bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-convergence of the critical cooling time-scale for fragmentation of self-gravitating discs
Authors: Meru Farzana , Bate Matthew R. 
Published: December 2010

Abstract
We carry out a resolution study on the fragmentation boundary of self-gravitating discs. We perform three-dimensional Smoothed Particle Hydrodynamics simulations of discs to determine whether the critical value of the cooling time-scale in units of the orbital time-scale, βcrit, converges with increasing resolution. Using particle numbers ranging from 31 250 to 16 million (the highest resolution simulations to date) we do not find convergence. Instead, fragmentation occurs for longer cooling time-scales as the resolution is increased. These results suggest that at the very least, the critical value of the cooling time-scale is longer than previously thought. However, the absence of convergence also raises the question of whether or not a critical value exists. In light of these results, we caution against using cooling time-scale or gravitational stress arguments to deduce whether gravitational instability may or may not have been the formation mechanism for observed planetary systems.
Gone FISHing: Clinical Lessons Learned in Brain Tumor Molecular Diagnostics over the Last Decade
Authors: Horbinski Craig , Miller C Ryan , Perry Arie 
Published: December 2010

AbstractFluorescencein situhybridization (FISH) is a powerful, morphology‐based technique to assess targeted copy number alterations or gene rearrangements in formalin‐fixed, paraffin‐embedded tissues. It has a wide range of applications in routine clinical contexts to identify cytogenetic biomarkers for more accurate diagnosis and prognostic stratification. This review and update addresses practical uses of FISH as a molecular diagnostic tool in the setting of brain tumors, including gliomas, embryonal neoplasms, ependymomas and meningiomas, focusing on key genetic biomarkers, such as 1p19q codeletion, epidermal growth factor receptor (EGFR) gene amplification,BRAFrearrangement and many others. Also discussed are lessons learned over the past decade, including common technical issues to consider when implementing and interpreting FISH results in a clinical setting.
Tracing phenotypic reversibility of pancreatic β‐cells in vitro
Authors: Minami Kohtaro , Miyawaki Kazumasa , Hara Manami , Yamada Shuichi , Seino Susumu 
Published: December 2010

AbstractAims/Introduction:  Studies have suggested that pancreatic β‐cells undergo dedifferentiation during proliferation in vitro. However, due to limitations of the methodologies used, the question remains whether such dedifferentiated cells can redifferentiate into β‐cells.Materials and Methods:  We have established a method for cell tracing in combination with fluorescence‐activated cell sorter (FACS). Using this method, mouse pancreatic β‐cells labeled with green fluorescent protein (GFP) under the control of the insulin promoter are collected by FACS. These β‐cells can be traced and characterized throughout the culture process, even when insulin becomes undetectable, because the cells are also marked with monomeric red fluorescent protein (mRFP) driven by the CAG promoter.Results:  When cultured with fetal mouse pancreatic cells, FACS sorted β‐cells lost GFP expression, but retained mRFP expression. The cells also lost expressions of genes characteristic of the β‐cell phenotype, such as Pdx1 and glucokinase, indicating dedifferentiation. More than 30% of such dedifferentiated pancreatic β‐cells were detected in S or G2/M phase. Furthermore, these dedifferentiated cells redifferentiated into insulin‐expressing cells on cultivation with a MEK1/2 inhibitor.Conclusions:  Our data provide direct evidence that pre‐existing β‐cells can undergo dedifferentiation and redifferentiation in vitro, their phenotype is reversible and that dedifferentiation in β‐cells is associated with progression of the cell cycle. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00051.x, 2010)
The Integrin αvβ3-5 Ligand MFG-E8 Is a p63/p73 Target Gene in Triple-Negative Breast Cancers but Exhibits Suppressive Functions in ER+ and erbB2+ Breast Cancers
Authors: Yang Chuanwei , Hayashida Tetsu , Forster Nicole , Li Cuiqi , Shen Dejun , Maheswaran Shyamala , Chen Li , Anderson Karen S. , Ellisen Leif W. , Sgroi Dennis , Schmidt Emmett V. 
Published: December 2010

Abstract
The progression from preinvasive lesion to invasive carcinoma is a critical step contributing to breast cancer lethality. We identified downregulation of milk fat globule-EGF factor 8 (MFG-E8) as a contributor to breast cancer progression using microarray analysis of laser capture microdissected (LCM) tissues. We first identified MFG-E8 downregulation in invasive lesions in transgenic mammary tumor models, which were confirmed in LCM-isolated human invasive ductal carcinomas compared with patient-matched normal tissues. In situ analyses of MFG-E8 expression in estrogen receptor (ER) positive cases confirmed its downregulation during breast cancer progression and small inhibitory MFG-E8 RNAs accelerated ER+ breast cancer cell proliferation. MFG-E8 also decreased in erbB2+ human cancers and erbB2 transgenic mice lacking MFG-E8 showed accelerated tumor formation. In contrast, MFG-E8 expression was present at high levels in triple-negative (ER−, PgR−, erbB2−) breast cancers, cell lines, and patient sera. Knockdown, chromatin immunoprecipitation, and reporter assays all showed that p63 regulates MFG-E8 expression, and MFG-E8 knockdowns sensitized triple-negative breast cancers to cisplatin treatment. Taken together, our results show that MFG-E8 is expressed in triple-negative breast cancers as a target gene of the p63 pathway, but may serve a suppressive function in ER+ and erbB2+ breast cancers. Its potential use as a serum biomarker that contributes to the pathogenesis of triple-negative breast cancers urges continued evaluation of its differential functions. Cancer Res; 71(3); 937–45. ©2010 AACR.
Dynamic Mathematical Modeling of IL13-Induced Signaling in Hodgkin and Primary Mediastinal B-Cell Lymphoma Allows Prediction of Therapeutic Targets
Authors: Raia Valentina , Schilling Marcel , Böhm Martin , Hahn Bettina , Kowarsch Andreas , Raue Andreas , Sticht Carsten , Bohl Sebastian , Saile Maria , Möller Peter , Gretz Norbert , Timmer Jens , Theis Fabian , Lehmann Wolf-Dieter , Lichter Peter , Klingmüller Ursula 
Published: December 2010

Abstract
Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) share a frequent constitutive activation of JAK (Janus kinase)/STAT signaling pathway. Because of complex, nonlinear relations within the pathway, key dynamic properties remained to be identified to predict possible strategies for intervention. We report the development of dynamic pathway models based on quantitative data collected on signaling components of JAK/STAT pathway in two lymphoma-derived cell lines, MedB-1 and L1236, representative of PMBL and cHL, respectively. We show that the amounts of STAT5 and STAT6 are higher whereas those of SHP1 are lower in the two lymphoma cell lines than in normal B cells. Distinctively, L1236 cells harbor more JAK2 and less SHP1 molecules per cell than MedB-1 or control cells. In both lymphoma cell lines, we observe interleukin-13 (IL13)-induced activation of IL4 receptor α, JAK2, and STAT5, but not of STAT6. Genome-wide, 11 early and 16 sustained genes are upregulated by IL13 in both lymphoma cell lines. Specifically, the known STAT-inducible negative regulators CISH and SOCS3 are upregulated within 2 hours in MedB-1 but not in L1236 cells. On the basis of this detailed quantitative information, we established two mathematical models, MedB-1 and L1236 model, able to describe the respective experimental data. Most of the model parameters are identifiable and therefore the models are predictive. Sensitivity analysis of the model identifies six possible therapeutic targets able to reduce gene expression levels in L1236 cells and three in MedB-1. We experimentally confirm reduction in target gene expression in response to inhibition of STAT5 phosphorylation, thereby validating one of the predicted targets. Cancer Res; 71(3); 693–704. ©2010 AACR.
Pharmacokinetically Guided Phase 1 Trial of the IGF-1 Receptor Antagonist RG1507 in Children with Recurrent or Refractory Solid Tumors
Authors: Bagatell R. , Herzog C.E. , Trippett T.M , Grippo J.F. , Cirrincione-Dall G. , Fox E. , Macy M. , Bish J. , Whitcomb P. , Aikin A. , Wright G. , Yurasov S. , Balis F.M. , Gore L. 
Published: December 2010

Abstract
Purpose: This pediatric phase I study was designed to identify the doses of RG1507, a monoclonal antibody against the Type 1 Insulin-like Growth Factor Receptor (IGF1R), that achieves exposures equivalent to those achieved in adults at recommended doses.
Experimental Design: Children with relapsed or refractory solid tumors were treated using the same doses and administration schedules of RG1507 (3 and 9 mg/kg/wk, and 16 mg/kg every 3 weeks [q3W]) as those studied in adults. Detailed pharmacokinetic (PK) sampling was performed after the first dose; selected peak and trough levels were subsequently obtained. Target exposures were ≥85% of mean areas under concentration x time curves (AUCs) in adults at doses of 9 mg/kg/wk and 16 mg/kg q3W. A maximum tolerated dose could be identified if dose-limiting toxicities (DLT) occurred.
Results: Thirty-one evaluable patients aged 3–17 years were enrolled at 3 mg/kg/wk (n = 3), 9 mg/kg/wk (n = 18), or 16 mg/kg q3W (n = 10). There were no DLTs. At 9 mg/kg/wk the mean AUC0–7d (21,000 μg h/mL) exceeded the target (16,000 μg h/mL). At 16 mg/kg q3W, the mean AUC021d (70,000 μg h/mL) exceeded the target (59,400 μg h/mL). Clearance normalized to body weight was age dependent. There were no objective responses. Seven patients had stable disease for &gt;12 weeks, including two patients with osteosarcoma with stable disease for 52+ and 78+ weeks.
Conclusions: The recommended doses of RG1507 in children with solid tumors are 9 mg/kg/wk and 16 mg/kg q3W. This flexible design is well suited for trials of agents associated with limited toxicity. Clin Cancer Res; 17(3); 611–9. ©2010 AACR.
Endothelial Cell EphrinB2-Dependent Activation of Monocytes in Arteriosclerosis
Authors: Braun Jennifer , Hoffmann Sabrina C. , Feldner Anja , Ludwig Thomas , Henning Rob , Hecker Markus , Korff Thomas 
Published: December 2010

Objective—
The expression of ephrinB2 in endothelial cells delineates their arterial phenotype and is a prerequisite for the development of the embryonic vasculature. Whereas the role of ephrinB2 in the microcirculation has been studied extensively, its expression and function in adult arteries is hardly understood.

Methods and Results—
Our analyses showed that in mouse arteries, ephrinB2 is located on the luminal surface of endothelial cells and may physically interact with monocyte EphB receptors. Moreover, transdifferentiation of human monocytes into macrophages was associated with an increase in EphB2 expression, and exposing monocytes to immobilized ephrinB2 resulted in phosphorylation of the receptor followed by an increased expression of proinflammatory chemokines such as interleukin-8 and monocyte chemotactic protein-1/CCL2. Relating to the (patho)physiological relevance of these findings, immunofluorescence analyses revealed that ephrinB2 is most abundantly expressed in endothelial cells at arteriosclerosis predilection sites of the mouse aorta. Subsequent analyses indicated that monocyte adhesion to aortic segments abundantly expressing ephrinB2 is strongly enhanced and that endothelial cell ephrinB2 forward signaling is sufficient to upregulate cytokine expression in monocytes.

Conclusion—
These observations suggest a hitherto unknown link between vascular ephrinB2 expression and the proinflammatory activation of monocytes that may contribute to the pathogenesis of arteriosclerosis.
Protease-Activated Receptor Signaling in Platelets Activates Cytosolic Phospholipase A2αDifferently for Cyclooxygenase-1 and 12-Lipoxygenase Catalysis
Authors: Holinstat Michael , Boutaud Olivier , Apopa Patrick L. , Vesci Joanne , Bala Manju , Oates John A. , Hamm Heidi E. 
Published: December 2010

Objective—The rate-limiting step in the biosynthesis of thromboxane A2(TxA2) and 12-hydroxyeicosatetraenoic acid (12-HETE) by platelets is activation of cytosolic phospholipase A2α(cPLA2α), which releases arachidonic acid, which is the substrate for cyclooxygenase-1 (COX-1) and 12-lipoxygenase. We evaluated signaling via the human platelet thrombin receptors, protease-activated receptor (PAR) 1 and PAR4, to the activation of cPLA2α, which provides a substrate for the biosynthesis of TxA2and 12-HETE.Methods and Results—Stimulating washed human platelets resulted in delayed biosynthesis of 12-HETE, which continues after maximal formation of TxA2is completed, suggesting that 12-HETE is not formed by the same pool of arachidonic acid that provides a substrate to COX-1. PAR1-induced formation of TxA2was inhibited by the phosphatidylinositol kinase inhibitor LY294002, whereas this inhibitor did not block 12-HETE biosynthesis. Both 1-butanol and propranolol also blocked TxA2biosynthesis but did not inhibit 12-HETE formation.Conclusion—The concerted evidence indicates that the platelet thrombin receptors signal activation of cPLA2αcoupled to COX-1 by a pathway different from that signaling activation of the cPLA2αcoupled to 12-lipoxygenase.
β-Catenin Mediates Mechanically Regulated, Transforming Growth Factor-β1–Induced Myofibroblast Differentiation of Aortic Valve Interstitial Cells
Authors: Chen Jan-Hung , Chen Wen Li Kelly , Sider Krista L. , Yip Cindy Ying Yin , Simmons Craig A. 
Published: December 2010

Objective—
In calcific aortic valve disease, myofibroblasts and activation of the transforming growth factor-β1 (TGF-β1) and Wnt/β-catenin pathways are observed in the fibrosa, the stiffer layer of the leaflet, but their association is unknown. We elucidated the roles of β-catenin and extracellular matrix stiffness in TGF-β1-induced myofibroblast differentiation of valve interstitial cells (VICs).

Methods and Results—
TGF-β1 induced rapid β-catenin nuclear translocation in primary porcine aortic VICs in vitro through TGF-β receptor I kinase. Degrading β-catenin pharmacologically or silencing it with small interfering RNA inhibited TGF-β1-induced myofibroblast differentiation without altering Smad2/3 activity. Conversely, increasing β-catenin availability with Wnt3A alone did not induce differentiation. However, combining TGF-β1 and Wnt3A caused greater myofibroblast differentiation than TGF-β1 treatment alone. Notably, in VICs grown on collagen-coated PA gels with physiological stiffnesses, TGF-β1-induced β-catenin nuclear translocation and myofibroblast differentiation occurred only on matrices with fibrosa-like stiffness, but not ventricularis-like stiffness. In diseased aortic valves from pigs fed an atherogenic diet, myofibroblasts colocalized with increased protein expression of Wnt3A, β-catenin, TGF-β1, and phosphorylated Smad2/3 in the fibrosa.

Conclusion—
Myofibroblast differentiation of VICs involves matrix stiffness–dependent crosstalk between TGF-β1 and Wnt signaling pathways and may explain in part why the stiffer fibrosa is more susceptible to disease.
Guidelines for the Primary Prevention of Stroke
Authors: Goldstein Larry B. , Bushnell Cheryl D. , Adams Robert J. , Appel Lawrence J. , Braun Lynne T. , Chaturvedi Seemant , Creager Mark A. , Culebras Antonio , Eckel Robert H. , Hart Robert G. , Hinchey Judith A. , Howard Virginia J. , Jauch Edward C. , Levine Steven R. , Meschia James F. , Moore Wesley S. , Nixon J.V. (Ian) , Pearson Thomas A. 
Published: December 2010

Background and Purpose—
This guideline provides an overview of the evidence on established and emerging risk factors for stroke to provide evidence-based recommendations for the reduction of risk of a first stroke.

Methods—

Writing group members were nominated by the committee chair on the basis of their previous work in relevant topic areas and were approved by the American Heart Association (AHA) Stroke Council Scientific Statement Oversight Committee and the AHA Manuscript Oversight Committee. The writing group used systematic literature reviews (covering the time since the last review was published in 2006 up to April 2009), reference to previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and when appropriate, formulate recommendations using standard AHA criteria (
Tables 1
and
2
). All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. The guideline underwent extensive peer review by the Stroke Council leadership and the AHA scientific statements oversight committees before consideration and approval by the AHA Science Advisory and Coordinating Committee.

Results—
Schemes for assessing a person's risk of a first stroke were evaluated. Risk factors or risk markers for a first stroke were classified according to potential for modification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (well documented or less well documented). Nonmodifiable risk factors include age, sex, low birth weight, race/ethnicity, and genetic predisposition. Well-documented and modifiable risk factors include hypertension, exposure to cigarette smoke, diabetes, atrial fibrillation and certain other cardiac conditions, dyslipidemia, carotid artery stenosis, sickle cell disease, postmenopausal hormone therapy, poor diet, physical inactivity, and obesity and body fat distribution. Less well-documented or potentially modifiable risk factors include the metabolic syndrome, excessive alcohol consumption, drug abuse, use of oral contraceptives, sleep-disordered breathing, migraine, hyperhomocysteinemia, elevated lipoprotein(a), hypercoagulability, inflammation, and infection. Data on the use of aspirin for primary stroke prevention are reviewed.

Conclusion—
Extensive evidence identifies a variety of specific factors that increase the risk of a first stroke and that provide strategies for reducing that risk.
EPITHET
Authors: Nagakane Yoshinari , Christensen Soren , Brekenfeld Caspar , Ma Henry , Churilov Leonid , Parsons Mark W. , Levi Christopher R. , Butcher Kenneth S. , Peeters Andre , Barber P. Alan , Bladin Christopher F. , De Silva Deidre A. , Fink John , Kimber Thomas E. , Schultz David W. , Muir Keith W. , Tress Brian M. , Desmond Patricia M. , Davis Stephen M. , Donnan Geoffrey A. 
Published: December 2010

Background and Purpose—
The Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) was a prospective, randomized, double-blinded, placebo-controlled, phase II trial of alteplase between 3 and 6 hours after stroke onset. The primary outcome of infarct growth attenuation on MRI with alteplase in mismatch patients was negative when mismatch volumes were assessed volumetrically, without coregistration, which underestimates mismatch volumes. We hypothesized that assessing the extent of mismatch by coregistration of perfusion and diffusion MRI maps may more accurately allow the effects of alteplase vs placebo to be evaluated.

Methods—
Patients were classified as having mismatch if perfusion-weighted imaging divided by coregistered diffusion-weighted imaging volume ratio was >1.2 and total coregistered mismatch volume was ≥10 mL. The primary outcome was a comparison of infarct growth in alteplase vs placebo patients with coregistered mismatch.

Results—

Of 99 patients with baseline diffusion-weighted imaging and perfusion-weighted imaging, coregistration of both images was possible in 95 patients. Coregistered mismatch was present in 93% (88/95) compared to 85% (81/95) with standard volumetric mismatch. In the coregistered mismatch patients, of whom 45 received alteplase and 43 received placebo, the primary outcome measure of geometric mean infarct growth was significantly attenuated by a ratio of 0.58 with alteplase compared to placebo (1.02 vs 1.77; 95% CI, 0.33–0.99;
P
=0.0459).

Conclusions—
When using coregistration techniques to determine the presence of mismatch at study entry, alteplase significantly attenuated infarct growth. This highlights the necessity for a randomized, placebo-controlled, phase III clinical trial of alteplase using penumbral selection beyond 3 hours.
Association of Circulating Inflammatory Markers With Recurrent Vascular Events After Stroke
Authors: Whiteley William , Jackson Caroline , Lewis Steff , Lowe Gordon , Rumley Ann , Sandercock Peter , Wardlaw Joanna , Dennis Martin , Sudlow Cathie 
Published: December 2010

Background and Purpose—
Inflammatory markers may be associated with recurrent vascular events after stroke. We aimed to determine the association between IL-6, C-reactive protein, fibrinogen and white cell count, with recurrent vascular events after stroke, and to compare the association between circulating inflammatory markers with the risk of death from vascular vs nonvascular causes.

Methods—
We prospectively recruited patients with acute stroke (n=817) and followed them for up to 4 years for the occurrence of fatal or nonfatal recurrent stroke, myocardial infarction or fatal vascular events, and death from any cause (n=159).

Results—

The delay to assessment was a median of 10 days. The adjusted incidence of the outcome cluster recurrent stroke, myocardial infarction or vascular death after stroke was significantly higher with higher levels of IL-6 (75
th
to 25
th
percentile hazard ratio, 1.56; 95% CI, 1.37–1.77), C-reactive protein (75
th
to 25
th
percentile hazard ratio, 1.08; 95% CI, 1.04–1.11), and fibrinogen (75
th
to 25
th
percentile hazard ratio, 1.45; 95% CI, 1.24–1.72). The associations between inflammatory markers and death were stronger than with recurrent vascular events. The associations of inflammatory markers with vascular and nonvascular deaths were similar.

Conclusions—
Although inflammatory markers were associated with an increased risk of recurrent vascular events and vascular death after stroke, they were also associated with nonvascular causes of death, suggesting that inflammatory markers do not play a causal role specifically in the generation of recurrent vascular events after stroke. Future studies of the prediction of recurrent vascular events after stroke should concentrate on clinical variables or different blood markers.
Diagnosing a Patent Foramen Ovale in Children
Authors: Hubail Zakariya , Lemler Matthew , Ramaciotti Claudio , Moore Jay , Ikemba Catherine 
Published: December 2010

Background and Purpose—
Transesophageal echocardiography (TEE) is the gold standard for the diagnosis of a patent foramen ovale in adults. In children, acoustic windows on transthoracic echocardiography (TTE) are better than in adults; thus, an invasive TEE may not be necessary. Our goal was to assess the validity of TTE with agitated saline injection for the diagnosis of a patent foramen ovale in children using TEE as the gold standard.

Methods—
Fifty consecutive pediatric patients >1 year of age referred for TEE were prospectively enrolled. Imaging included 2-dimensional, color Doppler, and agitated saline contrast injections with and without Valsalva by TTE followed by TEE. Interpreters of the TTE were blinded to TEE results. Studies were categorized as “inconclusive” if the TTE images were inadequate for definitive diagnosis by the blinded interpreter.

Results—
TTE results were considered conclusive in 43 of 50 (86%) patients. Among the 43 conclusive studies, the 2 modalities disagreed in 1 patient. TTE had a positive predictive value of 100%, negative predictive value 97%, sensitivity of 88%, and specificity of 100% for detecting a patent foramen ovale.

Conclusions—
TTE with agitated saline injection is diagnostic for the assessment of atrial septal integrity in the majority of children.