Comparison of VMAT‐SABR treatment plans with flattening filter (FF) and flattening filter‐free (FFF) beam for localized prostate cancer

Chung, Jin&#x2010,Beom,Kim, Jae&#x2010,Sung,Eom, Keun&#x2010,Yong,Kim, In&#x2010,Ah,Kang, Sang&#x2010,Won,Lee, Jeong&#x2010,Woo,Kim, Jin&#x2010,Young,Suh, Tae&#x2010,Suk unknown 2015 Journal of applied clinical medical physics Vol.16 No.6

<P>The purpose of this study is to investigate the feasibility of using a flattening filter‐free (FFF) beam with an endorectal balloon for stereotactic ablative body radiotherapy (SABR) of clinically localized prostate cancer. We assessed plans of SABR with volumetric‐modulated arc therapy (VMAT) that used a flattening filter (FF) beam and an FFF beam and compared the verification results of dosimetric quality assurance for all pretreatment plans. A total of 20 patients with prostate cancer were enrolled in the study. SABR plans using VMAT with two full arcs were optimized in the Eclipse treatment planning system. All plans prescribed 42.7 Gy in 7 fractions of 6.1 Gy each. Four SABR plans were computed for each patient: two with FF beams and two with FFF beams of 6 and 10 MV. For all plans, the cumulative dose‐volume histograms (DVHs) for the target volumes and organs at risk (OARs) were recorded and compared. Pretreatment quality assurance (QA) was performed using the I'm<I>RT</I> MatriXX system and radiochromic EBT3 film to verify treatment delivery, and gamma analysis was used to quantify the agreement between calculations and measurements. In addition, total monitor units (MUs) and delivery time were investigated as technical parameters of delivery. All four plans achieved adequate dose conformity to the target volumes and had comparable dosimetric data. The DVHs of all four plans for each patient were very similar. All plans were highly conformal with CI<1.05 and CN>0.90, and the doses were homogeneous (HI = 0.08–0.15). Sparing for the bladder and rectum was slightly better with the 10 MV FF and FFF plans than with the 6 MV FF and FFF plans, but the difference was negligible. However, there was no significant difference in sparing for the other OARs. The mean agreement with the 3%/3% mm criterion was higher than 97% for verifying all plans. For the 2%/2% mm criterion, the corresponding agreement values were more than 90%, which showed that the plans were acceptable. The mean MUs and delivery time used were 1701±101 and 3.02±0.17 min for 6 MV FF, 1870±116 and 2.01±0.01 min for 6 MV FFF, 1471±86 and 2.68±0.14 min for 10 MV FF, and 1619±101 and 2.00±0.00 min for 10 MV FFF, respectively. In the current study, the dose distributions of the prostate SABR plans using 6 and 10 MV FFF beams were similar to those using 6 and 10 MV FF beams. However, this study confirmed that SABR treatment using an FFF beam had an advantage with respect to delivery time. In addition, all pretreatment plans were verified as acceptable and their results were comparable. Therefore, the results of this study suggest that the use of an FFF beam for prostate SABR is a feasible and efficient technique, if carefully applied.</P><P>PACS numbers: 87.55.D, 87.55.dk</P>

Overexpression of <i>OsERF48</i> causes regulation of <i>OsCML16</i> , a calmodulin‐like protein gene that enhances root growth and drought tolerance

Jung, Harin,Chung, Pil Joong,Park, Su&#x2010,Hyun,Redillas, Mark Christian Felipe Reveche,Kim, Youn Shic,Suh, Joo&#x2010,Won,Kim, Ju&#x2010,Kon BLACKWELL 2017 PLANT BIOTECHNOLOGY JOURNAL Vol.15 No.10

<P><B>Summary</B></P><P>The AP2/ERF family is a plant‐specific transcription factor family whose members have been associated with various developmental processes and stress tolerance. Here, we functionally characterized the drought‐inducible <I>OsERF48</I>, a group Ib member of the rice ERF family with four conserved motifs, CMI‐1, ‐2, ‐3 and ‐4. A transactivation assay in yeast revealed that the C‐terminal CMI‐1 motif was essential for OsERF48 transcriptional activity. When <I>OsERF48</I> was overexpressed in an either a root‐specific (ROXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP>) or whole‐body (OXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP>) manner, transgenic plants showed a longer and denser root phenotype compared to the nontransgenic (NT) controls. When plants were grown on a 40% polyethylene glycol‐infused medium under <I>in vitro</I> drought conditions, ROXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> plants showed a more vigorous root growth than OXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> and NT plants. In addition, the ROXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> plants exhibited higher grain yield than OXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> and NT plants under field‐drought conditions. We constructed a putative <I>OsERF48</I> regulatory network by cross‐referencing ROXO<SUP><I>s</I></SUP>ERF<SUP><I>48</I></SUP> root‐specific RNA‐seq data with a co‐expression network database, from which we inferred the involvement of 20 drought‐related genes in <I>OsERF48</I>‐mediated responses. These included genes annotated as being involved in stress signalling, carbohydrate metabolism, cell‐wall proteins and drought responses. They included, <I>OsCML16</I>, a key gene in calcium signalling during abiotic stress, which was shown to be a direct target of OsERF48 by chromatin immunoprecipitation‐qPCR analysis and a transient protoplast expression assay. Our results demonstrated that OsERF48 regulates <I>OsCML16</I>, a calmodulin‐like protein gene that enhances root growth and drought tolerance.</P>

K _Ca 3.1 upregulation preserves endothelium‐dependent vasorelaxation during aging and oxidative stress

Choi, Shinkyu,Kim, Ji Aee,Li, Hai&#x2010,yan,Shin, Kyong&#x2010,Oh,Oh, Goo Taeg,Lee, Yong&#x2010,Moon,Oh, Seikwan,Pewzner&#x2010,Jung, Yael,Futerman, Anthony H.,Suh, Suk Hyo BLACKWELL PUBLISHING 2016 AGING CELL Vol.15 No.5

<P><B>Summary</B></P><P>Endothelial oxidative stress develops with aging and reactive oxygen species impair endothelium‐dependent relaxation (EDR) by decreasing nitric oxide (NO) availability. Endothelial K<SUB>Ca</SUB>3.1, which contributes to EDR, is upregulated by H<SUB>2</SUB>O<SUB>2</SUB>. We investigated whether K<SUB>Ca</SUB>3.1 upregulation compensates for diminished EDR to NO during aging‐related oxidative stress. Previous studies identified that the levels of ceramide synthase 5 (CerS5), sphingosine, and sphingosine 1‐phosphate were increased in aged wild‐type and CerS2 mice. In primary mouse aortic endothelial cells (MAECs) from aged wild‐type and CerS2 null mice, superoxide dismutase (SOD) was upregulated, and catalase and glutathione peroxidase 1 (GPX1) were downregulated, when compared to MAECs from young and age‐matched wild‐type mice. Increased H<SUB>2</SUB>O<SUB>2</SUB> levels induced Fyn and extracellular signal‐regulated kinases (ERKs) phosphorylation and K<SUB>Ca</SUB>3.1 upregulation. Catalase/GPX1 double knockout (catalase<SUP>−/−</SUP>/GPX1<SUP>−/−</SUP>) upregulated K<SUB>Ca</SUB>3.1 in MAECs. NO production was decreased in aged wild‐type, CerS2 null, and catalase<SUP>−/−</SUP>/GPX1<SUP>−/−</SUP>MAECs. However, K<SUB>Ca</SUB>3.1 activation‐induced, NG‐nitro‐<SMALL>L</SMALL>‐arginine‐, and indomethacin‐resistant EDR was increased without a change in acetylcholine‐induced EDR in aortic rings from aged wild‐type, CerS2 null, and catalase<SUP>−/−</SUP>/GPX1<SUP>−/−</SUP> mice. CerS5 transfection or exogenous application of sphingosine or sphingosine 1‐phosphate induced similar changes in levels of the antioxidant enzymes and upregulated K<SUB>Ca</SUB>3.1. Our findings suggest that, during aging‐related oxidative stress, SOD upregulation and downregulation of catalase and GPX1, which occur upon altering the sphingolipid composition or acyl chain length, generate H<SUB>2</SUB>O<SUB>2</SUB> and thereby upregulate K<SUB>Ca</SUB>3.1 expression and function via a H<SUB>2</SUB>O<SUB>2</SUB>/Fyn‐mediated pathway. Altogether, enhanced K<SUB>Ca</SUB>3.1 activity may compensate for decreased NO signaling during vascular aging.</P>

Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle via KC _a 1.1 upregulation

Choi, Shinkyu,Kim, Ji Aee,Kim, Tae Hun,Li, Hai&#x2010,yan,Shin, Kyong&#x2010,Oh,Lee, Yong&#x2010,Moon,Oh, Seikwan,Pewzner&#x2010,Jung, Yael,Futerman, Anthony H.,Suh, Suk Hyo BLACKWELL PUBLISHING 2015 AGING CELL Vol.14 No.6

<P><B>Summary</B></P><P>KC<SUB>a</SUB>1.1 regulates smooth muscle contractility by modulating membrane potential, and age‐associated changes in KC<SUB>a</SUB>1.1 expression may contribute to the development of motility disorders of the gastrointestinal tract. Sphingolipids (SLs) are important structural components of cellular membranes whose altered composition may affect KC<SUB>a</SUB>1.1 expression. Thus, in this study, we examined whether altered SL composition due to aging may affect the contractility of gastric smooth muscle (GSM). We studied changes in ceramide synthases (CerS) and SL levels in the GSM of mice of varying ages and compared them with those in young CerS2‐null mice. The levels of C16‐ and C18‐ceramides, sphinganine, sphingosine, and sphingosine 1‐phosphate were increased, and levels of C22, C24:1 and C24 ceramides were decreased in the GSM of both aged wild‐type and young CerS2‐null mice. The altered SL composition upregulated KC<SUB>a</SUB>1.1 and increased KC<SUB>a</SUB>1.1 currents, while no change was observed in KC<SUB>a</SUB>1.1 channel activity. The upregulation of KC<SUB>a</SUB>1.1 impaired intracellular Ca2+ mobilization and decreased phosphorylated myosin light chain levels, causing GSM contractile dysfunction. Additionally, phosphoinositide 3‐kinase, protein kinase C<SUB>ζ</SUB>, c‐Jun N‐terminal kinases, and nuclear factor kappa‐B were found to be involved in KC<SUB>a</SUB>1.1 upregulation. Our findings suggest that age‐associated changes in SL composition or CerS2 ablation upregulate KC<SUB>a</SUB>1.1 via the phosphoinositide 3‐kinase/protein kinase C<SUB>ζ</SUB>/c‐Jun N‐terminal kinases/nuclear factor kappa‐B‐mediated pathway and impair Ca2+ mobilization, which thereby induces the contractile dysfunction of GSM. CerS2‐null mice exhibited similar effects to aged wild‐type mice; therefore, CerS2‐null mouse models may be utilized for investigating the pathogenesis of aging‐associated motility disorders.</P>

Phase‐sensitive, dual‐acquisition, single‐slab, 3D, turbo‐spin‐echo pulse sequence for simultaneous <i>T</i>₂‐weighted and fluid‐attenuated whole‐brain imaging

Park, Jaeseok,Park, Suhyung,Yeop Kim, Eung,Suh, Jin&#x2010,Suck Wiley Subscription Services, Inc., A Wiley Company 2010 Magnetic resonance in medicine Vol.63 No.5

<P><B>Abstract</B></P><P>Conventional <I>T</I><SUB>2</SUB>‐weighted turbo/fast spin echo imaging is clinically accepted as the most sensitive method to detect brain lesions but generates a high signal intensity of cerebrospinal fluid (CSF), yielding diagnostic ambiguity for lesions close to CSF. Fluid‐attenuated inversion recovery can be an alternative, selectively eliminating CSF signals. However, a long time of inversion, which is required for CSF suppression, increases imaging time substantially and thereby limits spatial resolution. The purpose of this work is to develop a phase‐sensitive, dual‐acquisition, single‐slab, three‐dimensional, turbo/fast spin echo imaging, simultaneously achieving both conventional <I>T</I><SUB>2</SUB>‐weighted and fluid‐attenuated inversion recovery–like high‐resolution whole‐brain images in a single pulse sequence, without an apparent increase of imaging time. Dual acquisition in each time of repetition is performed, wherein an in phase between CSF and brain tissues is achieved in the first acquisition, while an opposed phase, which is established by a sequence of a long refocusing pulse train with variable flip angles, a composite flip‐down restore pulse train, and a short time of delay, is attained in the second acquisition. A CSF‐suppressed image is then reconstructed by weighted averaging the in‐ and opposed‐phase images. Numerical simulations and in vivo experiments are performed, demonstrating that this single pulse sequence may replace both conventional <I>T</I><SUB>2</SUB>‐weighted imaging and fluid‐attenuated inversion recovery. Magn Reson Med 63:1422–1430, 2010. © 2010 Wiley‐Liss, Inc.</P>

A static multi‐slit collimator system for scatter reduction in cone‐beam CT

Chang, Jina,Kim, Siyong,Jang, Doh&#x2010,Yun,Suh, Tae&#x2010,Suk John Wiley and Sons Inc. 2010 Journal of applied clinical medical physics Vol.11 No.4

<P>A multiple‐slit collimator (MSC) design was introduced for scatter reduction in cone‐beam computed tomography (CBCT). Unlike most other collimators, the open and closed septa of the proposed MSC are placed in an equi‐angular interval on a circular track of the central sagittal plane. Therefore, one gantry rotation provides only the half of necessary dataset and two gantry rotations are needed to obtain full information. During the first gantry rotation, the MSC position relative to the source is fixed. For the second rotation, the MSC is rotated by the equi‐angle interval. We assume signals under the closed septa are totally attributed to scatter radiation. Then, scatter contributions under open septa are determined by interpolating them.</P><P>Monte Carlo (MC) simulations for two virtual phantoms (one with a simple geometry and the other with two heterogeneities simulating the bone and the lung) were performed to evaluate the effectiveness of the system. Using the method developed, we could obtain images with significant scatter reduction. Contrast ratio (CR) improvement factors were 1.165 in a 2D projection view, and 1.210 and 1.223 at the central and peripheral slice of the reconstructed CBCT image of the simple geometry phantom.</P><P>This preliminary study demonstrated that the proposed MSC, together with the imaging process technique, had a great potential to reduce scatter contribution in CBCT. Further studies will be performed to investigate the effect of various factors, such as reducing the detector size, increasing the number of history of MC simulation, and including many structures with different densities.</P><P>PACS number: 87.57.C</P>

The growth of brain tumors can be suppressed by multiple transplantation of mesenchymal stem cells expressing cytosine deaminase

Chang, Da&#x2010,Young,Yoo, Seung&#x2010,Wan,Hong, Youngtae,Kim, Sujeong,Kim, Se Joong,Yoon, Sung&#x2010,Hwa,Cho, Kyung&#x2010,Gi,Paek, Sun Ha,Lee, Young&#x2010,Don,Kim, Sung&#x2010,Soo,Suh‐,Kim Wiley Subscription Services, Inc., A Wiley Company 2010 International journal of cancer: Journal internati Vol.127 No.8

<P><B>Abstract</B></P><P>Suicide genes have recently emerged as an attractive alternative therapy for the treatment of various types of intractable cancers. The efficacy of suicide gene therapy relies on efficient gene delivery to target tissues and the localized concentration of final gene products. Here, we showed a potential <I>ex vivo</I> therapy that used mesenchymal stem cells (MSCs) as cellular vehicles to deliver a bacterial suicide gene, cytosine deaminase (CD) to brain tumors. MSCs were engineered to produce CD enzymes at various levels using different promoters. When co‐cultured, CD‐expressing MSCs had a bystander, anti‐cancer effect on neighboring C6 glioma cells in proportion to the levels of CD enzymes that could convert a nontoxic prodrug, 5‐fluorocytosine (5‐FC) into cytotoxic 5‐fluorouracil (5‐FU) <I>in vitro</I>. Consistent with the <I>in vitro</I> results, for early stage brain tumors induced by intracranial inoculation of C6 cells, transplantation of CD‐expressing MSCs reduced tumor mass in proportion to 5‐FC dosages. However, for later stage, established tumors, a single treatment was insufficient, but only multiple transplantations were able to successfully repress tumor growth. Our findings indicate that the level of total CD enzyme activity is a critical parameter that is likely to affect the clinical efficacy for CD gene therapy. Our results also highlight the potential advantages of autograftable MSCs compared with other types of allogeneic stem cells for the treatment of recurrent glioblastomas through repetitive treatments.</P>

MicroRNA‐320a and microRNA‐4496 attenuate <i>Helicobacter pylori</i> cytotoxin‐associated gene A (CagA)‐induced cancer‐initiating potential and chemoresistance by targeting β‐catenin and ATP‐binding casse

Kang, Dong Woo,Yang, Eun Sun,Noh, Yu Na,Hwang, Won Chan,Jo, Se&#x2010,Young,Suh, Young&#x2010,Ah,Park, Won Sang,Choi, Kang&#x2010,Yell,Min, Do Sik John Wiley Sons, Ltd 2017 The Journal of pathology Vol.241 No.5

<P><B>Abstract</B></P><P>Infection with <I>Helicobacter pylori</I> is closely linked to an increased risk of gastric cancer. Although cytotoxin‐associated gene A (CagA), a major virulence factor of <I>H. pylori</I>, is known to be a causal factor for gastric carcinogenesis, the molecular link between CagA and gastric cancer‐initiating cell (CIC)‐like properties remains elusive. Here, we demonstrate that CagA is required for increased expression of β‐catenin and its target CIC markers via downregulation of microRNA (miR)‐320a and miR‐4496. CagA promoted gastric CIC properties and was responsible for chemoresistance. miR‐320a and miR‐4496 attenuated the <I>in vitro</I> self‐renewal and tumour‐initiating capacity of CagA‐expressing CICs by targeting β‐catenin. Moreover, miR‐320a and miR‐4496 decreased CagA‐induced chemoresistance by targeting ATP‐binding cassette, subfamily G, member 2 (ABCG2) at the transcriptional and post‐transcriptional levels, respectively. Combination therapy with 5‐fluorouracil and miR‐320a/miR‐4496 suppressed gastric tumourigenesis and metastatic potential in an orthotopic mouse model, probably via suppression of CagA‐induced CIC properties and chemoresistance. Our results provide novel evidence that CIC properties, chemoresistance and tumourigenesis associated with <I>H. pylori</I> are linked to CagA‐induced upregulation of β‐catenin and ABCG2. These data provide novel insights into the molecular mechanisms of CagA‐induced carcinogenisis and the therapeutic potential of of miR‐320a and miR‐4496. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</P>

15‐deoxy‐Δ^12,14‐prostaglandin J₂ inhibits human immunodeficiency virus‐1 tat‐induced monocyte chemoattractant protein‐1/CCL2 production by blocking the extracellular signal‐regulated

Kim, Sang Eun,Lee, Eun Ok,Yang, Ji Hye,Kang, Ji Hee Lee,Suh, Yoo&#x2010,Hun,Chong, Young Hae Wiley Subscription Services, Inc., A Wiley Company 2012 JOURNAL OF NEUROSCIENCE RESEARCH - Vol.90 No.9

<P><B>Abstract</B></P><P>Human immunodeficiency virus (HIV)‐induced inflammation, and its consequences within the central nervous system (CNS), must be countered by multiple pharmacologic agents, and 15‐deoxy‐Δ<SUP>12,14</SUP>‐prostaglandin J<SUB>2</SUB> (15d‐PGJ2) may hold promise in the treatment of pathologies associated with this inflammatory response. 15d‐PGJ2 can repress the inflammatory response by means of peroxisome proliferator‐activated receptor‐γ (PPARγ)‐dependent and ‐independent mechanisms. However, its precise role and antiinflammatory mechanism in the hippocampus remain poorly understood. In the present study, rat hippocampal slices were stimulated with full‐length HIV‐1 Tat protein to investigate the role of 15d‐PGJ2 8in the hippocampal inflammatory response. Pretreatment of slices with 15d‐PGJ2 markedly reduced Tat‐induced monocyte chemoattractant protein‐1 (MCP‐1/CCL2) production. Interestingly, the PPARγ antagonist GW9662 did not inhibit action of 15d‐PGJ2, confirming the latter's PPARγ‐independent mechanism of mediating antiinflammatory effects. Despite 15d‐PGJ2's increasing the expression of heme oxygenase‐1 (HO‐1), its action was not abrogated by the HO‐1 inhibitor zinc protoporphyrin IX (ZnPPIX), nor was it recapitulated by HO‐1 inducers such as cobalt protoporphyrin (CoPP). Moreover, short interfering RNA (siRNA)‐directed knockdown of HO‐1 did not abolish the antiinflammatory action of 15d‐PGJ2 against Tat‐induced MCP‐1 production in human microglia‐like THP‐1 cells. Conversely, 15d‐PGJ2 suppressed Tat‐induced ERK1/2 activation, decreasing MCP‐1 production upon Tat stimulation. The NADPH oxidase inhibitors DPI and apocynin also abrogated Tat‐stimulated ERK1/2 activation, reducing MCP‐1 production. Collectively, these data demonstrate that the antiinflammatory effects of 15d‐PGJ2 on the hippocampus are exerted through inhibition of Tat‐mediated ERK1/2 activation, coupled with that of a redox‐sensitive pathway, independent of PPARγ and HO‐1. © 2012 Wiley Periodicals, Inc.</P>

P2Y12 antagonist attenuates eosinophilic inflammation and airway hyperresponsiveness in a mouse model of asthma

Suh, Dong&#x2010,Hyeon,Trinh, Hoang Kim Tu,Liu, Jing&#x2010,Nan,Pham, Le Duy,Park, Sang Myun,Park, Hae&#x2010,Sim,Shin, Yoo Seob CAROL DAVILA UNIVERSITY PRESS 2016 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.20 No.2

<P><B>Abstract</B></P><P>Leukotriene E4 (LTE4) that plays a key role in airway inflammation is expressed on platelets and eosinophils. We investigated whether blocking of the P2Y12 receptor can suppress eosinophilic inflammation in a mouse model of asthma because platelets and eosinophils share this receptor to be activated. BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed by OVA nebulization. On each challenge day, clopidogrel, a P2Y12 antagonist was administered 30 min. before each challenge. Forty‐eight hours after the last OVA challenge, mice were assessed for airway hyperresponsiveness (AHR), cell composition and cytokine levels, including chemokine ligand 5 (CCL5), in bronchoalveolar lavage (BAL) fluid. EOL cells were treated with LTE4, with or without clopidogrel treatment, and intracellular and extracellular eosinophil cationic protein (ECP) expressions were measured to find the inhibiting function of P2Y12 antagonist on eosinophilic activation. The levels of P2Y12 expression were increased markedly in the lung homogenates of OVA‐sensitized and ‐challenged mice after platelet depletion. Administration of clopidogrel decreased AHR and the number of airway inflammatory cells, including eosinophils, in BAL fluid following OVA challenge. These results were associated with decreased levels of Th2 cytokines and CCL5. Histological examination showed that inflammatory cells as well as mucus‐containing goblet cells were reduced in clopidogrel‐administered mice compared to vehicle‐treated mice. Clopidogrel inhibited extracellular ECP secretion after LTE4 stimulation in EOL‐1 cells. Clopidogrel could prevent development of AHR and airway inflammation in a mouse model of asthma. P2Y12 can be a novel therapeutic target to the suppression of eosinophils in asthma.</P>