bluuebunny/crossref_metadata_2025 huggingface dataset:
ON THE TRUE AND SPURIOUS EIGENVALUES BY USING THE REAL OR THE IMAGINARY-PART OF THE METHOD OF FUNDAMENTAL SOLUTIONS
Authors: CHEN I. L. , LEE Y. T. , KUO P. S. , CHEN J. T.
Published: January 2013

In this paper, the method of fundamental solutions (MFS) of real-part or imaginary-part kernels is employed to solve two-dimensional eigenproblems. The occurring mechanism of spurious eigenvalues for circular and elliptical membranes is examined. It is found that the spurious eigensolution using the MFS depends on the location of the fictitious boundary where the sources are distributed. By employing the singular value decomposition technique, the common left unitary vectors of the true eigenvalue for the single- and double-layer potential approaches are found while the common right unitary vectors of the spurious eigenvalue are obtained. Dirichlet and Neumann eigenproblems are both considered. True eigenvalues are dependent on the boundary condition while spurious eigenvalues are different in the different approach, single-layer or double-layer potential MFS. Two examples of circular and elliptical membranes are numerically demonstrated to see the validity of the present method and the results are compared well with the theoretical prediction.
LICENSING AGRICULTURAL INTELLECTUAL PROPERTY: HOW SHOULD PUBLIC R&D INSTITUTIONS IN DEVELOPING COUNTRIES RESPOND?
Authors: PAYUMO JANE G. , GRIMES HOWARD D. , JONES KEITH J.
Published: January 2013

In the 21st century, licensing is the most common vehicle by which Intellectual Property Rights (IPR), especially for agricultural biotechnology, are transferred from inventors to users. In this paper, we argue that due to the strong association between IPR and agricultural biotechnology, technology transfer (e.g., licensing), needs to be conducted differently for agricultural biotechnology products. We examine two important licensing mechanisms: the patent license and material transfer agreements, and their unique features, and issues associated with their use. And yet, it's important to note that these legal instruments for agricultural biotechnology are contextual, case-specific, and may even be country-specific. We hope that this paper can serve as a starting point for discussion, and/or a guide for public research institutions in developing countries to more effectively use these technology transfer tools. We also present a few case examples that highlight the experiences of other national research institutions in handling these legal mechanisms. Learning from these experiences may help other institutions maximize benefits while minimizing cost and risk under the new context of technology transfer for agricultural innovations.
Variability-tolerant workload allocation for MPSoC energy minimization under real-time constraints
Authors: Paterna Francesco , Acquaviva Andrea , Papariello Francesco , Desoli Giuseppe , Benini Luca
Published: January 2013

Sub-50nm CMOS technologies are affected by significant variability, which causes power and performance variations among nominally similar cores in MPSoC platforms. This undesired heterogeneity threatens execution predictability and energy efficiency. We propose two techniques to allocate sets of barrier-synchronized tasks. The first technique models allocation as an ILP and achieves optimal results, but requires an offline solver. The second technique adopts a two-stage heuristic approach, and it can be adapted to work online. We tested our approach on the virtual prototype of a next-generation industrial multicore platform. Experimental results demonstrate that our approach minimizes deadline violations while increasing energy efficiency.
A passivity approach for model-based compositional design of networked control systems
Authors: Koutsoukos Xenofon , Kottenstette Nicholas , Hall Joseph , Eyisi Emeka , Leblanc Heath , Porter Joseph , Sztipanovits Janos
Published: January 2013

The integration of physical systems through computing and networking has become pervasive, a trend now known as cyber-physical systems (CPS). Functionality in CPS emerges from the interaction of networked computational and physical objects. System design and integration are particularly challenging because fundamentally different physical and computational design concerns intersect. The impact of these interactions is the loss of compositionality which creates tremendous challenges. The key idea in this article is to use passivity for decoupling the control design of networked systems from uncertainties such as time delays and packet loss, thus providing a fundamental simplification strategy that limits the complexity of interactions. The main contribution is the application of the approach to an experimental case study of a networked multi-robot system. We present a networked control architecture that ensures the overall system remains stable in spite of implementation uncertainties such as network delays and data dropouts, focusing on the technical details required for the implementation. We describe a prototype domain-specific modeling language and automated code generation tools for the design of networked control systems on top of passivity that facilitate effective system configuration, deployment, and testing. Finally, we present experimental evaluation results that show decoupling of interlayer interactions.
Control-theoretic cyber-physical system modeling and synthesis
Authors: Shin Donghwa , Park Jaehyun , Kim Younghyun , Seo Jaeam , Chang Naehyuck
Published: January 2013

A joint optimization of the physical system and the cyber world is one of the key problems in the design of a cyber-physical system (CPS). The major mechanical forces and/or chemical reactions in a plant are commonly modified by actuators in the balance-of-plant (BOP) system. More powerful actuators requires more power, but generally increase the response of the physical system powered by the electrical energy generated by the physical system. To maximize the overall output of a power generating plant therefore requires joint optimization of the physical system and the cyber world, and this is a key factor in the design of a CPS.

We introduce a systematic approach to the modeling and synthesis of a CPS that emphasize joint power optimization, using an active direct methanol fuel cell (DMFC) as a case study. Active DMFC systems are superior to passive DMFCs in terms of fuel efficiency thanks to their BOP system, which includes pumps, air blowers, and fans. However, designing a small-scale active DMFC with the best overall system efficiency requires the BOP system to be jointly optimized with the DMFC stack operation, because the BOP components are powered by the stack. Our approach to this synthesis problem involves i) BOP system characterization, ii) integrated DMFC system modeling, iii) configuring a system for the maximum net power output through design space exploration, iv) synthesis of feedback control tasks, and v) implementation.
Robust architectures for embedded wireless network control and actuation
Authors: Pajic Miroslav , Chernoguzov Alexander , Mangharam Rahul
Published: January 2013

Networked cyber-physical systems are fundamentally constrained by the tight coupling and closed-loop control of physical processes. To address actuation in such closed-loop wireless control systems there is a strong need to rethink the communication architectures and protocols for reliability, coordination, and control. We introduce the Embedded Virtual Machine (EVM), a programming abstraction where controller tasks with their control and timing properties are maintained across physical node boundaries and functionality is capable of migrating to the most competent set of physical controllers. In the context of process and discrete control, an EVM is the distributed runtime system that dynamically selects primary-backup sets of controllers given spatial and temporal constraints of the underlying wireless network. EVM-based algorithms allow network control algorithms to operate seamlessly over less reliable wireless networks with topological changes. They introduce new capabilities such as predictable outcomes during sensor/actuator failure, adaptation to mode changes, and runtime optimization of resource consumption. An automated design flow from Simulink to platform-independent domain-specific languages, and subsequently, to platform-dependent code generation is presented. Through case studies in discrete and process control we demonstrate the capabilities of EVM-based wireless network control systems.
Adaptive real-time scheduling for legacy multimedia applications
Authors: Cucinotta Tommaso , Checconi Fabio , Abeni Luca , Palopoli Luigi
Published: January 2013

Multimedia applications are often executed on standard personal computers. The absence of established standards has hindered the adoption of real-time scheduling solutions in this class of applications. Developers have adopted a wide range of heuristic approaches to achieve an acceptable timing behavior but the result is often unreliable. We propose a mechanism to extend the benefits of real-time scheduling to
legacy
applications based on the combination of two techniques: (1) a real-time monitor that observes and infers the activation period of the application, and (2) a feedback mechanism that adapts the scheduling parameters to improve its real-time performance.
Beyond Recommendations
Authors: Brown Barry
Published: January 2013

Online review Web sites have enabled new interactions between companies and their customers. In this article we draw on interviews with users, reviewers, and establishments to explore how local review Web sites can change interactions around local places. Review Web sites such as Yelp and Tripadvisor allow customers to “previsit” establishments and areas of a city before an actual visit. The collection of a large numbers of user-generated reviews has also created a new genre of writing, with reviewers gaining considerable pleasure from passing on word of mouth and influencing others’ choices. Reviews also offer a new channel of communication between establishments, customers, and competitors. We discuss how review Web sites can be designed to cater for a broader range of interactions around reviews beyond a focus on recommendations.
All You Need is Love
Authors: Hassenzahl Marc , Heidecker Stephanie , Eckoldt Kai , Diefenbach Sarah , Hillmann Uwe
Published: January 2013

A wealth of evidence suggests that love, closeness, and intimacy---in short relatedness---are important for people’s psychological well-being. Nowadays, however, couples are often forced to live apart. Accordingly, there has been a growing and flourishing interest in designing technologies that mediate (and create) a feeling of relatedness when being separated, beyond the explicit verbal communication and simple emoticons available technologies offer. This article provides a review of 143 published artifacts (i.e., design concepts, technologies). Based on this, we present six strategies used by designers/researchers to create a relatedness experience: Awareness, expressivity, physicalness, gift giving, joint action, and memories. We understand those strategies as starting points for the experience-oriented design of technology.
On the impact of storage in residential power distribution systems
Authors: Ardakanian Omid , Rosenberg Catherine , Keshav S.
Published: January 2013

It is anticipated that energy storage will be incorporated into the distribution network component of the future smart grid to allow desirable features such as distributed generation integration and reduction in the peak demand. There is, therefore, an urgent need to understand the impact of storage on distribution system planning. In this paper, we focus on the effect of storage on the loading of neighbourhood pole-top transformers. We apply a probabilistic sizing technique originally developed for sizing buffers and communication links in telecommunications networks to jointly size storage and transformers in the distribution network. This allows us to compute the potential gains from transformer upgrade de- ferral due to the addition of storage. We validate our results through numerical simulation using measurements of home load in a testbed of 20 homes and demonstrate that our guidelines allow local distribution companies to defer trans- former upgrades without reducing reliability.
Electric grid balancing through lowcost workload migration
Authors: Chiu David , Stewart Christopher , McManus Bart
Published: January 2013

Energy production must continuously match demand on the electric grid. A deficiency can lead to service disruptions, and a surplus can place tremendous stress on grid components, potentially causing major blackouts. To manage this balance, grid operators must increase or lower power generation, with only a few minutes to react. The grid balancing problem has also impeded the pace of integrating bountiful renewable resources (e.g., wind), whose generation is intermittent. An emerging plan to mitigate this problem is demand response, i.e., for grid operators to alter the electricity usage behavior of the masses through real-time price signals. But due to prohibitively high infrastructure costs and societal-scale adoption, tangible demand response mechanisms have so far been elusive.

We believe that altering the usage patterns of a multitude of data centers can be a tangible, albeit initial, step towards affecting demand response. Growing in both density and size, today's data center designs are shaped by the increasing awareness of energy costs and carbon footprint. We posit that shifting computational workloads (and thus, demand) across geographic regions to match electricity supply may help balance the grid. In this paper we will first present a real grid balancing problem experienced in the Pacfic Northwest. We then propose a symbiotic relationship between data centers and grid operators by showing that mutual cost benefits can be accessible. Finally, we argue for a low cost workload migration mechanism, and pose overarching challenges in designing this framework.
RateOptimal scheduling schemes for asynchronous InputQueued packet switches
Authors: Bonald Thomas , Cuda Davide
Published: January 2013

The performance of input-queued packet switches critically depends on the scheduling scheme that connects the input ports to the output ports. We show that, when packets are switched asynchronously, simple scheduling schemes where contention is solved locally at each input or output can achieve rate optimality, without any speed-up of the internal transmission rate.
Memory management for many-core processors with software configurable locality policies
Authors: Zhou Jin , Demsky Brian
Published: January 2013

As processors evolve towards higher core counts, architects will develop more sophisticated memory systems to satisfy the cores' increasing thirst for memory bandwidth. Early many-core processor designs suggest that future memory systems will likely include multiple controllers and distributed cache coherence protocols. Many-core processors that expose memory locality policies to the software system provide opportunities for automatic tuning that can achieve significant performance benefits.

Managed languages typically provide a simple heap abstraction. This paper presents techniques that bridge the gap between the simple heap abstraction of modern languages and the complicated memory systems of future processors. We present a NUMA-aware approach to garbage collection that balances the competing concerns of data locality and heap utilization to improve performance. We combine a lightweight approach for measuring an application's memory behavior with an online, adaptive algorithm for tuning the cache to optimize it for the specific application's behaviors.

We have implemented our garbage collector and cache tuning algorithm and present results on a 64-core TILEPro64 processor.
Barriers reconsidered, friendlier still!
Authors: Yang Xi , Blackburn Stephen M. , Frampton Daniel , Hosking Antony L.
Published: January 2013

Read and write barriers mediate access to the heap allowing the collector to control and monitor mutator actions. For this reason, barriers are a powerful tool in the design of any heap management algorithm, but the prevailing wisdom is that they impose significant costs. However, changes in hardware and workloads make these costs a moving target. Here, we measure the cost of a range of useful barriers on a range of modern hardware and workloads. We confirm some old results and overturn others. We evaluate the microarchitectural sensitivity of barrier performance and the differences among benchmark suites. We also consider barriers in context, focusing on their behavior when used in combination, and investigate a known pathology and evaluate solutions. Our results show that read and write barriers have average overheads as low as 5.4% and 0.9% respectively. We find that barrier overheads are more exposed on the workload provided by the modern DaCapo benchmarks than on old SPECjvm98 benchmarks. Moreover, there are differences in barrier behavior between in-order and out-of- order machines, and their respective memory subsystems, which indicate different barrier choices for different platforms. These changing costs mean that algorithm designers need to reconsider their design choices and the nature of their resulting algorithms in order to exploit the opportunities presented by modern hardware.
new Scala() instance of Java
Authors: Sewe Andreas , Mezini Mira , Sarimbekov Aibek , Ansaloni Danilo , Binder Walter , Ricci Nathan , Guyer Samuel Z.
Published: January 2013

While often designed with a single language in mind, managed runtimes like the Java virtual machine (JVM) have become the target of not one but many languages, all of which benefit from the runtime's services. One of these services is automatic memory management. In this paper, we compare and contrast the memory behaviour of programs written in Java and Scala, respectively, two languages which both target the same platform: the JVM. We both analyze core object demographics like object lifetimes as well as secondary properties of objects like their associated monitors and identity hash-codes. We find that objects in Scala programs have lower survival rates and higher rates of immutability, which is only partly explained by the memory behaviour of objects representing closures or boxed primitives. Other metrics vary more by benchmark than language.
Exploiting the structure of the constraint graph for efficient points-to analysis
Authors: Nasre Rupesh
Published: January 2013

Points-to analysis is a key compiler analysis. Several memory related optimizations use points-to information to improve their effectiveness. Points-to analysis is performed by building a constraint graph of pointer variables and dynamically updating it to propagate more and more points-to information across its subset edges. So far, the structure of the constraint graph has been only trivially exploited for efficient propagation of information, e.g., in identifying cyclic components or to propagate information in topological order. We perform a careful study of its structure and propose a new inclusion-based flow-insensitive context-sensitive points-to analysis algorithm based on the notion of dominant pointers. We also propose a new kind of pointer-equivalence based on dominant pointers which provides significantly more opportunities for reducing the number of pointers tracked during the analysis. Based on this hitherto unexplored form of pointer-equivalence, we develop a new context-sensitive flow insensitive points-to analysis algorithm which uses incremental dominator update to efficiently compute points-to information. Using a large suite of programs consisting of SPEC 2000 benchmarks and five large open source programs we show that our points-to analysis is 88% faster than BDD-based Lazy Cycle Detection and 2× faster than Deep Propagation. We argue that our approach of detecting dominator-based pointer-equivalence is a key to improve points-to analysis efficiency.
Findings and implications from data mining the IMC review process
Authors: Beverly Robert , Allman Mark
Published: January 2013

The computer science research paper review process is largely human and time-intensive. More worrisome, review processes are frequently questioned, and often non-transparent. This work advocates applying computer science methods and tools to the computer science review process. As an initial exploration, we data mine the submissions, bids, reviews, and decisions from a recent top-tier computer networking conference. We empirically test several common hypotheses, including the existence of readability, citation, call-for-paper adherence, and topical bias. From our findings, we hypothesize review process methods to improve fairness, efficiency, and transparency.
Hotnets 2012 highlights
Authors: Godfrey P. Brighten
Published: January 2013

This article captures some of the discussion and insights from this year's ACM Workshop on Hot Topics in Networks (HotNets-XI).
Effects of caffeine and/or nasal CPAP treatment on laryngeal chemoreflexes in preterm lambs
Authors: Boudaa Nadia , Samson Nathalie , Carrière Vincent , Germim Pamela Samanta , Pasquier Jean-Charles , Bairam Aida , Praud Jean-Paul
Published: January 2013

Current knowledge suggests that laryngeal chemoreflexes (LCR) are involved in the occurrence of certain neonatal apneas/bradycardias, especially in the preterm newborn. While caffeine and/or nasal continuous positive airway pressure (nCPAP) are the most frequent options used for treating apneas in preterm newborns, their effects on LCR-related apneas/bradycardias are virtually unknown. The aim of the present study was to test the hypothesis that caffeine and/or nCPAP decreases LCR-related cardiorespiratory inhibition in a preterm ovine model. Seven preterm lambs were born vaginally on gestational day 133 (normal gestation: 147 days) after intramuscular injections of betamethasone and mifepristone. Five days after birth, a chronic surgical instrumentation was performed to record states of alertness, electrocardiogram, systemic arterial pressure, and electromyographic activity of a laryngeal constrictor muscle, as well as to insert a transcutaneous supraglottal catheter. LCR were induced in quiet sleep under four conditions: 1) control (without caffeine or nCPAP); 2) nCPAP (5 cmH2O, without caffeine); 3) caffeine (10 mg/kg infused intravenously for 30 min, without nCPAP); and 4) nCPAP + caffeine. Our results showed that nCPAP consistently blunted LCR-related cardiorespiratory inhibition vs. control condition, contrary to caffeine whose overall effect was nonsignificant. In addition, nCPAP condition was characterized by a more consistent and rapid arousal after HCl injection. No significant differences were observed between all tested conditions with regard to swallowing and cough. It is concluded that nCPAP should be further assessed for its usefulness in treating neonatal apneas linked to LCR.
Epigenetic regulation of muscle phenotype and adaptation: a potential role in COPD muscle dysfunction
Authors: Barreiro Esther , Sznajder Jacob I.
Published: January 2013

Quadriceps muscle dysfunction occurs in one-third of patients with chronic obstructive pulmonary disease (COPD) in very early stages of their condition, even prior to the development of airway obstruction. Among several factors, deconditioning and muscle mass loss are the most relevant contributing factors leading to this dysfunction. Moreover, epigenetics, defined as the process whereby gene expression is regulated by heritable mechanisms that do not affect DNA sequence, could be involved in the susceptibility to muscle dysfunction, pathogenesis, and progression. Herein, we review the role of epigenetic mechanisms in muscle development and adaptation to environmental factors such as immobilization and exercise, and their implications in the pathophysiology and susceptibility to muscle dysfunction in COPD. The epigenetic modifications identified so far include DNA methylation, histone acetylation and methylation, and non-coding RNAs such as microRNAs (miRNAs). In the present review, we describe the specific contribution of epigenetic mechanisms to the regulation of embryonic myogenesis, muscle structure and metabolism, immobilization, and exercise, and in muscles of COPD patients. Events related to muscle development and regeneration and the response to exercise and immobilization are tightly regulated by epigenetic mechanisms. These environmental factors play a key role in the outcome of muscle mass and function as well as in the susceptibility to muscle dysfunction in COPD. Future research remains to be done to shed light on the specific target pathways of miRNA function and other epigenetic mechanisms in the susceptibility, pathogenesis, and progression of COPD muscle dysfunction.
Airway exchange of highly soluble gases
Authors: Hlastala Michael P. , Powell Frank L. , Anderson Joseph C.
Published: January 2013

Highly blood soluble gases exchange with the bronchial circulation in the airways. On inhalation, air absorbs highly soluble gases from the airway mucosa and equilibrates with the blood before reaching the alveoli. Highly soluble gas partial pressure is identical throughout all alveoli. At the end of exhalation the partial pressure of a highly soluble gas decreases from the alveolar level in the terminal bronchioles to the end-exhaled partial pressure at the mouth. A mathematical model simulated the airway exchange of four gases (methyl isobutyl ketone, acetone, ethanol, and propylene glycol monomethyl ether) that have high water and blood solubility. The impact of solubility on the relative distribution of airway exchange was studied. We conclude that an increase in water solubility shifts the distribution of gas exchange toward the mouth. Of the four gases studied, ethanol had the greatest decrease in partial pressure from the alveolus to the mouth at end exhalation. Single exhalation breath tests are inappropriate for estimating alveolar levels of highly soluble gases, particularly for ethanol.
Responses of vestibular nucleus neurons to inputs from the hindlimb are enhanced following a bilateral labyrinthectomy
Authors: McCall Andrew A. , Moy Jennifer D. , Puterbaugh Sonya R. , DeMayo William M. , Yates Bill J.
Published: January 2013

Vestibular nucleus neurons have been shown to respond to stimulation of afferents innervating the limbs. However, a limitation in the potential translation of these findings is that they were obtained from decerebrate or anesthetized animals. The goal of the present study was to determine whether stimulation of hindlimb nerves similarly affects vestibular nucleus neuronal activity in conscious cats, and whether the responsiveness of neurons to the stimuli is altered following a bilateral labyrinthectomy. In labyrinth-intact animals, the firing rate of 24/59 (41%) of the neurons in the caudal vestibular nucleus complex was affected by hindlimb nerve stimulation. Most responses were excitatory; the median response latency was 20 ms, but some units had response latencies as short as 10 ms. In the first week after a bilateral labyrinthectomy, the proportion of vestibular nucleus neurons that responded to hindlimb nerve stimulation increased slightly (to 24/55 or 44% of units). However, during the subsequent postlabyrinthectomy survival period, the proportion of vestibular nucleus neurons with hindlimb inputs increased significantly (to 30/49 or 61% of units). Stimuli to hindlimb nerves needed to elicit neuronal responses was consistently over three times the threshold for eliciting an afferent volley. These data show that inputs from hindlimb afferents smaller than those innervating muscle spindles and Golgi tendon organs affect the processing of information in the vestibular nuclei, and that these inputs are enhanced following a bilateral labyrinthectomy. These findings have implications for the development of a limb neuroprosthetics device for the management of bilateral vestibular loss.
Reliability and validity of ultrasound measurements of muscle fascicle length and pennation in humans: a systematic review
Authors: Kwah Li Khim , Pinto Rafael Z. , Diong Joanna , Herbert Robert D.
Published: January 2013

Ultrasound imaging is widely used to measure architectural features of human skeletal muscles in vivo. We systematically reviewed studies of the reliability and validity of two-dimensional ultrasound measurement of muscle fascicle lengths or pennation angles in human skeletal muscles. A comprehensive search was conducted in June 2011. Thirty-six reliability studies and six validity studies met the inclusion criteria. Data from these studies indicate that ultrasound measurements of muscle fascicle lengths are reliable across a broad range of experimental conditions [intraclass correlation coefficient (ICC) and r values were always > 0.6, and coefficient of variation values were always < 10%]. The reliability of measurements of pennation angles is broadly similar (ICC and r values were always > 0.5 and coefficient of variation values were always < 14%). Data on validity are less extensive and probably less robust, but suggest that measurement of fascicle lengths and pennation angles are accurate (ICC > 0.7) under certain conditions, such as when large limb muscles are imaged in a relaxed state and the limb or joint remains stationary. Future studies on validity should consider ways to test for the validity of two-dimensional ultrasound imaging in contracted or moving muscles and the best method of probe alignment.
BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma
Authors: Frederick Dennie T. , Piris Adriano , Cogdill Alexandria P. , Cooper Zachary A. , Lezcano Cecilia , Ferrone Cristina R. , Mitra Devarati , Boni Andrea , Newton Lindsay P. , Liu Chengwen , Peng Weiyi , Sullivan Ryan J. , Lawrence Donald P. , Hodi F. Stephen , Overwijk Willem W. , Lizée Gregory , Murphy George F. , Hwu Patrick , Flaherty Keith T. , Fisher David E. , Wargo Jennifer A.
Published: January 2013

Purpose: To evaluate the effects of BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma.

Experimental Design: Thirty-five biopsies were collected from 16 patients with metastatic melanoma pretreatment (day 0) and at 10 to 14 days after initiation of treatment with either BRAF inhibitor alone (vemurafenib) or BRAF + MEK inhibition (dabrafenib + trametinib) and were also taken at time of progression. Biopsies were analyzed for melanoma antigens, T-cell markers, and immunomodulatory cytokines.

Results: Treatment with either BRAF inhibitor alone or BRAF + MEK inhibitor was associated with an increased expression of melanoma antigens and an increase in CD8+ T-cell infiltrate. This was also associated with a decrease in immunosuppressive cytokines [interleukin (IL)-6 and IL-8] and an increase in markers of T-cell cytotoxicity. Interestingly, expression of exhaustion markers TIM-3 and PD1 and the immunosuppressive ligand PDL1 was increased on treatment. A decrease in melanoma antigen expression and CD8 T-cell infiltrate was noted at time of progression on BRAF inhibitor alone and was reversed with combined BRAF and MEK inhibition.

Conclusions: Together, these data suggest that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T-cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy. Interestingly, markers of T-cell exhaustion and the immunosuppressive ligand PDL1 are also increased with BRAF inhibition, further implying that immune checkpoint blockade may be critical in augmenting responses to BRAF-targeted therapy in patients with melanoma. Clin Cancer Res; 19(5); 1225–31. ©2013 AACR.
New Strategies in the Treatment of Ovarian Cancer: Current Clinical Perspectives and Future Potential
Authors: Banerjee Susana , Kaye Stanley B.
Published: January 2013

The treatment of ovarian cancer is set to undergo rapid changes, as strategies incorporating molecular targeted therapies begin to take shape. These are based on a better appreciation of approaches targeting the tumor microenvironment as well as specific subtypes of the disease, with distinct molecular aberrations. Targeting the VEGF pathway through bevacizumab is clearly effective, with positive randomized trials at all disease stages; targeting defective homologous recombination repair pathways with PARP inhibitors is also proving successful in a substantial proportion of patients with high-grade serous ovarian cancer. In this article, we will review progress in these two leading areas and also discuss the potential for targeting other pathways and receptors that may be activated in ovarian cancer, including the RAS/RAF/MEK and PI3K/AKT/mToR pathways, the ErbB and IGF family of receptors, mitotic check points, and also the folate receptor. Here, single-agent therapy may play a role in selected cases but essential components of future strategies should include combination treatments aimed at dealing with the key problem of drug resistance, together with rational approaches to patient selection. Clin Cancer Res; 19(5); 961–8. ©2013 AACR.
The influence of factor V Leiden and G20210A prothrombin mutation on the presence of residual vein obstruction after idiopathic deep-vein thrombosis of the lower limbs
Authors: Legnani Cristina , Pengo Vittorio , Ghirarduzzi Angelo , Testa Sophie , Poli Daniela , Prisco Domenico , Tripodi Armando , Palareti Gualtiero , Cosmi Benilde ,   for the PROLONG Investigators FCSA, Italian Federation of Anticoagulation Clinics
Published: January 2013

It was our aim to assess whether factor V Leiden (FVL) and G20210A prothrombin (FII) mutation are associated with the presence of residual vein obstruction (RVO) after a standard course of anticoagulation for a first episode of idiopathic proximal deep-vein thrombosis (DVT) of the lower limbs, with or without symptomatic pulmonary embolism (PE). Patients were enrolled in two prospective multicentre studies: PROLONG and PROLONG II. RVO was detected by compression ultra-sonography according to the method of Prandoni on the day of anticoagulation withdrawal. Patients were also screened for FVL and FII mutation. The presence of FVL and/or FII mutation was determined in 872/963 (90.5%) patients, in 753 of whom RVO was assessed. FVL was significantly less frequent among subjects with isolated PE (7/176:4%) than among patients with either DVT and PE (15/133:11.3%; p=0.0018) or isolated DVT (89/563:15.8%; p<0.0001), confirming the FVL paradox. The rate of FII mutation was similar among patients with isolated PE (11/176:6.2%) and patients with either DVT and PE (12/133:9%) or isolated DVT (52/563:9.2%). FVL and FII mutation were not significantly associated with RVO at the multivariate analysis in all patients, although data suggest that FVL and FII mutation may have a differential effect on RVO in the subgroups of patients with DVT and DVT plus PE patients. Male sex and isolated DVT were significantly associated with RVO in all patients. In conclusion, male sex and isolated DVT are associated with RVO, while FVL and FII mutations are not significantly associated with RVO in this study.
Vascular Function During Prolonged Progression and Regression of Atherosclerosis in Mice
Authors: Miller Jordan D. , Chu Yi , Castaneda Lauren E. , Serrano Kristine M. , Brooks Robert M. , Heistad Donald D.
Published: January 2013

Objective—

Endothelial dysfunction is associated with atherosclerosis in mice, but it is difficult to reduce cholesterol levels enough to study regression of atherosclerosis in genetically modified mice. The goal of this study was to examine vascular structure and function before and after reducing elevated plasma lipid levels with a genetic switch in Reversa mice, and identify novel mechanisms contributing to structural and functional improvements in the vasculature after reduction of blood lipids.

Methods and Results—

After 6 months of hypercholesterolemia, endothelial function (maximum relaxation to acetylcholine) in aorta was impaired and responses to nitric oxide were unaffected. Further impairment in endothelial function was observed after 12 months of hypercholesterolemia and was associated with reductions in sensitivity to nitric oxide. Expression of dihydrofolate reductase was reduced at 6 and 12 months, and addition of the tetrahydrobiopterin precursor sepiapterin significantly improved endothelial function. Reducing cholesterol levels at 6 months normalized dihydrofolate reductase expression and prevented further impairment in endothelial function. Similar functional changes were observed after 12 months of hypercholesterolemia followed by 2 months of lipid lowering.

Conclusion—

Our data suggest that endothelial dysfunction after prolonged hypercholesterolemia is the result of both impairment of sensitivity to nitric oxide and reduced nitric oxide synthase cofactor bioavailability. Both of these changes can be prevented by normalizing blood lipids during moderately severe or advanced atherosclerosis.
Diabetes Causes Bone Marrow Endothelial Barrier Dysfunction by Activation of the RhoA–Rho-Associated Kinase Signaling Pathway
Authors: Mangialardi Giuseppe , Katare Rajesh , Oikawa Atsuhiko , Meloni Marco , Reni Carlotta , Emanueli Costanza , Madeddu Paolo
Published: January 2013

Objective—

Diabetes mellitus causes bone marrow (BM) microangiopathy. This study aimed to investigate the mechanisms responsible for BM endothelial dysfunction in diabetes mellitus.

Methods and Results—

The analysis of differentially expressed transcripts in BM endothelial cells (BMECs) from type-1 diabetic and nondiabetic mice showed an effect of diabetes mellitus on signaling pathways controlling cell death, migration, and cytoskeletal rearrangement. Type-1 diabetic-BMECs displayed high reactive oxygen species levels, increased expression and activity of RhoA and its associated protein kinases Rho-associated kinase 1/Rho-associated kinase 2, and reduced Akt phosphorylation/activity. Likewise, diabetes mellitus impaired Akt-related BMEC functions, such as migration, network formation, and angiocrine factor-releasing activity, and increased vascular permeability. Moreover, high glucose disrupted BMEC contacts through Src tyrosine kinase phosphorylation of vascular endothelial cadherin. These alterations were prevented by constitutively active Akt (myristoylated Akt), Rho-associated kinase inhibitor Y-27632, and Src inhibitors. Insulin replacement restored BMEC abundance, as assessed by flow cytometry analysis of the endothelial marker MECA32, and endothelial barrier function in BM of type-1 diabetic mice.

Conclusion—

Redox-dependent activation of RhoA/Rho-associated kinase and Src/vascular endothelial cadherin signaling pathways, together with Akt inactivation, contribute to endothelial dysfunction in diabetic BM. Metabolic control is crucial for maintenance of endothelial cell homeostasis and endothelial barrier function in BM of diabetic mice.
Matrix Gla Protein Gene Polymorphism Is Associated With Increased Coronary Artery Calcification Progression
Authors: Cassidy-Bushrow Andrea E. , Bielak Lawrence F. , Levin Albert M. , Sheedy Patrick F. , Turner Stephen T. , Boerwinkle Eric , Lin Xihong , Kardia Sharon L.R. , Peyser Patricia A.
Published: January 2013

Objective—

Matrix gla protein (MGP) inhibits arterial and cartilaginous calcification. A threonine to alanine (Thr83Ala) polymorphism (codon 83) in
MGP
is associated with myocardial infarction and femoral artery calcification. We examined the association of the
MGP
Thr83Ala polymorphism with quantity and progression of coronary artery calcification (CAC), a noninvasive measure of subclinical coronary atherosclerosis.

Methods and Results—

In 605 participants of the Epidemiology of Coronary Artery Calcification Study, generalized linear mixed models were fit to determine the association of
MGP
Thr83Ala with CAC quantity and progression. There was a significant additive relation between
MGP
Thr83Ala and CAC progression (
P
=0.001). In the fully adjusted model, every 1 Ala83 allele increase was associated with an estimated 1.9% (95% confidence interval, 0.7%–3.0%) per year since baseline larger increase in CAC quantity. A proxy single nucleotide polymorphism for
MGP
Thr83Ala (rs6488724) was similarly associated with CAC progression in an independent cohort from the Genetic Epidemiology Network of Arteriopathy (GENOA) study.

Conclusion—

Increased risk of myocardial infarction associated with
MGP
ThrAla83 genotype observed elsewhere may be related to faster progression of subclinical coronary atherosclerosis.
MGP
genotype could be a potential candidate for identifying individuals at increased risk of atherosclerotic disease who would benefit from aggressive primary prevention strategies.
T-Helper 2 Immunity Is Associated With Reduced Risk of Myocardial Infarction and Stroke
Authors: Engelbertsen Daniel , Andersson Linda , Ljungcrantz Irena , Wigren Maria , Hedblad Bo , Nilsson Jan , Björkbacka Harry
Published: January 2013

Objective—

Experimental studies in mice have attributed T-helper (Th) 1 and Th2 cells important roles in atherosclerosis, but the clinical importance of these cells in cardiovascular disease (CVD) remains to be clarified. Here, we investigated associations between Th1 and Th2 cells, carotid intima-media thickness, and cardiovascular risk.

Methods and Results—

Blood drawn at baseline and incident cardiovascular events during 15-year follow-up were assessed in 700 participants. Baseline Th1 (CD3
+
CD4
+
interferon-γ
+
) and Th2 (CD3
+
CD4
+
interleukin-4
+
) cells were analyzed by flow cytometry, and cytokine-release from activated mononuclear leukocytes was measured by multiplex technology. High numbers of Th2 cells were independently associated with decreased mean common carotid intima-media thickness. High numbers of Th2 cells were also independently associated with a reduced risk of acute myocardial infarction in women (hazard ratio, 0.19; 95% confidence interval, 0.06–0.56;
P
=0.002 for the highest versus the lowest tertile of Th2 cells). Moreover, release of the Th2 cytokine interleukin-4 from activated mononuclear leukocytes was independently associated with a reduced risk of CVD. No independent associations between Th1 cells and carotid intima-media thickness or CVD risk were found.

Conclusion—

Our observations provide the first clinical evidence for a protective role of Th2 immunity in CVD. They also suggest this protection is more prominent in women than in men. In spite of convincing evidence from experimental studies, we found no support for a role of Th1 immunity in CVD.
In Vivo Suppression of MicroRNA-24 Prevents the Transition Toward Decompensated Hypertrophy in Aortic-Constricted Mice
Authors: Li Rong-Chang , Tao Jin , Guo Yun-Bo , Wu Hao-Di , Liu Rui-Feng , Bai Yan , Lv Zhi-Zhen , Luo Guan-Zheng , Li Lin-Lin , Wang Meng , Yang Hua-Qian , Gao Wei , Han Qi-De , Zhang You-Yi , Wang Xiu-Jie , Xu Ming , Wang Shi-Qiang
Published: January 2013

Rationale:

During the transition from compensated hypertrophy to heart failure, the signaling between L-type Ca
2+
channels in the cell membrane/T-tubules and ryanodine receptors in the sarcoplasmic reticulum becomes defective, partially because of the decreased expression of a T-tubule–sarcoplasmic reticulum anchoring protein, junctophilin-2. MicroRNA (miR)-24, a junctophilin-2 suppressing miR, is upregulated in hypertrophied and failing cardiomyocytes.

Objective:

To test whether miR-24 suppression can protect the structural and functional integrity of L-type Ca
2+
channel–ryanodine receptor signaling in hypertrophied cardiomyocytes.

Methods and Results:

In vivo silencing of miR-24 by a specific antagomir in an aorta-constricted mouse model effectively prevented the degradation of heart contraction, but not ventricular hypertrophy. Electrophysiology and confocal imaging studies showed that antagomir treatment prevented the decreases in L-type Ca
2+
channel–ryanodine receptor signaling fidelity/efficiency and whole-cell Ca
2+
transients. Further studies showed that antagomir treatment stabilized junctophilin-2 expression and protected the ultrastructure of T-tubule–sarcoplasmic reticulum junctions from disruption.

Conclusions:

MiR-24 suppression prevented the transition from compensated hypertrophy to decompensated hypertrophy, providing a potential strategy for early treatment against heart failure.
Essential and Unexpected Role of Yin Yang 1 to Promote Mesodermal Cardiac Differentiation
Authors: Gregoire Serge , Karra Ravi , Passer Derek , Deutsch Marcus-André , Krane Markus , Feistritzer Rebecca , Sturzu Anthony , Domian Ibrahim , Saga Yumiko , Wu Sean M.
Published: January 2013

Rationale:

Cardiogenesis is regulated by a complex interplay between transcription factors. However, little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs).

Objective:

To identify novel regulators of mesodermal cardiac lineage commitment.

Methods and Results:

We performed a bioinformatic-based transcription factor binding site analysis on upstream promoter regions of genes that are enriched in embryonic stem cell–derived CPCs. From 32 candidate transcription factors screened, we found that Yin Yang 1 (YY1), a repressor of sarcomeric gene expression, is present in CPCs in vivo. Interestingly, we uncovered the ability of YY1 to transcriptionally activate Nkx2.5, a key marker of early cardiogenic commitment. YY1 regulates Nkx2.5 expression via a 2.1-kb cardiac-specific enhancer as demonstrated by in vitro luciferase-based assays, in vivo chromatin immunoprecipitation, and genome-wide sequencing analysis. Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with Gata4 at a nearby chromatin. Cardiac mesoderm–specific loss-of-function of YY1 resulted in early embryonic lethality. This was corroborated in vitro by embryonic stem cell–based assays in which we showed that the overexpression of YY1 enhanced the cardiogenic differentiation of embryonic stem cells into CPCs.

Conclusions:

These results demonstrate an essential and unexpected role for YY1 to promote cardiogenesis as a transcriptional activator of Nkx2.5 and other CPC-enriched genes.
Effect of Low-Dose Aspirin on Functional Outcome From Cerebral Vascular Events in Women
Authors: Rist Pamela M. , Buring Julie E. , Kase Carlos S. , Kurth Tobias
Published: January 2013

Background and Purpose—

Although aspirin is effective in prevention of stroke, fewer studies have examined the impact of aspirin on stroke morbidity.

Methods—

The Women’s Health Study is a completed randomized, placebo-controlled trial designed to test the effect of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer, which enrolled 39 876 women. We used multinomial logistic regression to evaluate the relationship between randomized aspirin assignment and functional outcomes from stroke. Possible functional outcomes were neither stroke nor transient ischemic attack (TIA), modified Rankin scale (mRS) score 0 to 1, 2 to 3, and 4 to 6.

Results—

After a mean of 9.9 years of follow-up, 460 confirmed strokes (366 ischemic, 90 hemorrhagic, and 4 unknown type) and 405 confirmed TIAs occurred. With regard to total and ischemic stroke, women who were randomized to aspirin had a nonsignificant decrease in risk of any outcome compared to women not randomized to aspirin. This decrease in risk only reached statistical significance for those experiencing TIA compared to participants without stroke or TIA (odds ratio=0.77; 95% confidence interval, 0.63–0.94). For hemorrhagic stroke, a nonsignificant increase in the risk of achieving an mRS score 2 to 3 or 4 to 6 compared with no stroke or TIA was observed for the women randomized to aspirin compared to those randomized to placebo.

Conclusions—

Results from this large randomized clinical trial provide evidence that 100 mg of aspirin every other day may reduce the risk of ischemic cerebral vascular events but does not have differential effects on functional outcomes from stroke.