bluuebunny/crossref_metadata_2025 huggingface dataset:
“Saurornitholestes”robustusis a troodontid (Dinosauria: Theropoda)
Authors: Evans David C. , Larson Derek W. , Cullen Thomas M. , Sullivan Robert M.
Published: May 2014

The holotype of Saurornitholestes robustus (SMP VP-1955) from the upper Kirtland Formation (De-na-zin Member), originally identified as a dromaeosaurid, is here re-identified as an indeterminate troodontid theropod. The frontal has no diagnostic dromaeosaurid characters, but is shown to have several features unique to troodontids among deinonychosaurs, including the shallow lateral wall defining the fossae for the olfactory system, the exclusion of the supratemporal fossa from the dorsal surface of the frontal, and a raised orbital rim. The size and morphology of SMP VP-1955 is also consistent with better-known troodontid material from the late Campanian of Alberta, and as preserved, the Kirtland specimen is indistinguishable from comparable Alberta material. The revised identification of SMP VP-1955 provides the first non-dental skeletal record of a troodontid from the Kirtland Formation, and a rare record of this clade from the Kirtlandian land-vertebrate age.
PROLIFERATION OF NON-TARIFF MEASURES IN CHINA — THEIR RELEVANCE FOR ASEAN
Authors: DEVADASON EVELYN S. , CHENAYAH SANTHA
Published: May 2014

This paper explores various non-tariff measures (NTMs) that co-exist in China and that directly influence imports into the country. Given the intensity and scope of technical measures imposed by China, the directional impacts of technical barriers to trade (TBTs) on bilateral Association of Southeast Asian Nations (ASEAN)-China exports are investigated empirically using an augmented gravity model. The results imply that Chinese TBTs do have some trade depressing effects from the ASEAN perspective. However, sectoral trade effects of TBTs are important as dual effects exist even within some TBT intensive product groups. This informs the policy debate on the effects of NTMs from the ASEAN-China perspective more specifically, and the "South–South" context more generally on two fronts. First, the identification of specific trade restricting measures for the affected sectors will assist in determining policy priorities within the ASEAN-China context. Second, trade facilitation measures that increase the business costs to the ASEAN exporters also warrant attention in addressing the scale of market access issues in China.
A new type of nonsingular black-hole solution in general relativity
Authors: Klinkhamer F. R.
Published: May 2014

Certain exact solutions of the Einstein field equations over nonsimply-connected manifolds are reviewed. These solutions are spherically symmetric and have no curvature singularity. They provide a regularization of the standard Schwarzschild solution with a curvature singularity at the center. Spherically symmetric collapse of matter in ℝ4may result in these nonsingular black-hole solutions, if quantum-gravity effects allow for topology change near the center or if nontrivial topology is already present as a remnant from a quantum spacetime foam.
Implications of nonsymmetric metric theories for particle physics: New interpretation of the Pauli coupling
Authors: Teruel Ginés R. Pérez
Published: May 2014

In this work, we provide a possible geometrical interpretation of the spin of elementary particles. In particular, it is investigated how the wave equations of matter are altered by the addition of an antisymmetric contribution to the metric tensor. In this scenario, the explicit form of the matter wave equations is investigated in a general curved spacetime, and then the equations are particularized to the flat case. Unlike traditional approaches of Nonsymmetric Gravitational Theories (NGT), in which the gravitational field is responsible for breaking the symmetry of the flat Minkowski metric, we find more natural to consider that, in general, the metric of the spacetime could be nonsymmetric even in the flat case. The physical consequences of this assumption are explored in detail. Interestingly enough, it is found that the metric tensor splits into a bosonic and a fermionic; the antisymmetric part of the metric is very sensitive to the spin and turns out to be undetectable for spinless scalar particles. However, fermions couple to it in a nontrivial way (only when there are interactions). In addition, the Pauli coupling is derived automatically as a consequence of the nonsymmetric nature of the metric.
The outer detector of Borexino
Authors: Göger-Neff M. , Lewke T. , Oberauer L. , Wurm M.
Published: May 2014

The performance of the Borexino Outer Detector is described. It is a large water Cherenkov detector for identifying cosmic muons, penetrating the whole detector system. The Outer Detector is important for tagging cosmic muon generated background events in Borexino. Here, we present the muon identification efficiency and show the capability of muon tracking reconstruction.
Thermal resonating Hartree–Bogoliubov theory based on the projection method
Authors: Nishiyama Seiya , da Providência João , Ohnishi Hiromasa
Published: May 2014

We propose a rigorous thermal resonating mean-field theory (Res-MFT). A state is approximated by superposition of multiple MF wavefunctions (WFs) composed of non-orthogonal Hartree–Bogoliubov (HB) WFs. We adopt a Res-HB subspace spanned by Res-HB ground and excited states. A partition function (PF) in a SO (2N) coherent state representation (CS Reps) |g 〉(N: Number of single-particle states) is expressed as Tr (e-βH) = 2N-1∫〈g|e-βH|g〉dg (β = 1/kBT). Introducing a projection operator P to the Res-HB subspace, the PF in the Res-HB subspace is given as Tr (Pe-βH), which is calculated within the Res-HB subspace by using the Laplace transform of e-βH and the projection method. The variation of the Res-HB free energy is made, which leads to a thermal HB density matrix [Formula: see text] expressed in terms of a thermal Res-FB operator [Formula: see text] as [Formula: see text]. A calculation of the PF by an infinite matrix continued fraction (IMCF) is cumbersome and a procedure of tractable optimization is too complicated. Instead, we seek for another possible and more practical way of computing the PF and the Res-HB free energy within the Res-MFT.
Equilibrium geometries, electronic and magnetic properties of small AunNi- (n = 1-9) clusters
Authors: Tang Cui-Ming , Chen Xiao-Xu , Yang Xiang-Dong
Published: May 2014

Geometrical, electronic and magnetic properties of small Au n Ni - (n = 1-9) clusters have been investigated based on density functional theory (DFT) at PW91P86 level. An extensive structural search shows that the relative stable structures of Au n Ni - (n = 1-9) clusters adopt 2D structure for n = 1-5, 7 and 3D structure for n = 6, 8-9. And the substitution of a Ni atom for an Au atom in the [Formula: see text] cluster obviously changes the structure of the host cluster. Moreover, an odd–even alternation phenomenon has been found for HOMO–LUMO energy gaps, indicating that the relative stable structures of the Au n Ni - clusters with odd-numbered gold atoms have a higher relative stability. Finally, the natural population analysis (NPA) and the vertical detachment energies (VDE) are studied, respectively. The theoretical values of VDE are reported for the first time to our best knowledge.
A geometric approach to dislocation densities in semiconductors
Authors: Bakke K. , Moraes F.
Published: May 2014

Dislocation densities threading semiconductor crystals are a problem for device developers. Among the issues presented by the defect density is the appearance of the so-called shallow levels. In this work, we introduce a geometric model to explain the origin of the observed shallow levels. We show that a uniform distribution of screw dislocations acts as an effective uniform magnetic field which yields electronic bound states even in the presence of a repulsive Coulomb-like potential. This introduces energy levels within the band gap, increasing the carrier concentration in the region threaded by the dislocation density and adding additional recombination paths other than the near band-edge recombination. Our results suggest that one might use a magnetic field to destroy the dislocation density bound states and therefore minimize its effects on the charge carriers.
Active galactic nuclei and their role in galaxy evolution: The infrared perspective
Authors: Caputi K. I.
Published: May 2014

The remarkable progress made in infrared (IR) astronomical instruments over the last 10–15 years has radically changed our vision of the extragalactic IR sky, and overall understanding of galaxy evolution. In particular, this has been the case for the study of active galactic nuclei (AGN), for which IR observations provide a wealth of complementary information that cannot be derived from data in other wavelength regimes. In this review, I summarize the unique contribution that IR astronomy has recently made to our understanding of AGN and their role in galaxy evolution, including both physical studies of AGN at IR wavelengths, and the search for AGN among IR galaxies in general. Finally, I identify and discuss key open issues that should be possible to address with forthcoming IR telescopes.
MANAGEMENT OF FLEXOR TENDON INJURIES — PART 1: AUSTRALIAN CONTRIBUTIONS
Authors: Tolerton Sarah K. , Lawson Richard D. , Tonkin Michael A.
Published: May 2014

This review article describes the contribution of Australian authors to the basic science and clinical management of flexor tendon injuries.
POSTEROLATERAL ROTATORY INSTABILITY OF THE ELBOW AFTER CORRECTIVE OSTEOTOMY FOR PREVIOUSLY ASYMPTOMATIC CUBITUS VARUS DEFORMITY
Authors: Seo Sang Gyo , Gong Hyun Sik , Lee Young Ho , Rhee Seung Hwan , Lee Hyuk Jin , Baek Goo Hyun
Published: May 2014

Background: We identified a subset of patients who had posterolateral rotatory instability (PLRI) following corrective osteotomy for asymptomatic cubitus varus deformity. We aimed to identify risk factors for PLRI in such patients by comparing this subgroup to patients who did not demonstrate PLRI following osteotomy.

Methods: We retrospectively reviewed the medical records and radiographs of 22 patients with cubitus varus that underwent corrective osteotomy at our institution between 2003 and 2010. All patients underwent surgery for cosmetic reasons, and no patient reported functional problems such as PLRI or ulnar nerve symptoms pre-operatively. We sought to identify differences between those that experienced an increase in PLRI after osteotomy (PLRI group) and those that did not (non-PLRI group) with regard to demographics, degree of deformity, amount of surgical correction, and final outcomes.

Results: Five patients had PLRI after osteotomy, and all five subsequently underwent lateral ulnar collateral ligament reconstruction using a triceps tendon graft. No statistically significant difference was observed between the PLRI and non-PLRI groups in terms of demographics, degree of deformity, amount of surgical correction, range of motion, and final Mayo Elbow Performance Index (MEPI) and the Disabilities of Arm, Shoulder, and Hand (DASH) scores. However, the PLRI group had marginally greater medial displacement of the distal fragment.

Conclusions: This study demonstrates that PLRI can become apparent after corrective osteotomy for cubitus varus in the absence of clinical symptoms of instability preoperatively. We suggest that careful examination for PLRI should be performed after surgical correction for cubitus varus deformity, and surgeons should be prepared to proceed with simultaneous reconstruction of the lateral ligaments of the elbow.
ANATOMY OF THE EXTENSOR POLLICIS BREVIS ASSOCIATED WITH AN EXTENSION MECHANISM OF THE THUMB METACARPOPHALANGEAL JOINT
Authors: Shigematsu Shinsuke , Shimizu Hiroyuki , Beppu Moroe , Hirata Kazuaki
Published: May 2014

This study aimed to determine whether the extensor pollicis longus (EPL) or abductor pollicis longus (APL) can replace the function of thumb extension in hands in which the extensor pollicis brevis (EPB) is absent. Cadaver dissection was performed to examine anatomical association between the interphalangeal (IP) joint and metacarpophalangeal (MP) joint of the thumb, as well as extension mechanism in clinical cases.

EPB insertion could be classified into eight types, and the EPB was absent in 7.6% of all cases. In hands without an EPB, the width of the EPL tendon tended to be wider, and the number of APL tendons was significantly greater than in hands with an EPB.

In hands without an EPB, the EPL and APL may replace the function of the EPB. As a result, a greater load is imposed on these two tendons than in hands with the EPB.
TREATMENT OF EXTRA-ARTICULAR DISTAL RADIAL MALUNION WITH PERCUTANEOUS OSTEOTOMY AND AN INTRAMEDULLARY IMPLANT
Authors: Takahashi Mitsuhiko , Tonogai Ichiro , Sairyo Koichi
Published: May 2014

Purpose: Distal radius malunion is often seen after distal radius fracture. We performed a less invasive but secure corrective surgery using an intramedullary implant combined with percutaneous osteotomy. The purpose of this study was to evaluate the results of this surgical technique.

Patients and methods: Three patients with malunion of a distal radius fracture were included. We assessed the wrist joint disability scores pre-operatively and at the final follow-up an average of 21 months after surgery. We also performed radiological assessments of volar tilt, radial inclination, and ulnar variance.

Results: All three patients achieved excellent clinical results with an average joint disability score of 93.3 at the final follow-up. The radiological parameters improved without any post-operative correction loss.

Discussion: Intramedullary implant combined with percutaneous osteotomy provides sufficient stability after correction of distal radius malunion and avoids the complications associated with the use of a volar plate.
INTRAOSSEOUS XANTHOMA OF THE DISTAL RADIUS — A CASE REPORT
Authors: Kumar Kannan Karuppiah , Manon-Matos Yorell , Thirkannad Sunil
Published: May 2014

An intraosseous xanthoma is a very rare condition. It has an aggressive appearance on radiographs mimicking primary or metastatic malignant bone tumors. We report a case of intraosseous xanthoma of the distal radius in a 51-year-old male with no history of hyperlipidaemia. To the best of our knowledge, this condition has not been reported so far in the wrist and forearm region. The lesion was successfully excised and at last follow-up, there were no signs of recurrence and patient has been symptom-free.
SPONTANEOUS RUPTURE OF EPL AND ECRB TENDONS IN A WASHERWOMAN: AN UNUSUAL PHENOMENON
Authors: Jain Anuj , Goyal Naveen , Mishra Puneet
Published: May 2014

Spontaneous rupture of the extensor pollicis longus (EPL) tendon is rare, and spontaneous non-traumatic rupture of both extensor pollicis longus (EPL) and extensor carpi radialis brevis (ECRB) tendons is not reported in literature. Rupture of EPL is usually associated with rheumatoid arthritis, systemic or local steroid injections, fractures of the wrist and repetitive and excessive abnormal motion of the wrist joint. We describe a case of spontaneous rupture of the EPL and ECRB tendons in a female patient, washerwoman by occupation, with no predisposing factor. Exploration of the tendons along with end to end tendon repair was done with excellent results. We describe the possible mechanism of the injury and result after one year follow up.
WRIST ARTHRODESIS IN CHILDREN — A NEW TECHNIQUE: CASE PRESENTATION
Authors: El-Kazzi Wissam , Bahm Jörg , Schuind Frédéric
Published: May 2014

Wrist arthrodesis is exceptionally performed in children. The main indication is severe wrist flexion contracture resulting from Volkmann's ischaemia or spasticity. In such cases, a proximal row carpectomy is usually necessary to allow the wrist to be positioned in neutral position. In young children, it is essential to preserve the distal radius growth plate, to prevent physeal closure. In these very particular indications, with high stresses along the stretched palmar soft-tissues, Kirschner wire fixation provides poor stability, and plate fixation is contra-indicated. Radio-metacarpal external fixation is an excellent alternative, preserving the distal radius growth plate and offering sufficient stability. This technique was used in a seven-year-old girl suffering from Volkmann's ischaemic contracture, treated by first carpal bone resection and subsequent arthrodesis with radio-metacarpal external fixation. Bone healing was achieved in three months, with a five years follow-up preservation of the distal radius growth plate.
Value-Based File Retention
Authors: Wijnhoven Fons , Amrit Chintan , Dietz Pim
Published: May 2014

Several file retention policy methods propose that a file retention policy should be based on file value. Though such a retention policy might increase the value of accessible files, the method to arrive at such a policy is underresearched. This article discusses how one can arrive at a method for developing file retention policies based on the use values of files. The method’s applicability is initially assessed through a case study at Capgemini, Netherlands. In the case study, we hypothesize that one can develop a file retention policy by testing causal relations between file attributes (as used by file retention methods) and the use value of files. Unfortunately, most file attributes used by file retention methods have a weak correlation with file value, resulting in the conclusion that these methods do not well select out high- and low-value files. This would imply the ineffectiveness of the used attributes in our study or errors in our conceptualization of file value. We continue with the last possibility and develop indicators for file utility (with low utility being waste). With this approach we were able to detect waste files, in a sample of files, with an accuracy of 80%. We therefore not only suggest further research in information waste detection as part of a file retention policy, but also to further explore other file attributes that could better predict file value and file utility.
A Methodology and Architecture Embedding Quality Assessment in Data Integration
Authors: Martin Nigel , Poulovassilis Alexandra , Wang Jianing
Published: May 2014

Data integration aims to combine heterogeneous information sources and to provide interfaces for accessing the integrated resource. Data integration is a collaborative task that may involve many people with different degrees of experience, knowledge of the application domain, and expectations relating to the integrated resource. It may be difficult to determine and control the quality of an integrated resource due to these factors. In this article, we propose a data integration methodology that has embedded within it iterative quality assessment and improvement of the integrated resource. We also propose an architecture for the realisation of this methodology. The quality assessment is based on an ontology representation of different users’ quality requirements and of the main elements of the integrated resource. We use description logic as the formal basis for reasoning about users’ quality requirements and for validating that an integrated resource satisfies these requirements. We define quality factors and associated metrics which enable the quality of alternative global schemas for an integrated resource to be assessed quantitively, and hence the improvement which results from the refinement of a global schema following our methodology to be measured. We evaluate our approach through a large-scale real-life case study in biological data integration in which an integrated resource is constructed from three autononous proteomics data sources.
Animal models of gastrointestinal and liver diseases. New mouse models for studying dietary prevention of colorectal cancer
Authors: Fleet James C.
Published: May 2014

Colorectal cancer is a heterogeneous disease that is one of the major causes of cancer death in the U.S. There is evidence that lifestyle factors like diet can modulate the course of this disease. Demonstrating the benefit and mechanism of action of dietary interventions against colon cancer will require studies in preclinical models. Many mouse models have been developed to study colon cancer but no single model can reflect all types of colon cancer in terms of molecular etiology. In addition, many models develop only low-grade cancers and are confounded by development of the disease outside of the colon. This review will discuss how mice can be used to model human colon cancer and it will describe a variety of new mouse models that develop colon-restricted cancer as well as more advanced phenotypes for studies of late-state disease.
Increased acid responsiveness in vagal sensory neurons in a guinea pig model of eosinophilic esophagitis
Authors: Hu Youtian , Liu Zhenyu , Yu Xiaoyun , Pasricha Pankaj J. , Undem Bradley J. , Yu Shaoyong
Published: May 2014

Eosinophilic esophagitis (EoE) is characterized with eosinophils and mast cells predominated allergic inflammation in the esophagus and present with esophageal dysfunctions such as dysphagia, food impaction, and heartburn. However, the underlying mechanism of esophageal dysfunctions is unclear. This study aims to determine whether neurons in the vagal sensory ganglia are modulated in a guinea pig model of EoE. Animals were actively sensitized by ovalbumin (OVA) and then challenged with aerosol OVA inhalation for 2 wk. This results in a mild esophagitis with increases in mast cells and eosinophils in the esophageal wall. Vagal nodose and jugular neurons were disassociated, and their responses to acid, capsaicin, and transient receptor potential vanilloid type 1 (TRPV1) antagonist AMG-9810 were studied by calcium imaging and whole cell patch-clamp recording. Compared with naïve animals, antigen challenge significantly increased acid responsiveness in both nodose and jugular neurons. Their responses to capsaicin were also increased after antigen challenge. AMG-9810, at a concentration that blocked capsaicin-evoked calcium influx, abolished the increase in acid-induced activation in both nodose and jugular neurons. Vagotomy strongly attenuated those increased responses of nodose and jugular neurons to both acid and capsaicin induced by antigen challenge. These data for the first time demonstrated that prolonged antigen challenge significantly increases acid responsiveness in vagal nodose and jugular ganglia neurons. This sensitization effect is mediated largely through TRPV1 and initiated at sensory nerve endings in the peripheral tissues. Allergen-induced enhancement of responsiveness to noxious stimulation by acid in sensory nerve may contribute to the development of esophageal dysfunctions such as heartburn in EoE.
RANTES (CCL5) reduces glucose-dependent secretion of glucagon-like peptides 1 and 2 and impairs glucose-induced insulin secretion in mice
Authors: Pais Ramona , Zietek Tamara , Hauner Hans , Daniel Hannelore , Skurk Thomas
Published: May 2014

Type 2 diabetes is associated with elevated circulating levels of the chemokine RANTES and with decreased plasma levels of the incretin hormone glucagon-like peptide 1 (GLP-1). GLP-1 is a peptide secreted from intestinal L-cells upon nutrient ingestion. It enhances insulin secretion from pancreatic β-cells and protects from β-cell loss but also promotes satiety and weight loss. In search of chemokines that may reduce GLP-1 secretion we identified RANTES and show that it reduces glucose-stimulated GLP-1 secretion in the human enteroendocrine cell line NCI-H716, blocked by the antagonist Met-RANTES, and in vivo in mice. RANTES exposure to mouse intestinal tissues lowers transport function of the intestinal glucose transporter SGLT1, and administration in mice reduces plasma GLP-1 and GLP-2 levels after an oral glucose load and thereby impairs insulin secretion. These data show that RANTES is involved in altered secretion of glucagon-like peptide hormones most probably acting through SGLT1, and our study identifies the RANTES-receptor CCR1 as a potential target in diabetes therapy.
Glugacon-like peptide-2: broad receptor expression, limited therapeutic effect on intestinal inflammation and novel role in liver regeneration
Authors: El-Jamal Noura , Erdual Edmone , Neunlist Michel , Koriche Dine , Dubuquoy Caroline , Maggiotto Francois , Chevalier Julien , Berrebi Dominique , Dubuquoy Laurent , Boulanger Eric , Cortot Antoine , Desreumaux Pierre
Published: May 2014

The glucagon-like peptide 2 (GLP-2) is an intestinotrophic hormone with growth promoting and anti-inflammatory actions. However, the full biological functions of GLP-2 and the localization of its receptor (GLP-2R) remain controversial. Among cell lines tested, the expression of GLP-2R transcript was detected in human colonic myofibroblasts (CCD-18Co) and in primary culture of rat enteric nervous system but not in intestinal epithelial cell lines, lymphocytes, monocytes, or endothelial cells. Surprisingly, GLP-2R was expressed in murine (GLUTag), but not human (NCI-H716) enteroendocrine cells. The screening of GLP-2R mRNA in mice organs revealed an increasing gradient of GLP-2R toward the distal gut. An unexpected expression was detected in the mesenteric fat, mesenteric lymph nodes, bladder, spleen, and liver, particularly in hepatocytes. In two mice models of trinitrobenzene sulfonic acid (TNBS)- and dextran sulfate sodium (DSS)-induced colitis, the colonic expression of GLP-2R mRNA was decreased by 60% compared with control mice. Also, GLP-2R mRNA was significantly downregulated in intestinal tissues of inflammatory bowel disease patients. Therapeutically, GLP-2 showed a weak restorative effect on intestinal inflammation during TNBS-induced colitis as assessed by macroscopic score and inflammatory markers. Finally, GLP-2 treatment accelerated mouse liver regeneration following partial hepatectomy as assessed by histological and molecular analyses. In conclusion, the limited therapeutic effect of GLP-2 on colonic inflammation dampens its utility in the management of severe inflammatory intestinal disorders. However, the role of GLP-2 in liver regeneration is a novelty that might introduce GLP-2 into the management of liver diseases and emphasizes on the importance of elucidating other extraintestinal functions of GLP-2.
Sex differences in myosin heavy chain isoforms of human failing and nonfailing atria
Authors: Reiser Peter J. , Moravec Christine S.
Published: May 2014

Mammalian hearts express two myosin heavy chain (MHC) isoforms, which drive contractions with different kinetics and power-generating ability. The expression of the isoform that is associated with more rapid contraction kinetics and greater power output, MHC-α, is downregulated, with a concurrent increase in the relative amount of the slower isoform, MHC-β, during the progression to experimentally induced or disease-related heart failure. This change in protein expression has been well studied in right and left ventricles in heart failure models and in humans with failure. Relatively little quantitative data exists regarding MHC isoform expression shifts in human failing atria. We previously reported significant increases in the relative amount of MHC-β in the human failing left atrium. The results of that study suggested that there might be a sex-related difference in the level of MHC-β in the left atrium, but the number of female subjects was insufficient for statistical analysis. The objective of this study was to test whether there is, in fact, a sex-related difference in the level of MHC-β in the right and left atria of humans with cardiomyopathy. The results indicate that significant differences exist in atrial MHC isoform expression between men and women who are in failure. The results also revealed an unexpected twofold greater amount of MHC-β in the nonfailing left atrium of women, compared with men. The observed sex-related differences in MHC isoform expression could impact ventricular diastolic filling during normal daily activities, as well as during physiologically stressful events.
Distribution of normal human left ventricular myofiber stress at end diastole and end systole: a target for in silico design of heart failure treatments
Authors: Genet Martin , Lee Lik Chuan , Nguyen Rebecca , Haraldsson Henrik , Acevedo-Bolton Gabriel , Zhang Zhihong , Ge Liang , Ordovas Karen , Kozerke Sebastian , Guccione Julius M.
Published: May 2014

Ventricular wall stress is believed to be responsible for many physical mechanisms taking place in the human heart, including ventricular remodeling, which is frequently associated with heart failure. Therefore, normalization of ventricular wall stress is the cornerstone of many existing and new treatments for heart failure. In this paper, we sought to construct reference maps of normal ventricular wall stress in humans that could be used as a target for in silico optimization studies of existing and potential new treatments for heart failure. To do so, we constructed personalized computational models of the left ventricles of five normal human subjects using magnetic resonance images and the finite-element method. These models were calibrated using left ventricular volume data extracted from magnetic resonance imaging (MRI) and validated through comparison with strain measurements from tagged MRI (950 ± 170 strain comparisons/subject). The calibrated passive material parameter values were C0 = 0.115 ± 0.008 kPa and B0 = 14.4 ± 3.18; the active material parameter value was Tmax = 143 ± 11.1 kPa. These values could serve as a reference for future construction of normal human left ventricular computational models. The differences between the predicted and the measured circumferential and longitudinal strains in each subject were 3.4 ± 6.3 and 0.5 ± 5.9%, respectively. The predicted end-diastolic and end-systolic myofiber stress fields for the five subjects were 2.21 ± 0.58 and 16.54 ± 4.73 kPa, respectively. Thus these stresses could serve as targets for in silico design of heart failure treatments.
Neuromedin U: A Candidate Biomarker and Therapeutic Target to Predict and Overcome Resistance to HER-Tyrosine Kinase Inhibitors
Authors: Rani Sweta , Corcoran Claire , Shiels Liam , Germano Serena , Breslin Susan , Madden Stephen , McDermott Martina S. , Browne Brigid C. , O'Donovan Norma , Crown John , Gogarty Martina , Byrne Annette T. , O'Driscoll Lorraine
Published: May 2014

Intrinsic and acquired resistance to HER-targeting drugs occurs in a significant proportion of HER2-overexpressing breast cancers. Thus, there remains a need to identify predictive biomarkers that could improve patient selection and circumvent these types of drug resistance. Here, we report the identification of neuromedin U (NmU) as an extracellular biomarker in cells resistant to HER-targeted drugs. NmU overexpression occurred in cells with acquired or innate resistance to lapatinib, trastuzumab, neratinib, and afatinib, all of which displayed a similar trend upon short-term exposure, suggesting NmU induction may be an early response. An analysis of 3,489 cases of breast cancer showed NmU to be associated with poor patient outcome, particularly those with HER2-overexpressing tumors independent of established prognostic indicators. Ectopic overexpression of NmU in drug-sensitive cells conferred resistance to all HER-targeting drugs, whereas RNAi-mediated attenuation sensitized cells exhibiting acquired or innate drug resistance. Mechanistic investigations suggested that NmU acted through HSP27 as partner protein to stabilize HER2 protein levels. We also obtained evidence of functional NmU receptors on HER2-overexpressing cells, with the addition of exogenous NmU eliciting an elevation in HER2 and EGFR expression along with drug resistance. Finally, we found that NmU seemed to function in cell motility, invasion, and anoikis resistance. In vivo studies revealed that NmU attenuation impaired tumor growth and metastasis. Taken together, our results defined NmU as a candidate drug response biomarker for HER2-overexpressing cancers and as a candidate therapeutic target to limit metastatic progression and improve the efficacy of HER-targeted drugs. Cancer Res; 74(14); 3821–33. ©2014 AACR.
Molecular Imaging with Bioluminescence and PET Reveals Viral Oncolysis Kinetics and Tumor Viability
Authors: Kuruppu Darshini , Brownell Anna-Liisa , Shah Khalid , Mahmood Umar , Tanabe Kenneth K.
Published: May 2014

Viral oncolysis, the destruction of cancer cells by replicating virus, is an experimental cancer therapy that continues to be explored. The treatment paradigm for this therapy involves successive waves of lytic replication in cancer cells. At present, monitoring viral titer at sites of replication requires biopsy. However, repeat serial biopsies are not practically feasible for temporal monitoring of viral replication and tumor response in patients. Molecular imaging provides a noninvasive method to identify intracellular viral gene expression in real time. We imaged viral oncolysis and tumor response to oncolysis sequentially with bioluminescence and positron emission tomography (PET), revealing the kinetics of both processes in tumor xenografts. We demonstrate that virus replication cycles can be identified as successive waves of reporter expression that occur ∼2 days after the initial viral tumor infection peak. These waves correspond to virions that are released following a replication cycle. The viral and cellular kinetics were imaged with Fluc and Rluc bioluminescence reporters plus two 18F-labeled PET reporters FHBG [9-(4-18F-fluoro-3-[hydroxymethyl] butyl) guanine] and FLT (18F-3′-deoxy-3-′fluorothymidine), respectively. Correlative immunohistochemistry on tumor xenograft sections confirmed in vivo results. Our findings show how PET can be used to identify virus replication cycles and for real-time measurements of intratumoral replicating virus levels. This noninvasive imaging approach has potential utility for monitoring viral oncolysis therapy in patients. Cancer Res; 74(15); 4111–21. ©2014 AACR.
CSPG4-Specific Immunity and Survival Prolongation in Dogs with Oral Malignant Melanoma Immunized with Human CSPG4 DNA
Authors: Riccardo Federica , Iussich Selina , Maniscalco Lorella , Lorda Mayayo Saray , La Rosa Giuseppe , Arigoni Maddalena , De Maria Raffaella , Gattino Francesca , Lanzardo Stefania , Lardone Elena , Martano Marina , Morello Emanuela , Prestigio Simone , Fiore Alessandra , Quaglino Elena , Zabarino Sara , Ferrone Soldano , Buracco Paolo , Cavallo Federica
Published: May 2014

Purpose: Due to the many similarities with its human counterpart, canine malignant melanoma (cMM) is a valuable model in which to assess the efficacy of novel therapeutic strategies. The model is herein used to evaluate the immunogenicity, safety, and therapeutic efficacy of a human chondroitin sulfate proteoglycan-4 (hCSPG4) DNA-based vaccine. The fact that homology between hCSPG4 and cCSPG4 amino-acidic sequences stands at more than 80% provides the rationale for using an hCSPG4 DNA vaccine in the cMM model.

Experimental Design: Dogs with stage II–III surgically resected CSPG4-positive oral MM were subjected to monthly intramuscular plasmid administration, which was followed immediately by electroporation (electrovaccination) for at least 6, and up to 20, months. The immunogenicity, safety, and therapeutic efficacy of the vaccine have been evaluated.

Results: hCSPG4 electrovaccination caused no clinically relevant local or systemic side effects and resulted in significantly longer overall and disease-free survival times in 14 vaccinated dogs as compared with 13 nonvaccinated controls. All vaccinated dogs developed antibodies against both hCSPG4 and cCSPG4. Seven vaccinated dogs were also tested for a cCSPG4-specific T-cell response and only two gave a detectable interferon (IFN)γ response.

Conclusion: Xenogeneic electrovaccination against CSPG4 is able to overcome host unresponsiveness to the “self” antigen and seems to be effective in treating cMM, laying the foundation for its translation to a human clinical setting. Clin Cancer Res; 20(14); 3753–62. ©2014 AACR.
Molecular Pathways: The Immunogenic Effects of Platinum-Based Chemotherapeutics
Authors: Hato Stanleyson V. , Khong Andrea , de Vries I. Jolanda M. , Lesterhuis W. Joost
Published: May 2014

The platinum-based drugs cisplatin, carboplatin, and oxaliplatin belong to the most widely used chemotherapeutics in oncology, showing clinical efficacy against many solid tumors. Their main mechanism of action is believed to be the induction of cancer cell apoptosis as a response to their covalent binding to DNA. In recent years, this picture has increased in complexity, based on studies indicating that cellular molecules other than DNA may potentially act as targets, and that part of the antitumor effects of platinum drugs occurs through modulation of the immune system. These immunogenic effects include modulation of STAT signaling; induction of an immunogenic type of cancer cell death through exposure of calreticulin and release of ATP and high-mobility group protein box-1 (HMGB-1); and enhancement of the effector immune response through modulation of programmed death receptor 1-ligand and mannose-6-phosphate receptor expression. Both basic and clinical studies indicate that at least part of the antitumor efficacy of platinum chemotherapeutics may be due to immune potentiating mechanisms. Clinical studies exploiting this novel mechanism of action of these old cancer drugs have been initiated. Here, we review the literature on the immunogenic effects of platinum, summarize the clinical advances using platinum as a cytotoxic compound with immune adjuvant properties, and discuss the limitations to these studies and the gaps in our understanding of the immunologic effects of these drugs. Clin Cancer Res; 20(11); 2831–7. ©2014 AACR.
Inflammatory Myofibroblastic Tumors Harbor Multiple Potentially Actionable Kinase Fusions
Authors: Lovly Christine M. , Gupta Abha , Lipson Doron , Otto Geoff , Brennan Tina , Chung Catherine T. , Borinstein Scott C. , Ross Jeffrey S. , Stephens Philip J. , Miller Vincent A. , Coffin Cheryl M.
Published: May 2014

Inflammatory myofibroblastic tumor (IMT) is a neoplasm that typically occurs in children. The genetic landscape of this tumor is incompletely understood and therapeutic options are limited. Although 50% of IMTs harbor anaplastic lymphoma kinase (ALK) rearrangements, no therapeutic targets have been identified in ALK-negative tumors. We report for the first time that IMTs harbor other actionable targets, including ROS1 and PDGFRβ fusions. We detail the case of an 8-year-old boy with treatment-refractory ALK-negative IMT. Molecular tumor profiling revealed a ROS1 fusion, and he had a dramatic response to the ROS1 inhibitor crizotinib. This case prompted assessment of a larger series of IMTs. Next-generation sequencing revealed that 85% of cases evaluated harbored kinase fusions involving ALK, ROS1, or PDGFRβ. Our study represents the most comprehensive genetic analysis of IMTs to date and also provides a rationale for routine molecular profiling of these tumors to detect therapeutically actionable kinase fusions.

Significance: Our study describes the most comprehensive genomics-based evaluation of IMT to date. Because there is no “standard-of-care” therapy for IMT, the identification of actionable genomic alterations, in addition to ALK, is expected to redefine management strategies for patients with this disease. Cancer Discov; 4(8); 889–95. ©2014 AACR.

See related commentary by Le and Doebele, p. 870

This article is highlighted in the In This Issue feature, p. 855
Shear Stress–Initiated Signaling and Its Regulation of Endothelial Function
Authors: Zhou Jing , Li Yi-Shuan , Chien Shu
Published: May 2014

Atherosclerosis develops preferentially at branches and curvatures of the arterial tree, where blood flow pattern is disturbed rather than being laminar, and wall shear stress has an irregular distribution without defined directions. The endothelium in the atherosusceptible regions, in comparison to that in atheroresistant regions, shows activation of proproliferative and proinflammatory gene expressions, reduced production of nitric oxide (NO), increased leukocyte adhesion, and permeability, as well as other atheroprone phenotypes. Differences in gene expressions and cell phenotypes have been detected in endothelia residing in native atherosusceptible and atheroresistant regions of the arteries, or in arteries from animal models with artificial creation of disturbed flow. Similar results have also been shown in in vitro systems that apply controlled shear stresses with or without clear directions to cultured endothelial cells in fluid-dynamically designed flow-loading devices. The available evidence indicates that the coordination of multiple signaling networks, rather than individual separate pathways, links the mechanical signals to specific genetic circuitries in orchestrating the mechanoresponsive networks to evoke comprehensive genetic and functional responses.
Mediation of Cardiovascular Risk Factor Effects Through Subclinical Vascular Disease
Authors: Yeboah Joseph , Delaney Joseph A. , Nance Robin , McClelland Robyn L. , Polak Joseph F. , Sibley Christopher T. , Bertoni Alain , Burke Gregory L. , Carr J. Jeffery , Herrington David M.
Published: May 2014

Objective—

It is unclear to what extent subclinical cardiovascular disease (CVD) such as coronary artery calcium (CAC), carotid intima-media thickness (CIMT), and brachial flow-mediated dilation (FMD) are mediators of the known associations between traditional cardiovascular risk factors and incident CVD events. We assessed the portion of the effects of risk factors on incident CVD events that are mediated through CAC, CIMT, and FMD.

Approach and Results—

Six thousand three hundred fifty-five of 6814 Multi-Ethnic Study of Atherosclerosis participants were included. Nonlinear implementation of structural equation modeling (STATA mediation package) was used to assess whether CAC, CIMT, or FMD are mediators of the association between traditional risk factors and incident CVD event. Mean age was 62 years, with 47% men, 12% diabetics, and 13% current smokers. After a mean follow-up of 7.5 years, there were 539 CVD adjudicated events. CAC showed the highest mediation while FMD showed the least. Age had the highest percent of total effect mediated via CAC for CVD outcomes, whereas current cigarette smoking had the least percent of total effect mediated via CAC (percent [95% confidence interval]: 80.2 [58.8–126.7] versus 10.6 [6.1–38.5], respectively). Body mass index showed the highest percent of total effect mediated via CIMT (17.7 [11.6–38.9]); only a negligible amount of the association between traditional risk factors and CVD was mediated via FMD.

Conclusions—

Many of the risk factors for incident CVD (other than age, sex, and body mass index) showed a modest level of mediation via CAC, CIMT, and FMD, suggesting that current subclinical CVD markers may not be optimal intermediaries for gauging upstream risk factor modification.
Influence of Previous Heart Failure Hospitalization on Cardiovascular Events in Patients With Reduced and Preserved Ejection Fraction
Authors: Bello Natalie A. , Claggett Brian , Desai Akshay S. , McMurray John J.V. , Granger Christopher B. , Yusuf Salim , Swedberg Karl , Pfeffer Marc A. , Solomon Scott D.
Published: May 2014

Background—

Hospitalization for acute heart failure (HF) is associated with high rates of subsequent mortality and readmission. We assessed the influence of the time interval between previous HF hospitalization and randomization in the Candesartan in Heart failure: Reduction in Mortality and morbidity (CHARM) trials on clinical outcomes in patients with both reduced and preserved ejection fraction.

Methods and Results—

CHARM enrolled 7599 patients with New York Heart Association class II to IV HF, of whom 5426 had a history of previous HF hospitalization. Cox proportional hazards regression models were used to assess the association between time from previous HF hospitalization and randomization and the primary outcome of cardiovascular death or unplanned admission to hospital for the management of worsening HF during a median of 36.6 months. For patients with HF and reduced or preserved ejection fraction, rates of cardiovascular mortality and HF hospitalization were higher among patients with previous HF hospitalization than those without. The risk for mortality and hospitalization varied inversely with the time interval between hospitalization and randomization. Rates were higher for patients with HF and reduced ejection fraction within each category. Event rates for those with HF with preserved ejection fraction and a HF hospitalization in the 6 months before randomization were comparable with the rate in patients with HF and reduced ejection fraction with no previous HF hospitalization.

Conclusions—

Rates of cardiovascular death or HF hospitalization are greatest in those who have been previously hospitalized for HF. Independent of EF, rates of death and readmission decline as time from HF hospitalization to trial enrollment increased. Recent HF hospitalization identifies a high-risk population for future clinical trials in HF and reduced ejection fraction and HF with preserved ejection fraction.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00634400.
Impact of Collaterals on Successful Revascularization in Solitaire FR With the Intention for Thrombectomy
Authors: Liebeskind David S. , Jahan Reza , Nogueira Raul G. , Zaidat Osama O. , Saver Jeffrey L.
Published: May 2014

Background and Purpose—

Collaterals at angiography before endovascular therapy were analyzed to ascertain the effect on a novel end point of successful revascularization without symptomatic hemorrhage in the Solitaire FR With the Intention for Thrombectomy (SWIFT) study.

Methods—

Collateral grade (American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology) on baseline angiography was independently assessed, blind to other data, with statistical analyses delineating the relationship with clinical, laboratory, and imaging parameters.

Results—

Angiographic data on collaterals were available in 119 of 144 subjects (mean age, 67±12 years; 52% woman; median National Institutes of Health Stroke Scale, 18 [range, 8–28]). Worse collaterals were noted in subjects with elevated baseline blood glucose (
P
=0.013) and those with elevated baseline systolic blood pressure (
P
=0.039). Multivariate predictors of partial or worse collaterals included absence of prior hypertension (odds ratio, 4.049,
P
=0.012), smoking history (odds ratio, 3.822;
P
=0.013), and higher blood glucose (odds ratio, 1.017;
P
=0.022). Collaterals were strongly related to Alberta Stroke Program Early CT Score (ASPECTS) at baseline (0–1: median 8 [3–10]; 2–9 [5–10]; 3–9 [7–10]; 4–9 [8–10];
P
<0.001) and 24 hours (0–1: median 1 [0–5]; 2–6 [0–10]; 3–8 [0–10]; 4–8 [4–8];
P
<0.001). Better collaterals were linked with Thrombolysis in Cerebral Infarction 2b/3 reperfusion (
P
=0.019), better median National Institutes of Health Stroke Scale at day 7/discharge (
P
<0.001), and better day 90 modified Rankin Scale (
P
<0.001). Better collateral grade was associated with successful revascularization without symptomatic hemorrhage, mean 2.3 (95% confidence interval, 2.1–2.5) versus 1.9 (95% confidence interval, 1.7–2.2),
P
=0.021.

Conclusions—

Better collaterals were associated with lower glucose, lower blood pressure, smaller baseline infarcts in SWIFT, and greater likelihood of successful revascularization without hemorrhage and good clinical outcomes.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01054560.