bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Induction of Yes-Associated Protein Expression After Arterial Injury Is Crucial for Smooth Muscle Phenotypic Modulation and Neointima Formation
Authors: Wang Xiaobo , Hu Guoqing , Gao Xiangwei , Wang Yong , Zhang Wei , Harmon Erin Yund , Zhi Xu , Xu Zhengping , Lennartz Michelle R. , Barroso Margarida , Trebak Mohamed , Chen Ceshi , Zhou Jiliang 
Published: August 2012

Objective—
Abnormal proliferation and migration of vascular smooth muscle cells (SMCs) are the key events in the progression of neointima formation in response to vascular injury. The goal of this study is to investigate the functional role of a potent oncogene yes-associated protein (YAP) in SM phenotypic modulation in vitro and in vivo.

Methods and Results—
In vitro cell culture and in vivo in both mouse and rat arterial injury models YAP expression is significantly induced and correlated with the vascular SMC synthetic phenotype. Overexpression of YAP promotes SMC migration and proliferation while attenuating SM contractile gene expression. Conversely, knocking down endogenous YAP in SMCs upregulates SM gene expression but attenuates SMC proliferation and migration. Consistent with this, knocking down YAP expression in a rat carotid balloon injury model and genetic deletion of YAP, specifically, in vascular SMCs in mouse after carotid artery ligation injury attenuates injury-induced SM phenotypic switch and neointima formation.

Conclusion—
YAP plays a novel integrative role in SM phenotypic modulation by inhibiting SM-specific gene expression while promoting SM proliferation and migration in vitro and in vivo. Blocking the induction of YAP would be a potential therapeutic approach for ameliorating vascular occlusive diseases.
Facio-Genital Dysplasia-5 Regulates Matrix Adhesion and Survival of Human Endothelial Cells
Authors: Nakhaei-Nejad Maryam , Haddad George , Zhang Qiu-Xia , Murray Allan G. 
Published: August 2012

Objective—
The function of the endothelial cell (EC)-enriched Rho family guanine nucleotide exchange factor, facio-genital dysplasia-5 (FGD5), is poorly understood. We sought to determine whether FGD5 regulates endothelial cytoskeletal reorganization and angiogenesis.

Methods and Results—
We observed that FGD5 is expressed in primary human EC isolated from sites across the vasculature. Inhibition of FGD5 expression using RNA interference decreased the protein by ≈70%. In 3-dimensional vascular endothelial growth factor–stimulated angiogenesis in vitro, FGD5-deficient endothelial sprout protrusion was markedly blunted versus nonsilenced controls. FGD5 knockdown impaired adhesion to fibronectin and collagen IV and remodeling of matrix adhesion complexes. Similarly, monolayer electric impedance was decreased, and impedance increased at a slower rate after seeding FGD5-deficient cells versus controls, reflecting decreased EC spreading. Further, FGD5 plays a role in cell survival, because expression of cleaved caspase-3 was increased in FGD5-deficient EC after loss of cell−matrix contacts, and proapoptotic tumor necrosis factor-α stimulation elicited EC with subdiploid DNA content among FGD5-deficient EC. Mechanistically, the phosphatidylinositol 3-kinase/Akt pathway that regulates both adhesive and survival signal transduction pathways requires FGD5. Vascular endothelial growth factor–stimulated Akt phosphorylation and downstream forkhead box protein-O1 inactivation is inhibited by FGD5 loss.

Conclusion—
FGD5 regulates endothelial adhesion, survival, and angiogenesis by modulating phosphatidylinositol 3-kinase signaling.
Decreased Krev Interaction–Trapped 1 Expression Leads to Increased Vascular Permeability and Modifies Inflammatory Responses In Vivo
Authors: Corr Maripat , Lerman Irina , Keubel Julia M. , Ronacher Lisa , Misra Ravi , Lund Frances , Sarelius Ingrid H. , Glading Angela J. 
Published: August 2012

Objective—
The regulation of vascular permeability, leukocyte trafficking, and the integrity of endothelial cell–cell contacts are closely linked by a complex mechanism of interregulation. Here, we investigate the role of Krev interaction–trapped 1 (KRIT1), an adherens junction accessory protein required for cell–cell junction stability, in regulating these vascular functions.

Methods and Results—

Krit1

+/−

mice exhibited an enhanced edematous response to the complex inflammatory stimuli found in the passive K/BxN model of inflammatory arthritis and the murine air pouch model, yet leukocyte infiltration was unchanged. Correspondingly, reduced KRIT1 expression increased baseline arteriole and venule permeability 2-fold over that of wild-type littermates, as measured by intravital microscopy of the intact cremaster muscle vascular network, but this increase was not accompanied by increased leukocyte extravasation or activation. Direct stimulation with tumor necrosis factor-α induced increased permeability in wild-type mice, but surprisingly no increase over baseline levels was observed in
Krit1

+/−

mice, despite extensive leukocyte activation. Finally, adoptive transfer of
Krit1

+/−

bone marrow failed to increase permeability in wild-type mice. However, reduced expression of KRIT1 in the hematopoietic lineage dampened the differences observed in baseline permeability.

Conclusion—
Taken together, our data indicate an integral role for KRIT1 in microvessel homeostasis and the vascular response to inflammation.
Inverse Solution Mapping of Epicardial Potentials
Authors: Sapp John L. , Dawoud Fady , Clements John C. , Horáček B. Milan 
Published: August 2012

Background—
Catheter ablation of ventricular tachycardia (VT) is still one of the most challenging procedures in cardiac electrophysiology, limited, in part, by unmappable arrhythmias that are nonsustained or poorly tolerated. Calculation of the inverse solution from body surface potential mapping (sometimes known as ECG imaging) has shown tremendous promise and can rapidly map these arrhythmias, but we lack quantitative assessment of its accuracy in humans. We compared inverse solution mapping with computed tomography–registered electroanatomic epicardial contact catheter mapping to study the resolution of this technique, the influence of myocardial scar, and the ability to map VT.

Methods and Results—

For 4 patients undergoing epicardial catheter mapping and ablation of VT, 120-lead body surface potential mappings were obtained during implantable defibrillator pacing, catheter pacing from 79 epicardial sites, and induced VT. Inverse epicardial electrograms computed using individualized torso/epicardial surface geometries extracted from computed tomography images were compared with registered electroanatomic contact maps. The distance between estimated and actual epicardial pacing sites was 13±9 mm over normal myocardium with no stimulus-QRS delay but increased significantly over scar (
P
=0.013) or was close to scar (
P
=0.014). Contact maps during right ventricular pacing correlated closely to inverse solution isochrones. Maps of inverse epicardial potentials during 6 different induced VTs indicated areas of earliest activation, which correlated closely with clinically identified VT exit sites for 2 epicardial VTs.

Conclusions—
Inverse solution maps can identify sites of epicardial pacing with good accuracy, which diminishes over myocardial scar or over slowly conducting tissue. This approach can also identify epicardial VT exit sites and ventricular activation sequences.
Docosahexaenoic Acid, but Not Eicosapentaenoic Acid, Supplementation Reduces Vulnerability to Atrial Fibrillation
Authors: Ramadeen Andrew , Connelly Kim A. , Leong-Poi Howard , Hu Xudong , Fujii Hiroko , Laurent Gabriel , Domenichiello Anthony F. , Bazinet Richard P. , Dorian Paul 
Published: August 2012

Background—
The potential health benefits of ω-3 polyunsaturated fatty acids (PUFAs) usually are studied using a combination of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). This combination reduces vulnerability to experimentally induced atrial fibrillation (AF). It is unknown whether EPA and DHA have differential effects when taken alone. Using a model of pacing-induced atrial hemodynamic overload, we investigated the individual effects of EPA and DHA on vulnerability to AF and atrial remodeling.

Methods and Results—

Thirty-four dogs were randomized into 3 groups, all of which underwent simultaneous atrial and ventricular pacing at 220 beats per minute for 14 days. One group received purified DHA (≈1 g/d) orally for 21 days beginning 7 days before pacing began. Similarly, 1 group received ≈1 g/d purified EPA. In a third (control) group (No-PUFAs), 8 dogs received ≈1 g/d olive oil, and 12 were unsupplemented. Electrophysiological and echocardiographic measurements were taken at baseline and 21 days. Atrial tissue samples were collected at 21 days for histological and molecular analyses. Persistent AF inducibility was significantly reduced by DHA compared with No-PUFAs median [25–75 percentiles], 0% [0%–3%] for DHA versus 3.1% [2.2%–11%] for No-PUFAs;
P
=0.007) but not by EPA (3.4% [1.9%–8.9%]). DHA also reduced atrial fibrosis compared with No-PUFAs (11±6% versus 20±4%, respectively;
P
<0.05), whereas EPA did not (15±5%;
P
>0.05).

Conclusions—
DHA is more effective than EPA in attenuating AF vulnerability and atrial remodeling in structural remodeling–induced AF.
Assessing the Risk of Bleeding in Patients With Atrial Fibrillation
Authors: Lip Gregory Y. H. , Banerjee Amitava , Lagrenade Isabelle , Lane Deirdre A. , Taillandier Sophie , Fauchier Laurent 
Published: August 2012

Background—
Management decisions for thromboprophylaxis in atrial fibrillation need to balance the risk of stroke against serious hemorrhage. The objective of the present analysis is to compare the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65 years), Drugs/alcohol concomitantly (HAS-BLED) score against other older bleeding risk scores and the new Anticoagulation and Risk Factors in Atrial Fibrillation score in an atrial fibrillation cohort.

Methods and Results—
Patients diagnosed with nonvalvular atrial fibrillation in a 4-hospital institution between 2000 and 2010 were identified. Independent risk factors of bleeding were investigated using Cox regression. The predictive value of several bleeding risk schema was assessed using the c-statistic and net reclassification improvement. Oral anticoagulation use was highest in moderate-risk patients (59.8%) but only slightly more than high-risk (50.1%) and low-risk (46.4%) patients. Those at higher bleeding risk (HAS-BLED ≥3) were also at highest risk of stroke/thromboembolism or stroke/thromboembolism/death, as well as bleeding and all-cause mortality. On multivariable analysis, independent predictors of bleeding were age ≥75 years and age ≥65 years, alcohol excess, anemia, and heart failure. All risk scores had only modest predictive ability for bleeding, whether on vitamin K antagonist or not (c-statistic ≈0.6). When the HAS-BLED score was compared with other bleeding risk scores, the net reclassification improvement was significantly improved against all other scores tested.

Conclusions—
Current oral anticoagulation prescribing patterns would suggest that bleeding risk estimation by clinicians is poor and that oral anticoagulation prescribing does not reflect bleeding risk per se. The HAS-BLED score performs well in relation to predicting bleeding events compared with older bleeding scores and the Anticoagulation and Risk Factors in Atrial Fibrillation score, with significantly improved reclassification using HAS-BLED compared with all other bleeding risk scores tested.
Clinical and Histological Significance of Gadolinium Enhancement in Carotid Atherosclerotic Plaque
Authors: Millon Antoine , Boussel Loic , Brevet Marie , Mathevet Jean-Louis , Canet-Soulas Emmanuelle , Mory Cyril , Scoazec Jean-Yves , Douek Philippe 
Published: August 2012

Background and Purpose—
Although the ability of MRI to investigate carotid plaque composition is well established, the mechanism and the significance of plaque gadolinium (Gd) enhancement remain unknown. We evaluated clinical and histological significance of Gd enhancement of carotid plaque in patients undergoing endarterectomy for carotid stenosis.

Methods—
Sixty-nine patients scheduled for a carotid endarterectomy prospectively underwent a 3-T MRI. Carotid plaque enhancement was assessed on T1-weighted images performed before and 5 minutes after Gd injection. Enhancement was recorded according to its localization. Histological analysis was performed of the entire plaque and of the area with matched contrast enhancement on MR images.

Results—

Gd enhancement was observed in 59% patients. Three types of carotid plaques were identified depending on enhancement location (shoulder region, shoulder and fibrous cap, and central in the plaque). Fibrous cap rupture, intraplaque hemorrhage, and plaque Gd enhancement was significantly more frequent in symptomatic than in asymptomatic patients (
P
=0.043,
P
<0.0001, and
P
=0.034, respectively). After histological analysis, Gd enhancement was significantly associated with vulnerable plaque (American Heart Association VI,
P
=0.006), neovascularization (
P
<0.0001), macrophages (
P
=0.030), and loose fibrosis (
P
<0.0001). Prevalence of neovessels, macrophages, and loose fibrosis in the area of Gd enhancement was 97%, 87%, and 80%, respectively, and was different depending on the enhancement location in the plaque. Fibrous cap status and composition were different depending on the type of plaque.

Conclusions—
Gd enhancement of carotid plaque is associated with vulnerable plaque phenotypes and related to an inflammatory process.
Nonadditive Neuroprotection With Early Glutamate Receptor Blockade and Delayed Hypothermia After Asphyxia in Preterm Fetal Sheep
Authors: George Sherly A. , Barrett Robert D. , Bennet Laura , Mathai Sam , Jensen Ellen C. , Gunn Alistair J. 
Published: August 2012

Background and Purpose—

Hypothermia induced after perinatal hypoxia–ischemia is partially protective. This study examined whether early treatment with the noncompetitive N-methyl
-d-
aspartate receptor antagonist, dizocilpine, can augment neuroprotection with delayed hypothermia after severe asphyxia in preterm fetal sheep at 0.7 weeks gestation (equivalent to 28–32 weeks in humans).

Methods—
Fifty minutes after umbilical cord occlusion for 25 minutes, fetuses were randomized to either dizocilpine (2 mg/kg estimated fetal weight intravenously, then 0.07 mg/kg/h for 4 hours) and then after 5.5 hours to whole-body cooling to 3°C below baseline, or sham cooling, until 72 hours, and euthanized 7 days after umbilical cord occlusion.

Results—

Delayed hypothermia was associated with improved neuronal survival (
P
<0.02) and reduced microglia (
P
=0.004) and caspase-3-positive cells (
P
<0.01) compared with umbilical cord occlusion. Dizocilpine was associated with reduced microglia (
P
<0.05) but no effect on caspase-3 induction and improved survival only in CA1/2 (
P
<0.05) with no apparent additive effect with delayed hypothermia.

Conclusions—

Early N-methyl
-d-
aspartate blockade and a clinical regime of delayed whole-body hypothermia provide nonadditive neuroprotection in the preterm brain.
Analysis of cardiopulmonary bypass status in China: eight-year development trends
Authors: Zhao M , Wu B , Yang S , Long C 
Published: August 2012

Objective: To study the development of cardiopulmonary bypass (CPB) in the past 8 years and to come up with predictions and recommendations for the future in China. Methods: Domestic hospitals performing cardiovascular operations were supplied with questionnaires, annually (between 2003 and 2008), upon the number of on-pump and off-pump cardiovascular operations, oxygenators of different types and the number of extracorporeal membrane oxygenation (ECMO). All the hospitals in this study were divided into 8 grades, according to the number of cardiovascular operations. The market share of hospitals in each grade was analyzed. Results: The total anumber of cardiovascular operations was 170,547 in 2010, of which 136,753 were performed under CPB. The ratio of imported membrane oxygenators increased from 43.22% in 2003 to 59.75% in 2010, while bubble oxygenator composition decreased from 43.78% in 2003 to 14.59% in 2010. Forty-four hospitals carried out 206 cases of ECMO in 2010. There were 32 hospitals that performed cardiovascular operations of over 1,000 cases and their market share was 43%. There were 255 hospitals that performed cardiovascular operations in less than 50 cases and their market share was only 3%. Conclusions: CPB in China has gone through a rapid development in the past eight years. Medical resources for CPB should be concentrated and systematic training regulations should be established in the future.
Multi-hit ballistic impact on S-2 glass/SC15 thick-section composites: experiments
Authors: (Gama) Haque Bazle Z , Harrington Jessica L , Gillespie John W 
Published: August 2012

Multi-hit ballistic impact and damage behavior of thick-section composites are of interest to many military and aerospace applications. The effect of support spans on single-hit penetration resistance and the effect of relative distance between multiple impacts on the penetration resistance are the subject matter of the present investigation. In order to study the effect of support spans on penetration resistance, single-hit ballistic experiments are conducted on two plain-weave (PW) S-2 glass/SC15 composite laminates of thickness, 13.5 mm (22 layers, 22L) and 20.4 mm (33 layers, 33L), respectively at two different support span diameters, i.e. 102 mm and 203 mm. On the other hand, the effect of multiple impacts on penetration resistance has been investigated by impacting both the laminates (22L and 33L) at four additional radial shot locations (90 degrees apart) with a support span diameter of 203 mm. In both the impact scenarios, 0.50cal fragment simulating projectiles (0.50cal FSP) were used while the composite laminates were clamped between a cover and a support plate. In addition, the maximum dynamic deflection of the composite laminates were recorded using a thin aluminum witness plate at the rear end of the laminate, and the through-thickness ballistic damage of the composite laminates was investigated by sectioning through the impact centers, dying with an ink-alcohol solution, and taking optical photographs of the cross-sections. Results show that the single-hit ballistic limit velocity increases marginally with support span diameter investigated. The curvatures of the dynamic deflection profiles at the support edge suggest that the dynamic deflection was constrained by the smaller support span while the dynamic deflection was not constrained by the larger support span. There was no noticeable difference in the single-hit maximum dynamic deflection between the two laminate thicknesses as a function of impact velocity to ballistic limit velocity ratios. Single-hit through-thickness damage extended toward the edges of the larger support spans such that the subsequent multiple impacts were on partially damaged laminates; however, the pre-existing ballistic damage showed about 4.5% and 9.0% decrease in site specific multi-hit ballistic limit and energy, respectively.
Chromatin accessibility, p300, and histone acetylation define PML-RARα and AML1-ETO binding sites in acute myeloid leukemia
Authors: Saeed Sadia , Logie Colin , Francoijs Kees-Jan , Frigè Gianmaria , Romanenghi Mauro , Nielsen Fiona G. , Raats Lianne , Shahhoseini Maryam , Huynen Martijn , Altucci Lucia , Minucci Saverio , Martens Joost H. A. , Stunnenberg Hendrik G. 
Published: August 2012

Abstract
Chromatin accessibility plays a key role in regulating cell type specific gene expression during hematopoiesis but has also been suggested to be aberrantly regulated during leukemogenesis. To understand the leukemogenic chromatin signature, we analyzed acute promyelocytic leukemia, a subtype of leukemia characterized by the expression of RARα-fusion proteins, such as PML-RARα. We used nuclease accessibility sequencing in cell lines as well as patient blasts to identify accessible DNA elements and identified > 100 000 accessible regions in each case. Using ChIP-seq, we identified H2A.Z as a histone modification generally associated with these accessible regions, whereas unsupervised clustering analysis of other chromatin features, including DNA methylation, H2A.Zac, H3ac, H3K9me3, H3K27me3, and the regulatory factor p300, distinguished 6 distinct clusters of accessible sites, each with a characteristic functional makeup. Of these, PML-RARα binding was found specifically at accessible chromatin regions characterized by p300 binding and hypoacetylated histones. Identifying regions with a similar epigenetic make up in t(8;21) acute myeloid leukemia (AML) cells, another subtype of AMLs, revealed that these regions are occupied by the oncofusion protein AML1-ETO. Together, our results suggest that oncofusion proteins localize to accessible regions and that chromatin accessibility together with p300 binding and histone acetylation characterize AML1-ETO and PML-RARα binding sites.
HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk
Authors: Urayama Kevin Y. , Chokkalingam Anand P. , Metayer Catherine , Ma Xiaomei , Selvin Steve , Barcellos Lisa F. , Wiemels Joseph L. , Wiencke John K. , Taylor Malcolm , Brennan Paul , Dahl Gary V. , Moonsamy Priscilla , Erlich Henry A. , Trachtenberg Elizabeth , Buffler Patricia A. 
Published: August 2012

Abstract
The human leukocyte antigen (HLA) genes are candidate genetic susceptibility loci for childhood acute lymphoblastic leukemia (ALL). We examined the effect of HLA-DP genetic variation on risk and evaluated its potential interaction with 4 proxies for early immune modulation, including measures of infectious exposures in infancy (presence of older siblings, daycare attendance, ear infections) and breastfeeding. A total of 585 ALL cases and 848 controls were genotyped at the HLA-DPA1 and DPB1 loci. Because of potential heterogeneity in effect by race/ethnicity, we included only non-Hispanic white (47%) and Hispanic (53%) children and considered these 2 groups separately in the analysis. Logistic regression analyses showed an increased risk of ALL associated with HLA-DPB1*01:01 (odds ratio [OR] = 1.43, 95% CI, 1.01-2.04) with no heterogeneity by Hispanic ethnicity (P = .969). Analyses of DPB1 supertypes showed a marked childhood ALL association with DP1, particularly for high-hyperdiploid ALL (OR = 1.83; 95% CI, 1.20-2.78). Evidence of interaction was found between DP1 and older sibling (P = .036), and between DP1 and breastfeeding (P = .094), with both showing statistically significant DP1 associations within the lower exposure categories only. These findings support an immune mechanism in the etiology of childhood ALL involving the HLA-DPB1 gene in the context of an insufficiently modulated immune system.