bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prolongation of Overall Survival in Advanced Lung Adenocarcinoma Patients with the XAGE1 (GAGED2a) Antibody
Authors: Ohue Yoshihiro , Kurose Koji , Mizote Yu , Matsumoto Hirofumi , Nishio Yumi , Isobe Midori , Fukuda Minoru , Uenaka Akiko , Oka Mikio , Nakayama Eiichi 
Published: August 2014

Abstract
Purpose: The cancer/testis antigen XAGE1 (GAGED2a) is expressed in approximately 40% of advanced lung adenocarcinomas. We investigated the clinical relevance of the XAGE1 (GAGED2a) immune responses in patients with advanced lung adenocarcinoma.
Experimental Design: The XAGE1 (GAGED2a) antigen expression and EGFR mutation were determined with tumor tissues. The XAGE1 (GAGED2a) antibody and T-cell immune responses, as well as immune cell phenotypes, were analyzed with blood samples. Patients with EGFR wild-type (EGFRwt) tumors were treated with conventional platinum-based doublet chemotherapy and patients with EGFR-mutated (EGFRmt) tumors were treated with EGFR-TKI and conventional chemotherapy. The overall survival (OS) rates of the antibody-positive and -negative patients were investigated.
Results: The results showed that the OS of antibody-positive patients was prolonged significantly compared with that of antibody-negative patients with either XAGE1 (GAGED2a) antigen-positive EGFRwt (31.5 vs. 15.6 months, P = 0.05) or EGFRmt (34.7 vs. 11.1 months, P = 0.001) tumors. Multivariate analysis showed that the presence of the XAGE1 (GAGED2a) antibody was a strong predictor for prolonged OS in patients with XAGE1 (GAGED2a) antigen-positive tumors and in patients with either EGFRwt or EGFRmt tumors. On the other hand, XAGE1 (GAGED2a) antigen expression was a worse predictor in patients with EGFRmt tumors. Phenotypic and functional analyses of T cells indicated immune activation in the antibody-positive patients.
Conclusions: The findings suggest that production of the XAGE1 (GAGED2a) antibody predicts good prognosis for patients with lung adenocarcinoma as an immune biomarker and the protective effect of this naturally occurring immune response supports the concept of immunotherapy. Clin Cancer Res; 20(19); 5052–63. ©2014 AACR.
Low PIAS3 Expression in Malignant Mesothelioma Is Associated with Increased STAT3 Activation and Poor Patient Survival
Authors: Dabir Snehal , Kluge Amy , Kresak Adam , Yang Michael , Fu Pingfu , Groner Bernd , Wildey Gary , Dowlati Afshin 
Published: August 2014

AbstractPurpose: Deregulation of STAT3 activation is a hallmark of many cancer cells, and the underlying mechanisms are subject to intense investigation. We examined the extent of PIAS3 expression in mesothelioma cells and human tumor samples and determined the functional effects of PIAS3 expression on STAT3 signaling.Experimental design: We evaluated the expression of PIAS3 in mesothelioma tumors from patients and correlated the expression levels with the course of the disease. We also measured the effects of enhanced PIAS3 activity on STAT3 signaling, cellular growth, and viability in cultured mesothelioma cells.Results: Gene expression databases revealed that mesotheliomas have the lowest levels of PIAS3 transcripts among solid tumors. PIAS3 expression in human mesothelioma tumors is significantly correlated with overall survival intervals (P = 0.058). The high expression of PIAS3 is predictive of a favorable prognosis and decreases the probability of death within one year after diagnosis by 44%. PIAS3 expression is functionally linked to STAT3 activation in mesothelioma cell lines. STAT3 downregulation with siRNA or enhanced expression of PIAS3 both inhibited mesothelioma cell growth and induced apoptosis. Mesothelioma cells are sensitive to curcumin and respond by the induction of PIAS3. Corroborative evidence has been obtained from STAT3 inhibition experiments. Exposure of the cells to a peptide derived from the PIAS3 protein that interferes with STAT3 function resulted in apoptosis induction and the inhibition of cell growth.Conclusion: These results suggest that PIAS3 protein expression impacts survival in patients with mesothelioma and that PIAS3 activation could become a therapeutic strategy. Clin Cancer Res; 20(19); 5124–32. ©2014 AACR.
Inhibition of Endoglin–GIPC Interaction Inhibits Pancreatic Cancer Cell Growth
Authors: Pal Krishnendu , Pletnev Alexandre A. , Dutta Shamit K. , Wang Enfeng , Zhao Ruizhi , Baral Aradhita , Yadav Vinod Kumar , Aggarwal Suruchi , Krishnaswamy Soundararajan , Alkharfy Khalid M. , Chowdhury Shantanu , Spaller Mark R. , Mukhopadhyay Debabrata 
Published: August 2014

Abstract
Endoglin, a 180-kDa disulfide-linked homodimeric transmembrane receptor protein mostly expressed in tumor-associated endothelial cells, is an endogenous binding partner of GAIP-interacting protein, C terminus (GIPC). Endoglin functions as a coreceptor of TβRII that binds TGFβ and is important for vascular development, and consequently has become a compelling target for antiangiogenic therapies. A few recent studies in gastrointestinal stromal tumor (GIST), breast cancer, and ovarian cancer, however, suggest that endoglin is upregulated in tumor cells and is associated with poor prognosis. These findings indicate a broader role of endoglin in tumor biology, beyond angiogenic effects. The goal of our current study is to evaluate the effects of targeting endoglin in pancreatic cancer both in vitro and in vivo. We analyzed the antiproliferative effect of both RNAi-based and peptide ligand-based inhibition of endoglin in pancreatic cancer cell lines, the latter yielding a GIPC PDZ domain-targeting lipopeptide with notable antiproliferative activity. We further demonstrated that endoglin inhibition induced a differentiation phenotype in the pancreatic cancer cells and sensitized them against conventional chemotherapeutic drug gemcitabine. Most importantly, we have demonstrated the antitumor effect of both RNAi-based and competitive inhibitor–based blocking of endoglin in pancreatic cancer xenograft models in vivo. To our knowledge, this is the first report exploring the effect of targeting endoglin in pancreatic cancer cells. Mol Cancer Ther; 13(10); 2264–75. ©2014 AACR.
Circulating Soluble Receptor for Advanced Glycation End Product Identifies Patients With Bicuspid Aortic Valve and Associated Aortopathies
Authors: Branchetti Emanuela , Bavaria Joseph E. , Grau Juan B. , Shaw Richard E. , Poggio Paolo , Lai Eric K. , Desai Nimesh D. , Gorman Joseph H. , Gorman Robert C. , Ferrari Giovanni 
Published: August 2014

Objective—
A total of 30% to 50% of patients with bicuspid aortic valve (BAV) require surgery for aortic valve replacement (AVR), ascending aortic replacement (AA), or both. To prevent adverse aortic events, they are risk stratified using imperfect criteria based on imaging modalities. As a result, a significant number of dissections occur outside of the parameters suggested by the guidelines. Advanced glycation end products (AGEs) are associated with valve and vascular remodeling and trigger the release of a soluble receptor (soluble receptor for advanced glycation end product [sRAGE]). This study aims to characterize sRAGE as a diagnostic and risk-stratification tool for patients with BAV referred for surgery.

Approach and Results—

sRAGE was measured in 135 patients (BAV, n=74; tricuspid aortic valve, n=61) meeting inclusion criteria from 338 enrolled patients undergoing AVR and AA. Univariate and multivariate analyses were performed. sRAGE level was significantly associated with the presence of BAV, independent of age, sex, and common risk factors for vascular disease (
P
<0.001). Within the BAV cohort, patients referred for AA and AVR had higher sRAGE values than patients undergoing AVR only (
P
=0.002). Patients with BAV <60 years of age, presenting with both valve and aortic diseases (fast progressors), had higher sRAGE than older patients who only needed AVR (slow progressors). Histological analysis showed that sRAGE correlates with dysfunctional aortic microstructure and does not correlate with aortic diameter (
R
2
=0.007;
P
=0.51) or diameter/body surface area (
R
2
=0.011;
P
=0.42).

Conclusions—
These results show that elevated level of circulating sRAGE is associated with the presence of BAV and associated aortopathies, independent of aortic diameter.
Early Development of Calcific Aortic Valve Disease and Left Ventricular Hypertrophy in a Mouse Model of Combined Dyslipidemia and Type 2 Diabetes Mellitus
Authors: Le Quang Khai , Bouchareb Rihab , Lachance Dominic , Laplante Marc-André , Husseini Diala El , Boulanger Marie-Chloé , Fournier Dominique , Fang Xiang Ping , Avramoglu Rita Kohen , Pibarot Philippe , Deshaies Yves , Sweeney Gary , Mathieu Patrick , Marette André 
Published: August 2014

Objective—
This study aimed to determine the potential impact of type 2 diabetes mellitus on left ventricular dysfunction and the development of calcified aortic valve disease using a dyslipidemic mouse model prone to developing type 2 diabetes mellitus.

Approach and Results—

When compared with nondiabetic LDLr
−/−
/ApoB
100/100
, diabetic LDLr
−/−
/ApoB
100/100
/IGF-II mice exhibited similar dyslipidemia and obesity but developed type 2 diabetes mellitus when fed a high-fat/sucrose/cholesterol diet for 6 months. LDLr
−/−
/ApoB
100/100
/IGF-II mice showed left ventricular hypertrophy versus C57BL6 but not LDLr
−/−
/ApoB
100/100
mice. Transthoracic echocardiography revealed significant reductions in both left ventricular systolic fractional shortening and diastolic function in high-fat/sucrose/cholesterol fed LDLr
−/−
/ApoB
100/100
/IGF-II mice when compared with LDLr
−/−
/ApoB
100/100
. Importantly, we found that peak aortic jet velocity was significantly increased in LDLr
−/−
/ApoB
100/100
/IGF-II mice versus LDLr
−/−
/ApoB
100/100
animals on the high-fat/sucrose/cholesterol diet. Microtomography scans and Alizarin red staining indicated calcification in the aortic valves, whereas electron microscopy and energy dispersive x-ray spectroscopy further revealed mineralization of the aortic leaflets and the presence of inflammatory infiltrates in diabetic mice. Studies showed upregulation of hypertrophic genes (
anp
,
bnp
,
b-mhc
) in myocardial tissues and of osteogenic genes (
spp1
,
bglap
,
runx2
) in aortic tissues of diabetic mice.

Conclusions—

We have established the diabetes mellitus –prone LDLr
−/−
/ApoB
100/100
/IGF-II mouse as a new model of calcified aortic valve disease. Our results are consistent with the growing body of clinical evidence that the dysmetabolic state of type 2 diabetes mellitus contributes to early mineralization of the aortic valve and calcified aortic valve disease pathogenesis.
RP5-833A20.1/miR-382-5p/NFIA–Dependent Signal Transduction Pathway Contributes to the Regulation of Cholesterol Homeostasis and Inflammatory Reaction
Authors: Hu Yan-Wei , Zhao Jia-Yi , Li Shu-Fen , Huang Jin-Lan , Qiu Yu-Rong , Ma Xin , Wu Shao-Guo , Chen Zhi-Ping , Hu Ya-Rong , Yang Jun-Yao , Wang Yan-Chao , Gao Ji-Juan , Sha Yan-Hua , Zheng Lei , Wang Qian 
Published: August 2014

Objective—
Cardiovascular disease caused by atherosclerosis is the number one cause of death in Western countries and threatens to become the major cause of morbidity and mortality worldwide. Long noncoding RNAs are emerging as new players in gene regulation, but how long noncoding RNAs operate in the development of atherosclerosis remains unclear.

Approach and Results—
Using microarray analysis, we found that long noncoding RNA RP5-833A20.1 expression was upregulated, whereas nuclear factor IA (NFIA) expression was downregulated in human acute monocytic leukemia macrophage–derived foam cells. Moreover, we showed that long noncoding RNA RP5-833A20.1 may decreases NFIA expression by inducing hsa-miR-382-5p expression in vitro. We found that the RP5-833A20.1/hsa-miR-382-5p/NFIA pathway is essential to the regulation of cholesterol homeostasis and inflammatory responses in human acute monocytic leukemia macrophages. Lentivirus-mediated NFIA overexpression increased high-density lipoprotein cholesterol circulation, reduced low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol circulation, decreased circulation of inflammatory cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-α, and C-reactive protein, enhanced reverse cholesterol transport, and promoted regression of atherosclerosis in apolipoprotein E–deficient mice.

Conclusions—
Our findings indicated that the RP5-833A20.1/miR-382-5p/NFIA pathway was essential to the regulation of cholesterol homeostasis and inflammatory reactions and suggested that NFIA may represent a therapeutic target to ameliorate cardiovascular disease.
Integrating Genetic, Transcriptional, and Functional Analyses to Identify 5 Novel Genes for Atrial Fibrillation
Authors: Sinner Moritz F. , Tucker Nathan R. , Lunetta Kathryn L. , Ozaki Kouichi , Smith J. Gustav , Trompet Stella , Bis Joshua C. , Lin Honghuang , Chung Mina K. , Nielsen Jonas B. , Lubitz Steven A. , Krijthe Bouwe P. , Magnani Jared W. , Ye Jiangchuan , Gollob Michael H. , Tsunoda Tatsuhiko , Müller-Nurasyid Martina , Lichtner Peter , Peters Annette , Dolmatova Elena , Kubo Michiaki , Smith Jonathan D. , Psaty Bruce M. , Smith Nicholas L. , Jukema J. Wouter , Chasman Daniel I. , Albert Christine M. , Ebana Yusuke , Furukawa Tetsushi , Macfarlane Peter W. , Harris Tamara B. , Darbar Dawood , Dörr Marcus , Holst Anders G. , Svendsen Jesper H. , Hofman Albert , Uitterlinden Andre G. , Gudnason Vilmundur , Isobe Mitsuaki , Malik Rainer , Dichgans Martin , Rosand Jonathan , Van Wagoner David R. , Benjamin Emelia J. , Milan David J. , Melander Olle , Heckbert Susan R. , Ford Ian , Liu Yongmei , Barnard John , Olesen Morten S. , Stricker Bruno H.C. , Tanaka Toshihiro , Kääb Stefan , Ellinor Patrick T. 
Published: August 2014

Background—
Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.

Methods and Results—

To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (
expression quantitative trait loci
) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes
NEURL
(rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13–1.23;
P
=6.5×10
−16
),
GJA1
(rs13216675; RR=1.10; 95% CI, 1.06–1.14;
P
=2.2×10
−8
),
TBX5
(rs10507248; RR=1.12; 95% CI, 1.08–1.16;
P
=5.7×10
−11
), and
CAND2
(rs4642101; RR=1.10; 95% CI, 1.06–1.14;
P
=9.8×10
−9
). In Japanese, novel loci were identified near
NEURL
(rs6584555; RR=1.32; 95% CI, 1.26–1.39;
P
=2.0×10
−25
) and
CUX2
(rs6490029; RR=1.12; 95% CI, 1.08–1.16;
P
=3.9×10
−9
). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes
CAND2
(
P
=2.6×10
−19
),
GJA1
(
P
=2.66×10
−6
), and
TBX5
(
P
=1.36×10
−5
). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively).

Conclusions—
We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.
Circulating Omega-6 Polyunsaturated Fatty Acids and Total and Cause-Specific Mortality
Authors: Wu Jason H.Y. , Lemaitre Rozenn N. , King Irena B. , Song Xiaoling , Psaty Bruce M. , Siscovick David S. , Mozaffarian Dariush 
Published: August 2014

Background—
Although omega-6 polyunsaturated fatty acids (n-6 PUFA) have been recommended to reduce coronary heart disease (CHD), controversy remains about benefits versus harms, including concerns over theorized proinflammatory effects of n-6 PUFA. We investigated associations of circulating n-6 PUFA including linoleic acid (the major dietary PUFA), γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid, with total and cause-specific mortality in the Cardiovascular Health Study, a community-based U.S. cohort.

Methods and Results—

Among 2792 participants(aged ≥65 years) free of cardiovascular disease at baseline, plasma phospholipid n-6 PUFA were measured at baseline using standardized methods. All-cause and cause-specific mortality, and total incident CHD and stroke, were assessed and adjudicated centrally. Associations of PUFA with risk were assessed by Cox regression. During 34 291 person-years of follow-up (1992–2010), 1994 deaths occurred (678 cardiovascular deaths), with 427 fatal and 418 nonfatal CHD, and 154 fatal and 399 nonfatal strokes. In multivariable models, higher linoleic acid was associated with lower total mortality, with extreme-quintile hazard ratio =0.87 (
P
trend=0.005). Lower death was largely attributable to cardiovascular disease causes, especially nonarrhythmic CHD mortality (hazard ratio, 0.51; 95% confidence interval, 0.32–0.82;
P
trend=0.001). Circulating γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid were not significantly associated with total or cause-specific mortality (eg, for arachidonic acid and CHD death, the extreme-quintile hazard ratio was 0.97; 95% confidence interval, 0.70–1.34;
P
trend=0.87). Evaluated semiparametrically, linoleic acid showed graded inverse associations with total mortality (
P
=0.005). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA. Evaluating both n-6 and n-3 PUFA, lowest risk was evident with highest levels of both.

Conclusions—
High circulating linoleic acid, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.
Cyclogenesis Downstream of Extratropical Transition Analyzed by Q-Vector Partitioning Based on Flow Geometry
Authors: Riemer Michael , Baumgart Marlene , Eiermann Sven 
Published: August 2014

Abstract
During extratropical transition (ET), tropical cyclones exert a significant impact on the midlatitude circulation. Archetypical features of this impact are jet streak formation, amplification of the downstream trough, and modification of the associated downstream cyclogenesis. This study investigates the relative importance of the jet streak and the upper-level trough for cyclone development by quantifying the respective contributions to midtropospheric vertical motion using the Q-vector partitioning by J. C. Jusem and R. Atlas. Their framework is here extended from quasigeostrophic theory to alternative balance. The Q vector under alternative balance involves the nondivergent wind, instead of the geostrophic wind, and therefore represents more accurately the balanced dynamics associated with vertical motion, in particular downstream of ET where the flow often exhibits significant curvature associated with the amplified trough.
An idealized ET scenario and three real cases, the cyclones downstream of Hanna (2008), Choi-wan (2008), and Jangmi (2009), are analyzed. In all cases, the trough plays a prominent role in cyclone development. The jet streak plays a prominent, favorable role in the idealized ET scenario and downstream of Hanna. In contrast, the role of the jet streak downstream of Choi-wan is clearly of secondary importance. Interestingly, downstream of Jangmi the jet streak has a prominent but detrimental impact. It is concluded that amplified jet streaks associated with ET have the potential to be of significant importance for downstream cyclone development. The few cases considered in this study, however, point to a large case-to-case variability of the role of the jet streak.
The Sensitivity of a Numerically Simulated Idealized Squall Line to the Vertical Distribution of Aerosols
Authors: Lebo Zachary J. 
Published: August 2014

Abstract
Changes in the aerosol number concentration are reflected by changes in raindrop size and number concentration that ultimately affect the strength of cold pools via evaporation. Therefore, aerosol perturbations can potentially alter the balance between cold pool–induced and low-level wind shear–induced circulations. In the present work, simulations with increased aerosol loadings below approximately 3 km, between approximately 3 and 10 km, and at all vertical levels are performed to specifically address both the overall sensitivity of a squall line to the vertical distribution of aerosols and the extent to which low-level aerosols can affect the convective strength of the system. The results suggest that low-level aerosol perturbations have a negligible effect on the overall storm strength even though they act to enhance low-level latent heating rates. A tracer analysis shows that the low-level aerosols are either predominantly detrained at or below the freezing level or are rapidly lifted to the top of the troposphere or the lower stratosphere within the strongest convective cores. Moreover, it is shown that midlevel aerosol perturbations have nearly the same effect as perturbing the entire domain, increasing the convective updraft mass flux by more than 10%. These changes in strength are driven by a complex chain of events caused by smaller supercooled droplets, larger graupel, and larger raindrops. Combined, these changes tend to reduce the low-level bulk evaporation rate, thus weakening the cold pool and enhancing updraft strength. The results presented herein suggest that midlevel aerosol perturbations may exhibit a much larger effect on squall lines, at least in the context of this idealized framework.
A prospective interrupted time series study of interventions to improve the quality, rating, framing and structure of goal-setting in community-based brain injury rehabilitation
Authors: Hassett Leanne , Simpson Grahame , Cotter Rachel , Whiting Diane , Hodgkinson Adeline , Martin Diane 
Published: August 2014

Objective: To investigate whether the introduction of an electronic goals system followed by staff training improved the quality, rating, framing and structure of goals written by a community-based brain injury rehabilitation team. Design: Interrupted time series design. Intervention: Two interventions were introduced six months apart. The first intervention comprised the introduction of an electronic goals system. The second intervention comprised a staff goal training workshop. Methods: An audit protocol was devised to evaluate the goals. A random selection of goal statements from the 12 months prior to the interventions (Time 1 baseline) were compared with all goal statements written after the introduction of the electronic goals system (Time 2) and staff training (Time 3). All goals were de-identified for client and time-period, and randomly ordered. Results: A total of 745 goals (Time 1 n = 242; Time 2 n = 283; Time 3 n = 220) were evaluated. Compared with baseline, the introduction of the electronic goals system alone significantly increased goal rating, framing and structure (χ2 tests 144.7, 18.9, 48.1, respectively, p < 0.001). The addition of staff training meant that the improvement in goal quality, which was only a trend at Time 2, was statistically significant at Time 3 (χ2 15.0, p ≤ 001). The training also led to a further significant increase in the framing and structuring of goals over the electronic goals system (χ2 11.5, 12.5, respectively, p ≤ 0.001). Conclusion: An electronic goals system combined with staff training improved the quality, rating, framing and structure of goal statements.