bluuebunny/crossref_metadata_2025_split huggingface dataset:
An analysis of language models for high-performance communication in local-area networks
Authors: LeBlanc Thomas J. , Cook Robert P. 
Published: November 2016

In this paper we present an empirical analysis of language models for communication in distributed systems. We consider a computing environment in which a high-level, distributed programming language kernel is sufficient support for high-performance programming applications. We propose programming language support for such an environment and present the performance results of an implementation.
Using the distributed programming language StarMod as a context, we describe language constructs for message-based communication (including broadcast), remote invocation, and remote memory references. Each form of communication is integrated into StarMod in a consistent fashion maintaining the properties of transparency, modularity, and full parameter functionality. The costs and benefits associated with the various models of communication are analyzed based on the results of an implementation which runs on 8 PDP 11/23; microprocessors connected by a 1 megabit/second network.
Chymase-dependent production of angiotensin II: an old enzyme in old hearts
Authors: Froogh Ghezal , Pinto John T. , Le Yicong , Kandhi Sharath , Aleligne Yeabsra , Huang An , Sun Dong 
Published: November 2016

Age-dependent alteration of the renin-angiotensin system (RAS) and generation of angiotensin II (Ang II) are well documented. By contrast, RAS-independent generation of Ang II in aging and its responses to exercise have not been explored. To this end, we examined the effects of chymase, a secretory serine protease, on the angiotensin-converting enzyme (ACE)-independent conversion of Ang I to Ang II. We hypothesized that age-dependent alteration of cardiac Ang II formation is chymase dependent in nature and is prevented by exercise training. Experiments were conducted on hearts isolated from young (3 mo), aged sedentary (24 mo), and aged rats chronically exercised on a treadmill. In the presence of low Ang I levels and downregulation of ACE expression/activity, cardiac Ang II levels were significantly higher in aged than young rats, suggesting an ACE-independent response. Aged hearts also displayed significantly increased chymase expression and activity, as well as upregulation of tryptase, a biological marker of mast cells, confirming a mast cell-sourced increase in chymase. Coincidently, cardiac superoxide produced from NADPH oxidase (Nox) was significantly enhanced in aged rats and was normalized by exercise. Conversely, a significant reduction in cardiac expression of ACE2 followed by lower Ang 1-7 levels and downregulation of the Mas receptor (binding protein of Ang 1-7) in aged rats were completely reversed by exercise. In conclusion, local formation of Ang II is increased in aged hearts, and chymase is primarily responsible for this increase. Chronic exercise is able to normalize the age-dependent alterations via compromising chymase/Ang II/angiotensin type 1 receptor/Nox actions while promoting ACE2/Ang 1-7/MasR signaling.NEW & NOTEWORTHY Aging increases angiotensin-converting enzyme (ACE)-independent production of cardiac angiotensin II (Ang II), a response that is driven by chymase in an exercise-reversible manner. These findings highlight chymase, in addition to ACE, as an important therapeutic target in the treatment and prevention of Ang II-induced deterioration of cardiac function in the elderly.Listen to this article's corresponding podcast @ http://ajpheart.podbean.com/e/renin-angiotensin-system-signaling-in-aged-and-age-exercised-rats/ .
Intermittent parathyroid hormone administration attenuates endothelial dysfunction in old rats
Authors: Guers John J. , Prisby Rhonda D. , Edwards David G. , Lennon-Edwards Shannon 
Published: November 2016

Aging is an independent risk factor for cardiovascular disease and is characterized by a decline in endothelial function. Parathyroid hormone (PTH) administration has been shown to increase endothelial nitric oxide synthase (eNOS) expression. The purpose of this investigation was to determine the effect of intermittent PTH administration on aortic endothelial function in old rodents. We hypothesized that intermittent PTH administration would improve endothelial function in older rodents. Old (24-mo-old) and young (4-mo-old) Fischer-344 rats were given 10 injections of PTH 1–34 (43 μg·kg−1·day−1) or phosphate-buffered saline (100 μl/day) over 15 days. Endothelium-dependent relaxation of aortic rings in response to acetylcholine (10−9 to 10−5 M) was significantly impaired in old control (OC) compared with young control (YC) as indicated by a reduced area under the curve (AUC, 100 ± 6.28 vs. 54.08 ± 8.3%; P < 0.05) and impaired maximal relaxation (Emax, 70.1 ± 4.48 vs. 92.9 ± 4.38%; P < 0.05). Emax was improved in old animals treated with PTH (OPTH) (OC, 70.1 ± 4.48 vs. OPTH, 85 ± 7.48%; P < 0.05) as well as AUC (OC, 54.08 ± 8.3 vs. OPTH, 82.5 ± 5.7%; P < 0.05) while logEC50 was not different. Endothelial-independent relaxation in response to sodium nitroprusside was not different among groups. Aortic eNOS protein expression was significantly decreased in OC compared with YC ( P < 0.05). PTH treatment restored eNOS expression in OPTH animals ( P < 0.05). These data suggest that PTH may play a role in attenuating age-related impairments in aortic endothelial function. NEW & NOTEWORTHY We have demonstrated that intermittent parathyroid hormone administration can rescue age-related vascular dysfunction by improving endothelial-dependent dilation in the aorta of older rodents. This demonstrates a novel potential benefit of parathyroid hormone administration in aging.
Chemopreventive Effects of ROS Targeting in a Murine Model of BRCA1-Deficient Breast Cancer
Authors: Li Mo , Chen Qian , Yu Xiaochun 
Published: November 2016

Abstract
There remains great interest in practical strategies to limit the elevated risks of familial breast and ovarian cancers driven by BRCA1 mutation. Here, we report that limiting the production of reactive oxygen species (ROS) is sufficient to reduce DNA lesions and delay tumorigenesis in a murine model of BRCA1-deficient breast cancer. We documented a large amount of endogenous estrogen oxidative metabolites in the mammary gland of the model, which induced DNA adducts and apurinic/apyrimidinic sites associated with DNA double-strand breaks and genomic instability. Repressing estrogen oxidation via antioxidant treatments reduced oxidative DNA lesions and delayed the onset of mammary tumors. Overall our work suggests an answer to the long-standing question of why germline BRCA1 mutations cause tissue-specific tumors, in showing how tissue-specific, ROS-induced DNA lesions create a nongenetic force to promote mammary tumors in BRCA1-deficient mice. Our findings create a rationale for evaluating suitable antioxidant modalities as a chemopreventive strategy for familial breast cancer. Cancer Res; 77(2); 448–58. ©2016 AACR.
lncRNAs as Novel Indicators of Patients' Prognosis in Stage I Epithelial Ovarian Cancer: A Retrospective and Multicentric Study
Authors: Martini Paolo , Paracchini Lara , Caratti Giulia , Mello-Grand Maurizia , Fruscio Robert , Beltrame Luca , Calura Enrica , Sales Gabriele , Ravaggi Antonella , Bignotti Eliana , Odicino Franco E. , Sartori Enrico , Perego Patrizia , Katsaros Dionyssios , Craparotta Ilaria , Chiorino Giovanna , Cagnin Stefano , Mannarino Laura , Ceppi Lorenzo , Mangioni Costantino , Ghimenti Chiara , D'Incalci Maurizio , Marchini Sergio , Romualdi Chiara 
Published: November 2016

Abstract
Purpose: Stage I epithelial ovarian cancer (EOC) represents about 10% of all EOCs and is characterized by good prognosis with fewer than 20% of patients relapsing. As it occurs less frequently than advanced-stage EOC, its molecular features have not been thoroughly investigated. We have demonstrated that in stage I EOC miR-200c-3p can predict patients' outcome. In the present study, we analyzed the expression of long non-coding RNAs (lncRNA) to enable potential definition of a non-coding transcriptional signature with prognostic relevance for stage I EOC.
Experimental Design: 202 snap-frozen stage I EOC tumor biopsies, 47 of which relapsed, were gathered together from three independent tumor tissue collections and subdivided into a training set (n = 73) and a validation set (n = 129). Median follow up was 9 years. LncRNAs' expression profiles were correlated in univariate and multivariate analysis with overall survival (OS) and progression-free survival (PFS).
Results: The expression of lnc-SERTAD2-3, lnc-SOX4-1, lnc-HRCT1-1, and PVT1 was associated in univariate and multivariate analyses with relapse and poor outcome in both training and validation sets (P &lt; 0.001). Using the expression profiles of PVT1, lnc-SERTAD2-3, and miR-200c-3p simultaneously, it was possible to stratify patients into high and low risk. The OS for high- and low-risk individuals are 36 and 123 months, respectively (OR, 15.55; 95% confidence interval, 3.81–63.36).
Conclusions: We have identified a non-coding transcriptional signature predictor of survival and biomarker of relapse for stage I EOC. Clin Cancer Res; 23(9); 2356–66. ©2016 AACR.
BRAF and NRAS Locus-Specific Variants Have Different Outcomes on Survival to Colorectal Cancer
Authors: Summers Matthew G. , Smith Christopher G. , Maughan Timothy S. , Kaplan Richard , Escott-Price Valentina , Cheadle Jeremy P. 
Published: November 2016

Abstract
Purpose: Somatic mutation status at KRAS, BRAF, and NRAS is associated with prognosis in patients with advanced colorectal cancer (aCRC); however, it remains unclear whether there are intralocus, variant-specific differences in survival and other clinicopathologic parameters.
Experimental Design: We profiled 2,157 aCRCs for somatic mutations in KRAS, BRAF, and NRAS and determined microsatellite instability status. We sought inter- and intralocus correlations between mutations and variant-specific associations with survival and clinicopathology.
Results: KRAS mutations were rarely found together and those in codons 12 and 13 conferred poor prognosis [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.28–1.61; P = 6.4 × 10−10 and HR, 1.53; 95% CI, 1.26–1.86; P = 1.5 × 10−05, respectively]. For BRAF, more c.1781A&gt;G (p.D594G) CRCs carried RAS mutations [14% (3/21)] compared with c.1799T&gt;A (p.V600E) CRCs [1% (2/178), P = 9.0 × 10−03]. c.1799T&gt;A (p.V600E) was associated with poor prognosis (HR, 2.60; 95% CI, 2.06–3.28; P = 1.0 × 10−15), whereas c.1781A&gt;G (p.D594G) was not (HR, 1.30; 95% CI, 0.73–2.31; P = 0.37); this intralocus difference was significant (P = 0.04). More c.1799T&gt;A (p.V600E) colorectal cancers were found in the right colon [47% (47/100)], compared with c.1781A&gt;G (p.D594G) colorectal cancers [7% (1/15), P = 3.7 × 10−03]. For NRAS, 5% (3/60) of codon 61 mutant colorectal cancers had KRAS mutations compared with 44% (10/23) of codons 12 and 13 mutant colorectal cancers (P = 7.9 × 10−05). Codon 61 mutations conferred poor prognosis (HR, 1.47; 95% CI, 1.09–1.99; P = 0.01), whereas codons 12 and 13 mutations did not (HR, 1.29; 95% CI, 0.64–2.58; P = 0.48).
Conclusions: Our data show considerable intralocus variation in the outcomes of mutations in BRAF and NRAS. These data need to be considered in patient management and personalized cancer therapy. Clin Cancer Res; 23(11); 2742–9. ©2016 AACR.
Phase I Study of GDC-0425, a Checkpoint Kinase 1 Inhibitor, in Combination with Gemcitabine in Patients with Refractory Solid Tumors
Authors: Infante Jeffrey R. , Hollebecque Antoine , Postel-Vinay Sophie , Bauer Todd M. , Blackwood Elizabeth M. , Evangelista Marie , Mahrus Sami , Peale Franklin V. , Lu Xuyang , Sahasranaman Srikumar , Zhu Rui , Chen Yuan , Ding Xiao , Murray Elaine R. , Schutzman Jennifer L. , Lauchle Jennifer O. , Soria Jean-Charles , LoRusso Patricia M. 
Published: November 2016

Abstract
Purpose: Chk1 inhibition potentiates DNA-damaging chemotherapy by overriding cell-cycle arrest and genome repair. This phase I study evaluated the Chk1 inhibitor GDC-0425 given in combination with gemcitabine to patients with advanced solid tumors.
Experimental Design: Patients received GDC-0425 alone for a 1-week lead-in followed by 21-day cycles of gemcitabine plus GDC-0425. Gemcitabine was initially administered at 750 mg/m2 (Arm A), then increased to 1,000 mg/m2 (Arm B), on days 1 and 8 in a 3 + 3 + 3 dose escalation to establish maximum tolerated dose (MTD). GDC-0425 was initially administered daily for three consecutive days; however, dosing was abbreviated to a single day on the basis of pharmacokinetics and tolerability. TP53 mutations were evaluated in archival tumor tissue. On-treatment tumor biopsies underwent pharmacodynamic biomarker analyses.
Results: Forty patients were treated with GDC-0425. The MTD of GDC-0425 was 60 mg when administered approximately 24 hours after gemcitabine 1,000 mg/m2. Dose-limiting toxicities included thrombocytopenia (n = 5), neutropenia (n = 4), dyspnea, nausea, pyrexia, syncope, and increased alanine aminotransferase (n = 1 each). Common related adverse events were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). The GDC-0425 half-life was approximately 15 hours. There were two confirmed partial responses in patients with triple-negative breast cancer (TP53-mutated) and melanoma (n = 1 each) and one unconfirmed partial response in a patient with cancer of unknown primary origin.
Conclusions: Chk1 inhibition with GDC-0425 in combination with gemcitabine was tolerated with manageable bone marrow suppression. The observed preliminary clinical activity warrants further investigation of this chemopotentiation strategy. Clin Cancer Res; 23(10); 2423–32. ©2016 AACR.
Antibody Targeting GRP78 Enhances the Efficacy of Radiation Therapy in Human Glioblastoma and Non–Small Cell Lung Cancer Cell Lines and Tumor Models
Authors: Dadey David Y.A. , Kapoor Vaishali , Hoye Kelly , Khudanyan Arpine , Collins Andrea , Thotala Dinesh , Hallahan Dennis E. 
Published: November 2016

Abstract
Purpose: Non–small cell lung cancer (NSCLC) and glioblastoma multiforme (GBM) have poor median survival. NSCLC and GBM overexpress glucose regulated protein 78 (GRP78), which has a role in radioresistance and recurrence. In this study, we determined the effect of anti-GRP78 antibody and the combined effect of the anti-GRP78 antibody with ionizing radiation (XRT) on NSCLC and GBM cell lines both in vitro and in vivo.
Experimental Design: NSCLC and GBM cancer cell lines were treated with anti-GRP78 antibodies and evaluated for proliferation, colony formation, cell death, and PI3K/Akt/mTOR signaling. The efficacy of anti-GRP78 antibodies on tumor growth in combination with XRT was determined in vivo in mouse xenograft models.
Results: GBM and NSCLC cells treated with anti-GRP78 antibodies showed attenuated cell proliferation, colony formation, and enhanced apoptosis. GBM and NSCLC cells treated with anti-GRP78 antibodies also showed global suppression of PI3K/Akt/mTOR signaling. Combining antibody with XRT resulted in significant tumor growth delay in both NSCLC and GBM heterotopic tumor models.
Conclusions: Antibodies targeting GRP78 exhibited antitumor activity and enhanced the efficacy of radiation in NSCLC and GBM both in vitro and in vivo. GRP78 is a promising novel target, and anti-GRP78 antibodies could be used as an effective cancer therapy alone or in combination with XRT. Clin Cancer Res; 23(10); 2556–64. ©2016 AACR.
KTN0158, a Humanized Anti-KIT Monoclonal Antibody, Demonstrates Biologic Activity against both Normal and Malignant Canine Mast Cells
Authors: London Cheryl A. , Gardner Heather L. , Rippy Sarah , Post Gerald , La Perle Krista , Crew Linda , Lopresti-Morrow Lori , Garton Andrew J. , McMahon Gerald , LaVallee Theresa M. , Gedrich Richard 
Published: November 2016

Abstract
Purpose: KTN0158 is a novel anti-KIT antibody that potently inhibits wild-type and mutant KIT. This study evaluated the safety, biologic activity, and pharmacokinetic/pharmacodynamics profile of KTN0158 in dogs with spontaneous mast cell tumors (MCT) as a prelude to human clinical applications.
Experimental Design: Cell proliferation, KIT phosphorylation, and mast cell degranulation were evaluated in vitro. KTN0158 was administered to 4 research dogs to assess clinical effects and cutaneous mast cell numbers. Thirteen dogs with spontaneous MCT were enrolled into a prospective phase I dose-escalating open-label clinical study of KTN0158 evaluating 3 dose levels and 2 schedules and with weekly assessments for response and clinical toxicities.
Results: KTN0158 was a potent inhibitor of human and dog KIT activation and blocked mast cell degranulation in vitro. In dogs, KTN0158 was well tolerated and reduced cutaneous mast cell numbers in a dose-dependent manner. Clinical benefit of KTN0158 administration in dogs with MCT (n = 5 partial response; n = 7 stable disease) was observed regardless of KIT mutation status, and decreased KIT phosphorylation was demonstrated in tumor samples. Histopathology after study completion demonstrated an absence of neoplastic cells in the primary tumors and/or metastatic lymph nodes from 4 dogs. Reversible hematologic and biochemical adverse events were observed at doses of 10 and 30 mg/kg. The MTD was established as 10 mg/kg.
Conclusions: KTN0158 inhibits KIT phosphorylation, demonstrates an acceptable safety profile in dogs, and provides objective responses in canine MCT patients with and without activating KIT mutations, supporting future clinical evaluation of KTN0158 in people. Clin Cancer Res; 23(10); 2565–74. ©2016 AACR.
Significant Association of Annual Hospital Volume With the Risk of Inhospital Stroke or Death Following Carotid Endarterectomy but Likely Not After Carotid Stenting
Authors: Kuehnl Andreas , Tsantilas Pavlos , Knappich Christoph , Schmid Sofie , König Thomas , Breitkreuz Thorben , Zimmermann Alexander , Mansmann Ulrich , Eckstein Hans-Henning 
Published: November 2016

Background—
Associations between hospital volume and the risk of stroke or death following carotid endarterectomy (CEA) and carotid artery stenting (CAS) on a national level in Germany were analyzed.

Methods and Results—

Secondary data analysis using microdata from the nationwide statutory German quality assurance database on all surgical or endovascular carotid interventions on the extracranial carotid artery between 2009 and 2014. Hospitals were categorized into empirically determined quintiles according to the annual case volume. The resulting volume thresholds were 10, 25, 46, and 79 for CEA and 2, 6, 12, and 26 for CAS procedures. The primary outcome was any stroke or death before hospital discharge. For risk-adjusted analyses, a multilevel regression model was applied. The analysis included 161 448 CEA and 17 575 CAS procedures. In CEA patients, the crude risk of stroke or death decreased monotonically from 4.2% (95% confidence interval, 3.6%–4.9%) in low-volume hospitals (first quintile 1–10 CEA per year) to 2.1% (2.0%–2.2%) in hospitals providing ≥80 CEA per year (fifth quintile;
P
<0.001 for trend). The overall risk of any stroke or death in CAS patients was 3.7% (3.5%–4.0%), but no trend on annual volume was seen (
P
=0.304). Risk-adjusted analyses confirmed a significant inverse relationship between hospital volume (categorized or continuous) and the risk of stroke or death after CEA but not CAS procedures.

Conclusions—
An inverse volume–outcome relationship in CEA-treated patients was demonstrated. No significant association between hospital volume and the risk of stroke or death was found for CAS.
Sealing Intermediate Nonobstructive Coronary Saphenous Vein Graft Lesions With Drug-Eluting Stents as a New Approach to Reducing Cardiac Events
Authors: Rodés-Cabau Josep , Jolly Sanjit S. , Cairns John , Mansour Samer , L’Allier Philippe L. , Teefy Patrick J. , Graham John J. , Le May Michel R. , Cantor Warren J. , Wood David , Balasubramanian Kumar , DeLarochellière Robert , Dzavik Vlad 
Published: November 2016

Background—
The objective of this study was to assess the efficacy of sealing intermediate nonobstructive coronary saphenous vein graft (SVG) lesions with drug-eluting stents (DES; paclitaxel- or everolimus-eluting stents) for reducing major adverse cardiac events (MACE).

Methods and Results—

This was a randomized controlled multicenter clinical trial that enrolled patients with a previous coronary artery bypass graft who had developed at least 1 intermediate nonobstructive SVG lesion (30%–60% diameter stenosis by visual estimation). Patients were randomized (1:1) to DES implantation (SVG-DES) or medical treatment (SVG-MT) of the target SVG lesion. The primary efficacy outcome was the first occurrence of MACE defined as the composite of cardiac death, myocardial infarction, or coronary revascularization related to the target SVG during the duration of follow-up (minimum of 2 years). Secondary efficacy outcomes included MACE related to the target SVG lesion and overall MACE. A total of 125 patients (mean age 70±9 years, 87% men) were included, with a mean time from coronary artery bypass graft of 12±5 years. Sixty and 65 patients were allocated to the SVG-DES and SVG-MT groups, respectively. There were no events related to the target SVG at 30 days. After a median follow-up of 3.4 (interquartile range: 2.8–3.9) years, the MACE rate related to the target SVG was not significantly different in the 2 groups (SVG-DES: 15.0%, SVG-MT: 20.0%; hazard ratio, 0.65; 95% confidence interval, 0.23–1.53;
P
=0.33). There were no significant differences between groups in MACE related to the target SVG lesion (SVG-DES: 10.0%, SVG-MT: 16.9%; hazard ratio, 0.53; 95% confidence interval, 0.20–1.43;
P
=0.21) or global MACE (SVG-DES: 36.7%, SVG-MT: 44.6%; hazard ratio, 0.73; 95% confidence interval, 0.42–1.27;
P
=0.26).

Conclusions—
Sealing intermediate nonobstructive SVG lesions with DES was safe but was not associated with a significant reduction of cardiac events at 3-year follow-up.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01223443.
Assessing Hospital Performance After Percutaneous Coronary Intervention Using Big Data
Authors: Spertus Jacob V. , T. Normand Sharon-Lise , Wolf Robert , Cioffi Matt , Lovett Ann , Rose Sherri 
Published: November 2016

Background—
Although risk adjustment remains a cornerstone for comparing outcomes across hospitals, optimal strategies continue to evolve in the presence of many confounders. We compared conventional regression-based model to approaches particularly suited to leveraging big data.

Methods and Results—
We assessed hospital all-cause 30-day excess mortality risk among 8952 adults undergoing percutaneous coronary intervention between October 1, 2011, and September 30, 2012, in 24 Massachusetts hospitals using clinical registry data linked with billing data. We compared conventional logistic regression models with augmented inverse probability weighted estimators and targeted maximum likelihood estimators to generate more efficient and unbiased estimates of hospital effects. We also compared a clinically informed and a machine-learning approach to confounder selection, using elastic net penalized regression in the latter case. Hospital excess risk estimates range from −1.4% to 2.0% across methods and confounder sets. Some hospitals were consistently classified as low or as high excess mortality outliers; others changed classification depending on the method and confounder set used. Switching from the clinically selected list of 11 confounders to a full set of 225 confounders increased the estimation uncertainty by an average of 62% across methods as measured by confidence interval length. Agreement among methods ranged from fair, with a κ statistic of 0.39 (SE: 0.16), to perfect, with a κ of 1 (SE: 0.0).

Conclusions—
Modern causal inference techniques should be more frequently adopted to leverage big data while minimizing bias in hospital performance assessments.