bluuebunny/crossref_metadata_2025_split huggingface dataset:
Typed objects in JavaScript
Authors: Matsakis Nicholas D. , Herman David , Lomov Dmitry 
Published: May 2015

JavaScript's typed arrays have proven to be a crucial API for many JS applications, particularly those working with large amounts of data or emulating other languages. Unfortunately, the current typed array API offers no means of abstraction. Programmers are supplied with a simple byte buffer that can be viewed as an array of integers or floats, but nothing more.
This paper presents a generalization of the typed arrays API entitled typed objects. The typed objects API is slated for inclusion in the upcoming ES7 standard. The API gives users the ability to define named types, making typed arrays much easier to work with. In particular, it is often trivial to replace uses of existing JavaScript objects with typed objects, resulting in better memory consumption and more predictable performance.
The advantages of the typed object specification go beyond convenience, however. By supporting opacity---that is, the ability to deny access to the raw bytes of a typed object---the new typed object specification makes it possible to store objects as well as scalar data and also enables more optimization by JIT compilers.
Sweeten your JavaScript
Authors: Disney Tim , Faubion Nathan , Herman David , Flanagan Cormac 
Published: May 2015

Lisp and Scheme have demonstrated the power of macros to enable programmers to evolve and craft languages. In languages with more complex syntax, macros have had less success. In part, this has been due to the difficulty in building expressive hygienic macro systems for such languages. JavaScript in particular presents unique challenges for macro systems due to ambiguities in the lexing stage that force the JavaScript lexer and parser to be intertwined.
In this paper we present a novel solution to the lexing ambiguity of JavaScript that enables us to cleanly separate the JavaScript lexer and parser by recording enough history during lexing to resolve ambiguities. We give an algorithm for this solution along with a proof that it does in fact correctly resolve ambiguities in the language. Though the algorithm and proof we present is specific to JavaScript, the general technique can be applied to other languages with ambiguous grammars. With lexer and parser separated, we then implement an expressive hygienic macro system for JavaScript called sweet.js.
Supporting Differentiated Services in Computers via Programmable Architecture for Resourcing-on-Demand (PARD)
Authors: Ma Jiuyue , Sui Xiufeng , Sun Ninghui , Li Yupeng , Yu Zihao , Huang Bowen , Xu Tianni , Yao Zhicheng , Chen Yun , Wang Haibin , Zhang Lixin , Bao Yungang 
Published: May 2015

This paper presents PARD, a programmable architecture for resourcing-on-demand that provides a new programming interface to convey an application's high-level information like quality-of-service requirements to the hardware. PARD enables new functionalities like fully hardware-supported virtualization and differentiated services in computers. PARD is inspired by the observation that a computer is inherently a network in which hardware components communicate via packets (e.g., over the NoC or PCIe). We apply principles of software-defined networking to this intra-computer network and address three major challenges. First, to deal with the semantic gap between high-level applications and underlying hardware packets, PARD attaches a high-level semantic tag (e.g., a virtual machine or thread ID) to each memory-access, I/O, or interrupt packet. Second, to make hardware components more manageable, PARD implements programmable control planes that can be integrated into various shared resources (e.g., cache, DRAM, and I/O devices) and can differentially process packets according to tag-based rules. Third, to facilitate programming, PARD abstracts all control planes as a device file tree to provide a uniform programming interface via which users create and apply tag-based rules.
Full-system simulation results show that by co-locating latencycritical memcached applications with other workloads PARD can improve a four-core computer's CPU utilization by up to a factor of four without significantly increasing tail latency. FPGA emulation based on a preliminary RTL implementation demonstrates that the cache control plane introduces no extra latency and that the memory control plane can reduce queueing delay for high-priority memory-access requests by up to a factor of 5.6.
GPU Concurrency
Authors: Alglave Jade , Batty Mark , Donaldson Alastair F. , Gopalakrishnan Ganesh , Ketema Jeroen , Poetzl Daniel , Sorensen Tyler , Wickerson John 
Published: May 2015

Concurrency is pervasive and perplexing, particularly on graphics processing units (GPUs). Current specifications of languages and hardware are inconclusive; thus programmers often rely on folklore assumptions when writing software.
To remedy this state of affairs, we conducted a large empirical study of the concurrent behaviour of deployed GPUs. Armed with litmus tests (i.e. short concurrent programs), we questioned the assumptions in programming guides and vendor documentation about the guarantees provided by hardware. We developed a tool to generate thousands of litmus tests and run them under stressful workloads. We observed a litany of previously elusive weak behaviours, and exposed folklore beliefs about GPU programming---often supported by official tutorials---as false.
As a way forward, we propose a model of Nvidia GPU hardware, which correctly models every behaviour witnessed in our experiments. The model is a variant of SPARC Relaxed Memory Order (RMO), structured following the GPU concurrency hierarchy.
Secalonic Acid-D Represses HIF1α/VEGF-Mediated Angiogenesis by Regulating the Akt/mTOR/p70S6K Signaling Cascade
Authors: Guru Santosh Kumar , Pathania Anup Singh , Kumar Suresh , Ramesh Deshidi , Kumar Manjeet , Rana Satiander , Kumar Ajay , Malik Fayaz , Sharma P.R. , Chandan B.K. , Jaglan Sundeep , Sharma J.P. , Shah Bhahwal Ali , Tasduq Sheikh Abdullah , Lattoo Surrinder K. , Faruk Abdul , Saxena A.K. , Vishwakarma R.A. , Bhushan Shashi 
Published: May 2015

Abstract
Tumor angiogenesis is a validated target for therapeutic intervention, but agents that are more disease selective are needed. Here, we report the isolation of secalonic acid-D (SAD), a mycotoxin from a novel source that exhibits potent antiangiogenic antitumor activity. SAD inhibited multiple HIF1α/VEGF-arbitrated angiogenesis dynamics as scored in human umbilical vascular endothelial cells and human MCF-7 breast tumor xenografts. Similarly, SAD suppressed VEGF-induced microvessel sprouting from rat aortic ring and blood vessel formation in the Matrigel plug assay in C57/BL6J mice. Under normoxic or hypoxic conditions, SAD inhibited cell survival through the Akt/mTOR/p70S6K pathway, with attendant effects on key proangiogenesis factors, including HIF1α, VEGFR, and MMP-2/MMP-9. These effects were reversed by cotreatment with the Akt inhibitors perifosine and GSK69069 or by the addition of neutralizing VEGF antibodies. The apoptotic properties of SAD were determined to be both extrinsic and intrinsic in nature, whereas the cell-cycle inhibitory effects were mediated by altering the level of key G1–S transition-phase proteins. In experimental mouse models of breast cancer, SAD dosing produced no apparent toxicities (either orally or intraperitoneal) at levels that yielded antitumor effects. Taken together, our findings offered a preclinical validation and mechanistic definition of the antiangiogenic activity of a novel mycotoxin, with potential application as a cancer-selective therapeutic agent. Cancer Res; 75(14); 2886–96. ©2015 AACR.
Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma
Authors: Bertrand Florie , Rochotte Julia , Colacios Céline , Montfort Anne , Tilkin-Mariamé Anne-Françoise , Touriol Christian , Rochaix Philippe , Lajoie-Mazenc Isabelle , Andrieu-Abadie Nathalie , Levade Thierry , Benoist Hervé , Ségui Bruno 
Published: May 2015

AbstractTNF plays a dual, still enigmatic role in melanoma, either acting as a cytotoxic cytokine or favoring a tumorigenic inflammatory microenvironment. Herein, the tumor growth of melanoma cell lines expressing major histocompatibility complex class I molecules at high levels (MHC-Ihigh) was dramatically impaired in TNF-deficient mice, and this was associated with enhanced tumor-infiltrating CD8+ T lymphocytes. Immunodepletion of CD8 T cells fully restored melanoma growth in TNF−/− mice. Systemic administration of Etanercept inhibited MHC-Ihigh melanoma growth in immunocompetent but not in immunodeficient (IFNγ−/−, nude, or CD8−/−) mice. MHC-Ihigh melanoma growth was also reduced in mice lacking TNF-R1, but not TNF-R2. TNF−/− and TNF-R1−/− mice as well as Etanercept-treated WT mice displayed enhanced intratumor content of high endothelial venules surrounded by high CD8+ T-cell density. Adoptive transfer of activated TNF-R1–deficient or –proficient CD8+ T cells in CD8-deficient mice bearing B16K1 tumors demonstrated that TNF-R1 deficiency facilitates the accumulation of live CD8+ T cells into the tumors. Moreover, in vitro experiments indicated that TNF triggered activated CD8+ T cell death in a TNF-R1–dependent manner, likely limiting the accumulation of tumor-infiltrating CD8+ T cells in TNF/TNF-R1–proficient animals. Collectively, our observations indicate that TNF-R1–dependent TNF signaling impairs tumor-infiltrating CD8+ T-cell accumulation and may serve as a putative target to favor CD8+ T-cell–dependent immune response in melanoma. Cancer Res; 75(13); 2619–28. ©2015 AACR.
NKX3.1 Suppresses TMPRSS2–ERG Gene Rearrangement and Mediates Repair of Androgen Receptor–Induced DNA Damage
Authors: Bowen Cai , Zheng Tian , Gelmann Edward P. 
Published: May 2015

Abstract
TMPRSS2 gene rearrangements occur at DNA breaks formed during androgen receptor–mediated transcription and activate expression of ETS transcription factors at the early stages of more than half of prostate cancers. NKX3.1, a prostate tumor suppressor that accelerates the DNA repair response, binds to androgen receptor at the ERG gene breakpoint and inhibits both the juxtaposition of the TMPRSS2 and ERG gene loci and also their recombination. NKX3.1 acts by accelerating DNA repair after androgen-induced transcriptional activation. NKX3.1 influences the recruitment of proteins that promote homology-directed DNA repair. Loss of NKX3.1 favors recruitment to the ERG gene breakpoint of proteins that promote error-prone nonhomologous end-joining. Analysis of prostate cancer tissues showed that the presence of a TMPRSS2–ERG rearrangement was highly correlated with lower levels of NKX3.1 expression consistent with the role of NKX3.1 as a suppressor of the pathogenic gene rearrangement. Cancer Res; 75(13); 2686–98. ©2015 AACR.
Mendelian Randomization Study of Body Mass Index and Colorectal Cancer Risk
Authors: Thrift Aaron P. , Gong Jian , Peters Ulrike , Chang-Claude Jenny , Rudolph Anja , Slattery Martha L. , Chan Andrew T. , Locke Adam E. , Kahali Bratati , Justice Anne E. , Pers Tune H. , Gallinger Steven , Hayes Richard B. , Baron John A. , Caan Bette J. , Ogino Shuji , Berndt Sonja I. , Chanock Stephen J. , Casey Graham , Haile Robert W. , Du Mengmeng , Harrison Tabitha A. , Thornquist Mark , Duggan David J. , Le Marchand Loïc , Lindor Noralane M. , Seminara Daniela , Song Mingyang , Wu Kana , Thibodeau Stephen N. , Cotterchio Michelle , Win Aung Ko , Jenkins Mark A. , Hopper John L. , Ulrich Cornelia M. , Potter John D. , Newcomb Polly A. , Hoffmeister Michael , Brenner Hermann , White Emily , Hsu Li , Campbell Peter T. 
Published: May 2015

Abstract
Background: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer.
Methods: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study–identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis.
Results: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10–1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m2, 1.50; 95% CI, 1.13–2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26–2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73–1.92).
Conclusions: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation.
Impact: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1024–31. ©2015 AACR.
Prediagnostic Physical Activity and Colorectal Cancer Survival: Overall and Stratified by Tumor Characteristics
Authors: Hardikar Sheetal , Newcomb Polly A. , Campbell Peter T. , Win Aung Ko , Lindor Noralane M. , Buchanan Daniel D. , Makar Karen W. , Jenkins Mark A. , Potter John D. , Phipps Amanda I. 
Published: May 2015

AbstractBackground: Physical activity is associated with a lower incidence of colorectal cancer; however, the relationship of physical activity with colorectal cancer survival is not yet clear. We evaluated the association between prediagnostic physical activity and colorectal cancer survival, overall and accounting for tumor markers associated with colorectal cancer survival: BRAF and KRAS mutation status and microsatellite instability (MSI) status.Methods: Participants were 20- to 74-year-old colorectal cancer patients diagnosed between 1998 and 2007 from the population-based Seattle Colon Cancer Family Registry (S-CCFR). Self-reported physical activity in the years preceding colorectal cancer diagnosis was summarized as average metabolic equivalent task hours per week (MET-h/wk; n = 1,309). Somatic BRAF and KRAS mutations and MSI status were evaluated on a subset of patients (n = 1043). Cox regression was used to estimate HRs and 95% confidence intervals (CI) for overall and disease-specific survival after adjusting for relevant confounders. Stratified analyses were conducted across categories of BRAF, KRAS, and MSI, as well as tumor stage and site.Results: Higher prediagnostic recreational physical activity was associated with significantly more favorable overall survival (HR for highest vs. lowest category, 0.70; 95% CI, 0.52–0.96); associations were similar for colorectal cancer–specific survival. Results consistently indicated a favorable association with physical activity across strata defined by tumor characteristics.Conclusion: Individuals who were physically active before colorectal cancer diagnosis experienced better survival than those who were inactive or minimally active.Impact: Our results support existing physical activity recommendations for colorectal cancer patients and suggest that the beneficial effect of activity is not specific to a particular molecular phenotype of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1130–7. ©2015 AACR.
Lung Cancer in the Era of Precision Medicine
Authors: Politi Katerina , Herbst Roy S. 
Published: May 2015

Abstract
The past decade has been transformative for lung cancer patients, physicians, and scientists. The discovery of EGFR mutations that confer sensitivity to tyrosine kinase inhibitors in lung adenocarcinomas in 2004 heralded the beginning of the era of precision medicine for lung cancer. Indeed, it precipitated concerted efforts by many investigators to define molecular subgroups of lung cancer, characterize the genomic landscape of lung cancer subtypes, identify novel therapeutic targets, and define mechanisms of sensitivity and resistance to targeted therapies. The fruits of these efforts are visible every day now in lung cancer clinics: Patients receive molecular testing to determine whether their tumor harbors an actionable mutation, new and improved targeted therapies that can overcome resistance to first-generation drugs are in clinical trials, and drugs targeting the immune system are showing activity in patients. This extraordinary promise is tempered by the sobering fact that even the newest treatments for metastatic disease are rarely curative and are effective only in a small fraction of all patients. Ongoing and future efforts to find new vulnerabilities of lung cancers, unravel the complexity of drug resistance, increase the efficacy of immunotherapies, and perform biomarker-driven clinical trials are necessary to improve outcomes for patients with lung cancer. Clin Cancer Res; 21(10); 2213–20. ©2015 AACR.
See all articles in this CCR Focus section, “Progress in Lung Cancer.”
Squamous Cell Lung Cancer: From Tumor Genomics to Cancer Therapeutics
Authors: Gandara David R. , Hammerman Peter S. , Sos Martin L. , Lara Primo N. , Hirsch Fred R. 
Published: May 2015

Abstract
Squamous cell lung cancer (SCC) represents an area of unmet need in lung cancer research. For the past several years, therapeutic progress in SCC has lagged behind the now more common non–small cell lung cancer histologic subtype of adenocarcinoma. However, recent efforts to define the complex biology underlying SCC have begun to bear fruit in a multitude of ways, including characterization of previously unknown genomic and signaling pathways, delineation of new, potentially actionable molecular targets, and subsequent development of a large number of agents directed against unique SCC-associated molecular abnormalities. For the first time, SCC-specific prognostic gene signatures and predictive biomarkers of new therapeutic agents are emerging. In addition, recent and ongoing clinical trials, including the Lung-MAP master protocol, have been designed to facilitate approval of targeted therapy–biomarker combinations. In this comprehensive review, we describe the current status of SCC therapeutics, recent advances in the understanding of SCC biology and prognostic gene signatures, and the development of innovative new clinical trials, all of which offer new hope for patients with advanced SCC. Clin Cancer Res; 21(10); 2236–43. ©2015 AACR.
See all articles in this CCR Focus section, “Progress in Lung Cancer.”
MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell Carcinoma
Authors: Mohan Suresh , Vander Broek Robert , Shah Sujay , Eytan Danielle F. , Pierce Matthew L. , Carlson Sophie G. , Coupar Jamie F. , Zhang Jialing , Cheng Hui , Chen Zhong , Van Waes Carter 
Published: May 2015

Abstract
Purpose: Head and neck squamous cell carcinomas exhibit variable sensitivity to inhibitors of the PI3K/mTOR pathway, an important target of genomic alterations in this cancer type. The mitogen-activated protein kinase kinase (MEK)/ERK/activator protein 1 (AP-1) and nuclear factor-κB (NF-κB) pathways are also frequently co-activated, but their roles in resistance mechanisms to PI3K/mTOR inhibitors and as therapeutic targets in head and neck squamous cell carcinoma (HNSCC) are not well defined.
Experimental Design: We determined the IC50s of dual PI3K/mTOR inhibitor PF-05212384 (PF-384) by XTT assays in 14 HNSCC lines with PI3K/Akt/mTOR cascade alterations. In two resistant models, we further characterized the molecular, cellular, and in vivo attributes and effects of combining PF-384 with MEK inhibitor PD-0325901 (PD-901).
Results: PF-384 IC50s varied between 0.75 and 133 nmol/L in 14 HNSCC lines with overexpression or mutations of PIK3CA, and sensitivity correlated with increased phospho-AKT(T308/S473). In resistant UMSCC-1 and -46 models, PF-384 increased G0-/G1-phase accumulation but weakly induced sub-G0 cell death. PF-384 inhibited direct targets of PI3K/mTOR, but incompletely attenuated co-activated ERK and UMSCC-1 xenograft growth in vivo. PD-901 strongly inhibited MEK/ERK targets, and the combination of PF-384 and PD-901 inhibited downstream NF-κB and AP-1 transactivation, and IL8 and VEGF production in vitro. PD-901 potently inhibited tumor growth alone and with PF384, enhanced antiproliferative, apoptotic, and anti-angiogenesis activity in vivo.
Conclusions: PI3K/mTOR inhibitor PF-384 exhibits variable activity in a panel of HNSCC cell lines with differing PIK3CA expression and mutation status. MEK inhibitor PD-901 overcomes resistance and enhances antitumor effects observed with PF-384 in vivo. Clin Cancer Res; 21(17); 3946–56. ©2015 AACR.
Aromatase Inhibitor–Mediated Downregulation of INrf2 (Keap1) Leads to Increased Nrf2 and Resistance in Breast Cancer
Authors: Khatri Raju , Shah Preeti , Guha Rupa , Rassool Feyruz V. , Tomkinson Alan E. , Brodie Angela , Jaiswal Anil K. 
Published: May 2015

Abstract
Aromatase inhibitors are effective drugs that reduce or eliminate hormone-sensitive breast cancer. However, despite their efficacy, resistance to these drugs can occur in some patients. The INrf2 (Keap1):Nrf2 complex serves as a sensor of drug/radiation-induced oxidative/electrophilic stress. INrf2 constitutively suppresses Nrf2 by functioning as an adapter protein for the Cul3/Rbx1-mediated ubiquitination/degradation of Nrf2. Upon stress, Nrf2 dissociates from INrf2, is stabilized, translocates to the nucleus, and coordinately induces a battery of cytoprotective gene expression. Current studies investigated the role of Nrf2 in aromatase inhibitor resistance. RT-PCR and immunoblot assays showed that aromatase inhibitor–resistant breast cancer LTLTCa and AnaR cells express lower INrf2 and higher Nrf2 protein levels, as compared with drug-sensitive MCF-7Ca and AC1 cells, respectively. The increase in Nrf2 was due to lower ubiquitination/degradation of Nrf2 in aromatase inhibitor–resistant cells. Higher Nrf2-mediated levels of biotransformation enzymes, drug transporters, and antiapoptotic proteins contributed to reduced efficacy of drugs and aversion to apoptosis that led to drug resistance. shRNA inhibition of Nrf2 in LTLTCa (LTLTCa-Nrf2KD) cells reduced resistance and sensitized cells to aromatase inhibitor exemestane. Interestingly, LTLTCa-Nrf2KD cells also showed reduced levels of aldehyde dehydrogenase, a marker of tumor-initiating cells and significantly decreased mammosphere formation, as compared with LTLTCa-Vector control cells. The results together suggest that persistent aromatase inhibitor treatment downregulated INrf2 leading to higher expression of Nrf2 and Nrf2-regulated cytoprotective proteins that resulted in increased aromatase inhibitor drug resistance. These findings provide a rationale for the development of Nrf2 inhibitors to overcome resistance and increase efficacy of aromatase inhibitors. Mol Cancer Ther; 14(7); 1728–37. ©2015 AACR.