bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gambogic Acid Inhibits STAT3 Phosphorylation through Activation of Protein Tyrosine Phosphatase SHP-1: Potential Role in Proliferation and Apoptosis
Authors: Prasad Sahdeo , Pandey Manoj K. , Yadav Vivek R. , Aggarwal Bharat B. 
Published: April 2011

AbstractThe transcription factor, STAT3, is associated with proliferation, survival, and metastasis of cancer cells. We investigated whether gambogic acid (GA), a xanthone derived from the resin of traditional Chinese medicine, Garcinia hanburyi (mangosteen), can regulate the STAT3 pathway, leading to suppression of growth and sensitization of cancer cells. We found that GA induced apoptosis in human multiple myeloma cells that correlated with the inhibition of both constitutive and inducible STAT3 activation. STAT3 phosphorylation at both tyrosine residue 705 and serine residue 727 was inhibited by GA. STAT3 suppression was mediated through the inhibition of activation of the protein tyrosine kinases Janus-activated kinase 1 (JAK1) and JAK2. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the GA-induced downregulation of STAT3, suggesting the involvement of a PTP. We also found that GA induced the expression of the PTP SHP-1. Deletion of the SHP-1 gene by siRNA suppressed the ability of GA to inhibit STAT3 activation and to induce apoptosis, suggesting the critical role of SHP-1 in its action. Moreover, GA downregulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) proteins, and this correlated with suppression of proliferation and induction of apoptosis. Overall, these results suggest that GA blocks STAT3 activation, leading to suppression of tumor cell proliferation and induction of apoptosis. Cancer Prev Res; 4(7); 1084–94. ©2011 AACR.
Dietary Fish Oil Promotes Colonic Apoptosis and Mitochondrial Proton Leak in Oxidatively Stressed Mice
Authors: Fan Yang-Yi , Ran Qitao , Toyokuni Shinya , Okazaki Yasumasa , Callaway Evelyn S. , Lupton Joanne R. , Chapkin Robert S. 
Published: April 2011

Abstract
An alteration of mitochondrial function can result in disruption of redox homeostasis and is associated with abnormal cancer cell growth. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. We had previously shown that n-3 polyunsaturated fatty acids (PUFA) promote colonocyte apoptosis, a marker of colon cancer risk, in part by enhancing phospholipid oxidation. To elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, we fed heterozygous SOD2Het, Gpx4Het, and transgenic Gpx4Tg mice diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 weeks. Our data showed that (i) genetic predeposition to oxidative stress facilitates apoptosis in the mouse colon (Gpx4Het &gt; SOD2Het &gt; Wt &gt; Gpx4Tg), (ii) dietary n-3 PUFA have an additive effect on the induction of apoptosis in Gpx4Het and SOD2Het mice; and (iii) dietary n-3 PUFA reverse the phenotype in oxidatively protected Gpx4Tg mice by elevating apoptosis to a level observed in wild-type (Wt; control) animals. Complimentary experiments examining colonic mitochondrial bioenergetic profiles indicate that FO-fed mice exhibit a significantly (P &lt; 0.05) increased respiration-induced proton leak relative to control CO treatment. This finding was consistent with a loss of membrane potential in response to chronic oxidative stress and supports the contention that n-3 PUFA alter mitochondrial metabolic activity, thereby enhancing apoptosis and reducing colon cancer risk. Cancer Prev Res; 4(8); 1267–74. ©2011 AACR.
Accurate Reconstruction of the Temporal Order of Mutations in Neoplastic Progression
Authors: Sprouffske Kathleen , Pepper John W. , Maley Carlo C. 
Published: April 2011

Abstract
The canonical route from normal tissue to cancer occurs through sequential acquisition of somatic mutations. Many studies have constructed a linear genetic model for tumorigenesis using the genetic alterations associated with samples at different stages of neoplastic progression from cross-sectional data. The common interpretation of these models is that they reflect the temporal order within any given tumor. Linear genetic methods implicitly neglect genetic heterogeneity within a neoplasm; each neoplasm is assumed to consist of one dominant clone. We modeled neoplastic progression of colorectal cancer using an agent-based model of a colon crypt and found clonal heterogeneity within our simulated neoplasms, as observed in vivo. Just 7.3% of cells within neoplasms acquired mutations in the same order as the linear model. In 41% of the simulated neoplasms, no cells acquired mutations in the same order as the linear model. We obtained similarly poor results when comparing the temporal order with oncogenetic tree models inferred from cross-sectional data. However, when we reconstructed the cell lineage of mutations within a neoplasm using several biopsies, we found that 99.7% cells within neoplasms acquired their mutations in an order consistent with the cell lineage mutational order. Thus, we find that using cross-sectional data to infer mutational order is misleading, whereas phylogenetic methods based on sampling intratumor heterogeneity accurately reconstructs the evolutionary history of tumors. In addition, we find evidence that disruption of differentiation is likely the first lesion in progression for most cancers and should be one of the few regularities of neoplastic progression across cancers. Cancer Prev Res; 4(7); 1135–44. ©2011 AACR.
Prevalence and Predictors of Carotid Wall Triple Line Pattern in a General Population Sample
Authors: Ryabikov Andrew , Malyutina Sofia , Halcox Julian , Nikitin Yuri , Marmot Michael , Bobak Martin 
Published: April 2011

Objective—
Carotid intima-media thickness (IMT) and plaques are markers of atherosclerosis and predict cardiovascular events. A specific sonographic triple line pattern (TLP) of the carotid wall has been identified in different conditions, but its origin and clinical significance are unclear. We examined the prevalence and predictors of TLP in a general population.

Methods and Results—

The study was conducted in random sample of the general population of Novosibirsk, Russia, within the international Health, Alcohol and Psychosocial Factors in Eastern Europe project. In a subsample of 418 men (aged 45 to 69), carotid IMT, the presence of atherosclerotic plaques, and the presence of TLP were assessed by ultrasound. The prevalence of TLP was 21%. It was associated with IMT (odds ratio=9.53 per 1 SD,
P
<0.001) and the presence of plaques (odds ratio=2.42,
P
=0.002). Other predictors of TLP in multivariate models included age, systolic blood pressure, total cholesterol, and smoking. In addition, infrequent consumption of high amounts of alcohol approximately doubled the risk of triple pattern.

Conclusion—
Our findings showed high prevalence of TLP of carotid wall in a general male population sample from a typical Russian city. This sonographic pattern was strongly associated with cardiovascular risk factors and diseases, bioimaging indicators of atherosclerosis, and episodic heavy drinking.
Gaps in the Ablation Line as a Potential Cause of Recovery From Electrical Isolation and Their Visualization Using MRI
Authors: Ranjan Ravi , Kato Ritsushi , Zviman Menekhem M. , Dickfeld Timm M. , Roguin Ariel , Berger Ronald D. , Tomaselli Gordon F. , Halperin Henry R. 
Published: April 2011

Background—
Ablation has become an important tool in treating atrial fibrillation and ventricular tachycardia, yet the recurrence rates remain high. It is well established that ablation lines can be discontinuous and that conduction through the gaps in ablation lines can be affected by tissue heating. In this study, we looked at the effect of tissue conductivity and propagation of electric wave fronts across ablation lines with gaps, using both simulations and an animal model.

Methods and Results—

For the simulations, we implemented a 2-dimensional bidomain model of the cardiac syncytium, simulating ablation lines with gaps of varying lengths, conductivity, and orientation. For the animal model, transmural ablation lines with a gap were created in 7 mongrel dogs. The gap length was progressively decreased until there was conduction block. The ablation line with a gap was then imaged using MRI and was correlated with histology. With normal conductivity in the gap and the ablation line oriented parallel to the fiber direction, the simulation predicted that the maximum gap length that exhibited conduction block was 1.4 mm. As the conductivity was decreased, the maximum gap length with conduction block increased substantially, that is, with a conductivity of 67% of normal, the maximum gap length with conduction block increased to 4 mm. In the canine studies, the maximum gap length that displayed conduction block acutely as measured by gross pathology correlated well (
R
2
of 0.81) with that measured by MRI.

Conclusions—
Conduction block can occur across discontinuous ablation lines. Moreover, with recovery of conductivity over time, ablation lines with large gaps exhibiting acute conduction block may recover propagation in the gap over time, allowing recurrences of arrhythmias. The ability to see gaps acutely using MRI will allow for targeting these sites for ablation.
Thoracoscopic Video-Assisted Pulmonary Vein Antrum Isolation, Ganglionated Plexus Ablation, and Periprocedural Confirmation of Ablation Lesions
Authors: Krul Sébastien P.J. , Driessen Antoine H.G. , van Boven Wim J. , Linnenbank André C. , Geuzebroek Guillaume S.C. , Jackman Warren M. , Wilde Arthur A.M. , de Bakker Jacques M.T. , de Groot Joris R. 
Published: April 2011

Background—
Thoracoscopic pulmonary vein isolation (PVI) and ganglionated plexus ablation is a novel approach in the treatment of atrial fibrillation (AF). We hypothesize that meticulous electrophysiological confirmation of PVI results in fewer recurrences of AF during follow-up.

Methods and Results—
Surgery was performed through 3 ports bilaterally. Ganglionated plexi were localized and subsequently ablated. PVI was performed and entry and exit block was confirmed. Additional left atrial ablation lines were created and conduction block verified in patients with nonparoxysmal AF. The left atrial appendage was removed. Freedom of AF was assessed by ECGs and Holter monitoring every 3 months or during symptoms of arrhythmia. Antiarrhythmic drugs were discontinued after 3 months and oral anticoagulants were discontinued according to the guidelines. Thirty-one patients were treated (16 paroxysmal AF, 13 persistent AF, 2 long-standing persistent AF). Thirteen patients with nonparoxysmal received additional left atrial ablation lines. After 1 year, 19 of 22 patients (86%) had no recurrences of AF, atrial flutter, or atrial tachycardia and were not using antiarrhythmic drugs (11/12 paroxysmal, 7/9 persistent, and 1/1 long-standing persistent). Three patients had a sternotomy because of uncontrolled bleeding during thoracoscopic surgery. Four adverse events were 1 hemothorax, 1 pneumothorax, and 2 pneumonia. No thromboembolic complications or mortality occurred.

Conclusions—
Thoracoscopic surgery with PVI and ganglionated plexus ablation for AF is a safe and successful procedure with a single procedure success rate of 86% at 1 year. Electrophysiological guided thorough PVI and additional left atrial ablation line creation presumably contributes in achieving a high success rate in the surgical treatment of AF.
A Novel
KCNJ2
Nonsense Mutation, S369X, Impedes Trafficking and Causes a Limited Form of Andersen-Tawil Syndrome
Authors: Doi Takahiro , Makiyama Takeru , Morimoto Takeshi , Haruna Yoshisumi , Tsuji Keiko , Ohno Seiko , Akao Masaharu , Takahashi Yoshiaki , Kimura Takeshi , Horie Minoru 
Published: April 2011

Background—

Mutations in
KCNJ2
, a gene encoding the inward rectifier K
+
channel Kir2.1, are associated with Andersen-Tawil syndrome (ATS), which is characterized by (1) ventricular tachyarrhythmias associated with QT (QU)-interval prolongation, (2) periodic paralysis, and (3) dysmorphic features.

Methods and Results—

We identified a novel
KCNJ2
mutation, S369X, in a 13-year-old boy with prominent QU-interval prolongation and mild periodic paralysis. The mutation results in the truncation at the middle of the cytoplasmic C-terminal domain that eliminates the endoplasmic reticulum (ER)-to-Golgi export signal. Current recordings from Chinese hamster ovary cells transfected with
KCNJ2
-S369X exhibited significantly smaller K
+
currents compared with
KCNJ2
wild type (WT) (1 μg each) (−84±14 versus −542±46 picoamperes per picofarad [pA/pF]; −140 mV;
P
<0.0001). Coexpression of the WT and S369X subunits did not show a dominant-negative suppression effect but yielded larger currents than those of WT+S369X (−724±98 pA/pF>−[84+542] pA/pF; 1 μg each; −140 mV). Confocal microscopy analysis showed that the fluorescent protein-tagged S369X subunits were predominantly retained in the ER when expressed alone; however, the expression of S369X subunits to the plasma membrane was partially restored when coexpressed with WT. Fluorescence resonance energy transfer analysis demonstrated direct protein-protein interactions between WT and S369X subunits in the intracellular compartment.

Conclusions—
The S369X mutation causes a loss of the ER export motif. However, the trafficking deficiency can be partially rescued by directly assembling with the WT protein, resulting in a limited restoration of plasma membrane localization and channel function. This alleviation may explain why our patient presented with a relatively mild ATS phenotype.
Genetic and Clinical Correlates of Early-Outgrowth Colony-Forming Units
Authors: Shaw Stanley Y. , Cheng Susan , Cupples L. Adrienne , Larson Martin G. , McCabe Elizabeth L. , Ngwa Julius S. , Wang Ying A. , Martin Roderick P. , Klein Rachael J. , Hashmi Basma , Ajijola Olujimi A. , Lau Evan , O'Donnell Christopher J. , Vasan Ramachandran S. , Cohen Kenneth S. , Wang Thomas J. 
Published: April 2011

Background—
Several bone marrow–derived cell populations may have angiogenic activity, including cells termed endothelial progenitor cells. Decreased numbers of circulating angiogenic cell populations have been associated with increased cardiovascular risk. However, few data exist from large, unselected samples, and the genetic determinants of these traits are unclear.

Methods and Results—

We examined the clinical and genetic correlates of early-outgrowth colony-forming units (CFUs) in 1799 participants of the Framingham Heart Study (mean age, 66 years; 54% women). Among individuals without cardiovascular disease (n=1612), CFU number was inversely related to advanced age (
P
=0.004), female sex (
P
=0.04), and triglycerides (
P
=0.008) and positively related to hormone replacement (
P
=0.008) and statin therapy (
P
=0.027) in stepwise multivariable analyses. Overall, CFU number was inversely related to the Framingham risk score (
P
=0.01) but not with prevalent cardiovascular disease. In genome-wide association analyses in the entire sample, polymorphisms were associated with CFUs at the
MOSC1
locus (
P
=3.3×10
−7
) and at the
SLC22A3-LPAL2-LPA
locus (
P
=4.9×10
−7
), a previously replicated susceptibility locus for myocardial infarction. Furthermore, alleles at the
SLC22A3-LPAL2-LPA
locus that were associated with decreased CFUs were also related to increased risk of myocardial infarction (
P
=1.1×10
−4
).

Conclusions—

In a community-based sample, early-outgrowth CFUs are inversely associated with select cardiovascular risk factors. Furthermore, genetic variants at the
SLC22A3-LPAL2-LPA
locus are associated with both decreased CFUs and an increased risk of myocardial infarction. These findings are consistent with the hypothesis that decreased circulating angiogenic cell populations promote susceptibility to myocardial infarction.
Coronary Artery Endothelial Transcriptome In Vivo
Authors: Civelek Mete , Manduchi Elisabetta , Riley Rebecca J. , Stoeckert Christian J. , Davies Peter F. 
Published: April 2011

Background—
Endothelial function is central to the localization of atherosclerosis. The in vivo endothelial phenotypic footprints of arterial bed identity and site-specific atherosusceptibility are addressed.

Methods and Results—
Ninety-eight endothelial cell samples from 13 discrete coronary and noncoronary arterial regions of varying susceptibilities to atherosclerosis were isolated from 76 normal swine. Transcript profiles were analyzed to determine the steady-state in vivo endothelial phenotypes. An unsupervised systems biology approach using weighted gene coexpression networks showed highly correlated endothelial genes. Connectivity network analysis identified 19 gene modules, 12 of which showed significant association with circulatory bed classification. Differential expression of 1300 genes between coronary and noncoronary artery endothelium suggested distinct coronary endothelial phenotypes, with highest significance expressed in gene modules enriched for biological functions related to endoplasmic reticulum (ER) stress and unfolded protein binding, regulation of transcription and translation, and redox homeostasis. Furthermore, within coronary arteries, comparison of endothelial transcript profiles of susceptible proximal regions to protected distal regions suggested the presence of ER stress conditions in susceptible sites. Accumulation of reactive oxygen species throughout coronary endothelium was greater than in noncoronary endothelium consistent with coronary artery ER stress and lower endothelial expression of antioxidant genes in coronary arteries.

Conclusions—
Gene connectivity analyses discriminated between coronary and noncoronary endothelial transcript profiles and identified differential transcript levels associated with increased ER and oxidative stress in coronary arteries consistent with enhanced susceptibility to atherosclerosis.
Regional Ischemic Vulnerability of the Brain to Hypoperfusion
Authors: Payabvash Seyedmehdi , Souza Leticia C.S. , Wang Yifei , Schaefer Pamela W. , Furie Karen L. , Halpern Elkan F. , Gonzalez R. Gilberto , Lev Michael H. 
Published: April 2011

Background and Purpose—
To characterize the spatial pattern of cerebral ischemic vulnerability to hypoperfusion in stroke patients.

Methods—

We included 90 patients who underwent admission CT perfusion and MRI within 12 hours of ischemic stroke onset. Infarcted brain lesions (“core”) were segmented from admission diffusion-weighted imaging and, along with the CT perfusion parameter maps, coregistered onto MNI-152 brain space, which was parcellated into 125 mirror cortical and subcortical regions per hemisphere. We tested the hypothesis that the percent infarction increment per unit of relative cerebral blood flow (rCBF) reduction differs statistically between regions using regression analysis to assess the interaction between regional rCBF and region variables. Next, for each patient, a “vulnerability index” map was constructed with voxel values equaling the product of that voxel's rCBF and infarction probability (derived from the MNI-152–transformed, binary, segmented, diffusion-weighted imaging lesions). Voxel-based rCBF threshold for core was determined within the upper 20
th
percentile of vulnerability index map voxel values.

Results—

Different regions had different percent infarction increase per unit rCBF reduction (
P
=0.001). The caudate body, putamen, insular ribbon, paracentral lobule, and precentral, middle, and inferior frontal gyri had the highest ischemic vulnerability to hypoperfusion. A voxel-based rCBF threshold of <0.42 optimally distinguished infarct core in the highly-vulnerable regions, whereas rCBF <0.16 distinguished core in the remainder of the brain.

Conclusions—
We demonstrated regional ischemic vulnerability of the brain to hypoperfusion in acute stroke patients. Location-specific, rather than whole-brain, rCBF thresholds may provide a more accurate metric for estimating infarct core using CT perfusion maps.
Global Cerebral Edema and Brain Metabolism After Subarachnoid Hemorrhage
Authors: Helbok Raimund , Ko Sang-Bae , Schmidt J. Michael , Kurtz Pedro , Fernandez Luis , Choi H. Alex , Connolly E. Sander , Lee Kiwon , Badjatia Neeraj , Mayer Stephan A. , Claassen Jan 
Published: April 2011

Background and Purpose—
Global cerebral edema is common among patients with poor-grade subarachnoid hemorrhage and is associated with poor outcome. Currently no targeted therapy exists largely due to an incomplete understanding of the underlying mechanisms.

Methods—
This is a prospective observational study including 39 consecutive patients with poor-grade subarachnoid hemorrhage with multimodal neuromonitoring. Levels of microdialysate lactate–pyruvate ratio, episodes of cerebral metabolic crisis (lactate-pyruvate ratio >40 and brain glucose <0.7 mmol/L), brain tissue oxygen tension, cerebral perfusion pressure, and transcranial Doppler sonography flow velocities were analyzed.

Results—

Median age was 54 years (range, 45 to 61 years) and 62% were female. Patients with global cerebral edema on admission (n=24 [62%]) had a higher incidence of metabolic crisis in the first 12 hours of monitoring (n=15 [15% versus 2%],
P
<0.05) and during the total time of neuromonitoring (20% versus 3%,
P
<0.001) when compared to those without global cerebral edema. There was no difference in brain tissue oxygen tension or cerebral perfusion pressure between the groups; however, in patients with global cerebral edema, a higher cerebral perfusion pressure was associated with lower lactate–pyruvate ratio (
P
<0.05). Episodes of metabolic crisis were associated with poor outcome (modified Rankin Scale score 5 or 6,
P
<0.05).

Conclusions—
In patients with poor-grade subarachnoid hemorrhage, global cerebral edema is associated with early brain metabolic distress.
Retinal Microvascular Signs and Functional Loss in Older Persons
Authors: Kim Dae Hyun , Newman Anne B. , Hajjar Ihab , Strotmeyer Elsa S. , Klein Ronald , Newton Elizabeth , Sarnak Mark J. , Burke Gregory L. , Lipsitz Lewis A. 
Published: April 2011

Background and Purpose—
We hypothesized that retinal microvascular signs are associated with executive dysfunction, slow gait, and depressive mood, which are characteristic features of microvascular disease affecting frontal subcortical regions of the brain.

Methods—
In the Cardiovascular Health Study, 1744 participants (mean age, 78) free of stroke had retinal photographs and carotid ultrasound during the 1997 to 1998 visit. We examined the cross-sectional association of retinal signs with the digit-symbol substitution test (DSST) score, gait speed, the Center for Epidemiologic Studies–Depression score, and depressive mood, defined as Center for Epidemiologic Studies–Depression score >9 or antidepressant use.

Results—

After adjusting for potential confounders, retinal signs were associated with lower DSST score (generalized arteriolar narrowing and arteriovenous nicking), slower gait (retinopathy), and depressive mood (generalized arteriolar narrowing). A higher number of retinal signs was associated with lower DSST score (−0.76 and −2.79 points for 1 sign and ≥2 signs versus none;
P
<0.001) and slower gait (−0.009 and −0.083 m/s;
P
=0.047), but not with the square root of Center for Epidemiologic Studies–Depression score (0.079 and −0.208;
P
=0.072). In addition, coexistence of retinal signs (generalized arteriolar narrowing and arteriovenous nicking) and carotid atherosclerosis was associated with lower DSST score compared with either process alone (
P
for interaction <0.01). Notably, further adjustment for ventricular size, white matter disease, and infarcts on MRI did not attenuate the association.

Conclusions—
Retinal signs are associated with executive dysfunction and slow gait, and possibly with depressive mood, suggesting a common process involving small vessels.