bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of the Na+/H+ Exchanger (NHE1) in Breast Cancer Metastasis
Authors: Amith Schammim R. , Fliegel Larry 
Published: February 2013

Abstract
The pH gradient in normal cells is tightly controlled by the activity of various pH-regulatory membrane proteins including the isoform protein of the Na+/H+ exchanger (NHE1). NHE1 is constitutively active in a neoplastic microenvironment, dysregulating pH homeostasis and altering the survival, differentiation, and proliferation of cancer cells, thereby causing them to become tumorigenic. Cytoplasmic alkalinization in breast cancer cells occurs as a result of increased NHE1 activity and, while much is known about the pathophysiologic role of NHE1 in tumor progression with regard to ion flux, the regulation of its activity on a molecular level is only recently becoming evident. The membrane domain of NHE1 is sufficient for ion exchange. However, its activity is regulated through the phosphorylation of key amino acids in the cytosolic domain as well as by its interaction with other intracellular proteins and lipids. Here, we review the importance of these regulatory sites and what role they may play in the disrupted functionality of NHE1 in breast cancer metastasis. Cancer Res; 73(4); 1259–64. ©2013 AACR.
Impaired Long-Term Expansion and Self-Renewal Potential of Pediatric Acute Myeloid Leukemia–Initiating Cells By PTK787/ZK 222584
Authors: Weidenaar Alida C. , ter Elst Arja , Kampen Kim R. , Meeuwsen-de Boer Tiny , Kamps Willem A. , Schuringa Jan Jacob , de Bont Eveline S.J.M. 
Published: February 2013

Abstract
Although most children with acute myeloid leukemia (AML) achieve complete remission, the relapse rate is 30% to 40%. Because it is thought that leukemia-initiating cells (LIC) are responsible for AML relapses, targeting these cells might improve outcome. Treatment of pediatric AML blasts with the receptor tyrosine kinase (RTK) inhibitor PTK787/ZK 222584 (PTK/ZK) induces cell death in vitro. However, the role of PTK/ZK inhibition on outgrowth of (pediatric) LICs is unknown. In this study, we cultured CD34+ cells from pediatric patients with AML on MS5 stromal cells in long-term cocultures. In analogy to adult AML, long-term expansion of leukemic cells up to 10 weeks could be generated in 9 of 13 pediatric AMLs. Addition of PTK/ZK to long-term cocultures significantly inhibited leukemic expansion in all samples, ranging from 4% to 80% growth inhibition at week 5 compared with untreated samples. In 75% of the samples, the inhibitory effect was more pronounced at week 10. Proteome profiler array analysis of downstream kinases revealed that PTK/ZK reduced activation of PI3K/Akt kinase signaling. Although main targets of PTK/ZK are VEGF receptors (VEGFR), no effect was seen on outgrowth of LICs when cultured with bevacizumab (monoclonal VEGFA-antibody), specific antibodies against VEGFR2 or VEGFR3, or exposed to stroma-derived VEGFA. These data suggest that the effect of PTK/ZK on LICs is not only dependent on inhibition of VEGFA/VEGFR signaling. Taken together, our data elucidated antileukemic properties of PTK/ZK in long-term expansion cultures, and suggest that targeting multiple RTKs by PTK/ZK might be a potential effective approach in eradicating (pediatric) LICs. Mol Cancer Res; 11(4); 339–48. ©2013 AACR.
Peroxisome Proliferator-Activated Receptor-γ Mutations Responsible for Lipodystrophy With Severe Hypertension Activate the Cellular Renin–Angiotensin System
Authors: Auclair Martine , Vigouroux Corinne , Boccara Franck , Capel Emilie , Vigeral Catherine , Guerci Bruno , Lascols Olivier , Capeau Jacqueline , Caron-Debarle Martine 
Published: February 2013

Objective—
Inactivating peroxisome proliferator-activated receptor-γ (PPARγ) mutations lead to a syndrome of familial partial lipodystrophy (FPLD3) associated with early-onset severe hypertension. PPARγ can repress the vascular renin–angiotensin system (RAS) and angiotensin II receptor 1 expression. We evaluated the relationships between PPARγ inactivation and cellular RAS using FPLD3 patients’ cells and human vascular smooth muscle cells expressing mutant or wild-type PPARγ.

Approach and Results—

We identified 2 novel
PPAR
G mutations, R165T and L339X, located in the DNA and ligand-binding domains of PPARγ, respectively in 4 patients from 2 FPLD3 families. In cultured skin fibroblasts and peripheral blood mononuclear cells from the 4 patients and healthy controls, we compared markers of RAS activation, oxidative stress, and inflammation, and tested the effect of modulators of PPARγ and angiotensin II receptor 1. We studied the impact of the 2 mutations on the transcriptional activity of PPARγ and on the vascular RAS in transfected human vascular smooth muscle cells. Systemic RAS was not altered in patients. However, RAS markers were overexpressed in patients’ fibroblasts and peripheral blood mononuclear cells, as in vascular cells expressing mutant PPARγ. Angiotensin II–mediated mitogen-activated protein kinase activity increased in patients’ fibroblasts, consistent with RAS constitutive activation. Patients’ cells also displayed oxidative stress and inflammation. PPARγ activation and angiotensin II receptor 1 mRNA silencing reversed RAS overactivation, oxidative stress, and inflammation, arguing for a role of angiotensin II receptor 1 in these processes.

Conclusions—

Two novel FPLD3-linked
PPAR
G mutations are associated with a defective transrepression of cellular RAS leading to cellular dysfunction, which might contribute to the specific FPLD3-linked severe hypertension.
CXCL12 Promotes the Stabilization of Atherosclerotic Lesions Mediated by Smooth Muscle Progenitor Cells in
Apoe
-Deficient Mice
Authors: Akhtar Shamima , Gremse Felix , Kiessling Fabian , Weber Christian , Schober Andreas 
Published: February 2013

Objective—
Unstable atherosclerotic lesions are prone to rupture, which leads to atherothrombosis. Chemokine (C-X-C motif) ligand 12 (CXCL12) promotes the mobilization and neointimal recruitment of smooth muscle progenitor cells (SPCs), and thereby mediates vascular repair. Moreover, treatment with SPCs stabilizes atherosclerotic lesions in mice. We investigated the role of CXCL12 in the treatment of unstable atherosclerotic lesions.

Approach and Results—

Intravenous injection of CXCL12 selectively increased the level of Sca1
+
Lin platelet derived growth factor receptor-β
+
SPCs in the circulation as determined by flow cytometry. Macrophage-rich lesions were induced by partial ligation of the carotid artery in
Apoe
−/−
mice. Repeated injection of CXCL12 reduced the macrophage content, increased the number of smooth muscle cells, increased the fibrous cap thickness, and increased the collagen content in these lesions. However, CXCL12 did not alter the lesion size or the luminal diameter of the carotid artery as determined by planimetry and micro-computed tomography, respectively. Recruitment of bone marrow–derived SPCs to the lesions was increased after treatment with CXCL12 in chimeric mice that expressed
SM22-LacZ
in bone marrow cells as determined by quantification of the number of lesional β-galactosidase–expressing cells. CXCL12 expression was upregulated in atherosclerotic arteries after CXCL12 treatment. Silencing of arterial CXCL12 expression during atherosclerosis promoted lesion formation and reduced the lesional smooth muscle cell content in CXCL12-treated mice.

Conclusions—
Systemic treatment with CXCL12 promotes a more stable atherosclerotic lesion phenotype and enhances the accumulation of SPCs in these lesions without promoting atherosclerosis. Thus, CXCL12-induced SPC mobilization appears a promising approach to treat unstable atherosclerosis.
Endocardial Versus Epicardial Ventricular Radiofrequency Ablation
Authors: Sacher Frederic , Wright Matthew , Derval Nicolas , Denis Arnaud , Ramoul Khaled , Roten Laurent , Pascale Patrizzio , Bordachar Pierre , Ritter Philippe , Hocini Meleze , Dos Santos Pierre , Haissaguerre Michel , Jais Pierre 
Published: February 2013

Background—
Contact force (CF) is an important determinant of lesion formation for atrial endocardial radiofrequency ablation. There are minimal published data on CF and ventricular lesion formation. We studied the impact of CF on lesion formation using an ovine model both endocardially and epicardially.

Methods and Results—

Twenty sheep received 160 epicardial and 160 endocardial ventricular radiofrequency applications using either a 3.5-mm irrigated-tip catheter (Thermocool, Biosense-Webster, n=160) or a 3.5 irrigated-tip catheter with CF assessment (Tacticath, Endosense, n=160), via percutaneous access. Power was delivered at 30 watts for 60 seconds, when either catheter/tissue contact was felt to be good or when CF>10 g with Tacticath. After completion of all lesions, acute dimensions were taken at pathology. Identifiable lesion formation from radiofrequency application was improved with the aid of CF information, from 78% to 98% on the endocardium (
P
<0.001) and from 90% to 100% on the epicardium (
P
=0.02). The mean total force was greater on the endocardium (39±18 g versus 21±14 g for the epicardium;
P
<0.001) mainly because of axial force. Despite the force–time integral being greater endocardially, epicardial lesions were larger (231±182 mm
3
versus 209±131 mm
3
;
P
=0.02) probably because of the absence of the heat sink effect of the circulating blood and covered a greater area (41±27 mm
2
versus 29±17 mm
2
;
P
=0.03) because of catheter orientation.

Conclusions—
In the absence of CF feedback, 22% of endocardial radiofrequency applications that are thought to have good contact did not result in lesion formation. Epicardial ablation is associated with larger lesions.
“Picture to Puncture”
Authors: Sun Chung-Huan J. , Nogueira Raul G. , Glenn Brenda A. , Connelly Kerrin , Zimmermann Susan , Anda Kim , Camp Deborah , Frankel Michael R. , Belagaje Samir R. , Anderson Aaron M. , Isakov Alexander P. , Gupta Rishi 
Published: February 2013

Background—
Comprehensive stroke centers allow for regionalization of subspecialty stroke care. Efficacy of endovascular treatments, however, may be limited by delays in patient transfer. Our goal was to identify where these delays occurred and to assess the impact of such delays on patient outcome.

Methods and Results—

This was a retrospective study evaluating patients treated with endovascular therapy from November 2010 to July 2012 at our institution. We compared patients transferred from outside hospitals with locally treated patients with respect to demographics, imaging, and treatment times. Good outcomes, as defined by 90-day modified Rankin Scale scores of 0 to 2, were analyzed by transfer status as well as time from initial computed tomography to groin puncture (“picture-to-puncture” time). A total of 193 patients were analyzed, with a mean age of 65.8±14.5 years and median National Institutes of Health Stroke Scale score of 19 (interquartile range, 15–23). More than two thirds of the patients (132 [68%]) were treated from referring facilities. Outside transfers were noted to have longer picture-to-puncture times (205 minutes [interquartile range, 162–274] versus 89 minutes [interquartile range, 70–119];
P
<0.001), which was attributable to the delays in transfer. This corresponded to fewer patients with favorable Alberta Stroke Program Early CT Scores on preprocedural computed tomographic imaging (Alberta Stroke Program Early CT Scores >7: 50% versus 76%;
P
<0.001) and significantly worse clinical outcomes (29% versus 51%;
P
=0.003). In a logistic regression model, picture-to-puncture times were independently associated with good outcomes (odds ratio, 0.994; 95% confidence interval, 0.990–0.999;
P
=0.009).

Conclusions—
Delays in picture-to-puncture times for interhospital transfers reduce the probability of good outcomes among treated patients. Strategies to reduce such delays herald an opportunity for hospitals to improve patient outcomes.
Erythropoietin Increases Neurogenesis and Oligodendrogliosis of Subventricular Zone Precursor Cells After Neonatal Stroke
Authors: Gonzalez Fernando F. , Larpthaveesarp Amara , McQuillen Patrick , Derugin Nikita , Wendland Michael , Spadafora Ruggero , Ferriero Donna M. 
Published: February 2013

Background and Purpose—
Stroke is a common cause of neonatal brain injury. The subventricular zone is a lifelong source of newly generated cells in rodents, and erythropoietin (EPO) treatment has shown benefit in different animal models of brain injury. The purpose of this study is to investigate the specific role of exogenous EPO on subventricular zone progenitor cell populations in response to neonatal stroke.

Methods—
Intraventricular injections of green fluorescent protein (GFP)–expressing lentivirus to label subventricular zone precursor cells were made in postnatal day 1 (P1) Long-Evans rats, which then underwent transient middle cerebral artery occlusion on P7. Middle cerebral artery occlusion and sham rats were treated with either vehicle or EPO (1000 U/kg) at reperfusion, 24 hours, and 7 days later. The density of double-labeled DCx+/GFP+, NeuN+/GFP+, O4+/GFP+, GFAP+/GFP+, as well as single-labeled GFP+ and Ki67+ cells, was calculated to determine cell fate outcome in the striatum at 72 hours and 2 weeks after stroke.

Results—
There was a significant increase in DCx+/GFP+ and NeuN+/GFP+ neurons and O4+/GFP+ oligodendrocyte precursors, with decreased GFAP+/GFP+ astrocytes at both time points in EPO-middle cerebral artery occlusion animals. There was also a significant increase in GFP+ cells and Ki67+ proliferating cells in EPO compared with vehicle-middle cerebral artery occlusion animals.

Conclusions—
These data suggest that subventricular zone neural progenitor cells proliferate and migrate to the site of injury after neonatal stroke and multiple doses of EPO, with a shift in cell fate toward neurogenesis and oligodendrogliosis at both early and late time points. The contribution of local cell proliferation and neurogenesis remains to be determined.
The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial
Authors: Butcher Kenneth S. , Jeerakathil Thomas , Hill Michael , Demchuk Andrew M. , Dowlatshahi Dariush , Coutts Shelagh B. , Gould Bronwen , McCourt Rebecca , Asdaghi Negar , Findlay J. Max , Emery Derek , Shuaib Ashfaq 
Published: February 2013

Background and Purpose—
Acute blood pressure (BP) reduction aimed at attenuation of intracerebral hemorrhage (ICH) expansion might also compromise cerebral blood flow (CBF). We tested the hypothesis that CBF in acute ICH patients is unaffected by BP reduction.

Methods—
Patients with spontaneous ICH <24 hours after onset and systolic BP > 150 mm Hg were randomly assigned to an intravenous antihypertensive treatment protocol targeting a systolic BP of <150 mm Hg (n=39) or <180 mm Hg (n=36). Patients underwent computed tomography perfusion imaging 2 hours postrandomization. The primary end point was perihematoma relative (relative CBF).

Results—

Treatment groups were balanced with respect to baseline systolic BP: 182±20 mm Hg (<150 mm Hg target group) versus 184±25 mm Hg (<180 mm Hg target group;
P
=0.60), and for hematoma volume: 25.6±30.8 versus 26.9±25.2 mL (
P
=0.66). Mean systolic BP 2 hours after randomization was significantly lower in the <150 mm Hg target group (140±19 vs 162±12 mm Hg;
P
<0.001). Perihematoma CBF (38.7±11.9 mL/100 g per minute) was lower than in contralateral homologous regions (44.1±11.1 mL/100 g per minute;
P
<0.001) in all patients. The primary end point of perihematoma relative CBF in the <150 mm Hg target group (0.86±0.12) was not significantly lower than that in the <180 mm Hg group (0.89±0.09;
P
=0.19; absolute difference, 0.03; 95% confidence interval −0.018 to 0.078). There was no relationship between the magnitude of BP change and perihematoma relative CBF in the <150 mm Hg (
R
=0.00005; 95% confidence interval, −0.001 to 0.001) or <180 mm Hg target groups (
R
=0.000; 95% confidence interval, −0.001 to 0.001).

Conclusions—
Rapid BP lowering after a moderate volume of ICH does not reduce perihematoma CBF. These physiological data indicate that acute BP reduction does not precipitate cerebral ischemia in ICH patients.

Clinical Trial Registration Information—

URL:
http://clinicaltrials.gov
. Unique Identifier: NCT00963976.
Thrombolysis in Stroke Despite Contraindications or Warnings?
Authors: Frank Benedikt , Grotta James C. , Alexandrov Andrei V. , Bluhmki Erich , Lyden Patrick , Meretoja Atte , Mishra Nishant K. , Shuaib Ashfaq , Wahlgren Nils G. , Weimar Christian , Lees Kennedy R. 
Published: February 2013

Background and Purpose—
Intravenous thrombolysis with alteplase is approved for acute ischemic stroke, but its use is limited by numerous contraindications and warnings arising from trial selection criteria or expert opinions. We examined outcomes from alteplase-treated versus untreated patients, registered in a trials archive, according to presence or absence of specified contraindications and warnings.

Methods—
We analyzed 90-day modified Rankin Scale across the whole distribution of scores using the Cochran–Mantel–Haenszel test, with adjustment for age and baseline National Institutes of Health Stroke Score, followed by proportional odds logistic regression analysis to estimate the odds ratios for preferred outcome.

Results—
We used data from 9613 ischemic stroke patients of whom 2755 were treated with thrombolysis. Adjusted odds ratios showed a broad trend of more favorable 3-month outcome associated with alteplase treatment versus no treatment in various subgroups of patients with contraindications and warnings; for example, 1.40 (95% confidence interval [CI], 1.14–1.70) in patients aged >80 (n=1805), 1.50 (95% CI, 1.03–2.18) in patients with combined history of prior stroke and diabetes mellitus (n=672), 1.42 (95% CI, 1.19–1.70) in patients on prior single antiplatelet agent (n=1626), 2.20 (95% CI, 1.12–4.32) in patients on oral anticoagulation, and International Normalized Ratio≤1.7 (n=157), 1.50 (95% CI, 1.15–1.97) in patients with baseline glucose >180 (n=879), and 1.57 (95% CI, 1.12–2.18) in patients with pretreatment National Institutes of Health Stroke Score >22 (n=620).

Conclusions—
This comprehensive retrospective analysis of various contraindications and warnings provides reassurance about benefits and risks of intravenous alteplase treatment in common clinical situations.
Unilateral Trade-related Climate Change Measures
Authors: Leal-Arcas Rafael 
Published: February 2013

Climate change mitigation has become one of the most relevant topics today, and it will continue for years to come. It is a concern that has implications in economics, law, science, human rights, technology, international relations and ethics, to name but a few fields of knowledge. Climate change is a global problem that knows no geographical barriers. International law is not well equipped to face the challenges of climate change. Global climate is an indivisible public good. International law currently faces the challenge of fragmentation and the need to bring greater coherence to a fragmented system in combating climate change. The aim of this article is to explain the trade implications of climate change mitigation policies by analyzing a couple of areas where the international regimes for trade and climate change mitigation/energy may potentially clash: 1) border carbon adjustments and 2) applying subsidies and similar measures in order to encourage environmentally-friendly technologies. After the introduction, Section 2 provides an analysis on the link between the legal regimes of international trade and climate change. Section 3 compares both regimes and Section 4 offers an overview of unilateral trade-related climate change measures. Section 5 examines the main WTO provisions on subsidies and analyzes the WTO cases on subsidies for renewable energy. Section 6 focuses on the inclusion of aviation in the EU Emission Trading Scheme (EU ETS) and the potential expansion of the EU ETS to the shipping industry. Section 7 concludes the article.
Antarctic Low-Tropospheric Humidity Inversions: 10-Yr Climatology
Authors: Nygård Tiina , Valkonen Teresa , Vihma Timo 
Published: February 2013

Abstract
Humidity inversions are nearly permanently present in the coastal Antarctic atmosphere. This is shown based on an investigation of statistical characteristics of humidity inversions at 11 Antarctic coastal stations using radiosonde data from the Integrated Global Radiosonde Archive (IGRA) from 2000 to 2009. The humidity inversion occurrence was highest in winter and spring, and high atmospheric pressure and cloud-free conditions generally increased the occurrence. A typical humidity inversion was less than 200 m deep and 0.2 g kg−1 strong, and a typical humidity profile contained several separate inversion layers. The inversion base height had notable seasonal variations, but generally the humidity inversions were located at higher altitudes than temperature inversions. Roughly half of the humidity inversions were associated with temperature inversions, especially near the surface, and humidity and temperature inversion strengths as well as depths correlated at several stations. On the other hand, approximately 60% of the humidity inversions were accompanied by horizontal advection of water vapor increasing with height, which is also a probable factor supporting humidity inversions. The spatial variability of humidity inversions was linked to the topography and the water vapor content of the air. Compared to previous results for the Arctic, the most striking differences in humidity inversions in the Antarctic were a much higher frequency of occurrence in summer, at least under clear skies, and a reverse seasonal cycle of the inversion height. The results can be used as a baseline for validation of weather prediction and climate models and for studies addressing changes in atmospheric moisture budget in the Antarctic.
Comments on “A Simple, Coherent Framework for Partitioning Uncertainty in Climate Predictions”
Authors: Northrop Paul J. 
Published: February 2013

Abstract
In a recent article Yip et al. present a simple, yet powerful, framework for partitioning uncertainty in multimodel climate ensembles. Simplicity is achieved by extracting from climate prediction ensembles a single subset with a convenient structure. Here, the analysis of predictions of twenty-first-century global temperature by Yip et al. is extended by analyzing all possible subsets. Findings can depend strongly on the particular dataset chosen, so relying on a single dataset may be misleading.
The Impact of Boundary Conditions on the Upstream Spreading of Bottom-Trapped Plumes
Authors: Matano Ricardo P. , Palma Elbio D. 
Published: February 2013

Abstract
This study shows that simulations of bottom-trapped plumes in periodic or closed domains generate a spurious cyclonic current that arrests the natural tendency of the plume to move upstream. Furthermore, it also shows that attempts to obstruct the upstream spreading lead to a bias of the fundamental characteristics of the plume.