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

Kim, Jung‐,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&#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>

Angiotensin II Causes Apoptosis of Adult Hippocampal Neural Stem Cells and Memory Impairment Through the Action on AMPK‐PGC1α Signaling in Heart Failure

Kim, Min&#x2010,Seok,Lee, Geun&#x2010,Hee,Kim, Yong&#x2010,Min,Lee, Byoung&#x2010,Wook,Nam, Hae Yun,Sim, U&#x2010,Cheol,Choo, Suk&#x2010,Jung,Yu, Seong&#x2010,Woon,Kim, Jae&#x2010,Joong,Kim Kwon, Yunh unknown 2017 Stem cells translational medicine Vol.6 No.6

<P><B>Abstract</B></P><P>Data are limited on the mechanisms underlying memory impairment in heart failure (HF). We hypothesized that angiotensin II (Ang II) may determine the fate of adult hippocampal neural stem cells (HCNs), a cause of memory impairment in HF. HCNs with neurogenesis potential were isolated and cultured from adult rat hippocampi. Ang II decreased HCN proliferation in dose‐ and time‐dependent manners. Moreover, Ang II treatment (1 µM) for 48 hours induced apoptotic death, which was attenuated by pretreatment with Ang II receptor blockers (ARBs). Ang II increased mitochondrial reactive oxygen species (ROS) levels, which was related to mitochondrial morphological changes and functional impairment. Moreover, ROS activated the AMP‐activated protein kinase (AMPK) and consequent peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α) expression, causing cell apoptosis. In the HF rat model induced by left anterior descending artery ligation, ARB ameliorated the spatial memory ability which decreased 10 weeks after ischemia. In addition, neuronal cell death, especially of newly born mature neurons, was observed in HF rat hippocampi. ARB decreased cell death and promoted the survival of newly born neural precursor cells and mature neurons. In conclusion, Ang II caused HCN apoptosis through mitochondrial ROS formation and subsequent AMPK‐PGC1α signaling. ARB improved learning and memory behaviors impaired by neuronal cell death in the HF animal model. These findings suggest that HCN is one treatment target for memory impairment in HF and that ARBs have additional benefits in HF combined with memory impairment. S<SMALL>TEM</SMALL> C<SMALL>ELLS</SMALL> T<SMALL>RANSLATIONAL</SMALL> M<SMALL>EDICINE</SMALL><I>2017;6:1491–1503</I></P>

Inhibition of VEGF ‐dependent angiogenesis and tumor angiogenesis by an optimized antibody targeting CLEC 14a

Kim, Taek&#x2010,Keun,Park, Chang Sik,Jang, Jihye,Kim, Mi Ra,Na, Hee&#x2010,Jun,Lee, Kangseung,Kim, Hyun Jung,Heo, Kyun,Yoo, Byong Chul,Kim, Young&#x2010,Myeong,Lee, Je&#x2010,Wook,Kim, Su Jin,Kim, Eu John Wiley and Sons Inc. 2018 MOLECULAR ONCOLOGY Vol.12 No.3

<P>The C‐type lectin‐like domain of CLEC14a (CLEC14a‐C‐type lectin‐like domain [CTLD]) is a key domain that mediates endothelial cell–cell contacts in angiogenesis. However, the role of CLEC14a‐CTLD in pathological angiogenesis has not yet been clearly elucidated. In this study, through complementarity‐determining region grafting, consecutive deglycosylation, and functional isolation, we generated a novel anti‐angiogenic human monoclonal antibody that specifically targets CLEC14a‐CTLD and that shows improved stability and homogeneity relative to the parental antibody. We found that this antibody directly inhibits CLEC14a‐CTLD‐mediated endothelial cell–cell contact and simultaneously downregulates expression of CLEC14a on the surface of endothelial cells. Using various <I>in vitro</I> and <I>in vivo</I> functional assays, we demonstrated that this antibody effectively suppresses vascular endothelial growth factor (VEGF)‐dependent angiogenesis and tumor angiogenesis of SNU182 human hepatocellular carcinoma, CFPAC‐1 human pancreatic cancer, and U87 human glioma cells. Furthermore, we also found that this antibody significantly inhibits tumor angiogenesis of HCT116 and bevacizumab‐adapted HCT116 human colorectal cancer cells. These findings suggest that antibody targeting of CLEC14a‐CTLD has the potential to suppress VEGF‐dependent angiogenesis and tumor angiogenesis and that CLEC14a‐CTLD may be a novel anti‐angiogenic target for VEGF‐dependent angiogenesis and tumor angiogenesis.</P>

Areca nut exposure increases secretion of tumor‐promoting cytokines in gingival fibroblasts that trigger DNA damage in oral keratinocytes

Illeperuma, Rasika P.,Kim, Do Kyeong,Park, Young Jin,Son, Hwa Kyung,Kim, Jue Young,Kim, Jinmi,Lee, Doo Young,Kim, Ki&#x2010,Yeol,Jung, Da&#x2010,Woon,Tilakaratne, Wanninayake M.,Kim, Jin Alan R. Liss, Inc 2015 International journal of cancer Vol.137 No.11

<▼1><P>Molecular crosstalk between cancer cells and fibroblasts has been an emerging hot issue in understanding carcinogenesis. As oral submucous fibrosis (OSF) is an inflammatory fibrotic disease that can potentially transform into squamous cell carcinoma, OSF has been considered to be an appropriate model for studying the role of fibroblasts during early stage carcinogenesis. In this sense, this study aims at investigating whether areca nut (AN)‐exposed fibroblasts cause DNA damage of epithelial cells. For this study, immortalized hNOF (hTERT‐hNOF) was used. We found that the levels of GRO‐α, IL‐6 and IL‐8 increased in AN‐exposed fibroblasts. Cytokine secretion was reduced by antioxidants in AN‐exposed fibroblasts. Increase in DNA double strand breaks (DSB) and 8‐oxoG FITC‐conjugate was observed in immortalized human oral keratinocytes (IHOK) after the treatment of cytokines or a conditioned medium derived from AN‐exposed fibroblasts. Cytokine expression and DNA damage were also detected in OSF tissues. The DNA damage was reduced by neutralizing cytokines or antioxidant treatment. Generation of reactive oxygen species (ROS) and DNA damage response, triggered by cytokines, were abolished when NADPH oxidase (NOX) 1 and 4 were silenced in IHOK, indicating that cytokine‐triggered DNA damage was caused by ROS generation through NOX1 and NOX4. Taken together, this study provided strong evidence that blocking ROS generation might be a rewarding approach for cancer prevention and intervention in OSF.</P></▼1><▼2><P><B>What's new?</B></P><P>Fibroblasts in the tumor microenvironment influence tumor initiation and growth and are of particular interest in oral submucous fibrosis (OSF), a progressive fibrotic disease of malignant potential. This study shows that the release of tumor‐promoting cytokines by fibroblasts exposed to areca nut, the primary cause of OSF, induce DNA damage in oral keratinocytes. The findings suggest that fibroblasts indirectly promote epithelial transformation in OSF by secreting cytokines, whereby DNA damage of epithelial cells is inflicted by reactive oxygen species generated <I>via</I> NADPH oxidases. These insights could inform the development of new therapeutic approaches for OSF.</P></▼2>

Neural retina leucine‐zipper regulates the expression of Ppp2r5c, the regulatory subunit of protein phosphatase 2A, in photoreceptor development

Kim, Jung‐,Woong,Jang, Sang&#x2010,Min,Kim, Chul&#x2010,Hong,An, Joo&#x2010,Hee,Kang, Eun&#x2010,Jin,Choi, Kyung&#x2010,Hee Blackwell Publishing Ltd 2010 FEBS JOURNAL Vol.277 No.24

<P>Protein phosphatase 2A plays an important role in balancing phosphorylation signals that are critical for cell proliferation and differentiation. Here, we report that <I>Ppp2r5c</I> (regulatory subunit of protein phosphatase 2A) expression was regulated by the transcription factor neural retina leucine‐zipper (Nrl) through enhancement of its transcriptional activity on the <I>Ppp2r5c</I> promoter. Using electrophoretic mobility shift assays and chromatin immunoprecipitation, we also found that Nrl bound directly to the Nrl‐response element on the <I>Ppp2r5c</I> promoter. The affinity of binding of Nrl to the <I>Ppp2r5c</I> promoter was tightly regulated during mouse photoreceptor development. Overall, these results suggest that <I>Ppp2r5c</I> expression is regulated by Nrl during retinogenesis through direct binding to the promoter region of <I>Ppp2r5c</I>.</P>

Large‐Scale Highly Ordered Chitosan‐Core Au‐Shell Nanopatterns with Plasmonic Tunability: A Top‐Down Approach to Fabricate Core–Shell Nanostructures

Baek, Youn&#x2010,Kyoung,Yoo, Seung Min,Kang, Taejoon,Jeon, Hwan&#x2010,Jin,Kim, Kyounghwan,Lee, Ji&#x2010,Sun,Lee, Sang Yup,Kim, Bongsoo,Jung, Hee&#x2010,Tae WILEY‐VCH Verlag 2010 Advanced functional materials Vol.20 No.24

<P><B>Abstract</B></P><P>A new strategy for fabricating highly ordered chitosan–Au core–shell nano­patterns with tunable surface plasmon resonance (SPR) properties is developed. This strategy combines fabrication of a chitosan nanopattern by using a soft‐nanoimprint technique with selective deposition of Au nanoparticles onto the patterned chitosan surface. The SPR response can be tuned by controlling the features of the resulting Au shell/polymer hybrid pattern, which makes these materials potentially useful in ultrasensitive optical sensors for molecular detection.</P>

PD‐L1 expression in <i>ROS1</i> ‐rearranged non‐small cell lung cancer: A study using simultaneous genotypic screening of <i>EGFR</i> , <i>ALK</i> , and <i>ROS1</i>

Lee, Jongmin,Park, Chan Kwon,Yoon, Hyoung&#x2010,Kyu,Sa, Young Jo,Woo, In Sook,Kim, Hyo Rim,Kim, Sue Youn,Kim, Tae&#x2010,Jung Wiley-Blackwells 2019 Thoracic cancer Vol.10 No.1

<P><B>Background</B></P><P>The aim of the current study was to investigate the prevalence and clinicopathologic characteristics of <I>ROS1</I>‐rearranged non‐small cell lung cancer (NSCLC) in routine genotypic screening in conjunction with the study of PD‐L1 expression, a biomarker for first‐line treatment decisions.</P><P><B>Methods</B></P><P>Reflex simultaneous genotypic screening for <I>EGFR</I> by peptide nucleic acid clamping, and <I>ALK</I> and <I>ROS1</I> by fluorescence in situ hybridization (FISH) was performed on consecutive NSCLC cases at the time of initial pathologic diagnosis. We evaluated genetic aberrations, clinicopathologic characteristics, and PD‐L1 tumor proportion score (TPS) using a PD‐L1 22C3 assay kit.</P><P><B>Results</B></P><P>In 407 consecutive NSCLC patients, simultaneous genotyping identified 14 (3.4%) <I>ROS1</I> and 19 (4.7%) <I>ALK</I> rearrangements, as well as 106 (26%) <I>EGFR</I> mutations. These mutations were mutually exclusive and were found in patients with similar clinical features, including younger age, a prevalence in women, adenocarcinoma, and advanced stage. The PD‐L1 assay was performed on 130 consecutive NSCLC samples. High PD‐L1 expression (TPS ≥ 50%) was observed in 29 (22.3%) tumors. PD‐L1 expression (TPS ≥ 1%) was significantly associated with wild type <I>EGFR</I>, while <I>ROS1</I> rearrangement was associated with high PD‐L1 expression. Of the 14 cases with <I>ROS1</I> rearrangement, 12 (85.7%) showed PD‐L1 expression and 5 (35.7%) showed high PD‐L1 expression.</P><P><B>Conclusion</B></P><P>In the largest consecutive routine Asian NSCLC cohort analyzed to date, we found that high PD‐L1 expression frequently overlapped with <I>ROS1</I> rearrangement, while it negatively correlated with <I>EGFR</I> mutations.</P>

Patient‐specific 17‐segment myocardial modeling on a bull's‐eye map

Jung, Joonho,Kim, Young&#x2010,Hak,Kim, Namkug,Yang, Dong Hyun unknown 2016 Journal of applied clinical medical physics Vol.17 No.5

<P>The purpose of this study was to develop and validate cardiac computed tomography (CT) quantitative analysis software with a patient‐specific, 17‐segment myocardial model that uses electrocardiogram (ECG)‐gated cardiac CT images to differentiate between normal controls and severe aortic stenosis (AS) patients. ECG‐gated cardiac CT images from 35 normal controls and 144 AS patients were semiautomatically segmented to create a patient‐specific, 17‐segment myocardial model. Two experts then manually determined the anterior and posterior interventricular grooves to be boundaries between the 1st and 2nd segments and between the 3rd and 4th segments, respectively, to correct the model. Each segment was automatically identified as follows. The outer angle of two boundaries was divided to differentiate the 1st, 4th, 5th, and 6th segments in the basal plane, whereas the inner angle divided the 2nd and 3rd segments. The segments of the midplane were similarly divided. Segmental area distributions were quantitatively evaluated on the bull's‐eye map on the basis of the morphological boundaries by measuring the area of each segment. Segmental areas of severe AS patients and normal controls were significantly different (t‐test, all p‐values<0.011) in the proposed model because the septal regions of the severe AS patients were smaller than those of normal controls and the difference was enough to divide the two groups. The capabilities of the 2D segmental areas (p<0.011) may be equivalent to those of 3D segmental analysis (all p‐values<0.001) for differentiating the two groups (t‐test, all p‐values<0.001). The proposed method is superior to the conventional 17‐segment in relation to reflection of patient‐specific morphological variation and allows to obtain a more precise mapping between segments and the AHA recommended nomenclature. It can be used to differentiate severer AS patients and normal controls and also helps to understand the left ventricular morphology at a glance.</P><P>PACS number(s): 87.57.N‐, 87.57.R‐, 87.57.qp</P>

Synthesis and Structure–Activity Relationships of Gadolinium Complexes of DO3A–Benzothiazole Conjugates as Potential Theranostic Agents

Jung, Ki&#x2010,Hye,Kang, Sun&#x2010,Hee,Kang, Min&#x2010,Kyoung,Kim, Soyeon,Kim, Hee&#x2010,Kyung,Kim, Yeoun&#x2010,Hee,Ho Lee, Gang,Shim, Gyu&#x2010,Bo,Jung, Jae&#x2010,Chang,Chang, Yongmin,Kim, Tae WILEY‐VCH Verlag 2015 European journal of inorganic chemistry Vol.2015 No.4

<P><B>Abstract</B></P><P>The synthesis of two bifunctional chelates, 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acid (DO3A) conjugates of benzothiazoles (H<SUB>3</SUB>L<SUP>3a</SUP> and H<SUB>3</SUB>L<SUP>3b</SUP>), and the corresponding gadolinium complexes (GdL<SUP>3a</SUP> and GdL<SUP>3b</SUP>) was achieved. The intracellular and tumor‐specific nature of GdL<SUP>3a</SUP> and GdL<SUP>3b</SUP> were confirmed by magnetic resonance images of the cytosols and nuclei of various cell lines. The two complexes displayed antitumor activities with varying degrees of growth‐inhibition and total‐growth‐inhibition values depending on the types of tumor cells. They caused morphological changes in tumor cell lines at much lower concentrations of gadolinium ([Gd] ≥ 50 μ<SMALL>M</SMALL>) than their predecessors, DO3A–(<I>p</I>‐aniline benzothiazole) conjugates (H<SUB>3</SUB>L<SUP>1</SUP>), and its Gd<SUP>III</SUP> complex (GdL<SUP>1</SUP>) required concentrations that were almost four times as high ([Gd] ≥ 200 μ<SMALL>M</SMALL>).</P>

Effects of 60 Hz 14 µT magnetic field on the apoptosis of testicular germ cell in mice

Kim, Yoon&#x2010,Won,Kim, Hee&#x2010,Sung,Lee, Jin&#x2010,Sang,Kim, Young&#x2010,Jin,Lee, Sang&#x2010,Kon,Seo, Jae&#x2010,Nam,Jung, Kyeong&#x2010,Cheon,Kim, Nam,Gimm, Youn&#x2010,Myoung Wiley Subscription Services, Inc., A Wiley Company 2009 BioElectroMagnetics Vol.30 No.1

<P><B>Abstract</B></P><P>We recently reported that continuous exposure, for 8 weeks, of extremely low frequency (ELF) magnetic field (MF) of 0.1 or 0.5 mT might induce testicular germ cell apoptosis in BALB/c mice. In that report, the ELF MF exposure did not significantly affect the body weight or testicular weight, but significantly increased the incidence of testicular germ cell death. In the present study, we aimed to further characterize the effect of a 16‐week continuous exposure to ELF MF of 14 or 200 µT on testicular germ cell apoptosis in mice. There were no significant effects of MF on body weight and testosterone levels in mice. In TUNEL staining (In situ terminal deoxynucleotidyl transferase‐mediated deoxy‐UTP nick end labeling), germ cells showed a significantly higher apoptotic rate in exposed mice than in sham controls (<I>P</I> < 0.001). TUNEL‐positive cells were mainly spermatogonia. In an electron microscopic study, degenerating spermatogonia showed condensation of nuclear chromatin similar to apoptosis. These results indicate that apoptosis may be induced in spermatogenic cells in mice by continuous exposure to 60 Hz MF of 14 µT. Bioelectromagnetics 30:66–72, 2009. © 2008 Wiley‐Liss, Inc.</P>