Epidermal regeneration by <i>ent</i>‐16α, 17‐dihydroxy‐kauran‐19‐oic acid isolated from <i>Siegesbeckia pubescens</i>

Sung, S.&#x2010,H.,Park, S.&#x2010,H.,Song, S.&#x2010,Y.,Lee, S.&#x2010,J.,Lee, H.&#x2010,W.,Kim, S.&#x2010,H.,A Lee, M.,Yoon, I.&#x2010,S.,Kim, D.&#x2010,D.,Kang, S.,Sung, J.&#x2010,H. Blackwell Publishing Ltd 2011 Cell proliferation Vol.44 No.6

<P><B>Abstract</B></P><P><B>Objectives: </B> Keratinocyte stem/progenitor cells (KSCs) are known to regenerate epidermal tissue which they perform through to their great regenerative capacity.</P><P><B>Materials and methods: </B> Because stimulation of resident KSCs may regenerate epidermal tissue, we devised a strategy to find an appropriate KSC activator from natural products and to develop it as a skin‐rejuvenating agent.</P><P><B>Results: </B> <I>Ent</I>‐16α, 17‐dihydroxy‐kauran‐19‐oic acid (DHK) isolated from <I>Siegesbeckia pubescens</I> exhibited a KSC‐stimulating effect during screening of natural products. DHK increased proliferation and migration of KSCs using the Akt/ERK pathway. We further examined the mechanism of KSC stimulation and found that phosphorylation of Y1068 epithelial growth factor receptor (EGFR) was significantly increased. Functional inhibition of EGFR using neutralizing antibody and a chemical inhibitor, AG1478, attenuated DHK‐induced KSC stimulation. In a 3D culture model of KSCs, DHK treatment significantly induced establishment of fully stratified epidermis and increased numbers of p63‐positive cells. Likewise, DHK treatment significantly accelerated healing of epidermal wounds created by laser and dermatome, and increased p63‐positive cells, in animal models.</P><P><B>Conclusion: </B> Collectively, these results indicate that DHK regenerates epidermal tissue mainly through EGFR phosphorylation. As DHK has diverse advantages over recombinant growth factors for commercialization (that is long‐term stability and skin permeability), DHK might be applied to wound‐healing agents and to a basic materials used in cosmetics.</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>

Long‐term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors

Gambacorti&#x2010,Passerini, Carlo,Kantarjian, Hagop M.,Kim, Dong&#x2010,Wook,Khoury, Hanna J.,Turkina, Anna G.,Brü,mmendorf, Tim H.,Matczak, Ewa,Bardy&#x2010,Bouxin, Nathalie,Shapiro, Mark,Turnbu John Wiley and Sons Inc. 2015 American journal of hematology Vol.90 No.9

<P>Long‐term efficacy and safety of bosutinib (≥4 years follow‐up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated‐phase [AP, <I>n =</I> 79] chronic myeloid leukemia [CML], blast‐phase [BP, <I>n =</I> 64] CML, acute lymphoblastic leukemia [ALL, <I>n =</I> 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1–88.6), 2.8 (0.03–55.9), 0.97 (0.3–89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan‐Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (<I>n =</I> 9) for AP and pyrexia (<I>n =</I> 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib‐related [AP] per investigator). Responses were durable in ∼50% AP responders at 4 years (∼25% BP patients responded at year 1, suggesting possible bridge‐to‐transplant role in BP patients); toxicity was manageable.Am. J. Hematol. 90:755–768, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.</P>

Sequence variations of the locus‐specific 5′ untranslated regions of SLA class I genes and the development of a comprehensive genomic DNA‐based high‐resolution typing method for SLA‐2

Choi, H.,Le, M. T.,Lee, H.,Choi, M.&#x2010,K.,Cho, H.&#x2010,S.,Nagasundarapandian, S.,Kwon, O.&#x2010,J.,Kim, J.&#x2010,H.,Seo, K.,Park, J.&#x2010,K.,Lee, J.&#x2010,H.,Ho, C.&#x2010,S.,Park, C. Munksgaard 2015 Tissue antigens Vol.86 No.4

<P><B>Abstract</B></P><P>The genetic diversity of the major histocompatibility complex (MHC) class I molecules of pigs has not been well characterized. Therefore, the influence of MHC genetic diversity on the immune‐related traits of pigs, including disease resistance and other MHC‐dependent traits, is not well understood. Here, we attempted to develop an efficient method for systemic analysis of the polymorphisms in the epitope‐binding region of swine leukocyte antigens (SLA) class I genes. We performed a comparative analysis of the last 92 bp of the 5′ untranslated region (UTR) to the beginning of exon 4 of six SLA classical class I‐related genes, SLA‐1, ‐2, ‐3, ‐4, ‐5, and ‐<I>9</I>, from 36 different sequences. Based on this information, we developed a genomic polymerase chain reaction (PCR) and direct sequencing‐based comprehensive typing method for SLA‐2. We successfully typed SLA‐2 from 400 pigs and 8 cell lines, consisting of 9 different pig breeds, and identified 49 SLA‐2 alleles, including 31 previously reported alleles and 18 new alleles. We observed differences in the composition of SLA‐2 alleles among different breeds. Our method can be used to study other SLA class I loci and to deepen our knowledge of MHC class I genes in pigs.</P>

Serum Concentrations of Leptin and Adiponectin in Dogs with Myxomatous Mitral Valve Disease

Kim, H.&#x2010,S.,Kang, J.&#x2010,H.,Jeung, E.&#x2010,B.,Yang, M.&#x2010,P. John Wiley and Sons Inc. 2016 Journal of veterinary internal medicine Vol.30 No.5

<P><B>Background</B></P><P>The concentrations of circulating adipokines in dogs with myxomatous mitral valve disease (MMVD) have not been investigated in detail.</P><P><B>Objectives</B></P><P>To determine whether serum concentrations of adipokines differ between healthy dogs and dogs with MMVD and whether circulating concentrations depend on the severity of heart failure resulting from MMVD.</P><P><B>Animals</B></P><P>In the preliminary study, 30 healthy dogs and 17 client‐owned dogs with MMVD, and in the subsequent study, 30 healthy dogs and 46 client‐owned dogs with MMVD.</P><P><B>Methods</B></P><P>Prospective case‐controlled observational study. In the preliminary study, serum concentrations of leptin, adiponectin, resistin, visfatin, interleukin (IL)‐1β, IL‐6, IL‐10, IL‐18, and tumor necrosis factor‐α were measured. In the subsequent study, MMVD dogs were divided into three groups according to the International Small Animal Cardiac Health Council (ISACHC) classification, and serum concentrations of leptin and adiponectin were measured.</P><P><B>Results</B></P><P>In the preliminary study, serum leptin and adiponectin concentrations differed significantly between dogs with MMVD and healthy dogs. Serum leptin (<I>P</I> = .0013) concentrations were significantly higher in dogs with MMVD than in healthy dogs, whereas adiponectin (<I>P</I> = .0009) concentrations were significantly lower in dogs with MMVD. However, we observed no significant differences in the other variables. In the subsequent study, dogs classified as ISACHC class 3 had higher serum concentrations of leptin (<I>P</I> = .0022) than healthy dogs but ISACHC class 1 or 2 dogs did not. Serum adiponectin concentrations were significantly lower in ISACHC class 1 (<I>P</I> < .0001) dogs than in healthy dogs, whereas adiponectin concentrations in ISACHC class 3 dogs were significantly higher than in ISACHC class 1 dogs (<I>P</I> = .0081).</P><P><B>Conclusions and Clinical Importance</B></P><P>Circulating concentrations of leptin and adiponectin might be altered in dogs with MMVD.</P>

Effects of Addition Level and Chemical Type of Propionate Precursors in Dicarboxylic Acid Pathway on Fermentation Characteristics and Methane Production by Rumen Microbes In vitro

Li, X.Z.,Yan, C.G.,Choi, S.H.,Long, R.J.,Jin, G.L.,Song, Man K. Asian Australasian Association of Animal Productio 2009 Animal Bioscience Vol.22 No.1

Two in vitro experiments were conducted to examine the effects of propionate precursors in the dicarboxylic acid pathway on ruminal fermentatation characteristics, $CH_4$ production and degradation of feed by rumen microbes. Fumarate or malate as sodium salts (Exp. 1) or acid type (Exp. 2) were added to the culture solution (150 ml, 50% strained rumen fluid and 50% artificial saliva) to achieve final concentrations of 0, 8, 16 and 24 mM, and incubated anaerobically for 0, 1, 3, 6, 9 and 12 h at $39^{\circ}C$. For both experiments, two grams of feed consisting of 70% concentrate and 30% ground alfalfa (DM basis) were prepared in a nylon bag, and were placed in a bottle containing the culture solution. Addition of fumarate or malate in both sodium salt and acid form increased (p<0.0001) pH of culture solution at 3, 6, 9 and 12 h incubations. The pH (p<0.0001) and total volatile fatty acids (VFA, p<0.05) were enhanced by these precursors as sodium salt at 3, 6 and 9 h incubations, and pH (p<0.001) and total VFA (p<0.01) from fumarate or malate in acid form were enhanced at a late stage of fermentation (9 h and 12 h) as the addition level increased. pH was higher (p<0.001) for fumarate than for malate as sodium salt at 3 h and 6 h incubations. Propionate ($C_3$) proportion was increased (p<0.0001) but those of $C_2$ (p<0.05) and $C_4$ (p<0.01 - p<0.001) were reduced by the addition of sodium salt precursors from 3 h to 12 incubation times while both precursors in acid form enhanced (p<0.011 - p<0.0001) proportion of $C_3$ from 6h but reduced (p<0.018 - p<0.0005) $C_4$ proportion at incubation times of 1, 3, 9 and 12 h. Proportion of $C_3$ was increased (p<0.05 - p<0.0001) at all incubation times by both precursors as sodium salt while that of $C_3$ was increased (p<0.001) from 6h but $C_4$ proportion was decreased by both precursors in acid form as the addition level increased. Proportion of $C_3$ was higher (p<0.01 - p<0.001) for fumarate than malate as sodium salt from 6 h incubation but was higher for malate than fumarate in acid form at 9 h (p<0.05) and 12 h (p<0.01) incubation times. Increased levels (16 and 24 mM) of fumarate or malate as sodium salt (p<0.017) and both precursors in acid form (p<0.028) increased the total gas production, but no differences were found between precursors in both chemical types. Propionate precursors in both chemical types clearly reduced (p<0.0001 - p<0.0002) $CH_4$ production, and the reduction (p<0.001 - p<0.0001) was dose dependent as the addition level of precursors increased. The $CH_4$ generated was smaller (p<0.01 - p<0.0001) for fumarate than for malate in both chemical types. Addition of fumarate or malate as sodium type reduced (p<0.004) dry matter degradation while both precursors in both chemical types slightly increased neutral detergent fiber degradability of feed in the nylon bag.

A combinatorial constraint satisfaction problem dichotomy classification conjecture

Ne&#x161,et&#x159,il, Jaroslav,Siggers, Mark H.,Zá,dori, Lá,szló Elsevier 2010 European journal of combinatorics : Journal europ& Vol.31 No.1

<P><B>Abstract</B></P><P>We further generalise a construction–the <I>fibre construction</I>–that was developed in an earlier paper of the first two authors. The extension in this paper gives a polynomial-time reduction of CSP(H) for any relational system H to CSP(P) for any relational system P that meets a certain technical partition condition, that of being <SUB>K3</SUB>-<I>partitionable</I>.</P><P>Moreover, we define an equivalent condition on P, that of being <I>block projective</I>, and using this show that our construction proves NP-completeness for exactly those CSPs that are conjectured to be NP-complete by the CSP dichotomy classification conjecture made by Bulatov, Jeavons and Krohkin, and by Larose and Zádori. We thus provide two new combinatorial versions of the CSP dichotomy classification conjecture.</P><P>As with our previous version of the fibre construction, we are able to address restricted versions of the dichotomy conjecture. In particular, we reduce the Feder–Hell–Huang conjecture to the CSP dichotomy classification conjecture, and we prove the Kostochka–Nešetřil–Smolíková conjecture. Although these results were proved independently by Jonsson et al. and Kun respectively, we give different, shorter, proofs.</P>

Induction of bone formation by <i>Escherichia coli</i>‐expressed recombinant human bone morphogenetic protein‐2 using block‐type macroporous biphasic calcium phosphate in orthotopic and ectopic rat models

Park, J&#x2010,C.,So, S&#x2010,S.,Jung, I&#x2010,H.,Yun, J&#x2010,H.,Choi, S&#x2010,H.,Cho, K&#x2010,S.,Kim, C&#x2010,S. Blackwell Publishing Ltd 2011 Journal of periodontal research Vol.46 No.6

<P><I>Park J‐C, So S‐S, Jung I‐H, Yun J‐H, Choi S‐H, Cho K‐S, Kim C‐S. Induction of bone formation by</I> Escherichia coli<I>‐expressed recombinant human bone morphogenetic protein‐2 using block‐type macroporous biphasic calcium phosphate in orthotopic and ectopic rat models. J Periodont Res 2011; 46: 682–690. © 2011 John Wiley & Sons A/S</I></P><P><B>Background and Objective: </B> The potential of the <I>Escherichia coli</I>‐expressed recombinant human bone morphogenetic protein‐2 (ErhBMP‐2) to support new bone formation/maturation using a block‐type of macroporous biphasic calcium phosphate (bMBCP) carrier was evaluated in an orthotopic and ectopic rat model.</P><P><B>Material and Methods: </B> Critical‐size (Φ 8 mm) calvarial defects and subcutaneous pockets in 32 Sprague–Dawley rats received implants of rhBMP‐2 (2.5 μg) in a bMBCP carrier or bMBCP alone (control). Implant sites were evaluated using histological and histometric analysis following 2‐ and 8‐wk healing intervals (eight animals/group/interval).</P><P><B>Results: </B> ErhBMP‐2/bMBCP supported significantly greater bone formation at 2 and 8 wk (10.8% and 25.4%, respectively) than the control at 2 and 8 wk (5.3% and 14.0%, respectively) in calvarial defects (<I>p</I> < 0.01). Bone formation was only observed for the ErhBMP‐2/bMBCP ectopic sites and was significantly greater at 8 wk (7.5%) than at 2 wk (4.5%) (<I>p</I> < 0.01). Appositional and endochondral bone formation was usually associated with a significant increase in fatty marrow at 8 wk. The bMBCP carrier showed no evidence of bioresorption.</P><P><B>Conclusion: </B> ErhBMP‐2/bMBCP induced significant bone formation in both calvarial and ectopic sites. Further study appears to be required to evaluate the relevance of the bMBCP carrier.</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>

Psychiatry

Guze, Batty H.,Freedman, Daniel X. MediMedia Korea 1991 JAMA-Korea Vol.6 No.11