bluuebunny/crossref_metadata_2025_split huggingface dataset:
SOX5/6/21 Prevent Oncogene-Driven Transformation of Brain Stem Cells
Authors: Kurtsdotter Idha , Topcic Danijal , Karlén Alexandra , Singla Bhumica , Hagey Daniel W. , Bergsland Maria , Siesjö Peter , Nistér Monica , Carlson Joseph W. , Lefebvre Veronique , Persson Oscar , Holmberg Johan , Muhr Jonas 
Published: July 2017

Abstract
Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult. Cancer Res; 77(18); 4985–97. ©2017 AACR.
Atrioventricular Nodal Reentrant Tachycardia in Patients With Congenital Heart Disease
Authors: Papagiannis John , Beissel Daniel Joseph , Krause Ulrich , Cabrera Michel , Telishevska Marta , Seslar Stephen , Johnsrude Christopher , Anderson Charles , Tisma-Dupanovic Svjetlana , Connelly Diana , Avramidis Dimosthenis , Carter Christopher , Kornyei Laszlo , Law Ian , Von Bergen Nicholas , Janusek Jan , Silva Jennifer , Rosenthal Eric , Willcox Mark , Kubus Peter , Hessling Gabriele , Paul Thomas 
Published: July 2017

Background—
The relationship of atrioventricular nodal reentrant tachycardia to congenital heart disease (CHD) and the outcome of catheter ablation in this population have not been studied adequately.

Methods and Results—

A multicenter retrospective study was performed on patients with CHD who had atrioventricular nodal reentrant tachycardia and were treated with catheter ablation. There were 109 patients (61 women), aged 22.1±13.4 years. The majority, 86 of 109 (79%), had CHD resulting in right heart pressure or volume overload. Patients were divided into 2 groups: group A (n=51) with complex CHD and group B (n=58) with simple CHD. There were no significant differences between groups in patients’ growth parameters, use of 3-dimensional imaging, and type of ablation (radiofrequency versus cryoablation). Procedure times (251±117 versus 174±94 minutes;
P
=0.0006) and fluoroscopy times (median 20.8 versus 16.6 minutes;
P
=0.037) were longer in group A versus group B. There were significant differences between groups in the acute success of ablation (82% versus 97%;
P
=0.04), risk of atrioventricular block (14 versus 0%;
P
=0.004), and need for chronic pacing (10% versus 0%;
P
=0.008). There was no permanent atrioventricular block in patients who underwent cryoablation. After 3.2±2.7 years of follow-up, long-term success was 86% in group A and 100% in group B (
P
=0.004).

Conclusions—
Atrioventricular nodal reentrant tachycardia can complicate the course of patients with CHD. This study demonstrates that the outcome of catheter ablation is favorable in patients with simple CHD. Patients with complex CHD have increased risk of procedural failure and atrioventricular block.
Stand-Alone Pulmonary Vein Isolation Versus Pulmonary Vein Isolation With Additional Substrate Modification as Index Ablation Procedures in Patients With Persistent and Long-Standing Persistent Atrial Fibrillation
Authors: Fink Thomas , Schlüter Michael , Heeger Christian-Hendrik , Lemes Christine , Maurer Tilman , Reissmann Bruno , Riedl Johannes , Rottner Laura , Santoro Francesco , Schmidt Boris , Wohlmuth Peter , Mathew Shibu , Sohns Christian , Ouyang Feifan , Metzner Andreas , Kuck Karl-Heinz 
Published: July 2017

Background—
Pulmonary vein isolation (PVI) for persistent atrial fibrillation is associated with limited success rates and often requires multiple procedures to maintain stable sinus rhythm. In the prospective and randomized Alster-Lost-AF trial (Ablation at St. Georg Hospital for Long-Standing Persistent Atrial Fibrillation), we sought to assess, in patients with symptomatic persistent or long-standing persistent atrial fibrillation, the outcomes of initial ablative strategies comprising either stand-alone PVI (PVI-only approach) or a stepwise approach of PVI followed by complex fractionated atrial electrogram ablation and linear ablation (Substrate-modification approach).

Methods and Results—

Patients were randomized 1:1 to stand-alone PVI or PVI plus substrate modification. The primary study end point was freedom from recurrence of any atrial tachyarrhythmia, outside a 90-day blanking period, at 12 months. A total of 124 patients were enrolled, with 118 patients included in the analysis (61 in the PVI-only group, 57 in the Substrate-modification group). Atrial tachyarrhythmias recurred in 28 PVI-only group patients and 24 Substrate-modification group patients, for 1-year freedom from tachyarrhythmia recurrence after a single ablation procedure of 54% (95% confidence interval, 43%–68%) in the PVI-only and 57% (95% confidence interval, 46%–72%) in the Substrate-modification group (
P
=0.86). Twenty-four patients in the PVI-only group (39%) and 18 in the Substrate-modification group (32%) were without arrhythmia recurrence and off antiarrhythmic drug therapy at the end of the 12-month follow-up.

Conclusions—
In patients with persistent and long-standing persistent atrial fibrillation, no significant difference was observed in 12-month freedom from atrial tachyarrhythmias between an index ablative approach of stand-alone PVI and a stepwise approach of PVI plus complex fractionated atrial electrogram and linear ablation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00820625.
Tachycardia-Induced J-Wave Changes in Patients With and Without Idiopathic Ventricular Fibrillation
Authors: Aizawa Yoshiyasu , Takatsuki Seiji , Nishiyama Takahiko , Kimura Takehiro , Kohsaka Shun , Kaneko Yoshiaki , Inden Yasuya , Takahashi Naohiko , Nagase Satoshi , Aizawa Yoshifusa , Fukuda Keichi 
Published: July 2017

Background—
To know the underlying mechanisms of J waves, the response to atrial pacing was studied in patients with idiopathic ventricular fibrillation (IVF) and patients with non-IVF.

Methods and Results—

In 8 patients with IVF, the J-wave amplitude was measured before, during, and after atrial pacing. All patients had episodes of ventricular fibrillation without structural heart disease. The responses of J waves were compared with those of the 17 non-IVF control subjects who revealed J waves but no history of cardiac arrest and underwent electrophysiological study. The IVF patients were younger than the non-IVF patients (28±10 versus 52±14 years, respectively;
P
=0.002) and had larger J waves with more extensive distribution. J waves decreased from 0.35±0.26 to 0.22±0.23 mV (
P
=0.025) when the RR intervals were shortened from 782±88 to 573±162 ms (
P
=0.001). A decrease (≥0.05 mV) in the J-wave amplitude was observed in 6 of the 8 patients. In addition, 1 patient showed a distinct reduction of J waves in the unipolar epicardial leads. In contrast, J waves were augmented in the 17 non-IVF subjects from 0.27±0.09 to 0.38±0.10 mV (
P
<0.001): augmented in 9 and unchanged in the 8 subjects. The different response patterns of J waves to rapid pacing suggest different mechanisms: early repolarization in IVF patients and conduction delay in non-IVF patients.

Conclusions—
The response to atrial pacing was different between the IVF and non-IVF patients, which suggests the presence of different mechanisms for the genesis of J waves.
Visual and Quantitative Assessment of Coronary Stenoses at Angiography Versus Fractional Flow Reserve
Authors: Adjedj Julien , Xaplanteris Panagiotis , Toth Gabor , Ferrara Angela , Pellicano Mariano , Ciccarelli Giovanni , Floré Vincent , Barbato Emanuele , De Bruyne Bernard 
Published: July 2017

Background—
The correlation between angiographic assessment of coronary stenoses and fractional flow reserve (FFR) is weak. Whether and how risk factors impact the diagnostic accuracy of angiography is unknown. We sought to evaluate the diagnostic accuracy of angiography by visual estimate and by quantitative coronary angiography when compared with FFR and evaluate the influence of risk factors (RF) on this accuracy.

Methods and Results—

In 1382 coronary stenoses (1104 patients), percent diameter stenosis by visual estimation (DS
VE
) and by quantitative coronary angiography (DS
QCA
) was compared with FFR. Patients were divided into 4 subgroups, according to the presence of RFs, and the relationship between DS
VE
, DS
QCA
, and FFR was analyzed. Overall, DS
VE
was significantly higher than DS
QCA
(
P
<0.0001); nonetheless, when examined by strata of DS, DS
VE
was significantly smaller than DS
QCA
in mild stenoses, although the reverse held true for severe stenoses. Compared with FFR, a large scatter was observed for both DS
VE
and DS
QCA
. When using a dichotomous FFR value of 0.80, C statistic was significantly higher for DS
VE
than for DS
QCA
(0.712 versus 0.640, respectively;
P
<0.001). C statistics for DS
VE
decreased progressively as RFs accumulated (0.776 for ≤1 RF, 0.750 for 2 RFs, 0.713 for 3 RFs and 0.627 for ≥4 RFs;
P
=0.0053). In addition, in diabetics, the relationship between FFR and angiographic indices was particularly weak (C statistics: 0.524 for DS
VE
and 0.511 for DS
QCA
).

Conclusions—

Overall, DS
VE
has a better diagnostic accuracy than DS
QCA
to predict the functional significance of coronary stenosis. The predictive accuracy of angiography is moderate in patients with ≤1 RFs, but weakens as RFs accumulate, especially in diabetics.
Dynamic Edematous Response of the Human Heart to Myocardial Infarction
Authors: Fernández-Jiménez Rodrigo , Barreiro-Pérez Manuel , Martin-García Ana , Sánchez-González Javier , Agüero Jaume , Galán-Arriola Carlos , García-Prieto Jaime , Díaz-Pelaez Elena , Vara Pedro , Martinez Irene , Zamarro Ivan , Garde Beatriz , Sanz Javier , Fuster Valentin , Sánchez Pedro L. , Ibanez Borja 
Published: July 2017

Background:
Clinical protocols aimed to characterize the post–myocardial infarction (MI) heart by cardiac magnetic resonance (CMR) need to be standardized to take account of dynamic biological phenomena evolving early after the index ischemic event. Here, we evaluated the time course of edema reaction in patients with ST-segment–elevation MI by CMR and assessed its implications for myocardium-at-risk (MaR) quantification both in patients and in a large-animal model.

Methods:
A total of 16 patients with anterior ST-segment–elevation MI successfully treated by primary angioplasty and 16 matched controls were prospectively recruited. In total, 94 clinical CMR examinations were performed: patients with ST-segment–elevation MI were serially scanned (within the first 3 hours after reperfusion and at 1, 4, 7, and 40 days), and controls were scanned only once. T2 relaxation time in the myocardium (T2 mapping) and the extent of edema on T2-weighted short-tau triple inversion-recovery (ie, CMR-MaR) were evaluated at all time points. In the experimental study, 20 pigs underwent 40-minute ischemia/reperfusion followed by serial CMR examinations at 120 minutes and 1, 4, and 7 days after reperfusion. Reference MaR was assessed by contrast-multidetector computed tomography during the index coronary occlusion. Generalized linear mixed models were used to take account of repeated measurements.

Results:
In humans, T2 relaxation time in the ischemic myocardium declines significantly from early after reperfusion to 24 hours, and then increases up to day 4, reaching a plateau from which it decreases from day 7. Consequently, edema extent measured by T2-weighted short-tau triple inversion-recovery (CMR-MaR) varied with the timing of the CMR examination. These findings were confirmed in the experimental model by showing that only CMR-MaR values for day 4 and day 7 postreperfusion, coinciding with the deferred edema wave, were similar to values measured by reference contrast-multidetector computed tomography.

Conclusions:
Post-MI edema in patients follows a bimodal pattern that affects CMR estimates of MaR. Dynamic changes in post–ST-segment–elevation MI edema highlight the need for standardization of CMR timing to retrospectively delineate MaR and quantify myocardial salvage. According to the present clinical and experimental data, a time window between days 4 and 7 post-MI seems a good compromise solution for standardization. Further studies are needed to study the effect of other factors on these variables.
Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling
Authors: Amyere Mustapha , Revencu Nicole , Helaers Raphaël , Pairet Eleonore , Baselga Eulalia , Cordisco Maria , Chung Wendy , Dubois Josée , Lacour Jean-Philippe , Martorell Loreto , Mazereeuw-Hautier Juliette , Pyeritz Reed E. , Amor David J. , Bisdorff Annouk , Blei Francine , Bombei Hannah , Dompmartin Anne , Brooks David , Dupont Juliette , González-Enseñat Maria Antonia , Frieden Ilona , Gérard Marion , Kvarnung Malin , Hanson-Kahn Andrea Kwan , Hudgins Louanne , Léauté-Labrèze Christine , McCuaig Catherine , Metry Denise , Parent Philippe , Paul Carle , Petit Florence , Phan Alice , Quere Isabelle , Salhi Aicha , Turner Anne , Vabres Pierre , Vicente Asuncion , Wargon Orli , Watanabe Shoji , Weibel Lisa , Wilson Ashley , Willing Marcia , Mulliken John B. , Boon Laurence M. , Vikkula Miikka 
Published: July 2017

Background:

Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified
RASA1
mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs.

Methods:
We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro.

Results:

We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in
EPHB4
in 5 families that cosegregated with CM-AVM. Overall, screening of
EPHB4
detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs.

Conclusions:

We found
EPHB4
mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics
RASA1
-related CM-AVM1 and also hereditary hemorrhagic telangiectasia.
RASA1
-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.
Evaluating the Impact and Cost-Effectiveness of Statin Use Guidelines for Primary Prevention of Coronary Heart Disease and Stroke
Authors: Heller David J. , Coxson Pamela G. , Penko Joanne , Pletcher Mark J. , Goldman Lee , Odden Michelle C. , Kazi Dhruv S. , Bibbins-Domingo Kirsten 
Published: July 2017

Background:
Statins are effective in the primary prevention of atherosclerotic cardiovascular disease. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline expands recommended statin use, but its cost-effectiveness has not been compared with other guidelines.

Methods:
We used the Cardiovascular Disease Policy Model to estimate the cost-effectiveness of the ACC/AHA guideline relative to current use, Adult Treatment Panel III guidelines, and universal statin use in all men 45 to 74 years of age and women 55 to 74 years of age over a 10-year horizon from 2016 to 2025. Sensitivity analyses varied costs, risks, and benefits. Main outcomes were incremental cost-effectiveness ratios and numbers needed to treat for 10 years per quality-adjusted life-year gained.

Results:
Each approach produces substantial benefits and net cost savings relative to the status quo. Full adherence to the Adult Treatment Panel III guideline would result in 8.8 million more statin users than the status quo, at a number needed to treat for 10 years per quality-adjusted life-year gained of 35. The ACC/AHA guideline would potentially result in up to 12.3 million more statin users than the Adult Treatment Panel III guideline, with a marginal number needed to treat for 10 years per quality-adjusted life-year gained of 68. Moderate-intensity statin use in all men 45 to 74 years of age and women 55 to 74 years of age would result in 28.9 million more statin users than the ACC/AHA guideline, with a marginal number needed to treat for 10 years per quality-adjusted life-year gained of 108. In all cases, benefits would be greater in men than women. Results vary moderately with different risk thresholds for instituting statins and statin toxicity estimates but depend greatly on the disutility caused by daily medication use (pill burden).

Conclusions:
At a population level, the ACC/AHA guideline for expanded statin use for primary prevention is projected to treat more people, to save more lives, and to cost less compared with Adult Treatment Panel III in both men and women. Whether individuals benefit from long-term statin use for primary prevention depends more on the disutility associated with pill burden than their degree of cardiovascular risk.
The Optimal Timing of Stage 2 Palliation for Hypoplastic Left Heart Syndrome
Authors: Meza James M. , Hickey Edward J. , Blackstone Eugene H. , Jaquiss Robert D.B. , Anderson Brett R. , Williams William G. , Cai Sally , Van Arsdell Glen S. , Karamlou Tara , McCrindle Brian W. 
Published: July 2017

Background:
In infants requiring 3-stage single-ventricle palliation for hypoplastic left heart syndrome, attrition after the Norwood procedure remains significant. The effect of the timing of stage 2 palliation (S2P), a physician-modifiable factor, on long-term survival is not well understood. We hypothesized that an optimal interval between the Norwood and S2P that both minimizes pre-S2P attrition and maximizes post-S2P survival exists and is associated with individual patient characteristics.

Methods:
The National Institutes of Health/National Heart, Lung, and Blood Institute Pediatric Heart Network Single Ventricle Reconstruction Trial public data set was used. Transplant-free survival (TFS) was modeled from (1) Norwood to S2P and (2) S2P to 3 years by using parametric hazard analysis. Factors associated with death or heart transplantation were determined for each interval. To account for staged procedures, risk-adjusted, 3-year, post-Norwood TFS (the probability of TFS at 3 years given survival to S2P) was calculated using parametric conditional survival analysis. TFS from the Norwood to S2P was first predicted. TFS after S2P to 3 years was then predicted and adjusted for attrition before S2P by multiplying by the estimate of TFS to S2P. The optimal timing of S2P was determined by generating nomograms of risk-adjusted, 3-year, post-Norwood, TFS versus the interval from the Norwood to S2P.

Results:
Of 547 included patients, 399 survived to S2P (73%). Of the survivors to S2P, 349 (87%) survived to 3-year follow-up. The median interval from the Norwood to S2P was 5.1 (interquartile range, 4.1–6.0) months. The risk-adjusted, 3-year, TFS was 68±7%. A Norwood-S2P interval of 3 to 6 months was associated with greatest 3-year TFS overall and in patients with few risk factors. In patients with multiple risk factors, TFS was severely compromised, regardless of the timing of S2P and most severely when S2P was performed early. No difference in the optimal timing of S2P existed when stratified by shunt type.

Conclusions:
In infants with few risk factors, progressing to S2P at 3 to 6 months after the Norwood procedure was associated with maximal TFS. Early S2P did not rescue patients with greater risk factor burdens. Instead, referral for heart transplantation may offer their best chance at long-term survival.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00115934.
The Effects of Public Access Defibrillation on Survival After Out-of-Hospital Cardiac Arrest
Authors: Bækgaard Josefine S. , Viereck Søren , Møller Thea Palsgaard , Ersbøll Annette Kjær , Lippert Freddy , Folke Fredrik 
Published: July 2017

Background:
Despite recent advances, the average survival after out-of-hospital cardiac arrest (OHCA) remains <10%. Early defibrillation by an automated external defibrillator is the most important intervention for patients with OHCA, showing survival proportions >50%. Accordingly, placement of automated external defibrillators in the community as part of a public access defibrillation program (PAD) is recommended by international guidelines. However, different strategies have been proposed on how exactly to increase and make use of publicly available automated external defibrillators. This systematic review aimed to evaluate the effect of PAD and the different PAD strategies on survival after OHCA.

Methods:
PubMed, Embase, and the Cochrane Library were systematically searched on August 31, 2015 for observational studies reporting survival to hospital discharge in OHCA patients where an automated external defibrillator had been used by nonemergency medical services. PAD was divided into 3 groups according to who applied the defibrillator: nondispatched lay first responders, professional first responders (firefighters/police) dispatched by the Emergency Medical Dispatch Center (EMDC), or lay first responders dispatched by the EMDC.

Results:
A total of 41 studies were included; 18 reported PAD by nondispatched lay first responders, 20 reported PAD by EMDC-dispatched professional first responders (firefighters/police), and 3 reported both. We identified no qualified studies reporting survival after PAD by EMDC-dispatched lay first responders. The overall survival to hospital discharge after OHCA treated with PAD showed a median survival of 40.0% (range, 9.1–83.3). Defibrillation by nondispatched lay first responders was associated with the highest survival with a median survival of 53.0% (range, 26.0–72.0), whereas defibrillation by EMDC-dispatched professional first responders (firefighters/police) was associated with a median survival of 28.6% (range, 9.0–76.0). A meta-analysis of the different survival outcomes could not be performed because of the large heterogeneity of the included studies.

Conclusions:
This systematic review showed a median overall survival of 40% for patients with OHCA treated by PAD. Defibrillation by nondispatched lay first responders was found to correlate with the highest impact on survival in comparison with EMDC-dispatched professional first responders. PAD by EMDC-dispatched lay first responders could be a promising strategy, but evidence is lacking.