bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adipocyte-Derived Fibroblasts Promote Tumor Progression and Contribute to the Desmoplastic Reaction in Breast Cancer
Authors: Bochet Ludivine , Lehuédé Camille , Dauvillier Stéphanie , Wang Yuan Yuan , Dirat Béatrice , Laurent Victor , Dray Cédric , Guiet Romain , Maridonneau-Parini Isabelle , Le Gonidec Sophie , Couderc Bettina , Escourrou Ghislaine , Valet Philippe , Muller Catherine 
Published: August 2013

Abstract
Cancer-associated fibroblasts (CAF) comprise the majority of stromal cells in breast cancers, yet their precise origins and relative functional contributions to malignant progression remain uncertain. Local invasion leads to the proximity of cancer cells and adipocytes, which respond by phenotypical changes to generate fibroblast-like cells termed as adipocyte-derived fibroblasts (ADF) here. These cells exhibit enhanced secretion of fibronectin and collagen I, increased migratory/invasive abilities, and increased expression of the CAF marker FSP-1 but not α-SMA. Generation of the ADF phenotype depends on reactivation of the Wnt/β-catenin pathway in response to Wnt3a secreted by tumor cells. Tumor cells cocultivated with ADFs in two-dimensional or spheroid culture display increased invasive capabilities. In clinical specimens of breast cancer, we confirmed the presence of this new stromal subpopulation. By defining a new stromal cell population, our results offer new opportunities for stroma-targeted therapies in breast cancer. Cancer Res; 73(18); 5657–68. ©2013 AACR.
Increased Frequency of ICOS+ CD4 T Cells as a Pharmacodynamic Biomarker for Anti-CTLA-4 Therapy
Authors: Ng Tang Derek , Shen Yu , Sun Jingjing , Wen Sijin , Wolchok Jedd D. , Yuan Jianda , Allison James P. , Sharma Padmanee 
Published: August 2013

Abstract
Pharmacodynamic biomarkers can play an important role in understanding whether a therapeutic agent has “hit its target” to impact biologic function. A pharmacodynamic biomarker for anti-CTLA-4 therapy remains to be elucidated. We previously reported that anti-CTLA-4 therapy increases the frequency of CD4 T cells expressing the inducible costimulator (ICOS) molecule. To determine whether the frequency of ICOS+ CD4 T cells could be used as a pharmacodynamic biomarker for anti-CTLA-4 therapy, we carried out flow cytometric studies and statistical analyses on data from 56 individuals, which included 10 healthy donors, 36 patients who received anti-CTLA-4 monoclonal antibody (mAb), and 10 patients who received treatment with a different immunomodulatory agent (gp100 DNA vaccine). After treatment with anti-CTLA-4 mAb (ipilimumab; Bristol-Myers Squibb), we detected a statistically significant increase in the frequency of ICOS+ CD4 T-cells. After two doses of anti-CTLA-4 therapy, the assay was found to have an estimated specificity of 96% [95% confidence interval (CI), 88–100] and sensitivity of 71% (95% CI, 54–85), with positive expression defined as a frequency that is more than the upper bound of 95% CI among baseline samples from all subjects. Our data suggest that an increased frequency of ICOS+ CD4 T cells measured by flow cytometry can be used as a reproducible pharmacodynamic biomarker to indicate biologic activity in the setting of anti-CTLA-4 therapy, which should enable appropriate immune monitoring to determine whether patients receiving anti-CTLA-4 monotherapy or combination treatment strategies are having an adequate biologic response. Cancer Immunol Res; 1(4); 229–34. ©2013 AACR.
Genetic association of five plasminogen activator inhibitor-1 (PAI-1) polymorphisms and idiopathic recurrent pregnancy loss in Korean women
Authors: Jeon Young Joo , Kim Young Ran , Lee Bo Eun , Choi Yi Seul , Kim Ji Hyang , Shin Ji Eun , Rah HyungChul , Cha Sun Hee , Lee Woo Sik , Kim Nam Keun 
Published: August 2013

SummaryPlasminogen activator inhibitor-1 (PAI-1) is important for maintaining pregnancy. Aberrantly increased PAI-1 levels may contribute to thrombosis and inflammation, leading to pregnancy loss. This study investigated the association of PAI-1 polymorphisms (PAI-1 rs2227631 [-844G>A], rs1799889 [-675 4G/5G], rs6092 [43G>A], rs2227694 [9785G>A], and rs7242 [11053T>G]) with idiopathic recurrent pregnancy loss (RPL) in Korean women. We screened 308 RPL patients and 227 control participants for five PAI-1 polymorphisms. Genotyping of PAI-1 was performed by polymerase chain reaction-restriction fragment length polymorphism assay. PAI-1 4G4G and -844AA/ 4G4G/11053GG genotypes were associated with RPL. PAI-1 -844A/4G/43G/9785G/11053G haplotype was connected to hypofibrinolytic status (i.e. increased levels of plasma PAI-1, increased numbers of platelets, reduced prothrombin time, and reduced activated partial thromboplastin time). Moreover, PAI-1 11053TG+GG frequency was positively related to plasma homocysteine and urate levels, whereas -844AA frequency was associated with plasma folate concentrations according to ordinal logistic regression analysis. Based on these results, we propose that PAI-1 -844G>A, 4G/5G, and 11053T>G polymorphisms are markers of RPL.
Subclinical Left Ventricular Dysfunction and Silent Cerebrovascular Disease
Authors: Russo Cesare , Jin Zhezhen , Homma Shunichi , Elkind Mitchell S.V. , Rundek Tatjana , Yoshita Mitsuhiro , DeCarli Charles , Wright Clinton B. , Sacco Ralph L. , Di Tullio Marco R. 
Published: August 2013

Background—
Silent brain infarcts (SBIs) and white matter hyperintensities are subclinical cerebrovascular lesions associated with incident stroke and cognitive decline. Left ventricular ejection fraction (LVEF) is a predictor of stroke in patients with heart failure, but its association with subclinical brain disease in the general population is unknown. Left ventricular global longitudinal strain (GLS) can detect subclinical cardiac dysfunction even when LVEF is normal. We investigated the relationship of LVEF and GLS with subclinical brain disease in a community-based cohort.

Methods and Results—

LVEF and GLS were assessed by 2-dimensional and speckle-tracking echocardiography in 439 participants free of stroke and cardiac disease from the Cardiovascular Abnormalities and Brain Lesions (CABL) study. SBIs and white matter hyperintensities were assessed by brain MRI. Mean age of the study population was 69±10 years, 61% were women, LVEF was 63.8±6.4%, GLS was −17.1±3.0%. SBIs were detected in 53 participants (12%), white matter hyperintensity volume was 0.63±0.86%. GLS was significantly lower in participants with SBI versus those without (−15.7±3.5% versus −17.3±2.9%,
P
<0.01), whereas no difference in LVEF was observed (63.3±8.6% versus 63.8±6.0%,
P
=0.60). In multivariate analysis, lower GLS was associated with SBI (odds ratio/unit decrease=1.18; 95% confidence interval, 1.05–1.33;
P
<0.01), whereas LVEF was not (odds ratio/unit increase=1.00; 95% confidence interval, 0.96–1.05;
P
=0.98). Lower GLS was associated with greater white matter hyperintensity volume (adjusted β=0.11,
P
<0.05), unlike LVEF (adjusted β=−0.04,
P
=0.42).

Conclusions—
Lower GLS was independently associated with subclinical brain disease in a community-based cohort without overt cardiac disease. GLS can provide additional information on cerebrovascular risk burden beyond LVEF assessment.
Brugada Syndrome Behind Complete Right Bundle-Branch Block
Authors: Aizawa Yoshiyasu , Takatsuki Seiji , Sano Motoaki , Kimura Takehiro , Nishiyama Nobuhiro , Fukumoto Kotaro , Tanimoto Yoko , Tanimoto Kojiro , Murata Mitsushige , Komatsu Takashi , Mitamura Hideo , Ogawa Satoshi , Funazaki Toshikazu , Sato Masahito , Aizawa Yoshifusa , Fukuda Keiichi 
Published: August 2013

Background—
The characteristic ECG of Brugada syndrome (BS) can be masked by complete right bundle-branch block (CRBBB) and exposed by resolution of the block or pharmacological or pacing maneuvers.

Methods and Results—

The study consisted of 11 patients who had BS and CRBBB. BS was diagnosed before the development of CRBBB, on the resolution of CRBBB, or from new characteristic ST-segment changes that could be attributable to BS. Structural heart diseases were excluded, and coronary spasm was excluded on the basis of a provocation test at catheterization. In 7 patients, BS was diagnosed before the development of CRBBB. BS was diagnosed when CRBBB resolved spontaneously (n=1) or by right ventricular pacing (n=3). The precipitating cause for the spontaneous resolution of CRBBB, however, was not apparent. On repeated ECGs, new additional upward-convex ST-segment elevation was found in V
2
or V
3
in 3 patients. In 2 patients, new ST-segment elevation was induced by class I
C
drugs. The QRS duration was more prolonged in patients with BS and CRBBB compared with age- and sex-matched controls: 170±13 versus 145±15 milliseconds in V
1
and 144±19 versus 128±7 milliseconds in V
5
(both
P
<0.0001). The amplitude of R in V
1
was larger in the BS patients than in the control subjects (
P
=0.0323), but that of R′ was similar (
P
=0.0560).

Conclusions—
BS can coexist behind CRBBB, and CRBBB can completely mask BS. BS might be demonstrated by relief of CRBBB or by spontaneous or drug-induced ST-segment elevation. The prevalence, mechanism, and clinical significance of a combination of CRBBB and BS are yet to be determined.
Selective Inhibition of the Master Regulator Transcription Factor Egr‐1 With Catalytic Oligonucleotides Reduces Myocardial Injury and Improves Left Ventricular Systolic Function in a Preclinical Model of Myocardial Infarction
Authors: Rayner Benjamin S. , Figtree Gemma A. , Sabaretnam Tharani , Shang Ping , Mazhar Jawad , Weaver James C. , Lay William N. , Witting Paul K. , Hunyor Stephen N. , Grieve Stuart M. , Khachigian Levon M. , Bhindi Ravinay 
Published: August 2013

Background

Egr‐1 is implicated in the pathogenesis of myocardial ischemia–reperfusion injury. The aim of this study was to ascertain the effectiveness of intracoronary delivery of
DNA
zyme targeting the transcription factor Egr‐1 at reperfusion following experimental myocardial ischemia.

Methods and Results

Functional
DNA
zyme targeting Egr‐1 or a size‐matched scrambled control were delivered via the intracoronary route immediately on reperfusion after 60 minutes' balloon occlusion of the left anterior descending coronary artery in a pig model of myocardial I/R injury (n=7 per treatment group). Heart function and extent of myocardial infarction were determined following intervention by echocardiography and cardiac magnetic resonance imaging, respectively. Hearts were removed and examined for molecular and histological markers of inflammation and apoptosis. Administration of functional
DNA
zyme led to an overall decrease in the expression of inflammatory markers including intracellular adhesion molecule‐1, tissue factor, and complement 3, with associated decreases in the extent of neutrophil infiltration, oxidative damage, and subsequent apoptosis within the infarct border zone. Functional significance was indicated by an increase in salvaged left ventricular myocardium (
P
=0.012), ejection fraction (
P
=0.002), and fractional area change (
P
=0.039) in the functional
DNA
zyme–treated group compared with the control.

Conclusions

Egr‐1 silencing through intracoronary delivery of a targeting
DNA
zyme at the time of reperfusion following acute myocardial ischemia decreases myocardial inflammation and apoptosis leading to improved cardiac function.
Angiotensin Receptor–Binding Protein ATRAP/
Agtrap
Inhibits Metabolic Dysfunction With Visceral Obesity
Authors: Maeda Akinobu , Tamura Kouichi , Wakui Hiromichi , Dejima Toru , Ohsawa Masato , Azushima Kengo , Kanaoka Tomohiko , Uneda Kazushi , Matsuda Miyuki , Yamashita Akio , Miyazaki Nobuko , Yatsu Keisuke , Hirawa Nobuhito , Toya Yoshiyuki , Umemura Satoshi 
Published: August 2013

Background
Metabolic disorders with visceral obesity have become a major medical problem associated with the development of hypertension, type 2 diabetes, and dyslipidemia and, ultimately, life‐threatening cardiovascular and renal diseases. Adipose tissue dysfunction has been proposed as the cause of visceral obesity‐related metabolic disorders, moving the tissue toward a proinflammatory phenotype.

Methods and Results

Here we first report that adipose tissues from patients and mice with metabolic disorders exhibit decreased expression of
ATRAP
/
Agtrap
, which is a specific binding modulator of the angiotensin
II
type 1 receptor, despite its abundant expression in adipose tissues from normal human and control mice. Subsequently, to examine a functional role of
ATRAP
in the pathophysiology of metabolic disorders, we produced homozygous
ATRAP
deficient (
Agtrap
−/−
) mice, which exhibited largely normal physiological phenotype at baseline. Under dietary high fat loading,
Agtrap
−/−
mice displayed systemic metabolic dysfunction, characterized by an increased accumulation of pad fat, hypertension, dyslipidemia, and insulin resistance, along with adipose tissue inflammation. Conversely, subcutaneous transplantation of donor fat pads overexpressing
ATRAP
derived from
Agtrap
transgenic mice to
Agtrap
−/−
recipient mice improved the systemic metabolic dysfunction.

Conclusions

These results demonstrate that
Agtrap
−/−
mice are an effective model of metabolic disorders with visceral obesity and constitute evidence that
ATRAP
plays a protective role against insulin resistance, suggesting a new therapeutic target in metabolic disorders. Identification of
ATRAP
as a novel receptor binding modulator of adipose tissue inflammation not only has cardiovascular significance but may have generalized implication in the regulation of tissue function.
Southeastern U.S. Daily Temperature Ranges Associated with the El Niño–Southern Oscillation
Authors: Gilford Daniel M. , Smith Shawn R. , Griffin Melissa L. , Arguez Anthony 
Published: August 2013

AbstractThe daily temperature range (DTR; daily maximum temperature minus daily minimum temperature) at 290 southeastern U.S. stations is examined with respect to the warm and cold phases of the El Niño–Southern Oscillation (ENSO) for the period of 1948–2009. A comparison of El Niño and La Niña DTR distributions during 3-month seasons is conducted using various metrics. Histograms show each station’s particular distribution. To compare directly the normalized distributions of El Niño and La Niña, a new metric (herein called conditional ratio) is produced and results are evaluated for significance at 95% confidence with a bootstrapping technique. Results show that during 3-month winter, spring, and autumn seasons DTRs above 29°F (16.1°C) are significantly more frequent during La Niña events and that DTRs below 15°F (8.3°C) are significantly more frequent during El Niño events. It is hypothesized that these results are associated spatially with cloud cover and storm tracks during each season and ENSO phase. Relationships between DTRs and ENSO-related relative humidity are examined. These results are pertinent to the cattle industry in the Southeast, allowing ranchers to plan for and mitigate threats posed by periods of low DTRs associated with the predicted phase of ENSO.
Quantifying Surface Energy Fluxes in the Vicinity of Inland-Tracking Tropical Cyclones
Authors: Andersen Theresa K. , Radcliffe David E. , Shepherd J. Marshall 
Published: August 2013

AbstractTropical cyclones (TCs) typically weaken or transition to extratropical cyclones after making landfall. However, there are cases of TCs maintaining warm-core structures and intensifying inland unexpectedly, referred to as TC maintenance or intensification events (TCMIs). It has been proposed that wet soils create an atmosphere conducive to TC maintenance by enhancing surface latent heat flux (LHF). In this study, “HYDRUS-1D” is used to simulate the surface energy balance in intensification regions leading up to four different TCMIs. Specifically, the 2-week magnitudes and trends of soil temperature, sensible heat flux (SHF), and LHF are analyzed and compared across regions. While TCMIs are most common over northern Australia, theoretically linked to large fluxes from hot sands, the results revealed that SHF and LHF are equally large over the south-central United States. Modern-Era Retrospective Analysis for Research and Applications (MERRA) 3-hourly LHF data were obtained for the same HYDRUS study regions as well as nearby ocean regions along the TC path 3 days prior (prestorm) to the TC appearance. Results indicate that the simulated prestorm mean LHF is similar in magnitude to that obtained from MERRA, with slightly lower values overall. The modeled 3-day mean fluxes over land are less than those found over the ocean; however, the maximum LHF over the 3-day period is greater over land (HYDRUS) than over the ocean (MERRA) for three of four cases. It is concluded that LHF inland can achieve similar magnitudes to that over the ocean during the daytime and should be pursued as a potential energy source for inland TCs.
Long-Term Variations of Broad-Scale Asian Summer Monsoon Circulation and Possible Causes
Authors: Zuo Zhiyan , Yang Song , Zhang Renhe , Jiang Pinping , Zhang Li , Wang Fang 
Published: August 2013

AbstractThe widely applied Webster–Yang index (WYI), which measures the broad-scale dynamical features of the Asian summer monsoon (ASM), has experienced robust interannual and interdecadal variations and a decreasing tendency, with apparent shifts in 1972. The WYI exhibits moderate variability and frequent positive phases before 1972, intensive interannual variability during 1972–98, and an obvious decreasing tendency and mainly negative phase afterward. The vertical shear easterly anomalies over the tropics/subtropics and the anomalous vertical shear anticyclonic circulation over Eurasia (Eu) are the background for the decreasing WYI, associated with reduced summer precipitation around the Bay of Bengal and Sumatra. On interdecadal time scales, the negative (positive) Atlantic multidecadal oscillation (AMO) is characterized by cooling (warming) in Eurasian tropospheric temperature (TT) via the North Atlantic Oscillation. Global warming manipulates the increasing tendency and the interannual variability of TT over the Indian Ocean (IO). The mutual effects of AMO on Eurasian TT and global warming on Indian Ocean TT correspond to the similar decreasing tendency and interdecadal shift of the difference in TT between Eurasia and the Indian Ocean (EuTT − IOTT) with those of the ASM. Thus, the AMO and global warming seem to cause the interdecadal variability of ASM. Although the interannual relationship between Niño-3 SST and ASM weakens recently as a result of the weakening tendency of ASM, the Niño-3 SST still plays an important role in ASM variability via EuTT − IOTT anomalies. In addition, the WYI in the National Centers for Environmental Prediction–National Center for Atmospheric Research (NCEP–NCAR) reanalysis shows a larger decreasing tendency for 1999–2010 compared to other reanalysis products, a plausible reason for the inconsistent variations between land–sea thermal contrast and the NCEP–NCAR WYI during that period.
How Important is Vegetation Phenology for European Climate and Heat Waves?
Authors: Lorenz Ruth , Davin Edouard L. , Lawrence David M. , Stöckli Reto , Seneviratne Sonia I. 
Published: August 2013

Abstract
It has been hypothesized that vegetation phenology may play an important role for the midlatitude climate. This study investigates the impact of interannual and intraseasonal variations in phenology on European climate using regional climate model simulations. In addition, it assesses the relative importance of interannual variations in vegetation phenology and soil moisture on European summer climate.
It is found that drastic phenological changes have a smaller effect on mean summer and spring climate than extreme changes in soil moisture (roughly ¼ of the temperature anomaly induced by soil moisture changes). However, the impact of phenological anomalies during heat waves is found to be more important. Generally, late and weak greening has amplifying effects and early and strong greening has dampening effects on heat waves; however, regional variations are found. The experiments suggest that in the extreme hot 2003 (western and central Europe) and 2007 (southeastern Europe) summers the decrease in leaf area index amplified the heat wave peaks by about 0.5°C for daily maximum temperatures (about half of the effect induced by soil moisture deficit). In contrast to earlier hypotheses, no anomalous early greening in spring 2003 is seen in the phenological dataset employed here. Hence, the results indicate that vegetation feedbacks amplified the 2003 heat wave but were not responsible for its initiation. In conclusion, the results suggest that phenology has a limited effect on European mean summer climate, but its impact can be as important as that induced by soil moisture anomalies in the context of specific extreme events.
The Impact of Ice Phase Cloud Parameterizations on Tropical Cyclone Prediction
Authors: Jin Yi , Wang Shouping , Nachamkin Jason , Doyle James D. , Thompson Gregory , Grasso Lewis , Holt Teddy , Moskaitis Jon , Jin Hao , Hodur Richard M. , Zhao Qingyun , Liu Ming , DeMaria Mark 
Published: August 2013

Abstract
The impact of ice phase cloud microphysical processes on prediction of tropical cyclone environment is examined for two microphysical parameterizations using the Coupled Ocean–Atmosphere Mesoscale Prediction System–Tropical Cyclone (COAMPS-TC) model. An older version of microphysical parameterization is a relatively typical single-moment scheme with five hydrometeor species: cloud water and ice, rain, snow, and graupel. An alternative newer method uses a hybrid approach of double moment in cloud ice and rain and single moment in the other three species. Basin-scale synoptic flow simulations point to important differences between these two schemes. The upper-level cloud ice concentrations produced by the older scheme are up to two orders of magnitude greater than the newer scheme, primarily due to differing assumptions concerning the ice nucleation parameterization. Significant (1°–2°C) warm biases near the 300-hPa level in the control experiments are not present using the newer scheme. The warm bias in the control simulations is associated with the longwave radiative heating near the base of the cloud ice layer. The two schemes produced different track and intensity forecasts for 15 Atlantic storms. Rightward cross-track bias and positive intensity bias in the control forecasts are significantly reduced using the newer scheme. Synthetic satellite imagery of Hurricane Igor (2010) shows more realistic brightness temperatures from the simulations using the newer scheme, in which the inner core structure is clearly discernible. Applying the synthetic satellite imagery in both quantitative and qualitative analyses helped to pinpoint the issue of excessive upper-level cloud ice in the older scheme.