RAR‐Related Orphan Receptor Gamma (ROR‐γ) Mediates Epithelial‐Mesenchymal Transition Of Hepatocytes During Hepatic Fibrosis

Kim, Sung Min,Choi, Jung Eun,Hur, Wonhee,Kim, Jung&#x2010,Hee,Hong, Sung Woo,Lee, Eun Byul,Lee, Joon Ho,Li, Tian Zhu,Sung, Pil Soo,Yoon, Seung Kew John Wiley and Sons Inc. 2017 Journal of cellular biochemistry Vol.118 No.8

<P><B>ABSTRACT</B></P><P>The epithelial‐mesenchymal transition (EMT) is involved in many different types of cellular behavior, including liver fibrosis. In this report, we studied a novel function of RAR‐related orphan receptor gamma (ROR‐γ) in hepatocyte EMT during liver fibrosis. To induce EMT in vitro, primary hepatocytes and FL83B cells were treated with TGF‐β1. Expression of ROR‐γ was analyzed by Western blot in the fibrotic mouse livers and human livers with cirrhosis. To verify the role of ROR‐γ in hepatocyte EMT, we silenced ROR‐γ in FL83B cells using a lentiviral short hairpin RNA (shRNA) vector. The therapeutic effect of ROR‐γ silencing was investigated in a mouse model of TAA‐induced fibrosis by hydrodynamic injection of plasmids. ROR‐γ expression was elevated in hepatocyte cells treated with TGF‐β1, and ROR‐γ protein levels were elevated in the fibrotic mouse livers and human livers with cirrhosis. Knockdown of ROR‐γ resulted in the attenuation of TGF‐β1‐induced EMT in hepatocytes. Strikingly, ROR‐γ bound to ROR‐specific DNA response elements (ROREs) in the promoter region of TGF‐β type I receptor (Tgfbr1) and Smad2, resulting in the downregulation of Tgfbr1 and Smad2 after silencing of ROR‐γ. Therapeutic delivery of shRNA against ROR‐γ attenuated hepatocyte EMT and ameliorated liver fibrosis in a mouse model of TAA‐induced liver fibrosis. Overall, our results suggest that ROR‐γ regulates TGF‐β‐induced EMT in hepatocytes during liver fibrosis. We suggest that ROR‐γ may become a potential therapeutic target in treating liver fibrosis. J. Cell. Biochem. 118: 2026–2036, 2017. © 2016 The Authors. <I>Journal of Cellular Biochemistry</I> Published by Wiley Periodicals Inc.</P>

Development of real‐time motion verification system using in‐room optical images for respiratory‐gated radiotherapy

Park, Yang&#x2010,Kyun,Son, Tae&#x2010,geun,Kim, Hwiyoung,Lee, Jaegi,Sung, Wonmo,Kim, Il Han,Lee, Kunwoo,Bang, Young&#x2010,bong,Ye, Sung‐,Joon John Wiley and Sons Inc. 2013 Journal of applied clinical medical physics Vol.14 No.5

<P>Phase‐based respiratory‐gated radiotherapy relies on the reproducibility of patient breathing during the treatment. To monitor the positional reproducibility of patient breathing against a 4D CT simulation, we developed a real‐time motion verification system (RMVS) using an optical tracking technology. The system in the treatment room was integrated with a real‐time position management system. To test the system, an anthropomorphic phantom that was mounted on a motion platform moved on a programmed breathing pattern and then underwent a 4D CT simulation with RPM. The phase‐resolved anterior surface lines were extracted from the 4D CT data to constitute 4D reference lines. In the treatment room, three infrared reflective markers were attached on the superior, middle, and inferior parts of the phantom along with the body midline and then RMVS could track those markers using an optical camera system. The real‐time phase information extracted from RPM was delivered to RMVS via in‐house network software. Thus, the real‐time anterior‐posterior positions of the markers were simultaneously compared with the 4D reference lines. The technical feasibility of RMVS was evaluated by repeating the above procedure under several scenarios such as ideal case (with identical motion parameters between simulation and treatment), cycle change, baseline shift, displacement change, and breathing type changes (abdominal or chest breathing). The system capability for operating under irregular breathing was also investigated using real patient data. The evaluation results showed that RMVS has a competence to detect phase‐matching errors between patient's motion during the treatment and 4D CT simulation. Thus, we concluded that RMVS could be used as an online quality assurance tool for phase‐based gating treatments.</P><P>PACS number: 87.55.Qr</P>

Methiozolin [5‐(2,6‐difluorobenzyl)oxymethyl‐5‐methyl‐3,3(3‐methylthiophen‐2‐yl)‐1,2‐isoxazoline], a new annual bluegrass (<i>Poa annua</i> L.) herbicide for turfgrasses

Koo, Suk&#x2010,Jin,Hwang, Ki&#x2010,Hwan,Jeon, Man&#x2010,Seok,Kim, Sung‐,Hun,Lim, Jongsoo,Lee, Dong&#x2010,Guk,Cho, Nam&#x2010,Gyu John Wiley Sons, Ltd 2014 Pest Management Science Vol.70 No.1

<P><B>Abstract</B></P><P><B>BACKGROUND</B></P><P><B>Selective control of annual bluegrass (<I>Poa annual</I> L.) has been difficult in turfgrasses. The potential of methiozolin in this area was investigated.</B></P><P><B>RESULTS</B></P><P><B>Methiozolin was safe on established zoysiagrass (<I>Zoysia japonica</I> Steud.), creeping bentgrass (<I>Agrostis palustris</I> Huds.), Kentucky bluegrass (<I>Poa pratensis</I> L.), and perennial ryegrass (<I>Lolium perenne</I> L.) at 1000 g ha<SUP>−1</SUP>, and controlled annual bluegrass with GR<SUB>50</SUB> values of 23, 52, 104, and 218 g ha<SUP>−1</SUP> at PRE, two‐, four‐ and eight‐leaf stage, respectively, in the greenhouse. When applied at early flowering, methiozolin suppressed >80% of annual bluegrass seed heads at 2000 g ha<SUP>−1</SUP>. <SUP>14</SUP>C‐Methiozolin was readily absorbed by both leaves and roots, but translocation was mainly acropetal. No herbicidal activity resulted from application to the leaf only; however, application to the soil surface only showed equivalent herbicidal activity to that of broadcast application to the leaf and soil. Methiozolin at 500 to 1000 g ha<SUP>−1</SUP> provided 80 to 100% control of annual bluegrass when applied in the fall with acceptable and temporary injury to creeping bentgrass, and about 60% control when applied in the spring with no bentgrass injury in the field.</B></P><P><B>CONCLUSION</B></P><P><B>Methiozolin is an excellent candidate for annual bluegrass management in turfgrasses. © 2013 Society of Chemical Industry</B></P>

Trend analysis of diabetic prevalence and incidence in a rural area of South Korea between 2003–2008

Jeong, Ji Yun,Kim, Jung&#x2010,Guk,Kim, Bo&#x2010,Wan,Moon, Seong Su,Kim, Hye&#x2010,Soon,Park, Keun&#x2010,Gyu,Won, Kyu Chang,Lee, Hyoung Woo,Yoon, Ji Sung,Shon, Ho&#x2010,Sang,Lee, Ji Hyun,Jung, Eui Blackwell Publishing Ltd 2010 Journal of diabetes investigation Vol.1 No.5

<P><B>Abstract</B></P><P><B>Aims/Introduction: </B> This study determined the change in prevalence of diabetes and prediabetes over a period of 5 years in South Korea. The incidence of diabetes and prediabetes and risk factors associated with the development of diabetes were also investigated.</P><P><B>Materials and Methods: </B> The Dalseong population‐based cohort survey recruited 1806 subjects who were over 20‐years‐old in 2003. Five years later, 1287 of the original subjects were re‐evaluated and 187 new subjects were added to the study. All participants completed a questionnaire, were given a physical examination, and provided blood samples for analysis including 2 h oral glucose tolerances.</P><P><B>Results: </B> Age‐adjusted prevalence of diabetes rose from 6.7% in 2003 to 9.1% in 2008. The prevalence of prediabetes also increased from 18.5% in 2003 to 28.4% in 2008. The incidence rates of diabetes and prediabetes were 18.3 per 1000 person‐years and 55.4 per 1000 person‐years, respectively. The development of diabetes was associated with impaired fasting glucose (IFG) (odds ratio [OR] 5.661), impaired glucose tolerance (IGT) (OR: 6.013), age (OR 1.013), and waist‐to‐hip ratio (OR 1.513). After excluding the IFG and IGT, systolic blood pressure (OR 1.023), high‐sensitivity C‐reactive protein (hsCRP; OR 1.097), triglyceride (OR 1.002) and waist‐to‐hip ratio (OR 1.696) were statistically significant risk factors in a multivariate logistic regression analysis.</P><P><B>Conclusions: </B> A significant rise in the prevalence of diabetes and prediabetes was observed between 2003 and 2008. In addition, this study newly demonstrated that waist‐to‐hip ratio and hsCRP were associated with the development of diabetes after adjusting for several confounding factors. <B>(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00045.x, 2010)</B></P>

Assessment of potential jaw‐tracking advantage using control point sequences of VMAT planning

Kim, Jung&#x2010,in,Park, Jong Min,Park, So&#x2010,Yeon,Choi, Chang Heon,Wu, Hong&#x2010,Gyun,Ye, Sung‐,Joon unknown 2014 Journal of applied clinical medical physics Vol.15 No.2

<P>This study aims to evaluate the potential jaw‐tracking advantage using control point sequences of volume volumetric‐modulated arc therapy (VMAT) planning. VMAT plans for patients with prostate and head and neck (H&N) cancers were converted into new static arc (SA) plans. The SA plan consisted of a series of static fields at each control point of the VMAT plan. All other machine parameters of the SA plan were perfectly identical to those of the original VMAT plan. The jaw‐tracking static arc (JTSA) plans were generated with fields that closed the jaws of each SA field into the multileaf collimators (MLCs) aperture. The dosimetric advantages of JTSA over SA were evaluated in terms of a dose‐volume histogram (DVH) of organ at risk (OAR) after renormalizing both plans to make the same target coverage. Both plans were delivered to the MatriXX‐based COMPASS system for 3D volume dose verification. The average jaw size reduction of the JTSA along the X direction was 3.1±0.9 cm for prostate patients and 6.9±1.9 cm for H&N patients. For prostate patients, the organs far from the target showed larger sparing (3.7%—8.1% on aver‐age) in JTSA than the organs adjacent to the target (1.1%—1.5%). For the H&N plans, the mean dose reductions for all organs ranged from 4.3% to 11.9%. The dose reductions were more significant in the dose regions of <SUB>D80</SUB>,<SUB>D90</SUB>, and <SUB>D95</SUB> than the dose regions of <SUB>D5</SUB>,<SUB>D10</SUB>, and <SUB>D20</SUB> for all patients. Likewise, the deliverability and reproducibility of jaw‐tracking plan were validated. The measured dosimetric advantage of JTSA over SA coincided with the calculated one above.</P><P>PACS numbers: 87.55.D‐, 87.55.ne</P>

Confidence limits for patient‐specific IMRT dose QA: a multi‐institutional study in Korea

Kim, Jung&#x2010,in,Chung, Jin&#x2010,Beom,Song, Ju&#x2010,Young,Kim, Sung Kyu,Choi, Yunseok,Choi, Chang Heon,Choi, Won Hoon,Cho, Byungchul,Kim, Jin Sung,Kim, Sung Jin,Ye, Sung‐,Joon John Wiley and Sons Inc. 2016 Journal of applied clinical medical physics Vol.17 No.1

<P>This study aims to investigate tolerance levels for patient‐specific IMRT dose QA (DQA) using the confidence limits (CL) determined by a multi‐institutional study. Eleven institutions participated in the multi‐institutional study in Korea. A total of 155 DQA measurements, consisting of point‐dose differences (high‐ and low‐dose regions) and gamma passing rates (composite and per‐field) for IMRT patients with brain, head and neck (H&N), abdomen, and prostate cancers were examined. The Shapiro‐Wilk test was used to evaluate the normality of data grouped by the treatment sites and the DQA methods. The confidence limit coefficients in cases of the normal distribution, and the two‐sided Student's <I>t</I>‐distribution were applied to determine the confidence limits for the grouped data. The Spearman's test was applied to assess the sensitivity of DQA results within the limited groups. The differences in CLs between the two confidence coefficients based on the normal and <I>t</I>‐distributions were negligible for the point‐dose data and the gamma passing rates with 3%/3 criteria. However, with 2%/2 criteria, the difference in CLs were 1.6% and 2.2% for composite and per‐field measurements, respectively. This resulted from the large standard deviation and the more sensitive criteria of 2%/2. There was no noticeable correlation among the different QA methods. Our multi‐institutional study suggested that the CL was not a suitable metric for defining the tolerance level when the statistics of the sample group did not follow the normality and had a large standard deviation.</P><P>PACS number: 87.55.Qr</P>

Delay of insulin initiation in patients with type 2 diabetes mellitus inadequately controlled with oral hypoglycemic agents (analysis of patient‐ and physician‐related factors): A prospective observational DIPP‐FACTOR study in Korea

Kim, Sin Gon,Kim, Nam Hoon,Ku, Bon Jeong,Shon, Ho Sang,Kim, Doo Man,Park, Tae Sun,Kim, Yong&#x2010,Seong,Kim, In Joo,Choi, Dong Seop John Wiley & Sons Ltd 2017 Journal of diabetes investigation Vol.8 No.3

<P><B>Abstract</B></P><P><B>Aims/Introduction</B></P><P>To assess the time to initiation of insulin therapy, and concurrently investigate both patient‐ and physician‐related factors associated with delaying insulin therapy in Korean patients with type 2 diabetes uncontrolled by oral hypoglycemic agents (OHAs).</P><P><B>Materials and Methods</B></P><P>This prospective, observational disease registry study was carried out across 69 centers in Korea. Type 2 diabetes patients who had received two or more OHAs within the past 5 years, had a glycated hemoglobin ≥8% in the past 6 months and had not received insulin were included. Data recorded on data collection forms during a 12‐month period were analyzed.</P><P><B>Results</B></P><P>Of 2168 patients enrolled, 1959 were evaluated and classified as the insulin‐initiated or insulin‐delayed group. Insulin was prescribed for just 20% of the patients during a 1‐year follow‐up period, and less than half (44.5%) of the patients who were taking two OHAs started insulin after 6 years. Patient‐related factors for delay in insulin initiation included older age, shorter duration of diabetes and lower glycated hemoglobin. Physician‐related factors included age (~50 to <60 years), sex (women) and number (<1000) of patients consulted per month. Patient refusal (33.6%) and physicians’ concerns of patient non‐compliance (26.5%) were the major physician‐reported reasons for delaying insulin therapy. Inconvenience of insulin therapy (51.6%) and fear of injection (48.2%) were the major reasons for patient refusal.</P><P><B>Conclusions</B></P><P>Insulin initiation is delayed in patients with type 2 diabetes uncontrolled by two or more OHAs in Korea. Patient‐ and physician‐related factors associated with this delay need to be addressed for better diabetes management.</P>

Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate‐induced colitis in mice due to increased intestinal permeability

Kim, Ye&#x2010,Ryung,Volpert, Giora,Shin, Kyong&#x2010,Oh,Kim, So&#x2010,Yeon,Shin, Sun&#x2010,Hye,Lee, Younghay,Sung, Sun Hee,Lee, Yong&#x2010,Moon,Ahn, Jung&#x2010,Hyuck,Pewzner&#x2010,Jung, Yael,Pa John Wiley and Sons Inc. 2017 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.21 No.12

<P><B>Abstract</B></P><P>Ceramides mediate crucial cellular processes including cell death and inflammation and have recently been implicated in inflammatory bowel disease. Ceramides consist of a sphingoid long‐chain base to which fatty acids of various length can be attached. We now investigate the effect of alerting the ceramide acyl chain length on a mouse model of colitis. Ceramide synthase (CerS) 2 null mice, which lack very‐long acyl chain ceramides with concomitant increase of long chain bases and C16‐ceramides, were more susceptible to dextran sodium sulphate‐induced colitis, and their survival rate was markedly decreased compared with that of wild‐type littermates. Using mixed bone‐marrow chimeric mice, we showed that the host environment is primarily responsible for intestinal barrier dysfunction and increased intestinal permeability. In the colon of CerS2 null mice, the expression of junctional adhesion molecule‐A was markedly decreased and the phosphorylation of myosin light chain 2 was increased. <I>In vitro</I> experiments using Caco‐2 cells also confirmed an important role of CerS2 in maintaining epithelial barrier function; CerS2‐knockdown <I>via </I>CRISPR‐Cas9 technology impaired barrier function. <I>In vivo</I> myriocin administration, which normalized long‐chain bases and C16‐ceramides of the colon of CerS2 null mice, increased intestinal permeability as measured by serum FITC‐dextran levels, indicating that altered SLs including deficiency of very‐long‐chain ceramides are critical for epithelial barrier function. In conclusion, deficiency of CerS2 influences intestinal barrier function and the severity of experimental colitis and may represent a potential mechanism for inflammatory bowel disease pathogenesis.</P>

Epidermal regeneration by <i>ent</i>‐16α, 17‐dihydroxy‐kauran‐19‐oic acid isolated from <i>Siegesbeckia pubescens</i>

Sung, S.&#x2010,H.,Park, S.&#x2010,H.,Song, S.&#x2010,Y.,Lee, S.&#x2010,J.,Lee, H.&#x2010,W.,Kim, S.&#x2010,H.,A Lee, M.,Yoon, I.&#x2010,S.,Kim, D.&#x2010,D.,Kang, S.,Sung, J.&#x2010,H. Blackwell Publishing Ltd 2011 Cell proliferation Vol.44 No.6

<P><B>Abstract</B></P><P><B>Objectives: </B> Keratinocyte stem/progenitor cells (KSCs) are known to regenerate epidermal tissue which they perform through to their great regenerative capacity.</P><P><B>Materials and methods: </B> Because stimulation of resident KSCs may regenerate epidermal tissue, we devised a strategy to find an appropriate KSC activator from natural products and to develop it as a skin‐rejuvenating agent.</P><P><B>Results: </B> <I>Ent</I>‐16α, 17‐dihydroxy‐kauran‐19‐oic acid (DHK) isolated from <I>Siegesbeckia pubescens</I> exhibited a KSC‐stimulating effect during screening of natural products. DHK increased proliferation and migration of KSCs using the Akt/ERK pathway. We further examined the mechanism of KSC stimulation and found that phosphorylation of Y1068 epithelial growth factor receptor (EGFR) was significantly increased. Functional inhibition of EGFR using neutralizing antibody and a chemical inhibitor, AG1478, attenuated DHK‐induced KSC stimulation. In a 3D culture model of KSCs, DHK treatment significantly induced establishment of fully stratified epidermis and increased numbers of p63‐positive cells. Likewise, DHK treatment significantly accelerated healing of epidermal wounds created by laser and dermatome, and increased p63‐positive cells, in animal models.</P><P><B>Conclusion: </B> Collectively, these results indicate that DHK regenerates epidermal tissue mainly through EGFR phosphorylation. As DHK has diverse advantages over recombinant growth factors for commercialization (that is long‐term stability and skin permeability), DHK might be applied to wound‐healing agents and to a basic materials used in cosmetics.</P>

Efficacy of nano‐particulated, water‐soluble erlotinib against intracranial metastases of EGFR ‐mutant lung cancer

Kim, Dong Ha,Choi, Yun Jung,Sung, Ki Jung,Yoo, Seon&#x2010,A,Sung, Young Hoon,Kim, Jeong Kon,Choi, Chang&#x2010,Min,Yun, Miyong,Lee, Eun Yong,Jin, Yong Suk,Cook, Seungho,Rho, Jin Kyung,Lee, Jae Cheol John Wiley and Sons Inc. 2018 Molecular Oncology Vol.12 No.12

<P>Central nervous system (CNS) metastasis is one of the serious complications of epidermal growth factor receptor (EGFR)‐mutant lung cancer, which arises due to poor penetration of the brain–blood barrier by EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Although osimertinib, a third‐generation EGFR‐TKI, has efficacy against CNS metastases, further treatment modalities are still needed as some of these lesions do not respond to osimertinib, or undergo progression after an initial response to this drug if radiotherapy has already been conducted. Here, we investigated the efficacy of water‐soluble erlotinib (NUFS‐sErt) against these metastases. This agent was synthesized using a nano‐particulation platform technology utilizing fat and supercritical fluid (NUFS™) to resolve the low solubility problem that typically prevents the creation of injectable forms of EGFR‐TKIs. The average NUFS‐sErt particle size was 236.4 nm, and it showed time‐dependent dissolution in culture media. The effects of NUFS‐sErt were similar to those of conventional erlotinib in terms of inhibiting the proliferation of EGFR‐mutant lung cancer cells and suppressing EGFR signaling. In an intraperitoneal xenograft model of HCC827 cells, intraperitoneal administration of NUFS‐sErt produced a dose‐dependent inhibition of tumor growth and enhanced survival rate. Notably, the injection of NUFS‐sErt into the brain ventricle caused significant tumor growth inhibition in an intracranial xenograft model. Hence, our current findings indicate that NUFS‐sErt is a novel, water‐soluble form of erlotinib that can be administered using intraventricular or intrathecal injections. The target cases would be patients with a progressive CNS metastasis and no other therapeutic options. This drug could also be given intravenously to patients with swallowing difficulties or an inability to ingest due to a medical condition.</P>