bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)–based mutagenesis screen: high efficacy of drug combinations
Authors: Bradeen Heather A. , Eide Christopher A. , O'Hare Thomas , Johnson Kara J. , Willis Stephanie G. , Lee Francis Y. , Druker Brian J. , Deininger Michael W. 
Published: June 2006

AbstractBMS-354825 (dasatinib) and AMN107 (nilotinib) are potent alternate Abl inhibitors with activity against many imatinib mesylate–resistant BCR-ABL kinase domain (KD) mutants, except T315I. We used N-ethyl-N-nitrosourea (ENU)–exposed Ba/F3-p210BCR-ABL cells to compare incidence and types of KD mutants emerging in the presence of imatinib mesylate, dasatinib, and nilotinib, alone and in dual combinations. Although ENU is expected to induce mutations in multiple proteins, resistant clones were almost exclusively BCR-ABL KD mutant at relevant concentrations of nilotinib and dasatinib, consistent with a central role of KD mutations for resistance to these drugs. Twenty different mutations were identified with imatinib mesylate, 10 with nilotinib (including only 1 novel mutation, E292V) and 9 with dasatinib. At intermediate drug levels the spectrum narrowed to F317V and T315I for dasatinib and Y253H, E255V, and T315I for nilotinib. Thus, cross-resistance is limited to T315I, which is also the only mutant isolated at drug concentrations equivalent to maximal achievable plasma trough levels. With drug combinations maximal suppression of resistant clone outgrowth was achieved at lower concentrations compared with single agents, suggesting that such combinations may be equipotent to higher-dose single agents. However, sequencing uniformly revealed T315I, consistent with the need for a T315I inhibitor, to completely block resistance.
Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury
Authors: Khan Samina Yasmin , Kelher Marguerite R. , Heal Joanna M. , Blumberg Neil , Boshkov Lynn K. , Phipps Richard , Gettings Kelly F. , McLaughlin Nathan J. , Silliman Christopher C. 
Published: June 2006

AbstractTransfusion-related acute lung injury (TRALI) is a form of posttransfusion acute pulmonary insufficiency that has been linked to the infusion of biologic response modifiers (BRMs), including antileukocyte antibodies and lipids. Soluble CD40 ligand (sCD40L) is a platelet-derived proinflammatory mediator that accumulates during platelet storage. We hypothesized that human polymorpho-nuclear leukocytes (PMNs) express CD40, CD40 ligation rapidly primes PMNs, and sCD40L induces PMN-mediated cytotoxicity of human pulmonary microvascular endothelial cells (HMVECs). Levels of sCD40L were measured in blood components and in platelet concentrates (PCs) implicated in TRALI or control PCs that did not elicit a transfusion reaction. All blood components contained higher levels of sCD40L than fresh plasma, with apheresis PCs evidencing the highest concentration of sCD40L followed by PCs from whole blood, whole blood, and packed red blood cells (PRBCs). PCs implicated in TRALI reactions contained significantly higher sCD40L levels than control PCs. PMNs express functional CD40 on the plasma membrane, and recombinant sCD40L (10 ng/mL-1 μg/mL) rapidly (5 minutes) primed the PMN oxidase. Soluble CD40L promoted PMN-mediated cytotoxicity of HMVECs as the second event in a 2-event in vitro model of TRALI. We concluded that sCD40L, which accumulates during blood component storage, has the capacity to activate adherent PMNs, causing endothelial damage and possibly TRALI in predisposed patients.
In-vivo coronary flow profiling based on biplane angiograms: influence of geometric simplifications on the three-dimensional reconstruction and wall shear stress calculation
Authors: Wellnhofer Ernst , Goubergrits Leonid , Kertzscher Ulrich , Affeld Klaus 
Published: June 2006

Abstract

Background
Clinical studies suggest that local wall shear stress (WSS) patterns modulate the site and the progression of atherosclerotic lesions. Computational fluid dynamics (CFD) methods based on in-vivo three-dimensional vessel reconstructions have recently been shown to provide prognostically relevant WSS data. This approach is, however, complex and time-consuming. Methodological simplifications are desirable in porting this approach from bench to bedside. The impact of such simplifications on the accuracy of geometry and wall shear stress calculations has to be investigated.

Methods
We investigated the influence of two methods of lumen reconstruction, assuming circular versus elliptical cross-sections and using different resolutions for the cross-section reconstructions along the vessel axis. Three right coronary arteries were used, of which one represented a normal coronary artery, one with "obstructive", and one with "dilated" coronary atherosclerosis. The vessel volume reconstruction was performed with three-dimensional (3D) data from a previously validated 3D angiographic reconstruction of vessel cross-sections and vessel axis.

Results
The difference between the two vessel volumes calculated using the two evaluated methods is less than 1 %. The difference, of the calculated pressure loss, was between 2.5% and 8.5% for the evaluated methods. The distributions of the WSS histograms were nearly identical and strongly cross-correlated (0.91–0.95). The good agreement of the results was confirmed by a Chi-square test.

Conclusion
A simplified approach to the reconstruction of coronary vessel lumina, using circular cross-sections and a reduced axial resolution of about 0.8 mm along the vessel axis, yields sufficiently accurate calculations of WSS.
Combined IL-21 and Low-Dose IL-2 therapy induces anti-tumor immunity and long-term curative effects in a murine melanoma tumor model
Authors: He Hong , Wisner Preya , Yang Guojun , Hu Hong-Ming , Haley Dan , Miller William , O'Hara Aisling , Alvord W Gregory , Clegg Christopher H , Fox Bernard A , Urba Walter J , Walker Edwin B 
Published: June 2006

AbstractBackgroundIn vivo studies have recently demonstrated that interleukin 21 (IL-21) enhances the anti-tumor function of T-cells and NK cells in murine tumor models, and the combined use of IL-21 and IL-15 has resulted in prolonged tumor regression and survival in mice with previously established tumors. However, the combined anti-tumor effects of IL-21 and low dose IL-2 have not been studied even though IL-2 has been approved for human use, and, at low dose administration, stimulates the proliferation of memory T cells, and does not significantly increase antigen-induced apoptosis or regulatory T cell (Treg) expansion. This study examined whether recombinant IL-21 alone or in combination with low-dose IL-2 could improve the in vivo anti-tumor function of naïve, tumor-antigen specific CD8+T cells in a gp10025–33T cell receptor transgenic pmel murine melanoma model.MethodsCongenic C57BL/6 (Ly5.2) mice bearing subcutaneous B16F10 melanoma tumors were sublethally irradiated to induce lymphopenia. After irradiation naive pmel splenocytes were adoptively transferred, and mice were immunized with bone marrow-derived dendritic cells pulsed with human gp10025–33(hgp10025–33). Seven days after vaccination groups of mice received 5 consecutive days of intraperitoneal administration of IL-2 alone (20 × 103IU), IL-21 alone (20 μg) or IL-21 and IL-2. Control animals received no cytokine therapy.ResultsIL-21 alone and IL-2 alone both delayed tumor progression, but only IL-21 significantly augmented long-term survival (20%) compared to the control group. However, combination therapy with IL-21 and IL-2 resulted in the highest long-term (>150 days) tumor-free survival frequency of 46%. Animals that were tumor-free for > 150 days demonstrated tumor-specific protection after rechallenge with B16F10 melanoma cells. At peak expansion (21 days post vaccination), the combination of IL-21 plus IL-2 resulted in a 2- to 3-fold higher absolute number of circulating tumor antigen-specific pmel CD8+T cells than was stimulated by IL-2 or IL-21 alone. Pmel CD8+T cells were predominantly partitioned into central memory (CD62L+/CD127+) or effector-memory (CD62L-/CD127+) phenotypes by day 28-post vaccination in IL-21 + IL-2 treated mice.ConclusionThese observations support the potential use of IL-21 and low-dose IL-2 therapy in combination with a tumor-antigen vaccine and lymphopenic conditioning in future cancer clinical trials to maintain high numbers of anti-tumor memory CD8+T cells with the potential to sustain long term tumor regression and survival.
Inhibition of protein geranylgeranylation induces apoptosis in synovial fibroblasts
Authors: Connor Alison M , Berger Stuart , Narendran Aru , Keystone Edward C 
Published: June 2006

AbstractStatins, competitive inhibitors of hydroxymethylglutaryl-CoA reductase, have recently been shown to have a therapeutic effect in rheumatoid arthritis (RA). In RA, synovial fibroblasts in the synovial lining, are believed to be particularly important in the pathogenesis of disease because they recruit leukocytes into the synovium and secrete angiogenesis-promoting molecules and proteases that degrade extracellular matrix. In this study, we show a marked reduction in RA synovial fibroblast survival through the induction of apoptosis when the cells were cultured with statins. Simvastatin was more effective in RA synovial fibroblasts than atorvastatin, and both statins were more potent on tumor necrosis factor-α-induced cells. In contrast, in osteoarthritis synovial fibroblasts, neither the statin nor the activation state of the cell contributed to the efficacy of apoptosis induction. Viability of statin-treated cells could be rescued by geranylgeraniol but not by farnesol, suggesting a requirement for a geranylgeranylated protein for synovial fibroblast survival. Phase partitioning experiments confirmed that in the presence of statin, geranylgeranylated proteins are redistributed to the cytoplasm. siRNA experiments demonstrated a role for Rac1 in synovial fibroblast survival. Western blotting showed that the activated phosphorylated form of Akt, a protein previously implicated in RA synovial fibroblast survival, was decreased by about 75%. The results presented in this study lend further support to the importance of elevated pAkt levels to RA synovial fibroblast survival and suggest that statins might have a beneficial role in reducing the aberrant pAkt levels in patients with RA. The results may also partly explain the therapeutic effect of atorvastatin in patients with RA.
Visceral Adiposity and Endothelial Lipase
Authors: Paradis Marie-Eve , Badellino Karen O. , Rader Daniel J. , Tchernof André , Richard Christian , Luu-The Van , Deshaies Yves , Bergeron Jean , Archer Wiedad R. , Couture Patrick , Bergeron Nathalie , Lamarche Benoı̂t 
Published: June 2006

AbstractContext: Overexpression of endothelial lipase (EL) has been shown to reduce plasma high-density lipoprotein cholesterol levels in animal models. However, the extent to which EL contributes to modulate the deteriorated high-density lipoprotein profile observed in obesity in humans is less clear.Objectives: The objectives of this study were to investigate the association between levels of obesity and visceral adiposity in particular and plasma EL concentrations.Methods: Postheparin plasma EL concentrations were measured by ELISA and visceral adiposity by computed tomography in a sample of 80 sedentary men in good health. EL mRNA levels in abdominal sc and omental adipose tissues obtained during abdominal hysterectomies were measured in another sample of 14 women.Results: Plasma EL levels were positively correlated with body mass index (R = 0.46, P &lt; 0.0001), visceral adipose tissue accumulation (R = 0.44, P &lt; 0.0001), and a proatherogenic lipid profile including increased plasma cholesterol and triglycerides. However, EL mRNA levels were similar in sc and omental AT and were 10,000-fold lower than lipoprotein lipase mRNA levels in those tissues.Conclusions: Increased visceral adiposity is significantly correlated with elevated plasma EL levels, but this association is unlikely to be causal and may reflect other common metabolic alterations.
Integration of Prolactin and Glucocorticoid Signaling at the β-Casein Promoter and Enhancer by Ordered Recruitment of Specific Transcription Factors and Chromatin Modifiers
Authors: Kabotyanski Elena B. , Huetter Markus , Xian Wa , Rijnkels Monique , Rosen Jeffrey M. 
Published: June 2006

AbstractLactogenic hormone regulation of β-casein gene expression in mammary epithelial cells provides an excellent system in which to perform kinetic studies of chromatin remodeling and transcriptional activation. Using HC11 cells as a model, we have investigated the effects of prolactin (Prl) and glucocorticoids both singly and in combination at different time points after hormone treatment. Using chromatin immunoprecipitation analysis, we have determined the dynamics of assembly and disassembly of signal transducer and activator of transcription 5, glucocorticoid receptor, CCAAT enhancer binding protein β, and Ying Yang-1 at the hormonally activated β-casein proximal promoter as well as the distal mouse β-casein enhancer located approximately −6 kb upstream of the transcription start site. Prl alone resulted in a rapid recruitment of both signal transducer and activator of transcription 5 and histone deacetylase 1 to the β-casein promoter and enhancer, and reciprocally the dissociation of Ying Yang-1 from the proximal promoter. In addition, we have examined the recruitment of coactivator p300 and determined chromatin acetylation status as a function of hormonal treatment. Finally, we have established the time course of RNA polymerase II and phospho-RNA polymerase II accumulation at the β-casein promoter and enhancer after stimulation with hydrocortisone and Prl. Although glucocorticoids alone led to a rapid increase in histone H3 acetylation, treatment with both hormones was required for stable association of p300 and phospho-RNA polymerase II at both the promoter and enhancer. Collectively, these data suggest a model for the assembly of a multiprotein complex that helps to define how the signaling pathways controlled by these lactogenic hormones are integrated to regulate β-casein gene expression.
The isolated perfused rat liver: standardization of a time-honoured model
Authors: Bessems M , 't Hart N A , Tolba R , Doorschodt B M , Leuvenink H G D , Ploeg R J , Minor T , van Gulik T M 
Published: June 2006

For many years, the isolated perfused rat liver (IPRL) model has been used to investigate the physiology and pathophysiology of the rat liver. This in vitro model provides the opportunity to assess cellular injury and liver function in an isolated setting. This review offers an update of recent developments regarding the IPRL set-up as well as the viability parameters that are used, with regards to liver preservation and ischaemia and reperfusion mechanisms. A review of the literature was performed into studies regarding liver preservation or liver ischaemia and reperfusion. An overview of the literature is given with particular emphasis on perfusate type and volume, reperfusion pressure, flow, temperature, duration of perfusion, oxygenation and on applicable viability parameters (liver damage and function). The choice of IPRL set-up depends on the question examined and on the parameters of interest. A standard technique is cannulation of the portal vein, bile duct and caval vein with pressure-controlled perfusion at 20 cm H2O (15 mmHg) to reach a perfusion flow of approximately 3 mL/min/g liver weight. The preferred perfusion solution is Krebs–Henseleit buffer, without albumin. The usual volume is 150–300 cm3, oxygenated to a pO2 of more than 500 mmHg. The temperature of the perfusate is maintained at 37°C. Standardized markers should be used to allow comparison with other experiments.
Successful Treatment and Cerebrospinal Fluid Penetration of Oral Linezolid in a Patient with Coagulase-Negative Staphylococcus Ventriculitis
Authors: Boak Lauren M , Li Jian , Spelman Denis , du Cros Philipp , Nation Roger L , Rayner Craig R 
Published: June 2006

Objective: TO describe a case of coagulase-negative Staphylococcus ventriculitis successfully treated with oral linezolid, for which good cerebrospinal fluid (CSF) penetration was observed. Case Summary: A 69-year-old man had an extraventricular drain inserted following a right cerebellar infarct. On day 6, the CSF culture was positive for coagulase-negative staphylococci; intravenous vancomycin 1 g daily was initiated to treat ventriculitis. A ventriculoperitoneal shunt, inserted on day 35 to manage communicating hydrocephalus, was subsequently removed as symptoms suggesting infection presented. Coagulase-negative Staphylococcus was isolated from shunt reservoir aspirate, and intrathecal vancomycin 10 mg daily was added to the treatment regimen. On day 61, vancomycin was stopped and oral linezolid 600 mg twice daily was started. Linezolid was discontinued 22 days later, with no evidence of ongoing infection. Four blood samples were collected around the seventh dose of linezolid and 5 CSF samples were collected on separate days during treatment. Linezolid concentrations were measured in plasma and CSF by HPLC. Using an ADAPT II maximum a priori Bayesian estimator module, a 2 compartment pharmacokinetic model was fitted to the plasma linezolid concentration data and CSF:predicted plasma concentration ratios (ranging from 0.27 to 1.02) were derived. All CSF concentrations exceeded the reported 90% minimum inhibitory concentration of 2 mg/L for linezolid against coagulase-negative staphylococci. Discussion: Evidence of the effectiveness of linezolid against central nervous system infections is growing; however, limited data exist describing its CSF penetration. Oral linezolid exhibited good CSF penetration in this patient, which corresponded to positive clinical response. Conclusions: Oral linezolid may play a valuable role in the treatment of multiresistant gram-positive central nervous system infections.
A Comparison of Two Sub-structuring Techniques for Representing the Modal Properties of Tires
Authors: Tsihlas D. , Lacroix T. , Clayton B. 
Published: June 2006

Abstract
Different numerical sub-structuring techniques for the representation of tire modal behavior have been developed in the past 20 years. By using these numerical techniques reduced dynamic models are obtained which can not only be used for internal studies but also be provided to the automobile industry and linked to reduced dynamic vehicle models in order to optimize the coupled vehicle-tire response for noise vibration and harshness purposes. Two techniques that have been developed in a custom-made finite element code are presented: 1) the component mode synthesis type models for which the wheel center interface is free and 2) the Craig and Bampton type models for which the wheel center interface is fixed. For both techniques the interface between the tire and the ground is fixed. The choice of fixed or free wheel center boundary condition is arbitrary. In this paper we will compare the formulation of these two numerical methods, and we will show the equivalency of both methods by showing the results obtained in terms of frequency and transfer functions. We will show that the two methods are equivalent in principle and the reduced dynamic models can be converted from one to the other. The advantages-disadvantages of each method will be discussed along with a comparison with experimentally obtained results.
An Analytical Transient Tire Model
Authors: Ghazi Zadeh A. , Fahim A. 
Published: June 2006

Abstract
The dynamics of a vehicle's tires is a major contributor to the vehicle stability, control, and performance. A better understanding of the handling performance and lateral stability of the vehicle can be achieved by an in-depth study of the transient behavior of the tire. In this article, the transient response of the tire to a steering angle input is examined and an analytical second order tire model is proposed. This model provides a means for a better understanding of the transient behavior of the tire. The proposed model is also applied to a vehicle model and its performance is compared with a first order tire model.
Torsional Crack Growth Test to Simulate Belt Edge Deformation
Authors: Fleischman T. S. , Kerchman V. , Ebbott T. G. 
Published: June 2006

Abstract
The study of fatigue crack growth resistance for tire belt compounds is motivated by the high deformation cycles inherent in the belt edge region of radial tires. To improve the understanding of fatigue in this region, a test has been developed to simulate crack growth in shear (mode III). A rubber disk with a circumferential pre-crack is tested in cyclic torsion to simulate belt edge interlaminar shear cycles. Theoretical, numerical [finite element analysis (FEA)] and experimental methods have been employed to investigate and quantify the response. A recent improvement to the analysis considers nonlinear elastic material behavior which is characteristic of carbon black-filled tire compounds. The best agreement between torsional test results and results from typical thin sheet geometries was found for lightly reinforced compounds; crack branching often complicates results for more highly reinforced compounds. Fracture surfaces are examined for evidence of non-planar crack growth to help interpret the results.
Application of the Finite Element Method in Screening of Body Turn up Heights for Radial Truck Tires
Authors: Yan X. 
Published: June 2006

Abstract
A method is described to predict relative body turn up endurance of radial truck tires using the finite element method. The elastomers in the tire were simulated by incompressible elements for which the nonlinear mechanical properties were described by the Mooney-Rivlin model. The belt, carcass, and bead were modeled by an equivalent orthotropic material model. The contact constraint of a radial tire structure with a flat foundation and rigid rim was treated using the variable constraint method. Three groups of tires with different body turn up heights under inflation and static footprint loading were analyzed by using the finite element method. Based on the detail analysis for stress analysis parameters in the critical regions in the tires, the relative body turn up edge endurance was predicted.
Analysis of Contact Stresses on the Tread Rubber Blocks with Slip
Authors: Kim D-M. , Park I-J. 
Published: June 2006

Abstract
The tread rubber block of tire in contact with the roadway plays an important role of holding the frictional forces between the tire and the road in driving and braking. In this paper, a theoretical study based on the energy method is presented on the contact pressure of the tread block under the compressive forces with the slip between the tread block and the contact surfaces, by using a 2-D model of tread rubber block. Then, the slip-starting position is obtained by the theoretical analysis together with experimental results for the compressive force and deflection, which depends on the contact surface conditions. The experimental studies are conducted to verify the predicted results. Good agreement is obtained between these theoretical and experimental results for contact pressure and slip-starting position of the tread rubber block.