bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of bodyweight on the efficacy and safety of ixekizumab: results from an integrated database of three randomised, controlled Phase 3 studies of patients with moderate‐to‐severe plaque psoriasis
Authors: Reich K. , Puig L. , Mallbris L. , Zhang L. , Osuntokun O. , Leonardi C. 
Published: April 2017

AbstractBackgroundThere is concern that increased bodyweight may impact efficacy of some therapies used to treat psoriasis.ObjectiveTo evaluate the effect of bodyweight on response to ixekizumab treatment in patients with moderate‐to‐severe psoriasis.MethodsPatients were characterized under three bodyweight categories (<80 kg, 80 to <100 kg, ≥100 kg) in this preplanned subgroup analysis from an integrated database of three multicenter, randomised, double‐blind, controlled Phase 3 clinical studies (UNCOVER‐1, UNCOVER‐2 and UNCOVER‐3). In the first 12 weeks of each study, patients were randomly assigned to receive subcutaneous placebo, 80‐mg ixekizumab every 2 weeks (IXE Q2W) or every 4 weeks (IXE Q4W) after a starting dose of 160‐mg ixekizumab, or 50‐mg etanercept twice weekly (UNCOVER‐2 and UNCOVER‐3 only).ResultsThis analysis included 3855 patients with baseline bodyweight in the IXE Q4W (N = 1159), IXE Q2W (N = 1168), placebo (N = 789) and etanercept (N = 739) groups. Distribution of patients across bodyweight categories was similar between treatment groups. Baseline demographics and patients characteristics were generally consistent across treatment groups within each bodyweight category. Across all bodyweight categories, a significantly higher percentage of patients treated with IXE Q2W or IXE Q4W than with placebo or etanercept achieved PASI 75, PASI 90 or PASI 100 at Week 12. No meaningful differences in PASI 75 response rates were observed across bodyweight categories. Some numerical differences in PASI 90 and PASI 100 response rates were observed between bodyweight categories with IXE Q2W providing numerically higher response rates than IXE Q4W. The incidence of treatment‐emergent adverse events was similar in the treatment groups and across bodyweight categories.ConclusionIxekizumab was efficacious in the treatment of moderate‐to‐severe psoriasis regardless of bodyweight. The safety profile of ixekizumab was also similar across bodyweight categories, and no safety signals were identified specific to any of the bodyweight categories.
The Mediterranean dietary pattern as the diet of choice for non‐alcoholic fatty liver disease: Evidence and plausible mechanisms
Authors: Zelber‐Sagi Shira , Salomone Federico , Mlynarsky Liat 
Published: April 2017

AbstractNon‐alcoholic fatty liver disease (NAFLD) has become a major global health burden, leading to increased risk for cirrhosis, hepatocellular carcinoma, type‐2 diabetes and cardiovascular disease. Lifestyle intervention aiming at weight reduction is the most established treatment. However, changing the dietary composition even without weight loss can also reduce steatosis and improve metabolic alterations as insulin resistance and lipid profile. The Mediterranean diet (MD) pattern has been proposed as appropriate for this goal, and was recommended as the diet of choice for the treatment of NAFLD by the EASL‐EASD‐EASO Clinical Practice Guidelines. The MD has an established superiority in long term weight reduction over low fat diet, but it improves metabolic status and steatosis even without it. However, the effect on liver inflammation and fibrosis was tested only in few observational studies with positive results. Furthermore, considering the strong association between NAFLD and diabetes and CVD, the MD has a highly established advantage in prevention of these diseases, demonstrated in randomized clinical trials. The individual components of the MD such as olive oil, fish, nuts, whole grains, fruits, and vegetables, have been shown to beneficially effect or negatively correlate with NAFLD, while consumption of components that characterize a Western dietary pattern as soft drinks, fructose, meat and saturated fatty acids have been shown to have detrimental association with NAFLD. In this review we will cover the epidemiological evidence and the plausible molecular mechanisms by which the MD as a whole and each of its components can be of benefit in NAFLD.
Mitochondria‐targeted antioxidant mitoquinone deactivates human and rat hepatic stellate cells and reduces portal hypertension in cirrhotic rats
Authors: Vilaseca Marina , García‐Calderó Héctor , Lafoz Erica , Ruart Maria , López‐Sanjurjo Cristina Isabel , Murphy Michael P. , Deulofeu Ramon , Bosch Jaume , Hernández‐Gea Virginia , Gracia‐Sancho Jordi , García‐Pagán Juan Carlos 
Published: April 2017

AbstractBackground & AimsIn cirrhosis, activated hepatic stellate cells (HSC) play a major role in increasing intrahepatic vascular resistance and developing portal hypertension. We have shown that cirrhotic livers have increased reactive oxygen species (ROS), and that antioxidant therapy decreases portal pressure. Considering that mitochondria produce many of these ROS, our aim was to assess the effects of the oral mitochondria‐targeted antioxidant mitoquinone on hepatic oxidative stress, HSC phenotype, liver fibrosis and portal hypertension.MethodsEx vivo: Hepatic stellate cells phenotype was analysed in human precision‐cut liver slices in response to mitoquinone or vehicle. In vitro: Mitochondrial oxidative stress was analysed in different cell type of livers from control and cirrhotic rats. HSC phenotype, proliferation and viability were assessed in LX2, and in primary human and rat HSC treated with mitoquinone or vehicle. In vivo: CCl4‐ and thioacetamide‐cirrhotic rats were treated with mitoquinone (5 mg/kg/day) or the vehicle compound, DecylTPP, for 2 weeks, followed by measurement of oxidative stress, systemic and hepatic haemodynamic, liver fibrosis, HSC phenotype and liver inflammation.ResultsMitoquinone deactivated human and rat HSC, decreased their proliferation but with no effects on viability. In CCl4‐cirrhotic rats, mitoquinone decreased hepatic oxidative stress, improved HSC phenotype, reduced intrahepatic vascular resistance and diminished liver fibrosis. These effects were associated with a significant reduction in portal pressure without changes in arterial pressure. These results were further confirmed in the thioacetamide‐cirrhotic model.ConclusionWe propose mitochondria‐targeted antioxidants as a novel treatment approach against portal hypertension and cirrhosis.
New variants of CRISPR RNA‐guided genome editing enzymes
Authors: Murovec Jana , Pirc Žan , Yang Bing 
Published: April 2017

SummaryCRISPR‐mediated genome editing using the Streptococcus pyogenes Cas9 enzyme is revolutionizing life science by providing new, precise, facile and high‐throughput tools for genetic modification by the specific targeting of double‐strand breaks in the genome of hosts. Plant biotechnologists have extensively used the S. pyogenes Cas9‐based system since its inception in 2013. However, there are still some limitations to its even broader usage in plants. Major restrictions, especially in agricultural biotechnology, are the currently unclear regulatory status of plants modified with CRISPR/Cas9 and the lack of suitable delivery methods for some plant species. Solutions to these limitations could come in the form of new variants of genome editing enzymes that have recently been discovered and have already proved comparable to or even better in performance than S. pyogenes CRISPR/Cas9 in terms of precision and ease of delivery in mammal cells. Although some of them have already been tested in plants, most of them are less well known in the plant science community. In this review, we describe the following new enzyme systems engineered for genome editing, transcriptional regulation and cellular imaging—C2c2 from L. shahii; Cas9 from F. novicida, S. aureus, S. thermophiles, N. meningitidis; Cpf1 from F. novicida, Acidaminococcus and Lachnospiraceae; nickase, split, enhanced and other Cas9 variants from S. pyogenes; catalytically inactive SpCas9 linked to various nuclease or gene‐regulating domains—with an emphasis on their advantages in comparison with the broadly used SpCas9. In addition, we discuss new possibilities they offer in plant biotechnology.
Silencing of SlPL, which encodes a pectate lyase in tomato, confers enhanced fruit firmness, prolonged shelf‐life and reduced susceptibility to grey mould
Authors: Yang Lu , Huang Wei , Xiong Fangjie , Xian Zhiqiang , Su Deding , Ren Maozhi , Li Zhengguo 
Published: April 2017

SummaryPectate lyase genes have been documented as excellent candidates for improvement of fruit firmness. However, implementation of pectate lyase in regulating fruit postharvest deterioration has not been fully explored. In this report, 22 individual pectate lyase genes in tomato were identified, and one pectate lyase gene SlPL (Solyc03g111690) showed dominant expression during fruit maturation. RNA interference of SlPL resulted in enhanced fruit firmness and changes in pericarp cells. More importantly, the SlPL‐RNAi fruit demonstrated greater antirotting and pathogen‐resisting ability. Compared to wild‐type, SlPL‐RNAi fruit had higher levels of cellulose and hemicellulose, whereas the level of water‐soluble pectin was lower. Consistent with this, the activities of peroxidase, superoxide dismutase and catalase were higher in SlPL‐RNAi fruit, and the malondialdehyde concentration was lower. RNA‐Seq results showed large amounts of differentially expressed genes involved in hormone signalling, cell wall modification, oxidative stress and pathogen resistance. Collectively, these data demonstrate that pectate lyase plays an important role in both fruit softening and pathogen resistance. This may advance knowledge of postharvest fruit preservation in tomato and other fleshy fruit.
Identification and Characterization of a Nationwide Danish Adult Common Variable Immunodeficiency Cohort
Authors: Westh L. , Mogensen T. H. , Dalgaard L. S. , Bernth Jensen J. M. , Katzenstein T. , Hansen A.‐B. E. , Larsen O. D. , Terpling S. , Nielsen T. L. , Larsen C. S. 
Published: April 2017

AbstractIn this study, we identified all adults living in Denmark diagnosed with common variable immunodeficiency (CVID) and characterized them according to clinical presentation and EUROclass classification. Using a retrospective, cross‐sectional design, possible CVID patients were identified in the Danish National Patient Register and Centers in Denmark treating patients with primary immunodeficiencies. The CVID diagnosis was verified by review of medical records. One‐hundred‐seventy‐nine adults with CVID were identified. This corresponds to a prevalence of 1:26,000. The median age at onset of symptoms was 29 years with no sex difference. The median age at diagnosis was 40 years. Males were diagnosed earlier with a peak in the fourth decade of life, whereas females were diagnosed later with a peak in the sixth decade. The median diagnostic delay was seven years. Recurrent sinopulmonary infections were seen in 92.7% of the patients. The prevalence of non‐infectious complications was similar to that of previously reported cohorts: bronchiectasis (35.8%), splenomegaly (22.4%), lymphadenopathy (26.3%), granulomatous inflammation (3.9%) and idiopathic thrombocytopenic purpura (14.5%). Non‐infectious complications were strongly associated with B cell phenotype, with all having a reduced number of isotype‐switched memory B cells. One‐hundred‐seventy (95%) were treated with immunoglobulin replacement therapy, primarily administered subcutaneously. According to international guidelines, diagnostic evaluation was inadequate in most cases. This study emphasizes the need for improved diagnostic criteria and more awareness of CVID as a differential diagnosis. Diagnosis and management of CVID patients is a challenge requiring specialists with experience in the field of PID.
C‐Glycosyltransferases catalyzing the formation of di‐C‐glucosyl flavonoids in citrus plants
Authors: Ito Takamitsu , Fujimoto Shunsuke , Suito Fumiaki , Shimosaka Makoto , Taguchi Goro 
Published: April 2017

SummaryCitrus plants accumulate many kinds of flavonoids, including di‐C‐glucosyl flavonoids, which have attracted considerable attention due to their health benefits. However, the biosynthesis of di‐C‐glucosyl flavonoids has not been elucidated at the molecular level. Here, we identified the C‐glycosyltransferases (CGTs) FcCGT (UGT708G1) and CuCGT (UGT708G2) as the primary enzymes involved in the biosynthesis of di‐C‐glucosyl flavonoids in the citrus plants kumquat (Fortunella crassifolia) and satsuma mandarin (Citrus unshiu), respectively. The amino acid sequences of these CGTs were 98% identical, indicating that CGT genes are highly conserved in the citrus family. The recombinant enzymes FcCGT and CuCGT utilized 2‐hydroxyflavanones, dihydrochalcone, and their mono‐C‐glucosides as sugar acceptors and produced corresponding di‐C‐glucosides. The Km and kcat values of FcCGT toward phloretin were <0.5 μm and 12.0 sec−1, and those toward nothofagin (3ʹ‐C‐glucosylphloretin) were 14.4 μm and 5.3 sec−1, respectively; these values are comparable with those of other glycosyltransferases reported to date. Transcripts of both CGT genes were found to concentrate in various plant organs, and particularly in leaves. Our results suggest that di‐C‐glucosyl flavonoid biosynthesis proceeds via a single enzyme using either 2‐hydroxyflavanones or phloretin as a substrate in citrus plants. In addition, Escherichia coli cells expressing CGT genes were found to be capable of producing di‐C‐glucosyl flavonoids, which is promising for commercial production of these valuable compounds.
Performance management of small water treatment plant operations: a decision support system
Authors: Stein Dan , Achari Gopal , Langford Cooper H. , Dore Mohammed H. I. , Haider Husnain , Zhang Kejiang , Sadiq Rehan 
Published: April 2017

AbstractA decision support system (DSS) is developed to optimise the performance of different operations of small water treatment systems to improve day‐to‐day decisions. The support system includes a data management system, knowledge‐based system, performance assessment of different unit processes, fault tree analyses, preventive and corrective actions and event tree analysis (ETA). Performance assessment identifies the critical events (failures) and fault tree analysis identifies the interrelationships between the critical events and the root causes. Fault trees are developed based on the information obtained from events of waterborne outbreaks, responses to questionnaires by the participating smaller utilities, state‐of‐the‐art literature review and personal communication with the operators. ETA is used to identify the potential health outcomes which are further integrated with the quantitative microbial risk assessment. The developed DSS is advanced to an automated user friendly program that can be used by treatment plant operators to assess system performance.
Outcomes in Cochrane systematic reviews related to wound care: An investigation into prespecification
Authors: Liu Zhenmi , Saldanha Ian J. , Margolis David , Dumville Jo C. , Cullum Nicky A. 
Published: April 2017

AbstractThe choice of outcomes in systematic reviews of the effects of interventions is crucial, dictating which data are included and analyzed. Full prespecification of outcomes in systematic reviews can reduce the risk of outcome reporting bias but, this issue has not been widely investigated. This study is the first to analyze the nature and specification of outcomes used in Cochrane Wounds (CW) systematic reviews. Adequacy of outcome specification was assessed using a five‐element framework of key outcome components: outcome domain, specific measurement, specific metric, method of aggregation, and time points. We identified all CW review titles associated with a protocol published on or before October 1, 2014. We categorized all reported outcome domains and recorded whether they were primary or secondary outcomes. We explored outcome specification for outcome domains reported in 25% or more of the eligible protocols. We included 106 protocols and 126 outcome domains; 24.6% (31/126) domains were used as primary outcomes at least once. Eight domains were reported in ≥25% of protocols: wound healing, quality of life, costs, adverse events, resource use, pain, wound infection, and mortality. Wound healing was the most completely specified outcome domain (median 3; interquartile range [IQR] =1–5) along with resource use (median 3; IQR 2–4). Quality of life (median 1; IQR 1–3), pain (median 1; IQR 1–3), and costs (median 1; IQR 1–4) were the least completely specified outcome domains. Outcomes are frequently poorly prespecified and the elements of metric, aggregation, and time‐point are rarely adequately specified. We strongly recommend that reviewers be more vigilant about prespecifying outcomes, using the five‐element framework. Better prespecification is likely to improve review quality by reducing bias in data abstraction and analysis, and by reducing subjectivity in the decision of which outcomes to extract; it may also improve outcome specification in clinical trial design and reporting.
GHK‐Cu‐liposomes accelerate scald wound healing in mice by promoting cell proliferation and angiogenesis
Authors: Wang Xinying , Liu Baoquan , Xu Qiang , Sun Haiyang , Shi Meijun , Wang Dan , Guo Meihua , Yu Jiawen , Zhao Chunhui , Feng Bin 
Published: April 2017

AbstractGlycyl‐l‐histidyl‐l‐lysine (GHK)‐Cu is considered to be an activator of tissue remodeling, and has been used in cosmetic products. In this study, we prepared liposomes encapsulating GHK‐Cu and analyzed their effect on human umbilical vein endothelial cells (HUVECs) proliferation and scald wound healing in mice. The nanoscaled GHK‐Cu‐liposomes promoted HUVECs proliferation, with a 33.1% increased rate. Flow cytometry analysis showed increased cell number at G1 stage and decreased cell number at G2 stage after GHK‐Cu‐liposomes treatment. Western blotting indicated that the expression of vascular endothelial growth factor and fibroblast grow factors‐2 were both enhanced, as well as cell cycle‐related proteins CDK4 and CyclinD1. In a mice scald model, angiogenesis in burned skin treated with GHK‐Cu‐liposomes was better compared with free GHK‐Cu, and immunofluorescence analysis showed enhanced signal of CD31 and Ki67 in GHK‐Cu‐liposomes treated mice. Moreover, the wound healing time was shortened to 14 days post injury. Our results provide the evidence that GHK‐Cu‐liposomes could be utilized as a treatment for skin wounds.
Sustainable effectiveness of single‐treatment autologous fat grafting in adherent scars
Authors: Jaspers Mariëlle E.H. , Brouwer Katrien M. , van Trier Antoine J.M. , Middelkoop Esther , van Zuijlen Paul P.M. 
Published: April 2017

AbstractFollowing severe injury, not just the skin but also the subcutis may be destroyed. Consequently, the developing scar can become adherent to underlying structures. Reconstruction of the subcutis can be achieved by autologous fat grafting. Our aim was to evaluate the long‐term scar outcome after single‐treatment autologous fat grafting using a comprehensive scar evaluation protocol. Scar assessment was performed preoperatively in 40 patients. A 12‐month follow‐up assessment was performed in 36 patients, using the Cutometer, the Patient and Observer Scar Assessment Scale, and DSM II ColorMeter. The Cutometer parameters elasticity and maximal extension improved with 28 and 22% (both p < 0.001), respectively. Nearly all scores of the scar assessment scale decreased significantly, which corresponds to improved scar quality. In addition, the mean melanin score was ameliorated over time. Thus, we demonstrated the sustainable effectiveness of single‐treatment autologous fat grafting in adherent scars, indicated by improved pliability, and overall scar quality.
The effect of pH on cell viability, cell migration, cell proliferation, wound closure, and wound reepithelialization: In vitro and in vivo study
Authors: Kruse Carla R. , Singh Mansher , Targosinski Stefan , Sinha Indranil , Sørensen Jens A. , Eriksson Elof , Nuutila Kristo 
Published: April 2017

AbstractWound microenvironment plays a major role in the process of wound healing. It contains various external and internal factors that participate in wound pathophysiology. The pH is an important factor that influences wound healing by changing throughout the healing process. Several previous studies have investigated the role of pH in relation to pathogens but studies concentrating on the effects of pH on wound healing itself are inconclusive. The purpose of this study was to comprehensively and in a controlled fashion investigate the effect of pH on wound healing by studying its effect on human primary keratinocyte and fibroblast function in vitro and on wound healing in vivo. In vitro, primary human keratinocytes and fibroblasts were cultured in different levels of pH (5.5–12.5) and the effect on cell viability, proliferation, and migration was studied. A rat full‐thickness wound model was used to investigate the effect of pH (5.5–9.5) on wound healing in vivo. The effect of pH on inflammation was monitored by measuring IL‐1
concentrations from wounds and cell cultures exposed to different pH environments. Our results showed that both skin cell types tolerated wide range of pH very well. They further demonstrated that both acidic and alkaline environments decelerated cell migration in comparison to neutral environments and interestingly alkaline conditions significantly enhanced cell proliferation. Results from the in vivo experiments indicated that a prolonged, strongly acidic wound environment prevents both wound closure and reepithelialization while a prolonged alkaline environment did not have any negative impact on wound closure or reepithelialization. Separately, both in vitro and in vivo studies showed that prolonged acidic conditions significantly increased the expression of IL‐1
in fibroblast cultures and in wound fluid, whereas prolonged alkaline conditions did not result in elevated amounts of IL‐1
.