bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondria-regulated formation of endothelium-derived extracellular vesicles shifts the mediator of flow-induced vasodilation
Authors: Freed Julie K. , Durand Matthew J. , Hoffmann Brian R. , Densmore John C. , Greene Andrew S. , Gutterman David D. 
Published: February 2017

To examine the effect of endothelium-derived extracellular vesicles (eEVs) on the mediator of flow-induced dilation (FID), composition, formation, and functional effects on the mediator of FID were examined from two different eEV subtypes, one produced from ceramide, while the other was produced from plasminogen-activator inhibitor 1 (PAI-1). Using video microscopy, we measured internal-diameter changes in response to increases in flow in human adipose resistance arteries acutely exposed (30 min) to eEVs derived from cultured endothelial cells exposed to ceramide or PAI-1. FID was significantly impaired following exposure to 500K/ml (K = 1,000) of ceramide-induced eEVs (Cer-eEVs) but unaffected by 250K/ml. FID was reduced in the presence of PEG-catalase following administration of 250K/ml of Cer-eEVs and PAI-1 eEVs, whereas Nω-nitro-l-arginine methyl ester (l-NAME) had no effect. Pathway analysis following protein composition examination using liquid chromatography tandem mass spectrometry (LC-MS/MS) demonstrated that both subtypes were strongly linked to similar biological functions, primarily, mitochondrial dysfunction. Flow cytometry was used to quantify eEVs in the presence or absence of l-phenylalanine-4′-boronic acid (PBA) and mitochondria-targeted [93-boronophenyl)methyl]triphenyl-phosphonium (mito-PBA), cytosolic and mitochondrial-targeted antioxidants, respectively. eEV formation was significantly and dramatically reduced with mito-PBA treatment. In conclusion, eEVs have a biphasic effect, with higher doses impairing and lower doses shifting the mediator of FID from nitric oxide (NO) to hydrogen peroxide (H2O2). Despite differences in protein content, eEVs may alter vascular function in similar directions, regardless of the stimulus used for their formation. Furthermore, mitochondrial ROS production is required for the generation of these vesicles. NEW & NOTEWORTHY The vascular effect of endothelium-derived extracellular vesicles (eEVs) is biphasic, with higher doses decreasing the magnitude of flow-induced dilation (FID) compared with lower doses that shift the mediator of FID from nitric oxide to H2O2. eEVs may cause vascular dysfunction via similar pathways despite being formed from different stimuli, although both require mitochondrial reactive oxygen species for their formation.
Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone
Authors: Rathkopf Dana E. , Antonarakis Emmanuel S. , Shore Neal D. , Tutrone Ronald F. , Alumkal Joshi J. , Ryan Charles J. , Saleh Mansoor , Hauke Ralph J. , Bandekar Rajesh , Maneval Edna Chow , de Boer Carla J. , Yu Margaret K. , Scher Howard I. 
Published: February 2017

Abstract
Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC).
Experimental Design: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment.
Results: Forty-six patients enrolled in the AAP-naïve (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months–not reached) and 3.7 months (95% CI, 2.8–5.6 months), and median time on treatment 21 months (range, 2.6–37.5) and 4.9 months (range, 1.3–23.2), for the AAP-naïve and post-AAP cohorts, respectively. Eighty percent (95% CI, 59–93) and 64% (95% CI, 43–82) of AAP-naïve and 43% (95% CI, 22–66) and 10% (95% CI, 1–30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain.
Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naïve and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544–51. ©2017 AACR.
Hypoxia Selectively Enhances Integrin α5β1 Receptor Expression in Breast Cancer to Promote Metastasis
Authors: Ju Julia A. , Godet Inês , Ye I Chae , Byun Jungmin , Jayatilaka Hasini , Lee Sun Joo , Xiang Lisha , Samanta Debangshu , Lee Meng Horng , Wu Pei-Hsun , Wirtz Denis , Semenza Gregg L. , Gilkes Daniele M. 
Published: February 2017

Abstract
Metastasis is the leading cause of breast cancer mortality. Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix (ECM) in the metastatic process. Therefore, the contribution of potential ECM-binding receptors in this process was explored. Using a bioinformatics approach, the expression of all integrin receptor subunits, in two independent breast cancer patient datasets, were analyzed to determine whether integrin status correlates with a validated hypoxia-inducible gene signature. Subsequently, a large panel of breast cancer cell lines was used to validate that hypoxia induces the expression of integrins that bind to collagen (ITGA1, ITGA11, ITGB1) and fibronectin (ITGA5, ITGB1). Hypoxia-inducible factors (HIF-1 and HIF-2) are directly required for ITGA5 induction under hypoxic conditions, which leads to enhanced migration and invasion of single cells within a multicellular 3D tumor spheroid but did not affect migration in a 2D microenvironment. ITGB1 expression requires HIF-1α, but not HIF-2α, for hypoxic induction in breast cancer cells. ITGA5 (α5 subunit) is required for metastasis to lymph nodes and lungs in breast cancer models, and high ITGA5 expression in clinical biopsies is associated with an increased risk of mortality.
Implications: These results reveal that targeting ITGA5 using inhibitors that are currently under consideration in clinical trials may be beneficial for patients with hypoxic tumors. Mol Cancer Res; 15(6); 723–34. ©2017 AACR.
OTX2 Activity at Distal Regulatory Elements Shapes the Chromatin Landscape of Group 3 Medulloblastoma
Authors: Boulay Gaylor , Awad Mary E. , Riggi Nicolo , Archer Tenley C. , Iyer Sowmya , Boonseng Wannaporn E. , Rossetti Nikki E. , Naigles Beverly , Rengarajan Shruthi , Volorio Angela , Kim James C. , Mesirov Jill P. , Tamayo Pablo , Pomeroy Scott L. , Aryee Martin J. , Rivera Miguel N. 
Published: February 2017

AbstractMedulloblastoma is the most frequent malignant pediatric brain tumor and is divided into at least four subgroups known as WNT, SHH, Group 3, and Group 4. Here, we characterized gene regulation mechanisms in the most aggressive subtype, Group 3 tumors, through genome-wide chromatin and expression profiling. Our results show that most active distal sites in these tumors are occupied by the transcription factor OTX2. Highly active OTX2-bound enhancers are often arranged as clusters of adjacent peaks and are also bound by the transcription factor NEUROD1. These sites are responsive to OTX2 and NEUROD1 knockdown and could also be generated de novo upon ectopic OTX2 expression in primary cells, showing that OTX2 cooperates with NEUROD1 and plays a major role in maintaining and possibly establishing regulatory elements as a pioneer factor. Among OTX2 target genes, we identified the kinase NEK2, whose knockdown and pharmacologic inhibition decreased cell viability. Our studies thus show that OTX2 controls the regulatory landscape of Group 3 medulloblastoma through cooperative activity at enhancer elements and contributes to the expression of critical target genes.Significance: The gene regulation mechanisms that drive medulloblastoma are not well understood. Using chromatin profiling, we find that the transcription factor OTX2 acts as a pioneer factor and, in cooperation with NEUROD1, controls the Group 3 medulloblastoma active enhancer landscape. OTX2 itself or its target genes, including the mitotic kinase NEK2, represent attractive targets for future therapies. Cancer Discov; 7(3); 288–301. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 235
Effect of Sleep-Disordered Breathing on Appropriate Implantable Cardioverter-Defibrillator Therapy in Patients With Heart Failure
Authors: Kwon Younghoon , Koene Ryan J. , Kwon Osung , Kealhofer Jessica V. , Adabag Selcuk , Duval Sue 
Published: February 2017

Background—
Patients with heart failure and reduced ejection fraction are at increased risk of malignant ventricular arrhythmias. Implantable cardioverter-defibrillator (ICD) is recommended to prevent sudden cardiac death in some of these patients. Sleep-disordered breathing (SDB) is highly prevalent in this population and may impact arrhythmogenicity. We performed a systematic review and meta-analysis of prospective studies that assessed the impact of SDB on ICD therapy.

Methods and Results—
Relevant prospective studies were identified in the Ovid MEDLINE, EMBASE, and Google Scholar databases. Weighted risk ratios of the association between SDB and appropriate ICD therapies were estimated using random effects meta-analysis. Nine prospective cohort studies (n=1274) were included in this analysis. SDB was present in 52% of the participants. SDB was associated with a 55% higher risk of appropriate ICD therapies (45% versus 28%; risk ratio, 1.55; 95% confidence interval, 1.32–1.83). In a subgroup analysis based on the subtypes of SDB, the risk was higher in both central (risk ratio, 1.50; 95% confidence interval, 1.11–2.02) and obstructive (risk ratio, 1.43; 95% confidence interval, 1.01–2.03) sleep apnea.

Conclusions—
SDB is associated with an increased risk of appropriate ICD therapy in patients with heart failure and reduced ejection fraction.
Familial Occurrence of Atrioventricular Nodal Reentrant Tachycardia
Authors: Michowitz Yoav , Anis-Heusler Adi , Reinstein Eyal , Tovia-Brodie Oholi , Glick Aharon , Belhassen Bernard 
Published: February 2017

Background—
Atrioventricular nodal reentrant tachycardia (AVNRT) is considered a sporadic disease occurring in ≈22.5 cases per 10 000 in the general population. We define the prevalence and characteristics of familial AVNRT among patients who underwent radiofrequency ablation.

Methods and Results—

Ablation reports of all patients with familial AVNRT (at least 2 first-degree family members) who underwent radiofrequency ablation in our institution and in another hospital were reviewed. There were 1587 patients from our institution, of whom 20 had ≥1 first-degree relatives with AVNRT. This indicates a familial AVNRT prevalence of 127 cases per 10 000 (95% confidence interval, 82–196/10 000). First-degree relatives of patients with AVNRT presented a hazard ratio of at least 3.6 for exhibiting AVNRT compared with the general population. After inclusion of 4 families with familial AVNRT who underwent ablation at another hospital our population study comprised a total of 24 families (50 patients) with AVNRT. Patients at ablation were younger in the familial AVNRT group when compared with the sporadic AVNRT group (44.2±19 versus 54.8±18 years old,
P
=0.0001). The male/female ratio was similar, with female predominance. The supraventricular tachycardia mechanism was typical slow/fast reentry in most cases in both groups. The most common familial relationship in our 24 families included a parent and a child in 67% of cases and less often 2 siblings (29%).

Conclusions—
Familial AVNRT prevalence is higher than previously believed suggesting that this arrhythmia may have a genetic component. Autosomal dominance with incomplete penetrance is the most likely mode of inheritance.
Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies
Authors: Hedman Åsa K. , Mendelson Michael M. , Marioni Riccardo E. , Gustafsson Stefan , Joehanes Roby , Irvin Marguerite R. , Zhi Degui , Sandling Johanna K. , Yao Chen , Liu Chunyu , Liang Liming , Huan Tianxiao , McRae Allan F. , Demissie Serkalem , Shah Sonia , Starr John M. , Cupples L. Adrienne , Deloukas Panos , Spector Timothy D. , Sundström Johan , Krauss Ronald M. , Arnett Donna K. , Deary Ian J. , Lind Lars , Levy Daniel , Ingelsson Erik 
Published: February 2017

Background—
Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications.

Methods and Results—

To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine–guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (
P
<1.08E-07) and replicated 33 (at Bonferroni-corrected
P
<0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglycerides and high-density lipoprotein cholesterol (HDL-C; cg27243685;
P
=8.1E-26 and 9.3E-19) was associated with
cis
-expression of a reverse cholesterol transporter (
ABCG1; P
=7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15–1.66;
P
=0.0007). We found significant
cis
-methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels (
P
TC
=0.004,
P
HDL-C
=0.008 and
P
triglycerides
=0.00003) and coronary heart disease (
P
=0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at
APOB
were
cis
-methylation quantitative trait loci for a low-density lipoprotein cholesterol–related differentially methylated locus.

Conclusions—
We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events.
Detection and Monitoring of Acute Myocarditis Applying Quantitative Cardiovascular Magnetic Resonance
Authors: von Knobelsdorff-Brenkenhoff Florian , Schüler Johannes , Dogangüzel Serkan , Dieringer Matthias A. , Rudolph Andre , Greiser Andreas , Kellman Peter , Schulz-Menger Jeanette 
Published: February 2017

Background—
Cardiovascular magnetic resonance based on the Lake Louise Criteria is used to make the diagnosis of acute myocarditis. Novel quantitative parametric mapping techniques promise to overcome some of its limitations. We aimed to evaluate quantitative cardiovascular magnetic resonance to detect and monitor acute myocarditis.

Methods and Results—

Eighteen patients with clinical diagnosis of acute myocarditis (25 years [23–38 years]; 78% males) were prospectively enrolled and repeatedly underwent cardiovascular magnetic resonance at 1.5 T seven days (5–10 days) after symptom onset (FU0), after 5 weeks (FU1), and after 6 months (FU2). Eighteen age- and sex-matched healthy subjects served as controls. Cardiovascular magnetic resonance included imaging of edema, hyperemia, necrosis, and fibrosis using semiquantitative T2-weighted spin echo, T2 mapping, and T1 mapping before and 3 and 10 minutes after gadobutrol administration. Extracellular volume for diffuse and late gadolinium enhancement for focal fibrosis were assessed. Compared with controls, patients had significantly higher global T2 times at FU0 (55.1 ms [53.3–57.2 ms] versus 50.2 ms [49.2–52.0 ms];
P
<0.001) and at FU1 (52.0 ms [52.0–53.2 ms];
P
=0.007), which normalized at FU2 (50.9 ms [49.6–53.3 ms];
P
=0.323). Global native T1 times in patients were elevated acutely (1004 ms [988–1048 ms] versus 975 ms [957–1004 ms];
P
=0.002) and remained elevated throughout the follow-up (FU1: 998 ms [990–1027 ms];
P
=0.014; FU2: 1000 ms [972–1027 ms];
P
=0.044). Global extracellular volume fraction was statistically not different between patients and controls (
P
=0.057). 77.8% (14/18) of patients had focal late gadolinium enhancement. T2 ratio was significantly elevated in patients with myocarditis at FU0 (2.2 [2.0–2.3] versus 1.6 [1.5–1.7];
P
<0.001). The difference decreased during follow-up (FU1: 1.9 [1.7–1.9];
P
=0.001 and FU2: 1.7 [1.7–1.8];
P
=0.053). The diagnostic accuracy to discriminate between patients with acute myocarditis and healthy controls was 86% for T2>52 ms, 78% for native T1>981 ms, 74% for extracellular volume fraction >0.24, and 100% for T2 ratio >1.9.

Conclusions—
Although both T2 and T1 mapping reliably detected acute myocarditis, only T2 mapping discriminated between acute and healed stages, underlining the incremental value of T2 mapping.
Optimal Adenosine Stress for Maximum Stress Perfusion, Coronary Flow Reserve, and Pixel Distribution of Coronary Flow Capacity by Kolmogorov–Smirnov Analysis
Authors: Kitkungvan Danai , Lai Dejian , Zhu Hongjian , Roby Amanda E. , Johnson Nils P. , Steptoe Derek D. , Patel Monica B. , Kirkeeide Richard , Gould K. Lance 
Published: February 2017

Background—
Different adenosine stress imaging protocols have not been systemically validated for absolute myocardial perfusion and coronary flow reserve (CFR) by positron emission tomography, where submaximal stress precludes assessing physiological severity of coronary artery disease.

Methods and Results—
In 127 volunteers, serial rest–stress positron emission tomography scans using rubidium-82 with various adenosine infusion protocols identified (1) the protocol with maximum stress perfusion and CFR, (2) test–retest precision in same subject, (3) stress perfusion and CFR after adenosine compared with dipyridamole, (4) heterogeneity of coronary flow capacity combining stress perfusion and CFR, and (5) potential relevance for patients with risk factors or coronary artery disease. The adenosine 6-minute infusion with rubidium-82 injection at 3 minutes caused CFR that was significantly 15.7% higher than the 4-minute adenosine infusion with rubidium-82 injection at 2 minutes and significantly more homogeneous by Kolmogorov–Smirnov analysis for histograms of 1344 pixel range of perfusion in paired positron emission tomographies. In a coronary artery disease cohort separate from volunteers of this study, compared with the 3/6-minute protocol, the 2/4-minute adenosine protocol would potentially have changed 332 of 1732 (19%) positron emission tomographies at low-risk physiological severity CFR ≥2.3 to CFR <2.0, thereby implying high-risk quantitative severity potentially appropriate for interventions but because of suboptimal stress of the 2/4 protocol in some patients.

Conclusions—
The 6-minute adenosine infusion with rubidium-82 activation at 3 minutes produced CFR that averaged 15.7% higher than that in the 2/4-minute protocol, thereby potentially providing essential information for personalized management in some patients.
Evaluation of Timing and Route of Epinephrine in a Neonatal Model of Asphyxial Arrest
Authors: Vali Payam , Chandrasekharan Praveen , Rawat Munmun , Gugino Sylvia , Koenigsknecht Carmon , Helman Justin , Jusko William J. , Mathew Bobby , Berkelhamer Sara , Nair Jayasree , Wyckoff Myra H. , Lakshminrusimha Satyan 
Published: February 2017

Background

Epinephrine administered by low umbilical venous catheter (
UVC
) or endotracheal tube (
ETT
) is indicated in neonates who fail to respond to positive pressure ventilation and chest compressions at birth. Pharmacokinetics of
ETT
epinephrine via fluid‐filled lungs or
UVC
epinephrine in the presence of fetal shunts is unknown. We hypothesized that epinephrine administered by
ETT
or low
UVC
results in plasma epinephrine concentrations and rates of return of spontaneous circulation (
ROSC
) similar to right atrial (
RA
) epinephrine.

Methods and Results

Forty‐four lambs were randomized into the following groups:
RA
epinephrine (0.03 mg/kg), low
UVC
epinephrine (0.03 mg/kg), postcompression
ETT
epinephrine (0.1 mg/kg), and precompression
ETT
epinephrine (0.1 mg/kg). Asystole was induced by umbilical cord occlusion. Resuscitation was initiated following 5 minutes of asystole. Thirty‐eight of 44 lambs achieved
ROSC
(10/11, 9/11, and 12/22 in the
RA
,
UVC
, and
ETT
groups, respectively; subsequent
RA
epinephrine resulted in a total
ROSC
of 19/22 in the
ETT
groups). Median time (interquartile range) to achieve
ROSC
was significantly longer in the
ETT
group (including those that received
RA
epinephrine) compared to the intravenous group (4.5 [2.9–7.4] versus 2 [1.9–3] minutes;
P
=0.02).
RA
and low
UVC
epinephrine administration achieved comparable peak plasma epinephrine concentrations (470±250 versus 450±190 ng/mL) by 1 minute compared to
ETT
values of 130±60 ng/mL at 5 minutes;
P
=0.03. Following
ROSC
with
ETT
epinephrine alone, there was a delayed peak epinephrine concentration (652±240 ng/mL).

Conclusions

The absorption of
ETT
epinephrine is low and delayed at birth.
RA
and low
UVC
epinephrine rapidly achieve high plasma concentrations resulting in
ROSC
.
Cost‐Effectiveness of Intensifying Lipid‐Lowering Therapy With Statins Based on Individual Absolute Benefit in Coronary Artery Disease Patients
Authors: Stam‐Slob Manon C. , van der Graaf Yolanda , Greving Jacoba P. , Dorresteijn Jannick A.N. , Visseren Frank L.J. 
Published: February 2017

Background

A validated prediction model estimates the absolute benefit of intensive versus standard lipid‐lowering therapy (
LLT
) with statins on next major cardiovascular events for individual patients with coronary artery disease. We aimed to assess whether targeting intensive
LLT
therapy to
coronary artery disease
patients with the highest predicted absolute benefit is cost‐effective compared to treating all with standard or all with intensive
LLT
.

Methods and Results

A lifetime Markov model was constructed for
coronary artery disease
patients (n=10 000) with mean age 61 years. Number of
major cardiovascular events
, (non) vascular death, costs, and quality‐adjusted life years (
QALY
s) were estimated for the following strategies: (1) standard
LLT
for all (reference strategy); (2) intensive
LLT
for those with 5‐year absolute
major cardiovascular events
risk reduction (
ARR
) ≥3%, ≥2.3%, or ≥1.5% (corresponding to ≥20%, ≥15%, or ≥10% 5‐year
major cardiovascular events
risk); and (3) intensive
LLT
for all. With intensive
LLT
for those with ≥3% 5‐year
ARR
(13% of patients), 380
QALY
s were gained for €2423/
QALY
. Using a threshold of ≥2.3%
ARR
(26% of patients), 630
QALY
s were gained for €5653/
QALY
. Using a threshold of ≥1.5%
ARR
(56% of patients), 1020
QALY
s were gained for €10 960/
QALY
. By treating all intensively, 1410
QALY
s were gained (0.14
QALY
per patient) for €17 223/
QALY
. With benefit‐based treatment, 0.16 to 0.17
QALY
was gained per treated patient.

Conclusions

Intensive
LLT
with statins for all coronary artery disease patients results in the highest overall
QALY
gain against acceptable costs. However, the number of
QALY
s gained with intensive
LLT
by statins in individual patients can be increased with selective benefit‐based treatment.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifiers:
NCT
00327691 and
NCT
00159835