bluuebunny/crossref_metadata_2025_split huggingface dataset:
MPLS-TE and MPLS VPNS with openflow
Authors: Sharafat Ali Reza , Das Saurav , Parulkar Guru , McKeown Nick 
Published: December 2011

We demonstrate MPLS Traffic Engineering (MPLS-TE) and MPLS-based Virtual Private Networks (MPLS VPNs) using OpenFlow [1] and NOX [6]. The demonstration is the outcome of an engineering experiment to answer the following questions: How hard is it to implement a complex control plane on top of a network controller such as NOX? Does the global vantage point in NOX make the implementation easier than the traditional method of implementing it on every switch, embedded in the data plane? We implemented every major feature of MPLS-TE and MPLS-VPN in just 2,000 lines of code, compared to much larger lines of code in the more traditional approach, such as Quagga-MPLS. Because NOX maintains a consistent, up-to-date topology map, the MPLS control plane features are quite simple to implement. And its simplicity makes it easy to extend: We have easily added several new features; something a network operator could do to customize their network to meet their customers' needs.
The demo consists of two parts: MPLS-TE services and then MPLS VPN driven by a GUI.
Separating ownership topology and encapsulation with generic universe types
Authors: Dietl Werner , Drossopoulou Sophia , Müller Peter 
Published: December 2011

Ownership is a powerful concept to structure the object store and to control aliasing and modifications of objects. This article presents an ownership type system for a Java-like programming language with generic types.
Like our earlier Universe type system, Generic Universe Types structure the heap hierarchically. In contrast to earlier work, we separate the enforcement of an ownership topology from an encapsulation system. The topological system uses an existential modifier to express that no ownership information is available statically. On top of the topological system, we build an encapsulation system that enforces the owner-as-modifier discipline. This discipline does not restrict aliasing, but requires modifications of an object to be initiated by its owner. This allows owner objects to control state changes of owned objects—for instance, to maintain invariants. Separating the topological system from the encapsulation system allows for a cleaner formalization, separation of concerns, and simpler reuse of the individual systems in different contexts.
ATM Mutations in Patients with Hereditary Pancreatic Cancer
Authors: Roberts Nicholas J. , Jiao Yuchen , Yu Jun , Kopelovich Levy , Petersen Gloria M. , Bondy Melissa L. , Gallinger Steven , Schwartz Ann G. , Syngal Sapna , Cote Michele L. , Axilbund Jennifer , Schulick Richard , Ali Syed Z. , Eshleman James R. , Velculescu Victor E. , Goggins Michael , Vogelstein Bert , Papadopoulos Nickolas , Hruban Ralph H. , Kinzler Kenneth W. , Klein Alison P. 
Published: December 2011

Abstract
Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with &gt;200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition.
Significance: The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes. Cancer Discovery; 2(1): 41–6. ©2011 AACR.
Read the Commentary on this article by Bakker and de Winter, p. 14
This article is highlighted in the In This Issue feature, p. 1
Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer Cells
Authors: Marcotte Richard , Brown Kevin R. , Suarez Fernando , Sayad Azin , Karamboulas Konstantina , Krzyzanowski Paul M. , Sircoulomb Fabrice , Medrano Mauricio , Fedyshyn Yaroslav , Koh Judice L.Y. , van Dyk Dewald , Fedyshyn Bohdana , Luhova Marianna , Brito Glauber C. , Vizeacoumar Franco J. , Vizeacoumar Frederick S. , Datti Alessandro , Kasimer Dahlia , Buzina Alla , Mero Patricia , Misquitta Christine , Normand Josee , Haider Maliha , Ketela Troy , Wrana Jeffrey L. , Rottapel Robert , Neel Benjamin G. , Moffat Jason 
Published: December 2011

AbstractGenomic analyses are yielding a host of new information on the multiple genetic abnormalities associated with specific types of cancer. A comprehensive description of cancer-associated genetic abnormalities can improve our ability to classify tumors into clinically relevant subgroups and, on occasion, identify mutant genes that drive the cancer phenotype (“drivers”). More often, though, the functional significance of cancer-associated mutations is difficult to discern. Genome-wide pooled short hairpin RNA (shRNA) screens enable global identification of the genes essential for cancer cell survival and proliferation, providing a “functional genomic” map of human cancer to complement genomic studies. Using a lentiviral shRNA library targeting ∼16,000 genes and a newly developed, dynamic scoring approach, we identified essential gene profiles in 72 breast, pancreatic, and ovarian cancer cell lines. Integrating our results with current and future genomic data should facilitate the systematic identification of drivers, unanticipated synthetic lethal relationships, and functional vulnerabilities of these tumor types.Significance: This study presents a resource of genome-scale, pooled shRNA screens for 72 breast, pancreatic, and ovarian cancer cell lines that will serve as a functional complement to genomics data, facilitate construction of essential gene profiles, help uncover synthetic lethal relationships, and identify uncharacterized genetic vulnerabilities in these tumor types. Cancer Discovery; 2(2); 172–89. © 2011 AACR.This article is highlighted in the In This Issue feature, p. 95.
Peroxisome Proliferator–Activated Receptor-γ Activation Induces 11β-Hydroxysteroid Dehydrogenase Type 1 Activity in Human Alternative Macrophages
Authors: Chinetti-Gbaguidi Giulia , Bouhlel Mohamed Amine , Copin Corinne , Duhem Christian , Derudas Bruno , Neve Bernadette , Noel Benoit , Eeckhoute Jerome , Lefebvre Philippe , Seckl Jonathan R. , Staels Bart 
Published: December 2011

Objective—
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the intracellular reduction of inactive cortisone to active cortisol, the natural ligand activating the glucocorticoid receptor (GR). Peroxisome proliferator– activated receptor-γ (PPARγ) is a nuclear receptor controlling inflammation, lipid metabolism, and the macrophage polarization state. In this study, we investigated the impact of macrophage polarization on the expression and activity of 11β-HSD1 and the role of PPARγ therein.

Methods and Results—
11β-HSD1 gene expression is higher in proinflammatory M1 and anti-inflammatory M2 macrophages than in resting macrophages, whereas its activity is highest in M2 macrophages. Interestingly, PPARγ activation induces 11β-HSD1 enzyme activity in M2 macrophages but not in resting macrophages or M1 macrophages. Consequently, human M2 macrophages displayed enhanced responsiveness to the 11β-HSD1 substrate cortisone, an effect amplified by PPARγ induction of 11β-HSD1 activity, as illustrated by an increased expression of GR target genes.

Conclusion—
Our data identify a positive cross-talk between PPARγ and GR in human M2 macrophages via the induction of 11β-HSD1 expression and activity.
Role for the Guanine Nucleotide Exchange Factor Phosphatidylinositol-3,4,5-Trisphosphate–Dependent Rac Exchanger 1 in Platelet Secretion and Aggregation
Authors: Qian Feng , Le Breton Guy C. , Chen Jia , Deng Jing , Christman John W. , Wu Dianqing , Ye Richard D. 
Published: December 2011

Objective—
Recent studies have shown a role for Rac1 in regulating platelet functions, but how Rac1 is activated in platelets remains unclear. Phosphatidylinositol-3,4,5-trisphosphate–dependent Rac exchanger 1 (P-Rex1) was originally identified in neutrophils that regulates phagocyte functions. We sought to examine whether P-Rex1 plays a role in platelet activation.

Methods and Results—

Western blotting showed P-Rex1 expression in mouse and human platelets. Mice lacking P-Rex1 exhibited prolonged bleeding time and increased rebleeding. When challenged with low doses of the G protein-coupled receptor (GPCR) agonists U46619 and thrombin, P-Rex1
−/−
platelets displayed significantly reduced secretion and aggregation compared with wild-type platelets. Increasing the concentration of these agonists could overcome the defect. Platelet aggregation induced by collagen, a non-GPCR agonist, was also compromised in the absence of P-Rex1. Along with these phenotypic changes were impaired Rac1 activation; reduced ATP secretion; and decreased phosphorylation of Akt, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase in P-Rex1
−/−
platelets on agonist stimulation.

Conclusion—
These results demonstrate for the first time the presence of P-Rex1 in platelets as well as its role in platelet secretion and aggregation induced by low-dose agonists for GPCR and by collagen.
Incremental Value of Biochemical and Echocardiographic Measures in Prediction of Ischemic Stroke
Authors: Karas Maria G. , Devereux Richard B. , Wiebers David O. , Whisnant Jack P. , Best Lyle G. , Lee Elisa T. , Howard Barbara V. , Roman Mary J. , Umans Jason G. , Kizer Jorge R. 
Published: December 2011

Background and Purpose—
American Indians have high rates of stroke. Improved risk stratification could enhance prevention, but the ability of biochemical and echocardiographic markers of preclinical disease to improve stroke prediction is not well-defined.

Methods—
We evaluated such markers as predictors of ischemic stroke in a community-based cohort of American Indians without prevalent cardiovascular or renal disease. Laboratory markers included C-reactive protein, fibrinogen, urine albumin-to-creatinine ratio, and glycohemoglobin (HbA1c), whereas echocardiographic parameters comprised left atrial diameter, left ventricular mass, mitral annular calcification, and the ratio of early to late mitral diastolic velocities. Predictive performance was judged by indices of discrimination, reclassification, and calibration.

Results—

After adjustment for standard risk factors, only HbA1c, albuminuria, and left atrial diameter were significantly associated with first ischemic stroke. Addition of HbA1c, although not urine albumin-to-creatinine ratio, to a basic clinical model significantly improved the C-statistic (0.714 versus 0.695;
P
=0.044), whereas left atrial diameter modestly enhanced integrated discrimination improvement (0.90%;
P
=0.004), but not the C-statistic (0.701;
P
=0.528). When combined with HbA1c, left atrial diameter further increased integrated discrimination improvement (1.81%;
P
<0.001) but not the C-statistic (0.716). No marker achieved significant net reclassification improvement.

Conclusions—
In this cohort at high cardiometabolic risk, HbA1c emerged as the foremost predictor of ischemic stroke when added to traditional risk factors, affording substantially improved discrimination, with a more modest contribution for left atrial diameter. These findings bolster the role of HbA1c in cardiovascular risk assessment among persons with glycometabolic disorders and provide impetus for further study of the incremental value of echocardiography in high-risk populations.
Dietary Protein Sources and the Risk of Stroke in Men and Women
Authors: Bernstein Adam M. , Pan An , Rexrode Kathryn M. , Stampfer Meir , Hu Frank B. , Mozaffarian Dariush , Willett Walter C. 
Published: December 2011

Background and Purpose—
Few dietary protein sources have been studied prospectively in relation to stroke. We examined the relation between foods that are major protein sources and risk of stroke.

Methods—
We prospectively followed 84 010 women aged 30 to 55 years at baseline and 43 150 men aged 40 to 75 years at baseline without diagnosed cancer, diabetes, or cardiovascular disease. Diet was assessed repeatedly by a standardized and validated questionnaire. We examined the association between protein sources and incidence of stroke using a proportional hazard model adjusted for stroke risk factors.

Results—
During 26 and 22 years of follow-up in women and men, respectively, we documented 2633 and 1397 strokes, respectively. In multivariable analyses, higher intake of red meat was associated with an elevated risk of stroke, whereas a higher intake of poultry was associated with a lower risk. In models estimating the effects of exchanging different protein sources, compared with 1 serving/day of red meat, 1 serving/day of poultry was associated with a 27% (95% CI, 12%–39%) lower risk of stroke, nuts with a 17% (95% CI. 4%–27%) lower risk, fish with a 17% (95% CI, 0%–30%) lower risk, low-fat dairy with an 11% (95% CI, 5%–17%) lower risk, and whole-fat dairy with a 10% (95% CI, 4%–16%) lower risk. We did not see significant associations with exchanging legumes or eggs for red meat.

Conclusions—
These data suggest that stroke risk may be reduced by replacing red meat with other dietary sources of protein.
Stenting Versus Surgery in Patients With Carotid Stenosis After Previous Cervical Radiation Therapy
Authors: Fokkema Margriet , den Hartog Anne G. , Bots Michiel L. , van der Tweel Ingeborg , Moll Frans L. , de Borst Gert Jan 
Published: December 2011

Background and Purpose—
Patients with both carotid stenosis and previously cervical radiation therapy are considered “high risk” for carotid endarterectomy (CEA). Carotid angioplasty and stenting (CAS) seems a reasonable alternative, but neither the operative risk for CEA nor the effectiveness of CAS has been proven. The purpose of this study was to evaluate perioperative and long-term outcome of both procedures in patients with radiation therapy.

Methods—
A systematic search strategy with the synonyms “carotid artery stenosis” and “cervical irradiation” was conducted in MEDLINE and EMBASE databases. To provide and compare estimates of outcomes, pooled and metaregression analyses were performed.

Results—

Twenty-seven articles comprising 533 patients undergoing radiation therapy (361 CAS and 172 CEA) fulfilled our inclusion criteria. Pooled analysis showed perioperative risk for “any cerebrovascular adverse event” (CVE) of 3.9% (95% CI, 2.3%–6.7%) in CAS studies against 3.5% (95% CI, 1.5%–8.0%) in CEA studies (
P
=0.77). Risk for cranial nerve injury (CNI) after CEA was 9.2% (95% CI, 3.7%–21.1%) versus none after CAS. Late outcome showed rates of CVE favoring CEA (
P
=0.014). The rate of restenosis >50% was significantly higher in patients treated with CAS compared with CEA (
P
<0.003).

Conclusions—
Both CAS and CEA proved to be feasible revascularization techniques with low risk for CVE. Although patients undergoing CEA had more temporary CNI, higher rates of late CVE and restenosis were identified after CAS.
Use of Secondary Medical Prophylaxis and Clinical Outcome Among Patients With Ischemic Stroke
Authors: Palnum Kaare Haurvig , Mehnert Frank , Andersen Grethe , Ingeman Annette , Krog Birgitte Randrup , Bartels Paul Daniel , Johnsen Søren Paaske 
Published: December 2011

Background and Purpose—
Although secondary medical prevention strategies in patients with stroke are well established, only sparse data exist regarding their effectiveness in routine care. We examined the effectiveness in a nationwide, population-based follow-up study.

Methods—
Using data from the Danish National Indicator Project (DNIP), 28 612 patients hospitalized for ischemic stroke in 2003 to 2006 were identified. Information on drug use and outcomes was by individual-level record linkage with national medical databases. Hazard ratios were computed for death, myocardial infarction, and recurrent stroke according to drug use after hospital discharge.

Results—
Treatment with antiplatelets, oral anticoagulants, antihypertensives, or statins was associated with a lower risk of the combined end point of death, myocardial infarction, or recurrent stroke during a mean follow-up period of 2.7 years (adjusted hazard ratios [HRs] from 0.44 [95% CI, 0.39–0.49] to 0.94 [95% CI, 0.89–0.99]). All drug classes were associated with lower risk of death (adjusted HRs from 0.36 [95% CI, 0.32–0.41] to 0.85 [95% CI, 0.80–0.90]), with oral anticoagulant treatment in patients with atrial fibrillation being particularly effective in elderly women (>80 years; adjusted HR, 0.35; 95% CI, 0.28–0.45). Oral anticoagulant treatment was associated with a lower risk of recurrent stroke (adjusted HR, 0.58; 95% CI, 0.47–0.73), and statins were associated with a lower risk of myocardial infarction (adjusted HR, 0.84; 95% CI, 0.73–0.97) and recurrent stroke (adjusted HR, 0.86; 95% CI, 0.79–0.92).

Conclusions—
Secondary medical prophylaxis after ischemic stroke was associated with improved outcome in routine settings. Although these findings are of an observational nature, they tend to support the results from previous randomized trials.
Hippocampal Neuronal Atrophy and Cognitive Function in Delayed Poststroke and Aging-Related Dementias
Authors: Gemmell Elizabeth , Bosomworth Helen , Allan Louise , Hall Roslyn , Khundakar Ahmad , Oakley Arthur E. , Deramecourt Vincent , Polvikoski Tuomo M. , O'Brien John T. , Kalaria Raj N. 
Published: December 2011

Background and Purpose—
We have previously shown delayed poststroke dementia in elderly (≥75 years old) stroke survivors is associated with medial temporal lobe atrophy; however, the basis of the structural and functional changes is unknown.

Methods—
Using 3-dimensional stereological methods, we quantified hippocampal pyramidal neuronal volumes and densities in a total of 95 postmortem samples from demented and nondemented poststroke survivors within our prospective Cognitive Function after Stroke study and subjects pathologically diagnosed with vascular dementia, Alzheimer disease, and mixed Alzheimer disease and vascular dementia syndrome.

Results—

Hippocampal CA1 but not CA2 subfield neuron density was affected in poststroke, Alzheimer disease, vascular dementia, and mixed dementia groups relative to control subjects (
P
<0.05). Neuronal volume was reduced in the poststroke dementia relative to poststroke nondemented group in both CA1 and CA2, although there were no apparent differences in neuronal density. Poststroke nondemented neuronal volumes were similar to control subjects but greater than in all dementias (
P
<0.05). Neuronal volumes positively correlated with global cognitive function and memory function in both CA1 and CA2 in poststroke subjects (
P
<0.01). Degrees of neuronal atrophy and loss were similar in the poststroke dementia and vascular dementia groups. However, in the entorhinal cortex layer V, neuronal volumes were only impaired in the mixed and Alzheimer disease groups (
P
<0.05).

Conclusions—
Our results suggest hippocampal neuronal atrophy is an important substrate for dementia in both cerebrovascular and neurodegenerative disease.
Asymmetric Pattern of Cerebrovascular Lesions in Patients After Left Ventricular Assist Device Implantation
Authors: Kato Tomoko S. , Ota Takeyoshi , Schulze P. Christian , Farr Maryjane , Jorde Ulrich , Takayama Hiroo , Naka Yoshifumi , Yamashita Toru , Mancini Donna M. 
Published: December 2011

Background and Purpose—
Stroke is a major adverse event after left ventricular assist device (LVAD) surgery. The purpose of this study was to describe differences in hemispheric distribution of stroke in LVAD patients.

Methods—
We reviewed 317 consecutive patients who underwent LVAD surgery between November 2000 and July 2011. Stroke during LVAD support was analyzed.

Results—
In total, 46 strokes occurred at 76.0±96.8 days postoperatively. Among the 46 strokes, 27 events (58.7%) occurred in right hemisphere, 13 events (28.2%) in the left hemisphere, 3 events (8.7%) occurred bilaterally, and 2 events (4.3%) were vertebrobasilar lesions. The right hemispheric stroke was significantly more common in patients with postoperative infection compared with left hemispheric events.

Conclusions—
Stroke after LVAD implantation has a right hemispheric predominance. This finding suggests LVAD-related thrombus in the setting of infection and/or the anatomic configuration of LVAD outflow cannula-ascending aorta anastomosis to be highly associated with stroke after LVAD surgery.
α7 Nicotinic Acetylcholine Receptor Agonism Confers Neuroprotection Through GSK-3β Inhibition in a Mouse Model of Intracerebral Hemorrhage
Authors: Krafft Paul R. , Altay Orhan , Rolland William B. , Duris Kamil , Lekic Tim , Tang Jiping , Zhang John H. 
Published: December 2011

Background and Purpose—
Perihematomal edema formation and consequent cell death contribute to the delayed brain injury evoked by intracerebral hemorrhage (ICH). We aimed to evaluate the effect of α7 nicotinic acetylcholine receptor (α7nAChR) stimulation on behavior, brain edema, and neuronal apoptosis. Furthermore, we aimed to determine the role of the proapoptotic glycogen synthase kinase-3β (GSK-3β) after experimental ICH.

Methods—
Male CD-1 mice (n=109) were subjected to intracerebral infusion of autologous blood (n=88) or sham surgery (n=21). ICH animals received vehicle administration, 4 or 12 mg/kg of α7nAChR agonist PHA-543613, 12 mg/kg of α7nAChR agonist PNU-282987, 6 mg/kg of α7nAChR antagonist methyllycaconitine (MLA), 15 μg/kg of phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, or PHA-543613 combined with MLA or wortmannin. Behavioral deficits and brain water content were evaluated at 24 and 72 hours after surgery. Western blotting and immunofluorescence staining were used for the quantification and localization of activated Akt (p-Akt), GSK-3β (p-GSK-3β), and cleaved caspase-3 (CC3). Neuronal cell death was quantified through terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL).

Results—

α7nAChR stimulation improved neurological outcome and reduced brain edema at 24 and 72 hours after surgery (
P
<0.05 compared with vehicle). Furthermore, PHA-543613 treatment increased p-Akt and decreased p-GSK-3β and CC3 expressions in the ipsilateral hemisphere (
P
<0.05, respectively), which was reversed by MLA and wortmannin. P-Akt, p-GSK-3β, and CC3 were generally localized in neurons. PHA-543613 reduced neuronal cell death in the perihematomal area (
P
<0.05).

Conclusions—
α7nAChR stimulation improved functional and morphological outcomes after experimental ICH in mice. PHA-543613 reduced the expression of proapoptotic GSK-3β through the PI3K-Akt signaling pathway.