bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amplification of 1q32.1 Refines the Molecular Classification of Endometrial Carcinoma
Authors: Depreeuw Jeroen , Stelloo Ellen , Osse Elisabeth M. , Creutzberg Carien L. , Nout Remi A. , Moisse Matthieu , Garcia-Dios Diego A. , Dewaele Michael , Willekens Karen , Marine Jean-Christophe , Matias-Guiu Xavier , Amant Frédéric , Lambrechts Diether , Bosse Tjalling 
Published: September 2017

AbstractPurpose: Molecular classification of endometrial cancer identified distinct molecular subgroups. However, the largest subset of endometrial cancers remains poorly characterized and is referred to as the “nonspecific molecular profile” (NSMP) subgroup. Here, we aimed at refining the classification of this subgroup by profiling somatic copy-number aberrations (SCNAs).Experimental Design: SCNAs were analyzed in 141 endometrial cancers using whole-genome SNP arrays and pooled with 361 endometrial cancers from The Cancer Genome Atlas. Genomic Identification of Significant Targets in Cancer (GISTIC) identified statistically enriched SCNAs and penalized Cox regression assessed survival effects. The prognostic significance of relevant SCNAs was validated using multiplex ligation-dependent probe amplification in 840 endometrial cancers from the PORTEC-1/2 trials. Copy-number status of genes was correlated with gene expression to identify potential cancer drivers. One plausible oncogene was validated in vitro using antisense oligonucleotide-based strategy.Results: SCNAs affecting chromosome 1q32.1 significantly correlated with worse relapse-free survival (RFS) in the NSMP subgroup (HR, 2.12; 95% CI, 1.26–3.59; P = 0.005). This effect was replicated in NSMP endometrial cancers from PORTEC-1/2 (HR, 2.34; 95% CI, 1.17–4.70; P = 0.017). A new molecular classification including the 1q32.1 amplification improved risk prediction of recurrence. MDM4 gene expression strongly correlated with 1q32.1 amplification. Silencing MDM4 inhibited cell growth in cell lines carrying 1q32.1 amplification, but not in those without MDM4 amplification. Vice versa, increasing MDM4 expression in nonamplified cell lines stimulated cell proliferation.Conclusions: 1q32.1 amplification was identified as a prognostic marker for poorly characterized NSMP endometrial cancers, refining the molecular classification of this subgroup. We functionally validated MDM4 as a potential oncogenic driver in the 1q32.1 region. Clin Cancer Res; 23(23); 7232–41. ©2017 AACR.
Phase III Clinical Trial (RERISE study) Results of Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia
Authors: Kwak Jae-Yong , Kim Sung-Hyun , Oh Suk Joong , Zang Dae Young , Kim Hawk , Kim Jeong-A , Do Young Rok , Kim Hyeoung Joon , Park Joon Seong , Choi Chul Won , Lee Won Sik , Mun Yeung-Chul , Kong Jee Hyun , Chung Joo Seop , Shin Ho-Jin , Kim Dae-Young , Park Jinny , Jung Chul Won , Bunworasate Udomsak , Comia Narcisa Sonia , Jootar Saengsuree , Reksodiputro Arry Harryanto , Caguioa Priscilla B. , Lee Sung-Eun , Kim Dong-Wook 
Published: September 2017

Abstract
Purpose: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for chronic phase chronic myeloid leukemia (CML-CP) in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP.
Experimental Design: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily radotinib doses, or imatinib daily. The primary endpoint was major molecular response (MMR) by 12 months.
Results: Two hundred forty-one patients were randomized to receive radotinib 300 mg (n = 79) or 400 mg twice-daily (n = 81), or imatinib 400 mg daily (n = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg twice-daily (46%) versus imatinib (30%; P = 0.0044 and P = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; P = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction.
Conclusions: Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome–positive CML-CP. This trial was registered at www.clinicaltrials.gov as NCT01511289. Clin Cancer Res; 23(23); 7180–8. ©2017 AACR.
Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870)
Authors: Pili Roberto , Quinn David I. , Hammers Hans J. , Monk Paul , George Saby , Dorff Tanya B. , Olencki Thomas , Shen Li , Orillion Ashley , Lamonica Dominick , Fragomeni Roberto S. , Szabo Zsolt , Hutson Alan , Groman Adrienne , Perkins Susan M. , Piekarz Richard , Carducci Michael A. 
Published: September 2017

Abstract
Purpose: On the basis of preclinical data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high-dose IL2 in a renal cell carcinoma model by downregulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clinical study with entinostat and high-dose IL2 in patients with metastatic clear cell renal cell carcinoma (ccRCC).
Experimental Design: Clear cell histology, no prior treatments, and being sufficiently fit to receive high-dose IL2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, orally every 14 days) and a fixed standard dose of IL2 (600,000 U/kg i.v.). Each cycle was 85 days. The primary endpoint was objective response rate and toxicity. Secondary endpoints included progression-free survival and overall survival.
Results: Forty-seven patients were enrolled. At a median follow-up of 21.9 months, the objective response rate was 37% [95% confidence interval (CI), 22%–53%], the median progression-free survival was 13.8 months (95% CI, 6.0–18.8), and the median overall survival was 65.3 months (95% CI, 52.6.-65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Tregs were observed following treatment with entinostat, and lower numbers were associated with response (P = 0.03).
Conclusions: This trial suggests a promising clinical activity for entinostat in combination with high-dose IL2 in ccRCC patients and provides the first example of an epigenetic agent being rationally combined with immunotherapy. Clin Cancer Res; 23(23); 7199–208. ©2017 AACR.
A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin–Drug Conjugate (LDC)
Authors: Shimomura Osamu , Oda Tatsuya , Tateno Hiroaki , Ozawa Yusuke , Kimura Sota , Sakashita Shingo , Noguchi Masayuki , Hirabayashi Jun , Asashima Makoto , Ohkohchi Nobuhiro 
Published: September 2017

Abstract
Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumor-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin–glycan pairs. The selected lectin was fused with a bacterial exotoxin for the construction of a lectin–drug conjugate (LDC), and its safety and antitumor effects were evaluated. A specific affinity between a recombinant bacterial C-type lectin (rBC2LC-N) and Capan-1 was identified, and its positivity was confirmed in 69 human samples. In contrast to the belief that all lectins mediate harmful hemagglutination, rBC2LC-N did not cause hemagglutination with human erythrocytes and was safely administered to mice. The 50% inhibitory concentration of LDC to Capan-1 (1.04 pg/mL = 0.0195 pmol/L) was 1/1,000 lower than that reported for conventional immunotoxins. The intraperitoneal administration of LDC reduced the tumor weight from 390 to 130.8 mg (P &lt; 0.01) in an orthotopic model and reduced the number of nodules from 48 to 3 (P &lt; 0.001) and improved survival from 62 to 105 days in a peritoneal dissemination model (P &lt; 0.0001). In addition, the effect of LDC was reproduced in nodules from patient-derived PDAC xenografts through intravenous injection. Herein, we show the concept of utilizing lectins as drug carriers to target glycans on the cancer cell surface, highlighting new insights into cancer treatments. Mol Cancer Ther; 17(1); 183–95. ©2017 AACR.
J Curve in Patients Randomly Assigned to Different Systolic Blood Pressure Targets
Authors: Kalkman Deborah N. , Brouwer Tom F. , Vehmeijer Jim T. , Berger Wouter R. , Knops Reinoud E. , de Winter Robbert J. , Peters Ron J. , van den Born Bert-Jan H. 
Published: September 2017

Background:
Low systolic blood pressure (SBP) values are associated with an increased risk of cardiovascular events, giving rise to the so-called J-curve phenomenon. We assessed the association between on-treatment SBP levels, cardiovascular events, and all-cause mortality in patients randomized to different SBP targets.

Methods:
Data from 2 large randomized trials that randomly allocated hypertensive patients at high risk for cardiovascular disease to intensive (SBP<120 mm Hg) or conventional (SBP<140 mm Hg) treatment were pooled and harmonized for outcomes and follow-up duration. Using natural cubic splines, we plotted the hazard ratio for all-cause mortality and cardiovascular events against the mean on-treatment SBP per treatment group.

Results:
The pooled data consisted of 194 875 on-treatment SBP measurements in 13 946 patients (98.9%). During a median follow-up of 3.3 years, cardiovascular events occurred in 1014 patients (7.3%), and 502 patients died (3.7%). For both blood pressure targets, an identical shape of the J curve was present, with a nadir for cardiovascular events and all-cause mortality just below the SBP target. Patients in the lowest SBP stratum were older, had a higher body mass index, smoked more often, and had a higher frequency of diabetes mellitus and cardiovascular events.

Conclusions:
Low on-treatment SBP levels are associated with increased cardiovascular events and all-cause mortality. This association is independent of the attained blood pressure level because the J curve aligns with the SBP target. Our results suggest that the benefit or risk associated with intensive blood pressure–lowering treatment can be established only via randomized clinical trials.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifiers: NCT01206062 and NCT00000620.
Multistate 5‐Year Initiative to Improve Care for Out‐of‐Hospital Cardiac Arrest: Primary Results From the HeartRescue Project
Authors: van Diepen Sean , Girotra Saket , Abella Benjamin S. , Becker Lance B. , Bobrow Bentley J. , Chan Paul S. , Fahrenbruch Carol , Granger Christopher B. , Jollis James G. , McNally Bryan , White Lindsay , Yannopoulos Demetris , Rea Thomas D. 
Published: September 2017

Background
The HeartRescue Project is a multistate public health initiative focused on establishing statewide out‐of‐hospital cardiac arrest (OHCA) systems of care to improve case capture and OHCA care in the community, by emergency medical services (EMS), and at hospital level.

Methods and Results

From 2011 to 2015 in the 5 original HeartRescue states, all adults with EMS–treated OHCA due to a presumed cardiac cause were included. In an adult population of 32.8 million, a total of 64 988 OHCAs—including 10 046 patients with a bystander‐witnessed OHCA with a shockable rhythm—were treated by 330 EMS agencies. From 2011 to 2015, the case‐capture rate for all‐rhythm OHCA increased from an estimated 39.0% (n=6762) to 89.2% (n=16 103;
P
<0.001 for trend). Overall survival to hospital discharge was 11.4% for all rhythms and 34.0% in the subgroup with bystander‐witnessed OHCA with a shockable rhythm. We observed modest temporal increases in bystander cardiopulmonary resuscitation (41.8–43.5%,
P
<0.001 for trend) and bystander automated external defibrillator application (3.2–5.6%,
P
<0.001 for trend) in the all‐rhythm group, although there were no temporal changes in survival. There were marked all‐rhythm survival differences across the 5 states (8.0–16.1%,
P
<0.001) and across participating EMS agencies (2.7–26.5%,
P
<0.001).

Conclusions
In the initial 5 years, the HeartRescue Project developed a population‐based OHCA registry and improved statewide case‐capture rates and some processes of care, although there were no early temporal changes in survival. The observed survival variation across states and EMS systems presents a future challenge to elucidate the characteristics of high‐performing systems with the goal of improving OHCA care and survival.
Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice
Authors: Milasan Andreea , Jean Gabriel , Dallaire François , Tardif Jean‐Claude , Merhi Yahye , Sorci‐Thomas Mary , Martel Catherine 
Published: September 2017

Background
Subcutaneously injected lipid‐free apoA‐I (apolipoprotein A‐I) reduces accumulation of lipid and immune cells within the aortic root of hypercholesterolemic mice without increasing high‐density lipoprotein–cholesterol concentrations. Lymphatic vessels are now recognized as prerequisite players in the modulation of cholesterol removal from the artery wall in experimental conditions of plaque regression, and particular attention has been brought to the role of the collecting lymphatic vessels in early atherosclerosis‐related lymphatic dysfunction. In the present study, we address whether and how preservation of collecting lymphatic function contributes to the protective effect of apoA‐I.

Methods and Results

Atherosclerotic
Ldlr

−/−

mice treated with low‐dose lipid‐free apoA‐I showed enhanced lymphatic transport and abrogated collecting lymphatic vessel permeability in atherosclerotic
Ldlr

−/−

mice when compared with albumin‐control mice. Treatment of human lymphatic endothelial cells with apoA‐I increased the adhesion of human platelets on lymphatic endothelial cells, in a bridge‐like manner, a mechanism that could strengthen endothelial cell–cell junctions and limit atherosclerosis‐associated collecting lymphatic vessel dysfunction. Experiments performed with blood platelets isolated from apoA‐I‐treated
Ldlr

−/−

mice revealed that apoA‐I decreased ex vivo platelet aggregation. This suggests that in vivo apoA‐I treatment limits platelet thrombotic potential in blood while maintaining the platelet activity needed to sustain adequate lymphatic function.

Conclusions
Altogether, we bring forward a new pleiotropic role for apoA‐I in lymphatic function and unveil new potential therapeutic targets for the prevention and treatment of atherosclerosis.
For-Profit Hospital Status and Carotid Artery Stent Utilization in US Hospitals Performing Carotid Revascularization
Authors: Chandler Justin V. , George Benjamin P. , Kelly Adam G. , Holloway Robert G. 
Published: September 2017

Background and Purpose—
Carotid artery stenting may be an economically attractive procedure for hospitals and physicians. We sought to identify the association of hospital ownership (nonprofit versus for-profit) on carotid artery stenting (CAS) versus carotid endarterectomy utilization in US hospitals.

Methods—

Using the Nationwide Inpatient Sample admissions for cerebrovascular disease from 2008 to 2011, we identified all private, nonfederal US hospitals performing at least 20 carotid revascularization procedures annually, including carotid artery stenting (
International Classification of Diseases
-Ninth Revision 00.63) or carotid endarterectomy (
International Classification of Diseases
-Ninth Revision 38.12). We used a multilevel multivariable logistic regression controlling for patient demographics, comorbidities, and hospital characteristics, to assess the effect of hospital ownership on CAS use.

Results—

Across 723 hospitals (600 nonprofit, 123 for-profit), 66 731 carotid revascularization admissions were identified. Approximately 1 in 5 (n=11 641; 17.4%) revascularizations received CAS. The mean CAS rate among nonprofit hospitals was 17.5 per 100 revascularizations (median, 11.5; interquartile range, 5.2–24.5), and the mean CAS rate among for-profit hospitals was 24.2 per 100 revascularizations (median, 16.0; interquartile range, 6.7–33.3;
P
<0.001). Adjusting for patient and hospital characteristics, for-profit hospital designation was associated with greater odds of CAS (adjusted odds ratio, 1.45; 95% confidence interval, 1.07–1.98).

Conclusions—
For-profit hospital ownership is associated with a higher rate of CAS compared to nonprofit hospitals in those receiving carotid revascularization. Further research is needed to understand the individual- and system-level factors driving this difference.
CHA
2
DS
2
-VASc Score for Identifying Truly Low-Risk Atrial Fibrillation for Stroke
Authors: Kim Tae-Hoon , Yang Pil-Sung , Kim Daehoon , Yu Hee Tae , Uhm Jae-Sun , Kim Jong-Youn , Pak Hui-Nam , Lee Moon-Hyoung , Joung Boyoung , Lip Gregory Y.H. 
Published: September 2017

Background and Purpose—

As the threshold of stroke risk for initiating oral anticoagulants is lowered after the introduction of the nonvitamin K antagonist oral anticoagulants, the focus of stroke prevention in patients with nonvalvular atrial fibrillation has shifted away from predicting high-risk patients toward initially identifying patients with a truly low risk of ischemic stroke, who do not need antithrombotic therapy. We tested the predictive ability of the congestive heart failure, hypertension, age ≥75, diabetes mellitus, prior stroke or transient ischemic attack (doubled; CHADS
2
), congestive heart failure, hypertension, age ≥75 (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled), vascular disease, age 65 to 74, female (CHA
2
DS
2
-VASc), and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk stratification schemes in oral anticoagulants naive patients with atrial fibrillation in a Korean nationwide sample cohort.

Methods—
From January 2002 to December 2008, a total of 5855 oral anticoagulant naive patients with nonvalvular atrial fibrillation aged ≥20 years were enrolled from Korea National Health Insurance Service-Sample Cohort database and were followed-up until December 2013.

Results—

At baseline, the proportions categorized as low risk using CHADS
2
, CHA
2
DS
2
-VASc, and ATRIA risk stratification schemes were 1049 (17.9%), 860 (14.7%), and 3280 (56.0%), respectively. During follow-up, the low-risk category using CHADS
2
, CHA
2
DS
2
-VASc, and ATRIA scores was retained in 811 (13.9%), 667 (11.4%), and 2729 (46.6%) patients, respectively. Rates of ischemic stroke (100 person-years) in the low risk categories of CHADS
2
, CHA
2
DS
2
-VASc, and ATRIA scores were 0.42, 0.26, and 1.43, respectively. CHA
2
DS
2
-VASc had the best sensitivity (98.8% versus 85.7% in CHADS
2
and 74.8% in ATRIA) and negative predictive value (98.8% versus 95.3% for CHADS
2
and 93.7% for ATRIA) for the prediction of stroke incidence and was best for the prediction of the absence of ischemic stroke during 5 years of follow-up (odds ratio, 16.4 [95% confidence interval, 8.8–30.8]).

Conclusions—

The CHA
2
DS
2
-VASc score shows good performance in defining truly low-risk Asian patients with atrial fibrillation for stroke compared with CHADS
2
and ATRIA scores.
Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa
Authors: Siegal Deborah , Lu Genmin , Leeds Janet M. , Karbarz Mark , Castillo Janice , Mathur Vandana , Hutchaleelaha Athiwat , Sinha Uma , Kitt Michael , McClure Matt , Hollenbach Stanley J. , Curnutte John T. , Conley Pamela B. , Crowther Mark 
Published: September 2017

Key Points
Andexanet reversed apixaban anticoagulation in healthy volunteers within minutes after administration and for the duration of infusion. Andexanet was generally well tolerated, with no evidence of prothrombotic activity in preclinical models and in healthy subjects.
Changes in Thyroid Hormones Levels and Metabolism in Dairy Cows around Calving
Authors: Fiore Enrico , Giambelluca Sonia , Morgante Massimo , Piccione Giuseppe , Vazzana Irene , Contiero Barbara , Orefice Tiziana , Arfuso Francesca , Gianesella Matteo 
Published: September 2017

AbstractThe hormonal activity of the thyroid gland has an important role in ruminants for the modulation of metabolic variables. In this study changes in thyroid hormones and biochemical parameters in dairy cows around calving were evaluated and the critical thyroid hormones thresholds for predicting the risk of ketosis were estimated. Blood samples were collected from 82 dairy cows at 5±3 days pre-partum and 5±3 days postpartum. Serum values of triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), non-esterified fatty acids (NEFA), β-hydroxybutyrate (BHB), insulin, glucose, Ca, Cl, Mg, P, K, Na, aspartate transaminase (AST), alanine transaminase (ALT) and urea were evaluated. Signifi cant decrease in the levels of T3, T4 and TSH was found in the postpartum period. The values of T3 and T4 were negatively correlated with NEFA and BHB levels, and TSH values were negatively correlated with NEFA. A critical T3 threshold was found by means of ROC analysis for predicting the risk of ketosis. T3 values < 1.23 nmol/L were associated with BHB > 1.10 mmol/L in postpartum, which represents the BHB threshold commonly used as the indicator of hyperketonaemia. The results confirm that the peripartum period is accompanied by marked changes in circulating thyroid hormone profile that is correlated with lipomobilization predictors.
Physiological Effects of Balanced Anesthesia during Dental Procedures in Brown Bears (Ursus Arctos)
Authors: Yanev Aminkov Bogdan , Hristov Mehandzhiyski Nikolay , Zlatozarova Zlateva-Panayotova Nadya , Bogdanov Aminkov Konstantin , Marinov Marinov Georgi 
Published: September 2017

AbstractThe goal of the present study was to monitor the physiological effects of a standardized balanced anesthetic protocol in brown bears (Ursus arctos) during routine dental procedures. Physiological parameters (rectal temperature, heart rate, respiratory rate and oxygen saturation) were evaluated in twelve brown bears, anesthetized with a balanced drug combination for 90 minutes during dental procedures. The animals were kept in the „Park for Dancing Bears“ Belitza, Bulgaria. A standardized premedication protocol of a combined intramuscular injection of tiletamine HCl and zolazepam HCl (Zoletil 100® Virbac, France) 1mg/kg, medetomidine HCl 0.003mg/kg and 0.05 mg/kg of butorphanol was administered intramuscularly. Anesthesia was induced intravenously with a combined bolus of ketamine at 2 mg/kg and propofol at 2 mg/kg, and maintained with a constant rate infusion (CRI) of ketamine at 0.8 mg/kg/h and propofol 0.04 at mg/kg/min. Rectal temperature decreased significantly during anesthesia, whereas: heart rate, respiratory rate and oxygen saturation were stable with no significant changes in these parameters for the duration of anesthesia. In conclusion, this anesthetic drug combination is suitable for oral surgery of medium duration in brown bears.