategies to inhibit nuclear FGFR1 in ER+/FGFR1 overexpressing breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3905DOI Listing
May 2021

The SARS-CoV-2 RNA interactome.

Mol Cell 2021 Apr 27. Epub 2021 Apr 27.

Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea; School of Biological Sciences, Seoul National University, Seoul, Republic of Korea. Electronic address:

SARS-CoV-2 is an RNA virus whose success as a pathogen relies on its abilities to repurpose host RNA-binding proteins (RBPs) and to evade antiviral RBPs. To uncover the SARS-CoV-2 RNA interactome, we here develop a robust ribonucleoprotein (RNP) capture protocol and identify 109 host factors that directly bind to SARS-CoV-2 RNAs. Applying RNP capture on another coronavirus, HCoV-OC43, revealed evolutionarily conserved interactions between coronaviral RNAs and host proteins. Transcriptome analyses and knockdown experiments delineated 17 antiviral RBPs, including ZC3HAV1, TRIM25, PARP12, and SHFL, and 8 proviral RBPs, such as EIF3D and CSDE1, which are responsible for co-opting multiple steps of the mRNA life cycle. This also led to the identification of LARP1, a downstream target of the mTOR signaling pathway, as an antiviral host factor that interacts with the SARS-CoV-2 RNAs. Overall, this study provides a comprehensive list of RBPs regulating coronaviral replication and opens new avenues for therapeutic interventions.
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http://dx.doi.org/10.1016/j.molcel.2021.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075806PMC
April 2021

Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes.

Nat Commun 2021 05 10;12(1):2579. Epub 2021 May 10.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-021-22338-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110798PMC
May 2021

The incidence of the healthcare costs of chronic conditions.

Int J Health Econ Manag 2021 May 4. Epub 2021 May 4.

Department of Health Administration and Policy, George Mason University, 4400 University Dr. MS 1J3, Fairfax, VA, USA.

Who pays for the costs of chronic conditions? In this paper, we examine whether 50-64-year old workers covered by employer-sponsored insurance bear healthcare costs of chronic conditions in the form of lower wages. Using a difference-in-differences approach with data from the Health and Retirement Study, we find that workers with chronic diseases receive significantly lower wages than healthy workers when they are covered by employer-sponsored insurance. Our findings suggest that higher healthcare costs of chronic conditions can explain the substantial part of the wage gap between workers with and without chronic diseases.
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http://dx.doi.org/10.1007/s10754-021-09305-6DOI Listing
May 2021

The complete chloroplast genome of a traditional medicinal plant.

Mitochondrial DNA B Resour 2021 Apr 5;6(4):1332-1334. Epub 2021 Apr 5.

Tradition Korean Medicine Research Team, National Development Institute of Korean Medicine, Jangheung, South Korea.

is a rare native plant attributed with analgesic, gallbladder-supportive, and other functions in China and the Republic of Korea. However, the complete chloroplast genome sequence of the native plant has not been determined. In this study, we sequenced the complete chloroplast genome sequence, and examined the molecular phylogeny and genetic information of . The total chloroplast genome of was 154,871 bp in length with a large single-copy region (85,089 bp), small single-copy region (17,714 bp), and pair of inverted repeats regions (26,034 bp). The chloroplast genome encoded a total of 176 genes, including 131 protein-coding genes, 37 tRNA genes, and eight rRNA genes. The phylogenetic tree indicated that was the most closely related to
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http://dx.doi.org/10.1080/23802359.2021.1907802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023639PMC
April 2021

The Impact of Connecticut's Paid Sick Leave Law on the Use of Preventive Services.

Am J Prev Med 2021 Jun 20;60(6):812-819. Epub 2021 Apr 20.

Department of Health Administration and Policy, George Mason University, Fairfax, Virginia.

Introduction: Paid sick leave laws have received more attention in recent years as a way to improve public health. This study estimates the impact of paid sick leave laws on the use of preventive services using a quasi-experimental design created by the implementation of Connecticut's paid sick leave law in 2012, the first statewide mandate in the U.S.

Methods: Data were obtained from the 2007-2018 Behavioral Risk Factor Surveillance System. The analyses were conducted from spring 2018 to fall 2019. This study applied a difference-in-differences model to examine preventive service use (routine checkups, influenza vaccinations, dental visits, Pap tests, mammograms, and clinical breast examinations) in Connecticut and other New England states before and after the implementation of Connecticut's paid sick leave law in 2012.

Results: The use of preventive services increased in Connecticut compared with other New England states after implementation of Connecticut's paid sick leave law. Specifically, the rate of routine checkups (2.7 percentage points, p<0.001), influenza vaccinations (2.1 percentage points, p<0.01), dental visits (2.3 percentage points, p<0.01), and Pap tests (2.6 percentage points, p<0.01) increased compared with other New England states.

Conclusions: This study found that adult workers' use of preventive services increased in Connecticut after implementation of its paid sick leave law. State-paid sick leave laws can improve public health by supporting the use of preventive care services among workers.
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http://dx.doi.org/10.1016/j.amepre.2020.12.023DOI Listing
June 2021

The complete chloroplast genome of a traditional medicinal plant.

Mitochondrial DNA B Resour 2021 Mar 15;6(3):870-871. Epub 2021 Mar 15.

National Development Institute of Korean Medicine, Jangheung, South Korea.

is a rare native plant attributed with analgesic, gallbladder-supportive, and other functions in China and the Republic of Korea. However, the complete chloroplast genome sequence of the native plant has not been determined. In this study, we sequenced the complete chloroplast genome sequence, and examined the molecular phylogeny and genetic information of . The total chloroplast genome of was 154,871 bp in length with a large single-copy region (85,089 bp), small single-copy region (17,714 bp), and pair of inverted repeats regions (26,034 bp). The chloroplast genome encoded a total of 176 genes, including 131 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. The phylogenetic tree indicated that was most closely related to
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http://dx.doi.org/10.1080/23802359.2021.1886006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971250PMC
March 2021

Replication of heterologous glycoprotein-expressing chimeric recombinant snakehead rhabdoviruses (rSHRVs) and viral hemorrhagic septicemia viruses (rVHSVs) at different temperatures.

Virus Res 2021 May 13;297:198392. Epub 2021 Mar 13.

Department of Aquatic Life Medicine, Pukyong National University, Busan, 48513, South Korea. Electronic address:

Water temperature is an important environmental factor for the outbreaks of fish rhabdovirus diseases. In the present study, to know the role of piscine rhabdoviral glycoproteins in the determination of replication temperature, several chimeric snakehead rhabdoviruses (SHRVs) and viral hemorrhagic septicemia viruses (VHSVs) expressing heterologous glycoproteins (rSHRV-Gvhsv, SHRV expressing VHSV G protein; rSHRV-Gsvcv, SHRV expressing spring viremia of carp virus G protein; rVHSV-Gshrv, VHSV expressing SHRV G protein; rVHSV-Gsvcv, VHSV expressing SVCV G protein) were generated using reverse genetics, and their replication characteristics at different temperatures were investigated. Furthermore, based on SHRV minigenome containing a reporter gene, the role of VHSV N, P, and L proteins in the determination of VHSV's low-temperature replication was investigated. In Epithelioma papulosum cyprini (EPC) cells, rSHRV-Gvhsv could replicate only at low temperatures (15 and 20 °C) but not at 25 and 28 °C, while rSHRV-Gsvcv could replicate both low and high temperatures, indicating that VHSV G protein is a critical factor that determines the limit of replication-possible temperatures in VHSV. The range of replication-possible temperature of chimeric VHSVs (rVHSV-Gshrv and rVHSV-Gsvcv) was not different from that of rVHSV-wild (replicated only at 15 and 20 °C) in spite of having the G protein of high temperature-replicating viruses, suggesting that not only G protein but also other viral protein(s) would be involved in the determination of replication-possible temperature limit in VHSV. Cells harboring SHRV minigenome that expressing eGFP as a reporter protein were co-transfected with heterologous combinations of helper plasmids of SHRV and VHSV, through which we could exclude VHSV N and P proteins for the low-temperature replication of VHSV, because cells harboring SHRV minigenome showed fluorescence at high temperatures when VHSV N or P protein encoding plasmids were supplied. However, no fluorescence was observed in cells co-transfected with plasmids encoding SHRV N, SHRV P and VHSV L protein at all tested temperatures, suggesting that the combination of SHRV N, P and VHSV L proteins could not form a functional ribonucleoprotein (RNP) complex. Although we could not directly demonstrate the involvement of VHSV L protein in the temperature limit of VHSV replication, it is highly probable that not only VHSV G protein but also VHSV L protein may participate in the determination of VHSV replication temperature.
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http://dx.doi.org/10.1016/j.virusres.2021.198392DOI Listing
May 2021

Hospital-Based Health Care Worker Perceptions of Personal Risk Related to COVID-19.

J Am Board Fam Med 2021 Feb;34(Suppl):S103-S112

From the Department of Anesthesiology and Critical Care Medicine, George Washington School of Medicine & Health Sciences, Washington, DC (EC, RS, IY, GH, IB, DY, ERH); George Washington School of Medicine and Health Sciences, Washington, DC (K-ML); Department of Emergency Medicine, George Washington School of Medicine and Health Sciences, Washington, DC (DY); School of Nursing, George Washington University, Washington, DC (BM).

Background: Health care workers treating Coronavirus disease 2019 (COVID-19) patients face significant stressors such as caring for critically ill and dying patients, physically demanding care requiring new degrees of personal protective equipment use, risk of contracting the disease, and putting loved ones at risk. This study investigates the stress impact from COVID-19 exposure and how nurses and medical providers (eg, physicians, nurse practitioners, physician assistants) experience these challenges differently.

Methods: An electronic, self-administered questionnaire was sent to all hospital staff over 6 weeks surveying exposure to COVID-19 patients and degree of stress caused by this exposure. Responses from medical providers and nurses were analyzed for significant contributors to stress levels, as well as comparing responses from medical providers versus nurses.

Results: Stress levels from increased risk of disease contraction while on the job, fear of transmitting it to family or friends, and the resulting social stigma were highest in medical staff during the COVID-19 pandemic. Compared with medical providers, nurses had nearly 4 times the odds of considering job resignation due to COVID-19. However, most health care workers (77.4% of medical providers and 52.9% of nurses) strongly agreed or agreed with the statements indicating high levels of altruism in their desire to treat COVID-19 patients.

Conclusion: The significant stress burden placed on nurses likely contributes to increased thoughts of job resignation. However, health care providers displayed high levels of altruism during this time of extreme crisis, despite their personal risks of caring for COVID-19 patients.
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http://dx.doi.org/10.3122/jabfm.2021.S1.200343DOI Listing
February 2021

Assessment of Dietary Habits Using the Diet Quality Index-International in Cerebrovascular and Cardiovascular Disease Patients.

Nutrients 2021 Feb 7;13(2). Epub 2021 Feb 7.

Health Promotion Center, Seoul National University Bundang Hospital, Seongnam 13620, Korea.

Improvement of dietary habits is recommended for the management of cerebrovascular and cardiovascular diseases (CCVD). This study aimed to evaluate the dietary habits of CCVD patients and compare them with the general population by using the Diet Quality Index-International (DQI-I). Data from the Korean National Health and Nutrition Examination Surveys (2013-2016) were used. Cardiovascular diseases included myocardial infarction, angina pectoris, and heart failure; and cerebrovascular diseases included stroke, cerebral infarction, and hemorrhage. In total, 12,683 subjects over 20 years old were included, comprising 718 CCVD patients and 11,965 non-CCVD subjects. Survey-weighted multiple linear regression analyses with adjustment for covariates were used to compare DQI-I scores. The mean total DQI-I scores for the CCVD and non-CCVD groups were 66.7 ± 9.2 and 67.8 ± 9.2, respectively. After adjusting for covariates, the CCVD group had DQI-I scores significantly lower than the non-CCVD group (coefficient -1.13, -value = 0.011). In the analysis of each DQI-I component, the CCVD group had lower scores for variety (coefficient -0.54, -value = 0.004) and adequacy (coefficient -0.86, -value = 0.001). In this study, using nationally representative data, dietary habits of CCVD patients were shown to be lower in quality than non-CCVD subjects. Therefore, evaluation and education of adequate dietary habits are needed in the management of CCVD patients.
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http://dx.doi.org/10.3390/nu13020542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914702PMC
February 2021

EGFR mutation testing and TKI treatment patterns among veterans with stage III and IV non-small cell lung cancer.

Cancer Treat Res Commun 2021 29;27:100327. Epub 2021 Jan 29.

Duke Clinical Research Institute, Duke University School of Medicine, Durham, VA, United States; Department of Population Health Sciences, Duke University School of Medicine, Durham, VA, United States; Department of Veteran Affairs Medical Center, Durham, NC, United States.

Background: Epidermal growth factor receptor (EGFR) mutation testing is recommended in metastatic non-small cell lung cancer (NSCLC). The objective of this study was to assess changes in EGFR mutation testing patterns and tyrosine kinase inhibitor (TKI) use in US veterans with stage III-IV NSCLC between 2013 and 2017.

Patients And Methods: Retrospective study using linked data from Department of Veterans Affairs (VA) Cancer Registry System, Corporate Data Warehouse, commercial laboratories, and clinical notes. Generalized linear mixed models accounting for clustering by VA facility were used to determine factors associated with EGFR mutation testing.

Results: From 2013 to 2017, EGFR mutation testing increased from 29.5% to 38.4% among veterans with stage III-IV NSCLC and from 47.0% to 57.4% among veterans with stage IV non-squamous disease. Factors associated with increased odds of testing included being married, Medicare enrollment, and adenocarcinoma histology. Factors associated with decreased odds of testing included Medicaid eligibility, stage III disease, increasing age, being a current or former smoker, increasing Charlson-Deyo comorbidity score, and receiving cancer care in the South. Appropriate use of a TKI rose from 2013 to 2017 (17.2% to 74.1%).

Conclusion: EGFR mutation testing rates increased to almost 60% in the stage IV non-squamous NSCLC population in 2017, with residual opportunity for further increase. Several sociodemographic characteristics, comorbidities, and geographic regions were associated with EGFR mutation testing suggestive of inequitable testing decisions. Appropriate use of TKI improved drastically from 2013 to 2017 demonstrating rapidly changing practice patterns through the adoption phase of new treatment options.
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http://dx.doi.org/10.1016/j.ctarc.2021.100327DOI Listing
January 2021

Characterization of the complete chloroplast genome of (Asparagaceae: Nolinoideae) isolated in Korea.

Mitochondrial DNA B Resour 2020 Jul 20;5(3):2874-2875. Epub 2020 Jul 20.

National Development Institute of Korean Medicine, Jangheung-gun, South Korea.

is used as an important medicinal plant for fatigue, cough, and inflammation in South Korea. Here, we report the complete chloroplast genome of . The total genome size of the chloroplast is 157,076 bp with a large single-copy region (LSC: 85,374 bp), a small single-copy region (SSC: 18,748 bp), and inverted repeat regions (IRa and IRb: 26,477 bp). The GC content of the chloroplast was 37.6%. The cp genome encoded a set of 129 genes, including 83 protein-coding genes, 38 tRNA genes, and 8 rRNA genes. The phylogenetic tree analysis indicated that is closely related to .
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http://dx.doi.org/10.1080/23802359.2020.1787898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782188PMC
July 2020

Tryptophanyl-tRNA Synthetase Sensitizes Hormone Receptor-Positive Breast Cancer to Docetaxel-Based Chemotherapy.

J Breast Cancer 2020 Dec 10;23(6):599-609. Epub 2020 Dec 10.

Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.

Purpose: A relatively low response to chemotherapy has been reported for hormone receptor (HR)-positive breast cancer. In this study, we investigated the role of tryptophanyl-transfer RNA synthetase WARS) in the chemotherapeutic response of HR-positive breast cancer.

Methods: Pre-chemotherapeutic needle biopsy samples of 45 HR-positive breast cancer patients undergoing the same chemotherapeutic regimen were subjected to immunohistochemistry. To investigate the biological functions of WARS in HR-positive breast cancer, we conducted cell viability assay, flow cytometry analysis, caspase activity assay, Quantitative real-time polymerase chain reaction, and western blotting using WARS gene-modulated HR-positive breast cancer cells (T47D, ZR-75-1, and MCF7).

Results: WARS overexpression in HR-positive breast cancer patients showed a significant correlation with favorable chemotherapy response. Downregulation of WARS increased cell viability following docetaxel treatment in tumor cell lines. On the other hand, WARS overexpression sensitized the therapeutic response to docetaxel. Additionally, downregulation of WARS caused a decrease in the number of apoptotic cell populations by docetaxel. Poly (ADP-ribose) polymerase cleavage and caspase 3/7 activity were increased in docetaxel-treated tumor cells with WARS overexpression.

Conclusion: Our results suggest that WARS might be a potential predictor for chemotherapy response in patients with HR-positive breast cancer as well as a novel molecular target to improve chemosensitivity.
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http://dx.doi.org/10.4048/jbc.2020.23.e67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779724PMC
December 2020

Combined the SMAC mimetic and BCL2 inhibitor sensitizes neoadjuvant chemotherapy by targeting necrosome complexes in tyrosine aminoacyl-tRNA synthase-positive breast cancer.

Breast Cancer Res 2020 11 25;22(1):130. Epub 2020 Nov 25.

Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.

Background: Chemotherapy is the standard treatment for breast cancer; however, the response to chemotherapy is disappointingly low. Here, we investigated the alternative therapeutic efficacy of novel combination treatment with necroptosis-inducing small molecules to overcome chemotherapeutic resistance in tyrosine aminoacyl-tRNA synthetase (YARS)-positive breast cancer.

Methods: Pre-chemotherapeutic needle biopsy of 143 invasive ductal carcinomas undergoing the same chemotherapeutic regimen was subjected to proteomic analysis. Four different machine learning algorithms were employed to determine signature protein combinations. Immunoreactive markers were selected using three common candidate proteins from the machine-learning algorithms and verified by immunohistochemistry using 123 cases of independent needle biopsy FFPE samples. The regulation of chemotherapeutic response and necroptotic cell death was assessed using lentiviral YARS overexpression and depletion 3D spheroid formation assay, viability assays, LDH release assay, flow cytometry analysis, and transmission electron microscopy. The ROS-induced metabolic dysregulation and phosphorylation of necrosome complex by YARS were assessed using oxygen consumption rate analysis, flow cytometry analysis, and 3D cell viability assay. The therapeutic roles of SMAC mimetics (LCL161) and a pan-BCL2 inhibitor (ABT-263) were determined by 3D cell viability assay and flow cytometry analysis. Additional biologic process and protein-protein interaction pathway analysis were performed using Gene Ontology annotation and Cytoscape databases.

Results: YARS was selected as a potential biomarker by proteomics-based machine-learning algorithms and was exclusively associated with good response to chemotherapy by subsequent immunohistochemical validation. In 3D spheroid models of breast cancer cell lines, YARS overexpression significantly improved chemotherapy response via phosphorylation of the necrosome complex. YARS-induced necroptosis sequentially mediated mitochondrial dysfunction through the overproduction of ROS in breast cancer cell lines. Combination treatment with necroptosis-inducing small molecules, including a SMAC mimetic (LCL161) and a pan-BCL2 inhibitor (ABT-263), showed therapeutic efficacy in YARS-overexpressing breast cancer cells.

Conclusions: Our results indicate that, before chemotherapy, an initial screening of YARS protein expression should be performed, and YARS-positive breast cancer patients might consider the combined treatment with LCL161 and ABT-263; this could be a novel stepwise clinical approach to apply new targeted therapy in breast cancer patients in the future.
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http://dx.doi.org/10.1186/s13058-020-01367-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687715PMC
November 2020

A versatile oblique plane microscope for large-scale and high-resolution imaging of subcellular dynamics.

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

Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, United States.

We present an oblique plane microscope (OPM) that uses a bespoke glass-tipped tertiary objective to improve the resolution, field of view, and usability over previous variants. Owing to its high numerical aperture optics, this microscope achieves lateral and axial resolutions that are comparable to the square illumination mode of lattice light-sheet microscopy, but in a user friendly and versatile format. Given this performance, we demonstrate high-resolution imaging of clathrin-mediated endocytosis, vimentin, the endoplasmic reticulum, membrane dynamics, and Natural Killer-mediated cytotoxicity. Furthermore, we image biological phenomena that would be otherwise challenging or impossible to perform in a traditional light-sheet microscope geometry, including cell migration through confined spaces within a microfluidic device, subcellular photoactivation of Rac1, diffusion of cytoplasmic rheological tracers at a volumetric rate of 14 Hz, and large field of view imaging of neurons, developing embryos, and centimeter-scale tissue sections.
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http://dx.doi.org/10.7554/eLife.57681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707824PMC
November 2020

Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer.

Nat Commun 2020 10 30;11(1):5488. Epub 2020 Oct 30.

Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.

The 17q23 amplicon is associated with poor outcome in ER breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. Here, we interrogate transcriptome data from primary breast tumors and find that among genes in 17q23, PRR11 is a key gene associated with a poor response to therapeutic estrogen suppression. PRR11 promotes estrogen-independent proliferation and confers endocrine resistance in ER breast cancers. Mechanistically, the proline-rich motif-mediated interaction of PRR11 with the p85α regulatory subunit of PI3K suppresses p85 homodimerization, thus enhancing insulin-stimulated binding of p110-p85α heterodimers to IRS1 and activation of PI3K. PRR11-amplified breast cancer cells rely on PIK3CA and are highly sensitive to PI3K inhibitors, suggesting that PRR11 amplification confers PI3K dependence. Finally, genetic and pharmacological inhibition of PI3K suppresses PRR11-mediated, estrogen-independent growth. These data suggest ER/PRR11-amplified breast cancers as a novel subgroup of tumors that may benefit from treatment with PI3K inhibitors and antiestrogens.
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http://dx.doi.org/10.1038/s41467-020-19291-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599336PMC
October 2020

Comparison of the accuracy of intraoral scans between complete-arch scan and quadrant scan.

Prog Orthod 2020 Oct 1;21(1):36. Epub 2020 Oct 1.

Department of Orthodontics, School of Dentistry, Chonnam National University, 33 Yongbong-ro, Buk-gu, Gwangju, 61186, South Korea.

Objective: To compare the accuracy of complete-arch scans and quadrant scans obtained using a direct chairside intraoral scanner.

Material And Methods: Intraoral scans were obtained from 20 adults without missing teeth except for the third molar. Maxillary and mandibular complete-arch scans were carried out, and 4 quadrant scans for each arch were performed to obtain right posterior, right anterior, left anterior, and left posterior quadrant scans. Complete-arch scans and quadrant scans were compared with corresponding model scans using best-fit surface-based registration. Shell/shell deviations were computed for complete-arch scans and quadrant scans and compared between the complete-arch scans and each quadrant scans. In addition, shell/shell deviations were calculated also for each individual tooth in complete-arch scans to evaluate factors which influence the accuracy of intraoral scans.

Results: Complete-arch scans showed relatively greater errors (0.09 ~ 0.10 mm) when compared to quadrant scans (0.05 ~ 0.06 mm). The errors were greater in the maxillary scans than in the mandibular scans. The evaluation of errors for each tooth showed that the errors were greater in posterior teeth than in anterior teeth. Comparing the right and left errors, the right side posterior teeth showed a more substantial variance than the left side in the mandibular scans.

Conclusion: The scanning accuracy has a difference between complete-arch scanning and quadrant scanning, particularly in the posterior teeth. Careful consideration is needed to avoid scanning inaccuracy for maxillary or mandibular complete-arch, particularly in the posterior area because a complete-arch scan might have potential error than a quadrant scan.
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http://dx.doi.org/10.1186/s40510-020-00337-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527390PMC
October 2020

Evaluation of mandibular position for splint therapy using a virtual articulator.

J Clin Orthod 2020 Aug;54(8):466-472

Department of Orthodontics, School of Dentistry, Chonnam National University, Gwangju, Korea. Graduate School of Dentistry, Kyung Hee University, Seoul, and in the private practice of orthodontics in Yeosu, Korea.

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August 2020

Sex differences in acute bleeding and vascular complications following percutaneous coronary intervention between 2003 and 2016: Trends from the Dartmouth Dynamic Registry.

Cardiovasc Revasc Med 2020 Jul 29. Epub 2020 Jul 29.

Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America; Section of Cardiovascular Medicine, Heart and Vascular Center, Dartmouth Hitchcock Medical Center, Hanover, NH, United States of America.

Background: Women undergoing percutaneous coronary intervention (PCI) are at higher risk for bleeding and vascular complications than men. Multiple approaches have been utilized to reduce bleeding in the modern era of PCI, including radial access, reduced GP IIb/IIIa inhibitor use, increased vascular closure device use, smaller sheath size and novel antithrombotic regimens. Nevertheless, few studies have assessed the impact of these techniques on the gap between men and women for such complications following PCI. We sought to quantify bleeding and vascular complications over time between men and women.

Methods: We queried The Dartmouth Dynamic Registry for consecutive PCI's performed between January 2003 and June 2016. Demographic information, procedural characteristics, and in-hospital outcomes were collected and compared between men and women over the years.

Results: We reviewed 15,284 PCI cases, of which 4384 (29%) were performed in women. Radial access increased from none in 2003 to nearly 40% in 2016. Use of GP IIb/IIIa and femoral access decreased substantially over the same time. Bleeding and vascular complication rates decreased significantly in women (13.2% to 3%; 6.5% to 0.8%, respectively) and men (3.5% to 0.7%, 3.4% to 0.7%, respectively). The overall bleeding and vascular complication rates decreased more for women than men, narrowing the gender gap.

Conclusions: The incidence of bleeding and vascular complications fell between 2003 and 2016 in both men and women. Vascular complications have become less common over time, and based on our analysis, there was no longer any difference between the sexes for this outcome. Bleeding following PCI has decreased in both sexes over time; however, women continue to bleed more than men.
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http://dx.doi.org/10.1016/j.carrev.2020.07.028DOI Listing
July 2020

Effect of artifact area on cone beam computed tomography scans when integrated with intraoral scans.

Oral Surg Oral Med Oral Pathol Oral Radiol 2021 Apr 14;131(4):468-474. Epub 2020 Aug 14.

Associate Professor, Department of Orthodontics, School of Dentistry, Chonnam National University, Gwangju, Korea. Electronic address:

Objective: The aim of this study was to examine whether integration accuracy increases upon removing artifacts from the registration area when integrating maxillofacial cone beam computed tomography (CBCT) scans and intraoral scans.

Study Design: Three methods were implemented according to the region of interest (ROI): R0, all teeth included as the registration area (artifacts included); R1, anterior teeth included as the registration area (artifacts in premolars and molars not included); and R2, anterior teeth and second molars included as the registration area (artifacts in premolars and first molars not included). Discrepancies between the 2 images were evaluated by using color-mapping methods. The average surface distance was calculated by measuring the shell/shell deviations for overall discrepancies and 3-dimensional distances between the surface points on the 2 images for registration discrepancies.

Results: The R1 method showed more discrepancies between the CBCT and intraoral scans compared with the other 2 methods. The R2 method showed smaller overall discrepancy values compared with the R1 method. Most CBCT artifacts were located in the posterior area. Registration discrepancies were greatest in the x-dimension.

Conclusions: The results suggest that intraoral and CBCT scans might be integrated by using a registration method that involves exclusion of artifacts and inclusion of the second molar on both sides.
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http://dx.doi.org/10.1016/j.oooo.2020.08.008DOI Listing
April 2021

Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program.

PLoS One 2020 25;15(8):e0237430. Epub 2020 Aug 25.

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, United States of America.

Background & Aims: Given ongoing challenges in non-invasive non-alcoholic liver disease (NAFLD) diagnosis, we sought to validate an ALT-based NAFLD phenotype using measures readily available in electronic health records (EHRs) and population-based studies by leveraging the clinical and genetic data in the Million Veteran Program (MVP), a multi-ethnic mega-biobank of US Veterans.

Methods: MVP participants with alanine aminotransferases (ALT) >40 units/L for men and >30 units/L for women without other causes of liver disease were compared to controls with normal ALT. Genetic variants spanning eight NAFLD risk or ALT-associated loci (LYPLAL1, GCKR, HSD17B13, TRIB1, PPP1R3B, ERLIN1, TM6SF2, PNPLA3) were tested for NAFLD associations with sensitivity analyses adjusting for metabolic risk factors and alcohol consumption. A manual EHR review assessed performance characteristics of the NAFLD phenotype with imaging and biopsy data as gold standards. Genetic associations with advanced fibrosis were explored using FIB4, NAFLD Fibrosis Score and platelet counts.

Results: Among 322,259 MVP participants, 19% met non-invasive criteria for NAFLD. Trans-ethnic meta-analysis replicated associations with previously reported genetic variants in all but LYPLAL1 and GCKR loci (P<6x10-3), without attenuation when adjusted for metabolic risk factors and alcohol consumption. At the previously reported LYPLAL1 locus, the established genetic variant did not appear to be associated with NAFLD, however the regional association plot showed a significant association with NAFLD 279kb downstream. In the EHR validation, the ALT-based NAFLD phenotype yielded a positive predictive value 0.89 and 0.84 for liver biopsy and abdominal imaging, respectively (inter-rater reliability (Cohen's kappa = 0.98)). HSD17B13 and PNPLA3 loci were associated with advanced fibrosis.

Conclusions: We validate a simple, non-invasive ALT-based NAFLD phenotype using EHR data by leveraging previously established NAFLD risk-associated genetic polymorphisms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237430PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447043PMC
October 2020

Genetic determinants of increased body mass index mediate the effect of smoking on increased risk for type 2 diabetes but not coronary artery disease.

Hum Mol Genet 2020 11;29(19):3327-3337

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Clinical observations have linked tobacco smoking with increased type 2 diabetes risk. Mendelian randomization analysis has recently suggested smoking may be a causal risk factor for type 2 diabetes. However, this association could be mediated by additional risk factors correlated with smoking behavior, which have not been investigated. We hypothesized that body mass index (BMI) could help to explain the association between smoking and diabetes risk. First, we confirmed that genetic determinants of smoking initiation increased risk for type 2 diabetes (OR 1.21, 95% CI: 1.15-1.27, P = 1 × 10-12) and coronary artery disease (CAD; OR 1.21, 95% CI: 1.16-1.26, P = 2 × 10-20). Additionally, 2-fold increased smoking risk was positively associated with increased BMI (~0.8 kg/m2, 95% CI: 0.54-0.98 kg/m2, P = 1.8 × 10-11). Multivariable Mendelian randomization analyses showed that BMI accounted for nearly all the risk smoking exerted on type 2 diabetes (OR 1.06, 95% CI: 1.01-1.11, P = 0.03). In contrast, the independent effect of smoking on increased CAD risk persisted (OR 1.12, 95% CI: 1.08-1.17, P = 3 × 10-8). Causal mediation analyses agreed with these estimates. Furthermore, analysis using individual-level data from the Million Veteran Program independently replicated the association of smoking behavior with CAD (OR 1.24, 95% CI: 1.12-1.37, P = 2 × 10-5), but not type 2 diabetes (OR 0.98, 95% CI: 0.89-1.08, P = 0.69), after controlling for BMI. Our findings support a model whereby genetic determinants of smoking increase type 2 diabetes risk indirectly through their relationship with obesity. Smokers should be advised to stop smoking to limit type 2 diabetes and CAD risk. Therapeutic efforts should consider pathophysiology relating smoking and obesity.
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http://dx.doi.org/10.1093/hmg/ddaa193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689293PMC
November 2020

A rapid and convenient screening method for detection of restricted monensin, decoquinate, and lasalocid in animal feed by applying SERS and chemometrics.

Food Chem Toxicol 2020 Oct 30;144:111633. Epub 2020 Jul 30.

Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, 77843, United States.

The surface-enhanced activities of size- and shape-controlled gold nanoparticles (AuNPs) with superior chemical stability were investigated to explore a possible development of a simple and non-destructive spectroscopic method to help the regulatory agency's analytical services for rapid detection and characterization of selected antimicrobials in animal feeds. Feed samples spiked at different concentration ranges of antimicrobials were evaluated using AuNPs as a surface-enhanced Raman spectroscopy (SERS) agent. The collected SERS spectra were mathematically preprocessed for further analysis. The classification models obtained 100% predictive accuracy with zero or little misclassification. The first two canonical variables (p = 0.001) could explain >95% of the variability in preprocessed spectral data. Most chemometric models for predicting MON, DEC, and LAS concentrations showed a high predictive accuracy (r > 0.90), lower predictive error (<20 mg/kg), and satisfactory regression quality (slope close to 1.0). The statistical results showed no statistically significant difference between the reference and SERS predicted values (p > 0.05). The findings and implications from the study indicate that SERS would be a powerful and efficient technique possessing a great potential serving as an excellent monitoring and screening tool for antimicrobial contaminated samples in the on-site analysis.
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http://dx.doi.org/10.1016/j.fct.2020.111633DOI Listing
October 2020

A Different Perspective on Cholesteric Liquid Crystals Reveals Unique Color and Polarization Changes.

ACS Appl Mater Interfaces 2020 Aug 11;12(33):37400-37408. Epub 2020 Aug 11.

Air Force Research Laboratory, Materials and Manufacturing Directorate, Wright-Patterson AFB, Ohio 45433, United States.

Planar cholesteric liquid crystals (CLCs) are well known for having vibrant reflective coloration that is associated with the handedness and the pitch length of the helicoidal twist of the liquid crystalline molecules. If one observes these films at oblique angles, the reflected colors blue-shift with increasing angles from normal. On the other hand, uniform lying helix (ULH) CLCs, where the helicoidal axis lies in the plane of the substrate, are well-known but are not typically associated with vibrant colors. Here, we examine the unique optical properties of CLCs at oblique incidence angles, specifically the spectral and polarization changes associated with switching between planar and ULH CLCs for various incidence angles. At small angles of incidence (0° < ψ < 45°, where ψ is the angle of incidence relative to the surface normal at the substrate-CLC interface), the electrically driven helical reorientation from planar to ULH results in a blue-shifting of the color and circularly polarized to unpolarized switching behavior. At large angles (45° < ψ < 90°), the behavior is reversed, with a red-shifting color change occurring and the polarization switching from unpolarized to circularly polarized. Modeling of the light propagation through ULH CLCs is used to confirm the change in position and polarization characteristic of the reflection band with incidence angle observed experimentally. This study provides a new perspective on ULH CLCs and reveals a unique reconfigurable angular chromaticity.
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http://dx.doi.org/10.1021/acsami.0c09845DOI Listing
August 2020

Stability of 3-deoxyanthocyanin pigment structure relative to anthocyanins from grains under microwave assisted extraction.

Food Chem 2020 Dec 6;333:127494. Epub 2020 Jul 6.

Texas A&M University, Department of Soil & Crop Science/ Nutrition & Food Science, 2474 TAMU, College Station, TX 77843, USA; JR Simplot, Caldwell, ID 83606, USA. Electronic address:

Sorghum derived 3-deoxyanthocyanin (DXA) pigments are stable relative to their anthocyanin analogs, and are of growing interest in food applications. However, the 3DXA are poorly extractable from grain tissue. This work aimed to determine the relative stability and extractability of sorghum 3-DXA vs anthocyanins from maize and cowpea under microwave-assisted extraction (MAE). UV-Vis and UPLC-MS/MS spectrometry were used to characterize the properties. The 3-DXA remained structurally stable to MAE conditions up to 1200 W/100 °C/30 min. MAE increased sorghum 3-DXA yield 100% versus control (3100 vs 1520 mg/g). On the other hand, both maize and cowpea anthocyanins were unstable and rapidly degraded under MAE. Cell wall-derived ferulate esters were detected in sorghum and maize MAE extracts, indicating cell wall degradation occurred during MAE. Thus the enhanced extraction of 3-DXA under MAE was due to their structural stability, along with improved diffusion from cell matrix due to microwave-induced sorghum cell wall disruption.
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http://dx.doi.org/10.1016/j.foodchem.2020.127494DOI Listing
December 2020

Construction reproducibility of a composite tooth model composed of an intraoral-scanned crown and a cone-beam computed tomography-scanned root.

Korean J Orthod 2020 Jul;50(4):229-237

Department of Orthodontics, School of Dentistry, Chonnam National University, Gwangju, Korea.

Objective: To evaluate the construction reproducibility of a composite tooth model (CTM) composed of an intraoral-scanned crown and a cone-beam computed tomography (CBCT)-scanned root.

Methods: The study assessed 240 teeth (30 central incisors, 30 canines, 30 second premolars, and 30 first molars in the maxillary and mandibular arches) from 15 young adult patients whose pre-treatment intraoral scan and CBCT were available. Examiner-Reference (3 years' experience in CTM construction) and Examiners-A and Examiner-B (no experience) constructed the individual CTMs independently by performing the following steps: image acquisition and processing into a three-dimensional model, integration of intraoral-scanned crowns and CBCT-scanned teeth, and replacement of the CBCT-scanned crown with the intraoral-scanned crown. The tooth axis angle in terms of mesiodistal angulation and buccolingual inclination of the CTMs constructed by the three examiners were measured. To assess the construction reproducibility of CTMs, intraclass correlation coefficient (ICC) assessments were performed.

Results: The ICC values of mesiodistal angulation and buccolingual inclination among the 3 examiners showed excellent agreement (0.950-0.992 and 0.965-0.993; 0.976-0.994 and 0.973-0.995 in the maxillary and mandibular arches, respectively).

Conclusions: The CTM showed excellent construction reproducibility in mesiodistal angulation and buccolingual inclination regardless of the construction skill and experience levels of the examiners.
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http://dx.doi.org/10.4041/kjod.2020.50.4.229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369385PMC
July 2020