bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Aberrant VHL/HIF Pathway Elements in Predicting Clinical Outcome to Pazopanib Therapy in Patients with Metastatic Clear-Cell Renal Cell Carcinoma
Authors: Choueiri Toni K. , Fay André P. , Gagnon Robert , Lin Ying , Bahamon Brittany , Brown Victoria , Rosenberg Jonathan E. , Hutson Thomas E. , Baker-Neblett Katherine L. , Carpenter Christopher , Liu Yuan , Pandite Lini , Signoretti Sabina 
Published: July 2013

Abstract
Purpose: Inactivation of von Hippel-Lindau (VHL) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIF) and overexpression of HIF target genes, such as VEGF and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking.
Experimental Design: We analyzed tumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616. We evaluated several components of the VHL/HIF pathway: VHL gene inactivation (mutation and/or methylation), HIF-1α and HIF-2α immunohistochemistry staining, and HIF-1α transcriptional signature. We evaluated the association of these biomarkers with best overall response rate (ORR) and progression-free survival (PFS) to pazopanib, a standard first-line VEGF-targeted agent.
Results: The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had VHL mutation or methylation. VHL gene status did not correlate with ORR or PFS. Similarly, HIF-1α (65 samples) and HIF-2α (66 samples) protein levels (high vs. low) did not correlate with ORR or PFS to pazopanib. The HIF-1α transcriptional signature (46 samples) was enriched in tumors expressing high HIF-1α levels. However, the HIF-1α gene expression signature was not associated with clinical outcome to pazopanib.
Conclusions: In patients with advanced clear-cell RCC, several potential biomarkers along the VHL/HIF-1α/HIF-2α axis were not found to be predictive for pazopanib activity. Additional efforts must continue to identify biomarkers associated with clinical outcome to VEGF-targeted agents in metastatic RCC. Clin Cancer Res; 19(18); 5218–26. ©2013 AACR.
Dietary Polyphenols Suppress Elevated Levels of Proinflammatory Mediators and Aromatase in the Mammary Gland of Obese Mice
Authors: Subbaramaiah Kotha , Sue Erika , Bhardwaj Priya , Du Baoheng , Hudis Clifford A. , Giri Dilip , Kopelovich Levy , Zhou Xi Kathy , Dannenberg Andrew J. 
Published: July 2013

AbstractIn postmenopausal women, obesity is a risk factor for the development of hormone receptor–positive breast cancer driven by estrogen. After menopause, aromatization of androgen precursors in adipose tissue is a major synthetic source of estrogen. Recently, in mouse models and women, we identified an obesity–inflammation–aromatase axis. This obesity-induced inflammation is characterized by crown-like structures (CLS) consisting of dead adipocytes encircled by macrophages in breast white adipose tissue. CLS occur in association with NF-κB activation, elevated levels of proinflammatory mediators, and increased aromatase expression. Saturated fatty acids released from adipocytes have been linked to obesity-related white adipose tissue inflammation. Here we found that stearic acid, a prototypic saturated fatty acid, stimulated Akt-dependent activation of NF-κB resulting in increased levels of proinflammatory mediators [TNF-α, interleukin (IL)-1β, COX-2] in macrophages leading, in turn, to the induction of aromatase. Several polyphenols (resveratrol, curcumin, epigallocatechin gallate) blocked these inductive effects of stearic acid. Zyflamend, a widely used polyherbal preparation that contains numerous polyphenols, possessed similar suppressive effects. In a mouse model of obesity, treatment with Zyflamend suppressed levels of phospho-Akt, NF-κB binding activity, proinflammatory mediators, and aromatase in the mammary gland. Collectively, these results suggest that targeting the activation of NF-κB is a promising approach for reducing levels of proinflammatory mediators and aromatase in inflamed mouse mammary tissue. Further investigation in obese women is warranted. Cancer Prev Res; 6(9); 886–97. ©2013 AACR.
Impact of Stepwise Ablation on the Biatrial Substrate in Patients With Persistent Atrial Fibrillation and Heart Failure
Authors: Jones David G. , Haldar Shouvik K. , Jarman Julian W.E. , Johar Sofian , Hussain Wajid , Markides Vias , Wong Tom 
Published: July 2013

Background—
Ablation of persistent atrial fibrillation can be challenging, often involving not only pulmonary vein isolation (PVI) but also additional linear lesions and ablation of complex fractionated electrograms (CFE). We examined the impact of stepwise ablation on a human model of advanced atrial substrate of persistent atrial fibrillation in heart failure.

Methods and Results—

In 30 patients with persistent atrial fibrillation and left ventricular ejection fraction ≤35%, high-density CFE maps were recorded biatrially at baseline, in the left atrium (LA) after PVI and linear lesions (roof and mitral isthmus), and biatrially after LA CFE ablation. Surface area of CFE (mean cycle length ≤120 ms) remote to PVI and linear lesions, defined as CFE area, was reduced after PVI (18.3±12.03 to 10.2±7.1 cm
2
;
P
<0.001) and again after linear lesions (7.7±6.5 cm
2
;
P
=0.006). Complete mitral isthmus block predicted greater CFE reduction (
P
=0.02). Right atrial CFE area was reduced by LA ablation, from 25.9±14.1 to 12.9±11.8 cm
2
(
P
<0.001). Estimated 1-year arrhythmia-free survival was 72% after a single procedure. Incomplete linear lesion block was an independent predictor of arrhythmia recurrence (hazard ratio, 4.69; 95% confidence interval, 1.05–21.06;
P
=0.04).

Conclusions—
Remote LA CFE area was progressively reduced following PVI and linear lesions, and LA ablation reduced right atrial CFE area. Reduction of CFE area at sites remote from ablation would suggest either regression of the advanced atrial substrate or that these CFE were functional phenomena. Nevertheless, in an advanced atrial fibrillation substrate, linear lesions after PVI diminished the target area for CFE ablation, and complete lesions resulted in a favorable clinical outcome.
Benefit of Warfarin Compared With Aspirin in Patients With Heart Failure in Sinus Rhythm
Authors: Homma Shunichi , Thompson John L.P. , Sanford Alexandra R. , Mann Douglas L. , Sacco Ralph L. , Levin Bruce , Pullicino Patrick M. , Freudenberger Ronald S. , Teerlink John R. , Graham Susan , Mohr J.P. , Massie Barry M. , Labovitz Arthur J. , Di Tullio Marco R. , Gabriel André P. , Lip Gregory Y.H. , Estol Conrado J. , Lok Dirk J. , Ponikowski Piotr , Anker Stefan D. 
Published: July 2013

Background—
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin.

Methods and Results—

We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier (
P
for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48–0.84;
P
=0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88–1.35;
P
=0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52–0.89;
P
=0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02–1.53;
P
=0.03).

Conclusions—
In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00041938.
Prognostic Value of Indeterminable Anaerobic Threshold in Heart Failure
Authors: Agostoni Piergiuseppe , Corrà Ugo , Cattadori Gaia , Veglia Fabrizio , Battaia Elisa , La Gioia Rocco , Scardovi Angela B. , Emdin Michele , Metra Marco , Sinagra Gianfranco , Limongelli Giuseppe , Raimondo Rosa , Re Federica , Guazzi Marco , Belardinelli Romualdo , Parati Gianfranco , Magrì Damiano , Fiorentini Cesare , Cicoira Mariantonietta , Salvioni Elisabetta , Giovannardi Marta , Mezzani Alessandro , Scrutinio Domenico , Di Lenarda Andrea , Mantegazza Valentina , Ricci Roberto , Apostolo Anna , Iorio AnnaMaria , Paolillo Stefania , Palermo Pietro , Contini Mauro , Vassanelli Corrado , Passino Claudio , Piepoli Massimo F. 
Published: July 2013

Background—
In patients with heart failure (HF), during maximal cardiopulmonary exercise test, anaerobic threshold (AT) is not always identified. We evaluated whether this finding has a prognostic meaning.

Methods and Results—

We recruited and prospectively followed up, in 14 dedicated HF units, 3058 patients with systolic (left ventricular ejection fraction <40%) HF in stable clinical conditions, New York Heart Association class I to III, who underwent clinical, laboratory, echocardiographic, and cardiopulmonary exercise test investigations at study enrollment. We excluded 921 patients who did not perform a maximal exercise, based on lack of achievement of anaerobic metabolism (peak respiratory quotient ≤1.05). Primary study end point was a composite of cardiovascular death and urgent cardiac transplant, and secondary end point was all-cause death. Median follow-up was 3.01 (1.39–4.98) years. AT was identified in 1935 out of 2137 patients (90.54%). At multivariable logistic analysis, failure in detecting AT resulted significantly in reduced peak oxygen uptake and higher metabolic exercise and cardiac and kidney index score value, a powerful prognostic composite HF index (
P
<0.001). At multivariable analysis, the following variables were significantly associated with primary study end point: peak oxygen uptake (% pred;
P
<0.001; hazard ratio [HR]=0.977; confidence interval [CI]=0.97–0.98), ventilatory efficiency slope (
P
=0.01; HR=1.02; CI=1.01–1.03), hemoglobin (
P
<0.05; HR=0.931; CI=0.87–1.00), left ventricular ejection fraction (
P
<0.001; HR=0.948; CI=0.94–0.96), renal function (modification of diet in renal disease;
P
<0.001; HR=0.990; CI=0.98–0.99), sodium (
P
<0.05; HR=0.967; CI=0.94–0.99), and AT nonidentification (
P
<0.05; HR=1.41; CI=1.06–1.89). Nonidentification of AT remained associated to prognosis also when compared with metabolic exercise and cardiac and kidney index score (
P
<0.01; HR=1.459; CI=1.09–1.10). Similar results were obtained for the secondary study end point.

Conclusions—
The inability to identify AT most often occurs in patients with severe HF, and it has an independent prognostic role in HF.
Analysis of a Historical (1981–2010) Temperature Record of the Punjab Province of Pakistan
Authors: Abbas Farhat 
Published: July 2013

Abstract
Prolonged droughts and uneven monsoons have adversely affected socioeconomic and environmental conditions of Pakistan, especially of the Punjab province. Analysis of historical (1981–2010) daily minimum and maximum temperatures from five cities in semiarid Punjab, Pakistan, was carried out to evaluate spatial and temporal patterns in thermal regimes. A total of 13 climate change indices were calculated using daily minimum and maximum temperatures and analyzed for trend using RClimDex, a program written in the statistical software package R. A nonparametric Mann–Kendall test and Sen's slope estimates were used to determine the statistical significance and magnitude of a trend, respectively. Observed trends in selected indices during 1981–2010 suggest an overall warming in the region. Over the analysis period, the regionally averaged occurrence of extreme cold (10th percentile) nights and days has decreased by −3.94 nights per decade and −0.61 days per decade, respectively. Occurrence of extreme hot (90th percentile) nights and days has increased by 4.19 nights per decade and 0.92 days per decade, respectively. The number of summer days has increased by almost 3 days per decade on average at four out of the five cities. Multan was the only city where the number of summer days has declined by 5 days per decade. Regionally averaged increase in tropical nights was 8.35 nights per decade. Regional warming will dictate increased crop water requirements in this semiarid region agriculture, which is already under water-scarce conditions, especially in the Faisalabad district, where saline groundwater is not suitable for crops.
ENSO Transition, Duration, and Amplitude Asymmetries: Role of the Nonlinear Wind Stress Coupling in a Conceptual Model
Authors: Choi Kit-Yan , Vecchi Gabriel A. , Wittenberg Andrew T. 
Published: July 2013

The El Niño–Southern Oscillation (ENSO) exhibits well-known asymmetries: 1) warm events are stronger than cold events, 2) strong warm events are more likely to be followed by cold events than vice versa, and 3) cold events are more persistent than warm events. Coupled GCM simulations, however, continue to underestimate many of these observed features. To shed light on these asymmetries, the authors begin with a widely used delayed-oscillator conceptual model for ENSO and modify it so that wind stress anomalies depend more strongly on SST anomalies (SSTAs) during warm conditions, as is observed. Then the impact of this nonlinearity on ENSO is explored for three dynamical regimes: self-sustained oscillations, stochastically driven oscillations, and self-sustained oscillations disrupted by stochastic forcings. In all three regimes, the nonlinear air–sea coupling preferentially strengthens the feedbacks (both positive and delayed negative) during the ENSO warm phase—producing El Niños that grow to a larger amplitude and overshoot more rapidly and consistently into the opposite phase, than do the La Niñas. Finally, the modified oscillator is applied to observational records and to control simulations from two global coupled ocean–atmosphere–land–ice models [Geophysical Fluid Dynamics Laboratory Climate Model version 2.1 (GFDL CM2.1) and version 2.5 (GFDL CM2.5)] to elucidate the causes of their differing asymmetries.
Team Performance in Networked Supervisory Control of Unmanned Air Vehicles
Authors: McKendrick Ryan , Shaw Tyler , de Visser Ewart , Saqer Haneen , Kidwell Brian , Parasuraman Raja 
Published: July 2013

Objective: Assess team performance within a networked supervisory control setting while manipulating automated decision aids and monitoring team communication and working memory ability. Background: Networked systems such as multi–unmanned air vehicle (UAV) supervision have complex properties that make prediction of human-system performance difficult. Automated decision aid can provide valuable information to operators, individual abilities can limit or facilitate team performance, and team communication patterns can alter how effectively individuals work together. We hypothesized that reliable automation, higher working memory capacity, and increased communication rates of task-relevant information would offset performance decrements attributed to high task load. Method: Two-person teams performed a simulated air defense task with two levels of task load and three levels of automated aid reliability. Teams communicated and received decision aid messages via chat window text messages. Results: Task Load × Automation effects were significant across all performance measures. Reliable automation limited the decline in team performance with increasing task load. Average team spatial working memory was a stronger predictor than other measures of team working memory. Frequency of team rapport and enemy location communications positively related to team performance, and word count was negatively related to team performance. Conclusion: Reliable decision aiding mitigated team performance decline during increased task load during multi-UAV supervisory control. Team spatial working memory, communication of spatial information, and team rapport predicted team success. Application: An automated decision aid can improve team performance under high task load. Assessment of spatial working memory and the communication of task-relevant information can help in operator and team selection in supervisory control systems.
A new variant of statistical convergence
Authors: Mohiuddine Syed Abdul , Alotaibi Abdullah , Mursaleen Mohammad 
Published: July 2013

Abstract
In this paper we study the notion of statistical

(
A
,
λ
)

-summability, which is a generalization of statistical A-summability. We study here many other related concepts and its relations with statistical convergence and λ-statistical convergence and provide some interesting examples.
Cortical spreading depression as a target for anti-migraine agents
Authors: Costa Cinzia , Tozzi Alessandro , Rainero Innocenzo , Cupini Letizia Maria , Calabresi Paolo , Ayata Cenk , Sarchielli Paola 
Published: July 2013

AbstractSpreading depression (SD) is a slowly propagating wave of neuronal and glial depolarization lasting a few minutes, that can develop within the cerebral cortex or other brain areas after electrical, mechanical or chemical depolarizing stimulations. Cortical SD (CSD) is considered the neurophysiological correlate of migraine aura. It is characterized by massive increases in both extracellular K+and glutamate, as well as rises in intracellular Na+and Ca2+. These ionic shifts produce slow direct current (DC) potential shifts that can be recorded extracellularly. Moreover, CSD is associated with changes in cortical parenchymal blood flow.CSD has been shown to be a common therapeutic target for currently prescribed migraine prophylactic drugs. Yet, no effects have been observed for the antiepileptic drugs carbamazepine and oxcarbazepine, consistent with their lack of efficacy on migraine. Some molecules of interest for migraine have been tested for their effect on CSD. Specifically, blocking CSD may play an enabling role for novel benzopyran derivative tonabersat in preventing migraine with aura. Additionally, calcitonin gene-related peptide (CGRP) antagonists have been recently reported to inhibit CSD, suggesting the contribution of CGRP receptor activation to the initiation and maintenance of CSD not only at the classic vascular sites, but also at a central neuronal level. Understanding what may be lying behind this contribution, would add further insights into the mechanisms of actions for “gepants”, which may be pivotal for the effectiveness of these drugs as anti-migraine agents.CSD models are useful tools for testing current and novel prophylactic drugs, providing knowledge on mechanisms of action relevant for migraine.
White matter disintegration in cluster headache
Authors: Szabó Nikoletta , Kincses Zsigmond Tamás , Párdutz Árpád , Tóth Eszter , Szok Délia , Csete Gergő , Vécsei László 
Published: July 2013

Abstract

Background
Previous studies in primary headache disorders showed microstructural alterations in the white matter as measured by diffusion imaging. However these investigations are not in full agreement and some of those, especially in cluster headache, restricted the analysis to only a limited number of diffusion parameters. Therefore, in the current study we examined white matter microstructure in cluster headache patients.

Methods
Diffusion weighted MRI images with 60 directions were acquired from thirteen patients with cluster headache and sixteen age-matched healthy controls. Tract based spatial statistics were used to compare white matter integrity in the core of the fibre bundles. Correlation of the diffusion parameters with cumulative number of headache days was examined.

Results
There was a significant increment of the mean, axial and perpendicular diffusivity in widespread white matter regions in the frontal, parietal, temporal and occipital lobes. Reduced fractional anisotropy was found in the corpus callosum and some frontal and parietal white matter tracts mainly in the contralateral side of the pain. Axial diffusivity showed negative correlation to the number of the headache attacks.

Conclusions
The in vivo analysis of microstructural alterations in cluster headache provides important features of the disease, which might offer a deeper insight into the pathomechanism of the disease.
Evidence of antimicrobial resistance-conferring genetic elements among pneumococci isolated prior to 1974
Authors: Wyres Kelly L , van Tonder Andries , Lambertsen Lotte M , Hakenbeck Regine , Parkhill Julian , Bentley Stephen D , Brueggemann Angela B 
Published: July 2013

Abstract
Background
Antimicrobial resistance among pneumococci has greatly increased over the past two to three decades. Resistance to tetracycline (tet(M)), chloramphenicol (cat) and macrolides (erm(B) and/or mef(A/E)) is generally conferred by acquisition of specific genes that are associated with mobile genetic elements, including those of the Tn916 and Tn5252 families. The first tetracycline-, chloramphenicol- and macrolide-resistant pneumococci were detected between 1962 and 1970; however, until now the oldest pneumococcus shown to harbour Tn916 and/or Tn5252 was isolated in 1974. In this study the genomes of 38 pneumococci isolated prior to 1974 were probed for the presence of tet(M), cat, erm(B), mef(A/E) and int (integrase) to indicate the presence of Tn916/ Tn5252-like elements.

Results
Two Tn916-like, tet(M)-containing, elements were identified among pneumococci dated 1967 and 1968. The former element was highly similar to that of the PMEN1 multidrug-resistant, globally-distributed pneumococcal reference strain, which was isolated in 1984. The latter element was associated with a streptococcal phage. A third, novel genetic element, designated ICESp PN1, was identified in the genome of an isolate dated 1972. ICESp PN1 contained a region of similarity to Tn5252, a region of similarity to a pneumococcal pathogenicity island and novel lantibiotic synthesis/export-associated genes.

Conclusions
These data confirm the existence of pneumococcal Tn916 elements in the first decade within which pneumococcal tetracycline resistance was described. Furthermore, the discovery of ICESp PN1 demonstrates the dynamic variability of pneumococcal genetic elements and is contrasted with the evidence for Tn916 stability.