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>

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>

<i>Bacillus</i>‐derived poly‐γ‐glutamic acid attenuates allergic airway inflammation through a Toll‐like receptor‐4‐dependent pathway in a murine model of asthma

Lee, K.,Kim, S.&#x2010,H.,Yoon, H. J.,Paik, D. J.,Kim, J. M.,Youn, J. Blackwell Publishing Ltd 2011 Clinical and experimental allergy Vol.41 No.8

<P><B>Summary</B></P><P><B>Background </B> Asthma is an inflammatory disease of the airways that is mediated by Th2 responses. Poly‐γ‐glutamic acid (γ‐PGA) is an extracellular polymeric compound that is synthesized by <I>Bacillus</I> cells. Previously, we found that γ‐PGA promoted Th1 cell development in a manner dependent on antigen‐presenting cells, but inhibited Th2 cell development.</P><P><B>Objective </B> To investigate the effect of γ‐PGA on dendritic cells (DCs), and its potential for treating Th2‐mediated allergic asthma.</P><P><B>Methods </B> Wild‐type, Toll‐like receptor (TLR)‐2 deficient, and TLR‐4‐defective mice were used. DCs derived from the bone marrow and extracted from the lung were stimulated with γ‐PGA and assayed for the expression of signalling molecules, costimulatory molecules, and cytokines. Mice were sensitized and challenged with ovalbumin (OVA) to induce asthma. They were repeatedly injected intranasally with γ‐PGA before and during the challenge period, and inflammation and structural remodelling of the airways were examined.</P><P><B>Results </B> γ‐PGA selectively signalled conventional DCs to activate NF‐κB and mitogen‐activated protein kinase, leading to the up‐regulation of CD86, CD40, and IL‐12, but not IL‐10 and IL‐6. These effects of γ‐PGA were dependent on TLR‐4 and independent of TLR‐2. Importantly, the intranasal administration of γ‐PGA to OVA‐sensitized/challenged mice reduced the airway hyperresponsiveness and allergic inflammation such as leucocyte influx, goblet cell hyperplasia, eosinophilia, and Th2 cytokine production. In addition to lowered IgE titres, the treatment of mice with γ‐PGA significantly reduced the multiplication and Th2 polarization of mediastinal lymph node T cells upon allergen‐specific restimulation. These anti‐asthmatic effects of γ‐PGA were also abolished in TLR‐4‐defective mice.</P><P><B>Conclusions and Clinical Relevance </B> Our data indicate that γ‐PGA activates DCs to favour Th1 cell induction through a TLR‐4‐dependent pathway and alleviates pathologic symptoms in a Th2‐biased asthmatic model. These findings highlight the potential of γ‐PGA for the treatment of asthma and other allergic disease in which Th2 polarization plays an important role.</P><P> <I>Cite this as</I>: K. Lee, S.‐H. Kim, H. J. Yoon, D. J. Paik, J. M. Kim and J. Youn, <I>Clinical & Experimental Allergy</I>, 2011 (41) 1143–1156.</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>

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>

Serum Adipokine Concentrations in Dogs with Acute Pancreatitis

Paek, J.,Kang, J.&#x2010,H.,Kim, H.&#x2010,S.,Lee, I.,Seo, K.W.,Yang, M.&#x2010,P. John Wiley and Sons Inc. 2014 Journal of veterinary internal medicine Vol.28 No.6

<P><B>Background</B></P><P>Limited information is available about the role of adipokines in the development and progression of acute pancreatitis (AP) in dogs.</P><P><B>Objectives</B></P><P>To determine whether the circulating concentrations of adipokines differed between healthy dogs and dogs with AP, and whether the circulating concentrations differed between AP survivors and AP nonsurvivors.</P><P><B>Animals</B></P><P>Twenty‐eight healthy dogs and 25 client‐owned dogs with AP.</P><P><B>Methods</B></P><P>Prospective observational cohort study of 25 client‐owned dogs with newly diagnosed AP and 28 otherwise healthy dogs with similar body condition scores. The serum concentrations of leptin, adiponectin, resistin, visfatin, interleukin (IL)‐1β, IL‐6, IL‐10, IL‐18, and tumor necrosis factor (TNF)‐α were measured.</P><P><B>Results</B></P><P>The serum concentrations of leptin (<I>P </I>=<I> </I>.0021), resistin (<I>P </I>=<I> </I>.0010), visfatin (<I>P </I><<I> </I>.0001), IL‐1β (<I>P </I><<I> </I>.0001), IL‐6 (<I>P </I>=<I> </I>.0002), IL‐10 (<I>P </I><<I> </I>.0001), and IL‐18 (<I>P </I><<I> </I>.0001) were significantly higher in dogs with AP than healthy dogs, whereas the adiponectin concentration (<I>P </I>=<I> </I>.0011) was significantly lower. There were significant differences in the serum concentrations of leptin (<I>P </I>=<I> </I>.028) and adiponectin (<I>P </I>=<I> </I>.046) in survivors and nonsurvivors. After the disappearance of clinical signs, the concentrations of resistin (<I>P </I>=<I> </I>.037) and IL‐1β (<I>P </I>=<I> </I>.027) decreased significantly, whereas the serum concentrations of leptin (<I>P </I>><I> </I>.999), adiponectin (<I>P </I>=<I> </I>.11), visfatin (<I>P </I>=<I> </I>.83), IL‐6 (<I>P </I>=<I> </I>.82), IL‐10 (<I>P </I>=<I> </I>.82), IL‐18 (<I>P </I>=<I> </I>.56), and TNF‐α (<I>P </I>=<I> </I>.94) did not differ significantly.</P><P><B>Conclusion and Clinical Importance</B></P><P>This study showed that dysregulation of adipokines might be involved in the pathogenesis of AP. In addition, leptin and adiponectin are likely to be associated with mortality rate in AP.</P>

Upstream kinases of plant Sn RK s are involved in salt stress tolerance

Barajas&#x2010,Lopez, Juan de Dios,Moreno, Jose Ramon,Gamez&#x2010,Arjona, Francisco M.,Pardo, Jose M.,Punkkinen, Matleena,Zhu, Jian&#x2010,Kang,Quintero, Francisco J.,Fujii, Hiroaki John Wiley and Sons Inc. 2018 The Plant journal Vol.93 No.1

<▼1><P><B>Summary</B></P><P>Sucrose non‐fermenting 1‐related protein kinases (SnRKs) are important for plant growth and stress responses. This family has three clades: SnRK1, SnRK2 and SnRK3. Although plant SnRKs are thought to be activated by upstream kinases, the overall mechanism remains obscure. Geminivirus Rep‐Interacting Kinase (GRIK)1 and GRIK2 phosphorylate SnRK1s, which are involved in sugar/energy sensing, and the <I>grik1‐1 grik2‐1</I> double mutant shows growth retardation under regular growth conditions. In this study, we established another Arabidopsis mutant line harbouring a different allele of gene <I>GRIK1</I> (<I>grik1‐2 grik2‐1</I>) that grows similarly to the wild‐type, enabling us to evaluate the function of GRIKs under stress conditions. In the <I>grik1‐2 grik2‐1</I> double mutant, phosphorylation of SnRK1.1 was reduced, but not eliminated, suggesting that the <I>grik1‐2</I> mutation is a weak allele. In addition to high sensitivity to glucose, the <I>grik1‐2 grik2‐1</I> mutant was sensitive to high salt, indicating that GRIKs are also involved in salinity signalling pathways. Salt Overly Sensitive (SOS)2, a member of the SnRK3 subfamily, is a critical mediator of the response to salinity. GRIK1 phosphorylated SOS2 <I>in vitro</I>, resulting in elevated kinase activity of SOS2. The salt tolerance of <I>sos2</I> was restored to normal levels by wild‐type SOS2, but not by a mutated form of SOS2 lacking the T168 residue phosphorylated by GRIK1. Activation of SOS2 by GRIK1 was also demonstrated in a reconstituted system in yeast. Our results indicate that GRIKs phosphorylate and activate SnRK1 and other members of the SnRK3 family, and that they play important roles in multiple signalling pathways <I>in vivo</I>.</P></▼1><▼2><P><B>Significance Statement</B></P><P>Since plants face diverse, often coincidental stresses throughout their lifetime, they have to integrate multiple signals to organize growth, development and stress responses. This work shows that GRIKs, which are essential players in sugar signalling pathway as upstream kinases of SnRK1s, also work in salt tolerance of Arabidopsis and identified SOS2, a SnRK3, as a potential substrate of GRIKs in the salinity signalling pathway.</P></▼2>

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>

<i>Neuregulin 3</i> does not confer risk for schizophrenia and smooth pursuit eye movement abnormality in a Korean population

Pasaje, C.&#x2010,F.,Bae, J.&#x2010,S.,Park, B.&#x2010,L.,Cheong, H. S.,Kim, J.&#x2010,H.,Park, T.&#x2010,J.,Lee, J.&#x2010,S.,Kim, Y.,Park, C.&#x2010,S.,Kim, B.&#x2010,J.,Cha, B.,Kim, J. W.,Choi, W. Blackwell Publishing Ltd 2011 Genes, brain, and behavior Vol.10 No.8

<P><B>Located on chromosome 10q22‐q23, the human <I>neuregulin3</I> (<I>NRG3</I>) is considered to be a strong positional and functional candidate gene for schizophrenia pathogenesis. Several case–control studies examining the association of polymorphisms in <I>NRG3</I> with schizophrenia and/or related traits such as delusion have been reported recently in cohorts of Han Chinese, Ashkenazi Jews, Australians and white Americans of Western European ancestry. Thus, this study aimed to comprehensively investigate the association of <I>NRG3</I> genetic variations with the risk of schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. Using TaqMan assay, six single‐nucleotide polymorphisms (SNPs) in the intronic region of <I>NRG3</I> were genotyped and two major haplotypes were identified in 435 patients with schizophrenia as cases and 393 unrelated healthy individuals as controls. A total of 113 schizophrenia patients underwent an eye tracking task, and degree of SPEM abnormality was measured using the logarithmic values of the signal/noise (Ln <I>S</I>/<I>N</I>) ratio. Differences in frequency distributions were analyzed using logistic and regression models following various modes of genetic inheritance and controlling for age and sex as covariates. Subsequent analysis revealed that the frequency distributions of <I>NRG3</I> polymorphisms and haplotypes were similar between schizophrenia patients and healthy controls of Korean ethnicity. Furthermore, no significant differences were observed between the genetic variants tested for SPEM abnormality. By elucidating a lack of association in a Korean population, findings from this study may contribute to the understanding of the genetic etiology focusing on the role of <I>NRG3</I> in schizophrenia pathogenesis.</B></P>

Advances in <i>J</i>‐integral estimation of circumferentially surface cracked pipes

CHO, D.&#x2010,H.,SEO, H.&#x2010,B.,KIM, Y.&#x2010,J.,CHANG, Y.&#x2010,S.,JHUNG, M.&#x2010,J.,CHOI, Y.&#x2010,H. Blackwell Publishing Ltd 2011 Fatigue & Fracture of Engineering Materials and St Vol.34 No.9

<P><B>ABSTRACT</B></P><P>This paper describes enhanced <I>J</I>‐integral estimation schemes for pipes with circumferential semi‐elliptical cracks subjected to tensile loading, global bending and internal pressure. These schemes are given in two different forms to cover the wide ranges of geometries and material parameters; the modified GE/EPRI method and the modified reference stress method. In the former method, new plastic influence functions for fully plastic <I>J</I>‐integral estimation are developed based on extensive three‐dimensional finite element calculations. In the latter method, new optimized reference loads are suggested and utilized to predict the <I>J</I> values. To verify the feasibility of these two schemes, <I>J</I>‐integral values obtained from further detailed FE analyses are compared to those from the proposed schemes. Because the estimated <I>J</I>‐integrals agree fairly well with the detailed FE analysis results, the new solutions can be applied for accurate structural integrity assessment of different size pipes with a circumferential surface crack.</P>