bluuebunny/crossref_metadata_2025_split huggingface dataset:
FERMI LAT OBSERVATION OF CENTAURUS A RADIO GALAXY
Authors: SAHAKYAN N. V. 
Published: November 2013

The results of analysis of approximately 3 year gamma-ray observations (August 2008–July 2011) of the core of radio galaxy Centaurus A with the Fermi Large Area Telescope (Fermi LAT) are presented. Binned likelihood analysis method applying to the data shows that below several GeV the spectrum can be described by a single power-law with photon index Γ = 2.73 ± 0.06. However, at higher energies the new data show significant excess above the extrapolation of the energy spectrum from low energies. The comparison of the corresponding Spectral Energy Distribution (SED) at GeV energies with the SED in the TeV energy band reported by the H.E.S.S. collaboration shows that we deal with two or perhaps even three components of gamma-radiation originating from different regions located within the central 10 kpc of Centaurus A. The analysis of gamma-ray data of Centaurus A lobe accumulated from the beginning of the operation until November 14, 2011 show extension of the HE gamma-ray emission beyond the WMAP radio image in the case of the Northern lobe [9]. The possible origins of gamma-rays from giant radio lobes of Centaurus A are discussed in the context of hadronic and leptonic scenarios.
MEASUREMENT OF COSMIC RAY SPECTRUM AND ANISOTROPY WITH ARGO-YBJ
Authors:   (on behalf of the ARGO-YBJ Collaboration), DI SCIASCIO G. 
Published: November 2013

In this paper we report on the observation of the anisotropy of cosmic ray arrival direction at different angular scales with ARGO-YBJ. Evidence of new few-degree excesses throughout the sky region 195° ≤ R.A. ≤ 315° is presented for the first time. We report also on the measurement of the light-component (p+He) spectrum of primary cosmic rays in the range 5–200 TeV.
Targeting microRNAs in Pancreatic Cancer: Microplayers in the Big Game
Authors: Khan Sheema , Ansarullah  , Kumar Deepak , Jaggi Meena , Chauhan Subhash C. 
Published: November 2013

AbstractThe prognosis of patients with pancreatic cancer is extremely poor, and current systemic therapies result in only marginal survival rates for patients. The era of targeted therapies has offered a new avenue to search for more effective therapeutic strategies. Recently, microRNAs (miRNA) that are small noncoding RNAs (18–24 nucleotides) have been associated with a number of diseases, including cancer. Disruption of miRNAs may have important implications in cancer etiology, diagnosis, and treatment. So far, focus has been on the mechanisms that are involved in translational silencing of their targets to fine tune gene expression. This review summarizes the approach for rational validation of selected candidates that might be involved in pancreatic tumorigenesis, cancer progression, and disease management. Herein, we also focus on the major issues hindering the identification of miRNAs, their linked pathways and recent advances in understanding their role as diagnostic/prognostic biomarkers, and therapeutic tools in dealing with this disease. miRNAs are expected to be robust clinical analytes, valuable for clinical research and biomarker discovery. Cancer Res; 73(22); 6541–7. ©2013 AACR.
Cancerous Inhibitor of Protein Phosphatase 2A, an Emerging Human Oncoprotein and a Potential Cancer Therapy Target
Authors: Khanna Anchit , Pimanda John E. , Westermarck Jukka 
Published: November 2013

Abstract
Protein phosphatase 2A (PP2A) complexes function as tumor suppressors by inhibiting the activity of several critical oncogenic signaling pathways. Consequently, inhibition of the PP2A phosphatase activity is one of many prerequisites for the transformation of normal human cells into cancerous cells. However, mechanisms for PP2A inactivation in human cancers are poorly understood. The aberrant expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), a recently identified endogenous PP2A inhibitor in malignant cells, is one such mechanism. Various independent studies have validated CIP2A's role in promoting tumor growth and resistance to apoptosis and senescence-inducing therapies. Notably, high CIP2A expression predicts poor patient prognosis in several human cancer types. Among the oncogenic proteins dephosphorylated by PP2A, the MYC oncoprotein, which is phosphorylated at serine 62, has surfaced as a marker for the oncogenic activity of CIP2A. The positive-feedback loop between CIP2A and MYC augments the activity of MYC in cancer cells. In addition, CIP2A promotes the phosphorylation and activity of additional oncoproteins, including E2F1 and AKT. However, CIP2A is not essential for normal mouse growth and development. These findings indicate that CIP2A is a novel anticancer target based on PP2A reactivation and inhibition of the oncogenic activity of its downstream effectors. The potential approaches and feasibility of targeting CIP2A are discussed here. Cancer Res; 73(22); 6548–53. ©2013 AACR.
Acceleration of Biliary Cholesterol Secretion Restores Glycemic Control and Alleviates Hypertriglyceridemia in Obese
db
/
db
Mice
Authors: Su Kai , Sabeva Nadezhda S. , Wang Yuhuan , Liu Xiaoxi , Lester Joshua D. , Liu Jingjing , Liang Shuang , Graf Gregory A. 
Published: November 2013

Objective—
Recent studies support a role for cholesterol in the development of obesity and nonalcoholic fatty liver disease. Mice lacking the ABCG5 ABCG8 (G5G8) sterol transporter have reduced biliary cholesterol secretion and are more susceptible to steatosis, hepatic insulin resistance, and loss of glycemic control when challenged with a high-fat diet. We hypothesized that accelerating G5G8-mediated biliary cholesterol secretion would correct these phenotypes in obese mice.

Approach and Results—

Obese (
db
/
db
) male and their lean littermates were administered a cocktail of control adenovirus or adenoviral vectors encoding ABCG5 and ABCG8 (AdG5G8). Three days after viral administration, measures of lipid and glucose homeostasis were determined, and tissues were collected for biochemical analyses. AdG5G8 increased biliary cholesterol and fecal sterol elimination. Fasting glucose and triglycerides declined, and glucose tolerance improved in obese mice expressing G5G8 compared with mice receiving control adenovirus. These changes were associated with a reduction in phosphorylated eukaryotic initiation factor 2α and c-Jun N-terminal kinase in liver, suggesting alleviation of endoplasmic reticulum stress. Phosphorylated insulin receptor and protein kinase B were increased, indicating restored hepatic insulin signaling. However, there was no reduction in hepatic triglycerides after the 3-day treatment period.

Conclusions—

Accelerating biliary cholesterol secretion restores glycemic control and reduces plasma triglycerides in obese
db
/
db
mice.
Modeling of Arrhythmogenic Right Ventricular Cardiomyopathy With Human Induced Pluripotent Stem Cells
Authors: Caspi Oren , Huber Irit , Gepstein Amira , Arbel Gil , Maizels Leonid , Boulos Monther , Gepstein Lior 
Published: November 2013

Background—
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disorder resulting from desmosomal protein mutations. ARVC is characterized pathologically by fibrofatty infiltration and clinically by arrhythmias and sudden cardiac death. We aimed to establish a patient-/disease-specific human induced pluripotent stem cell (hiPSC) model of ARVC.

Methods and Results—

Dermal fibroblasts were obtained from 2 patients with ARVC with plakophilin-2 (
PKP2
) mutations, reprogrammed to generate hiPSCs, coaxed to differentiate into cardiomyocytes (CMs), and then compared with healthy control hiPSC-derived CMs (hiPSC-CMs). Real-time polymerase chain reaction showed a significant decrease in the expression of
PKP2
in the ARVC-hiPSC-CMs. Immunostainings revealed reduced densities of PKP2, the associated desmosomal protein plakoglobin, and the gap-junction protein connexin-43. Electrophysiological assessment demonstrated prolonged field potential rise time in the ARVC-hiPSC-CMs. Transmission electron microscopy identified widened and distorted desmosomes in the ARVC-hiPSC-CMs. Clusters of lipid droplets were identified in the ARVC-CMs that displayed the more severe desmosomal pathology. This finding was associated with upregulation of the proadipogenic transcription factor peroxisome proliferator-activated receptor-γ. Exposure of the cells to apidogenic stimuli augmented desmosomal distortion and lipid accumulation. The latter phenomenon was prevented by application of a specific inhibitor of glycogen synthase kinase 3β (6-bromoindirubin-3'-oxime).

Conclusions—
This study highlights the unique potential of the hiPSC technology for modeling inherited cardiac disorders in general and ARVC specifically. The hiPSC-CMs were demonstrated to recapitulate the ARVC phenotype in the dish, provide mechanistic insights into early disease pathogenesis, and provide a unique platform for drug discovery and testing in this disorder.
Role of Extracellular RNA in Atherosclerotic Plaque Formation in Mice
Authors: Simsekyilmaz Sakine , Cabrera-Fuentes Hector A. , Meiler Svenja , Kostin Sawa , Baumer Yvonne , Liehn Elisa A. , Weber Christian , Boisvert William A. , Preissner Klaus T. , Zernecke Alma 
Published: November 2013

Background—
Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Extracellular RNA (eRNA) has recently been implicated to become enriched at sites of tissue damage and to act as a proinflammatory mediator. Here, we addressed the role of eRNA in high-fat diet–induced atherosclerosis and neointima formation after injury in atherosclerosis-prone mice.

Methods and Results—

The presence of eRNA was revealed in atherosclerotic lesions from high-fat diet–fed low-density lipoprotein receptor–deficient (
Ldlr
−/−
) mice in a time-progressive fashion. RNase activity in plasma increased within the first 2 weeks (44±9 versus 70±7 mU/mg protein;
P
=0.0012), followed by a decrease to levels below baseline after 4 weeks of high-fat diet (44±9 versus 12±2 mU/mg protein;
P
<0.0001). Exposure of bone marrow–derived macrophages to eRNA resulted in a concentration-dependent upregulation of the proinflammatory mediators tumor necrosis factor-α, arginase-2, interleukin-1β, interleukin-6, and interferon-γ. In a model of accelerated atherosclerosis after arterial injury in apolipoprotein E–deficient (
ApoE

−/−

) mice, treatment with RNase1 diminished the increased plasma level of eRNA evidenced after injury. Likewise, RNase1 administration reduced neointima formation in comparison with vehicle-treated
ApoE

−/−

controls (25.0±6.2 versus 46.9±6.9×10
3
μm
2
,
P
=0.0339) and was associated with a significant decrease in plaque macrophage content. Functionally, RNase1 treatment impaired monocyte arrest on activated smooth muscle cells under flow conditions in vitro and inhibited leukocyte recruitment to injured carotid arteries in vivo.

Conclusions—
Because eRNA is associated with atherosclerotic lesions and contributes to inflammation-dependent plaque progression in atherosclerosis-prone mice, its targeting with RNase1 may serve as a new treatment option against atherosclerosis.
Endothelial Fate Mapping in Mice With Pulmonary Hypertension
Authors: Qiao Lina , Nishimura Toshihiko , Shi Lingfang , Sessions Dane , Thrasher Ama , Trudell James R. , Berry Gerald J. , Pearl Ronald G. , Kao Peter N. 
Published: November 2013

Background—
Pulmonary endothelial injury triggers a reparative program, which in susceptible individuals is characterized by neointima formation, vascular narrowing, and the development of pulmonary arterial hypertension. The neointimal cells in human pathological plexiform lesions frequently coexpress smooth muscle α-actin and the endothelial von Willebrand antigen, creating a question about their cellular lineage of origin.

Methods and Results—

Experimental pulmonary hypertension with neointima formation develops in C57Bl/6 mice subjected to left pneumonectomy followed 1 week later by jugular vein injection of monocrotaline pyrrole (20 μg/μL and 1 μL/g; group P/MCTP). Compared with the group vehicle, by day 35, group P/MCTP developed higher right ventricular systolic pressure (54±5 versus 25±2 mm Hg;
P
<0.01) and right ventricular hypertrophy (0.58±0.16 versus 0.26±0.05;
P
<0.01). Transgenic vascular endothelial-cadherin Cre recombinase or Tie-2 Cre mice were intercrossed with mTomato/mGreen fluorescent protein double-fluorescent Cre reporter mice to achieve endothelial genetic lineage marking with membrane-targeted green fluorescent protein. In control mice, few endothelial lineage–marked cells lining the lumen of small pulmonary arteries demonstrate expression of smooth muscle α-actin. Concurrent with the development of pulmonary hypertension, endothelial lineage–marked cells are prominent in the neointima and exhibit expression of smooth muscle α-actin and smooth muscle myosin heavy chain. Human pulmonary arterial hypertension neointimal lesions contain cells that coexpress endothelial CD31 or von Willebrand antigen and smooth muscle α-actin.

Conclusion—
Neointimal cells in pulmonary hypertension include contributions from the endothelial genetic lineage with induced expression of smooth muscle α-actin and smooth muscle myosin heavy chain.
Syncope in High-Risk Cardiomyopathy Patients With Implantable Defibrillators: Frequency, Risk Factors, Mechanisms, and Association With Mortality
Authors: Ruwald Martin H. , Okumura Ken , Kimura Takeshi , Aonuma Kazutaka , Shoda Morio , Kutyifa Valentina , Ruwald Anne-Christine H. , McNitt Scott , Zareba Wojciech , Moss Arthur J. 
Published: November 2013

Background—
There is a relative paucity of studies investigating the mechanisms of syncope among heart failure patients with implantable cardioverter-defibrillators, and it is controversial whether nonarrhythmogenic syncope is associated with increased mortality.

Methods and Results—

The Multicenter Automatic Defibrillator Implantation Trial–Reduce Inappropriate Therapy (MADIT-RIT) randomized 1500 patients to 3 different implantable cardioverter-defibrillator programming arms: (1) Conventional programming with therapy for ventricular tachycardia ≥170 bpm; (2) high-rate cutoff with therapy for ventricular tachycardia ≥200 bpm and a monitoring zone at 170 to 199 bpm, and (3) prolonged 60-second delay with a monitoring zone before therapy. Syncope was a prespecified safety end point that was adjudicated independently. Multivariable Cox models were used to identify risk factors associated with syncope and to analyze subsequent risk of mortality. During follow-up, 64 of 1500 patients (4.3%) had syncope. The incidence of syncope was similar across the 3 treatment arms. Prognostic factors for all-cause syncope included the presence of ischemic cardiomyopathy (hazard ratio [HR], 2.48; 95% confidence interval [CI], 1.42–4.34;
P
=0.002), previous ventricular arrhythmias (HR, 2.99; 95% CI, 1.18–7.59;
P
=0.021), left ventricular ejection fraction ≤25% (HR, 1.65; 95% CI, 0.98–2.77;
P
=0.059), and younger age (by 10 years; HR, 1.25; 95% CI, 1.00–1.52;
P
=0.046). Syncope was associated with increased risk of death regardless of its cause (arrhythmogenic syncope: HR, 4.51; 95% CI, 1.39–14.64,
P
=0.012; nonarrhythmogenic syncope: HR, 2.97; 95% CI, 1.07–8.28,
P
=0.038).

Conclusions—
Innovative programming of implantable cardioverter-defibrillators with therapy for ventricular tachycardia ≥200 bpm or a long delay is not associated with increased risk of arrhythmogenic or all-cause syncope, and syncope caused by slow ventricular tachycardias (<200 bpm) is a rare event. The clinical risk factors associated with syncope are related to increased cardiovascular risk profile, and syncope is associated with increased mortality irrespective of the cause.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00947310.
Remote Ischemic Perconditioning as an Adjunct Therapy to Thrombolysis in Patients With Acute Ischemic Stroke
Authors: Hougaard Kristina Dupont , Hjort Niels , Zeidler Dora , Sørensen Leif , Nørgaard Anne , Hansen Troels Martin , von Weitzel-Mudersbach Paul , Simonsen Claus Z. , Damgaard Dorte , Gottrup Hanne , Svendsen Kristina , Rasmussen Peter Vestergaard , Ribe Lars R. , Mikkelsen Irene K. , Nagenthiraja Kartheban , Cho Tae-Hee , Redington Andrew N. , Bøtker Hans Erik , Østergaard Leif , Mouridsen Kim , Andersen Grethe 
Published: November 2013

Background and Purpose—
Remote ischemic preconditioning is neuroprotective in models of acute cerebral ischemia. We tested the effect of prehospital rPerC as an adjunct to treatment with intravenous alteplase in patients with acute ischemic stroke.

Methods—
Open-label blinded outcome proof-of-concept study of prehospital, paramedic-administered rPerC at a 1:1 ratio in consecutive patients with suspected acute stroke. After neurological examination and MRI, patients with verified stroke receiving alteplase treatment were included and received MRI at 24 hours and 1 month and clinical re-examination after 3 months. The primary end point was penumbral salvage, defined as the volume of the perfusion–diffusion mismatch not progressing to infarction after 1 month.

Results—

Four hundred forty-three patients were randomized after provisional consent, 247 received rPerC and 196 received standard treatment. Patients with a nonstroke diagnosis (n=105) were excluded from further examinations. The remaining patients had transient ischemic attack (n=58), acute ischemic stroke (n=240), or hemorrhagic stroke (n=37). Transient ischemic attack was more frequent (
P
=0.006), and National Institutes of Health Stroke Scale score on admission was lower (
P
=0.016) in the intervention group compared with controls. Penumbral salvage, final infarct size at 1 month, infarct growth between baseline and 1 month, and clinical outcome after 3 months did not differ among groups. After adjustment for baseline perfusion and diffusion lesion severity, voxelwise analysis showed that rPerC reduced tissue risk of infarction (
P
=0.0003).

Conclusions—
Although the overall results were neutral, a tissue survival analysis suggests that prehospital rPerC may have immediate neuroprotective effects. Future clinical trials should take such immediate effects, and their duration, into account.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00975962.
Cerebral Vasomotor Reactivity and Risk of Mortality
Authors: Portegies Marileen L.P. , de Bruijn Renée F.A.G. , Hofman Albert , Koudstaal Peter J. , Ikram M. Arfan 
Published: November 2013

Background and Purpose—
Accumulating vascular pathology in cerebral arteries leads to impaired cerebral vasomotor reactivity. In turn, impaired cerebral vasomotor reactivity is a risk factor for stroke in clinical populations. It remains unclear whether impaired cerebral vasomotor reactivity also reflects more systemic vascular damage. We investigated whether cerebral vasomotor reactivity is associated with the risk of mortality, focusing particularly on cardiovascular mortality independent from stroke.

Methods—
Between 1997 and 1999, 1695 participants from the Rotterdam Study underwent cerebral vasomotor reactivity measurements using transcranial Doppler. Follow-up was complete until January 1, 2011. We assessed the associations between cerebral vasomotor reactivity and mortality using Cox proportional hazards models, adjusting for age, sex, and blood pressure changes and subsequently for cardiovascular risk factors. We additionally censored for incident stroke.

Results—
During 17 004 person-years, 557 participants died, of whom 181 due to a cardiovascular cause. In the fully adjusted model, the hazard ratio per SD decrease in vasomotor reactivity was 1.10 (95% confidence interval [CI], 1.01–1.19) for all-cause mortality, 1.09 (95% CI, 0.94–1.26) for cardiovascular mortality, and 1.10 (95% CI, 0.99–1.21) for noncardiovascular mortality. These associations remained unchanged after censoring for incident stroke.

Conclusions—
We found that lower cerebral vasomotor reactivity is associated with an increased risk of death. Incident stroke does not affect this association, suggesting that a lower cerebral vasomotor reactivity reflects a generally impaired vascular system.
Incidence of Oral Anticoagulant–Associated Intracerebral Hemorrhage in the Netherlands
Authors: Schols Angel M.R. , Schreuder Floris H.B.M. , van Raak Elisabeth P.M. , Schreuder Tobien H.C.M.L. , Rooyer Fergus A. , van Oostenbrugge Robert J. , Staals Julie 
Published: November 2013

Background and Purpose—
The aim of this study was to estimate the annual adult incidence and risk of intracerebral hemorrhage (ICH) and oral anticoagulant–associated ICH (OAC-ICH) in the Netherlands.

Methods—
We retrospectively selected all consecutive adult patients with a nontraumatic ICH seen in 1 of 3 hospitals in the region South-Limburg, the Netherlands, from 2007 to 2009. Crude incidences were age-adjusted to Dutch and European population.

Results—
We identified 652 ICH cases, of which 168 (25.8%) were OAC associated. The adult Dutch age-adjusted annual incidence of ICH and OAC-ICH was 34.8 (95% confidence interval, 32.0–37.8) and 8.7 (95% confidence interval, 7.3–10.3) per 100 000 person-years, respectively. The absolute risk of OAC-ICH was estimated at 0.46% per patient-year of OAC treatment.

Conclusions—
The annual incidences of ICH and OAC-ICH are relatively high in the Netherlands when compared with international literature.
Therapeutic Hypothermia After Recanalization in Patients With Acute Ischemic Stroke
Authors: Hong Ji Man , Lee Jin Soo , Song Hee-Jung , Jeong Hye Seon , Choi Huimahn Alex , Lee Kiwon 
Published: November 2013

Background and Purpose—
Therapeutic hypothermia improves outcomes in experimental stroke models, especially after ischemia-reperfusion injury. We investigated the clinical and radiological effects of therapeutic hypothermia in acute ischemic stroke patients after recanalization.

Methods—
A prospective cohort study at 2 stroke centers was performed. We enrolled patients with acute ischemic stroke in the anterior circulation with an initial National Institutes of Health Stroke Scale ≥10 who had successful recanalization (≥thrombolysis in cerebral ischemia, 2b). Patients at center A underwent a mild hypothermia (34.5°C) protocol, which included mechanical ventilation, and 48-hour hypothermia and 48-hour rewarming. Patients at center B were treated according to the guidelines without hypothermia. Cerebral edema, hemorrhagic transformation, good outcome (3-month modified Rankin Scale, ≤2), mortality, and safety profiles were compared. Potential variables at baseline and during the therapy were analyzed to evaluate for independent predictors of good outcome.

Results—

The hypothermia group (n=39) had less cerebral edema (
P
=0.001), hemorrhagic transformation (
P
=0.016), and better outcome (
P
=0.017) compared with the normothermia group (n=36). Mortality, hemicraniectomy rate, and medical complications were not statistically different. After adjustment for potential confounders, therapeutic hypothermia (odds ratio, 3.0; 95% confidence interval, 1.0–8.9;
P
=0.047) and distal occlusion (odds ratio, 7.3; 95% confidence interval; 1.3–40.3;
P
=0.022) were the independent predictors for good outcome. Absence of cerebral edema (odds ratio, 5.4; 95% confidence interval, 1.6–18.2;
P
=0.006) and no medical complications (odds ratio, 9.3; 95% confidence interval, 2.2–39.9;
P
=0.003) were also independent predictors for good outcome during the therapy.

Conclusions—
In patients with ischemic stroke, after successful recanalization, therapeutic hypothermia may reduce risk of cerebral edema and hemorrhagic transformation, and lead to improved clinical outcomes.