Publications by authors named "Sang-Guk Lee"

93 Publications

Development and validation of a novel sepsis biomarker based on amino acid profiling.

Clin Nutr 2021 Jun 21;40(6):3668-3676. Epub 2021 May 21.

Department of Laboratory Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea. Electronic address:

Background & Aims: Sepsis is a potentially fatal condition influenced by pathogens and host factors. Current sepsis biomarkers such as white blood cell count and C-reactive protein and procalcitonin levels show unsatisfactory performance in terms of diagnostic sensitivity and specificity in clinical practice. Thus, we developed and validated a new sepsis biomarker based on amino acid profiling.

Methods: We used two independent groups. The training and validation groups included 161 and 22 healthy controls, 123 and 50 patients with systemic inflammatory response syndrome, and 115 and 45 patients with sepsis, respectively. Using mass spectrometry, we measured and analyzed serum amino acid levels to select candidate amino acids that could differentiate sepsis from other conditions. Then, several possible multivariate indexes were developed by generating formulae with different combinations of candidate amino acids. The formula showing the best performance was selected and validated further.

Results: Kynurenine, tryptophan, phenylalanine, arginine, aspartic acid, glutamic acid, and glutamine were selected as candidate amino acids. Ten possible formulae were generated, and the formula with the highest diagnostic performance, which included kynurenine, tryptophan, phenylalanine, and arginine, was selected. In the validation group, the area under the receiving operating characteristic curve of the selected multivariate index (0.931) was similar to that of procalcitonin (0.945). Moreover, the generated multivariate index showed potential as a prognostic marker.

Conclusions: Serum amino acid composition in patients with sepsis differs significantly from that in healthy individuals and patients with inflammation only. The newly developed multivariate index is expected to be implementable as a sepsis biomarker in clinical practice in the near future.
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http://dx.doi.org/10.1016/j.clnu.2021.05.008DOI Listing
June 2021

Quantitative Analysis of Immunosuppressive Drugs Using Tungsten Disulfide Nanosheet-Assisted Laser Desorption Ionization Mass Spectrometry.

ACS Nano 2021 06 7;15(6):10141-10152. Epub 2021 Jun 7.

Safety Measurement Institute, Korea Research Institute of Standards and Science (KRISS), Daejeon 34113, Korea.

For organ transplantation patients, the therapeutic drug monitoring (TDM) of immunosuppressive drugs is essential to prevent the toxicity or rejection of the organ. Currently, TDM is done by immunoassays or liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods; however, these methods lack specificity or are expensive, require high levels of skill, and offer limited sample throughput. Although matrix-assisted (MA) laser desorption ionization (LDI) mass spectrometry (MS) can provide enhanced throughput and cost-effectiveness, its application in TDM is limited due to the limitations of the matrixes such as a lack of sensitivity and reproducibility. Here, we present an alternative quantification method for the TDM of the immunosuppressive drugs in the blood of organ transplant patients by utilizing laser desorption ionization mass spectrometry (LDI-MS) based on a tungsten disulfide nanosheet, which is well-known for its excellent physicochemical properties such as a strong UV absorbance and high electron mobility. By adopting a microliquid inkjet printing system, a high-throughput analysis of the blood samples with enhanced sensitivity and reproducibility was achieved. Furthermore, up to 80 cases of patient samples were analyzed and the results were compared with those of LC-MS/MS by using Passing-Bablok regression and Bland-Altman analysis to demonstrate that our LDI-MS platform is suitable to replace current TDM techniques. Our approach will facilitate the rapid accurate analysis of blood samples from a large number of patients for immunosuppressive drug prescriptions.
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http://dx.doi.org/10.1021/acsnano.1c02016DOI Listing
June 2021

Age-group-specific reference intervals for anti-Müllerian hormone and its diagnostic performance for polycystic ovary syndrome in a Korean population.

J Clin Lab Anal 2021 Jul 7;35(7):e23861. Epub 2021 Jun 7.

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

Background: We established age-group-specific reference intervals for serum anti-Müllerian hormone (AMH) levels in a Korean population and investigated the effectiveness of AMH assay for polycystic ovary syndrome (PCOS) diagnosis.

Methods: We analyzed serum levels of AMH, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) from 1540 Korean women. Subjects were divided into three groups: healthy, benign gynecologic diseases, and PCOS. Age-group-specific reference intervals and AMH diagnostic performance were estimated.

Results: The PCOS group had a median AMH level of 7.0 µg/L, which was higher than for the healthy (1.8 µg/L) and the benign gynecologic diseases (2.7 µg/L) groups. The upper 97.5% reference limits for age groups 12-20 years, 21-34 years, and 35-46 years were 13.2 µg/L, 15.8 µg/L, and 6.6 µg/L, respectively. The area under the curve (AUC) values to estimate AMH ability to discriminate PCOS from healthy women for each age group were 0.741, 0.785, and 0.789, respectively. AUCs for LH/FSH were 0.719, 0.672, and 0.590.

Conclusions: The better diagnostic ability of AMH over LH/FSH in women of late childbearing ages indicates that age and other clinical characteristics should be considered when interpreting these test results.
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http://dx.doi.org/10.1002/jcla.23861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274997PMC
July 2021

Revisiting the Role of Insulin-like Growth Factor-1 Measurement After Surgical Treatment of Acromegaly.

J Clin Endocrinol Metab 2021 Jun;106(7):e2589-e2599

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

Context: In the management of growth hormone (GH)-secreting pituitary adenomas, the oral glucose tolerance test (OGTT) has been the gold standard not only for diagnoses but also for the determination of biochemical remission. Insulin-like growth factor-1 (IGF-1) is an essential biomarker, although it should be adjusted for both age and sex.

Objective: We evaluated whether IGF-1 levels could serve as a reliable alternative to an OGTT for disease monitoring after the surgical treatment of acromegaly. We retrospectively reviewed the medical records of 320 patients who underwent surgical resection of their GH-secreting pituitary tumors at the Severance hospital. Receiver operator characteristic (ROC) analyses were performed to validate the accuracy of IGF-1 levels for the assessment of remission. In addition, regression analyses were performed to identify factors associated with discrepancy between OGTT and IGF-1 levels.

Results: Except for 1 week after surgery, ROC analyses showed an area under the curve of greater than 0.8 for IGF-1 at all time points. Of 320 patients, 270 achieved endocrine remission after surgery alone. Among these patients, IGF-1 levels were normalized in 250 patients. The mean duration from surgery to IGF-1 normalization was 4.7 months. Regression analyses demonstrated that risk of failed IGF-1 normalization was increased by 3.1-fold when the tumor invaded the cavernous sinus and increased by 9.0-fold in patients with incomplete tumor removal.

Conclusion: IGF-1 level is a reliable alternative to OGTT and plays a valuable role in monitoring acromegaly status.
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http://dx.doi.org/10.1210/clinem/dgab186DOI Listing
June 2021

Diagnosis of severe sepsis using phospholipids enzymatic assay based on cyclic voltammetry.

Enzyme Microb Technol 2021 Mar 16;144:109728. Epub 2020 Dec 16.

Department of Materials Science and Engineering, Yonsei University, Seoul, Republic of Korea. Electronic address:

In this work phospholipid quantification was carried out using an enzymatic assay based on cyclic voltammetry of the condensation product of N-ethyl-N-(2-hydroxy-3-sulfopropyl)-3,5-dimethoxyaniline sodium salt (DAOS) and 4-aminoantipyrine (4-AP) with a graphite electrode. For the optimization of electrochemical measurement for the product, electrochemical properties such as the electrochemical window, double layer capacitance (Cdl) and electron transfer rate (kapp) were analyzed for a graphite-electrode and Au-electrode. The phospholipid enzymatic assay based the on electrochemical measurement using the graphite electrode was applied to the diagnosis of sepsis for sera from healthy volunteers (n = 16), patients with systemic inflammatory response syndrome (SIRS, n = 16) and severe sepsis patients (n = 24). Finally, the phospholipid quantification results from the electrochemical measurement were statistically compared with the conventional method based on optical density measurement.
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http://dx.doi.org/10.1016/j.enzmictec.2020.109728DOI Listing
March 2021

Concordance of Three Automated Procalcitonin Immunoassays at Medical Decision Points.

Ann Lab Med 2021 Jul;41(4):419-423

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

Procalcitonin (PCT) is a useful bacterial infection biomarker with the potential for guiding antibiotic therapy. We evaluated the concordance of three automated PCT immunoassays: Kryptor (BRAHMS GmbH, Hennigsdorf, Germany), Atellica IM 1600 (Siemens Healthcare Diagnostics, Munich, Germany), and Cobas e801 (Roche Diagnostics, Mannheim, Germany). In 119 serum samples with a PCT concentration <5.00 μg/L, Kryptor (reference assay) was compared with the other two immunoassays by Spearman's rank correlation, regression analysis, and concordance at two antibiotic stewardship medical decision points: 0.25 and 0.50 μg/L. The Atellica IM 1600 and Cobas e801 results showed high correlations with those of Kryptor, with correlation coefficient (ρ) values of 0.97 and 0.99, respectively. However, negative biases were observed in both immunoassays (slope/y-intercept: 0.75/-0.00 for Atellica IM 1600; 0.88/-0.01 for Cobas e801). Atellica IM 1600 and Cobas e801 demonstrated excellent concordance with Kryptor at both medical decision points, with linearly weighted κ values of 0.90 and 0.92, respectively, despite discrepancies, which were more prominent at the 0.25 μg/L medical decision point. Based on these biases and discrepancies, the alternate use of different PCT immunoassays in repeat examinations is inadvisable. Standardization is required before comparing the results of different PCT immunoassays.
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http://dx.doi.org/10.3343/alm.2021.41.4.419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884194PMC
July 2021

Gut microbiota-derived metabolite trimethylamine N-oxide as a biomarker in early Parkinson's disease.

Nutrition 2021 03 21;83:111090. Epub 2020 Nov 21.

Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea. Electronic address:

Objectives: This study aimed to investigate the potential of using changes in the plasma levels of trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, as a biomarker in early Parkinson's disease (PD).

Methods: Plasma TMAO levels were measured in 85 patients with drug-naïve early stage PD and 20 healthy controls. A linear mixed model was used to assess longitudinal changes in levodopa-equivalent dose (LED) during follow-up (>2 y) in three tertile PD groups according to plasma TMAO levels. Additionally, a Cox regression analysis was performed to assess the effect of plasma TMAO levels on dementia conversion.

Results: Plasma TMAO levels of patients with PD were lower than those of healthy controls. A linear mixed model demonstrated that patients with PD and lower levels of TMAO (<4.75 μmol/L; i.e., lowest tertile group) exhibited faster increases in LED over time. The Cox regression model did not reveal that plasma TMAO level was associated with the risk for dementia conversion (P = 0.488). However, when we divided patients with PD into two subgroups according to bet cutoff TMAO level to maximize the log-rank statistics, the PD group with a low plasma TMAO level (<6.92 μmol/L) had a higher risk (with borderline statistical significance) for PD-dementia conversion than the group with a high TMAO level (hazard ratio: 7.565; 95% confidence interval, 1.004-57.019; P = 0.050).

Conclusions: The results demonstrate that lower baseline plasma TMAO levels are associated with faster increases in LED and tend to increase the risk for PD-dementia conversion, suggesting the prognostic implications of TMAO in early stage PD.
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http://dx.doi.org/10.1016/j.nut.2020.111090DOI Listing
March 2021

Immunosuppressive Drug Measurement by Liquid Chromatography Coupled to Tandem Mass Spectrometry: Interlaboratory Comparison in the Korean Clinical Laboratories.

Ann Lab Med 2021 May;41(3):268-276

Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.

Background: Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is increasingly used for immunosuppressive drug tests. However, most LC-MS/MS tests are laboratory-developed and their agreement is unknown in different Korean laboratories. This interlaboratory comparison study evaluated test reproducibility and identified potential error sources.

Methods: Test samples containing three concentrations of tacrolimus, sirolimus, everolimus, cyclosporine, and mycophenolic acid were prepared by pooling surplus samples from patients undergoing routine therapeutic drug monitoring and tested in duplicate in the participating 10 clinical laboratories. Reconstitution and storage experiments were conducted for the commonly used commercial calibrator set. The robust estimators of reproducibility parameters were calculated. Spearman's rank correlation coefficient (rho, ρ) was used to evaluate the correlation between drugs. Multiple linear regression was used to determine whether the experimental conditions alter the calibration curves.

Results: The reproducibility coefficient of variation exceeded 10% only for sirolimus concentrations 1 and 2 (10.8% and 12.5%, respectively) and everolimus concentrations 1 and 2 (12.3% and 11.4%, respectively). The percent difference values showed weak correlations between sirolimus and everolimus (ρ=0.334, =0.175). The everolimus calibration curve slope was significantly altered after reconstitution following prolonged 5°C storage ( =0.015 for 14 days; =0.025 for 28 days); the expected differences at 6 ng/mL were 0.598% for 14 days and 0.384% for 28 days.

Conclusions: LC-MS/MS test reproducibility for immunosuppressive drugs seems to be good in the Korean clinical laboratories. Continuous efforts are required to achieve test standardization and harmonization, especially for sirolimus and everolimus.
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http://dx.doi.org/10.3343/alm.2021.41.3.268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748092PMC
May 2021

Establishment of Reference Intervals for Serum Insulin-Like Growth Factor I in Korean Adult Population.

Endocrinol Metab (Seoul) 2020 12 20;35(4):960-964. Epub 2020 Nov 20.

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

Appropriate reference intervals of serum insulin-like growth factor I (IGF-I) is important for diagnosing and monitoring patients with growth hormone-related diseases. To establish reference intervals, adult individuals (n=1,334, 680 men and 654 women) were divided into six age groups (20-29, 30-39, 40-49, 50-59, 60-69, ≥70). Serum IGF-I was measured by chemiluminescence immunoassay (Liaison). Concordance of patient classification based on reference intervals, manufacturer's intervals, and standard deviation score (SDS) was evaluated. New reference intervals had higher upper and lower limits than those specified by the manufacturer. The agreement between classification using new reference interval and the manufacturer's reference interval, and that using new reference interval and SDS was 75.0% (weighted kappa, 0.17), 91.9% (weighted kappa, 0.51) in men and 91.0% (weighted kappa, 0.41), 92.5% (weighted kappa, 0.53) in women, respectively. Reference intervals should be established not only based on age and sex, but also on ethnicity and assay method.
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http://dx.doi.org/10.3803/EnM.2020.732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803604PMC
December 2020

Total and Exchangeable Copper Assay Using Inductively Coupled Plasma Mass Spectrometry and Establishment of a Pediatric Reference Interval.

Arch Pathol Lab Med 2021 Jul;145(7):877-882

From the Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea (Yim, Kim, S.-G. Lee).

Context.—: Recently, an exchangeable copper (CuEXC) assay has been suggested as a robust and feasible diagnostic tool for Wilson disease (WD). Although WD is a disorder that requires lifelong treatment and monitoring, few data are currently available regarding the status of copper levels in children.

Objective.—: To evaluate the performance of copper assays and establish a reference interval for total copper and CuEXC in the pediatric population.

Design.—: Serum samples from children aged 1-5 (n = 122), 6-12 (n = 125), and 13-18 years (n = 120) were analyzed. Total copper and CuEXC concentrations were directly measured using inductively coupled plasma mass spectrometry, and relative CuEXC levels were calculated. Total copper reference intervals, CuEXC levels, and relative CuEXC levels were determined based on the 2.5th and 97.5th percentiles of the data with 90% confidence intervals.

Results.—: There were significant differences in the median concentrations of total copper and relative CuEXC among the age groups. Reference intervals determined for total copper were 82 to 167, 75 to 139, and 64 to 133 μg/dL for children aged 1 to 5, 6 to 12, and 13 to 18 years, respectively. The reference intervals for CuEXC were 4.29 to 9.79, 4.02 to 9.09, and 3.55 to 8.25 μg/dL for children aged 1 to 5, 6 to 12, and 13 to 18 years, respectively. Among 11 patients with suspected WD, relative CuEXC values were elevated in all 3 diagnosed with WD.

Conclusions.—: The pediatric reference intervals derived in this study are expected to be useful for the diagnosis, differential diagnosis, treatment, and monitoring of pediatric patients with WD.
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http://dx.doi.org/10.5858/arpa.2020-0029-OADOI Listing
July 2021

Performance Evaluation of Thyroid Function Tests on a Novel Chemiluminescent Microparticle Immunoassay System.

J Appl Lab Med 2021 Mar;6(2):367-377

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

Background: The Alinity i system (Abbott), a recently developed automated immunoassay analyzer, has a compact footprint and a throughput of 200 tests per hour. Here, we present the first performance evaluation of thyroid function test (TFT) on the Alinity i system.

Methods: We performed precision, linearity, comparison, functional sensitivity, carryover, and reference interval verification of 4 hormones (Thyroid Stimulation Hormone; TSH, total T3, free T4, and total T4) using the reagents provided by the manufacturer following the guidelines of the Clinical Laboratory Standards Institute. The performance of Alinity i was compared to that of the Architect i2000 immunoassay analyzer (Abbott, US).

Results: The within-laboratory coefficients of variation for all the hormones were 1.6-3.6%. Linearity was observed for all the hormones over the entire tested analytical range (R2 ≥ 0.99). The results for all the evaluated hormones using Alinity i system strongly correlated (r ≥ 0.978) with those from Architect i2000. Functional sensitivity was lower than the lower limit of the analytical measurement range. Sample carryover was less than 1.0%.

Conclusions: TFTs on the Alinity i system showed acceptable performance in terms of precision, linearity, comparison, functional sensitivity, and carryover. Therefore, this system could be a useful laboratory tool for performing TFTs.
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http://dx.doi.org/10.1093/jalm/jfaa091DOI Listing
March 2021

Aggregation-driven fluorescence quenching of imidazole-functionalized perylene diimide for urea sensing.

Analyst 2020 Nov;145(22):7312-7319

Department of Chemical and Biomolecular Engineering, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Stimuli-responsive self-assembly of functional amphiphilic molecules by specific chemical stimulants is a promising strategy for sensor application. Herein, we demonstrate a fast optical detection of urea in human urine by exploiting bolaform perylene diimide functionalized with imidazoles (PDI-Hm), whose aggregation is induced by urea hydrolysis. The hydroxides produced from the enzymatic urea hydrolysis deprotonate the imidazoles to reduce electrostatic repulsion between PDI-Hm molecules in a HCl-methanol mixture, thereby leading to aggregation and consequent fluorescence quenching. The molecular interaction of PDI-Hm was further scrutinized to understand the aggregation behavior driven by the screening of electrical repulsion. As an optical sensing probe, PDI-Hm displays a prompt response (<1 min) to hydroxide and detection limit of 0.4 mM for urea. PDI-Hm incorporating urease offers considerable selectivity toward urea among various components in human urine. The urea sensing accuracy of this PDI-Hm fluorescence chemosensor is comparable to that of a clinical method, showing 93.4% consistency. Furthermore, the PDI-Hm was fabricated into a gel film allowed for the fast screening of excessive urea in urine.
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http://dx.doi.org/10.1039/d0an01252aDOI Listing
November 2020

Diagnosis and mortality prediction of sepsis via lysophosphatidylcholine 16:0 measured by MALDI-TOF MS.

Sci Rep 2020 08 14;10(1):13833. Epub 2020 Aug 14.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Sepsis remains a critical problem with high mortality worldwide, but there is still a lack of reliable biomarkers. We aimed to evaluate the serum lysophosphatidylcholine (LPC) 16:0 as a biomarker of sepsis using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Patients admitted to intensive care unit at Severance Hospital from March 2017 through June 2018 were prospectively enrolled. The inclusion criteria were the fulfillment of at least two criteria of systemic inflammatory response syndrome (SIRS) or the presence of sepsis. Of the 127 patients, 14 had non-infectious SIRS, 41 had sepsis, and 72 had septic shock. The mean serum LPC 16:0 concentration (µmol/L) in non-infectious SIRS was significantly higher than in patients with sepsis and septic shock (101.1 vs. 48.92, p < 0.05; 101.1 vs. 25.88, p < 0.001, respectively). The area under the curve (AUC) predicting 28-day mortality using ΔLPC16:0 (D1-D0) levels was 0.7, which was comparable with the APACHE II score (AUC 0.692) and SOFA score (AUC 0.67). Mechanical ventilation, CRRT, lactate, Δ LPC16:0 (D1-D0) less than the cut-off value were significantly associated with 28-day mortality in multivariable analysis. Our results suggest that LPC16:0 could be a useful biomarker for sepsis diagnosis and mortality prediction in ICU patients.
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http://dx.doi.org/10.1038/s41598-020-70799-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427783PMC
August 2020

Heterophile antibody interference associated with natural killer cell therapy.

Endocr J 2020 Dec 22;67(12):1187-1192. Epub 2020 Jul 22.

Department of Internal Medicine, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul 03722, Korea.

The adoptive transfer of ex vivo-expanded natural killer (NK) cells has recently been employed as an alternative cancer treatment in certain institutions. However, the safety profiles of this strategy remain uncharacterized. We evaluated three patients who exhibited elevated serum parathyroid hormone (PTH) levels without the relevant clinical manifestations and had a history of autologous NK cell therapy. The serum PTH concentration was measured using a second-generation PTH assay, and the serum thyroglobulin concentration was measured using a second-generation thyroglobulin assay. Subsequently, the PTH or thyroglobulin concentration obtained using heterophile-blocking tube (HBT) for a secondary confirmation assay was measured and compared with the result of the initial assay. The three patients had falsely elevated serum PTH and thyroglobulin levels owing to heterophile antibody interference associated with NK cell therapy that persisted for at least up to 12 months after the treatment and was confirmed by normalization of hormone levels after HBT treatment. We propose that certain types of mouse monoclonal antibodies used to stimulate NK cells can induce heterophile antibodies. Abnormal laboratory test results in individuals administered NK cell therapy without the relevant clinical manifestations must be examined in the context of heterophile antibody interference to avoid misdiagnosis and unnecessary testing.
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http://dx.doi.org/10.1507/endocrj.EJ20-0349DOI Listing
December 2020

SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease.

Nat Commun 2020 05 1;11(1):2127. Epub 2020 May 1.

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

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor's glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.
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http://dx.doi.org/10.1038/s41467-020-15983-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195385PMC
May 2020

Simultaneous Analysis of Multiple Cancer Biomarkers Using MALDI-TOF Mass Spectrometry Based on a Parylene-Matrix Chip.

J Am Soc Mass Spectrom 2020 Apr 24;31(4):917-926. Epub 2020 Mar 24.

Department of Materials Science and Engineering, Yonsei University, Seoul 03722, Korea.

Recently, the parylene-matrix chip was developed for quantitative analysis of small molecules less than 1 kDa. In this study, MALDI-TOF MS based on the parylene-matrix chip was performed to clinically diagnose intrahepatic cholangiocarcinoma (IHCC) and colorectal cancer (CRC). The parylene-matrix chip was applied for the detection of small cancer biomarkers, including -methyl-2-pyridone-5-carboxamide (2PY), glutamine, lysophosphatidylcholine (LPC) 16:0, and LPC 18:0. The feasibility of MALDI-TOF MS based on the parylene-matrix chip was confirmed via analysis of spot-to-spot and shot-to-shot reproducibility. Serum metabolite markers of IHCC, -methyl-2-pyridone-5-carboxamide (2PY), and glutamine were quantified using MALDI-TOF MS based on the parylene-matrix chip. For clinical diagnosis of CRC, two water-insoluble (barely soluble) biomarkers, lysophosphatidylcholine (LPC) 16:0 and LPC 18:0, were quantified. Finally, glutamine and LPC 16:0 were simultaneously detected at a range of concentrations in sera from colon cancer patients using the parylene-matrix chip. Thus, this method yielded high-throughput detection of cancer biomarkers for the mixture samples of water-soluble analytes (2PY and glutamine) and water-insoluble analytes (LPC 16:0 and LPC 18:0).
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http://dx.doi.org/10.1021/jasms.9b00102DOI Listing
April 2020

Identification of serum biomarkers for active pulmonary tuberculosis using a targeted metabolomics approach.

Sci Rep 2020 03 2;10(1):3825. Epub 2020 Mar 2.

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

Although tuberculosis (TB) is a severe health problem worldwide, the current diagnostic methods are far from optimal. Metabolomics is increasingly being used in the study of infectious diseases. We performed metabolome profiling to identify potential biomarkers in patients with active TB. Serum samples from 21 patients with active pulmonary TB, 20 subjects with latent TB infection (LTBI), and 28 healthy controls were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by multivariate and univariate analyses. Metabolic profiles indicated higher serum levels of glutamate, sulfoxy methionine, and aspartate and lower serum levels of glutamine, methionine, and asparagine in active TB patients than in LTBI subjects or healthy controls. The ratios between metabolically related partners (glutamate/glutamine, sulfoxy methionine/methionine, and aspartate/asparagine) were also elevated in the active TB group. There was no significant difference in the serum concentration of these metabolites according to the disease extent or risk of relapse in active TB patients. Novel serum biomarkers such as glutamate, sulfoxy methionine, aspartate, glutamine, methionine, and asparagine are potentially useful for adjunctive, rapid, and noninvasive pulmonary TB diagnosis.
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http://dx.doi.org/10.1038/s41598-020-60669-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052258PMC
March 2020

Developing a preoperative serum metabolome-based recurrence-predicting nomogram for patients with resected pancreatic ductal adenocarcinoma.

Sci Rep 2019 12 9;9(1):18634. Epub 2019 Dec 9.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.

We investigated the potential application of preoperative serum metabolomes in predicting recurrence in patients with resected pancreatic cancer. From November 2012 to June 2014, patients who underwent potentially curative pancreatectomy for pancreatic ductal adenocarcinoma were examined. Among 57 patients, 32 were men; 42 had pancreatic head cancers. The 57 patients could be clearly categorized into two main clusters using 178 preoperative serum metabolomes. Patients within cluster 2 showed earlier tumor recurrence, compared with those within cluster 1 (p = 0.034). A nomogram was developed for predicting the probability of early disease-free survival in patients with resected pancreatic cancer. Preoperative cancer antigen (CA) 19-9 levels and serum metabolomes PC.aa.C38_4, PC.ae.C42_5, and PC.ae.C38_6 were the most powerful preoperative clinical variables with which to predict 6-month and 1-year cancer recurrence-free survival after radical pancreatectomy, with a Harrell's concordance index of 0.823 (95% CI: 0.750-0.891) and integrated area under the curve of 0.816 (95% CI: 0.736-0.893). Patients with resected pancreatic cancer could be categorized according to their different metabolomes to predict early cancer recurrence. Preoperative detectable parameters, serum CA 19-9, PC.aa.C38_4, PC.ae.C42_5, and PC.ae.C38_6 were the most powerful predictors of early recurrence of pancreatic cancer.
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http://dx.doi.org/10.1038/s41598-019-55016-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901525PMC
December 2019

Performance Evaluation of Body Fluid Cellular Analysis Using the Beckman Coulter UniCel DxH 800, Sysmex XN-350, and UF-5000 Automated Cellular Analyzers.

Ann Lab Med 2020 Mar;40(2):122-130

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

Background: Automated cellular analyzers are expected to improve the analytical performance in body fluid (BF) analysis. We evaluated the analytical performance of three automated cellular analyzers and established optimum reflex analysis guidelines.

Methods: A total of 542 BF samples (88 cerebrospinal fluid [CSF] samples and 454 non-CSF samples) were examined using manual counting and three automated cellular analyzers: UniCel DxH 800 (Beckman Coulter), XN-350 (Sysmex), and UF-5000 (Sysmex). Additionally, 2,779 BF analysis results were retrospectively reviewed. For malignant cell analysis, the receiver operating characteristic (ROC) curve was used, and the detection of high fluorescence-BF cells (HF-BFs) using the XN-350 analyzer was compared with cytology results.

Results: All three analyzers showed good agreement for total nucleated cell (TNC) and red blood cell (RBC) counts, except for the RBC count in CSF samples using the UniCel DxH 800. However, variable degrees of differences were observed during differential cell counting. For malignant cell analysis, the area under the curve was 0.63 for the XN-350 analyzer and 0.76 for manual counting. We established our own reflex analysis guidelines as follows: HF-BFs <0.7/100 white blood cells (WBCs) is the criterion for quick scans with 100× magnification microscopic examination as a rule-out cut-off, while HF-BFs >83.4/100 WBCs or eosinophils >3.8% are the criteria for mandatory double check confirmation with 1,000× magnification examination.

Conclusions: The three automated analyzers showed good analytical performances. Application of reflex analysis guidelines is recommended for eosinophils and HF-BFs, and manual confirmation is warranted.
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http://dx.doi.org/10.3343/alm.2020.40.2.122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822009PMC
March 2020

MALDI-TOF Mass Spectrometry Based on Parylene-Matrix Chip for the Analysis of Lysophosphatidylcholine in Sepsis Patient Sera.

Anal Chem 2019 11 29;91(22):14719-14727. Epub 2019 Oct 29.

Department of Materials Science and Engineering , Yonsei University , 50 Yonsei-ro, Seodaemun-gu , Seoul 03722 , Republic of Korea.

In this work, medical diagnosis of sepsis was conducted via quantitative analysis of lysophosphatidylcholine 16:0 (LPC 16:0) by using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry based on a parylene-matrix chip. In the first step, specific mass peaks for the diagnosis of sepsis were searched by comparing MALDI-TOF mass spectra of sepsis patient sera with healthy controls and pneumonia patient sera. Two mass peaks at / = 496.3 and 518.3 were chosen as those that are specifically different for sepsis sera to compare with healthy controls and pneumonia patient sera. These mass peaks were identified to be protonated and sodium adducts of LPC 16:0 by using tandem mass spectra (MS and MS) of purely synthesized LPC 16:0 and extracted LPC 16:0 from a healthy control and a sepsis patient. In the next step, a standard curve for LPC 16:0 for the quantitative analysis of LPC 16:0 with MALDI-TOF MS based on the parylene-matrix chip was prepared, and the statistical correlation to the LC-MS analysis results was demonstrated by using the Bland-Altman test and Passing-Bablok regression. Finally, MALDI-TOF MS based on the parylene-matrix chip was used for the quantification of LPC 16:0 with sera from patients with severe sepsis and septic shock ( = 143), pneumonia patients ( = 12), and healthy sera ( = 31). The sensitivity and the selectivity of medical diagnosis of sepsis was estimated to be 97.9% and 95.5% by using MALDI-TOF MS based on the parylene-matrix chip, respectively.
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http://dx.doi.org/10.1021/acs.analchem.9b04019DOI Listing
November 2019

Elevation of the Gut Microbiota Metabolite Trimethylamine N-Oxide Predicts Stroke Outcome.

J Stroke 2019 Sep 30;21(3):350-352. Epub 2019 Sep 30.

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

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http://dx.doi.org/10.5853/jos.2019.00850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780019PMC
September 2019

Identification of new binding proteins of focal adhesion kinase using immunoprecipitation and mass spectrometry.

Sci Rep 2019 09 9;9(1):12908. Epub 2019 Sep 9.

Molecular Recognition Research Center, Korea Institute of Science and Technology (KIST), Seoul, 02792, South Korea.

Focal adhesion kinase (FAK) is a 125 kDa protein recruited as a participant in focal adhesion dynamics and serves as a signaling scaffold for the assembly and subsequent maturation of focal contact. Identification of new FAK binding proteins could reveal potential signaling targets and contribute to further development of therapeutic drugs in the treatment of colon cancer. Here, we applied a functional proteomic strategy to identify proteins that interact with FAK in human colon cancer cell line HCT-116. Proteins were targeted by coimmunoprecipitation with an anti-FAK antibody and resolved on 1D-SDS-PAGE. The gel was excised, reduced, alkylated, and trypsin digested. Tryptic peptides were separated by nano-LC-MS/MS by an LTQ-Orbitrap-Velos spectrometer. We identified 101 proteins in the immunocomplex under epithelial growth factor (EGF) stimulation. Three proteins, zyxin, nesprin-1, and desmoplakin, were discovered and validated using reciprocal immunoprecipitation and Western blot analysis. Then, we sought to study the biological relevance of these proteins by siRNA transfection of HCT-116 cells. According to the results, zyxin might play a central role as an upstream regulator to mediate critical cancer-related signaling pathways. Zyxin and nesprin-1 depletion significantly impaired cell migration and invasion capabilities. Additionally, we performed ELISA assays on serum samples from patients with colon cancer instead of cell models to quantify the protein levels of zyxin and nesprin-1. Our results suggested that zyxin and nesprin-1 are not only promising therapeutic targets but also potential diagnostic biomarkers for colon cancer.
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http://dx.doi.org/10.1038/s41598-019-49145-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733923PMC
September 2019

Comparison of five automated urine sediment analyzers with manual microscopy for accurate identification of urine sediment.

Clin Chem Lab Med 2019 Oct;57(11):1744-1753

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

Background While the introduction of automated urine analyzers is expected to reduce the labor involved, turnaround time and potential assay variations, microscopic examination remains the "gold standard" for the analysis of urine sediments. In this study, we evaluated the analytical and diagnostic performance of five recently introduced automated urine sediment analyzers. Methods A total of 1016 samples were examined using five automated urine sediment analyzers and manual microscopy. Concordance of results from each automated analyzer and manual microscopy were evaluated. In addition, image and microscopic review rates of each system were investigated. Results The proportional bias for red blood cells (RBCs), white blood cells (WBCs) and squamous epithelial cells in the automated urine sediment analyzers were within ±20% of values obtained using the manual microscope, except in the cases of RBCs and WBCs analyzed using URiSCAN PlusScope and Iris iQ200SPRINT, respectively. The sensitivities of Roche Cobas® u 701 and Siemens UAS800 for pathologic casts (73.6% and 81.1%, respectively) and crystals (62.2% and 49.5%, respectively) were high, along with high image review rates (24.6% and 25.2%, respectively). The detection rates for crystals, casts and review rates can be changed for the Sysmex UF-5000 platform according to cut-off thresholds. Conclusions Each automated urine sediment analyzer has certain distinct features, in addition to the common advantages of reducing the burden of manual processing. Therefore, laboratory physicians are encouraged to understand these features, and to utilize each system in appropriate ways, considering clinical algorithms and laboratory workflow.
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http://dx.doi.org/10.1515/cclm-2019-0211DOI Listing
October 2019

Development of Statistical Software for the Korean Laboratory Accreditation Program Using R Language: LaboStats.

Ann Lab Med 2019 Nov;39(6):552-560

Department of Laboratory Medicine, The Catholic University of Korea, Eunpyeong St. Mary's Hospital, Seoul, Korea.

Background: In Korea, the Korean Laboratory Accreditation Program (KLAP) has set minimum standards for verification of clinical test performance. This verification process is time-consuming and labor-intensive when performed manually. We developed a free, statistical software program for KLAP, using the R language (R Foundation for Statistical Computing, Vienna, Austria).

Methods: We used CLSI guidelines for the algorithm. We built graphic user interfaces, including data input, with Embarcadero Delphi EX4 (Embarcadero Technologies, Inc., Texas, USA). The R Base Package and MCR Package for Method Comparison Regression were used to implement statistical and graphical procedures.

Results: Our program LaboStats has six modules: parallel test, linearity, method comparison, precision, reference interval, and cutoff. Data can be entered into the field either manually or by copying and pasting from an MS Excel worksheet. Users can print out precise reports.

Conclusions: LaboStats can be useful for evaluating clinical test performance characteristics and preparing documents requested by KLAP.
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http://dx.doi.org/10.3343/alm.2019.39.6.552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660338PMC
November 2019

Use of Liquid Chromatography-Tandem Mass Spectrometry for Clinical Testing in Korean Laboratories: a Questionnaire Survey.

Ann Lab Med 2019 Sep;39(5):447-453

Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: The use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) has substantially increased in clinical laboratories worldwide. To assess the status of clinical LC-MS/MS testing in Korean laboratories, a questionnaire survey was performed by the Clinical Mass Spectrometry Research Committee of the Korean Society of Clinical Chemistry.

Methods: The questionnaire was distributed to 19 clinical laboratories performing clinical LC-MS/MS from April to May 2018. It asked about general characteristics of the laboratory and commonly utilized clinical LC-MS/MS tests: newborn screening, tacrolimus test, vitamin D test, and plasma metanephrine test. Frequency analysis and other statistical analyses were performed.

Results: A total of 17 laboratories responded. The median number of LC-MS/MS instruments, laboratory medicine physicians, and technicians in each laboratory was three, one, and two, respectively. Nine laboratory directors had >10 years of experience with clinical LC-MS/MS. For each LC-MS/MS test, at least two concentrations of QC materials were measured every 24 hours during clinical testing, and all laboratories used QC acceptability criteria based on their established QC means and SDs. All laboratories participated in an external quality assessment program. However, there was inter-laboratory variability in sample preparation methods, instruments, reagents, internal standards, and calibrators.

Conclusions: LC-MS/MS has been successfully introduced in Korean clinical laboratories and is used within a quality framework. Further efforts for harmonization on a nationwide basis could facilitate the widespread use of LC-MS/MS.
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http://dx.doi.org/10.3343/alm.2019.39.5.447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502944PMC
September 2019

Fasting serum bile acids concentration is associated with insulin resistance independently of diabetes status.

Clin Chem Lab Med 2019 07;57(8):1218-1228

Department of Laboratory Medicine, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea.

Background Bile acids (BAs) have been demonstrated to exert a variety of metabolic effects and alterations in BAs have been reported in patients with obesity, insulin resistance (IR) and type 2 diabetes mellitus (T2DM). However, it is unclear which metabolic condition is the main contributor to alterations in BAs. In this study, we investigate the associations between different BA profiles with glycemia, obesity or IR status. Methods Fasting serum concentrations of 15 BA species were determined in a total of 241 individuals (71 drug-naïve patients with T2DM, 95 patients with impaired fasting glucose [IFG], and 75 healthy controls. Results A comparison of the mean values of the BAs revealed no significant differences between normoglycemic controls and patients with IFG or T2DM. However, when the entire cohort was divided according to the presence of IR as determined by a homeostasis model assessment of insulin resistance (HOMA-IR) value >2.5, the levels of total BA and most species of BAs were significantly higher in patients with IR than in patients without. In the correlation analysis, most species of BAs, as well as total BA, were significantly associated with HOMA-IR levels. Furthermore, when the subjects were divided into four groups according to IR and diabetic status, subjects with IR had significantly higher total BAs than participants without IR both in diabetic and non-diabetic groups. Ultimately, multiple linear regression analysis identified HOMA-IR as the only significant contributor to most serum BA species. Conclusions Our findings support the essential role of IR in regulating BA metabolism and that this effect is independent of diabetic status.
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http://dx.doi.org/10.1515/cclm-2018-0741DOI Listing
July 2019

Optimal Dosing Regimen of Phenytoin for Korean Epilepsy Patients: From Premature Babies to the Elderly.

J Pharm Sci 2019 08 30;108(8):2765-2773. Epub 2019 Mar 30.

Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea. Electronic address:

Phenytoin has been decreasingly used because of the high interindividual variability in drug concentration and the narrow therapeutic window. Despite such drawbacks, phenytoin is still essential as a second-line therapy for status epilepticus when patients are resistant to benzodiazepines. This study aimed to develop a population pharmacokinetic model of phenytoin and to propose the optimal dose regimen of phenytoin in Korean epilepsy patients. Concentrations collected from electronic medical records for 117 patients, with 1 or 2 measurements per patient, were analyzed using NONMEM 7.3.0. One-compartment model with first-order elimination where allometry scaling was considered best described the data, yielding the estimates of V and CL of 68.19 (L) and 0.63 (L/h), respectively, for patients with a body weight of 60 kg. Covariate analyses showed that, after birth, clearance increases with age, reaching adult level at 4 years, and after 20 years, it decreases with age. Simulation results showed that the dosing interval should be reduced to achieve optimal dosing in neonates and infants, and the optimal dose required increases with weight. This work demonstrates that a model-based approach can serve as a useful tool to individualize phenytoin therapy.
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http://dx.doi.org/10.1016/j.xphs.2019.03.022DOI Listing
August 2019

Comparison of analytical performance of i-Smart 300 and pHOx ultra for the accurate determination of pleural fluid pH.

Pract Lab Med 2019 Mar 29;14:e00117. Epub 2019 Jan 29.

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

Background: Pleural fluid pH is an essential test for diagnosing complicated parapneumonic effusion. We evaluated the performance of two blood gas analyzers in measuring pleural fluid pH.

Methods: The i-STAT G3+ (Abbott) was used as a reference analyzer to evaluate the pH values obtained from other methods: the i-Smart 300 (i-SENS), the pHOx Ultra (Nova Biomedical), using a clot catcher to filter off microclot, and pH indicator paper. Within-device precision was performed using quality control materials. We compared pleural fluid pH (n = 86) by the above methods and analyzed the concordance rate at the level of the medical decision point, pH 7.2.

Results: The within-device coefficient of variations of pH were below 0.1% for all blood gas analyzers tested. The slopes of the regression equations for the i-Smart 300, pHOx Ultra, and pH indicator paper against the reference analyzer were 0.850 (95% confidence interval, CI, 0.800-0.896), 0.714 (95% CI, 0.671-0.766), and 1.105 (95% CI, 0.781-1.581), respectively. The kappa values for the i-Smart 300, pHOx Ultra, and pH indicator paper against the reference analyzer were 0.883 (95% CI, 0.656-1.110), 0.739 (95% CI, 0.393-1.084), and 0.464 (95% CI, 0.102-0.826), respectively.

Conclusions: The i-Smart 300 and pHOx Ultra demonstrated good analytical performance and diagnostic accuracy when determining pleural fluid pH compared with that by the i-STAT G3+, whereas the pH indicator paper showed unsatisfactory results.
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http://dx.doi.org/10.1016/j.plabm.2019.e00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378778PMC
March 2019

Spontaneous ketonuria and risk of incident diabetes: a 12 year prospective study.

Diabetologia 2019 05 20;62(5):779-788. Epub 2019 Feb 20.

Department of Preventive Medicine, Ajou University School of Medicine, 164 World cup-ro, Yeongtong-gu, Suwon, 16499, Republic of Korea.

Aims/hypothesis: Ketones may be regarded as a thrifty fuel for peripheral tissues, but their clinical prognostic significance remains unclear. We investigated the association between spontaneous fasting ketonuria and incident diabetes in conjunction with changes in metabolic variables in a large population-based observational study.

Methods: We analysed 8703 individuals free of diabetes at baseline enrolled in the Korean Genome and Epidemiology Study, a community-based 12 year prospective study. Individuals with (n = 195) or without fasting ketonuria were matched 1:4 by propensity score. Incident diabetes was defined as fasting plasma glucose ≥7.0 mmol/l, post-load 2 h glucose ≥11.1 mmol/l on biennial OGTTs, or current use of glucose-lowering medication. Using Cox regression models, HRs for developing diabetes associated with the presence of ketonuria at baseline were analysed.

Results: Over 12 years, of the 925 participants in the propensity score-matched cohort, 190 (20.5%) developed diabetes. The incidence rate of diabetes was significantly lower in participants with spontaneous ketonuria compared with those without ketonuria (HR 0.63; 95% CI 0.41, 0.97). Results were virtually identical when participants with fasting ketonuria were compared against all participants without ketonuria (after multivariate adjustment, HR 0.66; 95% CI 0.45, 0.96). During follow-up, participants with baseline ketonuria maintained lower post-load 1 h and 2 h glucose levels and a higher insulinogenic index despite comparable baseline values.

Conclusions/interpretation: The presence of spontaneous fasting ketonuria was significantly associated with a reduced risk of diabetes, independently of metabolic variables. Our findings suggest that spontaneous fasting ketonuria may have a potential preventive role in the development of diabetes.
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http://dx.doi.org/10.1007/s00125-019-4829-xDOI Listing
May 2019

Relationship Between Circulating Netrin-1 Concentration, Impaired Fasting Glucose, and Newly Diagnosed Type 2 Diabetes.

Front Endocrinol (Lausanne) 2018 23;9:691. Epub 2018 Nov 23.

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

The protein netrin-1 has demonstrated anti-inflammatory, tissue regeneration, and immune modulation properties. Although inflammation is a major contributing factor in the development of insulin resistance and type 2 diabetes, little is known about a possible relationship between serum netrin-1 and type 2 diabetes. Therefore, we investigated the association between circulating levels of netrin-1 and glycometabolic parameters predictive of type 2 diabetes. Serum samples were collected from 41 normal controls, 85 subjects with impaired fasting glucose (IFG), and 92 subjects with newly diagnosed type 2 diabetes. Clinical and laboratory parameters were assessed and netrin-1 levels were measured by commercial enzyme-linked immunosorbent assay. Spearman correlation analyses and multivariable-adjusted regression analyses were conducted to examine the relationship between serum netrin-1 levels and glycometabolic parameters. Serum netrin-1 levels in subjects with type 2 diabetes or IFG were significantly higher compared to normal controls (441.0, 436.6, and 275.9 pg/mL, respectively; for trend < 0.001). Serum netrin-1 levels were significantly positively correlated with fasting glucose, HbA, and insulin resistance index (all s < 0.01). Serum netrin-1 levels were independently associated with IFG or type 2 diabetes (standardized β = 0.405, < 0.001) after adjusting for covariates and potential confounders. In addition, the receiver operating characteristic (ROC) analysis showed that serum netrin-1 levels could identify the presence of IFG and type 2 diabetes with the area under the ROC curve (AUC) of 0.784 ( < 0.001). Our results suggest that elevated serum netrin-1 levels are significantly associated with the presence of IFG and type 2 diabetes.
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http://dx.doi.org/10.3389/fendo.2018.00691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265472PMC
November 2018