bluuebunny/crossref_metadata_2025_split huggingface dataset:
miRNA Biomarkers in Cyst Fluid Augment the Diagnosis and Management of Pancreatic Cysts
Authors: Matthaei Hanno , Wylie Dennis , Lloyd Maura B. , Dal Molin Marco , Kemppainen Jon , Mayo Skye C. , Wolfgang Christopher L. , Schulick Richard D. , Langfield Laura , Andruss Bernard F. , Adai Alex T. , Hruban Ralph H. , Szafranska-Schwarzbach Anna E. , Maitra Anirban 
Published: June 2012

AbstractPurpose: The diagnosis of pancreatic cystic lesions has increased dramatically. Most are benign, whereas some, such as intraductal papillary mucinous neoplasms (IPMN), represent precursors of pancreatic adenocarcinoma. Therapeutic stratification of IPMNs is challenging without precise information on dysplasia grade and presence of invasion. We assessed the diagnostic benefit of using miRNAs as biomarkers in pancreatic cyst fluid, focusing on IPMNs because of their frequency and malignant potential.Experimental Design: RNA was extracted from 55 microdissected formalin-fixed, paraffin-embedded (FFPE) IPMN specimens, and 65 cyst fluid specimens aspirated following surgical resection. Expression of 750 miRNAs was evaluated with TaqMan miRNA Arrays using 22 FFPE and 15 cyst fluid specimens. Differential expression of selected miRNA candidates was validated in 33 FFPE and 50 cyst fluid specimens using TaqMan miRNA Assays.Results: We identified 26 and 37 candidate miRNAs that distinguish low-grade from high-grade IPMNs using FFPE and cyst fluid specimens, respectively. A subset of 18 miRNAs, selected from FFPE and cyst fluid data, separated high-grade IPMNs from low-grade IPMNs, serous cystadenomas (SCA) and uncommon cysts, such as solid pseudopapillary neoplasms (SPN) and cystic pancreatic neuroendocrine tumors (PanNET). A logistic regression model using nine miRNAs allowed prediction of cyst pathology implying resection (high-grade IPMNs, PanNETs, and SPNs) versus conservative management (low-grade IPMNs, SCAs), with a sensitivity of 89%, a specificity of 100%, and area under the curve of 1.Conclusions: We found candidate miRNAs that helped identify patients with high-grade IPMN and exclude nonmucinous cysts. These classifiers will require validation in a prospective setting to ultimately confirm their clinical usefulness. Clin Cancer Res; 18(17); 4713–24. ©2012 AACR.
Deregulation of a Hox Protein Regulatory Network Spanning Prostate Cancer Initiation and Progression
Authors: Chen James L. , Li Jianrong , Kiriluk Kyle J. , Rosen Alex M. , Paner Gladell P. , Antic Tatjana , Lussier Yves A. , Vander Griend Donald J. 
Published: June 2012

AbstractPurpose: The aberrant activity of developmental pathways in prostate cancer may provide significant insight into predicting tumor initiation and progression, as well as identifying novel therapeutic targets. To this end, despite shared androgen-dependence and functional similarities to the prostate gland, seminal vesicle cancer is exceptionally rare.Experimental Design: We conducted genomic pathway analyses comparing patient-matched normal prostate and seminal vesicle epithelial cells to identify novel pathways for tumor initiation and progression. Derived gene expression profiles were grouped into cancer biomodules using a protein–protein network algorithm to analyze their relationship to known oncogenes. Each resultant biomodule was assayed for its prognostic ability against publically available prostate cancer patient gene array datasets.Results: Analyses show that the embryonic developmental biomodule containing four homeobox gene family members (Meis1, Meis2, Pbx1, and HoxA9) detects a survival difference in a set of watchful-waiting patients (n = 172, P = 0.05), identify men who are more likely to recur biochemically postprostatectomy (n = 78, P = 0.02), correlate with Gleason score (r = 0.98, P = 0.02), and distinguish between normal prostate, primary tumor, and metastatic disease. In contrast to other cancer types, Meis1, Meis2, and Pbx1 expression is decreased in poor-prognosis tumors, implying that they function as tumor suppressor genes for prostate cancer. Immunohistochemical staining documents nuclear basal-epithelial and stromal Meis2 staining, with loss of Meis2 expression in prostate tumors.Conclusion: These data implicate deregulation of the Hox protein cofactors Meis1, Meis2, and Pbx1 as serving a critical function to suppress prostate cancer initiation and progression. Clin Cancer Res; 18(16); 4291–302. ©2012 AACR.
Genome-Wide Somatic Copy Number Alterations in Low-Grade PanINs and IPMNs from Individuals with a Family History of Pancreatic Cancer
Authors: Hong Seung-Mo , Vincent Audrey , Kanda Mitsuro , Leclerc Julie , Omura Noriyuki , Borges Michael , Klein Alison P. , Canto Marcia Irene , Hruban Ralph H. , Goggins Michael 
Published: June 2012

AbstractPurpose: Characterizing the earliest chromosomal alterations of pancreatic precursor neoplasms from individuals with a familial aggregation of pancreatic cancer may provide clues as to the loci of pancreatic cancer susceptibility genes.Experimental Design: We used Illumina 370/660K SNP arrays to conduct genome-wide copy number analysis in 60 benign neoplasms [58 mostly low-grade pancreatic intraepithelial neoplasias (PanIN) and intraductal papillary mucinous neoplasms (IPMN) and two pancreatic neuroendocrine tumors (PNET)] and matched normal tissues from 16 individuals with a family history of pancreatic cancer. PanINs and IPMNs were analyzed for KRAS codon 12/13 mutations.Results: Of 40 benign neoplasms with adequate SNP calls and allele ratios, somatic chromosomal copy number changes were identifiable in only nine lesions, including eight of the 38 PanIN/IPMNs (two of which had identical alterations) and one of the two PNETs. Only two precursor lesions had more than one somatic copy number alteration. In contrast, the overwhelming majority (∼95%) of PanINs harbored KRAS mutations. The chromosomal alterations identified included nine chromosomal arms affected by chromosomal loss and two by chromosomal gain. Copy number loss spanning 9p21.3 was identified in three precursor lesions; two precursors had chromosomal losses affecting 6q and 17p.Conclusions: Low- and intermediate-grade PanINs and IPMNs from patients with a family history of pancreatic cancer harbor few if any somatic chromosomal alterations. The absence of a locus of recurrent chromosomal loss in most low-grade pancreatic cancer precursor lesions supports the hypothesis that there is no one tumor suppressor gene locus consistently involved in initiating familial pancreatic neoplasia. Clin Cancer Res; 18(16); 4303–12. ©2012 AACR.
Liver X Receptor Activation Reduces Angiogenesis by Impairing Lipid Raft Localization and Signaling of Vascular Endothelial Growth Factor Receptor-2
Authors: Noghero Alessio , Perino Alessia , Seano Giorgio , Saglio Elisa , Sasso Giuseppe Lo , Veglio Franco , Primo Luca , Hirsch Emilio , Bussolino Federico , Morello Fulvio 
Published: June 2012

Objective—
Liver X receptors (LXRα, LXRβ) are master regulators of cholesterol homeostasis. In the endothelium, perturbations of cell cholesterol have an impact on fundamental processes. We, therefore, assessed the effects of LXR activation on endothelial functions related to angiogenesis in vitro and in vivo.

Methods and Results—

LXR agonists (T0901317, GW3965) blunted migration, tubulogenesis, and proliferation of human umbilical vein endothelial cells. By affecting endothelial cholesterol homeostasis, LXR activation impaired the compartmentation of vascular endothelial growth factor receptor-2 in lipid rafts/caveolae and led to defective phosphorylation and downstream signaling of vascular endothelial growth factor receptor-2 upon vascular endothelial growth factor-A stimulation. Consistently, the antiangiogenic actions of LXR agonists could be prevented by coadministration of exogenous cholesterol. LXR agonists reduced endothelial sprouting from wild-type but not from LXRα
−/−
/LXRβ
−/−
knockout aortas and blunted the vascularization of implanted angioreactors in vivo. Furthermore, T0901317 reduced the growth of Lewis lung carcinoma grafts in mice by impairing angiogenesis.

Conclusion—
Pharmacological activation of endothelial LXRs reduces angiogenesis by restraining cholesterol-dependent vascular endothelial growth factor receptor-2 compartmentation and signaling. Thus, administration of LXR agonists could exert therapeutic effects in pathological conditions characterized by uncontrolled angiogenesis.
Crosstalk Between Reticular Adherens Junctions and Platelet Endothelial Cell Adhesion Molecule-1 Regulates Endothelial Barrier Function
Authors: Fernández-Martín Laura , Marcos-Ramiro Beatriz , Bigarella Carolina L. , Graupera Mariona , Cain Robert J. , Reglero-Real Natalia , Jiménez Anaïs , Cernuda-Morollón Eva , Correas Isabel , Cox Susan , Ridley Anne J. , Millán Jaime 
Published: June 2012

Objective—
Endothelial cells provide a barrier between the blood and tissues, which is reduced during inflammation to allow selective passage of molecules and cells. Adherens junctions (AJ) play a central role in regulating this barrier. We aim to investigate the role of a distinctive 3-dimensional reticular network of AJ found in the endothelium.

Methods and Results—
In endothelial AJ, vascular endothelial-cadherin recruits the cytoplasmic proteins β-catenin and p120-catenin. β-catenin binds to α-catenin, which links AJ to actin filaments. AJ are usually described as linear structures along the actin-rich intercellular contacts. Here, we show that these AJ components can also be organized in reticular domains that contain low levels of actin. Reticular AJ are localized in areas where neighboring cells overlap and encompass the cell adhesion receptor platelet endothelial cell adhesion molecule-1 (PECAM-1). Superresolution microscopy revealed that PECAM-1 forms discrete structures distinct from and distributed along AJ, within the voids of reticular domains. Inflammatory tumor necrosis factor-α increases permeability by mechanisms that are independent of actomyosin-mediated tension and remain incompletely understood. Reticular AJ, but not actin-rich linear AJ, were disorganized by tumor necrosis factor-α. This correlated with PECAM-1 dispersal from cell borders. PECAM-1 inhibition with blocking antibodies or small interfering RNA specifically disrupted reticular AJ, leaving linear AJ intact. This disruption recapitulated typical tumor necrosis factor-α–induced alterations of barrier function, including increased β-catenin phosphorylation, without altering the actomyosin cytoskeleton.

Conclusion—
We propose that reticular AJ act coordinately with PECAM-1 to maintain endothelial barrier function in regions of low actomyosin-mediated tension. Selective disruption of reticular AJ contributes to permeability increase in response to tumor necrosis factor-α.
Molecular Imaging of Vascular Endothelial Growth Factor Receptors in Graft Arteriosclerosis
Authors: Zhang Jiasheng , Razavian Mahmoud , Tavakoli Sina , Nie Lei , Tellides George , Backer Joseph M. , Backer Marina V. , Bender Jeffrey R. , Sadeghi Mehran M. 
Published: June 2012

Objective—
Vascular endothelial growth factor (VEGF) signaling plays a key role in the pathogenesis of vascular remodeling, including graft arteriosclerosis. Graft arteriosclerosis is the major cause of late organ failure in cardiac transplantation. We used molecular near-infrared fluorescent imaging with an engineered Cy5.5-labeled single-chain VEGF tracer (scVEGF/Cy) to detect VEGF receptors and vascular remodeling in human coronary artery grafts by molecular imaging.

Methods and Results—
VEGF receptor specificity of probe uptake was shown by flow cytometry in endothelial cells. In severe combined immunodeficiency mice, transplantation of human coronary artery segments into the aorta followed by adoptive transfer of allogeneic human peripheral blood mononuclear cells led to significant neointima formation in the grafts over a period of 4 weeks. Near-infrared fluorescent imaging of transplant recipients at 4 weeks demonstrated focal uptake of scVEGF/Cy in remodeling artery grafts. Uptake specificity was demonstrated using an inactive homolog of scVEGF/Cy. scVEGF/Cy uptake predominantly localized in the neointima of remodeling coronary arteries and correlated with VEGF receptor-1 but not VEGF receptor-2 expression. There was a significant correlation between scVEGF/Cy uptake and transplanted artery neointima area.

Conclusion—
Molecular imaging of VEGF receptors may provide a noninvasive tool for detection of graft arteriosclerosis in solid organ transplantation.
Genetic and Pharmacological Manipulation of Urotensin II Ameliorate the Metabolic and Atherosclerosis Sequalae in Mice
Authors: You Zhipeng , Genest Jacques , Barrette Pierre-Olivier , Hafiane Anouar , Behm David J. , D’Orleans-Juste Pedro , Schwertani Adel Giaid 
Published: June 2012

Objective—
Urotensin II (UII) is a potent vasoactive peptide that binds to the urotensin receptor–coupled receptor-14 (known as UT) and exerts a wide range of actions in humans and experimental animals. We tested the hypothesis that UII gene deletion or UT blockade ameliorate experimental atherosclerosis.

Methods and Results—

We observed a significant reduction in weight gain, visceral fat, blood pressure, circulating plasma lipids, and proatherogenic cytokines and improvement of glucose tolerance in UII knockout mice compared with wild type (
P
<0.05). Deletion of UII after an apolipoprotein E knockout resulted in a significant reduction in serum cytokines, adipokines, and aortic atherosclerosis compared with apolipoprotein E knockout mice. Similarly, treatment of apolipoprotein E knockout mice fed on high-fat diet with the UT antagonist SB657510A reduced weight gain, visceral fat, and hyperlipidemia and improved glucose tolerance (
P
<0.05) and attenuated the initiation and progression of atherosclerosis. The UT antagonist also decreased aortic extracellular signal-regulated kinase 1/2 phosphorylation and oxidant formation and serum level of cytokines (
P
<0.05).

Conclusion—
These findings demonstrate for the first time the role of UII gene deletion in atherosclerosis and suggest that the use of pharmaceutical agents aimed at blocking the UII pathway may provide a novel approach in the treatment of atherosclerosis and its associated precursors such as obesity, hyperlipidemia, diabetes mellitus, and hypertension.
Role of Endothelial N-Glycan Mannose Residues in Monocyte Recruitment During Atherogenesis
Authors: Scott David W. , Chen Jie , Chacko Balu K. , Traylor James G. , Orr Anthony W. , Patel Rakesh P. 
Published: June 2012

Objective—
Upregulated expression of endothelial adhesion molecules and subsequent binding to cognate monocytic receptors are established paradigms in atherosclerosis. However, these proteins are the scaffolds, with their posttranslational modification with sugars providing the actual ligands. We recently showed that tumor necrosis factor-α increased hypoglycosylated (mannose-rich) N-glycans on the endothelial surface. In the present study, our aim was to determine whether (1) hypoglycosylated N-glycans are upregulated by proatherogenic stimuli (oscillatory flow) in vitro and in vivo, and (2) mannose residues on hypoglycosylated endothelial N-glycans mediate monocyte rolling and adhesion.

Methods and Results—
Staining with the mannose-specific lectins concanavalin A and lens culinaris agglutinin was increased in human aortic endothelial cells exposed to oscillatory shear or tumor necrosis factor-α and at sites of plaque development and progression in both mice and human vessels. Increasing surface N-linked mannose by inhibiting N-glycan processing potentiated monocyte adhesion under flow during tumor necrosis factor-α stimulation. Conversely, enzymatic removal of high-mannose N-glycans, or masking mannose residues with lectins, significantly decreased monocyte adhesion under flow. These effects occurred without altering induced expression of adhesion molecule proteins.

Conclusion—
Hypoglycosylated (high mannose) N-glycans are present on the endothelial cell surface at sites of early human lesion development and are novel effectors of monocyte adhesion during atherogenesis.
Contribution of Fibrosis and the Autonomic Nervous System to Atrial Fibrillation Electrograms in Heart Failure
Authors: Koduri Hemantha , Ng Jason , Cokic Ivan , Aistrup Gary L. , Gordon David , Wasserstrom J. Andrew , Kadish Alan H. , Lee Richard , Passman Rod , Knight Bradley P. , Goldberger Jeffrey J. , Arora Rishi 
Published: June 2012

Background—
Fibrotic and autonomic remodeling in heart failure (HF) increase vulnerability to atrial fibrillation (AF). Because AF electrograms (EGMs) are thought to reflect the underlying structural substrate, we sought to (1) determine the differences in AF EGMs in normal versus HF atria and (2) assess how fibrosis and nerve-rich fat contribute to AF EGM characteristics in HF.

Methods and Results—
AF was induced in 20 normal dogs by vagal stimulation and in 21 HF dogs (subjected to 3 weeks of rapid ventricular pacing at 240 beats per minute). AF EGMs were analyzed for dominant frequency (DF), organization index, fractionation intervals (FIs), and Shannon entropy. In 8 HF dogs, AF EGM correlation with underlying fibrosis/fat/nerves was assessed. In HF compared with normal dogs, DF was lower and organization index/FI/Shannon entropy were greater. DF/FI were more heterogeneous in HF. Percentage fat was greater, and fibrosis and fat were more heterogeneously distributed in the posterior left atrium than in the left atrial appendage. DF/organization index correlated closely with %fibrosis. Heterogeneity of DF/FI correlated with the heterogeneity of fibrosis. Autonomic blockade caused a greater change in DF/FI/Shannon entropy in the posterior left atrium than left atrial appendage, with the decrease in Shannon entropy correlating with %fat.

Conclusions—
The amount and distribution of fibrosis in the HF atrium seems to contribute to slowing and increased organization of AF EGMs, whereas the nerve-rich fat in the HF posterior left atrium is positively correlated with AF EGM entropy. By allowing for improved detection of regions of dense fibrosis and high autonomic nerve density in the HF atrium, these findings may help enhance the precision and success of substrate-guided ablation for AF.
Relationship Between Arterial Partial Oxygen Pressure After Resuscitation From Cardiac Arrest and Mortality in Children
Authors: Ferguson Lee P. , Durward Andrew , Tibby Shane M. 
Published: June 2012

Background—
Observational studies in adults have shown a worse outcome associated with hyperoxia after resuscitation from cardiac arrest. Extrapolating from adult data, current pediatric resuscitation guidelines recommend avoiding hyperoxia. We investigated the relationship between arterial partial oxygen pressure and survival in patients admitted to the pediatric intensive care unit (PICU) after cardiac arrest.

Methods and Results—

We conducted a retrospective cohort study using the Pediatric Intensive Care Audit Network (PICANet) database between 2003 and 2010 (n=122 521). Patients aged <16 years with documented cardiac arrest preceding PICU admission and arterial blood gas analysis taken within 1 hour of PICU admission were included. The primary outcome measure was death within the PICU. The relationship between postarrest oxygen status and outcome was modeled with logistic regression, with nonlinearities explored via multivariable fractional polynomials. Covariates included age, sex, ethnicity, congenital heart disease, out-of-hospital arrest, year, Pediatric Index of Mortality-2 (PIM2) mortality risk, and organ supportive therapies. Of 1875 patients, 735 (39%) died in PICU. Based on the first arterial gas, 207 patients (11%) had hyperoxia (Pa
o
2
≥300 mm Hg) and 448 (24%) had hypoxia (Pa
o
2
<60 mm Hg). We found a significant nonlinear relationship between Pa
o
2
and PICU mortality. After covariate adjustment, risk of death increased sharply with increasing hypoxia (odds ratio, 1.92; 95% confidence interval, 1.80–2.21 at Pa
o
2
of 23 mm Hg). There was also an association with increasing hyperoxia, although not as dramatic as that for hypoxia (odds ratio, 1.25; 95% confidence interval, 1.17–1.37 at 600 mm Hg). We observed an increasing mortality risk with advancing age, which was more pronounced in the presence of congenital heart disease.

Conclusions—
Both severe hypoxia and, to a lesser extent, hyperoxia are associated with an increased risk of death after PICU admission after cardiac arrest.
Barotropic Impacts of Surface Friction on Eddy Kinetic Energy and Momentum Fluxes: An Alternative to the Barotropic Governor
Authors: Barnes Elizabeth A. , Garfinkel Chaim I. 
Published: June 2012

Abstract
As the surface drag is increased in a comprehensive general circulation model (GCM), the upper-level zonal winds decrease and eddy momentum flux convergence into the jet core increases. Globally averaged eddy kinetic energy decreases, a response that is inconsistent with the conventional barotropic governor mechanism whereby decreased barotropic shears encourage baroclinic wave growth. As the conventional barotropic governor appears insufficient to explain the entire response in the comprehensive GCM, the nondivergent barotropic model on the sphere is used to demonstrate an additional mechanism for the effect of surface drag on eddy momentum fluxes and eddy kinetic energy. Analysis of the pseudomomentum budget shows that increased drag modifies the background meridional vorticity gradient, which allows for enhanced eddy momentum flux convergence and decreased eddy kinetic energy in the presence of a constant eddy source. This additional feedback may explain the changes in eddy momentum fluxes observed in the comprehensive GCM and was likely present in previous work on the barotropic governor.
Upward Shift of the Atmospheric General Circulation under Global Warming: Theory and Simulations
Authors: Singh Martin S. , O’Gorman Paul A. 
Published: June 2012

Abstract
Many features of the general circulation of the atmosphere shift upward in response to warming in simulations of climate change with both general circulation models (GCMs) and cloud-system-resolving models. The importance of the upward shift is well known, but its physical basis and the extent to which it occurs coherently across variables are not well understood. A transformation is derived here that shows how an upward shift of a solution to the moist primitive equations gives a new approximate solution with higher tropospheric temperatures. According to the transformation, all variables shift upward with warming but with an additional modification to the temperature and a general weakening of the pressure velocity. The applicability of the vertical-shift transformation is explored using a hierarchy of models from adiabatic parcel ascents to comprehensive GCMs. The transformation is found to capture many features of the response to climate change in simulations with an idealized GCM, including the mid- and upper-tropospheric changes in lapse rate, relative humidity, and meridional wind. The transformation is less accurate when applied to simulations with more realistic GCMs, but it nonetheless captures some important features. Deviations from the simulated response are primarily due to the surface boundary conditions, which do not necessarily conform to the transformation, especially in the case of the zonal winds. The results allow for a physical interpretation of the upward shift in terms of the governing equations and suggest that it may be thought of as a coherent response of the general circulation of the mid- and upper troposphere.