bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer
Authors: Hammerman Peter S. , Sos Martin L. , Ramos Alex H. , Xu Chunxiao , Dutt Amit , Zhou Wenjun , Brace Lear E. , Woods Brittany A. , Lin Wenchu , Zhang Jianming , Deng Xianming , Lim Sang Min , Heynck Stefanie , Peifer Martin , Simard Jeffrey R. , Lawrence Michael S. , Onofrio Robert C. , Salvesen Helga B. , Seidel Danila , Zander Thomas , Heuckmann Johannes M. , Soltermann Alex , Moch Holger , Koker Mirjam , Leenders Frauke , Gabler Franziska , Querings Silvia , Ansén Sascha , Brambilla Elisabeth , Brambilla Christian , Lorimier Philippe , Brustugun Odd Terje , Helland Åslaug , Petersen Iver , Clement Joachim H. , Groen Harry , Timens Wim , Sietsma Hannie , Stoelben Erich , Wolf Jürgen , Beer David G. , Tsao Ming Sound , Hanna Megan , Hatton Charles , Eck Michael J. , Janne Pasi A. , Johnson Bruce E. , Winckler Wendy , Greulich Heidi , Bass Adam J. , Cho Jeonghee , Rauh Daniel , Gray Nathanael S. , Wong Kwok-Kin , Haura Eric B. , Thomas Roman K. , Meyerson Matthew 
Published: April 2011

Abstract
Although genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations that drive squamous cell cancer (SCC) of the lung. Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8% of lung SCCs and cell lines. Lung SCC cell lines harboring DDR2 mutations were selectively killed by knockdown of DDR2 by RNA interference or by treatment with the multitargeted kinase inhibitor dasatinib. Tumors established from a DDR2 mutant cell line were sensitive to dasatinib in xenograft models. Expression of mutated DDR2 led to cellular transformation that was blocked by dasatinib. A patient with lung SCC that responded to dasatinib and erlotinib treatment harbored a DDR2 kinase domain mutation. These data suggest that gain-of-function mutations in DDR2 are important oncogenic events and are amenable to therapy with dasatinib. Because dasatinib is already approved for use, these findings could be used to rapidly generate clinical trials.
Significance: DDR2 mutations are present in 4% of lung SCCs, and DDR2 mutations are associated with sensitivity to dasatinib. These findings provide a rationale for designing clinical trials with the FDA-approved drug dasatinib in patients with lung SCCs. Cancer Discovery; 1(1); 78–89. ©2011 AACR.
Read the Commentary on this article by Ohashi and Pao, p. 23
This article is highlighted in the In This Issue feature, p. 4
Peroxisome Proliferator–Activated Receptor-α Gene Level Differently Affects Lipid Metabolism and Inflammation in Apolipoprotein E2 Knock-In Mice
Authors: Lalloyer Fanny , Wouters Kristiaan , Baron Morgane , Caron Sandrine , Vallez Emmanuelle , Vanhoutte Jonathan , Baugé Eric , Shiri-Sverdlov Ronit , Hofker Marten , Staels Bart , Tailleux Anne 
Published: April 2011

Objective—
Peroxisome proliferator–activated receptor-α (PPARα) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPARα is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence of PPARα agonists on atherosclerosis in mice yielded conflicting results, and the implication of PPARα therein has not been assessed. The human apolipoprotein E2 knock-in (apoE2-KI) mouse is a model of mixed dyslipidemia, atherosclerosis, and nonalcoholic steatohepatitis (NASH). The aim of this study was to analyze, using homo- and heterozygous PPARα-deficient mice, the consequences of quantitative variations of PPARα gene levels and their response to the synthetic PPARα agonist fenofibrate on NASH and atherosclerosis in apoE2-KI mice.

Methods and Results—
Wild-type (+/+), heterozygous (+/−), and homozygous (−/−) PPARα-deficient mice in the apoE2-KI background were generated and subjected to a Western diet supplemented with fenofibrate or not supplemented. Western diet–fed PPARα−/− apoE2-KI mice displayed an aggravation of liver steatosis and inflammation compared with PPARα+/+ and PPARα+/− apoE2-KI mice, indicating a role of PPARα in liver protection. Moreover, PPARα expression was required for the fenofibrate-induced protection against NASH. Interestingly, fenofibrate treatment induced a similar response on hepatic lipid metabolism in PPARα+/+ and PPARα+/− apoE2-KI mice, whereas, for a maximal antiinflammatory response, both alleles of the PPARα gene were required. Surprisingly, atherosclerosis development was not significantly different among PPARα+/+, PPARα+/−, and PPARα−/− apoE2-KI mice. However, PPARα gene level determined both the antiatherosclerotic and vascular antiinflammatory responses to fenofibrate in a dose-dependent manner.

Conclusion—
These results demonstrate a necessary but quantitatively different role of PPARα in the modulation of liver metabolism, inflammation, and atherogenesis.
Src Phosphorylation of Endothelial Cell Surface Intercellular Adhesion Molecule-1 Mediates Neutrophil Adhesion and Contributes to the Mechanism of Lung Inflammation
Authors: Liu Guoquan , Vogel Stephen M. , Gao Xiaopei , Javaid Kamran , Hu Guochang , Danilov Sergei M. , Malik Asrar B. , Minshall Richard D. 
Published: April 2011

Objective—
The goal of this study was to determine whether tumor necrosis factor α (TNFα)–induced Src activation and intercellular adhesion molecule-1 (ICAM-1) phosphorylation rapidly increase endothelial cell adhesivity and polymorphonuclear leukocyte (PMN) sequestration independently of de novo ICAM-1 synthesis.

Methods and Results—

TNFα exposure of mouse lungs for 5 minutes produced a 3-fold increase in
125
I-anti-ICAM-1 monoclonal antibody (mAb) binding and
111
In oxine-labeled PMN sequestration, as well as Src activation, ICAM-1 Tyr518 phosphorylation, and phospho- Tyr518-ICAM-1 coimmunoprecipitation with actin. The response was absent in
Nox2
−/−
lungs or following Src inhibition. In COS-7 cells transfected with wild-type (WT), phospho-defective (Tyr518Phe), or phospho-mimicking (Tyr518Asp) mouse ICAM-1 cDNA constructs, TNFα increased the B
max
of YN1/1.7.4 anti-ICAM-1 mAb binding to WT-ICAM-1 but not to Tyr518Phe-ICAM-1, indicating increased binding avidity secondary to ICAM-1 phosphorylation. This effect was mimicked by expression of the Tyr518Asp-ICAM-1 mutant. TNFα also increased the staining intensity and cell surface clustering of YN1/1.7.4 mAb-labeled WT-ICAM-1 that colocalized with F-actin, which was not observed with Tyr518Phe-ICAM-1 but was recapitulated with Tyr518Asp-ICAM-1. Finally, overexpression of ICAM-1 in mouse lungs significantly increased lipopolysaccharide-induced transvascular albumin leakage and bronchoalveolar lavage PMN counts at 2 and 24 hours after lipopolysaccharide inhalation compared with lungs expressing the Tyr518Phe ICAM-1 mutant.

Conclusion—
Src-dependent phosphorylation of endothelial cell ICAM-1 Tyr518 induces PMN adhesion by promoting ICAM-1 clustering, which we propose mediates rapid-phase lung vascular accumulation of PMNs during inflammation.
Developing a Tool to Assess Quality of Stroke Care Across European Populations
Authors: Wellwood Ian , Wu Olivia , Langhorne Peter , McKevitt Christopher , Di Carlo Antonio , Rudd Anthony G. , Wolfe Charles D.A. ,   on behalf of the European Registers of Stroke (EROS) Collaborative Group
Published: April 2011

Background and Purpose—
There are significant differences in the provision of care and outcome after stroke across countries. The European Registers of Stroke study aimed to develop, test, and refine a tool to assess quality of care.

Methods—
We used a systematic review and grading of evidence for stroke care across the clinical pathway and developed and field-tested a quality tool that was delivered by post and later by site visit at 7 centers. Items were refined by using an algorithm that took into account the level of evidence, measurement properties, and consensus of opinion obtained using, the Delphi techniques.

Results—
The tool included 251 items across 11 domains, of which 214 items could be categorized by any level of evidence. Overall agreement between postal and site visit modes of delivery was acceptable (κ=0.77), with most items having a κ >0.5. The refinement process resulted in 2 practical versions of the tool (93 items and 22 items). Positive responses to items in the tool indicated implementation of evidence-based stroke care. In field testing, the proportion of positive responses to evidence-based items ranged from 43% to 79% across populations. Proportions of different types of evidence being implemented were similar: high quality 62%, limited quality 72%, and expert opinion 54% across the populations. More than half (4 of 7) of the centers provided stroke unit care and thrombolysis, but availability and access to inpatient rehabilitation varied significantly, with poor access to community follow-up for rehabilitation and medical management.

Conclusions—
The European Registers of Stroke Quality Assessment Tool has potential to be used as a framework to compare services and promote increased implementation of evidence-based care.
Adiponectin Level as a Consequence of Genetic Variation, but Not Leptin Level or Leptin
Authors: Bevan Steve , Meidtner Karina , Lorenz Matthias , Sitzer Matthias , Grant Peter J. , Markus Hugh S. 
Published: April 2011

Background and Purpose—
The adipocytokines adiponectin and leptin have been suggested as risk factors for cardiovascular disease, including stroke, acting through atherosclerosis. However, studies have provided conflicting results in underpowered cohorts with some suggesting that the leptin:adiponectin ratio is a better predictor of risk. We examined these associations with carotid intima-media thickness (IMT), a marker of early atherosclerosis and arterial remodeling and an independent predictor of stroke. We also examined association between genetic variants in the leptin and adiponectin genes and IMT.

Methods—
Adiponectin and leptin levels were determined in 990 individuals from the community Carotid Atherosclerosis Progression Study. Five variants in the gene encoding adiponectin and 7 in the gene encoding leptin were genotyped and their effects on circulating levels assessed. Both were then correlated with IMT.

Results—

Adiponectin levels negatively correlated with IMT (−0.079,
P
=0.013). There was no correlation between leptin levels or leptin:adiponectin ratio and IMT. Two variants in the
ADIPOQ
gene encoding adiponectin were associated with altered adiponectin levels, 1 of which (rs266729) was associated with IMT. There was also an interaction with body mass index (
P
=0.019) with the association being present in obese subjects (
P
=0.02).

Conclusions—
Our results support a causal role for adiponectin in early carotid IMT and suggest it may act through interaction with obesity. In contrast, we found no evidence of a role for leptin and no evidence that leptin:adiponectin ratio is a better predictor of risk that adiponectin levels alone.
Isoflurane Enhanced Hemorrhagic Transformation by Impairing Antioxidant Enzymes in Hyperglycemic Rats With Middle Cerebral Artery Occlusion
Authors: Hu Qin , Ma Qingyi , Zhan Yan , He Zhaohui , Tang Jiping , Zhou Changman , Zhang John 
Published: April 2011

Background and Purpose—
Because the potential neuroprotective effect of isoflurane is controversial, we attempted to study whether isoflurane after treatment provides neuroprotection in a rat model of hyperglycemia-induced ischemic hemorrhagic transformation.

Methods—
Rats received an injection of 50% dextrose (6 mL/kg intraperitoneally) and had a middle cerebral artery occlusion 30 minutes later. Four groups were included: sham-operated, ischemia/reperfusion, isoflurane treatment, and vehicle groups. In the treatment group, after 2 hours of ischemia, 2% isoflurane was administered at the onset of reperfusion. We measured the level of blood glucose at 0, 2.5, 4.5, and 6.5 hours after dextrose injection. Infarct and hemorrhagic volumes, neurological scores, oxidative stress (malondialdehyde, 4-hydroxy-2-nonenal, and nitrotyrosine) and the activities of superoxide dismutase and catalase were measured at 24 hours after ischemia.

Results—
Isoflurane had no effects on blood glucose, it failed to reduce infarct, hemorrhage volume, and brain edema, and it enhanced neurobehavioral deficits when compared with the ischemia/reperfusion group at 24 hours after middle cerebral artery occlusion. On the contrary, isoflurane exacerbated these parameters compared with the vehicle group. In addition, it increased the expressions of malondialdehyde, 4-hydroxy-2-nonenal, and nitrotyrosine, and it decreased the activities of superoxide dismutase and catalase compared to the vehicle group.

Conclusions—
Isoflurane after treatment worsened physiological and neurological outcomes in this ischemia hyperglycemia-induced hemorrhagic transformation possibly by impairing the antioxidant defense system.
Is the Montreal Cognitive Assessment Superior to the Mini-Mental State Examination to Detect Poststroke Cognitive Impairment?
Authors: Godefroy Olivier , Fickl Andreas , Roussel Martine , Auribault Caroline , Bugnicourt Jean Marc , Lamy Chantal , Canaple Sandrine , Petitnicolas Gil 
Published: April 2011

Background and Purpose—
A screening test is required to improve the diagnosis of poststroke cognitive impairment. The Montreal Cognitive Assessment (MoCA), a newly designed screening test, has been found to be more sensitive than Mini-Mental State Examination (MMSE), but its clinical value has not been established by means of a comprehensive neuropsychological battery. This study was designed to assess the value of MoCA and MMSE to detect poststroke cognitive impairment determined by a neuropsychological battery.

Methods—
Both screening tests and a neuropsychological battery were administered during the acute phase in 95 patients referred for recent infarct or hemorrhage. Raw MMSE and MoCA scores were used with published cutoffs and new cutoff scores for MMSE and MoCA were also computed after adjustment for age and education.

Results—

Using raw scores, MoCA was more frequently impaired (
P
=0.0001) than MMSE. MoCA showed good sensitivity (sensitivity, 0.94) but moderate specificity (specificity, 0.42; positive predictive value, 0.77; negative predictive value, 0.76), whereas an inverse profile was observed for MMSE (sensitivity, 0.66; specificity, 0.97; positive predictive value, 0.98; negative predictive value, 0.58). Adjusted scores with new cutoffs (MMSE
adj
≤24, MoCA
adj
≤20) provided good sensitivity and very good specificity for both tests (MMSE
adj
: sensitivity, 0.7, specificity, 0.97, positive predictive value, 0.98, negative predictive value, 0.61; MoCA
adj
: sensitivity, 0.67, specificity, 0.9, positive predictive value, 0.93, negative predictive value, 0.57). On receiver operating characteristic curve analysis, areas under the curve of all scores were >0.88.

Conclusions—
The previously reported high sensitivity of MoCA is associated with low specificity. Both screening tests are moderately sensitive to acute poststroke cognitive impairment. This study provides indications for the diagnosis of poststroke cognitive impairment.
The Importance of Size
Authors: Riedel Christian H. , Zimmermann Philip , Jensen-Kondering Ulf , Stingele Robert , Deuschl Günther , Jansen Olav 
Published: April 2011

Background and Purpose—
We hypothesize that in acute middle cerebral artery stroke, thrombus lengths measured in thin-slice nonenhanced CT images define a limit beyond which systemic thrombolysis will fail to recanalize occluded arteries.

Methods—
In 138 patients who presented with acute middle cerebral artery stroke and who were treated with intravenous thrombolysis (IVT), we measured lengths of thrombotic clots depicted as arterial hyperdensities in admission nonenhanced CT images with 2.5-mm slice width. Vascular recanalization was investigated after thrombolysis and recanalization results were related to thrombus lengths by logistic regression.

Results—
In 62 patients, IVT resulted in recanalization; among these patients, no thrombus length exceeded 8 mm. The median modified Rankin scale score at hospital discharge was 2. In the remaining 76 patients, thrombus lengths mostly exceeded 8 mm and IVT failed in recanalization. These patients were discharged with a median modified Rankin scale score of 5.

Conclusions—
This study shows that in acute middle cerebral artery stroke, IVT has nearly no potential to recanalize occluded vessels if thrombus length exceeds 8 mm.
Predictions of roll force under heavy-reduction hot rolling using a large-deformation constitutive model
Authors: Byon S M , Kim S I , Lee Y 
Published: April 2011

A large-deformation constitutive model applicable to the calculation of roll force and torque in heavy-reduction rolling has been presented. The concept of the volume fraction of dynamically recrystallized grains, which depicts the flow stress softening correctly with the level of strain, strain rate and temperature has been newly introduced in the proposed model. The material constants required in the proposed model have been obtained by a series of hot-torsion tests. A laboratory-scale hot-plate rolling experiment, together with three-dimensional finite element analysis coupled with the proposed model, has been performed to investigate the accuracy of the proposed constitutive model. The soundness of the proposed model has been demonstrated through a series of finite element simulations with temperature and reduction changed. The finite element predictions of roll force based on the proposed model and the experimental results was shown to be in fair agreement whereas those based on the Misaka-Yoshimoto model, in which dynamic recrystallization was not considered, failed to predict the roll force precisely at heavy reduction. The results also revealed that, for a typical reduction, the flow stress softening effect was not observed during deformation, whereas the effect was considerable when the material underwent heavy reduction.
The impact of uncertainty on product introduction in dispersed environments
Authors: Schofield M E , Gregory M 
Published: April 2011

This research addresses product introduction dispersed across locations and companies. A semiconductor design licensor that introduces products in a range of environments was studied: in some environments the subcomponent architectures of competitor products differ widely, while in others all competitor products have the same subcomponents. The approach adopted involved multiple detailed interviews covering the full range of participants in the product development processes from designers through project managers to directors. Reporting from these multiple informants was captured using a novel mapping approach that allowed participants to develop interactively their understanding of informal as well as formal processes at work within the company. It was found that the degree of architectural uncertainty is a major determinant of feasible organization structures for product introduction. It was also found that ‘microproduct’ architecture offers considerable freedom in the opportunities for dispersion of project activities. The degree of formality and structure in design technologies and their link to highly characterized production processes was identified as a key factor of this industry sector. The implications of these findings include the probability that (a) where design technologies can simulate product performance, dispersed teams with high priority can resolve architectural uncertainties; (b) a cross-functional team may not resolve architectural uncertainty as well as autonomous teams focused on subproducts (microproducts); (c) early entrants may benefit by allowing business units to adopt diverse approaches to product introduction, since architectural uncertainty may vary between products at different stages of their lives. This suggests that small high-technology companies may find it easier to expand into new geographies and product lines than was previously believed. Further work is necessary to make more confident statements about the linkage between product environment and team organization, but the ideas of architectural uncertainty and microproduct team organization may be of immediate interest to companies of all sizes when seeking to select appropriate product introduction processes and organization.
Machining-induced surface hardening due to large wear land
Authors: Mahajan V , Chou Y K 
Published: April 2011

This study experimentally investigated the attainable hardness and hardened depth at the part surfaces in steel machining with large tool wear, 1-2mm flank wear-land width. Hot-rolled AISI 4340 steel bars were turned on a lathe using ceramic inserts with machining forces monitored. Process parameter effects on the depths of the phase-transformed layers and hardened layers were studied with cutting forces and part surface roughness measured and analysed. The phase transformation depth (PTD) and hardened depth generally increase with increasing tool wear, cutting speed, and feed rate; however, they decrease or level off when further increasing the parameters. The maximum hardened depth, about 100 μm at a Knoop hardness of 450 HK500, has been repeatedly obtained at 1.65 mm flank wear land, 3 m/s cutting speed and 0.025 mm/rev feed rate. It is plausible that machining under aggressive conditions, i.e. a greater amount of tool wear, may be employed for surface hardening of some steel components. The analysis of variance (ANOVA) method was also applied to identify statistically significant factors and interactions between the factors. The ANOVA results of the PTD indicate that cutting speed, flank wear-land width, and feed rate, in that order, are all significant factors. In addition, there is a major interaction between feed rate and cutting speed to the PTD results. Furthermore, the cutting force results imply a strong correlation between the radial cutting forces and the PTD.
Mould pressure control in rotational moulding
Authors: Crawford R J , Spence A G , Cramez M C , Oliveira M J 
Published: April 2011

The technology of the rotational moulding of plastics has improved dramatically in recent years due to the recognition that measuring the temperature inside the mould is fundamental to process control. The next major advance will be made when the benefits of controlling the pressure inside the mould are fully utilized. A drawback of the rotational moulding process has always been the surface pinholes and internal bubbles that occur in the moulded part. These occur because, as the powder particles melt and coalesce, they trap pockets of air and it takes a considerable time for these to disappear. It is known that factors such as the viscosity of the polymer melt, the shape of the powder particles, the particle size and size distribution, the mould release agent and the metal used for the mould all affect the pinholing problem. However, the major factor that influences pinhole removal is mould pressure. If pressure is applied at a strategic point in the heating cycle, it can force trapped air out of the melted plastic. Indeed the use of mould pressurization can offer additional benefits such as cycle time reduction and significant improvements in the mechanical properties of the moulded part. However, few moulders make any attempt to monitor or control the mould pressure, mainly because its effect is not understood. This paper explains why mould pressure control throughout the moulding cycle is crucial to the rotational moulding industry in terms of, firstly, achieving good part quality and, secondly, reducing cycle times. It is also suggested that a fundamental change from passive venting to active venting of the mould is an important development that must occur in this industry.