bluuebunny/crossref_metadata_2025 huggingface dataset:
Design of the DRAGET Study: a multicentre controlled diagnostic study to assess the detection of acute rejection in patients with heart transplant by means of T2quantification with MRI in comparison to myocardial biopsies
Authors: Bonnemains Laurent , Cherifi Aboubaker , Girerd Nicolas , Odille Freddy , Felblinger Jacques
Published: October 2015

Introduction

Patients with heart transplant are screened for silent graft rejection by recurrent endomyocardial biopsies. MRI can detect the presence of oedema non-invasively by quantitatively measuring changes of the transverse relaxation time T2in the myocardium. Several monocentric studies have shown that T2quantification could help detect graft rejection in a less invasive way. DRAGET is a national multicentre diagnostic study designed to prove that T2quantification by MRI can detect graft rejection.

Methods and analysis

190 patients from 10 centres will undergo T2quantification and endomyocardial biopsy, within 24 h, 4 to 6 times during the first year after transplantation. T2will be computed by analysing a sequence of 10 images obtained from a short-axis slice. Specific phantoms will be used to calibrate the T2quantification on each MR scanner to cope with the different equipment (different vendors, magnetic field strength, etc). Specific pads with known T2will also be used during each examination and provide a quality check to cope with the different experimental conditions (temperature, etc). All MRI and biopsy data will be reinterpreted in our centre and reproducibility will be assessed. The primary outcome will be sensitivity and specificity of MRI. The secondary outcomes will be (1) prognostic values of T2, (2) reproducibility of each techniques, (3) number of adverse events during each procedures and (4) confidence of the physicians in T2.

Ethics and dissemination

Ethics approval has been obtained. The new MRI method will be disseminated at a national level and its practical usefulness will be assessed in centres not familiar with MRI T2quantification. The ultimate aim of the DRAGET project is to replace a strategy based solely on biopsy with one based on a first-line MRI (with biopsy only when needed) for a more efficient and less invasive detection of rejection.

Trial registration numbers

ANSM 2014-A00848-39,NCT02261870.
Fathers’ intelligence measured at age 18–20 years is associated with offspring smoking: linking the Swedish 1969 conscription cohort to the Swedish Survey of Living Conditions
Authors: Sörberg Wallin Alma , Lundin Andreas , Melin Bo , Hemmingsson Tomas
Published: October 2015

Background

An association between lower IQ of parents, measured early in life, and smoking among their offspring has been reported. The extent to which other background factors account for this association is unknown.

Methods

Data on IQ, smoking, mental health, social class, parental divorce and social problems in a cohort of men born during 1949–1951 and conscripted for military service in 1969 were linked to smoking data on 682 offspring interviewed in the Swedish Surveys of Living Conditions 1984–2009.

Results

In an age-adjusted model, a one-step decrease on a stanine scale was associated with an OR of 1.19 (95% CI 1.04 to 1.35) for offspring smoking. Adjusting for father's socioeconomic background and smoking, mental illness and social problems in youth only marginally lowered the OR's.

Conclusions

Lower IQ among fathers measured at ages 18–20 years was associated with smoking in their offspring. The association was not explained by father's social class in childhood or a higher prevalence of mental illness, social problems or smoking measured among the fathers in their late adolescence.
Modulation of the metabolism of cis-platin in blood plasma by glutathione
Authors: Sooriyaarachchi Melani , Gibson Matthew A. , Lima Bruno dos S. , Gailer Jürgen
Published: October 2015

The anticancer drug cis-platin (CP) is in worldwide clinical use to treat a variety of cancers, but is inherently associated with severe toxic side effects. Previous animal studies revealed that its neurotoxicity can be significantly reduced by the coadministration of l-glutathione (GSH) without affecting the anticancer effect. The underlying molecular mechanism, however, has remained elusive. Since the bloodstream is a likely biological compartment where CP-derived hydrolysis products may react with GSH, we have employed a recently developed metallomics tool to gain insight into the interaction of CP and GSH in rabbit plasma in vitro. After the addition of increasing GSH/CP molar ratios to plasma (25:1, 50:1, and 100:1), the determination of the Pt distribution 5 min and 2 h later revealed the formation of a Pt–GSH complex that did not bind to plasma proteins. The simultaneously obtained Zn distribution in plasma revealed a progressively more pronounced perturbation of the Zn metalloproteome with increasing GSH/CP molar ratios at the 5 min time point, which partially reversed at the 2 h time point. The formation of Pt–GSH species in plasma is therefore likely to be directly involved in the process by which GSH protects mammalian organisms from CP-induced neurotoxicity, nephrotoxicity, and possibly other organ-based toxicities.
The fine tuning of the cosmological constant in a conformal model
Authors: Jain Pankaj , Kashyap Gopal , Mitra Subhadip
Published: October 2015

We consider a conformal model involving two real scalar fields in which the conformal symmetry is broken by a soft mechanism and is not anomalous. One of these scalar fields is representative of the standard model Higgs. The model predicts exactly zero cosmological constant. In the simplest version of the model, some of the couplings need to be fine-tuned to very small values. We formulate the problem of fine tuning of these couplings. We argue that the problem arises since we require a soft mechanism to break conformal symmetry. The symmetry breaking is possible only if the scalar fields do not evolve significantly over the time scale of the Universe. Ignoring contributions due to quantum gravity, we present two solutions to this fine tuning problem. We argue that the problem is solved if the classical value of one of the scalar fields is super-Planckian, i.e. takes a value much larger than the Planck mass. The second solution involves introduction of a strongly coupled hidden sector that we call hypercolor. In this case, the conformal invariance is broken dynamically and triggers the breakdown of the electroweak symmetry. We argue that our analysis applies also to the case of the standard model Higgs multiplet.
Influence of next-nearest neighbor interaction on low temperature properties of the spin-1/2 one-dimensional ferromagnetic XY model
Authors: Yin Songqiu , Chen Yuan
Published: October 2015

In this paper, we apply spin-wave theory to the one-dimensional spin-1/2 ferromagnetic XY model with the next-nearest neighbor interaction. The thermodynamic divergences which the conventional spin-wave theory encounters with, are solved by implementing Takahashi’s idea through introducing a Lagrange multiplier in the Hamiltonian to keep zero magnetization. It is shown that the next-nearest neighbor interaction has an influence on the ground-state and low temperature properties of the system. The exponential laws which are induced by the next-nearest neighbor interaction, are found for heights of maxima of the specific heat and its coefficient, as well as the maximum and minimum of the susceptibility coefficient. The maximum positions of the specific heat and its coefficient fit well to the linear and exponential laws under the next-nearest neighbor interaction, respectively.
Study of the free volume fraction in polylactic acid (PLA) by thermal analysis
Authors: Abdallah A. , Benrekaa N.
Published: October 2015

The poly (lactic acid) or polylactide (PLA) is a biodegradable polymer with high modulus, strength and thermoplastic properties. In this work, the evolution of various properties of PLA is studied, such as glass transition temperature, mechanical modules and elongation percentage with the aim of investigating the free volume fraction. To do so, two thermal techniques have been used: the dynamic mechanical analysis (DMA) and dilatometry. The results obtained by these techniques are combined to go back to the structural properties of the studied material.
Compression approach of street networks considering the structural and functional features of streets
Authors: Liu Gang , He Jing , Zhang Xiping
Published: October 2015

The compression of networks is an important aspect of complex networks and spatial generalization. Previous studies show that the dual graph for street–street relationships more accurately reflects the morphological features of street networks than the traditional methods. In this study, a dual graph for street–street relationship is constructed based on complex networks theory. We introduce the concept of m-order neighbors and take into account the factors of the node’s degree, closeness centrality, betweenness centrality, and distance within the dual graph. We also consider the importance contributions of the node itself and its 1- to m-order neighbors and define the evaluation model of node importance. We then propose a street compression process based on the evaluation of node importance for dual graph by considering the structural and functional features of streets. The degree distribution and topological similarity index are introduced to evaluate the level of maintaining the global structure and topological characteristics of the road network and to validate the efficiency of the proposed method. A real urban road network is used for the experiments. Results show that the proposed approach can be used in selecting important streets that can retain the global structural properties and topological connectivity of the street network.
Improving Search-Based Schematic Layout by Parameter Manipulation
Authors: Chivers Daniel , Rodgers Peter
Published: October 2015

This paper reports on a method to improve the automated layout of schematic diagrams by widening the search space examined by the system. In search-based layout methods there are typically a number of parameters that control the search algorithm which do not affect the fitness function, but nevertheless have an impact on the final layout. We explore how varying three parameters (grid spacing, the starting distance of allowed node movement and the number of iterations) affects the resultant diagram in a hill-climbing layout system. Using an iterative process, we produce diagram layouts that are significantly better than those produced by ad-hoc parameter settings.
THE MULTI-CURVE POTENTIAL MODEL
Authors: NGUYEN THE ANH , SEIFRIED FRANK THOMAS
Published: October 2015

We develop a general class of multi-curve potential models for post-crisis interest rates. Our model features positive stochastic basis spreads, positive term structures, and analytic pricing formulae for interest rate derivatives. Making a quanto interpretation of LIBOR lending transactions, we use a multi-currency analogy to model multiple term structures and formulate a general, tractable model of multiple term structures. As a special case of our approach, we obtain a rational lognormal model that extends the original Flesaker–Hughston (1996) rational lognormal model to a multi-curve setting. In this setting we obtain analytic pricing formulae for caps and swaptions.
A New Systematic Approach to Derive Functionals and Nonclassical Conservation Laws
Authors: Shi Weichen
Published: October 2015

It is shown in detail that Noether's theorem represents a mathematical identity which always exists for any nondegenerate functional and includes two parts: one is Euler–Lagrange expression, and the other is a possible conservation law. If and only if any physical equations are the same as Euler–Lagrange expressions, the following three points follow: (i) there always exist conservation laws or, at least, balance laws; (ii) the symmetry transformations between inertial frames can be used first to check the absolute invariance; (iii) the field variables included in spacetime transformations can be canceled for absolute invariance, and space and time transformations are irrelevant. A theorem for getting nonclassical conservation laws from the general solution of a physical system is presented. The necessary conditions in a theorem's form are also presented to construct Lagrangians for second- and fourth-order partial differential equations (PDEs). Based on these theorems, the Lagrangians and conservation laws of nonlinear heat and KdV equations are constructed and given. For Boussinesq's solution, a nonclassical conservation integral is also found for application. Moreover, it is shown that there exists only the same conservation laws derived from the generalized variational principle as those of the principle of minimum potential energy in elasticity.
Intermittency and Changing Stability of Oxidative Activity of DNA in Chromosomes Inside Living Cells for Medical Diagnostics
Authors: Galich N. E.
Published: October 2015

We analyze the experimental data on fluorescence of DNA complexes inside neutrophils in flow cytometry with nanometer spatial resolution. Fluorescence visualizes oxidative activity of DNA and unusual statistics for DNA complex of full set of chromosomes. The exponential increasing of high-order central moments for fluctuations of fluorescence intensity characterizes the existence of intermittency in oxidative activity of DNA. Intermittency depends on the scales (on rank) of DNA networks in given cells. In the large-scale networks (with the scales[Formula: see text][Formula: see text][Formula: see text]12% size of the cells), here occurs the switching to the exponential decreasing of high-order central moments for fluctuations intensity, i.e. stable oxidative activity of DNA as it is assumed for small-scale gene networks. Distributions of Hölder’s averages and high-order moments for fluctuations intensity depend on the health status and can be used for high sensitive diagnostics of health. Intermittency of large-scale correlations reflects general natural property of DNA activity and immune response on various perturbations. Intermittency reflects the mutual actions of all large-scale correlations in dense fractal networks for DNA activity and synchronization of all excitations and correlations of all chromosomes in the cells.
Engineering of endothelial cell response on biphasic polyurethane matrix
Authors: Yuan Yuan , Cheah Calvin , Arzumand Ayesha , Luo Jing , Krishnan G. Rajesh , Sarkar Debanjan
Published: October 2015

Polyurethanes (PUs) are composed of soft and hard segments, and segmental interactions induce biphasic morphologies which can influence endothelial cell (EC) organization by regulating cell–matrix and cell–cell interactions. In this study, we explored this effect using poly(caprolactone) (PCL)-based PU, where the soft segment was composed of PCL and the hard segment was composed of hexamethylene diisocyanate (HDI) and L-tyrosine-based dipeptide (DTH). The composition of the PUs was varied by altering the PCL molecular weight and correspondingly, different phase morphologies were observed. Organization and functional state of ECs on these PUs showed that composition and phase morphology of PU have a significant effect on cellular response. The ECs formed an organized network with cord-like structures which resulted in interconnected loops when soft and hard segment fractions were phase-separated. VE-cadherin (for cell–cell adherence) and vinculin (for cell–matrix focal adhesion) localized at the tip of interconnecting cells in the tube structures indicated synchronized cell–cell and cell–matrix interactions.
Overall Coordination of Megacity Governance from a Regional Perspective
Authors: LIU Yong
Published: October 2015

The governance of megacities is a global problem, but not without way out [O’Sullivan. 2000. Urban Economics. 4th edn. Boston, MA: McGraw-Hill Company]. Overall speaking, in the short run, it mainly depends on strengthening the daily management of the city’s operation and digging out the potentials of the current infrastructure. And in the medium term, the city’s governance should rely on the further construction and improvement of the infrastructure, and greatly enhance the city’s capability of providing public products and services. And in the long run, the adjustment and dispersal of the city’s functions would be vital to finally realize a dynamic equilibrium between urban population and the capacity of urban infrastructure. In fact, all of these are related to the regional background of megacity governance, and should be taken into consideration together with the development of the megacity’s hinterland area, and then the problem can be properly solved.
Onset of Maikop sedimentation and cessation of Eocene arc volcanism in the Talysh Mountains, Azerbaijan
Authors: van der Boon A. , Kuiper K. F. , Villa G. , Renema W. , Meijers M. J. M. , Langereis C. G. , Aliyeva E. , Krijgsman W.
Published: October 2015

The Maikop Series forms an important source rock in the former Paratethys. Deposition is often interpreted as anoxic, linked to restriction of the Paratethys. The Pirembel formation in the Talysh Mountains (Azerbaijan) is attributed to the Maikop Series and was deposited above the Eocene volcanic Peshtasar formation. Dating the onset of anoxia could help to distinguish glacio-eustatic from tectonic causes of restriction. We integrated magnetostratigraphy and biostratigraphy to date the onset of Pirembel sedimentation and used geochemistry to characterize the tectonic setting of the Peshtasar volcanic rocks. The onset of Maikop sedimentation in the Talysh was determined to be 37.7 Ma, ruling out a link with the major sea-level drop at the Eocene–Oligocene Transition (33.9 Ma) and favouring a tectonic cause. Extrapolating the average sedimentation rate (34 cm kyr) suggests that the entire Pirembel formation belongs to the Late Eocene. We hypothesize that the end of volcanism is important in the transition to Pirembel sedimentation. The palaeomagnetic and geochemistry results for the volcanic rocks cluster in three groups, suggesting three distinct episodes of volcanism. Volcanic sills within the Eocene Arkevan formation plot exactly on these groups, confirming the relationship between the Arkevan and Peshtasar formations. Volcanic rocks of the Talysh show continental-arc signatures and may be related to an Eocene volcanic belt extending towards southeastern Iran.

Supplementary material:
The full analytical data of the Ar–Ar dating are available at
http://www.geolsoc.org.uk/SUP18851
Multiview Intrinsic Images of Outdoors Scenes with an Application to Relighting
Authors: Duchêne Sylvain , Riant Clement , Chaurasia Gaurav , Moreno Jorge Lopez , Laffont Pierre-Yves , Popov Stefan , Bousseau Adrien , Drettakis George
Published: October 2015

We introduce a method to compute intrinsic images for a multiview set of outdoor photos with cast shadows, taken under the same lighting. We use an automatic 3D reconstruction from these photos and the sun direction as input and decompose each image into reflectance and shading layers, despite the inaccuracies and missing data of the 3D model. Our approach is based on two key ideas. First, we progressively improve the accuracy of the parameters of our image formation model by performing iterative estimation and combining 3D lighting simulation with 2D image optimization methods. Second, we use the image formation model to express reflectance as a function of discrete visibility values for shadow and light, which allows to introduce a robust visibility classifier for pairs of points in a scene. This classifier is used for shadow labeling, allowing to compute high-quality reflectance and shading layers. Our multiview intrinsic decomposition is of sufficient quality to allow relighting of the input images. We create shadow-caster geometry which preserves shadow silhouettes and, using the intrinsic layers, we can perform multiview relighting with moving cast shadows. We present results on several multiview datasets, and show how it is now possible to perform image-based rendering with changing illumination conditions.
Optimal Tableau Method for Constructive Satisfiability Testing and Model Synthesis in the Alternating-Time Temporal Logic ATL
+
Authors: Cerrito Serenella , David Amélie , Goranko Valentin
Published: October 2015

We develop a sound, complete, and practically implementable tableau-based decision method for constructive satisfiability testing and model synthesis for the fragment ATL
+
of the full alternating-time temporal logic ALT
*
. The method extends in an essential way a previously developed tableau-based decision method for ATL and works in 2EXPTIME, which is the optimal worst-case complexity of the satisfiability problem for ATL
+
. We also discuss how suitable parameterizations and syntactic restrictions on the class of input ATL
+
formulas can reduce the complexity of the satisfiability problem.
Writing about accessibility
Authors: Hanson Vicki L. , Cavender Anna , Trewin Shari
Published: October 2015

In this forum we celebrate research that helps to successfully bring the benefits of computing technologies to children, older adults, people with disabilities, and other populations that are often ignored in the design of mass-marketed products.
--- Juan Pablo Hourcade, Editor
Coherent Raman Scattering Microscopy in Biology and Medicine
Authors: Zhang Chi , Zhang Delong , Cheng Ji-Xin
Published: October 2015

Advancements in coherent Raman scattering (CRS) microscopy have enabled label-free visualization and analysis of functional, endogenous biomolecules in living systems. When compared with spontaneous Raman microscopy, a key advantage of CRS microscopy is the dramatic improvement in imaging speed, which gives rise to real-time vibrational imaging of live biological samples. Using molecular vibrational signatures, recently developed hyperspectral CRS microscopy has improved the readout of chemical information available from CRS images. In this article, we review recent achievements in CRS microscopy, focusing on the theory of the CRS signal-to-noise ratio, imaging speed, technical developments, and applications of CRS imaging in bioscience and clinical settings. In addition, we present possible future directions that the use of this technology may take.
Signal Diversity, Sexual Selection, and Speciation
Authors: Schaefer H. Martin , Ruxton Graeme D.
Published: October 2015

Communication is ubiquitous. Developing a framework for the diversity of signals has important consequences for understanding alternative models of sexual selection and the processes contributing to speciation. In this article we review how models of neutral evolution in the perceptual space of signal perceivers provide a first step toward constructing a framework for signal diversity. We discuss how the distinction between additive and multiplicative effects of multimodal signaling represents a second step. We then assess how signal efficiency, reliability, and the aesthetics of perceivers provide distinct mechanisms for signals to be effective, thereby partly explaining signal diversity. Understanding the relative contribution of each of these mechanisms to the effectiveness of mate choice signals unravels the relative importance of alternative models of sexual selection. It can also help to distinguish whether divergence of communication is a driver or a consequence of speciation. Throughout the review we emphasize the importance of verification and learning in repeated interactions for understanding variation in signals.
The Thermodynamics of Marine Biogeochemical Cycles: Lotka Revisited
Authors: Vallino Joseph J. , Algar Christopher K.
Published: October 2015

Nearly 100 years ago, Alfred Lotka published two short but insightful papers describing how ecosystems may organize. Principally, Lotka argued that ecosystems will grow in size and that their cycles will spin faster via predation and nutrient recycling so as to capture all available energy, and that evolution and natural selection are the mechanisms by which this occurs and progresses. Lotka's ideas have often been associated with the maximum power principle, but they are more consistent with recent developments in nonequilibrium thermodynamics, which assert that complex systems will organize toward maximum entropy production (MEP). In this review, we explore Lotka's hypothesis within the context of the MEP principle, as well as how this principle can be used to improve marine biogeochemistry models. We need to develop the equivalent of a climate model, as opposed to a weather model, to understand marine biogeochemistry on longer timescales, and adoption of the MEP principle can help create such models.
Vaccination Against Dengue: Challenges and Current Developments
Authors: Guy Bruno , Lang Jean , Saville Melanie , Jackson Nicholas
Published: October 2015

Dengue is a growing threat worldwide, and the development of a vaccine is a public health priority. The completion of the active phase of two pivotal efficacy studies conducted in Asia and Latin America by Sanofi Pasteur has constituted an important step. Several other approaches are under development, and whichever technology is used, vaccine developers face several challenges linked to the particular nature and etiology of dengue disease. We start our review by defining questions and potential issues linked to dengue pathology and presenting the main types of vaccine approaches that have explored these questions; some of these candidates are in a late stage of clinical development. In the second part of the review, we focus on the Sanofi Pasteur dengue vaccine candidate, describing the steps from research to phase III efficacy studies. Finally, we discuss what could be the next steps, before and after vaccine introduction, to ensure that the vaccine will provide the best benefit with an acceptable safety profile to the identified target populations.
Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles
Authors: Hay Debbie L. , Pioszak Augen A.
Published: October 2015

It is now recognized that G protein–coupled receptors (GPCRs), once considered largely independent functional units, have a far more diverse molecular architecture. Receptor activity-modifying proteins (RAMPs) provide an important example of proteins that interact with GPCRs to modify their function. RAMPs are able to act as pharmacological switches and chaperones, and they can regulate signaling and/or trafficking in a receptor-dependent manner. This review covers recent discoveries in the RAMP field and summarizes the known GPCR partners and functions of RAMPs. We also discuss the first peptide-bound structures of RAMP-GPCR complexes, which give insight into the molecular mechanisms that enable RAMPs to alter the pharmacology and signaling of GPCRs.
Genome Integrity in Aging: Human Syndromes, Mouse Models, and Therapeutic Options
Authors: Vermeij Wilbert P. , Hoeijmakers Jan H.J. , Pothof Joris
Published: October 2015

Human syndromes and mouse mutants that exhibit accelerated but bona fide aging in multiple organs and tissues have been invaluable for the identification of nine denominators of aging: telomere attrition, genome instability, epigenetic alterations, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular communication, loss of proteostasis, cellular senescence and adult stem cell exhaustion. However, whether and how these instigators of aging interrelate or whether they have one root cause is currently largely unknown. Rare human progeroid syndromes and corresponding mouse mutants with resolved genetic defects highlight the dominant importance of genome maintenance for aging. A second class of aging-related disorders reveals a cross connection with metabolism. As genome maintenance and metabolism are closely interconnected, they may constitute the main underlying biology of aging. This review focuses on the role of genome stability in aging, its crosstalk with metabolism, and options for nutritional and/or pharmaceutical interventions that delay age-related pathology.
G Protein–Coupled Receptor Heteromers
Authors: Gomes Ivone , Ayoub Mohammed Akli , Fujita Wakako , Jaeger Werner C. , Pfleger Kevin D.G. , Devi Lakshmi A.
Published: October 2015

G protein–coupled receptors (GPCRs) compose one of the largest families of membrane proteins involved in intracellular signaling. They are involved in numerous physiological and pathological processes and are prime candidates for drug development. Over the past decade, an increasing number of studies have reported heteromerization between GPCRs. Many investigations in heterologous systems have provided important indications of potential novel pharmacology; however, the physiological relevance of these findings has yet to be established with endogenous receptors in native tissues. In this review, we focus on family A GPCRs and describe the techniques and criteria to assess their heteromerization. We conclude that advances in approaches to study receptor complex functionality in heterologous systems, coupled with techniques that enable specific examination of native receptor heteromers in vivo, are likely to establish GPCR heteromers as novel therapeutic targets.
Visual Adaptation
Authors: Webster Michael A.
Published: October 2015

Sensory systems continuously mold themselves to the widely varying contexts in which they must operate. Studies of these adaptations have played a long and central role in vision science, partly because the specific adaptations remain a powerful tool for dissecting vision by exposing the mechanisms that are adapting. That is, “if it adapts, it's there.” Many insights about vision have come from this use of adaptation, as a method. A second important trend has been the realization that the processes of adaptation are themselves essential to how vision works and thus likely operate at all levels. That is, “if it's there, it adapts.” This observation has focused interest on the mechanisms of adaptation as the target rather than the probe. Together, these approaches have led to an emerging view of adaptation as a fundamental and ubiquitous coding strategy impacting all aspects of how we see.
Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction
Authors: Mayorga Mari , Kiedrowski Matthew , Shamhart Patricia , Forudi Farhad , Weber Kristal , Chilian William M. , Penn Marc S. , Dong Feng
Published: October 2015

The stromal cell-derived factor-1 (SDF-1):CXCR4 is important in myocardial repair. In this study we tested the hypothesis that early upregulation of cardiomyocyte CXCR4 (CM-CXCR4) at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1:CXCR4 axis and improve cardiac repair. The effects of the hypoxia inducible factor (HIF) hydroxylase inhibitor dimethyloxalylglycine (DMOG) on CXCR4 expression was tested on H9c2 cells. In mice a myocardial infarction (MI) was produced in CM-CXCR4 null and wild-type controls. Mice were randomized to receive injection of DMOG (DMOG group) or saline (Saline group) into the border zone after MI. Protein and mRNA expression of CM-CXCR4 were quantified. Echocardiography was used to assess cardiac function. During hypoxia, DMOG treatment increased CXCR4 expression of H9c2 cells by 29 and 42% at 15 and 24 h, respectively. In vivo DMOG treatment increased CM-CXCR4 expression at 15 h post-MI in control mice but not in CM-CXCR4 null mice. DMOG resulted in increased ejection fraction in control mice but not in CM-CXCR4 null mice 21 days after MI. Consistent with greater cardiomyocyte survival with DMOG treatment, we observed a significant increase in cardiac myosin-positive area within the infarct zone after DMOG treatment in control mice, but no increase in CM-CXCR4 null mice. Inhibition of cardiomyocyte death in MI through the stabilization of HIF-1α requires downstream CM-CXCR4 expression. These data suggest that engagement of the SDF-1:CXCR4 axis through the early upregulation of CM-CXCR4 is a strategy for improving cardiac repair after MI.
Ozone-induced airway hyperresponsiveness: roles of ROCK isoforms
Authors: Lambert James A. , Song Weifeng
Published: October 2015

Acute ozone (O3) inhalation has been shown to cause airway and pulmonary epithelial injury with accompanying inflammation responses. Robust evidence exists that O3 induces airway hyperresponsiveness (AHR) in humans and in animal models. Several pathways exist that culminate in airway smooth muscle contraction, but the mechanism(s) by which O3 elicits AHR are unclear. Here, we review the recent report by Kasahara et al. (Kasahara DI, Mathews JA, Park CY, Cho Y, Hunt G, Wurmbrand AP, Liao JK, Shore SA. Am J Physiol Lung Cell Mol Physiol 309: L736–L746, 2015.) describing the role of two Rho kinase (ROCK) isoforms in O3-induced AHR utilizing a murine haploinsufficiency model. Compared with wild-type (WT) mice, the authors report that ROCK1+/− and ROCK2+/− mice exhibited significantly reduced AHR following acute exposure to O3. Additionally, WT mice treated with fasudil, an FDA-approved ROCK1/2 inhibitor, recapitulated reduction in AHR as seen in ROCK haplotypes. It was suggested that, although the two ROCK isoforms are both induced by Rho, they have different mechanisms by which they mediate O3-induced AHR: ROCK1 via hyaluronan signaling vs. ROCK2 acting downstream of inflammation at the level of airway smooth muscle contraction. These observations provide an important framework to develop novel ROCK-targeting therapies for acute O3-induced AHR.
Targeting the Neurokinin-1 Receptor Compromises Canonical Wnt Signaling in Hepatoblastoma
Authors: Ilmer Matthias , Garnier Agnès , Vykoukal Jody , Alt Eckhard , von Schweinitz Dietrich , Kappler Roland , Berger Michael
Published: October 2015

The substance P (SP)/NK-1 receptor (NK1R) complex represents an intriguing anticancer target for a variety of tumors, including hepatoblastoma (HB). Therefore, NK1R antagonists, such as the clinical drug aprepitant, recently have been proposed as potent anticancer agents. However, very little is known regarding the molecular basis of NK1R inhibition in cancer. Using reverse phase protein array, Western blot, Super TOP/FOP, confocal microscopy, and sphere formation ability (SFA) assays, we identified the AKT and Wnt signaling pathways as the key targets of aprepitant in three human HB cell lines (HepT1, HepG2, and HuH6). Following NK1R blockage, we observed decreased phosphorylation of p70S6K and 4E-BP1/2 and inhibition of the canonical Wnt pathway with subsequent decrease of HB cell growth. This effect was dependent of high baseline Wnt activity either by mutational status of β-catenin or extrinsic Wnt activation. Wnt inhibition seemed to be strengthened by disruption of the FOXM1–β-catenin complex. Furthermore, treatment of HB cells with aprepitant led to reduced expression of (liver) stemness markers (AFP, CD13, SOX2, NANOG, and OCT4) and SFA when grown under cancer stem cell conditions. Taken together, we show for the first time that targeting the SP/NK1R signaling cascade inhibits canonical Wnt signaling in HB cells. These findings reveal important insight into the molecular mechanisms of the SP/NK1R complex as a critical component in a model of pediatric liver cancer and may support the development of novel therapeutic interventions for HB and other Wnt-activated cancers. Mol Cancer Ther; 14(12); 2712–21. ©2015 AACR.
Dual Agonist Surrobody Simultaneously Activates Death Receptors DR4 and DR5 to Induce Cancer Cell Death
Authors: Milutinovic Snezana , Kashyap Arun K. , Yanagi Teruki , Wimer Carina , Zhou Sihong , O'Neil Ryann , Kurtzman Aaron L. , Faynboym Alexsandr , Xu Li , Hannum Charles H. , Diaz Paul W. , Matsuzawa Shu-ichi , Horowitz Michael , Horowitz Lawrence , Bhatt Ramesh R. , Reed John C.
Published: October 2015

Death receptors of the TNF family are found on the surface of most cancer cells and their activation typically kills cancer cells through the stimulation of the extrinsic apoptotic pathway. The endogenous ligand for death receptors 4 and 5 (DR4 and DR5) is TNF-related apoptosis-inducing ligand, TRAIL (Apo2L). As most untransformed cells are not susceptible to TRAIL-induced apoptosis, death receptor activators have emerged as promising cancer therapeutic agents. One strategy to stimulate death receptors in cancer patients is to use soluble human recombinant TRAIL protein, but this agent has limitations of a short half-life and decoy receptor sequestration. Another strategy that attempted to evade decoy receptor sequestration and to provide improved pharmacokinetic properties was to generate DR4 or DR5 agonist antibodies. The resulting monoclonal agonist antibodies overcame the limitations of short half-life and avoided decoy receptor sequestration, but are limited by activating only one of the two death receptors. Here, we describe a DR4 and DR5 dual agonist produced using Surrobody technology that activates both DR4 and DR5 to induce apoptotic death of cancer cells in vitro and in vivo and also avoids decoy receptor sequestration. This fully human anti-DR4/DR5 Surrobody displays superior potency to DR4- and DR5-specific antibodies, even when combined with TRAIL-sensitizing proapoptotic agents. Moreover, cancer cells were less likely to acquire resistance to Surrobody than either anti-DR4 or anti-DR5 monospecific antibodies. Taken together, Surrobody shows promising preclinical proapoptotic activity against cancer cells, meriting further exploration of its potential as a novel cancer therapeutic agent. Mol Cancer Ther; 15(1); 114–24. ©2015 AACR.
Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy
Authors: Sotillo Elena , Barrett David M. , Black Kathryn L. , Bagashev Asen , Oldridge Derek , Wu Glendon , Sussman Robyn , Lanauze Claudia , Ruella Marco , Gazzara Matthew R. , Martinez Nicole M. , Harrington Colleen T. , Chung Elaine Y. , Perazzelli Jessica , Hofmann Ted J. , Maude Shannon L. , Raman Pichai , Barrera Alejandro , Gill Saar , Lacey Simon F. , Melenhorst Jan J. , Allman David , Jacoby Elad , Fry Terry , Mackall Crystal , Barash Yoseph , Lynch Kristen W. , Maris John M. , Grupp Stephan A. , Thomas-Tikhonenko Andrei
Published: October 2015

The CD19 antigen, expressed on most B-cell acute lymphoblastic leukemias (B-ALL), can be targeted with chimeric antigen receptor–armed T cells (CART-19), but relapses with epitope loss occur in 10% to 20% of pediatric responders. We detected hemizygous deletions spanning the CD19 locus and de novo frameshift and missense mutations in exon 2 of CD19 in some relapse samples. However, we also discovered alternatively spliced CD19 mRNA species, including one lacking exon 2. Pull-down/siRNA experiments identified SRSF3 as a splicing factor involved in exon 2 retention, and its levels were lower in relapsed B-ALL. Using genome editing, we demonstrated that exon 2 skipping bypasses exon 2 mutations in B-ALL cells and allows expression of the N-terminally truncated CD19 variant, which fails to trigger killing by CART-19 but partly rescues defects associated with CD19 loss. Thus, this mechanism of resistance is based on a combination of deleterious mutations and ensuing selection for alternatively spliced RNA isoforms.

Significance: CART-19 yield 70% response rates in patients with B-ALL, but also produce escape variants. We discovered that the underlying mechanism is the selection for preexisting alternatively spliced CD19 isoforms with the compromised CART-19 epitope. This mechanism suggests a possibility of targeting alternative CD19 ectodomains, which could improve survival of patients with B-cell neoplasms. Cancer Discov; 5(12); 1282–95. ©2015 AACR.

See related commentary by Jackson and Brentjens, p. 1238.

This article is highlighted in the In This Issue feature, p. 1225
Sumoylation of the Tumor Suppressor Promyelocytic Leukemia Protein Regulates Arsenic Trioxide-Induced Collagen Synthesis in Osteoblasts
Authors: Xu Wen-Xiao , Liu Sheng-Zhi , Wu Di , Qiao Guo-Fen , Yan Jinglong
Published: October 2015

Background/Aims: Promyelocytic leukemia (PML) protein is a tumor suppressor that fuses with retinoic acid receptor-α (PML-RARα) to contribute to the initiation of acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) upregulates expression of TGF-β1, promoting collagen synthesis in osteoblasts, and ATO binds directly to PML to induce oligomerization, sumoylation, and ubiquitination. However, how ATO upregulates TGF-β1 expression is uncertain. Thus, we suggested that PML sumoylation is responsible for regulation of TGF-β1 protein expression. Methods: Kunming mice were treated with ATO, and osteoblasts were counted under scanning electron microscopy. Masson's staining was used to quantify collagen content. hFOB1.19 cells were transfected with siRNA against UBC9 or RNF4, and then treated with ATO or FBS. TGF-β1, PML expression, and sumoylation were quantified with Western blot, and collagen quantified via immunocytochemistry. Results: ATO enhanced osteoblast accumulation, collagen synthesis, and PML-NB formation in vivo. Knocking down UBC9 in hFOB1.19 cells inhibited ATO- and FBS-induced PML sumoylation, TGF-β1 expression, and collagen synthesis. Conversely, knocking down RNF4 enhanced ATO- and FBS-induced PML sumoylation, TGF-β1 expression, and collagen synthesis. Conclusion: These data suggest that PML sumoylation is required for ATO-induced collagen synthesis in osteoblasts.
Exogenous Bradykinin Inhibits Tissue Factor Induction and Deep Vein Thrombosis via Activating the eNOS/Phosphoinositide 3-Kinase/Akt Signaling Pathway
Authors: Dong Ruolan , Chen Wenshu , Feng Wenjing , Xia Congying , Hu Danli , Zhang Yanjun , Yang Yan , Wang Dao Wen , Xu Xizhen , Tu Ling
Published: October 2015

Background/Aims: Bradykinin has been shown to exert a variety of protective effects against vascular injury, and to reduce the levels of several factors involved in the coagulation cascade. A key determinant of thrombin generation is tissue factor (TF). However, whether bradykinin can regulate TF expression remains to be investigated. Methods: To study the effect of bradykinin on TF expression, we used Lipopolysaccharides (LPS) to induce TF expression in human umbilical vein endothelial cells and monocytes. Transcript levels were determined by RT-PCR, protein abundance by Western blotting. In the in vivo study, bradykinin and equal saline were intraperitoneally injected into mice for three days ahead of inferior cava vein ligation that we took to induce thrombus formation, after which bradykinin and saline were injected for another two days. Eventually, the mice were sacrificed and tissues were harvested for tests. Results: Exogenous bradykinin markedly inhibited TF expression in mRNA and protein level induced by LPS in a dose-dependent manner. Moreover, the NO synthase antagonist L-NAME and PI3K inhibitor LY294002 dramatically abolished the inhibitory effects of bradykinin on tissue factor expression. PI3K/Akt signaling pathway activation induced by bradykinin administration reduced the activity of GSK-3ß and MAPK, and reduced NF-κB level in the nucleus, thereby inhibiting TF expression. Consistent with this, intraperitoneal injection of C57/BL6 mice with bradykinin also inhibited the thrombus formation induced by ligation of inferior vena cava. Conclusion: Bradykinin suppressed TF protein expression in human umbilical vein endothelial cells and monocytes in vitro; in line with this, it inhibits thrombus formation induced by ligation of inferior vena cava in vivo.
Glia-Mediated Retinal Neuroinflammation as a Biomarker in Alzheimer's Disease
Authors: Madeira Maria Helena , Ambrósio António Francisco , Santiago Ana Raquel
Published: October 2015

Alzheimer's disease (AD) is the most common type of dementia worldwide; it is characterized by a progressive decline in cognitive functions and memory, resulting from synaptic and cell loss, and accompanied by a strong neuroinflammatory response. Besides the vast progress in the understanding of the pathophysiology of AD in the past decades, there is still no effective treatment. Moreover, the diagnosis occurs usually at an advanced stage of the disease, where the neurological damage has already occurred. The identification of biomarkers that would allow an early diagnosis of this disease is a major goal that would also help managing AD progression. Due to its cellular and physiological resemblances with the brain, the retina has long been regarded as a window to the brain. Several brain manifestations have been associated with retinal alterations. In AD patients, some structural and functional alterations in the retina can be associated with disease onset. However, only a few studies have focused on the alterations in retinal glial cells associated with AD. This review aims at giving an overview of the AD-associated retinal alterations, particularly in glial cells. The documented alterations in retinal glia will be discussed concerning their potential to predict the brain alterations occurring in AD.
Comparison of the Efficacy between Pemetrexed plus Platinum and Non-Pemetrexed plus Platinum as First-Line Treatment in Patients with Wild-Type Epidermal Growth Factor Receptor Nonsquamous Non-Small Cell Lung Cancer: A Retrospective Analysis
Authors: Kang Eun Joo , Min Kyung Hoon , Hur Gyu Young , Lee Sung Yong , Shim Jae Jeong , Kang Kyung Ho , Oh Sang Cheul , Seo Jae Hong , Kim Jun Suk
Published: October 2015

Background: Despite the development of molecular research and targeted therapy, patients with wild-type epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) still receive platinum doublet chemotherapy as the standard first-line treatment. We investigated the efficacy of first-line regimens in patients with wild-type EGFR nonsquamous NSCLC. Methods: We retrospectively analyzed the efficacy of various platinum doublet regimens as first-line treatments. Between 2007 and 2013, a total of 165 patients with wild-type EGFR nonsquamous NSCLC were included in this study. Results: Seventy-one (43.0%) patients were treated with pemetrexed plus platinum (PP) and 94 (57.0%) with non-pemetrexed plus platinum (NPP). The overall response rate was not different between the PP- and NPP-treated groups (26.8 vs. 28.7%, respectively; p = 0.78). The median progression-free survival (PFS) and overall survival (OS) also showed no differences between the two treatment groups (p = 0.12 for PFS, p = 0.42 for OS). The median PFS and OS for the PP group were 4.6 months (95% CI, 3.8-5.4) and 18.7 months (95% CI, 11.7-25.8), respectively, and for the NPP group, they were 4.2 months (95% CI, 3.4-5.0) and 12.2 months (95% CI, 10.3-14.1), respectively. In the subgroup analysis, most subgroups showed no significant difference in PFS and OS between the two treatment groups. Conclusion: Our data showed that the efficacy of various platinum doublet regimens was similar in patients with wild-type EGFR nonsquamous NSCLC.
Significance of the DNA-Histone Complex Level as a Predictor of Major Adverse Cardiovascular Events in Hemodialysis Patients: The Effect of Uremic Toxin on DNA-Histone Complex Formation
Authors: Jeong Jong Cheol , Kim Ji-Eun , Gu Ja-Yoon , Yoo Hyun Ju , Ryu Ji Won , Kim Dong Ki , Joo Kwon Wook , Kim Hyun Kyung
Published: October 2015

Background: Neutrophils can release the DNA-histone complex into circulation following exposure to inflammatory stimuli. This prospective study investigated whether the DNA-histone complex and other biomarkers could predict major cardiovascular adverse events (MACEs) in hemodialysis (HD) patients. Methods: The levels of circulating DNA-histone complexes, cell-free DNA, interleukin (IL)-6, and neutrophil elastase were measured in 60 HD patients and 28 healthy controls. MACE was assessed at 24 months. Uremic toxin-induced neutrophil released contents were measured in vitro. Results: Compared with controls, HD patients showed higher levels of DNA-histone complexes and IL-6. The DNA-histone complex level was inversely associated with the Kt/V. In a multivariable Cox analysis, the high level of DNA-histone complexes was a significant independent predictor of MACE. The uremic toxins induced DNA-histone complex formation in normal neutrophils in vitro. Conclusion: The DNA-histone complex is a potentially useful marker to predict MACE in HD patients. Uremic toxins induced DNA-histone complex formation in vitro.