bluuebunny/crossref_metadata_2025_split huggingface dataset:
Highly Potent, Anthracycline-based Antibody–Drug Conjugates Generated by Enzymatic, Site-specific Conjugation
Authors: Stefan Nikolas , Gébleux Rémy , Waldmeier Lorenz , Hell Tamara , Escher Marie , Wolter Fabian I. , Grawunder Ulf , Beerli Roger R. 
Published: March 2017

Abstract
Antibody–drug conjugates (ADC) are highly potent and specific antitumor drugs, combining the specific targeting of mAbs with the potency of small-molecule toxic payloads. ADCs generated by conventional chemical conjugation yield heterogeneous mixtures with variable pharmacokinetics, stability, safety, and efficacy profiles. To address these issues, numerous site-specific conjugation technologies are currently being developed allowing the manufacturing of homogeneous ADCs with predetermined drug-to-antibody ratios. Here, we used sortase-mediated antibody conjugation (SMAC) technology to generate homogeneous ADCs based on a derivative of the highly potent anthracycline toxin PNU-159682 and a noncleavable peptide linker, using the anti-HER2 antibody trastuzumab (part of Kadcyla) and the anti-CD30 antibody cAC10 (part of Adcetris). Characterization of the resulting ADCs in vitro and in vivo showed that they were highly stable and exhibited potencies exceeding those of ADCs based on conventional tubulin-targeting payloads, such as Kadcyla and Adcetris. The data presented here suggest that such novel and highly potent ADC formats may help to increase the number of targets available to ADC approaches, by reducing the threshold levels of target expression required. Mol Cancer Ther; 16(5); 879–92. ©2017 AACR.
Nucleome Analysis Reveals Structure–Function Relationships for Colon Cancer
Authors: Seaman Laura , Chen Haiming , Brown Markus , Wangsa Darawalee , Patterson Geoff , Camps Jordi , Omenn Gilbert S. , Ried Thomas , Rajapakse Indika 
Published: March 2017

AbstractChromosomal translocations and aneuploidy are hallmarks of cancer genomes; however, the impact of these aberrations on the nucleome (i.e., nuclear structure and gene expression) is not yet understood. Here, the nucleome of the colorectal cancer cell line HT-29 was analyzed using chromosome conformation capture (Hi-C) to study genome structure, complemented by RNA sequencing (RNA-seq) to determine the consequent changes in genome function. Importantly, translocations and copy number changes were identified at high resolution from Hi-C data and the structure–function relationships present in normal cells were maintained in cancer. In addition, a new copy number–based normalization method for Hi-C data was developed to analyze the effect of chromosomal aberrations on local chromatin structure. The data demonstrate that at the site of translocations, the correlation between chromatin organization and gene expression increases; thus, chromatin accessibility more directly reflects transcription. In addition, the homogeneously staining region of chromosome band 8q24 of HT-29, which includes the MYC oncogene, interacts with various loci throughout the genome and is composed of open chromatin. The methods, described herein, can be applied to the assessment of the nucleome in other cell types with chromosomal aberrations.Implications: Findings show that chromosome conformation capture identifies chromosomal abnormalities at high resolution in cancer cells and that these abnormalities alter the relationship between structure and function. Mol Cancer Res; 15(7); 821–30. ©2017 AACR.
Effects of Renal Artery Denervation on Ventricular Arrhythmias in a Postinfarct Model
Authors: Jackson Nicholas , Gizurarson Sigfús , Azam Mohammed Ali , King Benjamin , Ramadeen Andrew , Zamiri Nima , Porta-Sánchez Andreu , Al-Hesayen Abdul , Graham John , Kusha Marjan , Massé Stéphane , Lai Patrick F.H. , Parker John , John Rohan , Kiehl Tim-Rasmus , Nair Govind Krishna Kumar , Dorian Paul , Nanthakumar Kumaraswamy 
Published: March 2017

Background—
The therapeutic potential of renal denervation (RDN) for arrhythmias has not been fully explored. Detailed mechanistic evaluation is in order. The objective of the present study was to determine the antiarrhythmic potential of RDN in a postinfarct animal model and to determine whether any benefits relate to RDN-induced reduction of sympathetic effectors on the myocardium.

Methods and Results—

Pigs implanted with single-chamber implantable cardioverter defibrillators to record ventricular arrhythmias (VAs) were subjected to percutaneous coronary occlusion to induce myocardial infarction. Two weeks later, a sham or real RDN treatment was performed bilaterally using the St Jude EnligHTN basket catheter. Parameters of ventricular remodeling and modulation of cardio–renal sympathetic axis were monitored for 3 weeks after myocardial infarction. Histological analysis of renal arteries yielded a mean neurofilament score of healthy nerves that was significantly lower in the real RDN group than in sham controls; damaged nerves were found only in the real RDN group. There was a 100% reduction in the rate of spontaneous VAs after real RDN and a 75% increase in the rate of spontaneous VAs after sham RDN (
P
=0.03). In the infarcted myocardium, presence of sympathetic nerves and tissue abundance of neuropeptide-Y, an indicator of sympathetic nerve activities, were significantly lower in the RDN group. Peak and mean sinus tachycardia rates were significantly reduced after RDN.

Conclusions—
RDN in the infarcted pig model leads to reduction of postinfarction VAs and myocardial sympathetic effectors. This may form the basis for a potential therapeutic role of RDN in postinfarct VAs.
Weight Loss and Heart Failure
Authors: Sundström Johan , Bruze Gustaf , Ottosson Johan , Marcus Claude , Näslund Ingmar , Neovius Martin 
Published: March 2017

Background:
Associations of obesity with incidence of heart failure have been observed, but the causality is uncertain. We hypothesized that gastric bypass surgery leads to a lower incidence of heart failure compared with intensive lifestyle modification in obese people.

Methods:
We included obese people without previous heart failure from a Swedish nationwide registry of people treated with a structured intensive lifestyle program and the Scandinavian Obesity Surgery Registry. All analyses used inverse probability weights based on baseline body mass index and a propensity score estimated from baseline variables. Treatment groups were well balanced in terms of weight, body mass index, and most potential confounders. Associations of treatment with heart failure incidence, as defined in the National Patient Register, were analyzed with Cox regression.

Results:
The 25 804 gastric bypass surgery patients had on average lost 18.8 kg more weight after 1 year and 22.6 kg more after 2 years than the 13 701 lifestyle modification patients. During a median of 4.1 years, surgery patients had lower heart failure incidence than lifestyle modification patients (hazard ratio, 0.54; 95% confidence interval, 0.36–0.82). A 10-kg achieved weight loss after 1 year was related to a hazard ratio for heart failure of 0.77 (95% confidence interval, 0.60–0.97) in both treatment groups combined. Results were robust in sensitivity analyses.

Conclusions:
Gastric bypass surgery was associated with approximately one half the incidence of heart failure compared with intensive lifestyle modification in this study of 2 large nationwide registries. We also observed a graded association between increasing weight loss and decreasing risk of heart failure.
Transcatheter Heart Valve Selection and Permanent Pacemaker Implantation in Patients With Pre‐Existent Right Bundle Branch Block
Authors: van Gils Lennart , Tchetche Didier , Lhermusier Thibault , Abawi Masieh , Dumonteil Nicolas , Rodriguez Olivares Ramón , Molina‐Martin de Nicolas Javier , Stella Pieter R. , Carrié Didier , De Jaegere Peter P. , Van Mieghem Nicolas M. 
Published: March 2017

Background

Right bundle branch block is an established predictor for new conduction disturbances and need for a permanent pacemaker (
PPM
) after transcatheter aortic valve replacement. The aim of the study was to evaluate the absolute rates of transcatheter aortic valve replacement related
PPM
implantations in patients with pre‐existent right bundle branch block and categorize for different transcatheter heart valves.

Methods and Results

We pooled data on 306 transcatheter aortic valve replacement patients from 4 high‐volume centers in Europe and selected those with right bundle branch block at baseline without a previously implanted
PPM
. Logistic regression was used to evaluate whether
PPM
rate differed among transcatheter heart valves after adjustment for confounders. Mean age was 83±7 years and 63% were male. Median Society of Thoracic Surgeons score was 6.3 (interquartile range, 4.1–10.2). The following transcatheter valve designs were used: Medtronic CoreValve (n=130; Medtronic, Minneapolis, MN); Edwards Sapien
XT
(
ES
‐
XT
; n=124) and Edwards Sapien 3 (
ES
‐3; n=32; Edwards Lifesciences, Irvine, CA); and Boston Scientific Lotus (n=20; Boston Scientific Corporation, Marlborough, MA). Overall permanent pacemaker implantation rate post‐transcatheter aortic valve replacement was 41%, and per valve design: 75% with Lotus, 46% with CoreValve, 32% with
ES
‐
XT
, and 34% with
ES
‐3. The indication for
PPM
implantation was total atrioventricular block in 98% of the cases. Lotus was associated with a higher
PPM
rate than all other valves.
PPM
rate did not differ between
ES
‐
XT
and
ES
‐3. Ventricular paced rhythm at 30‐day and 1‐year follow‐up was present in 81% at 89%, respectively.

Conclusions

Right bundle branch block at baseline is associated with a high incidence of
PPM
implantation for all transcatheter heart valves.
PPM
rate was highest for Lotus and lowest for
ES
‐
XT
and
ES
‐3. Pacemaker dependency remained high during follow‐up.
Association Between Acute Kidney Disease and Intravenous Dye Administration in Patients With Acute Stroke
Authors: Demel Stacie L. , Grossman Aaron W. , Khoury Jane C. , Moomaw Charles J. , Alwell Kathleen , Kissela Brett M. , Woo Daniel , Flaherty Matthew L. , Ferioli Simona , Mackey Jason , De Los Rios la Rosa Felipe , Martini Sharyl , Adeoye Opeolu , Kleindorfer Dawn O. 
Published: March 2017

Background and Purpose—
Computed tomographic angiography and conventional angiography provide timely vascular anatomic information in patients with stroke. However, iodinated contrast dye may cause acute kidney injury (AKI). Within a large, biracial population, we examined in-hospital incidence of new or worsening kidney disease in patients with stroke and its association with administration of intravenous dye.

Methods—
All adult residents of the Greater Cincinnati/Northern Kentucky region with acute ischemic stroke or intracerebral hemorrhage who presented to an emergency department in 2010 were included. Prevalence of unsuspected kidney disease at the time of emergency department presentation and the incidence of AKI after admission in 2 groups of patients—those who did and those who did not receive intravenous dye—were determined.

Results—
In 2010, 2299 patients met inclusion criteria (89% ischemic stroke and 11% intracerebral hemorrhage); mean age 69 years (SD 15), 22% black, and 54% women. Among these patients, 37% had kidney disease at baseline, including 22% (516/2299) in whom this was unsuspected. Two percent (2%; 15/853) of patients with baseline kidney disease developed AKI during the hospital stay. Of those with no baseline kidney disease, 1% (14/14 467) developed AKI. There was no association between dye administration and new or worsening kidney disease.

Conclusions—
Although 22% of patients in the Greater Cincinnati/Northern Kentucky stroke population had unsuspected kidney disease, the incidence of new or worsening kidney disease was low, and AKI was not associated with dye administration. These findings confirm single-center reports that the risk of severe renal complications after contrast dye is small.
Decreased Adiponectin-Mediated Signaling Through the AdipoR2 Pathway Is Associated With Carotid Plaque Instability
Authors: Gasbarrino Karina , Zheng Huaien , Hafiane Anouar , Veinot John P. , Lai Chi , Daskalopoulou Stella S. 
Published: March 2017

Background and Purpose—
Adiponectin, the most abundantly secreted anti-inflammatory adipokine, protects against all stages of atherosclerotic plaque formation by acting on its receptors, AdipoR1 (adiponectin receptor 1) and AdipoR2 (adiponectin receptor 2). Through binding of AdipoR1, adiponectin leads to the activation of the AMPK (adenosine monophosphate–activated protein kinase) pathway, whereas stimulation of PPAR-α (peroxisome proliferator–activated receptor-α) is attributed to the binding of AdipoR2. However, the role of adiponectin and its receptors in plaque instability remains to be characterized. Thus, we aimed to investigate whether the adiponectin–AdipoR pathway is associated with carotid atherosclerotic plaque instability.

Methods—
The instability of plaque specimens obtained from patients who underwent a carotid endarterectomy (n=143) was assessed using gold standard histological classifications.

Results—

Using immunohistochemistry, we showed that adiponectin and AdipoR1/AdipoR2 are expressed in human carotid plaques and that their expression was localized most abundantly in areas of macrophage and foam cell accumulation. Unstable plaques expressed more adiponectin protein (Western blot,
P
<0.05) and less AdipoR2 mRNA (2.11-fold decrease,
P
<0.05) than stable plaques, whereas AdipoR1 expression remained similar between stable and unstable plaques. Beyond AdipoR1/AdipoR2 expression, a graded decrease in PPAR-α protein levels was observed in relation to carotid plaque instability (
P
<0.001), whereas AMPK phosphorylation was increased (
P
<0.05). Our in vitro model of plaque instability, involving the induction of foam cells from human THP-1 (Tamm–Horsfall protein 1) macrophages treated with acetylated low-density lipoprotein, supported our in vivo conclusions.

Conclusions—
An overall abundance of adiponectin with a decrease in AdipoR2 expression and activity was observed in unstable plaques, suggesting that reduced signaling through the AdipoR2 pathway, and not through AdipoR1, may contribute to plaque instability.
Quality of Acute Care and Long-Term Quality of Life and Survival
Authors: Cadilhac Dominique A. , Andrew Nadine E. , Lannin Natasha A. , Middleton Sandy , Levi Christopher R. , Dewey Helen M. , Grabsch Brenda , Faux Steve , Hill Kelvin , Grimley Rohan , Wong Andrew , Sabet Arman , Butler Ernest , Bladin Christopher F. , Bates Timothy R. , Groot Patrick , Castley Helen , Donnan Geoffrey A. , Anderson Craig S. 
Published: March 2017

Background and Purpose—
Uncertainty exists over whether quality improvement strategies translate into better health-related quality of life (HRQoL) and survival after acute stroke. We aimed to determine the association of best practice recommended interventions and outcomes after stroke.

Methods—
Data are from the Australian Stroke Clinical Registry during 2010 to 2014. Multivariable regression was used to determine associations between 3 interventions: received acute stroke unit (ASU) care and in various combinations with prescribed antihypertensive medication at discharge, provision of a discharge care plan, and outcomes of survival and HRQoL (EuroQoL 5-dimensional questionnaire visual analogue scale) at 180 days, by stroke type. An assessment was also made of outcomes related to the number of processes patients received.

Results—
There were 17 585 stroke admissions (median age 77 years, 47% female; 81% managed in ASUs; 80% ischemic stroke) from 42 hospitals (77% metropolitan) assessed. Cumulative benefits on outcomes related to the number of care processes received by patients. ASU care was associated with a reduced likelihood of death (hazard ratio, 0.49; 95% confidence interval, 0.43–0.56) and better HRQoL (coefficient, 21.34; 95% confidence interval, 15.50–27.18) within 180 days. For those discharged from hospital, receiving ASU+antihypertensive medication provided greater 180-day survival (hazard ratio, 0.45; 95% confidence interval, 0.38–0.52) compared with ASU care alone (hazard ratio, 0.64; 95% confidence interval, 0.54–0.76). HRQoL gains were greatest for patients with intracerebral hemorrhage who received care bundles involving discharge processes (range of increase, 11%–19%).

Conclusions—
Patients with stroke who receive best practice recommended hospital care have improved long-term survival and HRQoL.
Shifting Perceptions of Risk and Reward: Use of Anticoagulation in Patients With Acute Brain Ischemia and Atrial Fibrillation
Authors: Schwammenthal Yvonne , Tsabari Rakefet , Orion David , Merzlyak Oleg , Haratz Salo , Peretz Shlomi , Bornstein Natan M. , Ifergane Gal , Einhorn Michal , Schwammenthal Ehud , Geva Diklah , Tanne David 
Published: March 2017

Background and Purpose—
Despite overwhelming evidence for the benefits of anticoagulation in patients with brain ischemia and atrial fibrillation, vast underuse has been reported.

Methods—
Use of anticoagulation for secondary stroke prevention was assessed in the National Acute Stroke Israeli Survey registry (NASIS) of hospitalized patients with atrial fibrillation and acute brain ischemia. Logistic regression analysis was performed to evaluate the effects of clinical covariates on anticoagulation therapy at discharge, and anticoagulation use over time was assessed in subgroups of patients with identified barriers to anticoagulation utilization.

Results—

There were 1254 survivors of acute brain ischemia with atrial fibrillation (mean age 77.2±10.6 years; 57.7% female). Between 2004 and 2013, the proportion of patients discharged on anticoagulation increased from 55% to 76.2%, and among those without perceived contraindications from 70% to 96% (
P
<0.0001). Older age, greater stroke severity, earlier registry period, and presence of contraindications were independent predictors of withholding therapy. Increased anticoagulation use over the years was observed even in patients with barriers to anticoagulation use, including patients with potential contraindications (
P
<0.001).

Conclusions—
In survivors of acute brain ischemia with atrial fibrillation, we observed a substantial increase in anticoagulation utilization within less than a decade. This change was mainly driven by greater utilization of anticoagulation in subgroups with traditional clinical barriers to anticoagulation use, indicating a shift in physicians’ perceptions of the risk–benefit ratio of anticoagulation.
Increased Vascular Disease Mortality Risk in Prediabetic Korean Adults Is Mainly Attributable to Ischemic Stroke
Authors: Kim Nam Hoon , Kwon Tae Yeon , Yu Sungwook , Kim Nan Hee , Choi Kyung Mook , Baik Sei Hyun , Park Yousung , Kim Sin Gon 
Published: March 2017

Background and Purpose—
Prediabetes is a known risk factor for vascular diseases; however, its differential contribution to mortality risk from various vascular disease subtypes is not known.

Methods—
The subjects of the National Health Insurance Service in Korea (2002–2013) nationwide cohort were stratified into normal glucose tolerance (fasting glucose <100 mg/dL), impaired fasting glucose (IFG) stage 1 (100–109 mg/dL), IFG stage 2 (110–125 mg/dL), and diabetes mellitus groups based on the fasting glucose level. A Cox regression analysis with counting process formulation was used to assess the mortality risk for vascular disease and its subtypes—ischemic heart disease, ischemic stroke, and hemorrhagic stroke.

Results—
When adjusted for age, sex, and body mass index, IFG stage 2, but not stage 1, was associated with significantly higher all-cause mortality (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.18–1.34) and vascular disease mortality (HR, 1.27; 95% CI, 1.08–1.49) compared with normal glucose tolerance. Among the vascular disease subtypes, mortality from ischemic stroke was significantly higher (HR, 1.60; 95% CI, 1.18–2.18) in subjects with IFG stage 2 but not from ischemic heart disease and hemorrhagic stroke. The ischemic stroke mortality associated with IFG stage 2 remained significantly high when adjusted other modifiable vascular disease risk factors (HR, 1.51; 95% CI: 1.10–2.09) and medical treatments (HR, 1.75; 95% CI, 1.19–2.57).

Conclusions—
Higher IFG degree (fasting glucose, 110–125 mg/dL) was associated with increased all-cause and vascular disease mortality. The increased vascular disease mortality in IFG stage 2 was attributable to ischemic stroke, but not ischemic heart disease or hemorrhagic stroke in Korean adults.
Growth and Neurodevelopmental Outcomes of Early, High‐Dose Parenteral Amino Acid Intake in Very Low Birth Weight Infants: A Randomized Controlled Trial
Authors: Balakrishnan Maya , Jennings Alishia , Przystac Lynn , Phornphutkul Chanika , Tucker Richard , Vohr Betty , Stephens Bonnie E. , Bliss Joseph M. 
Published: March 2017

AbstractBackground: Administration of high‐dose parenteral amino acids (AAs) to premature infants within hours of delivery is currently recommended. This study compared the effect of lower and higher AA administration starting close to birth on short‐term growth and neurodevelopmental outcomes at 18–24 months corrected gestational age (CGA). Methods: Infants <1250 g birth weight (n = 168) were randomly assigned in a blinded fashion to receive parenteral nutrition providing 1–2 g/kg/d AA and advancing daily by 0.5 g/kg/d to a goal of 4 g/kg/d (standard AA) or 3–4 g/kg/d and advancing to 4 g/kg/d by day 1. The primary outcome was neurodevelopmental outcomes measured by the Bayley Scales of Infant and Toddler Development, Third Edition at 18–24 months CGA. Secondary outcomes were growth parameters at 36 weeks CGA among infants surviving to hospital discharge, serum bicarbonate, serum urea nitrogen, creatinine, AA profiles in the first week of life, and incidence of major morbidities and mortality. Results: No differences in neurodevelopmental outcome were detected between the high and low AA groups. Infants in the high AA group had significantly lower mean weight, length, and head circumference percentiles than those in the standard AA group at 36 weeks CGA and at hospital discharge. These differences did not persist after controlling for birth growth parameters, except for head circumference. Infants in the high AA group had higher mean serum urea nitrogen than the standard group on each day throughout the first week. Conclusion: Current recommendations for high‐dose AA starting at birth are not associated with improved growth or neurodevelopmental outcomes.