bluuebunny/crossref_metadata_2025 huggingface dataset:
Route‐external and Route‐internal Landmarks in Route Descriptions: Effects of Route Length and Map Design
Authors: Westerbeek Hans , Maes Alfons
Published: February 2013

Landmarks are basic ingredients in route descriptions. They often mark choice points: locations where travellers choose from different options how to continue the route. This study focuses on one of the loose ends in the taxonomy of landmarks. In a memory‐based production experiment in which respondents described routes they had seen on a map, we studied the distribution of two types of landmarks at choice points: route‐external and route‐internal descriptions (‘take left “at the barber shop” or “at the second intersection”’). We systematically varied route length and the degree of visual clutter in the map. Cluttered maps resulted in a higher proportion of external landmarks, which we explain in terms of their higher degree of referential robustness. Internal landmarks were preferred as routes were longer and thus required more memory load, suggesting that they are more basic or ‘skeletal’ in route descriptions. Copyright © 2013 John Wiley & Sons, Ltd.
Substantial Recoverable Energy Storage in Percolative Metallic Aluminum‐Polypropylene Nanocomposites
Authors: Fredin Lisa A. , Li Zhong , Lanagan Michael T. , Ratner Mark A. , Marks Tobin J.
Published: February 2013

Chemisorption of the activated metallocene polymerization catalyst derived from [rac‐ethylenebisindenyl]zirconium dichlororide (EBIZrCl2) on the native Al2O3 surfaces of metallic aluminum nanoparticles, followed by exposure to propylene, affords 0–3 metal‐isotactic polypropylene nanocomposites. The microstructures of these nanocomposites are characterized by X‐ray diffraction, transmission electron microscopy, scanning electron microscopy, and atomic force microscopy. Electrical measurements show that increasing the concentration of the filler nanoparticles increases the effective permittivity of the nanocomposites to ϵr values as high as 15.4. Because of the high contrast in the complex permittivities and conductivities between the metallic aluminum nanoparticles and the polymeric polypropylene matrix, these composites obey the percolation law for two‐phase composites, reaching maximum permittivities just before the percolation threshold volume fraction, vf ≈ 0.16. This unique method of in situ polymerization from the surface of metallic Al particles produces a new class of materials that perform as superior pulse‐power capacitors, with low leakage current densities of ≈10−7–10−9 A/cm2 at an applied field of 105 V/cm, low dielectric loss in the 100 Hz–1 MHz frequency range, and recoverable energy storage as high as 14.4 J/cm3.
Tuning the Redox Properties of Photochromic Diarylethenes by Introducing Electron‐Withdrawing Substituents
Authors: Berberich Martin , Würthner Frank
Published: February 2013

A series of seven photochromic diarylethenes (DAEs) with various electron‐withdrawing substituents and their respective closed‐form isomers (DAEC) were synthesized and the optical and redox properties of these photochromes were investigated by UV/vis absorption spectroscopy and cyclic voltammetry. Our comparative studies with these DAEs revealed that the absorption properties of the closed forms and the redox potentials of the open and closed isomers appreciably depend on the number and nature of the electron‐withdrawing groups introduced into the DAE unit. The DAE derivatives can be photochemically switched between two different states with different redox properties. Most prominently, photochrome 3 with two nitro groups has a first reduction potential for the open form 3 o of −1.51 V and for the corresponding closed form 3 c of −0.96 V, and, therefore, is particularly interesting as switchable electron‐acceptor moiety in photochromic systems.
An Upper Palaeolithic Landscape Analysis of Coastal Portugal Using Ground‐penetrating Radar
Authors: Conyers Lawrence B. , Daniels J. Michael , Haws Jonathan A. , Benedetti Michael M.
Published: February 2013

Ground‐penetrating mapping radar allows for the three‐dimensional reconstruction of ancient landscapes by interpreting geological horizons associated with archaeological sites. When the geological framework of a site can be placed in both time and space, ancient environments and people's usage and adaptation to landscapes can be studied. In coastal Portugal late Ice Age people discarded stone tools within aeolian sands that were deposited directly on a bedrock surface, which could be mapped using ground‐penetrating radar. That surface was then studied in three‐dimensions and the palaeotopography at the time people were using this area was mapped. It was found that these ancient people probably took shelter behind a small elevation rise on the edge of a series of streams that flowed toward a nearby floodplain. Using this type of analysis the environmental context of prehistoric activities and human behaviour of these people is provided in a way not possible using traditional archaeological methods. Copyright © 2013 John Wiley & Sons, Ltd.
Benzotriazole‐Containing D–π–A Conjugated Organic Dyes for Dye‐Sensitized Solar Cells
Authors: Yen Yung‐Sheng , Lee Chang‐Tze , Hsu Chih‐Yu , Chou Hsien‐Hsin , Chen Yung‐Chung , Lin Jiann T.
Published: February 2013

A series of metal‐free benzotriazole‐based dipolar dyes have been developed as sensitizers for dye‐sensitized solar cells (DSSCs). Different heteroaromatic rings such as furan, thiophene, and selenophene, were used in combination with benzotriazole as the conjugated spacer group. Light harvesting, charge recombination, and electron injection of the cells fabricated are affected by the heteroaromatic ring used in the spacer. The DSSC with the thiophene‐containing dye has the highest conversion efficiency of 6.20 %, which reaches 85 % of the standard cell based on N719.
Biomass Futures: an integrated approach for estimating the future contribution of biomass value chains to the European energy system and inform future policy formation
Authors: Panoutsou Calliope , Bauen Ausilio , Böttcher Hannes , Alexopoulou Efi , Fritsche Uwe , Uslu Ayla , van Stralen Joost N.P. , Elbersen Berien , Kretschmer Bettina , Capros Pantelis , Maniatis Kyriakos
Published: February 2013

The Biomass Futures project assessed the role of bioenergy in meeting Europe's renewable energy targets established by the 2009 Renewable Energy Directive for 2020 and provided outlooks to 2030 and 2050. This perspective sets the scene for the approaches followed within Biomass Futures, and presents the main issues addressed and the interactions of various models and participatory methods used. Moreover, it provides a short overview of the main results and the key recommendations stemming from the project. Detailed results for demand, supply, sustainability, and policy analysis work performed by the team are presented in the other papers within this issue. To be able to evaluate and prioritize the most important biomass value chains for energy and fuels at EU27 and member states, a substantial level of information is required based on harmonized methodologies and modeling tools as well as accurate and updated datasets for sustainable biomass potentials, technological efficiencies, costs, and sustainability impacts. The Biomass Futures integrated approach employed an interrelated set of qualitative and quantitative modeling frameworks in order to conduct sectoral market analyses, estimate the availability of biomass for energy, and model the demand and supply of bioenergy within the energy system. Continuous stakeholder involvement was ensured throughout the project by dedicated workshops, teleconferences, and targeted interviews while information was disseminated in the form of short and concise briefings addressed to the stakeholders. © 2013 Society of Chemical Industry and John Wiley & Sons, Ltd
Determination of alkaloids in Sinomenium acutum by field‐amplified sample stacking in capillary electrophoresis with chemiluminescene detection
Authors: Shi Guiying , Li Jiang , Yin Yingchun , Xu Xueqin , Chen Guonan
Published: February 2013

A simple and rapid capillary electrophoresis (CE) with an acidic potassium permanganate chemiluminescence (CL) detection method was developed to determine three alkaloids (curine, sinomenine and magnoflorine) simultaneously. A laboratory‐built CE–CL detection interface was used. The field‐amplified sample stacking technique was applied to the online concentration of alkaloids. Experimental conditions for CE separation and CL detection were investigated in detail to acquire optimum conditions. Under optimal conditions, the three alkaloids were baseline separated within 6 min, and the detection limits (S/N = 3) ranged from 0.03 µg/mL to 0.49 µg/mL. This method was successfully applied to determine the above three alkaloids in Sinomenium acutum, and the result of the determination of sinomenine was in good agreement with those given by high‐performance liquid chromatography and CE methods. In addition, a possible CL reaction mechanism of sinomenine–KMnO4–H2SO4 was proposed. Copyright © 2013 John Wiley & Sons, Ltd.
Mesenchymal stem cell durotaxis depends on substrate stiffness gradient strength
Authors: Vincent Ludovic G. , Choi Yu Suk , Alonso‐Latorre Baldomero , del Álamo Juan C. , Engler Adam J.
Published: February 2013

Mesenchymal stem cells (MSCs) respond to the elasticity of their environment, which varies between and within tissues. Stiffness gradients within tissues can result from pathological conditions, but also occur through normal variation, such as in muscle. MSC migration can be directed by shallow stiffness gradients before differentiating. Gradients with fine control over substrate compliance – both in range and rate of change (strength) – are needed to better understand mechanical regulation of MSC migration in normal and diseased states. We describe polyacrylamide stiffness gradient fabrication using three distinct systems, generating stiffness gradients of physiological (1 Pa/μm), pathological (10 Pa/μm), and step change (≥ 100Pa/μm) strength. All gradients spanned a range of physiologically relevant elastic moduli for soft tissues (1–12 kPa). MSCs migrated to the stiffest region on each gradient. Time‐lapse microscopy revealed that migration velocity correlated directly with gradient strength. Directed migration was reduced in the presence of the contractile agonist lysophosphatidic acid (LPA) and cytoskeleton‐perturbing drugs nocodazole and cytochalasin. LPA‐ and nocodazole‐treated cells remained spread and protrusive on the substrate, while cytochalasin‐treated cells did not. Nocodazole‐treated cells spread in a similar manner to untreated cells, but exhibited greatly diminished traction forces. These data suggest that a functional actin cytoskeleton is required for migration whereas microtubules are required for directed migration. The data also imply that, in vivo, MSCs may preferentially accumulate in regions of high elastic modulus and make a greater contribution to tissue repairs in these locations.
Development of a Group Contribution Method Based on UNIFAC Groups for the Estimation of Vapor Pressures of Pure Hydrocarbon Compounds
Authors: Rezakazemi M. , Marjani A. , Shirazian S.
Published: February 2013

A group contribution method based on UNIFAC groups was developed to estimate the vapor pressures of pure hydrocarbons at reduced temperatures (0.45–0.95). The maximum pressure for the correlation is 35 atm. Experimental vapor pressures for 456 hydrocarbons were collected and used to calculate model parameters. The developed model utilizes the combinatorial and the residual UNIFAC terms and the fugacity of pure hydrocarbons. The model parameters were fitted in two modes, using contributions from first‐order groups. In the first case, the Gibbs free energy was considered only as an explicit function of temperature, and in the second one, in addition to the temperature effect, the effect of the molecular structure was also considered. Taking the molecular structure into account significantly decreases the prediction error. Hence, a uniform linear relationship to structure is considered. In the modified models, the error in prediction of the vapor pressure in the temperature range discussed is less than 15 %.
Comparative study of Box–Behnken, central composite, and Doehlert matrix for multivariate optimization of Pb (II) adsorption onto Robinia tree leaves
Authors: Zolgharnein Javad , Shahmoradi Ali , Ghasemi Jahan B.
Published: February 2013

A comparative study of Box–Behnken, central composite, and Doehlert matrix was performed on the adsorption of Pb (II) by Robinia tree leaves in a batch system. As a case study, uptake capacity (q) and removal efficiency (R) of Pb (II) biosorption have been evaluated with all theses approaches. The advantages and limitations of these different response surface techniques have been experimentally considered. The results show the different statistical predictability of Doehlert matrix and Box–Behnken design at 95% confidence level comparable with some extent with that of central composite design at some extreme conditions. An environmental and economical comparison was also carried out between individual and simultaneous optimization of removal efficiency (R) and uptake capacity (q) using desirability function. Optimization of q proves only to have advantages over R or simultaneous optimization of R and q in this particular biosorption process. Copyright © 2013 John Wiley & Sons, Ltd.
How is a molecular polymorphism defined?
Authors: Schildgen Verena , Schildgen Oliver
Published: February 2013

In this commentary, the authors address the question of how molecular polymorphisms are defined. Despite an overwhelming amount of literature reporting on single‐nucleotide polymorphisms, there is still no harmonized definition of this term, which the authors believe is not acceptable in the area of personalized medicine.
On the Hopping Efficiency of Nanoparticles in the Electron Transfer across Self‐Assembled Monolayers
Authors: Liu Feng , Khan Kamran , Liang Jing‐Hong , Yan Jia‐Wei , Wu De‐Yin , Mao Bing‐Wei , Jensen Palle Skovhus , Zhang Jingdong , Ulstrup Jens
Published: February 2013

Redox reactions of solvated molecular species at gold‐electrode surfaces modified by electrochemically inactive self‐assembled molecular monolayers (SAMs) are found to be activated by introducing Au nanoparticles (NPs) covalently bound to the SAM to form a reactive Au–alkanedithiol–NP–molecule hybrid entity. The NP appears to relay long‐range electron transfer (ET) so that the rate of the redox reaction may be as efficient as directly on a bare Au electrode, even though the ET distance is increased by several nanometers. In this study, we have employed a fast redox reaction of surface‐confined 6‐(ferrocenyl) hexanethiol molecules and NPs of Au, Pt and Pd to address the dependence of the rate of ET through the hybrid on the particular NP metal. Cyclic voltammograms show an increasing difference in the peak‐to‐peak separation for NPs in the order Au<Pt<Pd, especially when the length of the alkanedithiol increases from octanedithiol to decanedithiol. The corresponding apparent rate constants, kapp, for decanedithiol are 1170, 360 and 14 s−1 for NPs of Au, Pt and Pd, respectively, indicating that the efficiency of NP mediation of the ET clearly depends on the nature of the NP. Based on a preliminary analysis rooted in interfacial electrochemical ET theory, combined with a simplified two‐step view of the NP coupling to the electrode and the molecule, this observation is referred to the density of electronic states of the NPs, reflected in a broadening of the molecular electron/NP bridge group levels and energy‐gap differences between the Fermi levels of the different metals.
Effect of laser‐induced nanocrystallisation on the properties of electroless Ni‐P/Ni‐W‐P duplex coatings
Authors: Liu H. , Guo R. X. , Bian J. S. , Liu Z.
Published: February 2013

This paper presents a comparative study of nanocrystallisation and the wear resistance of electroless plated Ni‐P/Ni‐W‐P duplex coatings with a single Ni‐W‐P coating before and after high‐ power diode laser treatment. Effects of the laser operating parameters on microstructures, in terms of crystallisation, porosity formation, phase transformation and grain growth, were investigated using scanning electron microscopy (SEM) with energy dispersive X‐ray spectroscopy (EDX) and quantitatively X‐ray Diffraction (XRD). Microhardness and wear behaviour of the coatings before and after laser treatment were evaluated by measurement of coating surface and cross‐section hardness as well as un‐lubricated friction and wear tests. The results revealed that in the case of laser treatment, the Ni‐P/Ni‐W‐P duplex coatings offered better wear resistance than the single Ni‐W‐P coating, while the as‐plated, single Ni‐W‐P coating showed better wear resistance than the Ni‐P/Ni‐W‐P duplex coatings. Adhesive wear mechanism prevails in the laser‐treated coatings when subjected to wear test against hardened steel material. The effects of microstructural characteristics in the coatings, in particularly the grain size of Ni3P phase and the degree of crystallisation, on the adhesive wear behaviour have been investigated and found to be dominant besides the effect of hardness.
Effector memory and late memory T cells accumulate in the blood of CMV‐carrying individuals but not in their cerebrospinal fluid
Authors: de Jongste Adriaan H. C. , de Graaf Marieke T. , van den Broek Patricia D. M. , Kraan Jaco , Sillevis Smitt Peter A. E. , Gratama Jan W.
Published: February 2013

Cytomegalovirus (CMV)‐carrying individuals have significantly higher levels of effector memory and late memory T lymphocytes in their blood than non‐carriers. To date, it is well recognized that the central nervous system is subjected to active immunosurveillance, as evidenced by the presence of central memory T cells in cerebrospinal fluid (CSF) of healthy individuals. In order to investigate whether levels of effector memory and late memory T cells were also increased in the CSF of CMV‐carrying individuals, we characterized CD4+ and CD8+ T‐cell subsets in CSF and blood of both groups. Effector memory and late memory T cells were only rarely seen in CSF, which was similar in CMV carriers and non‐carriers. In conclusion, there was no demonstrable difference in the numbers of CSF effector memory and late memory T cells between CMV seronegative and CMV seropositive individuals. © 2013 International Clinical Cytometry Society
Low clonogenic potential of circulating angiogenic cells is associated with lower density of capillaries in skeletal muscle in patients with impaired glucose tolerance
Authors: Prior Steven J. , Ryan Alice S.
Published: February 2013

Background

Reduced density of capillaries in skeletal muscle can limit insulin, glucose, and oxygen supply to the muscle, thereby contributing to worsening metabolism in older adults. The lower skeletal muscle capillarization in impaired glucose tolerance (IGT) may partially be due to circulating angiogenic cell dysfunction. Circulating angiogenic cells maintain the vasculature and promote angiogenesis, but circulating angiogenic cell number and function may be reduced in IGT. The goal of this study was to determine whether the clonogenic potential of circulating angiogenic cells is lower in IGT compared with normal‐glucose‐tolerant (NGT) controls and is associated with skeletal muscle capillarization.

Methods

Glucose tolerance, endothelial cell colony‐forming unit (CFU‐EC) number, and vastus lateralis capillary density were measured in sedentary, older (62 ± 1 years, mean ± SEM) men and women with NGT (n = 16) and IGT (n = 12).

Results

Adults with IGT had 43% lower CFU‐EC number (11.4 ± 2.3 versus 20.1 ± 2.0 colonies, p < 0.01) and 12% lower capillary density (291 ± 11 versus 330 ± 9 capillaries/mm2, p < 0.01) compared with those with NGT. In regression analyses, CFU‐EC number inversely correlated with 120‐min postprandial glucose in all subjects (r = −0.47, p < 0.05), and capillary density was directly associated with CFU‐EC number (r = 0.53, p < 0.05).

Conclusions

We conclude that the clonogenic potential of circulating angiogenic cells is lower in sedentary older adults with IGT and is associated with lower skeletal muscle capillarization. Low circulating angiogenic cell clonogenic potential in IGT suggests a state of impaired angiogenesis occurring prior to overt type 2 diabetes that may mediate early microvascular changes in the development and progression of IGT to type 2 diabetes. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
Tris(organotin)tungstogermanate, a Sandwich Organometallic Derivative of a Keggin‐Type Polyoxometalate: Synthesis and DFT Study
Authors: Liu Huizhang , Bandeira Nuno A. G. , Félix Vitor , Calhorda Maria José
Published: February 2013

A phenyltin‐containing Keggin‐based polyoxometalate has been synthesised and characterised by elemental analysis, infrared and electronic spectroscopy, and multinuclear NMR spectroscopy. Structural data, complemented by DFT calculations, suggests that three phenyltin groups connect two [α‐GeW9O34]10– moieties to form the [(C6H5SnOH)3(α‐GeW9O34)2]14– anion. Each tin atom displays a distorted‐octahedral environment, composed of two sets of equatorial oxygen atoms from two edge‐sharing WO6 octahedra of each [α‐GeW9O34]10– group, and one phenyl and one OH group in the axial positions. The DFT studies lend support to the experimental proposal of the molecular structure of this polyoxometalate. The similar energy of the limiting arrangements of phenyl groups demonstrates how their fluxionality occurs as a dynamical process in solution and explains the disorder in the solid.
Synthesis of Gemini Surfactants and Evaluation of Their Interfacial and Cytotoxic Properties: Exploring the Multifunctionality of Serine as Headgroup
Authors: Silva Sandra G. , Alves Cláudia , Cardoso Ana M. S. , Jurado Amália S. , Pedroso de Lima Maria C. , Vale M. Luísa C. , Marques Eduardo F.
Published: February 2013

Two series of novel cationic gemini surfactants based on the amino acid serine have been synthesized. These compounds contain long alkyl chains linked to the nitrogen atoms of the amino acid residues, as well as spacers interconnecting two carboxylic acid groups, through amide or ester bonds. The most efficient synthetic pathway was established; it involves the introduction of the spacers into the N,N‐dialkylated monomeric precursors by peptide condensation methods with diamines or diols, with subsequent methylation and deprotection to yield the final target surfactants. The effects of molecular structure, type of spacer linkage, and spacer length on the interfacial and cytotoxic properties of these gemini surfactants are reported and discussed; studies on gemini surfactants with amine linkages and other relevant homologous compounds (conventional bis‐quat gemini and monomeric surfactants) are also included. Overall, it is shown that cationic serine‐based gemini surfactants have enhanced interfacial properties and low cytotoxicities, offering potential use in technical and biological applications.
5,6‐Bis(octyloxy)benzo[c][1,2,5]thiadiazole‐Bridged Dyes for Dye‐Sensitized Solar Cells with High Open‐Circuit Voltage Performance
Authors: Chen Long , Li Xin , Ying Weijiang , Zhang Xiaoyu , Guo Fuling , Li Jing , Hua Jianli
Published: February 2013

Three new metal‐free dyes with a 5,6‐bis(octyloxy)benzo[c][1,2,5]thiadiazole core (DOBT‐I–III) have been designed and synthesized for use as DSSCs. Their absorption properties and electrochemical and photovoltaic performances have been investigated systematically. The DSSCs based on DOBT‐I–III show high open‐circuit voltages (Voc) of 829, 818, and 784 mV, respectively. Of the three dyes, DOBT‐III, which contains a thiophene‐bridging linker, exhibits the best photovoltaic performance: a short‐circuit photocurrent density (Jsc) of 12.74 mA cm–2 and a fill factor (FF) of 0.73, which corresponds to an overall conversion efficiency of 7.29 % under standard global AM 1.5 solar conditions.
The Sulfinyl Group as a Remote Chiral Auxiliary in Stereoselective Conjugate Additions of Alkyl Groups to α‐Methylidene Carbonyl Compounds Initiated by Et3B/O2
Authors: Fernández‐Salas José Antonio , Maestro M. Carmen , Rodríguez‐Fernández M. Mercedes , García Ruano José L.
Published: February 2013

Reactions of α‐[2‐(p‐tolylsulfinyl)phenyl] α‐methylidene carbonyl compounds 1 and 2 with alkyl radicals generated from Et3B/O2 and RI give, after protonation, β‐alkyl derivatives with a high degree of control of the configuration at the α carbon. In the case of aldehyde 2, when further combined with allylation of the carbonyl group, a one‐pot radical‐addition/protonation/allylation sequence provides a highly stereoselective synthesis of compounds bearing two adjacent chiral centres. The stereochemical course of the reaction is controlled by the sulfinyl group acting as a remote chiral auxiliary, and this group can be easily removed with tBuLi.
Sediment routing hypothesis for pool‐riffle maintenance
Authors: Milan David J.
Published: February 2013

This paper provides comprehensive evidence that sediment routing around pools is a key mechanism for pool‐riffle maintenance in sinuous upland gravel‐bed streams. The findings suggest that pools do not require a reversal in energy for them to scour out any accumulated sediments, if little or no sediments are fed into them. A combination of clast tracing using passive integrated transponder (PIT) tagging and bedload traps (positioned along the thalweg on the upstream riffle, pool entrance, pool exit and downstream riffle) are used to provide information on clast pathways and sediment sorting through a single pool‐riffle unit. Computational fluid dynamics (CFD) is also used to explore hydraulic variability and flow pathways. Clast tracing results provide a strong indication that clasts are not fed through pools, rather they are transported across point bar surfaces, or around bar edges (depending upon previous clast position, clast size, and event magnitude). Spatial variations in bedload transport were found throughout the pool‐riffle unit. The pool entrance bedload trap was often found to be empty, when the others had filled, further supporting the notion that little or no sediment was fed into the pool. The pool exit slope trap would occasionally fill with sediment, thought to be sourced from the eroding outer bank. CFD results demonstrate higher pool shear stresses (τ ≈ 140 N m–2) in a localized zone adjacent to an eroding outer bank, compared to the upstream and downstream riffles (τ ≈ 60 N m–2) at flows of 6 · 2 m3 s–1 (≈ 60% of the bankfull discharge) and above. There was marginal evidence for near‐bed velocity reversal. Near‐bed streamlines, produced from velocity vectors indicate that flow paths are diverted over the bar top rather than being fed through the thalweg. Some streamlines appear to brush the outer edge of the pool for the 4 · 9 m3 s–1 to 7 · 8 m3 s–1 (between 50 and 80% of the bankfull discharge) simulations, however complete avoidance was found for discharges greater than this. Copyright © 2013 John Wiley & Sons, Ltd.
Mechanistic Biomarkers Provide Early and Sensitive Detection of Acetaminophen-Induced Acute Liver Injury at First Presentation to Hospital
Authors: Antoine Daniel J. , Dear James W. , Lewis Philip Starkey , Platt Vivien , Coyle Judy , Masson Moyra , Thanacoody Ruben H. , Gray Alasdair J. , Webb David J. , Moggs Jonathan G. , Bateman Nicholas D. , Goldring Christopher E. , Park Kevin B.
Published: February 2013

Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA-122 (miR-122; high liver specificity), high mobility group box-1 (HMGB1; marker of necrosis), full-length and caspase-cleaved keratin-18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose.

Conclusion

: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies. (Hepatology 2013;58:777–787)
MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-Stat3 pathway
Authors: Yang Xin , Liang Lei , Zhang Xiao-Fei , Jia Hu-Liang , Qin Yi , Zhu Xu-Chao , Gao Xiao-Mei , Qiao Peng , Zheng Yan , Sheng Yuan-Yuan , Wei Jin-Wang , Zhou Hai-Jun , Ren Ning , Ye Qing-Hai , Dong Qiong-Zhu , Qin Lun-Xiu
Published: February 2013

Down-regulation of microRNA-26a (miR-26a) is associated with poor prognosis of hepatocellular carcinoma (HCC), but its functional mechanism in HCC remains unclear. In this study, we investigated the roles of miR-26a in tumor growth and metastasis of HCC and found that miR-26a was frequently down-regulated in HCC tissues. Down-regulation of miR-26a correlated with HCC recurrence and metastasis. Through gain- and loss-of-function studies, miR-26a was demonstrated to significantly inhibit in vitro cell proliferation, migration, and invasion. In addition, miR-26a induced G1 arrest and promoted apoptosis of HCC cells. Importantly, miR-26a suppressed in vivo tumor growth and metastasis in nude mice models bearing human HCC. Interleukin-6 (IL-6) was identified as a target of miR-26a. Knockdown of IL-6 induced effects on HCC cells similar to those induced by miR-26a. In contrast, IL-6 treatment abrogated the effects induced by miR-26a up-regulation. Moreover, miR-26a dramatically suppressed expression of signal transducer and activator of transcription 3 (Stat3) target genes, including Bcl-2, Mcl-1, cyclin D1, and MMP2. IL-6 treatment antagonized this effect, while knockdown of IL-6 by IL-6 short hairpin RNA (shIL-6) induced inhibitory effects on the expression of p-Stat3 and its main target genes, similar to miR-26a. The messenger RNA and protein levels of IL-6 inversely correlated with miR-26a in HCCs. Patients with high miR-26a or low IL-6 in HCC tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR-26a, IL-6, and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. Conclusion: miR-26a could suppress tumor growth and metastasis of HCC through IL-6-Stat3 signaling and is a novel prognostic marker and therapeutic target for HCC. (HEPATOLOGY 2013)
Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: A multicenter survey on safety and efficacy
Authors: Laleman Wim , Simon-Talero Macarena , Maleux Geert , Perez Mercedes , Ameloot Koen , Soriano German , Villalba Jordi , Garcia-Pagan Juan-Carlos , Barrufet Marta , Jalan Rajiv , Brookes Jocelyn , Thalassinos Evangelos , Burroughs Andrew K. , Cordoba Juan , Nevens Frederik
Published: February 2013

Refractory hepatic encephalopathy (HE) remains a major cause of morbidity in cirrhosis patients. Large spontaneous portosystemic shunts (SPSSs) have been previously suggested to sustain HE in these patients. We aimed to retrospectively assess the efficacy and safety of patients treated with embolization of large SPSSs for the treatment of chronic therapy-refractory HE in a European multicentric working group and to identify patients who may benefit from this procedure. Between July 1998 and January 2012, 37 patients (Child A6-C13, MELD [Model of Endstage Liver Disease] 5-28) with refractory HE were diagnosed with single large SPSSs that were considered eligible for embolization. On a short-term basis (i.e., within 100 days after embolization), 22 out of 37 patients (59.4%) were free of HE (

P

< 0.001 versus before embolization) of which 18 (48.6% of patients overall) remained HE-free over a mean follow-up period of 697 ± 157 days (

P

< 0.001 versus before embolization). Overall, we noted improved autonomy, decreased number of hospitalizations, and severity of the worst HE episode after embolization in three-quarters of the patients. Logistic regression identified the MELD score as strongest positive predictive factor of HE recurrence with a cutoff of 11 for patient selection. As to safety, we noted one major nonlethal procedure-related complication. There was no significant increase in

de novo

development or aggravation of preexisting varices, portal hypertensive gastropathy, or ascites.

Conclusion

: This multicenter European cohort study demonstrated a role for large SPSSs in chronic protracted or recurrent HE and substantiated the effectiveness and safety of embolization of these shunts, provided there is sufficient functional liver reserve.
Coexistent mutations of KRAS and PIK3CA affect the efficacy of NVP‐BEZ235, a dual PI3K/MTOR inhibitor, in regulating the PI3K/MTOR pathway in colorectal cancer
Authors: Kim Areumnuri , Lee Jung‐Eun , Lee Seung‐Sook , Kim Cherin , Lee Sun‐Joo , Jang Won‐Suk , Park Sunhoo
Published: February 2013

Colorectal cancer (CRC) with mutational activation of KRAS is observed frequently. In addition, PIK3CA mutations commonly coexist with KRAS mutations and lead to additive activation of the PI3K/MTOR signaling pathway. Here, we investigated how CRC cells that harbor KRAS and PIK3CA mutations affect sensitivity to inhibition of PI3K/MTOR with NVP‐BEZ235 (BEZ235). We selected CRC patient samples and assessed their mutational status. CRC patients with KRAS or PIK3CA mutations show activation of AKT and MTOR, particularly when KRAS and PIK3CA mutations coexist. Suppression of PI3K/MTOR by BEZ235 results in a growth inhibitory effect and enhanced apoptosis via BIM activation in KRAS mutant cells. Mutational activation of KRAS when accompanied by a PIK3CA mutation converges at PI3K/MTOR pathway activation, resulting in resistance to BEZ235. BIM knockdown blocked the apoptotic response to BEZ235 in KRAS mutant cells, suggesting that PI3K inhibition leads to BIM accumulation. Moreover, BEZ235 treatment resulted in induction of FOXO3A activity and its induced transcription of BIM activation, which sensitized cells to cytotoxic agents leading to apoptosis in double mutant cells in vitro and in vivo. Taken together, our data suggest that targeting PI3K/MTOR sensitizes cells to apoptosis, implying that activation of PI3K/MTOR signaling via KRAS or PIK3CA mutation is an important pathway in CRC cell growth. Based on these results, coexistent KRAS and PIK3CA mutations confer resistance to BEZ235 via suppression of BIM‐induced apoptosis, suggesting that combined treatment with conventional chemoagents is a potential strategy in the clinic.
Nuclear expression of Glycogen synthase kinase‐3β and lack of membranous β‐catenin is correlated with poor survival in colon cancer
Authors: Salim Tavga , Sjölander Anita , Sand‐Dejmek Janna
Published: February 2013

Dysregulation of Wnt/β‐catenin signaling is a hallmark of colon cancer. Glycogen synthase kinase‐3β (GSK‐3β) can be a positive regulator of survival and proliferation of cultured colon cancer cell but its role in clinical colon cancer is unknown. Our objectives were to evaluate the role of GSK‐3β in colon cancer. A tumor tissue microarray of primary colon cancers and metastases was used to evaluate expression and subcellular localization of GSK‐3β and β‐catenin. In total, 85 primary colon cancer samples were evaluated by immunohistochemistry. Immunoreactivity was correlated to known markers of adverse prognosis. Overall survival was the primary end‐point. We found nuclear accumulation of GSK‐3β in 39% (33/85) of evaluated tumors. Nuclear GSK‐3β was significantly associated with shorter overall survival (p = 0.008), larger tumor size (p = 0.015), distant metastasis (p = 0.029) and loss of membranous β‐catenin (p = 0.007). Loss of membranous β‐catenin occurred in 37% (30/82) of the tumors and was associated with poor survival (p = 0.016). The combination of nuclear GSK‐3β and lack of membrane β‐catenin occurred in a total of 26% of the studied tumors (21/61) and was significantly and independently associated with poor prognosis. Our results suggest that nuclear expression of GSK‐3β and loss of membrane β‐catenin identify a subset of colon carcinomas with worse prognosis.
Targeting the EP1 receptor reduces Fas ligand expression and increases the antitumor immune response in an in vivo model of colon cancer
Authors: O'Callaghan Grace , Ryan Aideen , Neary Peter , O'Mahony Caitlin , Shanahan Fergus , Houston Aileen
Published: February 2013

Despite studies demonstrating that inhibition of cyclooxygenase‐2 (COX‐2)‐derived prostaglandin E2 (PGE2) has significant chemotherapeutic benefits in vitro and in vivo, inhibition of COX enzymes is associated with serious gastrointestinal and cardiovascular side effects, limiting the clinical utility of these drugs. PGE2 signals through four different receptors (EP1–EP4) and targeting individual receptor(s) may avoid these side effects, while retaining significant anticancer benefits. Here, we show that targeted inhibition of the EP1 receptor in the tumor cells and the tumor microenvironment resulted in the significant inhibition of tumor growth in vivo. Both dietary administration and direct injection of the EP1 receptor‐specific antagonist, ONO‐8713, effectively reduced the growth of established CT26 tumors in BALB/c mice, with suppression of the EP1 receptor in the tumor cells alone less effective in reducing tumor growth. This antitumor effect was associated with reduced Fas ligand expression and attenuated tumor‐induced immune suppression. In particular, tumor infiltration by CD4+CD25+Foxp3+ regulatory T cells was decreased, whereas the cytotoxic activity of isolated splenocytes against CT26 cells was increased. F4/80+ macrophage infiltration was also decreased; however, there was no change in macrophage phenotype. These findings suggest that the EP1 receptor represents a potential target for the treatment of colon cancer.
High male chimerism in the female breast shows quantitative links with cancer
Authors: Dhimolea Eugen , Denes Viktoria , Lakk Monika , Al‐Bazzaz Sana , Aziz‐Zaman Sonya , Pilichowska Monika , Geck Peter
Published: February 2013

Clinical observations suggest that pregnancy provides protection against cancer. The mechanisms involved, however, remain unclear. Fetal cells are known to enter the mother's circulation during pregnancy and establish microchimerism. We investigated if pregnancy‐related embryonic/fetal stem cell integration plays a role in breast cancer. A high‐sensitivity Y‐chromosome assay was developed to trace male allogeneic cells (from male fetus) in females. Fixed‐embedded samples (n = 206) from both normal and breast cancer patients were screened for microchimerism. The results were combined with matching clinicopathological and histological parameters and processed statistically. The results show that in our samples (182 informative) more than half of healthy women (56%) carried male cells in their breast tissue for decades (n = 68), while only one out of five in the cancer sample pool (21%) (n = 114) (odds ratio = 4.75, CI at 95% 2.34–9.69; p = 0.0001). The data support the notion that a biological link may exist between chimerism and tissue‐integrity. The correlation, however, is non‐linear, since male microchimerism in excess (“hyperchimerism”) is also involved in cancer. The data suggest a link between hyperchimerism and HER2‐type cancers, while decreased chimerism (“hypochimerism”) associates with ER/PR‐positive (luminal‐type) breast cancers. Chimerism levels that correlate with protection appear to be non‐random and share densities with the mammary progenitor components of the stem cell lineage in the breast. The results suggest that protection may involve stem/progenitor level interactions and implicate novel quantitative mechanisms in chimerism biology.
Analgesic use and the risk of kidney cancer: A meta‐analysis of epidemiologic studies
Authors: Choueiri Toni K. , Je Youjin , Cho Eunyoung
Published: February 2013

Analgesics are the most commonly used over‐the‐counter drugs worldwide with certain analgesics having cancer prevention effect. The evidence for an increased risk of developing kidney cancer with analgesic use is mixed. Using a meta‐analysis design of available observational epidemiologic studies, we investigated the association between analgesic use and kidney cancer risk. We searched the MEDLINE and EMBASE databases to identify eligible case–control or cohort studies published in English until June 2012 for three categories of analgesics: acetaminophen, aspirin or other non‐steroidal anti‐inflammatory drugs (NSAIDs). Study‐specific effect estimates were pooled to compute an overall relative risk (RR) and its 95% confidence interval (CI) using a random‐effects model for each category of the analgesics. We identified 20 studies (14 with acetaminophen, 13 with aspirin and five with other NSAIDs) that were performed in six countries, including 8,420 cases of kidney cancer. Use of acetaminophen and non‐aspirin NSAIDs were associated with an increased risk of kidney cancer (pooled RR: 1.28; 95% CI: 1.15–1.44 and 1.25; 95% CI: 1.06–1.46, respectively). For aspirin use, we found no overall increased risk (pooled RR: 1.10; 95% CI: 0.95–1.28), except for non‐US studies (five studies, pooled RR: 1.17; 95% CI: 1.04–1.33). Similar increases in risks were seen with higher analgesic intake. In this largest meta‐analysis to date, we found that acetaminophen and non‐aspirin NSAIDs are associated with a significant risk of developing kidney cancer. Further work is needed to elucidate biologic mechanisms behind these findings.
Does removal of out‐of‐pocket costs for cervical and breast cancer screening work? A quasi‐experimental study to evaluate the impact on attendance, attendance inequality and average cost per uptake of a Japanese government intervention
Authors: Tabuchi Takahiro , Hoshino Takahiro , Nakayama Tomio , Ito Yuri , Ioka Akiko , Miyashiro Isao , Tsukuma Hideaki
Published: February 2013

Reducing out‐of‐pocket costs is known to improve mammography attendance, but an evidence gap remains concerning Pap smear testing. The Japanese government implemented a politically determined intervention to remove out‐of‐pocket costs for Pap smear tests and mammography attendance, costing US$148 million, in 2009. It targeted women when they reached the first year of a 5‐year age group (i.e., 20, 25, 30 years) with the aim of reducing attendance inequality. Our objective is to evaluate the intervention in terms of uptake and average cost per uptake for cancer screening attendance and to assess socioeconomic inequalities in cancer screening attendance pre‐ and postintervention. A quasi‐experimental study utilizing national repeated cross sections, observed pre‐ and postintervention, which compared intervention and comparison groups by the Difference‐in‐Differences method, was conducted. Outcome measures were uptake of cancer screening attendance resulting from the intervention with average cost per uptake and broad inequality indicators for cancer screening attendance according to socioeconomic inequality. In total, 34,043 age‐eligible, noninstitutionalized women were analyzed. Uptake among the overall population was 13.9% point in the age‐ and income‐adjusted model for Pap smear and 9.8% point for mammography, with an average cost of US$139 per uptake. The intervention increased inequality indicators in Pap smear attendance (more than +100%) but decreased inequality in mammography attendance (ranging from −12.9 to −74.1%) within the intervention group. In conclusion, removing out‐of‐pocket costs improves female cancer screening uptake in Japan but may not be cost‐saving. Although cost removal reduces inequalities in attendance for mammography, it appears to increase inequalities in Pap smear attendance.
Osseointegration of hydroxyapatite and remodeling‐resorption of tricalciumphosphate ceramics
Authors: Draenert Miriam , Draenert Alice , Draenert Klaus
Published: February 2013

Background: Cancellous bone defects surrounded by still intact bone structures never heal. Ceramics offer a solution providing osteoconductive scaffolds. Purpose: The purpose of the study is to evaluate whether structured β‐TCP and HA implants can reconstruct cancellous bone defects, which role micro‐ and macro‐porosity, stiffness and surface area play; finally the indication for both materials based on its resorbability. Material & Methods: 10 German Shepard dogs were operated on both tibial heads implanting shell‐like fully interconnected ceramic cylinders, using a wet grinding hollow drill coated with diamonds. β‐TCP was compared with HA. A polychromatic sequential labelling with 4 different fluorochromes controlled bone formation dynamics. Non‐decalcifying histology after perfusion fixation and vessel casting was performed. μ‐CT was combined with high resolution microradiography and histology on thin ground crossections. The stages after 6 weeks, 2, 3, 4 months and 15 months were evaluated. Results: In spite of osseointegration of HA and β‐TCP, the osseointegration of both materials was completely different. Both shell‐like bone void fillers were osseointegrated in a sandwich‐like manner. HA yielded primarily a reinforcement of the recipient's cancellous‐bone bed and full osseointegration after 4 months, whereas β‐TCP‐implants were fully osseointegrated after 6 weeks. HA did not show signs of resorption. The resorption of the β‐TCP resulted during remodelling. The final stage showed restitution “ad integrum” of the β‐TCP defects with a physiological architecture, whereas HA was integrated in the cancellous bone construction providing 600 μm measuring macropores showing osteoinductive properties. Microsc. Res. Tech. 76:370–380, 2013. © 2013 Wiley Periodicals, Inc.