Biology subjects

Kim, H. S.

Publications and source records attributed to Kim, H. S..

11 recordsLinked to original sources

bioRxiv2018

Meteorin-like (Metrnl) adipomyokine improves glucose tolerance in type 2 diabetes via AMPK pathway

Meteorin-like (metrnl) is a recently identified adipomyokine that has beneficial effects on glucose metabolism. However, its underlying mechanism of action is not completely understood. In this study, we have shown that a level of metrnl increase in vitro under electrical-pulse-stimulation (EPS) and in vivo in exercise mice, suggesting that metrnl is an exercise-induced myokine. In addition, metrnl increases glucose uptake through the calcium-dependent AMPK pathway. Metrnl also increases the phosphorylation of HDAC5, a transcriptional repressor of GLUT4, in an AMPK-dependent manner. Phosphorylated HDAC5 interacts with 14-3-3 proteins and sequesters them in the cytoplasm, resulting in the activation of GLUT4 transcription. The intraperitoneal injection of recombinant metrnl improves glucose tolerance in mice with high fat-induced obesity or type 2 diabetes (db/db), but this is not seen in AMPK {beta}1{beta}2 muscle-specific null mice (AMPK {beta}1{beta}2 MKO). In conclusion, we have demonstrated that metrnl induces beneficial effects on glucose metabolism via AMPK and is a promising therapeutic candidate for glucose-related diseases such as type 2 diabetes.

biochemistry↗

bioRxiv2018

Diagnosis and Prognosis Using Machine Learning Trained on BrainMorphometry and White Matter Connectomes

Accurate, reliable prediction of risk for Alzheimers disease (AD) is essential for early, disease-modifying therapeutics. Multimodal MRI, such as structural and diffusion MRI, is likely to contain complementary information of neurodegenerative processes in AD. Here we tested the utility of the multimodal MRI (T1-weighted structure and diffusion MRI), combined with high-throughput brain phenotyping--morphometry and structural connectomics--and machine learning, as a diagnostic tool for AD. We used, firstly, a clinical cohort at a dementia clinic (National Health Insurance Service-Ilsan Hospital [NHIS-IH]; N=211; 110 AD, 64 mild cognitive impairment [MCI], and 37 cognitively normal with subjective memory complaints [SMC]) to test the diagnostic models; and, secondly, Alzheimers Disease Neuroimaging Initiative (ADNI)-2 to test the generalizability. Our machine learning models trained on the morphometric and connectome estimates (number of features=34,646) showed optimal classification accuracy (AD/SMC: 97% accuracy, MCI/SMC: 83% accuracy; AD/MCI: 97% accuracy) in NHIS-IH cohort, outperforming a benchmark model (FLAIR-based white matter hyperintensity volumes). In ADNI-2 data, the combined connectome and morphometry model showed similar or superior accuracies (AD/HC: 96%; MCI/HC: 70%; AD/MCI: 75% accuracy) compared with the CSF biomarker model (t-tau, p-tau, and Amyloid {beta}, and ratios). In predicting MCI to AD progression in a smaller cohort of ADNI-2 (n=60), the morphometry model showed similar performance with 69% accuracy compared with CSF biomarker model with 70% accuracy. Our comparison of classifiers trained on structural MRI, diffusion MRI, FLAIR, and CSF biomarkers show the promising utility of the white matter structural connectomes in classifying AD and MCI in addition to the widely used structural MRI-based morphometry, when combined with machine learning.\n\nHighlightsO_LIWe showed the utility of multimodal MRI, combining morphometry and white matter connectomes, to classify the diagnosis of AD and MCI using machine learning.\nC_LIO_LIIn predicting the progression from MCI to AD, the morphometry model showed the best performance.\nC_LIO_LITwo independent clinical datasets were used in this study: one for model building, the other for generalizability testing.\nC_LI

neuroscience↗

bioRxiv2018

Peroxiredoxin-mediated HMGB1 oxidation and secretion in response to inflammatory stimuli

The nuclear protein HMGB1 (high mobility group box 1) is secreted by monocytesmacrophages in response to inflammatory stimuli and serves as a danger-associated molecular pattern. Acetylation and phosphorylation of HMGB1 are implicated in the regulation of its nucleocytoplasmic translocation for secretion, although inflammatory stimuli are also known to induce H2O2 production. Here we show that H2O2-induced oxidation of HMGB1 that results in formation of an intramolecular disulphide bond between Cys23 and Cys45 is necessary and sufficient for its nucleocytoplasmic translocation and secretion. The oxidation is catalysed by peroxiredoxin I (PrxI) and PrxII, which are first oxidized by H2O2 and then transfer their disulphide oxidation state to HMGB1. The disulphide form of HMGB1 showed a higher affinity for the nuclear exportin CRM1 compared with the reduced form. Lipopolysaccharide (LPS)-induced HMGB1 secretion was greatly attenuated in macrophages derived from PrxI or PrxII knockout mice, as was the LPS-induced increase in serum HMGB1 levels in these mice.

immunology↗

bioRxiv2018

Accurate Prediction of Alzheimer’s Disease Using Multi-Modal MRI and High-Throughput Brain Phenotyping

Accurate, reliable prediction of risk for Alzheimers disease (AD) is essential for early, disease-modifying therapeutics. Multimodal MRI, such as structural and diffusion MRI, is likely to contain complementary information of neurodegenerative processes in AD. Here we tested the utility of commonly available multimodal MRI (T1-weighted structure and diffusion MRI), combined with high-throughput brain phenotyping--morphometry and connectomics--and machine learning, as a diagnostic tool for AD. We used, firstly, a clinical cohort at a dementia clinic (study 1: Ilsan Dementia Cohort; N=211; 110 AD, 64 mild cognitive impairment [MCI], and 37 subjective memory complaints [SMC]) to test and validate the diagnostic models; and, secondly, Alzheimers Disease Neuroimaging Initiative (ADNI)-2 (study 2) to test the generalizability of the approach and the prognostic models with longitudinal follow up data. Our machine learning models trained on the morphometric and connectome estimates (number of features=34,646) showed optimal classification accuracy (AD/SMC: 97% accuracy, MCI/SMC: 83% accuracy; AD/MCI: 97% accuracy) with iterative nested cross-validation in a single-site study, outperforming the benchmark model (FLAIR-based white matter hyperintensity volumes). In a generalizability study using ADNI-2, the combined connectome and morphometry model showed similar or superior accuracies (AD/HC: 96%; MCI/HC: 70%; AD/MCI: 75% accuracy) as CSF biomarker model (t-tau, p-tau, and Amyloid {beta}, and ratios). We also predicted MCI to AD progression with 69% accuracy, compared with the 70% accuracy using CSF biomarker model. The optimal classification accuracy in a single-site dataset and the reproduced results in multi-site dataset show the feasibility of the high-throughput imaging analysis of multimodal MRI and data-driven machine learning for predictive modeling in AD.

neuroscience↗

bioRxiv2018

Onset, Time to Recurrence, and Recurrence Risk Factors of Myocardial Infarction and Ischemic Stroke: 10-Year Nationwide one-Million Population Database

Background and PurposeWe aimed to determine the differences in the pathophysiology of myocardial infarction (MI) and ischemic stroke (IS) and present their basic epidemiologic data for public health policy.\n\nMethodsWe included patients with a history of admission with diagnostic codes of MI and IS in the National Health Information Database (NHID) of the National Health Insurance Service (NHIS) Sample Cohort 2002-2013. We investigated the time to primary and secondary events, difference in incidence based on sex, time interval for the secondary event following the primary event in MI and IS, and the relative risk of recurrent events compared with that of primary events.\n\nResultsThe mean age of onset of IS was significantly higher than that of MI (65.67{+/-}12.25 vs. 60.4{+/-}13.07 years; P<0.05). The mean period from primary IS to secondary IS was significantly shorter than that from primary IS to secondary MI (2.09{+/-}2.80 vs. 5.35{+/-}2.90 years; P=0.016). The mean period from primary MI to secondary MI was significantly shorter than that from primary MI to secondary IS (2.30{+/-}2.75 vs. 5.16{+/-}3.26 years; P<0.001). The incidence of IS in men was significantly higher than that in women. The relative risk of recurrent IS and MI was greater than that of the primary event. In patients younger than 70 years, the incidence of MI was higher than that of IS, while in those above 70 years it was lower (P<0.05).\n\nConclusionsThe age at onset, time to recurrence, sex, and relative risks are significantly different between ischemic stroke and myocardial infarction, suggesting that the underlying pathophysiologic mechanisms might be different between the two.

epidemiology↗

bioRxiv2018

Socioeconomic status associated with carpal tunnel syndrome: A retrospective nationwide 11-year population-based cohort study in South Korea

ImportanceThere have only been a few large-scale studies that have included a risk factor analysis for CTS. No prior study has investigated the relationship between the occurrence of CTS and stratified socioeconomic status, which is closely related to a persons type of job.\n\nObjectiveTo confirm the known risk factors for CTS and also to determine the correlation between stratified socioeconomic status and the occurrence of CTS.\n\nDesignWe conducted this study using a retrospective cohort model based on the combined databases of the Korean National Health Insurance System from 2003-2013, a database compiled using information from a national periodic health-screening program that is used for reimbursement claims.\n\nSettingThe setting was a population-based retrospective cohort study.\n\nParticipantsFirst, we randomly sampled 514,795 patients who represented 10% of the 5,147,950 people who took part in periodic health screenings from 2002-2003. Existing CTS patients were excluded from this group. Therefore, this study finally included 512,942 participants and followed their medical records from 2003-2013.\n\nMain Outcomes and MeasuresDesired outcomes were the incidence rate of CTS and the hazard ratios according to stratified socioeconomic status.\n\nResultsA correlation analysis showed that CTS was more likely to occur in patients from a lower socioeconomic status.\n\nConclusions and RelevanceCTS was associated with people of a lower socioeconomic status who work in simple but repetitive manual labor jobs. We believe that the results of our study will be helpful to determine the pathophysiology of CTS and to set up a new industrial health policy for this condition.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat is the relationship between stratified socioeconomic status and the incidence of carpal tunnel syndrome (CTS)?\n\nFindingsIn this retrospective population-based cohort study that included 512,942 participants sampled from the Korean National Health Insurance System(KNHIS) database, the incidence rate and hazard ratios for CTS tended to increase with lower socioeconomic status.\n\nImplicationsLow socioeconomic status was identified as a risk factor for the incidence of CTS.

epidemiology↗

bioRxiv2018

Validation of known risk factors associated with carpal tunnel syndrome: A retrospective nationwide 11-year population-based cohort study in South Korea

Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the relationship between the previously known risk factors and occurrence of carpal tunnel syndrome (CTS)?\n\nFindingsIn this retrospective population-based cohort study that included 512,942 participants sampled from the Korean National Health Insurance System database, we determined the following known risk factors were related to the occurrence of CTS: the age of 40s, female, being overweight, diabetes, rheumatoid arthritis, gout, and Raynauds syndrome. However, ESRD, hypothyroidism and smoking were not correlated with CTS occurrence.\n\nImplicationsWe identified the age of 40s, female, overweight, diabetes, rheumatoid arthritis, gout, and Raynauds syndrome as risk factors for the occurrence of CTS.\n\nAbstractO_ST_ABSImportanceC_ST_ABSThere have been few large-scale studies that have included a risk factor analysis for CTS. No prior study has investigated and validated the relationship between the occurrence of CTS and known risk factors using nationwide health care database.\n\nObjectiveTo confirm the actual risk factors for CTS out of various known risk factors\n\nDesignWe conducted this study using a retrospective cohort model based on the combined two databases of the Korean National Health Insurance System; the national periodic health screening program database from 2002-2003 and health insurance database of reimbursement claims from 2003 through 2013.\n\nSettingA population-based retrospective cohort study.\n\nParticipantsFirst, we randomly sampled 514,795 patients who represented 10% of the 5,147,950 people who took part in periodic health screenings in 2002-2003. Existing CTS patients were excluded from this group. Therefore, this study finally included 512,942 participants and followed up their medical records from 2003-2013.\n\nMain Outcomes and MeasuresDesired outcomes were the incidence rate of CTS in patients with various risk factors and the hazard ratios of risk factors affecting the diseases occurrence.\n\nResultsThe incidence of CTS was highest in patients in the age of 40s, in the moderate obesity group, in females, and in patients with diabetes mellitus (DM). The hazard ratio analysis revealed that the following risk factors were strongly related to the occurrence of CTS: age of 40s, female, obesity, DM, rheumatoid arthritis, gout, and Raynauds syndrome. However, ESRD, hypothyroidism and smoking were not correlated with CTS occurrence.\n\nConclusions and RelevanceIn our large-scale cohort study, risk factors such as being in ones 40s, obesity, being female, suffering from DM, and rheumatoid arthritis were reaffirmed as those of CTS occurrence.

epidemiology↗

bioRxiv2018

10 Year Epidemiologic data of Parkinson`s Disease: A Nationwide Population-based Retrospective Cohort of South Korea

ObjectivesThe aims of this study were to determine the prevalence, incidence, and P/I ratio of Parkinsons disease (PD) in South Korea and to present basic epidemiological information on PD patients for making effective health policies.\n\nMethodsWe used National Health Insurance Service-National Sample Cohort (KNHIS-NSC) data to analyze the prevalence, incidence, and P/I ratio of PD from 2003 to 2013 and then followed up using the NHID in 2008 to obtain the hazard ratio (HR) of death in PD itself and other comorbidities from 2008 to 2013.\n\nResultsThe prevalence and incidence of PD increased rapidly from 72.9 and 32.8 in 2003 to 213.4 and 58.0 in 2013, and the P/I ratio increased from 2.22 in 2003 to 3.62 in 2013. The prevalence, incidence, and P/I ratio of PD were all higher in women than in men. The hazard ratio for death was significantly higher in PD patients (15.36) compared to subjects without the disease. Stroke was the most frequent cause of death in the PD patient population followed by cancer and pneumonia.\n\nConclusionThe prevalence, incidence, and P/I ratio of PD rapidly increased as the years progressed. This indirectly proves that the health insurance system in Korea is efficient and has allowed patients with PD to access medical facilities more easily. However, a newer public healthy strategy should be established for patients with PD because PD itself has a high HR for death, and patients with PD have a high mortality rate when stroke and pneumonia are also involved.\n\nDisclosureAll authors have reported no biomedical interests and potential conflicts of interests.

epidemiology↗

bioRxiv2018

Risk factors associated with Parkinson’s disease: An 11-year population-based South Korean study

ObjectiveTo validate various known risk factors of Parkinsonism and to establish basic information to formulate public health policy by using a 10-year follow-up cohort model.\n\nMethodsThis population based nation-wide study was performed using the National Health Insurance Database of reimbursement claims of the Health Insurance Review and Assessment Service of South Korea data on regular health check-ups in 2003 and 2004, with 10 years follow-up.\n\nResultsWe identified 7,746 patients with Parkinsonism. Old age, hypertension, diabetes, depression, anxiety, taking statin medication, high body mass index, non-smoking, non-alcohol drinking, and low socioeconomic status were each associated with an increase in the risk of Parkinsonism (fully adjusted Cox proportional hazards model: hazard ratio (HR) 1.259, 95% confidence interval (CI) 1.194-1.328 for hypertension, HR 1.255, 95% CI 1.186-1.329 for diabetes, HR 1.554, 95% CI 1.664-1.965 for depression, HR 1.808, 95% CI 1.462-1.652 for anxiety, and HR 1.157, 95% CI 1.072-1.250 for taking statin medication).\n\nConclusionsIn our study, old age, depression, anxiety, and a non-smoker status were found to be risk factors of Parkinsonism, in agreement with previous studies. However, sex, hypertension, diabetes, taking statin medication, non-drinking of Alcohol, and lower socioeconomic status have not been described as risk factors in previous studies and need further verification in future studies.

epidemiology↗

bioRxiv2018

Oncogenic role of sFRP2 in P53-mutant osteosarcoma development via autocrine and paracrine mechanism

Osteosarcoma (OS), the most common primary bone tumor, is highly metastatic with high chemotherapeutic resistance and poor survival rates. Using induced pluripotent stem cells (iPSCs) generated from Li-Fraumeni syndrome (LFS) patients, we investigated an oncogenic role of secreted frizzled-related protein 2 (sFRP2) in P53 mutation-associated OS development. Interestingly, we found that high sFRP2 expression in OS patient samples correlates with poor survival. Systems-level analyses identified that expression of sFRP2 increases during LFS OS development and can induce angiogenesis. Ectopic sFRP2 overexpression in normal osteoblast precursors is sufficient to suppress normal osteoblast differentiation and to promote OS phenotypes through induction of oncogenic molecules such as FOXM1 and CYR61 in a {beta}-catenin independent manner. Conversely, inhibition of sFRP2, FOXM1 or CYR61 represses the tumorigenic potential. In summary, these findings demonstrate the oncogenic role of sFRP2 in P53 mutation-associated OS development and that inhibition of sFRP2 is a potential therapeutic strategy.

cancer biology↗

bioRxiv2017

Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin against metastases in breast cancer

Most breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600-2000 subjects in epilepsy and autism. MuGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance.\n\nResults from three independent GWAS of 1000-2000 subjects each, which were made available under the National Institute of Healths \"Up For A Challenge\" (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids via alpha-cyclodextrins (CD) as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of {beta}1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells).\n\nBeta-cyclodextrins ({beta}CD) have already been shown to be effective in in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller CDs also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirms hydroxypropyl (HP)-CD to be twice as effective as HP{beta}CD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer.\n\nIf the previous successful animal studies with {beta}CDs are replicated with the safer and more effective CDs, clinical trials of adjuvant treatment with CDs are warranted. Ultimately, all breast cancer are expected to benefit from treatment with HPCD, but women with triplenegative breast cancer (TNBC) will benefit most, because they have fewer treatment options and their cancer advances more aggressively.

cancer biology↗