bluuebunny/crossref_metadata_2025_split huggingface dataset:
The DNA-Binding Polyamine Moiety in the Vectorized DNA Topoisomerase II Inhibitor F14512 Alters Reparability of the Consequent Enzyme-Linked DNA Double-Strand Breaks
Authors: Bombarde Oriane , Larminat Florence , Gomez Dennis , Frit Philippe , Racca Carine , Gomes Bruno , Guilbaud Nicolas , Calsou Patrick 
Published: June 2017

Abstract
Poisons of topoisomerase II (TOP2) kill cancer cells by preventing religation of intermediate DNA breaks during the enzymatic process and thus by accumulating enzyme–drug–DNA complexes called TOP2 cleavage-complex (TOP2cc). F14512 is a highly cytotoxic polyamine-vectorized TOP2 inhibitor derived from etoposide and currently in clinical trials. It was shown in vitro that F14512 has acquired DNA-binding properties and that the stability of TOP2cc was strongly increased. Paradoxically, at equitoxic concentrations in cells, F14512 induced less DNA breaks than etoposide. Here, we directly compared etoposide and F14512 for their rates of TOP2cc production and resolution in human cells. We report that targeting of TOP2α and not TOP2β impacts cell killing by F14512, contrary to etoposide that kills cells through targeting both isoforms. Then, we show that despite being more cytotoxic, F14512 is less efficient than etoposide at producing TOP2α cleavage-complex (TOP2αcc) in cells. Finally, we report that compared with TOP2αcc mediated by etoposide, those generated by F14512 persist longer in the genome, are not dependent on TDP2 for cleaning break ends from TOP2α, are channeled to a larger extent to resection-based repair processes relying on CtIP and BRCA1 and promote RAD51 recruitment to damaged chromatin. In addition to the addressing of F14512 to the polyamine transport system, the properties uncovered here would be particularly valuable for a therapeutic usage of this new anticancer compound. More generally, the concept of increasing drug cytotoxicity by switching the repair mode of the induced DNA lesions via addition of a DNA-binding moiety deserves further developments. Mol Cancer Ther; 16(10); 2166–77. ©2017 AACR.
IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma
Authors: Long Kristen B. , Tooker Graham , Tooker Evan , Luque Santiago Lombo , Lee Jae W. , Pan Xiaoqing , Beatty Gregory L. 
Published: June 2017

Abstract
Inflammation mediated by activation of JAK/STAT signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL6 receptor (IL6R) as a strategy to inhibit IL6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1Cre (KPC) mice. Plasma from patients with PDAC was assessed for its ability to activate STAT3/SOCS3 in human monocytes using immunofluorescence microscopy and quantitative gene expression assays. KPC mice and syngeneic mice (wild type and IL6−/−) implanted with KPC-derived cell lines were treated with an IL6R-blocking antibody (anti-IL6R). The impact of treatment on tumor growth in KPC mice and mice with KPC-derived tumor implants was monitored using ultrasonography and calipers, respectively. Tumors were analyzed by IHC to detect changes in STAT activation, tumor viability, and proliferation. We found that STAT3 was the most activated STAT protein in PDAC tumors from KPC mice. Plasma from patients with advanced PDAC stimulated STAT3/SOCS3 activation in human monocytes. In mice, anti-IL6R antibodies targeted Ly6Chi monocytes, inhibited STAT3 activation in tumor cells, and decreased tumor cell proliferation in vivo. IL6R blockade in combination with chemotherapy induced tumor cell apoptosis, tumor regressions, and improved overall survival. Overall, we show that IL6 signaling drives STAT3 activation in tumor cells and mediates chemoresistance in PDAC. Thus, disrupting IL6 signaling using anti-IL6R antibodies holds promise for improving chemotherapy efficacy in PDAC. Mol Cancer Ther; 16(9); 1898–908. ©2017 AACR.
Chemoprevention Uptake among Women with Atypical Hyperplasia and Lobular and Ductal Carcinoma In Situ
Authors: Trivedi Meghna S. , Coe Austin M. , Vanegas Alejandro , Kukafka Rita , Crew Katherine D. 
Published: June 2017

Abstract
Women with atypical hyperplasia and lobular or ductal carcinoma in situ (LCIS/DCIS) are at increased risk of developing invasive breast cancer. Chemoprevention with selective estrogen receptor modulators or aromatase inhibitors can reduce breast cancer risk; however, uptake is estimated to be less than 15% in these populations. We sought to determine which factors are associated with chemoprevention uptake in a population of women with atypical hyperplasia, LCIS, and DCIS. Women diagnosed with atypical hyperplasia/LCIS/DCIS between 2007 and 2015 without a history of invasive breast cancer were identified (N = 1,719). A subset of women (n = 73) completed questionnaires on breast cancer and chemoprevention knowledge, risk perception, and behavioral intentions. Descriptive statistics were generated and univariate and multivariable log-binomial regression were used to estimate the association between sociodemographic and clinical factors and chemoprevention uptake. In our sample, 29.3% had atypical hyperplasia, 23.3% had LCIS, and 47.4% had DCIS; 29.4% used chemoprevention. Compared with women with atypical hyperplasia, LCIS [RR, 1.43; 95% confidence interval (CI), 1.16–1.76] and DCIS (RR, 1.54; 95% CI, 1.28–1.86) were significantly associated with chemoprevention uptake, as was medical oncology referral (RR, 5.79; 95% CI, 4.80–6.98). Younger women were less likely to take chemoprevention (RR, 0.61; 95% CI, 0.42–0.87), and there was a trend toward increased uptake in Hispanic compared with non-Hispanic white women. The survey data revealed a strong interest in learning about chemoprevention, but there were misperceptions in personal breast cancer risk and side effects of chemoprevention. Improving communication about breast cancer risk and chemoprevention may allow clinicians to facilitate informed decision-making about preventative therapy. Cancer Prev Res; 10(8); 434–41. ©2017 AACR.
Pulmonary Vein Isolation Alone Versus Additional Linear Ablation in Patients With Persistent Atrial Fibrillation Converted to Paroxysmal Type With Antiarrhythmic Drug Therapy
Authors: Yu Hee Tae , Shim Jaemin , Park Junbeom , Kim In-Soo , Kim Tae-Hoon , Uhm Jae-Sun , Joung Boyoung , Lee Moon-Hyoung , Kim Young-Hoon , Pak Hui-Nam 
Published: June 2017

Background—
Atrial fibrillation (AF) type can vary depending on condition and timing, and some patients who initially present with persistent AF may be changed to paroxysmal AF after antiarrhythmic drug medication and cardioversion. We investigated whether circumferential pulmonary vein isolation (CPVI) alone is an effective rhythm control strategy in patients with persistent AF to paroxysmal AF.

Methods and Results—

We enrolled 113 patients with persistent AF to paroxysmal AF (male 75%, 60.4±10.1 years old) who underwent catheter ablation for nonvalvular AF at 3 tertiary hospitals. The participants were randomly assigned to 2 groups: CPVI alone (n=59) or CPVI plus linear ablation (CPVI+Line; posterior box+anterior line, n=54). Compared with the CPVI+Line, CPVI alone required shorter procedure (187.2±58.0 versus 211.2±63.9 min;
P
=0.043) and ablation times (4922.1±1110.5 versus 6205.7±1425.2 s;
P
<0.001) without difference in procedure-related major complication (3% versus 2%;
P
=0.611). Antiarrhythmic drug utility rates after ablation were not different between the 2 groups (22% versus 30%;
P
=0.356). Overall, AF-free survival (log-rank;
P
=0.206) and AF and antiarrhythmic drug–free survival (log-rank;
P
=0.321) were not different between groups.

Conclusions—
CPVI alone is an effective rhythm control strategy with a shorter procedure time in persistent AF patients converted to paroxysmal AF compared with CPVI with linear ablation.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02176616.
Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease
Authors: Haskell Gloria T. , Jensen Brian C. , Samsa Leigh Ann , Marchuk Daniel , Huang Wei , Skrzynia Cecile , Tilley Christian , Seifert Bryce A. , Rivera-Muñoz Edgar A. , Koller Beverly , Wilhelmsen Kirk C. , Liu Jiandong , Alhosaini Hassan , Weck Karen E. , Evans James P. , Berg Jonathan S. 
Published: June 2017

Background—
The genetic variation underlying many heritable forms of cardiovascular disease is incompletely understood, even in patients with strong family history or early age at onset.

Methods and Results—

We used whole exome sequencing to detect pathogenic variants in 55 patients with suspected monogenic forms of cardiovascular disease. Diagnostic analysis of established disease genes identified pathogenic variants in 21.8% of cases and variants of uncertain significance in 34.5% of cases. Three patients harbored heterozygous nonsense or splice-site variants in the nucleoporin genes
NUP37
,
NUP43
, and
NUP188
, which have not been implicated previously in cardiac disease. We also identified a heterozygous splice site variant in the nuclear envelope gene
SYNE1
in a child with severe dilated cardiomyopathy that underwent transplant, as well as in his affected father. To confirm a cardiovascular role for these candidate genes in vivo, we used morpholinos to reduce
SYNE1, NUP37,
and
NUP43
gene expression in zebrafish. Morphant embryos displayed cardiac abnormalities, including pericardial edema and heart failure. Furthermore, lymphoblasts from the patient carrying a
SYNE1
splice-site variant displayed changes in nuclear morphology and protein localization that are consistent with disruption of the nuclear envelope.

Conclusions—

These data expand the repertoire of pathogenic variants associated with cardiovascular disease and validate the diagnostic and research use of whole exome sequencing. We identify
NUP37
,
NUP43
, and
NUP188
as novel candidate genes for cardiovascular disease, and suggest that dysfunction of the nuclear envelope may be an under-recognized component of inherited cardiac disease in some cases.
Association Between Mutation Size and Cardiac Involvement in Myotonic Dystrophy Type 1
Authors: Chong-Nguyen Caroline , Wahbi Karim , Algalarrondo Vincent , Bécane Henri Marc , Radvanyi-Hoffman Hélène , Arnaud Pauline , Furling Denis , Lazarus Arnaud , Bassez Guillaume , Béhin Anthony , Fayssoil Abdallah , Laforêt Pascal , Stojkovic Tanya , Eymard Bruno , Duboc Denis 
Published: June 2017

Background—
In myotonic dystrophy type 1, the association between mutation size (CTG expansion) and the severity of cardiac involvement is controversial.

Methods and Results—
We selected 855 patients with myotonic dystrophy type 1 (women, 51%; median age, 37 years), with genetic testing performed at the moment of their initial cardiac evaluation, out of 1014 patients included in the Myotonic Dystrophy Type 1-Heart Registry between January 2000 and December 2015. We studied the association between CTG expansion size and other baseline characteristics and (1) cardiac involvement at baseline and (2) the incidence of death, sudden death, and other cardiac adverse events. At initial presentation, the median CTG expansion size was 530 (interquartile range, 300–830). In multivariate analysis, larger expansions were associated with the presence at baseline of conduction defects on the ECG and left ventricular systolic dysfunction. In a median 11.5 years of follow-up period, 210 patients died (25%), including 32 suddenly (4%). Supraventricular arrhythmias developed over lifetime in 166 patients (19%), sustained ventricular tachyarrhythmias in 17 (2%), and permanent pacemakers were implanted in 181 (21%). In Cox regression analyses, larger CTG expansions were significantly associated with (1) total death, sudden death, and pacemaker implantation in a model, including CTG expansion size, age, sex, diabetes mellitus, and (2) all end points except sudden death in a model including all baseline characteristics.

Conclusions—
The size of the CTG expansion in the blood of myotonic dystrophy type 1 patients is associated with total and sudden deaths, conduction defects, left ventricular dysfunction, and supraventricular arrhythmias.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique Identifier: NCT01136330
Genome-Wide Dynamics of Nascent Noncoding RNA Transcription in Porcine Heart After Myocardial Infarction
Authors: Kaikkonen Minna U. , Halonen Paavo , Liu Oscar Hsin-Fu , Turunen Tiia A. , Pajula Juho , Moreau Pierre , Selvarajan Ilakya , Tuomainen Tomi , Aavik Einari , Tavi Pasi , Ylä-Herttuala Seppo 
Published: June 2017

Background—
Microarrays and RNA sequencing are widely used to profile transcriptome remodeling during myocardial ischemia. However, the steady-state RNA analysis lacks in sensitivity to detect all noncoding RNA species and does not provide separation between transcriptional and post-transcriptional regulations. Here, we provide the first comprehensive analysis of nascent RNA profiles of mRNAs, primary micro-RNAs, long noncoding RNAs, and enhancer RNAs in a large animal model of acute infarction.

Methods and Results—
Acute infarction was induced by cardiac catheterization of domestic swine. Nuclei isolated from healthy, border zone, and ischemic regions of the affected heart were subjected to global run-on sequencing. Global run-on sequencing analysis indicated that half of affected genes are regulated at the level of transcriptional pausing. A gradient of induction of inflammatory mediators and repression of peroxisome proliferator-activated receptor signaling and oxidative phosphorylation was detected when moving from healthy toward infarcted area. In addition, we interrogated the transcriptional regulation of primary micro-RNAs and provide evidence that several arrhythmia-related target genes exhibit repression at post-transcriptional level. We identified 450 long noncoding RNAs differently regulated by ischemia, including novel conserved long noncoding RNAs expressed in antisense orientation to myocardial transcription factors GATA-binding protein 4, GATA-binding protein 6, and Krüppel-like factor 6. Finally, characterization of enhancers exhibiting differential expression of enhancer RNAs pointed a central role for Krüppel-like factor, MEF2C, ETS, NFY, ATF, E2F2, and NRF1 transcription factors in determining transcriptional responses to ischemia.

Conclusions—
Global run-on sequencing allowed us to follow the gradient of gene expression occurring in the ischemic heart and identify novel noncoding RNAs regulated by oxygen deprivation. These findings highlight potential new targets for diagnosis and treatment of myocardial ischemia.
Sex Differences in Mortality Based on United Network for Organ Sharing Status While Awaiting Heart Transplantation
Authors: Hsich Eileen M. , Blackstone Eugene H. , Thuita Lucy , McNamara Dennis M. , Rogers Joseph G. , Ishwaran Hemant , Schold Jesse D. 
Published: June 2017

Background—
There are sex differences in mortality while awaiting heart transplantation, and the reason remains unclear.

Methods and Results—
We included all adults in the Scientific Registry of Transplant Recipients placed on the heart transplant active waitlist from 2004 to 2015. The primary end point was all-cause mortality. Multivariable Cox proportional hazards models were performed to evaluate survival by United Network for Organ Sharing (UNOS) status at the time of listing. Random survival forest was used to identify sex interactions for the competing risk of death and transplantation. There were 33 069 patients (25% women) awaiting heart transplantation. This cohort included 7681 UNOS status 1A (26% women), 13 027 UNOS status 1B (25% women), and 12 361 UNOS status 2 (26% women). During a median follow-up of 4.3 months, 1351 women and 4052 men died. After adjusting for >20 risk factors, female sex was associated with a significant risk of death among UNOS status 1A (adjusted hazard ratio, 1.14; 95% confidence interval, 1.01–1.29) and UNOS status 1B (adjusted hazard ratio, 1.17; 95% confidence interval, 1.05–1.30). In contrast, female sex was significantly protective for time to death among UNOS status 2 (adjusted hazard ratio, 0.85; 95% confidence interval, 0.76–0.95). Sex differences in probability of transplantation were present for every UNOS status, and >20 sex interactions were identified for mortality and transplantation.

Conclusions—
When stratified by initial UNOS status, women had a higher mortality than men as UNOS status 1 and a lower mortality as UNOS status 2. With >20 sex interactions for mortality and transplantation, further evaluation is warranted to form a more equitable allocation system.
Pulmonary Hypertension Is Associated With a Higher Risk of Heart Failure Hospitalization and Mortality in Patients With Chronic Kidney Disease
Authors: Selvaraj Senthil , Shah Sanjiv J. , Ommerborn Mark J. , Clark Cheryl R. , Hall Michael E. , Mentz Robert J. , Qazi Saadia , Robbins Jeremy M. , Skelton Thomas N. , Chen Jiaying , Gaziano J. Michael , Djoussé Luc 
Published: June 2017

Background—
African Americans develop chronic kidney disease and pulmonary hypertension (PH) at disproportionately high rates. Little is known whether PH heightens the risk of heart failure (HF) admission or mortality among chronic kidney disease patients, including patients with non–end-stage renal disease.

Methods and Results—

We analyzed African Americans participants with chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m
2
or urine albumin/creatinine >30 mg/g) and available echocardiogram-derived pulmonary artery systolic pressure (PASP) from the Jackson Heart Study (N=408). We used Cox models to assess whether PH (PASP>35 mm Hg) was associated with higher rates of HF hospitalization and mortality. In a secondary, cross-sectional analysis, we examined the relationship between cystatin C (a marker of renal function) and PASP and potential mediators, including BNP (B-type natriuretic peptide) and endothelin-1. In our cohort, the mean age was 63±13 years, 70% were female, 78% had hypertension, and 22% had PH. Eighty-five percent of the participants had an estimated glomerular filtration rate >30 mL/min per 1.73 m
2
. During follow-up, 13% were hospitalized for HF and 27% died. After adjusting for potential confounders, including BNP, PH was found to be associated with HF hospitalization (hazard ratio, 2.37; 95% confidence interval, 1.15–4.86) and the combined outcome of HF hospitalization or mortality (hazard ratio, 1.84; confidence interval, 1.09–3.10). Log cystatin C was directly associated with PASP (adjusted β =2.5 [95% confidence interval, 0.8–4.1] per standard deviation change in cystatin C). Mediation analysis showed that BNP and endothelin-1 explained 56% and 40%, respectively, of the indirect effects between cystatin C and PASP.

Conclusions—
Among African Americans with chronic kidney disease, PH, which is likely pulmonary venous hypertension, was associated with a higher risk of HF admission and mortality.
Turbulent Kinetic Energy Assessed by Multipoint 4-Dimensional Flow Magnetic Resonance Imaging Provides Additional Information Relative to Echocardiography for the Determination of Aortic Stenosis Severity
Authors: Binter Christian , Gotschy Alexander , Sündermann Simon H. , Frank Michelle , Tanner Felix C. , Lüscher Thomas F. , Manka Robert , Kozerke Sebastian 
Published: June 2017

Background—
Turbulent kinetic energy (TKE), assessed by 4-dimensional (4D) flow magnetic resonance imaging, is a measure of energy loss in disturbed flow as it occurs, for instance, in aortic stenosis (AS). This work investigates the additional information provided by quantifying TKE for the assessment of AS severity in comparison to clinical echocardiographic measures.

Methods and Results—

Fifty-one patients with AS (67±15 years, 20 female) and 10 healthy age-matched controls (69±5 years, 5 female) were prospectively enrolled to undergo multipoint 4D flow magnetic resonance imaging. Patients were split into 2 groups (severe and mild/moderate AS) according to their echocardiographic mean pressure gradient. TKE values were integrated over the aortic arch to obtain peak TKE. Integrating over systole yielded total TKE
sys
and by normalizing for stroke volume, normalized TKE
sys
was obtained. Mean pressure gradient and TKE correlated only weakly (
R
2
=0.26 for peak TKE and
R
2
=0.32 for normalized TKE
sys
) in the entire study population including control subjects, while no significant correlation was observed in the AS patient group. In the patient population with dilated ascending aorta, both peak TKE and total TKE
sys
were significantly elevated (
P
<0.01), whereas mean pressure gradient was significantly lower (
P
<0.05). Patients with bicuspid aortic valves also showed significantly increased TKE metrics (
P
<0.01), although no significant difference was found for mean pressure gradient.

Conclusions—
Elevated TKE levels imply higher energy losses associated with bicuspid aortic valves and dilated ascending aortic geometries that are not assessable by current echocardiographic measures. These findings indicate that TKE may provide complementary information to echocardiography, helping to distinguish within the heterogeneous population of patients with moderate to severe AS.
Comparing Outcomes of Coronary Artery Bypass Grafting Among Large Teaching and Urban Hospitals in China and the United States
Authors: Zheng Zhe , Zhang Heng , Yuan Xin , Rao Chenfei , Zhao Yan , Wang Yun , Normand Sharon-Lise , Krumholz Harlan M. , Hu Shengshou 
Published: June 2017

Background—
Coronary artery disease is prevalent in China, with concomitant increases in the volume of coronary artery bypass grafting (CABG). The present study aims to compare CABG-related outcomes between China and the United States among large teaching and urban hospitals.

Methods and Results—

Observational analysis of patients aged ≥18 years, discharged from acute-care, large teaching and urban hospitals in China and the United States after hospitalization for an isolated CABG surgery. Data were obtained from the Chinese Cardiac Surgery Registry in China and the National Inpatient Sample in the United States. Analysis was stratified by 2 periods: 2007, 2008, and 2010; and 2011 to 2013 periods. The primary outcome was in-hospital mortality, and the secondary outcome was length of stay. The sample included 51 408 patients: 32 040 from 77 hospitals in the China-CABG group and 19 368 from 303 hospitals in the US-CABG group. In the 2007 to 2008, 2010 period and for all-age and aged ≥65 years, the China-CABG group had higher mortality than the US-CABG group (1.91% versus 1.58%,
P
=0.059; and 3.12% versus 2.20%,
P
=0.004) and significantly higher age-, sex-, and comorbidity-adjusted odds of death (odds ratio, 1.58; 95% confidential interval, 1.22–2.04; and odds ratio, 1.73; 95% confidential interval, 1.24–2.40). There were no significant mortality differences in the 2011 to 2013 period. For preoperative, postoperative, and total hospital stay, respectively, the median (interquartile range) length of stay across the entire study period between China-CABG and US-CABG groups were 9 (8) versus 1 (3), 9 (6) versus 6 (3), and 20 (12) versus 7 (5) days (all
P
<0.001). This difference did not change significantly over time.

Conclusions—
In 2011 to 2013, there was no significant difference in in-hospital mortality among patients who underwent an isolated CABG surgery in large teaching and urban hospitals in China and the United States. The longer length of stay in China may represent an opportunity for improvement.