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

Kim, Jung&#x2010,in,Chung, Jin&#x2010,Beom,Song, Ju‐,Young,Kim, Sung Kyu,Choi, Yunseok,Choi, Chang Heon,Choi, Won Hoon,Cho, Byungchul,Kim, Jin Sung,Kim, Sung Jin,Ye, Sung&#x2010,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>

Stretching‐Induced Growth of PEDOT‐Rich Cores: A New Mechanism for Strain‐Dependent Resistivity Change in PEDOT:PSS Films

Lee, Yoo&#x2010,Yong,Lee, Ji&#x2010,Hoon,Cho, Ju‐,Young,Kim, Na&#x2010,Rae,Nam, Dae&#x2010,Hyun,Choi, In&#x2010,Suk,Nam, Ki Tae,Joo, Young&#x2010,Chang WILEY‐VCH Verlag 2013 Advanced functional materials Vol.23 No.32

<P><B>Abstract</B></P><P>It remains a fundamental challenge in the development of stretchable electronics to understand how mechanical strain changes the electrical properties of materials. Although the piezoresistive behavior of poly(3,4‐ethylene‐ dioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) has been observed, its intrinsic origin is not yet fully understood because there are many extrinsic contributing factors and an experimental platform with which to assess such behavior has not been established. Here, systematic analysis shows that the matching Poisson's ratio and elastic modulus between PEDOT:PSS films and their underlying substrates is important in decoupling the factors that affect the material's piezoresistivity, allowing for tunable resistivity. Based on such a fundamental understanding, the conductivity of PEDOT:PSS can be controlled to be invariant and decrease as a function of applied tensile stress. Furthermore, a linear response of the resistivity with respect to mechanical strains of up to 60%, which has never before been realized, is shown. The irreversible conductivity enhancement is primarily caused by the coalescence‐induced growth of conductive PEDOT‐rich cores.</P>

A liver‐specific gene expression panel predicts the differentiation status of <i>in vitro</i> hepatocyte models

Kim, Dae&#x2010,Soo,Ryu, Jea&#x2010,Woon,Son, Mi&#x2010,Young,Oh, Jung&#x2010,Hwa,Chung, Kyung&#x2010,Sook,Lee, Sugi,Lee, Jeong&#x2010,Ju,Ahn, Jun&#x2010,Ho,Min, Ju‐,Sik,Ahn, Jiwon,Kang, Hyun Mi John Wiley and Sons Inc. 2017 Hepatology Vol.66 No.5

<P>Alternative cell sources, such as three‐dimensional organoids and induced pluripotent stem cell–derived cells, might provide a potentially effective approach for both drug development applications and clinical transplantation. For example, the development of cell sources for liver cell–based therapy has been increasingly needed, and liver transplantation is performed for the treatment for patients with severe end‐stage liver disease. Differentiated liver cells and three‐dimensional organoids are expected to provide new cell sources for tissue models and revolutionary clinical therapies. However, conventional experimental methods confirming the expression levels of liver‐specific lineage markers cannot provide complete information regarding the differentiation status or degree of similarity between liver and differentiated cell sources. Therefore, in this study, to overcome several issues associated with the assessment of differentiated liver cells and organoids, we developed a liver‐specific gene expression panel (LiGEP) algorithm that presents the degree of liver similarity as a “percentage.” We demonstrated that the percentage calculated using the LiGEP algorithm was correlated with the developmental stages of <I>in vivo</I> liver tissues in mice, suggesting that LiGEP can correctly predict developmental stages. Moreover, three‐dimensional cultured HepaRG cells and human pluripotent stem cell–derived hepatocyte‐like cells showed liver similarity scores of 59.14% and 32%, respectively, although general liver‐specific markers were detected. <I>Conclusion</I>: Our study describes a quantitative and predictive model for differentiated samples, particularly liver‐specific cells or organoids; and this model can be further expanded to various tissue‐specific organoids; our LiGEP can provide useful information and insights regarding the differentiation status of <I>in vitro</I> liver models. (H<SMALL>EPATOLOGY</SMALL> 2017;66:1662–1674).</P>

Tandem Iminium/Copper Catalysis: Highly Enantioselective Synthesis of α,β‐Disubstituted Aldehydes

Kim, Ju‐,Hye,Park, Eun&#x2010,Jin,Lee, Hwa&#x2010,Jung,Ho, Xuan&#x2010,Huong,Yoon, Hyo&#x2010,Sang,Kim, Pilsoo,Yun, Hoseop,Jang, Hye&#x2010,Young WILEY‐VCH Verlag 2013 European journal of organic chemistry Vol.2013 No.20

<P><B>Abstract</B></P><P>With the goal of synthesizing biologically and synthetically valuable products under environmentally benign and economic conditions, an asymmetric organocatalytic reaction was combined with a copper catalytic reaction. This iminium/copper catalysis allowed highly optically active α,β‐disubstituted aldehydes to be synthesized with good yields in one‐pot fashion. The β‐substitution took place through iminium‐catalyzed Michael addition of nitromethane or diethyl malonate to the α,β‐unsaturated aldehydes, followed by copper‐assisted addition of TEMPO (2,2,6,6‐tetramethylpiperidin‐1‐yloxyl) at the aldehyde α‐position. An iminium/copper‐catalyzed tandem addition product was converted into a 3,4,5‐trisubstituted piperidine for X‐ray crystallographic analysis.</P>

Visualization of myelination in GFP‐transgenic zebrafish

Jung, Seung&#x2010,Hyun,Kim, Suhyun,Chung, Ah&#x2010,Young,Kim, Hyun&#x2010,Taek,So, Ju‐,Hoon,Ryu, Jaeho,Park, Hae&#x2010,Chul,Kim, Cheol&#x2010,Hee Wiley‐Liss, Inc. 2010 Developmental dynamics Vol.239 No.2

<P><B>Abstract</B></P><P>The insulation of axons in the vertebrate nervous system by myelin is essential for efficient axonal conduction. Myelination disruption and remyelination failure can cause human diseases, such as multiple sclerosis and hereditary myelin diseases. However, despite progress in understanding myelination regulation, many important questions remain unanswered. To investigate the mechanisms underlying myelination in vivo, we generated transgenic zebrafish expressing enhanced green fluorescent protein (EGFP) under the control of the mbp promoter. This transgenic fish displayed faithful EGFP expression in oligodendrocytes and Schwann cells in embryonic and adult zebrafish. Interestingly, although myelination progressed continuously in the postembryonic central nervous system, some of the spinal cord regions were filled with unmyelinated axons even in the adult spinal cord, suggesting functional differences between myelinated and unmyelinated axons. Our results suggest that this transgenic zebrafish could be a valuable animal model to study oligodendrocyte differentiation and myelination in vivo. Developmental Dynamics 239:592–597, 2010. © 2009 Wiley‐Liss, Inc.</P>

Interleukin‐22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL in human synovial fibroblasts

Kim, Kyoung&#x2010,Woon,Kim, Hae&#x2010,Rim,Park, Jin&#x2010,Young,Park, Jin&#x2010,Sil,Oh, Hye&#x2010,Jwa,Woo, Yun&#x2010,Ju,Park, Mi&#x2010,Kyung,Cho, Mi&#x2010,La,Lee, Sang&#x2010,Heon Wiley Subscription Services, Inc., A Wiley Company 2012 Vol.64 No.4

<P><B>Abstract</B></P><P><B>Objective</B></P><P>To examine the regulatory role of interleukin‐22 (IL‐22) in the expression of RANKL and induction of osteoclastogenesis in rheumatoid arthritis (RA).</P><P><B>Methods</B></P><P>Concentrations of IL‐22 and RANKL in the serum and synovial fluid of RA patients were measured using enzyme‐linked immunosorbent assay. RA synovial fibroblasts were treated with recombinant human IL‐22 (rhIL‐22), and the expression of RANKL messenger RNA (mRNA) and protein was measured using real‐time polymerase chain reaction, Western blotting, and intracellular immunostaining. Human monocytes were cocultured with IL‐22–prestimulated RA synovial fibroblasts and macrophage colony‐stimulating factor, and osteoclastogenesis was assessed by counting the multinucleated cells (those staining positive for tartrate‐resistant acid phosphatase).</P><P><B>Results</B></P><P>The IL‐22 concentration in the synovial fluid was higher in RA patients than in patients with osteoarthritis (OA). The serum IL‐22 concentration was also higher in RA patients than in OA patients and healthy volunteers, and this correlated with serum titers of rheumatoid factor and anti–cyclic citrullinated peptide antibodies. In RA synovial fibroblasts treated with rhIL‐22, the expression of RANKL mRNA and protein was increased in a dose‐dependent manner. IL‐22–induced RANKL expression was down‐regulated significantly by the inhibition of p38 MAPK/NF‐κB or JAK‐2/STAT‐3 signaling. In human monocytes cocultured with IL‐22–prestimulated RA synovial fibroblasts in the absence of exogenous RANKL, the monocytes differentiated into osteoclasts, but this osteoclastogenesis decreased after p38 MAPK/NF‐κB or JAK‐2/STAT‐3 signaling was inhibited.</P><P><B>Conclusion</B></P><P>These results show that IL‐22 up‐regulates RANKL expression in RA synovial fibroblasts and induces osteoclastogenesis. These effects are mediated by the p38 MAPK/NF‐κB and JAK‐2/STAT‐3 signaling pathways.</P>

Immunity to melanoma mediated by 4‐1BB is associated with enhanced activity of tumour‐infiltrating lymphocytes

Ju, Seong&#x2010,A,Lee, Sang&#x2010,Chul,Kwon, Tae&#x2010,Hyoung,Heo, Sook&#x2010,Kyoung,Park, Sang&#x2010,Min,Paek, Ha&#x2010,Na,Suh, Jae&#x2010,Hee,Cho, Hong Rae,Kwon, Byungsuk,Kwon, Byoung S,Kim, B Nature Publishing Group 2005 Immunology and Cell Biology Vol.83 No.4

<P>4‐1BB costimulates T cells to carry out effector functions such as eradication of established tumours. 4‐1BB (CD137) is a member of the TNF receptor family, and its triggering by either 4‐1BB ligand or antibody ligation induces T‐cell activation and growth. We analysed tumour‐infiltrating lymphocytes (TIL) in the experimental B16F10 melanoma model to determine the mechanisms involved in 4‐1BB‐mediated tumour suppression. 4‐1BB<SUP>+/+</SUP> mice survived longer than 4‐1BB<SUP>–/–</SUP> mice, and survival was further prolonged by triggering 4‐1BB with an agonistic mAb. The number of metastatic B16F10 colonies in the lung was much greater in 4‐1BB<SUP>–/–</SUP> mice than in their 4‐1BB<SUP>+/+</SUP> littermates. Administration of agonistic anti‐4‐1BB mAb increased the number of TIL in the tumour masses in the lungs of 4‐1BB<SUP>+/+</SUP> mice. The numbers of CD4<SUP>+</SUP> T, CD8<SUP>+</SUP> T and CD11b<SUP>+</SUP> TIL increased in these mice. Anti‐4‐1BB mAb induced not only CD8<SUP>+</SUP> 4‐1BB<SUP>+</SUP> T cells but also a CD8<SUP>+</SUP> IFN‐γ<SUP>+</SUP> T‐cell population. B16F10 cells from the lungs of anti‐4‐1BB‐treated mice showed enhanced expression of MHC class Ι and II antigens compared with the same cells from control IgG‐treated mice. Thus, the increase in number of CD8<SUP>+</SUP> T cells and enhanced MHC Ι and II expression in B16F10 cells that result from augmented IFN‐γ production in response to anti‐4‐1BB mAb may lead to suppression of tumour growth and metastasis.</P>

Associations of serotonergic genes with poststroke emotional incontinence

Kim, Jae&#x2010,Min,Stewart, Robert,Kang, Hee&#x2010,Ju,Bae, Kyung&#x2010,Yeol,Kim, Sung&#x2010,Wan,Shin, Il&#x2010,Seon,Kim, Joon&#x2010,Tae,Park, Man&#x2010,Seok,Cho, Ki&#x2010,Hyun,Yoon, Jin&#x2010 John Wiley Sons, Ltd 2012 INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Vol.27 No.8

<P><B>Objectives</B></P><P>Poststroke emotional incontinence (PSEI) has been associated with serotonergic dysfunction. Polymorphisms of serotonin transporter (5‐HTT) and serotonin 2a receptor (5‐HTR2a) genes may regulate serotonergic signaling at brain synapses, and this study was to investigate associations with PSEI in an East Asian population.</P><P><B>Methods</B></P><P>In 276 stroke cases, PSEI was diagnosed by Kim's criteria. Covariates included age, gender, education, history of depression or stroke, current depression, and stroke severity and location. Genotypes were ascertained for 5‐HTT gene‐linked promoter region (5‐HTTLPR), serotonin transporter intron 2 variable number tandem repeat, 5‐HTR2a 1438A/G, and 5‐HTR2a 102 T/C. Associations with PSEI were estimated by using logistic regression models, and gene–gene interactions were investigated by using the generalized multifactor dimensionality reduction method.</P><P><B>Results</B></P><P>PSEI was present in 37 (13.4%) patients. The 5‐HTT gene‐linked promoter region <I>s</I>/<I>s</I> genotype was independently associated with PSEI. No associations with STin2 VNTR and 5‐HTR2a genes were found, and no significant gene–gene interactions were identified.</P><P><B>Conclusions</B></P><P>Stroke patients with 5‐HTTLPR <I>s</I> allele had higher susceptibility to PSEI, which underlines the potential role of serotonergic pathways in its etiology. Copyright © 2011 John Wiley & Sons, Ltd.</P>

<i>In vivo</i> and <i>ex vivo</i> evidence for ketamine‐induced hyperglutamatergic activity in the cerebral cortex of the rat: Potential relevance to schizophrenia

Kim, Sang&#x2010,Young,Lee, Hyunseung,Kim, Hyun&#x2010,Ju,Bang, Eunjung,Lee, Sung&#x2010,Ho,Lee, Do&#x2010,Wan,Woo, Dong&#x2010,Cheol,Choi, Chi&#x2010,Bong,Hong, Kwan Soo,Lee, Chulhyun,Choe, Bo&#x2010 John Wiley Sons, Ltd 2011 NMR in biomedicine Vol.24 No.10

<P>Subanesthetic doses of ketamine, a noncompetitive <I>N</I>‐methyl‐<SMALL>D</SMALL>‐aspartate (NMDA) receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in patients with schizophrenia. In the present study, <I>in vivo</I> <SUP>1</SUP>H‐MRS and <I>ex vivo</I> <SUP>1</SUP>H high‐resolution magic angle spinning (HR‐MAS) spectroscopy was used to examine the brain metabolism of rats treated with subanesthetic doses of ketamine (30 mg/kg) for 6 days. A single voxel localization sequence (PRESS, TR/TE = 4000/20 ms and NEX = 512) was used to acquire the spectra in a 30‐µl voxel positioned in the cerebral cortex (including mainly PFC) of the rats (ketamine group: <I>n</I> = 12; saline group: <I>n</I> = 12) anesthetized with isoflurane. After the <I>in vivo</I> <SUP>1</SUP>H‐MRS acquisition, the animals were sacrificed and the cerebral cortex tissues were extracted (ketamine group: <I>n</I> = 7; saline group: <I>n</I> = 7) for <I>ex vivo</I> <SUP>1</SUP>H HR‐MAS spectroscopy (CPMG sequence, 2.0‐s presaturation delay, 2.0‐s acquisition time, 128 transients and 4‐ms inter‐pulse delay) using a 500‐MHz NMR spectrometer. All proton metabolites were quantified using the LCModel. For the <I>in vivo</I> spectra, there was a significant increase in glutamate concentration in the cerebral cortex of the ketamine group compared with the controls (<I>p</I> < 0.05). For the <I>ex vivo</I> HR‐MAS spectra, there was a significant increase in the glutamate/total creatine ratio, and a decrease in the glutamine/total creatine and glutamine/glutamate ratios in the cerebral cortex tissue of the ketamine group compared with the controls. The results of the present study demonstrated that administration of subanesthetic doses of ketamine in the rat may exert at least part of their effect in the cerebral cortex by activation of glutamatergic neurotransmission. Copyright © 2011 John Wiley & Sons, Ltd.</P>

Pyridoxal‐5′‐phosphate phosphatase/chronophin induces astroglial apoptosis via actin‐depolymerizing factor/cofilin system in the rat brain following status epilepticus

Kim, Ji&#x2010,Eun,Ryu, Hea Jin,Kim, Min&#x2010,Ju,Kim, Dae&#x2010,Won,Kwon, Oh&#x2010,Shin,Choi, Soo Young,Kang, Tae&#x2010,Cheon Wiley Subscription Services, Inc., A Wiley Company 2010 Glia Vol.58 No.16

<P><B>Abstract</B></P><P>Actin‐depolymerizing factor (ADF)/cofilin is a small cytoskeletal protein that is a stimulus‐responsive mediator of actin dynamics. ADF/cofilin also translocates into mitochondria and nuclei in response to apoptotic stimuli for cytochrome c release. These ADF/cofilin translocations are negatively regulated by phosphorylation. Recently, it has been reported that pyridoxal‐5′‐phosphate (PLP) phosphatase/chronophin (PLPP/CIN) regulates phosphorylation of ADF/cofilin levels. Therefore, we investigated whether PLPP/CIN contributes to apoptosis‐like events via modulation of ADF/cofilin phosphorylation following status epilepticus (SE). In the present study, apoptosis‐like astroglial damages were detected in the dentate gyrus after SE. Upregulation of ADF/cofilin and PLPP/CIN expression in the cytoplasm and nucleus were accompanied by apoptosis‐like events. PLPP/CIN level showed a direct proportionality to nuclear translocation of ADF/cofilin. Moreover, nuclear accumulation of apoptosis‐inducing factor was simultaneously observed with that of ADF/cofilin. Tat‐PLPP/CIN pretreatment accelerated astroglial apoptosis‐like degeneration following SE, although Tat‐PLPP/CIN transduction alone could not induce apoptosis or necrosis in astrocytes. Therefore, our findings suggest that nuclear accumulation of ADF/cofilin itself may not induce apoptogenic events, but may play a synergic role in apoptosis‐like astroglial loss following SE. © 2010 Wiley‐Liss, Inc.</P>