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&#x2010,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>

Phenyl 2‐pyridyl ketoxime induces cellular senescence‐like alterations via nitric oxide production in human diploid fibroblasts

Yang, Kyeong Eun,Jang, Hyun&#x2010,Jin,Hwang, In&#x2010,Hu,Chung, Young&#x2010,Ho,Choi, Jong&#x2010,Soon,Lee, Tae&#x2010,Hoon,Chung, Yun&#x2010,Jo,Lee, Min&#x2010,Seung,Lee, Mi Young,Yeo, Eui&#x2010,J BLACKWELL PUBLISHING 2016 AGING CELL Vol.15 No.2

<P><B>Summary</B></P><P>Phenyl‐2‐pyridyl ketoxime (PPKO) was found to be one of the small molecules enriched in the extracellular matrix of near‐senescent human diploid fibroblasts (HDFs). Treatment of young HDFs with PPKO reduced the viability of young HDFs in a dose‐ and time‐dependent manner and resulted in senescence‐associated β‐galactosidase (SA‐β‐gal) staining and G2/M cell cycle arrest. In addition, the levels of some senescence‐associated proteins, such as phosphorylated ERK1/2, caveolin‐1, p53, p16<SUP>ink4a</SUP>, and p21<SUP>waf1</SUP>, were elevated in PPKO‐treated cells. To monitor the effect of PPKO on cell stress responses, reactive oxygen species (ROS) production was examined by flow cytometry. After PPKO treatment, ROS levels transiently increased at 30 min but then returned to baseline at 60 min. The levels of some antioxidant enzymes, such as catalase, peroxiredoxin II and glutathione peroxidase I, were transiently induced by PPKO treatment. SOD II levels increased gradually, whereas the SOD I and III levels were biphasic during the experimental periods after PPKO treatment. Cellular senescence induced by PPKO was suppressed by chemical antioxidants, such as N‐acetylcysteine, 2,2,6,6‐tetramethylpiperidinyloxy, and L‐buthionine‐(<I>S</I>,<I>R</I>)‐sulfoximine. Furthermore, PPKO increased nitric oxide (NO) production via inducible NO synthase (iNOS) in HDFs. In the presence of NOS inhibitors, such as L‐NG‐nitroarginine methyl ester and L‐NG‐monomethylarginine, PPKO‐induced transient NO production and SA‐β‐gal staining were abrogated. Taken together, these results suggest that PPKO induces cellular senescence in association with transient ROS and NO production and the subsequent induction of senescence‐associated proteins<B>.</B></P>

Plant‐expressed Fc‐fusion protein tetravalent dengue vaccine with inherent adjuvant properties

Kim, Mi Young,Copland, Alastair,Nayak, Kaustuv,Chandele, Anmol,Ahmed, Muhammad S.,Zhang, Qibo,Diogo, Gil R.,Paul, Matthew J.,Hofmann, Sven,Yang, Moon&#x2010,Sik,Jang, Yong&#x2010,Suk,Ma, Julian K&#x20 BLACKWELL 2018 PLANT BIOTECHNOLOGY JOURNAL Vol.16 No.7

<P><B>Summary</B></P><P>Dengue is a major global disease requiring improved treatment and prevention strategies. The recently licensed Sanofi Pasteur Dengvaxia vaccine does not protect children under the age of nine, and additional vaccine strategies are thus needed to halt this expanding global epidemic. Here, we employed a molecular engineering approach and plant expression to produce a humanized and highly immunogenic poly‐immunoglobulin G scaffold (PIGS) fused to the consensus dengue envelope protein III domain (cEDIII). The immunogenicity of this IgG Fc receptor‐targeted vaccine candidate was demonstrated in transgenic mice expressing human FcγRI/CD64, by induction of neutralizing antibodies and evidence of cell‐mediated immunity. Furthermore, these molecules were able to prime immune cells from human adenoid/tonsillar tissue <I>ex vivo</I> as evidenced by antigen‐specific CD4<SUP>+</SUP> and CD8<SUP>+</SUP> T‐cell proliferation, IFN‐γ and antibody production. The purified polymeric fraction of dengue PIGS (D‐PIGS) induced stronger immune activation than the monomeric form, suggesting a more efficient interaction with the low‐affinity Fcγ receptors on antigen‐presenting cells. These results show that the plant‐expressed D‐PIGS have the potential for translation towards a safe and easily scalable single antigen‐based tetravalent dengue vaccine.</P>

3′‐Sialyllactose protects against osteoarthritic development by facilitating cartilage homeostasis

Jeon, Jimin,Kang, Li&#x2010,Jung,Lee, Kwang Min,Cho, Chanmi,Song, Eun Kyung,Kim, Wook,Park, Tae Joo,Yang, Siyoung John Wiley and Sons Inc. 2018 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.22 No.1

<P><B>Abstract</B></P><P>3′‐Sialyllactose has specific physiological functions in a variety of tissues; however, its effects on osteoarthritic development remain unknown. Here, we demonstrated the function of 3′‐sialyllactose on osteoarthritic cartilage destruction. <I>In vitro</I> and <I>ex vivo</I>, biochemical and histological analysis demonstrated that 3′‐sialyllactose was sufficient to restore the synthesis of Col2a1 and accumulation of sulphated proteoglycan, a critical factor for cartilage regeneration in osteoarthritic development, and blocked the expression of Mmp3, Mmp13 and Cox2 induced by IL‐1β, IL‐6, IL‐17 and TNF‐α, which mediates cartilage degradation. Further, reporter gene assays revealed that the activity of Sox9 as a transcription factor for Col2a1 expression was accelerated by 3′‐sialyllactose, whereas the direct binding of NF‐κB to the <I>Mmp3</I>,<I> Mmp13</I> and <I>Cox2</I> promoters was reduced by 3′‐sialyllactose in IL‐1β‐treated chondrocytes. Additionally, IL‐1β induction of Erk phosphorylation and IκB degradation, representing a critical signal pathway for osteoarthritic development, was totally blocked by 3′‐sialyllactose in a dose‐dependent manner. <I>In vivo</I>, 3′‐sialyllactose protected against osteoarthritic cartilage destruction in an osteoarthritis mouse model induced by destabilization of the medial meniscus, as demonstrated by histopathological analysis. Our results strongly suggest that 3′‐sialyllactose may ameliorate osteoarthritic cartilage destruction by cartilage regeneration <I>via</I> promoting Col2a1 production and may inhibit cartilage degradation and inflammation by suppressing Mmp3, Mmp13 and Cox2 expression. The effects of 3′‐sialyllactose could be attributed in part to its regulation of Sox9 or NF‐κB and inhibition of Erk phosphorylation and IκB degradation. Taken together, these effects indicate that 3′‐sialyllactose merits consideration as a natural therapeutic agent for protecting against osteoarthritis.</P>

3′‐Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis

Kang, Li&#x2010,Jung,Kwon, Eun&#x2010,Soo,Lee, Kwang Min,Cho, Chanmi,Lee, Jae&#x2010,In,Ryu, Young Bae,Youm, Tae Hyun,Jeon, Jimin,Cho, Mi Ra,Jeong, Seon&#x2010,Yong,Lee, Sang&#x2010,Rae,Kim, Wook,Yang John Wiley and Sons Inc. 2018 British journal of pharmacology Vol.175 No.23

<P><B>Background and Purpose</B></P><P>3′‐Sialyllactose (3′‐SL) is a safe compound that is present in high levels in human milk. Although it has anti‐inflammatory properties and supports immune homeostasis, its effect on collagen‐induced arthritis (CIA) is unknown. In this study, we investigated the prophylactic and therapeutic effect of 3′‐SL on the progression of rheumatoid arthritis (RA) in <I>in vitro</I> and <I>in vivo</I> models.</P><P><B>Experimental Approach</B></P><P>The anti‐arthritic effect of 3′‐SL was analysed with fibroblast‐like synoviocytes <I>in vitro</I> and an <I>in vivo</I> mouse model of CIA. RT‐PCR, Western blotting and ELISA were performed to evaluate its effects <I>in vitro</I>. Histological analysis of ankle and knee joints of mice with CIA was performed using immunohistochemistry, as well as safranin‐O and haematoxylin staining.</P><P><B>Key Results</B></P><P>3′‐SL markedly alleviated the severity of CIA in the mice by reducing paw swelling, clinical scores, incidence rate, serum levels of inflammatory cytokines and autoantibody production. Moreover, 3′‐SL reduced synovitis and pannus formation and suppressed cartilage destruction by blocking secretion of chemokines, pro‐inflammatory cytokines, https://en.wikipedia.org/wiki/Matrix_metalloproteinases and osteoclastogenesis <I>via</I> NF‐κB signalling. Notably, phosphorylation of p65, which is a key protein in the NF‐κB signalling pathway, was totally blocked by 3′‐SL in the RA models.</P><P><B>Conclusions and Implications</B></P><P>3′‐SL ameliorated pathogenesis of CIA by suppressing catabolic factor expression, proliferation of inflammatory immune cells and osteoclastogenesis. These effects were mediated <I>via</I> blockade of the NF‐κB signalling pathway. Therefore, 3′‐SL exerted prophylactic and therapeutic effects and could be a novel therapeutic agent for the treatment of RA.</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>

Role of CXCR2 in the Ac‐PGP‐Induced Mobilization of Circulating Angiogenic Cells and its Therapeutic Implications

Kwon, Yang Woo,Lee, Seung Jun,Heo, Soon Chul,Lee, Tae Wook,Park, Gyu Tae,Yoon, Jung Won,Kim, Seung&#x2010,Chul,Shin, Ho Jin,Lee, Sang Chul,Kim, Jae Ho unknown 2018 Stem cells translational medicine Vol.8 No.3

<P><B>Abstract</B></P><P>Circulating angiogenic cells (CACs) have been implicated in the repair of ischemic tissues, and their mobilization from bone marrow is known to be regulated by the activations of chemokine receptors, including CXCR2 and CXCR4. This study was conducted to investigate the role of N‐acetylated proline‐glycine‐proline (Ac‐PGP; a collagen‐derived chemotactic tripeptide) on CAC mobilization and its therapeutic potential for the treatment of peripheral artery diseases. Ac‐PGP was administered daily to a murine hind limb ischemia model, and the effects of Ac‐PGP on blood perfusion and CAC mobilization (Sca1<SUP>+</SUP>Flk1<SUP>+</SUP> cells) into peripheral blood were assessed. Intramuscular administration of Ac‐PGP significantly improved ischemic limb perfusion and increased limb salvage rate by increasing blood vessel formation, whereas Ac‐PGP‐induced blood perfusion and angiogenesis in ischemic limbs were not observed in CXCR2‐knockout mice. In addition, Ac‐PGP‐induced CAC mobilization was found to occur in wild‐type mice but not in CXCR2‐knockout mice. Transplantation of bone marrow from green fluorescent protein (GFP) transgenic mice to wild‐type mice showed bone marrow‐derived cells homed to ischemic limbs after Ac‐PGP administration and that GFP‐positive cells contributed to the formation of ILB4‐positive capillaries and α smooth muscle actin (α‐SMA)‐positive arteries. These results suggest CXCR2 activation in bone marrow after Ac‐PGP administration improves blood perfusion and reduces tissue necrosis by inducing CAC mobilization. These findings suggest a new pharmaceutical basis for the treatment of critical limb ischemia. <SMALL>STEM CELLS TRANSLATIONAL MEDICINE</SMALL><I>2019;8:236&246</I></P>

Melatonin improves the meiotic maturation of porcine oocytes by reducing endoplasmic reticulum stress during in vitro maturation

Park, Hyo&#x2010,Jin,Park, Jae&#x2010,Young,Kim, Jin&#x2010,Woo,Yang, Seul&#x2010,Gi,Jung, Jae&#x2010,Min,Kim, Min&#x2010,Ji,Kang, Man&#x2010,Jong,Cho, Young Ho,Wee, Gabbine,Yang, Hee&#x2010,Young,Son John Wiley and Sons Inc. 2018 Journal of pineal research Vol.64 No.2

<P><B>Abstract</B></P><P>Under endoplasmic reticulum (ER)‐stress conditions, the unfolded protein response (UPR) generates a defense mechanism in mammalian cells. The regulation of UPR signaling is important in oocyte maturation, embryo development, and female reproduction of pigs. Recent studies have shown that melatonin plays an important role as an antioxidant to improve pig oocyte maturation. However, there is no report on the role of melatonin in the regulation of UPR signaling and ER‐stress during in vitro maturation (IVM) of porcine oocytes. Therefore, the objective of this study was to investigate the antioxidative effects of melatonin on porcine oocyte maturation through the regulation of ER‐stress and UPR signaling. We investigated the changes in the mRNA/protein expression levels of three UPR signal genes (Bip/Grp78, ATF4, P90/50ATF6, sXbp1, and CHOP) on oocytes, cumulus cells, and cumulus‐oocyte complexes (COCs) during IVM (metaphase I; 22 hours and metaphase II; 44 hours) by Western blot and reverse transcription‐polymerase chain reaction analysis. Treatment with the ER‐stress inducer, tunicamycin (Tm), significantly increased expression of UPR markers. Additionally, cumulus cell expansion and meiotic maturation of oocytes were reduced in COCs of Tm‐treated groups (1, 5, and 10 μg/mL). We confirmed the reducing effects of melatonin (0.1 μmol/L) on ER‐stress after pretreatment with Tm (5 μg/mL; 22 hours) in maturing COCs. Addition of melatonin (0.1 μmol/L) to Tm‐pretreated COCs recovered meiotic maturation rates and expression of most UPR markers. In conclusion, we confirmed a role for melatonin in the modulation of UPR signal pathways and reducing ER‐stress during IVM of porcine oocytes.</P>

The rice Os NAC 6 transcription factor orchestrates multiple molecular mechanisms involving root structural adaptions and nicotianamine biosynthesis for drought tolerance

Lee, Dong&#x2010,Keun,Chung, Pil Joong,Jeong, Jin Seo,Jang, Geupil,Bang, Seung Woon,Jung, Harin,Kim, Youn Shic,Ha, Sun&#x2010,Hwa,Choi, Yang Do,Kim, Ju&#x2010,Kon BLACKWELL 2017 PLANT BIOTECHNOLOGY JOURNAL Vol.15 No.6

<P><B>Summary</B></P><P>Drought has a serious impact on agriculture worldwide. A plant's ability to adapt to rhizosphere drought stress requires reprogramming of root growth and development. Although physiological studies have documented the root adaption for tolerance to the drought stress, underlying molecular mechanisms is still incomplete, which is essential for crop engineering. Here, we identified <I>OsNAC6</I>‐mediated root structural adaptations, including increased root number and root diameter, which enhanced drought tolerance. Multiyear drought field tests demonstrated that the grain yield of <I>OsNAC6</I> root‐specific overexpressing transgenic rice lines was less affected by drought stress than were nontransgenic controls. Genome‐wide analyses of loss‐ and gain‐of‐function mutants revealed that OsNAC6 up‐regulates the expression of direct target genes involved in membrane modification, nicotianamine (NA) biosynthesis, glutathione relocation, 3′‐phophoadenosine 5′‐phosphosulphate accumulation and glycosylation, which represent multiple drought tolerance pathways. Moreover, overexpression of <I>NICOTIANAMINE SYNTHASE</I> genes, direct targets of OsNAC6, promoted the accumulation of the metal chelator NA and, consequently, drought tolerance. Collectively, OsNAC6 orchestrates novel molecular drought tolerance mechanisms and has potential for the biotechnological development of high‐yielding crops under water‐limiting conditions.</P>

Serum Adipokine Concentrations in Dogs with Naturally Occurring Pituitary‐Dependent Hyperadrenocorticism

Cho, K.&#x2010,D.,Paek, J.,Kang, J.&#x2010,H.,Chang, D.,Na, K.&#x2010,J.,Yang, M.&#x2010,P. John Wiley and Sons Inc. 2014 Journal of veterinary internal medicine Vol.28 No.2

<P><B>Background</B></P><P>An excess of intra‐abdominal fat is observed frequently in dogs with hyperadrenocorticism (HAC). Adipokine dysregulation is a possible cause of complications related to visceral obesity, but little information is available on adipokine in dogs with naturally occurring HAC.</P><P><B>Objectives</B></P><P>To examine the differences in the circulating adipokines concentrations in overweight dogs with and without pituitary‐dependent HAC (PDH).</P><P><B>Animals</B></P><P>Thirty healthy dogs and 15 client‐owned dogs with PDH.</P><P><B>Methods</B></P><P>Case–controlled observational study, which enrolled 15 overweight dogs diagnosed with PDH and 30 otherwise healthy dogs of similar body condition score. Nine of 15 dogs with PDH were treated with low‐dose trilostane twice daily and reassessed after treatment.</P><P><B>Results</B></P><P>The serum leptin (<I>P</I> < .0001) and insulin (<I>P</I> < .0001) concentrations were significantly higher in the PDH group (leptin, 22.8 ± 8.8 [mean ± SD]; insulin, 9.1 ± 6.1) than the healthy group (leptin, 4.9 ± 3.7; insulin, 1.9 ± 0.9). However, there were no significant differences in the adiponectin, resistin, tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6, IL‐10, and IL‐18 levels between the 2 groups. In the PDH group, the serum cortisol concentrations had a linear association with the leptin concentrations, and there were significant decreases in the leptin (<I>P</I> = .0039) and insulin (<I>P</I> = .0039) levels after trilostane treatment. However, the leptin and insulin levels remained higher after trilostane treatment than in healthy control dogs with similar body condition score.</P><P><B>Conclusions and Clinical Importance</B></P><P>Hypercortisolemia in dogs with PDH might upregulate the circulating leptin levels. However, a large population‐based study will be necessary to determine whether the upregulation of leptin is involved directly with the complications caused by HAC.</P>