bluuebunny/crossref_metadata_2025 huggingface dataset:
A compiler framework for extracting superword level parallelism
Authors: Liu Jun , Zhang Yuanrui , Jang Ohyoung , Ding Wei , Kandemir Mahmut
Published: November 2016

SIMD (single-instruction multiple-data) instruction set extensions are quite common today in both high performance and embedded microprocessors, and enable the exploitation of a specific type of data parallelism called SLP (Superword Level Parallelism). While prior research shows that significant performance savings are possible when SLP is exploited, placing SIMD instructions in an application code manually can be very difficult and error prone. In this paper, we propose a novel automated compiler framework for improving superword level parallelism exploitation. The key part of our framework consists of two stages: superword statement generation and data layout optimization. The first stage is our main contribution and has two phases, statement grouping and statement scheduling, of which the primary goals are to increase SIMD parallelism and, more importantly, capture more superword reuses among the superword statements through global data access and reuse pattern analysis. Further, as a complementary optimization, our data layout optimization organizes data in memory space such that the price of memory operations for SLP is minimized. The results from our compiler implementation and tests on two systems indicate performance improvements as high as 15.2% over a state-of-the-art SLP optimization algorithm.
Logical inference techniques for loop parallelization
Authors: Oancea Cosmin E. , Rauchwerger Lawrence
Published: November 2016

This paper presents a fully automatic approach to loop parallelization that integrates the use of static and run-time analysis and thus overcomes many known difficulties such as nonlinear and indirect array indexing and complex control flow. Our hybrid analysis framework validates the parallelization transformation by verifying the independence of the loop's memory references. To this end it represents array references using the USR (uniform set representation) language and expresses the independence condition as an equation,
S
=0, where
S
is a set expression representing array indexes. Using a language instead of an array-abstraction representation for
S
results in a smaller number of conservative approximations but exhibits a potentially-high runtime cost. To alleviate this cost we introduce a language translation
F
from the USR set-expression language to an equally rich language of predicates (
F
(
S
) ==>
S
= 0). Loop parallelization is then validated using a novel logic inference algorithm that factorizes the obtained complex predicates (F(
S
)) into a sequence of sufficient independence conditions that are evaluated first statically and, when needed, dynamically, in increasing order of their estimated complexities. We evaluate our automated solution on 26 benchmarks from PERFECT-Club and SPEC suites and show that our approach is effective in parallelizing large, complex loops and obtains much better full program speedups than the Intel and IBM Fortran compilers.
Fully automatic and precise detection of thread safety violations
Authors: Pradel Michael , Gross Thomas R.
Published: November 2016

Concurrent, object-oriented programs often use thread-safe library classes. Existing techniques for testing a thread-safe class either rely on tests using the class, on formal specifications, or on both. Unfortunately, these techniques often are not fully automatic as they involve the user in analyzing the output. This paper presents an automatic testing technique that reveals concurrency bugs in supposedly thread-safe classes. The analysis requires as input only the class under test and reports only true positives. The key idea is to generate tests in which multiple threads call methods on a shared instance of the tested class. If a concurrent test exhibits an exception or a deadlock that cannot be triggered in any linearized execution of the test, the analysis reports a thread safety violation. The approach is easily applicable, because it is independent of hand-written tests and explicit specifications. The analysis finds 15 concurrency bugs in popular Java libraries, including two previously unknown bugs in the Java standard library.
Full abstraction for nominal Scott domains
Authors: Lösch Steffen , Pitts Andrew M.
Published: November 2016

We develop a domain theory within nominal sets and present programming language constructs and results that can be gained from this approach. The development is based on the concept of orbit-finite subset, that is, a subset of a nominal sets that is both finitely supported and contained in finitely many orbits. This concept appears prominently in the recent research programme of Bojanczyk et al. on automata over infinite languages, and our results establish a connection between their work and a characterisation of topological compactness discovered, in a quite different setting, by Winskel and Turner as part of a nominal domain theory for concurrency. We use this connection to derive a notion of Scott domain within nominal sets. The functionals for existential quantification over names and `definite description' over names turn out to be compact in the sense appropriate for nominal Scott domains. Adding them, together with parallel-or, to a programming language for recursively defined higher-order functions with name abstraction and locally scoped names, we prove a full abstraction result for nominal Scott domains analogous to Plotkin's classic result about PCF and conventional Scott domains: two program phrases have the same observable operational behaviour in all contexts if and only if they denote equal elements of the nominal Scott domain model. This is the first full abstraction result we know of for higher-order functions with local names that uses a domain theory based on ordinary extensional functions, rather than using the more intensional approach of game semantics.
The Lambda Lambda-Bar calculus
Authors: Goyet Alexis
Published: November 2016

We present a calculus which combines a simple, CCS-like representation of finite behaviors, with two dual binders λ and λ¯. Infinite behaviors are obtained through a syntactical fixed-point operator, which is used to give a translation of λ-terms. The duality of the calculus makes the roles of a function and its environment symmetrical. As usual, the environment is allowed to call a function at any given point, each time with a different argument. Dually, the function is allowed to answer any given call, each time with a different behavior. This grants terms in our language the power of functional references.

The inspiration for this language comes from game semantics. Indeed, its normal forms give a simple concrete syntax for finite strategies, which are inherently non-innocent. This very direct correspondence allows us to describe, in syntactical terms, a number of features from game semantics. The fixed-point expansion of translated λ-terms corresponds to the generation of infinite plays from the finite views of an innocent strategy. The syntactical duality between terms and co-terms corresponds to the duality between Player and Opponent. This duality also gives rise to a Böhm-out lemma.

The paper is divided into two parts. The first one is purely syntactical, and requires no background in game semantics. The second describes the fully abstract game model.
HALO
Authors: Vytiniotis Dimitrios , Peyton Jones Simon , Claessen Koen , Rosén Dan
Published: November 2016

Even well-typed programs can go wrong in modern functional languages, by encountering a pattern-match failure, or simply returning the wrong answer. An increasingly-popular response is to allow programmers to write contracts that express semantic properties, such as crash-freedom or some useful post-condition. We study the static verification of such contracts. Our main contribution is a novel translation to first-order logic of both Haskell programs, and contracts written in Haskell, all justified by denotational semantics. This translation enables us to prove that functions satisfy their contracts using an off-the-shelf first-order logic theorem prover.
Sigma*
Authors: Botinčan Matko , Babić Domagoj
Published: November 2016

We present Sigma*, a novel technique for learning symbolic models of software behavior. Sigma* addresses the challenge of synthesizing models of software by using symbolic conjectures and abstraction. By combining dynamic symbolic execution to discover symbolic input-output steps of the programs and counterexample guided abstraction refinement to over-approximate program behavior, Sigma* transforms arbitrary source representation of programs into faithful input-output models. We define a class of stream filters---programs that process streams of data items---for which Sigma* converges to a complete model if abstraction refinement eventually builds up a sufficiently strong abstraction. In other words, Sigma* is complete relative to abstraction. To represent inferred symbolic models, we use a variant of symbolic transducers that can be effectively composed and equivalence checked. Thus, Sigma* enables fully automatic analysis of behavioral properties such as commutativity, reversibility and idempotence, which is useful for web sanitizer verification and stream programs compiler optimizations, as we show experimentally. We also show how models inferred by Sigma* can boost performance of stream programs by parallelized code generation.
Social Predictors of Assistive Technology Proficiency Among Teachers of Students with Visual Impairments
Authors: Morash Valerie S. , Siu Yue-Ting
Published: November 2016

Assistive technology (AT) is critical for K-12 students who have visual impairments to engage with their education and is predictive of positive postsecondary outcomes and future employment. Teachers of students with visual impairments (TVIs) act as the primary gatekeepers of AT for these students. Unfortunately, only about 40% of TVIs integrate AT into their practice. Efforts to predict TVIs’ AT proficiency based on their preservice training have been unsuccessful. The current study proposes and confirms that TVIs’ AT proficiency is related to their identification with a social community of practice (CoP) that values AT. Results from
n
= 505 North American TVIs produced a Spearman’s correlation of ρ = 0.49 between estimated AT proficiency and CoP identification. The relationship was strongest among TVIs with lower AT proficiency and CoP identification. Results have implications for industry, researchers, teacher preparation programs, personnel who administer and train assistive technologies, and policymakers concerned with ensuring that AT is available to students who have visual impairments. Mere availability of AT is insufficient to ensure its successful introduction to K-12 students with visual impairments, which relies on TVIs’ AT proficiency for meaningful implementation. Developers and advocates of AT for K-12 students with visual impairments must consider the social context in which AT proficiency develops and provide appropriate social supports.
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.
The design of OWL a language for walking
Authors: Donner Marc D.
Published: November 2016

This paper describes the syntax, semantics, and design rationale for a programming language developed to provide real-time concurrent processes for the programming of a six legged walking robot.
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/ .
Inflammation and lung injury in an ovine model of extracorporeal membrane oxygenation support
Authors: Passmore Margaret R. , Fung Yoke L. , Simonova Gabriela , Foley Samuel R. , Dunster Kimble R. , Diab Sara D. , Tung John-Paul , Minchinton Robyn M. , McDonald Charles I. , Anstey Chris M. , Shekar Kiran , Fraser John F.
Published: November 2016

Extracorporeal membrane oxygenation (ECMO) is a life-saving treatment for patients with severe refractory cardiorespiratory failure. Exposure to the ECMO circuit is thought to trigger/exacerbate inflammation. Determining whether inflammation is the result of the patients' underlying pathologies or the ECMO circuit is difficult. To discern how different insults contribute to the inflammatory response, we developed an ovine model of lung injury and ECMO to investigate the impact of smoke-induced lung injury and ECMO in isolation and cumulatively on pulmonary and circulating inflammatory cells, cytokines, and tissue remodeling. Sheep receiving either smoke-induced acute lung injury (S-ALI) or sham injury were placed on veno-venous (VV) ECMO lasting either 2 or 24 h, with controls receiving conventional ventilation only. Lung tissue, bronchoalveolar fluid, and plasma were analyzed by RT-PCR, immunohistochemical staining, and zymography to assess inflammatory cells, cytokines, and matrix metalloproteinases. Pulmonary compliance decreased in sheep with S-ALI placed on ECMO with increased numbers of infiltrating neutrophils, monocytes, and alveolar macrophages compared with controls. Infiltration of neutrophils was also observed with S-ALI alone. RT-PCR studies showed higher expression of matrix metalloproteinases 2 and 9 in S-ALI plus ECMO, whereas IL-6 was elevated at 2 h. Zymography revealed higher levels of matrix metalloproteinase 2. Circulating plasma levels of IL-6 were elevated 1–2 h after commencement of ECMO alone. These data show that the inflammatory response is enhanced when a host with preexisting pulmonary injury is placed on ECMO, with increased infiltration of neutrophils and macrophages, the release of inflammatory cytokines, and upregulation of matrix metalloproteinases.
Aging exacerbates acute lung injury-induced changes of the air-blood barrier, lung function, and inflammation in the mouse
Authors: Kling Katharina Maria , Lopez-Rodriguez Elena , Pfarrer Christiane , Mühlfeld Christian , Brandenberger Christina
Published: November 2016

Acute lung injury (ALI) is characterized by hypoxemia, enhanced permeability of the air-blood barrier, and pulmonary edema. Particularly in the elderly, ALI is associated with increased morbidity and mortality. The reasons for this, however, are poorly understood. We hypothesized that age-related changes in pulmonary structure, function, and inflammation lead to a worse prognosis in ALI. ALI was induced in young (10 wk old) and old (18 mo old) male C57BL/6 mice by intranasal application of 2.5 mg lipopolysaccharide (LPS)/kg body wt or saline (control mice). After 24 h, lung function was assessed, and lungs were either processed for stereological or inflammatory analysis, such as bronchoalveolar lavage fluid (BALF) cytometry and qPCR. Both young and old mice developed severe signs of ALI, including alveolar and septal edema and enhanced inflammatory BALF cells. However, the pathology of ALI was more pronounced in old compared with young mice with nearly sixfold higher BALF protein concentration, twice the number of neutrophils, and significantly higher expression of neutrophil chemokine Cxcl1, adhesion molecule Icam-1, and metalloprotease-9, whereas the expression of tight junction protein occludin significantly decreased. The old LPS mice had thicker alveolar septa attributable to higher volumes of interstitial cells and extracellular matrix. Tissue resistance and elastance reflected observed changes at the ultrastructural level in the lung parenchyma in ALI of young and old mice. In summary, the pathology of ALI with advanced age in mice is characterized by a greater neutrophilic inflammation, leakier air-blood barrier, and altered lung function, which is in line with findings in elderly patients.
Soluble epoxide hydrolase deficiency or inhibition enhances murine hypoxic pulmonary vasoconstriction after lipopolysaccharide challenge
Authors: Wepler Martin , Beloiartsev Arkadi , Buswell Mary D. , Panigrahy Dipak , Malhotra Rajeev , Buys Emmanuel S. , Radermacher Peter , Ichinose Fumito , Bloch Donald B. , Zapol Warren M.
Published: November 2016

Hypoxic pulmonary vasoconstriction (HPV) is the response of the pulmonary vasculature to low levels of alveolar oxygen. HPV improves systemic arterial oxygenation by matching pulmonary perfusion to ventilation during alveolar hypoxia and is impaired in lung diseases such as the acute respiratory distress syndrome (ARDS) and in experimental models of endotoxemia. Epoxyeicosatrienoic acids (EETs) are pulmonary vasoconstrictors, which are metabolized to less vasoactive dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). We hypothesized that pharmacological inhibition or a congenital deficiency of sEH in mice would reduce the metabolism of EETs and enhance HPV in mice after challenge with lipopolysaccharide (LPS). HPV was assessed 22 h after intravenous injection of LPS by measuring the percentage increase in the pulmonary vascular resistance of the left lung induced by left mainstem bronchial occlusion (LMBO). After LPS challenge, HPV was impaired in sEH+/+, but not in sEH−/−mice or in sEH+/+mice treated acutely with a sEH inhibitor. Deficiency or pharmacological inhibition of sEH protected mice from the LPS-induced decrease in systemic arterial oxygen concentration (PaO2) during LMBO. In the lungs of sEH−/−mice, the LPS-induced increase in DHETs and cytokines was attenuated. Deficiency or pharmacological inhibition of sEH protects mice from LPS-induced impairment of HPV and improves the PaO2after LMBO. After LPS challenge, lung EET degradation and cytokine expression were reduced in sEH−/−mice. Inhibition of sEH might prove to be an effective treatment for ventilation-perfusion mismatch in lung diseases such as ARDS.
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.
Quantized Passive Dynamic Output Feedback Control with Actuator Failure
Authors: Li Zu-Xin , Zhou Ke-Xia , Wang Yan-Feng , Chen Hui-Ying , Qian Yi
Published: November 2016

This paper investigates the problem of passive dynamic output feedback control for fuzzy discrete nonlinear systems with quantization and actuator failures, where the measurement output of the system is quantized by a logarithmic quantizer before being transferred to the fuzzy controller. By employing the fuzzy-basis-dependent Lyapunov function, sufficient condition is established to guarantee the closed-loop system to be mean-square stable and the prescribed passive performance. Based on the sufficient condition, the fuzzy dynamic output feedback controller is proposed for maintaining acceptable performance levels in the case of actuator failures and quantization effects. Finally, a numerical example is given to show the usefulness of the proposed method.
Object Detection and Tracking-Based Camera Calibration for Normalized Human Height Estimation
Authors: Jung Jaehoon , Yoon Inhye , Lee Sangkeun , Paik Joonki
Published: November 2016

This paper presents a normalized human height estimation algorithm using an uncalibrated camera. To estimate the normalized human height, the proposed algorithm detects a moving object and performs tracking-based automatic camera calibration. The proposed method consists of three steps: (i) moving human detection and tracking, (ii) automatic camera calibration, and (iii) human height estimation and error correction. The proposed method automatically calibrates camera by detecting moving humans and estimates the human height using error correction. The proposed method can be applied to object-based video surveillance systems and digital forensic.
Chemopreventive Effects of ROS Targeting in a Murine Model of BRCA1-Deficient Breast Cancer
Authors: Li Mo , Chen Qian , Yu Xiaochun
Published: November 2016

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

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 < 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

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>G (p.D594G) CRCs carried RAS mutations [14% (3/21)] compared with c.1799T>A (p.V600E) CRCs [1% (2/178), P = 9.0 × 10−03]. c.1799T>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>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>A (p.V600E) colorectal cancers were found in the right colon [47% (47/100)], compared with c.1781A>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

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

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

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.
Inhibiting Insulin-Mediated β
2
-Adrenergic Receptor Activation Prevents Diabetes-Associated Cardiac Dysfunction
Authors: Wang Qingtong , Liu Yongming , Fu Qin , Xu Bing , Zhang Yuan , Kim Sungjin , Tan Ruensern , Barbagallo Federica , West Toni , Anderson Ethan , Wei Wei , Abel E. Dale , Xiang Yang K.
Published: November 2016

Background:

Type 2 diabetes mellitus (DM) and obesity independently increase the risk of heart failure by incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in the hearts of subjects with type-2 DM and obesity.

Methods:

High-fat diet feeding was used to induce obesity and DM in wild-type mice or mice lacking β
2
-adrenergic receptor (β
2
AR) or β-arrestin2. Wild-type mice fed with high-fat diet were treated with a β-blocker carvedilol or a GRK2 (G-protein-coupled receptor kinase 2) inhibitor. We examined signaling and cardiac contractile function.

Results:

High-fat diet feeding selectively increases the expression of phosphodiesterase 4D (PDE4D) in mouse hearts, in concert with reduced protein kinase A phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with DM. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and GRK2 and β-arrestin2-dependent transactivation of a β
2
AR-extracellular regulated protein kinase signaling cascade. Thus, pharmacological inhibition of β
2
AR or GRK2, or genetic deletion of β
2
AR or β-arrestin2, all significantly attenuate insulin-induced phosphorylation of extracellular regulated protein kinase and PDE4D induction to prevent DM-related contractile dysfunction.

Conclusions:

These studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify β
2
AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type 2 DM.
Treatment With Tissue Plasminogen Activator in the Golden Hour and the Shape of the 4.5-Hour Time-Benefit Curve in the National United States Get With The Guidelines-Stroke Population
Authors: Kim Joon-Tae , Fonarow Gregg C. , Smith Eric E. , Reeves Mathew J. , Navalkele Digvijaya D. , Grotta James C. , Grau-Sepulveda Maria V. , Hernandez Adrian F. , Peterson Eric D. , Schwamm Lee H. , Saver Jeffrey L.
Published: November 2016

Background:

Earlier tissue plasminogen activator treatment improves ischemic stroke outcome, but aspects of the time-benefit relationship still not well delineated are: (1) the degree of additional benefit accrued with treatment in the first 60 minutes after onset, and (2) the shape of the time-benefit curve through 4.5 hours.

Methods:

We analyzed patients who had acute ischemic stroke treated with intravenous tissue plasminogen activator within 4.5 hours of onset from the Get With The Guidelines-Stroke US national program. Onset-to-treatment time was analyzed as a continuous, potentially nonlinear variable and as a categorical variable comparing patients treated within 60 minutes of onset with later epochs.

Results:

Among 65 384 tissue plasminogen activator–treated patients, the median onset-to-treatment time was 141 minutes (interquartile range, 110–173) and 878 patients (1.3%) were treated within the first 60 minutes. Treatment within 60 minutes, compared with treatment within 61 to 270 minutes, was associated with increased odds of discharge to home (adjusted odds ratio, 1.25; 95% confidence interval, 1.07–1.45), independent ambulation at discharge (adjusted odds ratio, 1.22; 95% confidence interval, 1.03–1.45), and freedom from disability (modified Rankin Scale 0–1) at discharge (adjusted odds ratio, 1.72; 95% confidence interval, 1.21–2.46), without increased hemorrhagic complications or in-hospital mortality. The pace of decline in benefit of tissue plasminogen activator from onset-to-treatment times of 20 through 270 minutes was mildly nonlinear for discharge to home, with more rapid benefit loss in the first 170 minutes than later, and linear for independent ambulation and in-hospital mortality.

Conclusions:

Thrombolysis started within the first 60 minutes after onset is associated with best outcomes for patients with acute ischemic stroke, and benefit declined more rapidly early after onset for the ability to be discharged home. These findings support intensive efforts to organize stroke systems of care to improve the timeliness of thrombolytic therapy in acute ischemic stroke.