Publications by authors named "Sungeun Kim"

175 Publications

Clustering subtypes of breast cancer by combining immunohistochemistry profiles and metabolism characteristics measured using FDG PET/CT.

Cancer Imaging 2021 Sep 27;21(1):55. Epub 2021 Sep 27.

Department of Nuclear Medicine, Korea University College of Medicine, Seoul, Korea.

Background: The aim of this study was to investigate the effect of combining immunohistochemical profiles and metabolic information to characterize breast cancer subtypes.

Methods: This retrospective study included 289 breast tumors from 284 patients who underwent preoperative  F-fluorodeoxyglucose (FDG) positron emission tomography/ computed tomography (PET/CT). Molecular subtypes of breast cancer were classified as Hormonal, HER2, Dual (a combination of both Hormonal and HER2 features), and triple-negative (TN). Histopathologic findings and immunohistochemical results for Ki-67, EGFR, CK 5/6, and p53 were also analyzed. The maximum standardized uptake value (SUV) measured from FDG PET/CT was used to evaluate tumoral glucose metabolism.

Results: Overall, 182, 24, 47, and 36 tumors were classified as Hormonal, HER2, Dual, and TN subtypes, respectively. Molecular profiles of tumor aggressiveness and the tumor SUV revealed a gradual increase from the Hormonal to the TN type. The tumor SUV was significantly correlated with tumor size, expression levels of p53, Ki-67, and EGFR, and nuclear grade (all p < 0.001). In contrast, the tumor SUV was negatively correlated with the expression of estrogen receptors (r = - 0.234, p < 0.001) and progesterone receptors (r = - 0.220, p < 0.001). Multiple linear regression analysis revealed that histopathologic markers explained tumor glucose metabolism (adjusted R-squared value 0.238, p < 0.001). Tumor metabolism can thus help define breast cancer subtypes with aggressive/adverse prognostic features.

Conclusions: Metabolic activity measured using FDG PET/CT was significantly correlated with the molecular alteration profiles of breast cancer assessed using immunohistochemical analysis. Combining molecular markers and metabolic information may aid in the recognition and understanding of tumor aggressiveness in breast cancer and be helpful as a prognostic marker.
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http://dx.doi.org/10.1186/s40644-021-00424-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477513PMC
September 2021

Stress-Related Amygdala Metabolic Activity Is Associated With Low Bone Mineral Density in Postmenopausal Women: A Pilot F-FDG PET/CT Study.

Front Endocrinol (Lausanne) 2021 12;12:719265. Epub 2021 Aug 12.

Department of Nuclear Medicine, Korea University Anam Hospital, Seoul, South Korea.

Background: Psychological stress is associated with postmenopausal osteoporosis. However, the underlying mechanism of stress-related brain neural activity with osteoporosis is not fully elucidated. F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) is an established method to evaluate the metabolic activity of brain amygdala, a region involved in stress. We aimed to evaluate the relationship between metabolic activity of amygdala (AmygA) and osteoporosis in postmenopausal women.

Materials And Methods: A total of 115 postmenopausal women who underwent F-FDG PET/CT and dual-energy X-ray absorptiometry for routine health screening were enrolled in this study. AmygA was defined as the maximum standardized uptake value (SUVmax) of amygdala divided by the mean SUV of temporal lobe. The levels of psychological stress were measured using the Psychosocial Well-being Index-Short Form (PWI-SF).

Results: The participants with osteoporosis exhibited significantly higher AmygA than without osteoporosis (0.81 ± 0.16 . 0.61 ± 0.13, < 0.001). The AmygA value of 0.69 was suggested as an optimal cut-off value to identify participant with osteoporosis (sensitivity; 79.1%, specificity; 83.3%, area under the curve; 0.841, < 0.001). Furthermore, AmygA showed significant association with osteoporosis in postmenopausal woman by multivariate analysis. Psychological stress scale (PWI-SF) was well correlated with AmygA and AmygA was highest in high stress risk-, intermediate in moderate stress risk-, and lowest in healthy group.

Conclusions: AmygA measured by F-FDG PET/CT is associated with osteoporosis in postmenopausal women. Our results provide the possibility that stress-related neurobiological activity involving amygdala is linked with postmenopausal osteoporosis.
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http://dx.doi.org/10.3389/fendo.2021.719265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406934PMC
August 2021

N-Palmitoyl Serinol Stimulates Ceramide Production through a CB1-Dependent Mechanism in In Vitro Model of Skin Inflammation.

Int J Mol Sci 2021 Aug 2;22(15). Epub 2021 Aug 2.

Convergence Program of Material Science for Medicine and Pharmaceutics, Department of Food Science and Nutrition, Hallym University, Chuncheon 24252, Korea.

Ceramides, a class of sphingolipids containing a backbone of sphingoid base, are the most important and effective structural component for the formation of the epidermal permeability barrier. While ceramides comprise approximately 50% of the epidermal lipid content by mass, the content is substantially decreased in certain inflammatory skin diseases, such as atopic dermatitis (AD), causing improper barrier function. It is widely accepted that the endocannabinoid system (ECS) can modulate a number of biological responses in the central nerve system, prior studies revealed that activation of endocannabinoid receptor CB1, a key component of ECS, triggers the generation of ceramides that mediate neuronal cell fate. However, as the impact of ECS on the production of epidermal ceramide has not been studied, we here investigated whether the ECS stimulates the generation of epidermal ceramides in an IL-4-treated in vitro model of skin inflammation using N-palmitoyl serinol (PS), an analog of the endocannabinoid N-palmitoyl ethanolamine. Accordingly, an IL-4-mediated decrease in cellular ceramide levels was significantly stimulated in human epidermal keratinocytes (KC) following PS treatment through both de novo ceramide synthesis- and sphingomyelin hydrolysis-pathways. Importantly, PS selectively increases ceramides with long-chain fatty acids (FAs) (C22-C24), which mainly account for the formation of the epidermal barrier, through activation of ceramide synthase (CerS) 2 and Cer3 in IL-4-mediated inflamed KC. Furthermore, blockade of cannabinoid receptor CB1 activation by AM-251 failed to stimulate the production of total ceramide as well as long-chain ceramides in response to PS. These studies demonstrate that an analog of endocannabinoid, PS, stimulates the generation of specific ceramide species as well as the total amount of ceramides via the endocannabinoid receptor CB1-dependent mechanism, thereby resulting in the enhancement of epidermal permeability barrier function.
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http://dx.doi.org/10.3390/ijms22158302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348051PMC
August 2021

The effect of video-instructed versus audio-instructed dispatcher-assisted cardiopulmonary resuscitation on patient outcomes following out of hospital cardiac arrest in Seoul.

Sci Rep 2021 07 30;11(1):15555. Epub 2021 Jul 30.

EMS Situation Management Center, Seoul Emergency Operation Center, Seoul Metropolitan Fire & Disaster Headquarters, Seoul, South Korea.

We aimed to investigate whether video-instructed dispatcher-assisted (DA)-cardiopulmonary resuscitation (CPR) improved neurologic recovery and survival to discharge compared to audio-instructed DA-CPR in adult out-of-hospital cardiac arrest (OHCA) patients in a metropolitan city with sufficient experience and facilities. A retrospective cohort study was conducted for adult bystander-witnessed OHCA patients administered DA-CPR due to presumed cardiac etiology between January 1, 2018 and October 31, 2019 in Seoul, Korea. The primary and secondary outcomes were the differences in favorable neurologic outcome and survival to discharge rates in adult OHCA patients in the two instruction groups. Binary logistic regression analysis was performed to identify the outcome predictors after DA-CPR. A total of 2109 adult OHCA patients with DA-CPR were enrolled. Numbers of elderly patients in audio instruction and video instruction were 1260 (73.2%) and 214 (55.3%), respectively. Elderly patients and those outside the home or medical facility were more likely to receive video instruction. Favorable neurologic outcome was observed more in patients who received video-instructed DA-CPR (n = 75, 19.4%) than in patients who received audio-instructed DA-CPR (n = 117, 6.8%). The survival to discharge rate was also higher in video-instructed DA-CPR (n = 105, 27.1%) than in audio-instructed DA-CPR (n = 211, 12.3%). Video-instructed DA-CPR was significantly associated with neurologic recovery (aOR = 2.11, 95% CI 1.48-3.01) and survival to discharge (aOR = 1.81, 95% CI 1.33-2.46) compared to audio-instructed DA-CPR in adult OHCA patients after adjusting for age, gender, underlying diseases and CPR location. Video-instructed DA-CPR was associated with favorable outcomes in adult patients with OHCA in a metropolitan city equipped with sufficient experience and facilities.
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http://dx.doi.org/10.1038/s41598-021-95077-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324920PMC
July 2021

Autoimmune inflammatory rheumatic diseases and COVID-19 outcomes in South Korea: a nationwide cohort study.

Lancet Rheumatol 2021 Oct 18;3(10):e698-e706. Epub 2021 Jun 18.

Department of Pediatrics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.

Background: Real-world evidence on the association between autoimmune inflammatory rheumatic diseases, therapies related to these diseases, and COVID-19 outcomes are inconsistent. We aimed to investigate the potential association between autoimmune inflammatory rheumatic diseases and COVID-19 early in the COVID-19 pandemic.

Methods: We did an exposure-driven, propensity score-matched study using a South Korean nationwide cohort linked to general health examination records. We analysed all South Korean patients aged older than 20 years who underwent SARS-CoV-2 RT-PCR testing between Jan 1 and May 30, 2020, and received general health examination results from the Korean National Health Insurance Service. We defined autoimmune inflammatory rheumatic diseases (inflammatory arthritis and connective tissue diseases) based on the relevant ICD-10 codes, with at least two claims (outpatient or inpatient) within 1 year. The outcomes were positive SARS-CoV-2 RT-PCR test, severe COVID-19 (requirement of oxygen therapy, intensive care unit admission, application of invasive ventilation, or death), and COVID-19-related death. Adjusted odds ratios (ORs) with 95% CIs were estimated after adjusting for the potential confounders.

Findings: Between Jan 1 and May 30, 2020, 133 609 patients (70 050 [52·4%] female and 63 559 [47·6%] male) completed the general health examination and were tested for SARS-CoV-2; 4365 (3·3%) were positive for SARS-CoV-2, and 8297 (6·2%) were diagnosed with autoimmune inflammatory rheumatic diseases. After matching, patients with an autoimmune inflammatory rheumatic disease showed an increased likelihood of testing positive for SARS-CoV-2 (adjusted OR 1·19, 95% CI 1·03-1·40; p=0·026), severe COVID-19 outcomes (1·26, 1·02-1·59; p=0·041), and COVID-19-related death (1·69, 1·01-2·84; p=0·046). Similar results were observed in patients with connective tissue disease and inflammatory arthritis. Treatment with any dose of systemic corticosteroids or disease-modifying antirheumatic drugs (DMARDs) were not associated with COVID-19-related outcomes, but those receiving high dose (≥10 mg per day) of systemic corticosteroids had an increased likelihood of a positive SARS-CoV-2 test (adjusted OR 1·47, 95% CI 1·05-2·03; p=0·022), severe COVID-19 outcomes (1·76, 1·06-2·96; p=0·031), and COVID-19-related death (3·34, 1·23-8·90; p=0·017).

Interpretation: Early in the COVID-19 pandemic, autoimmune inflammatory rheumatic diseases were associated with an increased likelihood of a positive SARS-CoV-2 PCR test, worse clinical outcomes of COVID-19, and COVID-19-related deaths in South Korea. A high dose of systemic corticosteroid, but not DMARDs, showed an adverse effect on SARS-CoV-2 infection and COVID-19-related clinical outcomes.

Funding: National Research Foundation of Korea.
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http://dx.doi.org/10.1016/S2665-9913(21)00151-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213376PMC
October 2021

Phenotypic overlap between atopic dermatitis and autism.

BMC Neurosci 2021 06 22;22(1):43. Epub 2021 Jun 22.

Dept. of Dermatology, University of California, NCIRE, and Veterans Affairs Medical Center, 4150 Clement Street, MS 190, San Francisco, CA, 94121, USA.

Background: Autism, a childhood behavioral disorder, belongs to a large suite of diseases, collectively referred to as autism spectrum disorders (ASD). Though multifactorial in etiology, approximately 10% of ASD are associated with atopic dermatitis (AD). Moreover, ASD prevalence increases further as AD severity worsens, though these disorders share no common causative mutations. We assessed here the link between these two disorders in the standard, valproic acid mouse model of ASD. In prior studies, there was no evidence of skin involvement, but we hypothesized that cutaneous involvement could be detected in experiments conducted in BALB/c mice. BALB/c is an albino, laboratory-bred strain of the house mouse and is among the most widely used inbred strains used in animal experimentation.

Methods: We performed our studies in valproic acid (VPA)-treated BALB/c hairless mice, a standard mouse model of ASD. Mid-trimester pregnant mice received a single intraperitoneal injection of either valproic acid sodium salt dissolved in saline or saline alone on embryonic day 12.5 and were housed individually until postnatal day 21. Only the brain and epidermis appeared to be affected, while other tissues remain unchanged. At various postnatal time points, brain, skin and blood samples were obtained for histology and for quantitation of tissue sphingolipid content and cytokine levels.

Results: AD-like changes in ceramide content occurred by day one postpartum in both VPA-treated mouse skin and brain. The temporal co-emergence of AD and ASD, and the AD phenotype-dependent increase in ASD prevalence correlated with early appearance of cytokine markers (i.e., interleukin [IL]-4, 5, and 13), as well as mast cells in skin and brain. The high levels of interferon (IFN)γ not only in skin, but also in brain likely account for a significant decline in esterified very-long-chain N-acyl fatty acids in brain ceramides, again mimicking known IFNγ-induced changes in AD.

Conclusion: Baseline involvement of both AD and ASD could reflect concurrent neuro- and epidermal toxicity, possibly because both epidermis and neural tissues originate from the embryonic neuroectoderm. These studies illuminate the shared susceptibility of the brain and epidermis to a known neurotoxin, suggesting that the atopic diathesis could be extended to include ASD.
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http://dx.doi.org/10.1186/s12868-021-00645-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218496PMC
June 2021

Technique for analyzing the transfer of colored cosmetics onto face masks.

Skin Res Technol 2021 May 11. Epub 2021 May 11.

Skin Clinical Trials Center, OATC Inc., Seoul, South Korea.

Background: With the rapid spread of COVID-19, the makeup trend in the cosmetics market is changing as mask-wearing has become a common practice. This study was conducted to establish an objective and reliable method for analyzing the transfer of colored cosmetics onto face masks.

Methods: A total of 24 women participated in this test. The participants were requested to wear Korean Filter 94 masks after having applied colored cosmetics on their faces and lips. VISIA-CR was used to photograph the face, and a camera was used to photograph the mask, which had smeared the cosmetics. Each image was analyzed using the Image-pro 10 image analysis software.

Results: Immediately after applying the cosmetics, the intensity of the face decreased and the redness of the lips increased when compared with the results 30 minutes after washing the face. After wearing a mask, the intensity increased and the redness decreased when compared with immediately after applying the cosmetics. The area before and after the colored cosmetics smeared onto the mask was increased.

Conclusion: It is expected that this study could be used as a reference for further experiments on analysis of methods for preventing mask stains.
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http://dx.doi.org/10.1111/srt.13056DOI Listing
May 2021

The Role of Consecutive Plasma Copeptin Levels in the Screening of Delayed Cerebral Ischemia in Poor-Grade Subarachnoid Hemorrhage.

Life (Basel) 2021 Mar 25;11(4). Epub 2021 Mar 25.

Genetic and Research Inc., Chuncheon 24252, Korea.

The prognostic value of copeptin in subarachnoid hemorrhage (SAH) has been reported, but the prognosis was largely affected by the initial clinical severity. Thus, the previous studies are not very useful in predicting delayed cerebral ischemia (DCI) in poor-grade SAH patients. Here, we first investigated the feasibility of predicting DCI in poor-grade SAH based on consecutive measurements of plasma copeptin. We measured copeptin levels of 86 patients on days 1, 3, 5, 7, 9, 11, and 13 using ELISA. The primary outcome was the association between consecutive copeptin levels and DCI development. The secondary outcomes were comparison of copeptin with C-reactive protein (CRP) in predicting DCI. Additionally, we compared the prognostic value of transcranial Doppler ultrasonography (TCD) with copeptin using TCD alone to predict DCI. Increased copeptin (OR = 1.022, 95% CI: 1.008-1.037) and modified Fisher scale IV (OR = 2.841; 95% CI: 0.998-8.084) were closely related to DCI. Consecutive plasma copeptin measurements showed significant differences between DCI and non-DCI groups ( < 0.001). Higher CRP and DCI appeared to show a correlation, but it was not statistically significant. Analysis of copeptin changes with TCD appeared to predict DCI better than TCD alone with AUCROC differences of 0.072. Consecutive measurements of plasma copeptin levels facilitate the screening of DCI in poor-grade SAH patients.
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http://dx.doi.org/10.3390/life11040274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066417PMC
March 2021

Association of Inflammatory Metabolic Activity of Psoas Muscle and Acute Myocardial Infarction: A Preliminary Observational Study with F-FDG PET/CT.

Diagnostics (Basel) 2021 Mar 13;11(3). Epub 2021 Mar 13.

Department of Nuclear Medicine, Korea University Anam Hospital, Seoul 02841, Korea.

Inflamed skeletal muscle promotes chronic inflammation in atherosclerotic plaques, thereby contributing to the increased risk of coronary artery disease (CAD). In this study, we evaluated the metabolic activity of psoas muscle, using F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), and its association with carotid artery inflammation and acute myocardial infarction (AMI). In total, 90 participants (32 AMI, 33 chronic stable angina (CSA), and 25 control) were enrolled in this prospective study. Metabolic activity of skeletal muscle (SM) was measured by using maximum standardized uptake value (SUVmax) of psoas muscle, and corresponding psoas muscle area (SM area) was also measured. Carotid artery inflammation was evaluated by using the target-to background ratio (TBR) of carotid artery. SM SUVmax was highest in AMI, intermediate in CSA, and lowest in control group. SM SUVmax was significantly correlated with carotid artery TBR and systemic inflammatory surrogate markers. Furthermore, SM SUVmax was independently associated with carotid artery TBR and showed better predictability than SM area for the prediction of AMI. Metabolic activity of psoas muscle assessed by F-FDG PET/CT was associated with coronary plaque vulnerability and synchronized with the carotid artery inflammation in the participants with CAD. Furthermore, it may also be useful to predict AMI.
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http://dx.doi.org/10.3390/diagnostics11030511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999462PMC
March 2021

Changes in skin wrinkles and pores due to long-term mask wear.

Skin Res Technol 2021 Feb 27. Epub 2021 Feb 27.

Skin Clinical Trials Center, OATC Inc., Seoul, Korea.

Background: The spread of COVID-19 has made mask wear essential. Expecting that long-term mask wear would change the characteristics of skin, this study investigated changes in skin wrinkles and pores caused by long-term mask wear and whether or not use of moisturizers has an effect on any changes.

Materials And Methods: The study participants were 20 women who were instructed to wear a mask for at least 6 hours a day for 4 weeks. Measurements of skin wrinkles and pores were obtained before and after the 4 weeks of mask wear. The effects of application of a moisturizer were assessed by applying moisturizer within the mask-wearing area. They completed a questionnaire about skin changes at the end of the study period.

Results: After wearing the mask for 4 weeks, there was a significant increase in the skin wrinkles and pores; both variables decreased significantly in skin areas where a moisturizer had been applied. The results of the questionnaire-based survey indicated the study participants considered that long-term wearing of a mask had affected their skin.

Conclusion: Wearing a mask for extended periods increases skin wrinkles and pores and using a moisturizer when wearing the mask helps to reduce this problem.
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http://dx.doi.org/10.1111/srt.13019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014490PMC
February 2021

Effect of Exercise on Inflamed Psoas Muscle in Women with Obesity: A Pilot Prospective F-FDG PET/CT Study.

Diagnostics (Basel) 2021 Jan 24;11(2). Epub 2021 Jan 24.

Department of Nuclear Medicine, Korea University Anam Hospital, Seoul 02841, Korea.

Obesity increases inflammation in skeletal muscle thereby promoting systemic inflammation which leads to increased risk of cardiometabolic disease. This prospective study aimed to evaluate whether the metabolic activity of psoas muscle (PM) was associated with systemic inflammation, and whether physical exercise could reduce the PM metabolic activity evaluated by F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in women with obesity. A total of 23 women with obesity who participated in a 3-month physical exercise program were enrolled. F-FDG PET/CT was performed before the start of the program (baseline) and after completion of the program. The maximum standardized uptake value of psoas muscle (PM SUVmax) was used for the PM metabolic activity. The SUVmax of spleen and bone marrow, and the high-sensitivity C-reactive protein were used to evaluate the systemic inflammation. At baseline, PM SUVmax was strongly correlated with the systemic inflammation. The exercise program significantly reduced the PM SUVmax, in addition to adiposity and systemic inflammation. Furthermore, we found that the association between PM SUVmax and the systemic inflammation disappeared after completion of the exercise program. In women with obesity, PM SUVmax, assessed by F-FDG PET/CT, was associated with obesity-induced systemic inflammation and exercise reduced the PM SUVmax and eliminated its association with systemic inflammation.
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http://dx.doi.org/10.3390/diagnostics11020164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912214PMC
January 2021

Creation of bladder assembloids mimicking tissue regeneration and cancer.

Nature 2020 Dec 16;588(7839):664-669. Epub 2020 Dec 16.

Department of Life Sciences, Pohang University of Science and Technology, Pohang, South Korea.

Current organoid models are limited by their inability to mimic mature organ architecture and associated tissue microenvironments. Here we create multilayer bladder 'assembloids' by reconstituting tissue stem cells with stromal components to represent an organized architecture with an epithelium surrounding stroma and an outer muscle layer. These assembloids exhibit characteristics of mature adult bladders in cell composition and gene expression at the single-cell transcriptome level, and recapitulate in vivo tissue dynamics of regenerative responses to injury. We also develop malignant counterpart tumour assembloids to recapitulate the in vivo pathophysiological features of urothelial carcinoma. Using the genetically manipulated tumour-assembloid platform, we identify tumoural FOXA1, induced by stromal bone morphogenetic protein (BMP), as a master pioneer factor that drives enhancer reprogramming for the determination of tumour phenotype, suggesting the importance of the FOXA1-BMP-hedgehog signalling feedback axis between tumour and stroma in the control of tumour plasticity.
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http://dx.doi.org/10.1038/s41586-020-3034-xDOI Listing
December 2020

Association of glucose uptake of visceral fat and acute myocardial infarction: a pilot F-FDG PET/CT study.

Cardiovasc Diabetol 2020 09 24;19(1):145. Epub 2020 Sep 24.

Department of Nuclear Medicine, Korea University Anam Hospital, 73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.

Background: Inflamed visceral adipose tissue (VAT) facilitates chronic inflammation in atherosclerotic lesions thereby leading to increased risk of coronary artery disease (CAD). In this study, we evaluated the glucose uptake of VAT and the carotid artery with F-fluorodeoxyglucose positron emission tomography (F-FDG PET/CT) and their association with CAD, including acute myocardial infarction (AMI).

Methods: A total of 90 participants were enrolled (32 with AMI, 33 with chronic stable angina; CSA, and 25 control participants) and undertook F-FDG PET/CT. VAT glucose uptake was measured by using maximum standardized uptake value (SUVmax) of VAT region. The target-to-background ratio (TBR) of carotid artery was defined as the SUVmax of carotid artery divided by the SUVmax of jugular vein. The SUVmax of spleen, bone-marrow (BM), and high-sensitivity C-reactive protein (hsCRP) were used for the assessment of systemic inflammatory activity.

Results: VAT SUVmax was highest in participants with AMI, intermediate in participants with CSA, and lowest in control participants. Carotid artery TBR and systemic inflammatory surrogate markers including spleen SUVmax, BM SUVmax, and hsCRP were also higher in the AMI group than in the CSA or control group. Furthermore, VAT SUVmax showed significant positive correlation with carotid artery TBR, spleen SUVmax, BM SUVmax, and hsCRP. In multivariate linear regression and logistic regression analyses, VAT SUVmax was independently associated with carotid artery TBR and AMI.

Conclusions: Glucose uptake of VAT assessed by F-FDG PET/CT was associated with the severity of CAD and synchronized with the carotid artery inflammation in participants with CAD.
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http://dx.doi.org/10.1186/s12933-020-01115-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517810PMC
September 2020

Genome-wide transcriptome analysis identifies novel dysregulated genes implicated in Alzheimer's pathology.

Alzheimers Dement 2020 09 5;16(9):1213-1223. Epub 2020 Aug 5.

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.

Introduction: Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer's disease (LOAD).

Methods: We performed transcriptome-wide meta-analysis (N = 1440) of blood-based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis.

Results: We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aβ) accumulation, especially in the entorhinal cortex region. cis-expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10 ), where rs56388170 (most significant) was also significantly associated with global cortical Aβ deposition measured by [ F]Florbetapir positron emission tomography and CSF Aβ .

Discussion: RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.
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http://dx.doi.org/10.1002/alz.12092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541709PMC
September 2020

Visceral fat metabolic activity evaluated by F-FDG PET/CT is associated with osteoporosis in healthy postmenopausal Korean women.

Obes Res Clin Pract 2020 Jul - Aug;14(4):339-344. Epub 2020 Jun 17.

Department of Nuclear Medicine, Korea University Anam Hospital, Seoul, Republic of Korea. Electronic address:

Background: Traditionally, obesity has been regarded as protective against osteoporosis. However, recent accumulating evidences suggest that visceral obesity can increase the risk of osteoporosis and obesity-driven dysfunctional metabolic activity in visceral adipose tissue (VAT) is considered as a key underlying mechanism. Visceral obesity is known to increase during menopausal transition.F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) is an established method to assess the degree of VAT metabolic activity. We aimed to investigate the association between VAT metabolic activity evaluated by F-FDG PET/CT and osteoporosis in healthy postmenopausal Korean women.

Methods: A total of 115 postmenopausal women who underwent routine health check-up were enrolled in this study, retrospectively. They all underwent dual-energy X-ray absorptiometry and F-FDG PET/CT. Osteoporosis was defined as bone mineral density (BMD) T-score ≤ -2.5 at either lumbar spine or femoral neck. VAT metabolic activity was defined as the maximum standardized uptake value (SUVmax) of VAT divided by the SUVmax of subcutaneous adipose tissue (V/S ratio).

Results: The participants with osteoporosis showed significantly higher V/S ratio, age, body mass index, waist circumference, and postmenopausal period than the participants without osteoporosis. V/S ratio of 1.33 was proposed as an optimal cut-off value for identifying osteoporosis. Furthermore, V/S ratio was the most significant predictive factor for osteoporosis in postmenopausal woman by uni-and multivariate analyses. Interestingly, V/S ratio showed significant positive correlation with high sensitivity C-reactive protein, a surrogate marker for systemic inflammation.

Conclusion: VAT metabolic activity assessed by F-FDG PET/CT is associated with osteoporosis in healthy postmenopausal Korean women.
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http://dx.doi.org/10.1016/j.orcp.2020.05.008DOI Listing
August 2021

Harnessing peripheral DNA methylation differences in the Alzheimer's Disease Neuroimaging Initiative (ADNI) to reveal novel biomarkers of disease.

Clin Epigenetics 2020 06 15;12(1):84. Epub 2020 Jun 15.

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease impacting an estimated 44 million adults worldwide. The causal pathology of AD (accumulation of amyloid-beta and tau), precedes hallmark symptoms of dementia by more than a decade, necessitating development of early diagnostic markers of disease onset, particularly for new drugs that aim to modify disease processes. To evaluate differentially methylated positions (DMPs) as novel blood-based biomarkers of AD, we used a subset of 653 individuals with peripheral blood (PB) samples in the Alzheimer's disease Neuroimaging Initiative (ADNI) consortium. The selected cohort of AD, mild cognitive impairment (MCI), and age-matched healthy controls (CN) all had imaging, genetics, transcriptomics, cerebrospinal protein markers, and comprehensive clinical records, providing a rich resource of concurrent multi-omics and phenotypic information on a well-phenotyped subset of ADNI participants.

Results: In this manuscript, we report cross-diagnosis differential peripheral DNA methylation in a cohort of AD, MCI, and age-matched CN individuals with longitudinal DNA methylation measurements. Epigenome-wide association studies (EWAS) were performed using a mixed model with repeated measures over time with a P value cutoff of 1 × 10 to test contrasts of pairwise differential peripheral methylation in AD vs CN, AD vs MCI, and MCI vs CN. The most highly significant differentially methylated loci also tracked with Mini Mental State Examination (MMSE) scores. Differentially methylated loci were enriched near brain and neurodegeneration-related genes (e.g., BDNF, BIN1, APOC1) validated using the genotype tissue expression project portal (GTex).

Conclusions: Our work shows that peripheral differential methylation between age-matched subjects with AD relative to healthy controls will provide opportunities to further investigate and validate differential methylation as a surrogate of disease. Given the inaccessibility of brain tissue, the PB-associated methylation marks may help identify the stage of disease and progression phenotype, information that would be central to bringing forward successful drugs for AD.
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http://dx.doi.org/10.1186/s13148-020-00864-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294637PMC
June 2020

Use of inkjet-printed single cells to quantify intratumoral heterogeneity.

Biofabrication 2020 07 1;12(3):035030. Epub 2020 Jul 1.

Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.

Quantification of intratumoral heterogeneity is essential for designing effective therapeutic strategies in the age of personalized medicine. In this study, we used a piezoelectric inkjet printer to enable analysis of intratumoral heterogeneity in a bladder cancer for the first time. Patient-derived tumor organoids were dissociated into single cell suspension and used as a bioink. The individual cells were precisely allocated into a microwell plate by drop-on-demand inkjet printing without any additive or treatment, followed by culturing into organoids for further analysis. The sizes and morphologies of the organoids were observed, so as the expression of proliferation and apoptotic markers. The tumor organoids also showed heterogeneous responses against chemotherapeutic agent. Further, we quantified mRNA expression levels of representative luminal and basal genes in both type of tumor organoids. These results verify the heterogeneous expression of various genes among individual organoids. This study demonstrates that the fully automated inkjet printing technique can be used as an effective tool to sort cells for evaluating intratumoral heterogeneity.
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http://dx.doi.org/10.1088/1758-5090/ab9491DOI Listing
July 2020

Exercise training reduces inflammatory metabolic activity of visceral fat assessed by F-FDG PET/CT in obese women.

Clin Endocrinol (Oxf) 2020 08 1;93(2):127-134. Epub 2020 Jun 1.

Department of Nuclear Medicine, Korea University Anam Hospital, Seoul, Korea.

Objectives: Obesity plays pivotal roles in the increased risk of cardiometabolic disease via induction of the inflammatory reaction from macrophages in visceral adipose tissue (VAT), which may elevate the inflammatory activity of VAT. This prospective study aimed to evaluate whether the inflammatory activity of VAT existed in association with systemic inflammation, and whether exercise could ameliorate the inflammatory activity of VAT assessed by F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in obese women.

Design And Patients: A total of 23 obese women who participated in an exercise program were included. Subjects underwent F-FDG PET/CT before the start of the exercise program (baseline) and after the completion of the 3-month exercise program. For the assessment of VAT metabolic activity, the maximum standardized uptake value (SUVmax) and the mean standardized uptake value (SUVmean) were measured. The SUVmax of spleen, bone marrow (BM) and the high-sensitivity C-reactive protein (hsCRP) were used as a surrogate marker for systemic inflammation.

Results: Baseline SUVmax of VAT was positively correlated with the SUVmax of spleen, BM and hsCRP, whereas VAT SUVmean was not correlated. Exercise reduced SUVmax of VAT in addition to adiposity, the SUVmax of spleen, BM and hsCRP. However, VAT SUVmean was not significantly changed. Furthermore, the association of SUVmax of VAT, and the SUVmax of spleen, BM and hsCRP was no longer relevant after exercise.

Conclusion: In obese women, the SUVmax of VAT assessed by F-FDG PET/CT was associated with systemic inflammation and exercise reduced the SUVmax of VAT and abrogated its association with systemic inflammation.
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http://dx.doi.org/10.1111/cen.14216DOI Listing
August 2020

Blepharoptosis among Korean adults: age-related prevalence and threshold age for evaluation.

BMC Ophthalmol 2020 Mar 13;20(1):99. Epub 2020 Mar 13.

Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-Gu, Seoul, 137-701, South Korea.

Background: To evaluate the prevalence of blepharoptosis among Korean adults and the characteristics of blepharoptosis patients, and to determine an appropriate age threshold for recommending blepharoptosis evaluation.

Methods: The Korean National Health and Nutrition Examination Survey (KNHANES-V) was conducted in 2010-2012. We extracted data on 17,878 Korean adults aged more than and equal to 19 years included in KNHANES-V, and determined blepharoptosis prevalence according to age, to determine the cutoff age for recommending blepharoptosis evaluation. We also determined the possible association between blepharoptosis and obesity parameters, such as body mass index (BMI) and waist circumference (WC).

Results: There was astrong association between older age and the prevalence of blepharoptosis. The cutoff age for recommending blepharoptosis evaluation was 63 years for males, 70 years for females, and 66 years for all patients. Patients with a high BMI and large WC had a higher prevalence of blepharoptosis in all age groups except for those aged over 80 years. The association of blepharoptosis with BMI according to age group showed that in the 50-59 and 60-69 years age groups, blepharoptosis prevalence and BMI were higher. However, in the 70-79 and 80-89 years age groups, extremely obese patients (BMI > 30) showed a decreased blepharoptosis prevalence.

Conclusions: Moderate to severe blepharoptosis can result in poor visual function and exacerbate headaches and depression, leading to decreased quality of life. This study proposed an appropriate age threshold for recommending evaluation of patients with blepharoptosis among the general population of Korea.
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http://dx.doi.org/10.1186/s12886-020-01350-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071706PMC
March 2020

Exosomes from Human Adipose Tissue-Derived Mesenchymal Stem Cells Promote Epidermal Barrier Repair by Inducing de Novo Synthesis of Ceramides in Atopic Dermatitis.

Cells 2020 03 10;9(3). Epub 2020 Mar 10.

ExoCoBio Exosome Institute (EEI), ExoCoBio Inc., Seoul 08594, Korea.

Atopic dermatitis (AD) is a multifactorial, heterogeneous disease associated with epidermal barrier disruption and intense systemic inflammation. Previously, we showed that exosomes derived from human adipose tissue-derived mesenchymal stem cells (ASC-exosomes) attenuate AD-like symptoms by reducing multiple inflammatory cytokine levels. Here, we investigated ASC-exosomes' effects on skin barrier restoration by analyzing protein and lipid contents. We found that subcutaneous injection of ASC-exosomes in an oxazolone-induced dermatitis model remarkably reduced trans-epidermal water loss, while enhancing stratum corneum (SC) hydration and markedly decreasing the levels of inflammatory cytokines such as IL-4, IL-5, IL-13, TNF-α, IFN-γ, IL-17, and TSLP, all in a dose-dependent manner. Interestingly, ASC-exosomes induced the production of ceramides and dihydroceramides. Electron microscopic analysis revealed enhanced epidermal lamellar bodies and formation of lamellar layer at the interface of the SC and stratum granulosum with ASC-exosomes treatment. Deep RNA sequencing analysis of skin lesions demonstrated that ASC-exosomes restores the expression of genes involved in skin barrier, lipid metabolism, cell cycle, and inflammatory response in the diseased area. Collectively, our results suggest that ASC-exosomes effectively restore epidermal barrier functions in AD by facilitating the de novo synthesis of ceramides, resulting in a promising cell-free therapeutic option for treating AD.
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http://dx.doi.org/10.3390/cells9030680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140723PMC
March 2020

Histologic Lesions of Porto-Sinusoidal Vascular Disease Following Phlebotomy in Hemochromatosis.

Gastroenterology Res 2020 Feb 1;13(1):32-39. Epub 2020 Feb 1.

Anatomic Pathology, Albany Medical College, Albany, NY, USA.

Background: Phlebotomy induces regression of liver fibrosis in genetic hemochromatosis. We assessed the histologic changes in pre-phlebotomy and post-phlebotomy liver biopsies from patients with mutation as a model to study regression of fibrosis. We aimed to show that phlebotomy-induced histologic lesions overlap with porto-sinusoidal vascular disease (PSVD, also known as idiopathic non-cirrhotic portal hypertension), histologically.

Methods: A total of 51 biopsies (22 pre-phlebotomy and 29 post-phlebotomy) were reviewed, and three variables were studied: iron index indicative of the amount of accumulated iron (range 0 to 18), the combined score of vascular changes reflecting the presence of histological lesions that are described in PSVD (range 0 to 9) and the high-grade shunt vessel by calculating the proportion of portal tracts with shunt vessels, with a cutoff of 50%. Two-tailed Student's -test and Fisher's exact test were performed to compare the means of two variables and frequencies of the histologic lesions in two groups, respectively. A P-value < 0.05 was considered statistically significant.

Results: The iron index was higher in the pre-phlebotomy compared to post-phlebotomy group (P = 0.01). Compared to the pre-phlebotomy group, the combined score was higher in the post-phlebotomy group when the cases of advanced fibrosis were excluded (P = 0.023) and remained higher when patients with risk factors for PSVD were further excluded (P = 0.034). The high-grade shunt vessel tended to be more common in the post-phlebotomy group when advanced fibrosis was excluded; however, the statistical significance was marginal (P = 0.056).

Conclusions: Phlebotomy reduces hepatic iron load and induces histologic lesions of PSVD in patients with mutation. Our data support a postulation that some of the histologic lesions of PSVD represent vascular remodeling following a regression of fibrosis and may not be reflective of risk factors or etiopathogenesis of PSVD. Regressed fibrosis and PSVD may not be reliably distinguished in a limited sample, therefore warranting cautious interpretation in the right clinical context.
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http://dx.doi.org/10.14740/gr1236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011912PMC
February 2020

Culture, Manipulation, and Orthotopic Transplantation of Mouse Bladder Tumor Organoids.

J Vis Exp 2020 01 31(155). Epub 2020 Jan 31.

Department of Life Sciences, Pohang University of Science and Technology;

The development of advanced tumor models has long been encouraged because current cancer models have shown limitations such as lack of three-dimensional (3D) tumor architecture and low relevance to human cancer. Researchers have recently developed a 3D in vitro cancer model referred to as tumor organoids that can mimic the characteristics of a native tumor in a culture dish. Here, experimental procedures are described in detail for the establishment of bladder tumor organoids from a carcinogen-induced murine bladder tumor, including culture, passage, and maintenance of the resulting 3D tumor organoids in vitro. In addition, protocols to manipulate the established bladder tumor organoid lines for genetic engineering using lentivirus-mediated transduction are described, including optimized conditions for the efficient introduction of new genetic elements into tumor organoids. Finally, the procedure for orthotopic transplantation of bladder tumor organoids into the wall of the murine bladder for further analysis is laid out. The methods described in this article can facilitate the establishment of an in vitro model for bladder cancer for the development of better therapeutic options.
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http://dx.doi.org/10.3791/60469DOI Listing
January 2020

Characterization of glucose uptake metabolism in visceral fat by 18 F-FDG PET/CT reflects inflammatory status in metabolic syndrome.

PLoS One 2020 6;15(2):e0228602. Epub 2020 Feb 6.

Cardiovascular Center, Korea University Guro Hospital, Seoul, Republic of Korea.

Objective: The inflammatory activity of visceral adipose tissue (VAT) is elevated in metabolic syndrome (MS), and associated with vulnerability to atherosclerosis. Inflammation can be assessed by glucose uptake in atherosclerotic plaques. We investigated whether the glucose uptake of VAT, assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), is associated with systemic inflammatory status, and related to the number of MS components.

Methods: 18F-FDG PET/CT was performed in a total of 203 participants: 59 without MS component; M(0), 92 with one or two MS components; M(1-2), and 52 with MS. Glucose uptake in VAT was evaluated using the mean standardized uptake value (SUVmean) and the maximum SUV (SUVmax). Glucose uptakes of immune-related organs such as the spleen and bone marrow (BM) were evaluated using the SUVmax.

Results: VAT SUVmax correlated with high-sensitivity C-reactive protein (hsCRP) and the SUVmax of spleen and BM, which reflect the status of systemic inflammation. Both hsCRP and the SUVmax of the spleen and BM were higher in the MS group than in the M(1-2) or M(0) groups. In VAT, SUVmax increased with increasing number of MS components, while SUVmean decreased.

Conclusions: The SUVmax and SUVmean of VAT assessed by 18F-FDG PET/CT reflected inflammation-driven unique glucose metabolism in the VAT of MS patients, distinct from that of atherosclerotic plaques.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228602PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004347PMC
May 2020

Visceral fat metabolic activity evaluated by preoperative F-FDG PET/CT significantly affects axillary lymph node metastasis in postmenopausal luminal breast cancer.

Sci Rep 2020 Jan 28;10(1):1348. Epub 2020 Jan 28.

Department of Nuclear Medicine, Korea University Anam Hospital, Seoul, Republic of Korea.

Obesity is known to increase breast cancer risk and aggressiveness in postmenopausal luminal breast cancer and obesity-driven dysfunctional metabolic activity in visceral adipose tissue (VAT) is considered as one of the principal underlying mechanism. We aimed to investigate the relationship between VAT metabolic activity evaluated by preoperative F-FDG PET/CT and axillary lymph node (ALN) metastasis in postmenopausal luminal breast cancer patients. In total, 173 patients were enrolled in study. They all underwent preoperative F-FDG PET/CT and surgery. VAT metabolic activity was defined as the maximum standardized uptake value (SUVmax) of VAT divided by the SUVmax of subcutaneous adipose tissue (V/S ratio). In luminal breast cancer, the patients with ALN metastasis showed significantly higher V/S ratio than the patients without ALN metastasis. Furthermore, V/S ratio was significantly associated with ALN metastasis in luminal breast cancer patients. Erythrocyte sedimentation rate, which reflect the systemic inflammation, was significantly higher in ALN metastasis group than the negative ALN metastasis group in luminal breast cancer patients and showed significant positive correlation with V/S ratio. V/S ratio significantly affects the ALN metastasis status in postmenopausal luminal breast cancer patients and it may be useful as a potential biomarker of obesity-driven systemic inflammation associated with tumor aggressiveness.
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http://dx.doi.org/10.1038/s41598-020-57937-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987196PMC
January 2020

Activation of SIRT1 Enhances Epidermal Permeability Barrier Formation through Ceramide Synthase 2- and 3-Dependent Mechanisms.

J Invest Dermatol 2020 07 17;140(7):1435-1438.e5. Epub 2020 Jan 17.

Department of Food Science & Nutrition, and Convergence Program of Material Science for Medicine and Pharmaceutics, Hallym University, Chuncheon, Korea; Korean Institute of Nutrition, Hallym University, Chuncheon, Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.12.021DOI Listing
July 2020

SP-8356, a Novel Inhibitor of CD147-Cyclophilin A Interactions, Reduces Plaque Progression and Stabilizes Vulnerable Plaques in apoE-Deficient Mice.

Int J Mol Sci 2019 Dec 21;21(1). Epub 2019 Dec 21.

Institute for Inflammation Control, Korea University, Seoul 02841, Korea.

Interactions between CD147 and cyclophilin A (CypA) promote plaque rupture that causes atherosclerosis-related cardiovascular events, such as myocardial infarction and stroke. Here, we investigated whether SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one), a novel drug, can exert therapeutic effects against plaque progression and instability through disruption of CD147-CypA interactions in apolipoprotein E-deficient (ApoE KO) mice. Immunocytochemistry and immunoprecipitation analyses were performed to assess the effects of SP-8356 on CD147-CypA interactions. Advanced plaques were induced in ApoE KO mice via partial ligation of the right carotid artery coupled with an atherogenic diet, and SP-8356 (50 mg/kg) orally administrated daily one day after carotid artery ligation for three weeks. The anti-atherosclerotic effect of SP-8356 was assessed using histological and molecular approaches. SP-8356 interfered with CD147-CypA interactions and attenuated matrix metalloproteinase-9 activation. Moreover, SP-8356 induced a decreased in atherosclerotic plaque size in ApoE KO mice and stabilized plaque vulnerability by reducing the necrotic lipid core, suppressing macrophage infiltration, and enhancing fibrous cap thickness through increasing the content of vascular smooth muscle cells. SP-8356 exerts remarkable anti-atherosclerotic effects by suppressing plaque development and improving plaque stability through inhibiting CD147-CypA interactions. Our novel findings support the potential utility of SP-8356 as a therapeutic agent for atherosclerotic plaque.
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http://dx.doi.org/10.3390/ijms21010095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981359PMC
December 2019

Prognostic Value of Metabolic Information in Advanced Gastric Cancer Using Preoperative F-FDG PET/CT.

Nucl Med Mol Imaging 2019 Dec 18;53(6):386-395. Epub 2019 Nov 18.

1Department of Nuclear Medicine, Korea University Anam Hospital, 73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841 Republic of Korea.

Purpose: This study evaluated the usefulness of semiquantitative and volumetric PET parameters for predicting prognosis in patients with advanced gastric cancer (AGC).

Methods: We enrolled 213 patients who underwent F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) prior to curative surgery for AGC. Maximum standardized uptake value (SUVmax) and tumor-to-liver uptake ratio (TLR) were measured in all patients. Metabolic tumor volume (MTV) and total lesion glycolysis were measured in volume-measurable patients. For further quantification of FDG uptake, we developed PET prognostic scores by combining SUVmax and MTV (1: low SUVmax/low MTV; 2: high SUVmax/low MTV; 3: high SUVmax/high MTV). Comparison of PET parameters between recurrence and non-recurrence groups was performed. Univariate and multivariate analyses for recurrence-free survival (RFS) and overall survival (OS) were subsequently performed.

Results: The recurrence rate was 32.4% (69/213 patients). Mean SUVmax and mean MTV of the recurrence group were significantly higher than those of the non-recurrence group ( = 0.026 and = 0.025). TLR showed marginal significance ( = 0.051). In multivariate analysis for RFS including all patients, SUVmax ( = 0.022), TLR ( = 0.010), and PET score ( = 0.003) were independent prognostic factors. In post hoc analysis of PET score, significant differences in RFS were observed between PET scores 2 and 3 as well as scores 1 and 3. No significant difference in RFS was observed between scores 1 and 2. Only PET score was statistically significant for OS in univariate analysis. None of the PET parameters were statistically significant for OS in multivariate analysis.

Conclusion: High SUVmax and high MTV of the primary tumor suggest a high risk of recurrence for AGC patients. Even if SUVmax is similar, the prognosis may vary depending on MTV. Combining PET parameters results in a better prediction for prognosis.
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http://dx.doi.org/10.1007/s13139-019-00622-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898707PMC
December 2019

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

Mol Psychiatry 2019 Dec 6. Epub 2019 Dec 6.

University Medical Centre Hamburg-Eppendorf, House W34, 3.OG, Martinistr. 52, 20246, Hamburg, Germany.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
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http://dx.doi.org/10.1038/s41380-019-0605-zDOI Listing
December 2019

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019

A novel CD147 inhibitor, SP-8356, reduces neointimal hyperplasia and arterial stiffness in a rat model of partial carotid artery ligation.

J Transl Med 2019 08 20;17(1):274. Epub 2019 Aug 20.

Institute for Inflammation Control, Korea University, Seoul, South Korea.

Background: Neointimal hyperplasia and its related arterial stiffness are the crucial pathophysiological features in atherosclerosis and in-stent restenosis. Cluster of differentiation 147 (CD147), a member of the immunoglobulin super family that induces the expression of matrix metalloproteinase-9 (MMP-9) by dimerization, may play important roles in neointimal hyperplasia and may therefore be an effective target for the treatment of this condition. Here, we investigated whether a novel CD147 inhibitor SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) reduces neointimal hyperplasia and arterial stiffness in a rat model of partial carotid artery ligation.

Methods: Neointimal hyperplasia was induced in Sprague-Dawley rats by partial ligation of the right carotid artery combined with a high fat diet and vitamin D injection. Rats were subdivided into vehicle, SP-8356 (50 mg/kg), and rosuvastatin (10 mg/kg) groups. The drugs were administrated via intraperitoneal injections for 4 weeks. The elasticity of blood vessels was assessed by measuring pulse wave velocity using Doppler ultrasonography before sacrifice. Histomolecular analysis was carried out on harvested carotid arteries.

Results: SP-8356 significantly reduced MMP activity by inhibiting CD147 dimerization. SP-8356 reduced neointimal hyperplasia and prevented the deterioration of vascular elasticity. SP-8356 had a greater inhibitory effect on neointimal hyperplasia than did rosuvastatin. Furthermore, rosuvastatin did not improve vascular elasticity. SP-8356 increased the expression of smooth muscle myosin heavy chain (SM-MHC), but decreased the expression of collagen type III and MMP-9 in the neointimal region. In contrast to SP-8356, rosuvastatin did not alter the expression of SM-MHC or MMP-9.

Conclusions: The ability of SP-8356 to reduce neointimal hyperplasia and improve arterial stiffness in affected carotid artery suggests that SP-8356 could be a promising therapeutic drug for vascular remodeling disorders involving neointimal hyperplasia and arterial stiffness.
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http://dx.doi.org/10.1186/s12967-019-2024-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700999PMC
August 2019
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