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>

Efficacy and safety of ipragliflozin as an add‐on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: A randomized controlled trial

Han, Kyung&#x2010,Ah,Chon, Suk,Chung, Choon Hee,Lim, Soo,Lee, Kwan&#x2010,Woo,Baik, SeiHyun,Jung, Chang Hee,Kim, Dong&#x2010,Sun,Park, Kyong Soo,Yoon, Kun&#x2010,Ho,Lee, In&#x2010,Kyu,Cha, Bong&#x2010 Blackwell Publishing Ltd 2018 DIABETES OBESITY AND METABOLISM Vol.20 No.10

<P><B>Aim</B></P><P>To evaluate the efficacy and safety of ipragliflozin vs placebo as add‐on therapy to metformin and sitagliptin in Korean patients with type 2 diabetes mellitus (T2DM).</P><P><B>Methods</B></P><P>This double‐blind, placebo‐controlled, multi‐centre, phase III study was conducted in Korea in 2015 to 2017. Patients were randomized to receive either ipragliflozin 50 mg/day or placebo once daily for 24 weeks in addition to metformin and sitagliptin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to end of treatment (EOT).</P><P><B>Results</B></P><P>In total, 143 patients were randomized and 139 were included in efficacy analyses (ipragliflozin: 73, placebo: 66). Baseline mean (SD) HbA1c levels were 7.90 (0.69)% for ipragliflozin add‐on and 7.92 (0.79)% for placebo. The corresponding mean (SD) changes from baseline to EOT were −0.79 (0.59)% and 0.03 (0.84)%, respectively, in favour of ipragliflozin (adjusted mean difference −0.83% [95% CI −1.07 to −0.59]; <I>P</I> < .0001). More ipragliflozin‐treated patients than placebo‐treated patients achieved HbA1c target levels of <7.0% (44.4% vs 12.1%) and < 6.5% (12.5% vs 1.5%) at EOT (<I>P</I> < .05 for both). Fasting plasma glucose, fasting serum insulin, body weight and homeostatic model assessment of insulin resistance decreased significantly at EOT, in favour of ipragliflozin (adjusted mean difference −1.64 mmol/L, −1.50 μU/mL, −1.72 kg, and −0.99, respectively; <I>P</I> < .05 for all). Adverse event rates were similar between groups (ipragliflozin: 51.4%; placebo: 50.0%). No previously unreported safety concerns were noted.</P><P><B>Conclusions</B></P><P>Ipragliflozin as add‐on to metformin and sitagliptin significantly improved glycaemic variables and demonstrated a good safety profile in Korean patients with inadequately controlled T2DM.</P>

2′‐Hydroxycinnamaldehyde inhibits proliferation and induces apoptosis via signal transducer and activator of transcription 3 inactivation and reactive oxygen species generation

Yoon, Yae Jin,Kim, Young&#x2010,Hwan,Lee, Yu&#x2010,Jin,Choi, Jiyeon,Kim, Cheol&#x2010,Hee,Han, Dong Cho,Kwon, Byoung&#x2010,Mog John Wiley and Sons Inc. 2019 CANCER SCIENCE Vol.110 No.1

<P>Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway is a novel therapeutic strategy to treat human cancers with constitutively active STAT3. During the screening of natural products to find STAT3 inhibitors, we identified 2′‐hydroxycinnamaldehyde (HCA) as a STAT3 inhibitor, which was isolated from the stem bark of <I>Cinnamomum cassia</I>. In this study, we found that HCA inhibited constitutive and inducible STAT3 activation in STAT3‐activated DU145 prostate cancer cells. HCA selectively inhibited the STAT3 activity by direct binding to STAT3, which was confirmed by biochemical methods, including a pull‐down assay with biotin‐conjugated HCA, a drug affinity responsive target stability (DARTS) experiment and a cellular thermal shift assay (CETSA). HCA inhibited STAT3 phosphorylation at the tyrosine 705 residue, dimer formation, and nuclear translocation in DU145 cells, which led to a downregulation of STAT3 target genes. The downregulation of cell cycle progression and antiapoptosis‐related gene expression by HCA induced the accumulation of cells in the G0/G1 phase of the cell cycle and then induced apoptosis. We also found that reactive oxygen species (ROS) were involved in the HCA‐induced inhibition of STAT3 activation and cell proliferation because the suppressed p‐STAT3 level was rescued by glutathione or N‐acetyl‐L‐cysteine treatment, which are general ROS inhibitors. These results suggest that HCA could be a potent anticancer agent targeting STAT3‐activated tumor cells.</P>

22‐ S ‐Hydroxycholesterol protects against ethanol‐induced liver injury by blocking the auto/paracrine activation of MCP ‐1 mediated by LXRα

Na, Tae&#x2010,Young,Han, Young&#x2010,Hyun,Ka, Na&#x2010,Lee,Park, Han&#x2010,Su,Kang, Yun Pyo,Kwon, Sung Won,Lee, Byung&#x2010,Hoon,Lee, Mi&#x2010,Ock John WileySons, Ltd 2015 The Journal of pathology Vol.235 No.5

<P><B>Abstract</B></P><P>Chronic ethanol consumption causes hepatic steatosis and inflammation, which are associated with liver hypoxia. Monocyte chemoattractant protein‐1 (MCP‐1) is a hypoxia response factor that determines recruitment and activation of monocytes to the site of tissue injury. The level of MCP‐1 is elevated in the serum and liver of patients with alcoholic liver disease (ALD); however, the molecular details regarding the regulation of MCP‐1 expression are not yet understood completely. Here, we show the role of liver X receptor α (LXRα) in the regulation of MCP‐1 expression during the development of ethanol‐induced fatty liver injury, using an antagonist, 22‐S‐hydroxycholesterol (22‐S‐HC). First, administration of 22‐S‐HC attenuated the signs of liver injury with decreased levels of MCP‐1 and its receptor CCR2 in ethanol‐fed mice. Second, hypoxic conditions or treatment with the LXRα agonist GW3965 significantly induced the expression of MCP‐1, which was completely blocked by treatment with 22‐S‐HC or infection by shLXRα lentivirus in the primary hepatocytes. Third, over‐expression of LXRα or GW3965 treatment increased MCP‐1 promoter activity by increasing the binding of hypoxia‐inducible factor‐1α to the hypoxia response elements, together with LXRα. Finally, treatment with recombinant MCP‐1 increased the level of expression of LXRα and LXRα‐dependent lipid droplet accumulation in both hepatocytes and Kupffer cells. These data show that LXRα and its ligand‐induced up‐regulation of MCP‐1 and MCP‐1‐induced LXRα‐dependent lipogenesis play a key role in the autocrine and paracrine activation of MCP‐1 in the pathogenesis of alcoholic fatty liver disease, and that this activation may provide a promising new target for ALD therapy.Copyright © 2014 The Authors. <I>The Journal of Pathology</I> published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.</P>

Caveolin‐1 deficiency induces premature senescence with mitochondrial dysfunction

Yu, Dong&#x2010,Min,Jung, Seung Hee,An, Hyoung&#x2010,Tae,Lee, Sungsoo,Hong, Jin,Park, Jun Sub,Lee, Hyun,Lee, Hwayeon,Bahn, Myeong&#x2010,Suk,Lee, Hyung Chul,Han, Na&#x2010,Kyung,Ko, Jesang,Lee, Jae&# BLACKWELL PUBLISHING 2017 AGING CELL Vol.16 No.4

<P><B>Summary</B></P><P>Paradoxical observations have been made regarding the role of caveolin‐1 (Cav‐1) during cellular senescence. For example, caveolin‐1 deficiency prevents reactive oxygen species‐induced cellular senescence despite mitochondrial dysfunction, which leads to senescence. To resolve this paradox, we re‐addressed the role of caveolin‐1 in cellular senescence in human diploid fibroblasts, A549, HCT116, and Cav‐1<SUP><I>−/−</I></SUP> mouse embryonic fibroblasts. Cav‐1 deficiency (knockout or knockdown) induced cellular senescence via a p53‐p21‐dependent pathway, downregulating the expression level of the cardiolipin biosynthesis enzymes and then reducing the content of cardiolipin, a critical lipid for mitochondrial respiration. Our results showed that Cav‐1 deficiency decreased mitochondrial respiration, reduced the activity of oxidative phosphorylation complex I (CI), inactivated SIRT1, and decreased the NAD<SUP>+</SUP>/NADH ratio. From these results, we concluded that Cav‐1 deficiency induces premature senescence via mitochondrial dysfunction and silent information regulator 2 homologue 1 (SIRT1) inactivation.</P>

Downregulation of CHIP promotes ovarian cancer metastasis by inducing Snail‐mediated epithelial–mesenchymal transition

Park, Sun&#x2010,Mi,Park, Seung&#x2010,Ho,Ryu, Ki&#x2010,Jun,Kim, In&#x2010,Kyu,Han, Hyeontak,Kim, Hyo&#x2010,Jin,Kim, Seon&#x2010,Hee,Hong, Keun&#x2010,Seok,Kim, Hyemin,Kim, Minju,Cho, Bok Im,Heo, Je Elsevier Science B.V. Amsterdam 2019 MOLECULAR ONCOLOGY Vol.13 No.5

<P>The epithelial–mesenchymal transition (EMT) plays a pivotal role in the conversion of early‐stage tumors into invasive malignancies. The transcription factor Snail, an extremely unstable protein whose subcellular levels are regulated by many E3 ubiquitin ligases, promotes EMT as well as associated pathological characteristics including migration, invasion, and metastasis. Through yeast two‐hybrid screening, we identified the carboxyl terminus of Hsc70‐interacting protein (CHIP) as a novel Snail ubiquitin ligase that interacts with Snail to induce ubiquitin‐mediated proteasomal degradation. Inhibition of CHIP expression increases Snail protein levels, induces EMT, and enhances <I>in vitro</I> migration and invasion as well as <I>in vivo</I> metastasis of ovarian cancer cells. In turn, Snail depletion abrogates all phenomena induced by CHIP depletion. Finally, Snail and CHIP expression is inversely correlated in ovarian tumor tissues. These findings establish the CHIP–Snail axis as a post‐translational mechanism of EMT and cancer metastasis regulation.</P>

Comparison of 90‐day case‐fatality after ischemic stroke between two different stroke outcome registries using propensity score matching analysis

Yu, K&#x2010,H.,Hong, K&#x2010,S.,Lee, B&#x2010,C.,Oh, M&#x2010,S.,Cho, Y&#x2010,J.,Koo, J&#x2010,S.,Park, J&#x2010,M.,Bae, H&#x2010,J.,Han, M&#x2010,K.,Ju, Y&#x2010,S.,Kang, D&#x2010,W.,Appelros, P. Blackwell Publishing Ltd 2011 Acta neurologica Scandinavica Vol.123 No.5

<P>Yu K‐H, Hong K‐S, Lee B‐C, Oh M‐S, Cho Y‐J, Koo J‐S, Park J‐M, Bae H‐J, Han M‐K, Ju Y‐S, Kang D‐W, Appelros P, Norrving B, Terent A. Comparison of 90‐day case‐fatality after ischemic stroke between two different stroke outcome registries using propensity score matching analysis. 
Acta Neurol Scand: 2011: 123: 325–331. 
© 2010 John Wiley & Sons A/S.</P><P><B>Background – </B> It has not been clarified whether the disparity in ischemic stroke outcome between populations is caused by ethnic and geographic differences or by variations in case mix. Propensity score matching (PSM) analysis can overcome some analytical problems but is rarely used in stroke outcome research. This study was to compare the ischemic stroke case‐fatality between two PSM cohorts of Sweden and Korea.</P><P><B>Methods – </B> Prognostic variables related to baseline characteristics and stroke care were included in our PSM model. Then, we selected 7675 Swedish and 1220 Korean patients with ischemic stroke from each stroke registers and performed one‐to‐one matching based on propensity scores of each patient.</P><P><B>Results – </B> After PSM, all measured variables were well balanced in 1163 matched subjects, and the 90‐day case‐fatality was identical 6.2% (HR 0.997, 95%CI 0.905–1.099) in Sweden and Korea.</P><P><B>Conclusions – </B> No difference is found in the 90‐day case‐fatality in propensity score‐matched Swedish and Korean patients with ischemic stroke.</P>

Therapeutic effects of bee venom and its major component, melittin, on atopic dermatitis <i>in vivo</i> and <i>in vitro</i>

An, Hyun&#x2010,Jin,Kim, Jung&#x2010,Yeon,Kim, Woon&#x2010,Hae,Gwon, Mi&#x2010,Gyeong,Gu, Hye Min,Jeon, Min Ji,Han, Sang&#x2010,Mi,Pak, Sok Cheon,Lee, Chong&#x2010,Kee,Park, In Sook,Park, Kwan&#x2010 John Wiley and Sons Inc. 2018 British journal of pharmacology Vol.175 No.23

<P><B>Background and Purpose</B></P><P>Atopic dermatitis (AD) is a multifactorial skin condition with complex interactions of innate and adaptive immune responses. There are several existing therapies for AD, including topical glucocorticosteroids, emollients, phototherapies, calcineurin inhibitors and immunosuppressants, such as cyclosporine A. Although these therapies reduce inflammation, they also cause serious side effects. Therefore, it is necessary to develop new therapeutic approaches for AD treatment without side effects. There are several studies on natural materials or toxins, such as herbs, ginseng extract and snake venom, for AD treatment. However, treatment of AD with bee venom and its major component, melittin has rarely been studied.</P><P><B>Experimental Approach</B></P><P>Effects of bee venom and melittin were studied in a model of AD <I>in vivo</I> induced by 1‐chloro‐2,4‐dinitrobenzene (DNCB) in female Balb/c mice and in cultures of human keratinocytes, stimulated by TNF‐α/IFN‐γ. The potential pharmacological effects of bee venom and melittin on these <I>in vivo</I> and <I>in vitro</I> AD‐like skin disease models were studied.</P><P><B>Key Results</B></P><P>Bee venom and melittin exhibited potent anti‐atopic activities, shown by decreased AD‐like skin lesions, induced by DNCB in mice. <I>In vitro</I> studies using TNF‐α/IFN‐γ‐stimulated human keratinocytes showed that bee venom and melittin inhibited the increased expression of chemokines, such as CCL17 and CCL22, and pro‐inflammatory cytokines, including IL‐1β, IL‐6 and IFN‐γ, through the blockade of the NF‐κB and STAT signalling pathways.</P><P><B>Conclusions and Implications</B></P><P>Our results suggest that bee venom and melittin would be suitable for epicutaneous application, as topical administration is often appropriate for the treatment of AD.</P>

Efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes: A double‐blind randomized controlled trial ( INICOM study)

Lim, Soo,Han, Kyung Ah,Yu, JaeMyung,Chamnan, Parinya,Kim, Eun Sook,Yoon, Kun&#x2010,Ho,Kwon, Sam,Moon, Min Kyong,Lee, Kwan Woo,Kim, Dong&#x2010,Jun,Kim, Mikyung,Wongtanate, Manaj,Kim, Eun Young,Kim, S Blackwell Publishing Ltd 2017 Diabetes, obesity & metabolism Vol.19 No.1

<P><B>Background</B></P><P>Gemigliptin is a new dipeptidyl peptidase‐IV inhibitor. We investigated the efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes (T2D).</P><P><B>Methods</B></P><P>A total of 433 T2D patients with a glycosylated haemoglobin (HbA1c) level of 7.5% to 11.0% and a fasting plasma glucose (FPG) concentration <270 mg/dL were randomly assigned to 3 groups: (1) gemigliptin 50 mg qd + metformin 1000 to 2000 mg qd (titrated individually), (2) gemigliptin 50 mg qd, or (3) metformin 1000 to 2000 mg qd. The primary end‐point was the change in HbA1c level after 24 weeks. Secondary end‐points were the changes in FPG, insulin, proinsulin and C‐peptide levels. The percentages of responders who achieved an HbA1c level <7% (or <6.5%) were compared between treatment groups.</P><P><B>Results</B></P><P>Baseline HbA1c levels were 8.7% in all groups. The mean changes in HbA1c level from baseline to week 24 were −2.06%, −1.24% and −1.47% in the combination, gemigliptin monotherapy and metformin monotherapy groups, respectively. The 95% confidence intervals for between‐group differences in HbA1c changes were −1.02 to −0.63 in the combination group vs the gemigliptin group and −0.82 to −0.41 vs the metformin group, which confirmed the superiority of combination therapy. A significantly higher percentage of patients in the combination therapy group reached the target HbA1c level <7% (or <6.5%) compared with the monotherapy groups. No severe side effects were observed.</P><P><B>Conclusions</B></P><P>In T2D patients, the initial combination of gemigliptin and metformin had superior efficacy without safety concerns compared with monotherapy with either drug.</P>

Metformin and tenovin‐6 synergistically induces apoptosis through LKB1‐independent SIRT1 down‐regulation in non‐small cell lung cancer cells

Lee, Bo Bin,Kim, Yujin,Kim, Dongho,Cho, Eun Yoon,Han, Joungho,Kim, Hong Kwan,Shim, Young Mog,Kim, Duk&#x2010,Hwan John Wiley and Sons Inc. 2019 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.23 No.4

<P><B>Abstract</B></P><P>Sirtuin 1 (SIRT1) is known to play a role in a variety of tumorigenesis processes by deacetylating histone and non‐histone proteins; however, antitumour effects by suppressing SIRT1 activity in non‐small cell lung cancer (NSCLC) remain unclear. This study was designed to scrutinize clinicopathological significance of SIRT1 in NSCLC and investigate effects of metformin on SIRT1 inhibition. This study also evaluated new possibilities of drug combination using a SIRT1 inhibitor, tenovin‐6, in NSCLC cell lines. It was found that SIRT1 was overexpressed in 300 (62%) of 485 formalin‐fixed paraffin‐embedded NSCLC tissues. Its overexpression was significantly associated with reduced overall survival and poor recurrence‐free survival after adjusted for histology and pathologic stage. Thus, suppression of SIRT1 expression may be a reasonable therapeutic strategy for NSCLC. Metformin in combination with tenovin‐6 was found to be more effective in inhibiting cell growth than either agent alone in NSCLC cell lines with different liver kinase B1 (LKB1) status. In addition, metformin and tenovin‐6 synergistically suppressed SIRT1 expression in NSCLC cells regardless of LKB1 status. The marked reduction in SIRT1 expression by combination of metformin and tenovin‐6 increased acetylation of p53 at lysine 382 and enhanced p53 stability in LKB1‐deficient A549 cells. The combination suppressed SIRT1 promoter activity more effectively than either agent alone by up‐regulating hypermethylation in cancer 1 (HIC1) binding at SIRT1 promoter. Also, suppressed SIRT1 expression by the combination synergistically induced caspase‐3‐dependent apoptosis. The study concluded that metformin with tenovin‐6 may enhance antitumour effects through LKB1‐independent SIRT1 down‐regulation in NSCLC cells.</P>