bluuebunny/crossref_metadata_2025 huggingface dataset:
On understanding the energy consumption of ARM-based multicore servers
Authors: Tudor Bogdan Marius , Teo Yong Meng
Published: June 2013

There is growing interest to replace traditional servers with low-power multicore systems such as ARM Cortex-A9. However, such systems are typically provisioned for mobile applications that have lower memory and I/O requirements than server application. Thus, the impact and extent of the imbalance between application and system resources in exploiting energy efficient execution of server workloads is unclear. This paper proposes a trace-driven analytical model for understanding the energy performance of server workloads on ARM Cortex-A9 multicore systems. Key to our approach is the modeling of the degrees of CPU core, memory and I/O resource overlap, and in estimating the number of cores and clock frequency that optimizes energy performance without compromising execution time. Since energy usage is the product of utilized power and execution time, the model first estimates the execution time of a program. CPU time, which accounts for both cores and memory response time, is modeled as an M/G/1 queuing system. Workload characterization of high performance computing, web hosting and financial computing applications shows that bursty memory traffic fits a Pareto distribution, and non-bursty memory traffic is exponentially distributed. Our analysis using these server workloads reveals that not all server workloads might benefit from higher number of cores or clock frequencies. Applying our model, we predict the configurations that increase energy efficiency by 10% without turning off cores, and up to one third with shutting down unutilized cores. For memory-bounded programs, we show that the limited memory bandwidth might increase both execution time and energy usage, to the point where energy cost might be higher than on a typical x64 multicore system. Lastly, we show that increasing memory and I/O bandwidth can improve both the execution time and the energy usage of server workloads on ARM Cortex-A9 systems.
Data center demand response
Authors: Liu Zhenhua , Wierman Adam , Chen Yuan , Razon Benjamin , Chen Niangjun
Published: June 2013

Demand response is a crucial aspect of the future smart grid. It has the potential to provide significant peak demand reduction and to ease the incorporation of renewable energy into the grid. Data centers' participation in demand response is becoming increasingly important given the high and increasing energy consumption and the flexibility in demand management in data centers compared to conventional industrial facilities. In this extended abstract we briefly describe recent work in our full paper on two demand response schemes to reduce a data center's peak loads and energy expenditure: workload shifting and the use of local power generations. In our full paper, we conduct a detailed characterization study of coincident peak data over two decades from Fort Collins Utilities, Colorado and then develop two algorithms for data centers by combining workload scheduling and local power generation to avoid the coincident peak and reduce the energy expenditure. The first algorithm optimizes the expected cost and the second one provides a good worst-case guarantee for any coincident peak pattern. We evaluate these algorithms via numerical simulations based on real world traces from production systems. The results show that using workload shifting in combination with local generation can provide significant cost savings (up to 40% in the Fort Collins Utilities' case) compared to either alone.
FaRNet
Authors: Paredes-Oliva Ignasi , Barlet-Ros Pere , Dimitropoulos Xenofontas
Published: June 2013

Extracting knowledge from big network traffic data is a matter of foremost importance for multiple purposes ranging from trend analysis or network troubleshooting to capacity planning or traffic classification. An extremely useful approach to profile traffic is to extract and display to a network administrator the multi-dimensional hierarchical heavy hitters (HHHs) of a dataset. However, existing schemes for computing HHHs have several limitations: 1) they require significant computational overhead; 2) they do not scale to high dimensional data; and 3) they are not easily extensible. In this paper, we introduce a fundamentally new approach for extracting HHHs based on generalized frequent item-set mining (FIM), which allows to process traffic data much more efficiently and scales to much higher dimensional data than present schemes. Based on generalized FIM, we build and evaluate a traffic profiling system we call FaRNet. Our comparison with AutoFocus, which is the most related tool of similar nature, shows that FaRNet is up to three orders of magnitude faster.
Firming solar power
Authors: Ghiassi-Farrokhfal Yashar , Keshav Srinivasan , Rosenberg Catherine , Ciucu Florin
Published: June 2013

The high variability of solar power due to intrinsic diurnal variability, as well as additional stochastic variations due to cloud cover, have made it difficult for solar farms to participate in electricity markets that require pre-committed constant power generation. We study the use of battery storage to 'firm' solar power, that is, to remove variability so that such a pre-commitment can be made. Due to the high cost of storage, it is necessary to size the battery parsimoniously, choosing the minimum size to meet a certain reliability guarantee. Inspired by recent work that identifies an isomorphism between batteries and network buffers, we introduce a new model for solar power generation that models it as a stochastic traffic source. This permits us to use techniques from the stochastic network calculus to both size storage and to maximize the revenue that a solar farm owner can make from the day-ahead power market. Using a 10-year of recorded solar irradiance, we show that our approach attains 93% of the maximum revenue in a summer day that would have been achieved in daily market had the entire solar irradiance trace been known ahead of time.
Web performance bottlenecks in broadband access networks
Authors: Sundaresan Srikanth , Magharei Nazanin , Feamster Nick , Teixeira Renata , Crawford Sam
Published: June 2013

We present the first large-scale analysis of Web performance bottlenecks as measured from broadband access networks, using data collected from extensive home router deployments. We analyze the limits of throughput on improving Web performance and identify the contribution of critical factors such as DNS lookups and TCP connection establishment to Web page load times. We find that, as broadband speeds continue to increase, other factors such as TCP connection setup time, server response time, and network latency are often dominant performance bottlenecks. Thus, realizing a "faster Web" requires not only higher download throughput, but also optimizations to reduce both client and server-side latency.
Parallel scaling properties from a basic block view
Authors: Kambadur Melanie , Tang Kui , Lopez Joshua , Kim Martha A.
Published: June 2013

As software scalability lags behind hardware parallelism, understanding scaling behavior is more important than ever. This paper demonstrates how to use Parallel Block Vector (PBV) profiles to measure the scaling properties of multithreaded programs from a new perspective: the basic block's view. Through this lens, we guide users through quick and simple methods to produce high-resolution application scaling analyses. This method requires no manual program modification, new hardware, or lengthy simulations, and captures the impact of architecture, operating systems, threading models, and inputs. We apply these techniques to a set of parallel benchmarks, and, as an example, demonstrate that when it comes to scaling, functions in an application do not behave monolithically.
Computational analysis of cascading failures in power networks
Authors: Mazauric Dorian , Soltan Saleh , Zussman Gil
Published: June 2013

This paper focuses on cascading line failures in the transmission system of the power grid. Such a cascade may have a devastating effect not only on the power grid but also on the interconnected communication networks. Recent large-scale power outages demonstrated the limitations of epidemic- and percolation-based tools in modeling the cascade evolution. Hence, based on a linearized power flow model (that substantially differs from the classical packet flow models), we obtain results regarding the various properties of a cascade. Specifically, we consider performance metrics such as the the distance between failures, the length of the cascade, and the fraction of demand (load) satisfied after the cascade. We show, for example, that due to the unique properties of the model: (i) the distance between subsequent failures can be arbitrarily large and the cascade may be arbitrarily long, (ii) a large set of initial line failures may have a smaller effect than a failure of one of the lines in the set, and (iii) minor changes to the network parameters may have a significant impact. Moreover, we show that finding the set of lines whose removal has the most significant impact (under various metrics) is NP-Hard. Moreover, we develop a fast algorithm to recompute the flows at each step of the cascade. The results can provide insight into the design of smart grid measurement and control algorithms that can mitigate a cascade.
A first look at cellular network performance during crowded events
Authors: Shafiq Muhammad Zubair , Ji Lusheng , Liu Alex X. , Pang Jeffrey , Venkataraman Shobha , Wang Jia
Published: June 2013

During crowded events, cellular networks face voice and data traffic volumes that are often orders of magnitude higher than what they face during routine days. Despite the use of portable base stations for temporarily increasing communication capacity and free Wi-Fi access points for offloading Internet traffic from cellular base stations, crowded events still present significant challenges for cellular network operators looking to reduce dropped call events and improve Internet speeds. For effective cellular network design, management, and optimization, it is crucial to understand how cellular network performance degrades during crowded events, what causes this degradation, and how practical mitigation schemes would perform in real-life crowded events. This paper makes a first step towards this end by characterizing the operational performance of a tier-1 cellular network in the United States during two high-profile crowded events in 2012. We illustrate how the changes in population distribution, user behavior, and application workload during crowded events result in significant voice and data performance degradation, including more than two orders of magnitude increase in connection failures. Our findings suggest two mechanisms that can improve performance without resorting to costly infrastructure changes: radio resource allocation tuning and opportunistic connection sharing. Using trace-driven simulations, we show that more aggressive release of radio resources via 1-2 seconds shorter RRC timeouts as compared to routine days helps to achieve better tradeoff between wasted radio resources, energy consumption, and delay during crowded events; and opportunistic connection sharing can reduce connection failures by 95% when employed by a small number of devices in each cell sector.
Reuse-based online models for caches
Authors: Sen Rathijit , Wood David A.
Published: June 2013

We develop a reuse distance/stack distance based analytical modeling framework for efficient, online prediction of cache performance for a range of cache configurations and replacement policies LRU, PLRU, RANDOM, NMRU. Our framework unifies existing cache miss rate prediction techniques such as Smith's associativity model, Poisson variants, and hardware way-counter based schemes. We also show how to adapt LRU way-counters to work when the number of sets in the cache changes. As an example application, we demonstrate how results from our models can be used to select, based on workload access characteristics, last-level cache configurations that aim to minimize energy-delay product.
Queueing system topologies with limited flexibility
Authors: Tsitsiklis John N. , Xu Kuang
Published: June 2013

We study a multi-server model with n
flexible
servers and rn queues, connected through a fixed bipartite graph, where the level of flexibility is captured by the average degree, d(n), of the queues. Applications in content replication in data centers, skill-based routing in call centers, and flexible supply chains are among our main motivations. We focus on the scaling regime where the system size n tends to infinity, while the overall traffic intensity stays fixed. We show that a large capacity region (robustness) and diminishing queueing delay (performance) are jointly achievable even under very limited flexibility (d(n) l n). In particular, when d(n) gg ln n , a family of random-graph-based interconnection topologies is (with high probability) capable of stabilizing all admissible arrival rate vectors (under a bounded support assumption), while simultaneously ensuring a diminishing queueing delay, of order ln n/ d(n), as n-> ∞. Our analysis is centered around a new class of virtual-queue-based scheduling policies that rely on dynamically constructed partial matchings on the connectivity graph.
Defragmenting the cloud using demand-based resource allocation
Authors: Shanmuganathan Ganesha , Gulati Ajay , Varman Peter
Published: June 2013

Current public cloud offerings sell capacity in the form of pre-defined virtual machine (VM) configurations to their tenants. Typically this means that tenants must purchase individual VM configurations based on the peak demands of the applications, or be restricted to only scale-out applications that can share a pool of VMs. This diminishes the value proposition of moving to a public cloud as compared to server consolidation in a private virtualized datacenter, where one gets the benefits of statistical multiplexing between VMs belonging to the same or different applications. Ideally one would like to enable a cloud tenant to buy capacity in bulk and benefit from statistical multiplexing among its workloads. This requires the purchased capacity to be dynamically and transparently allocated among the tenant's VMs that may be running on different servers, even across datacenters. In this paper, we propose two novel algorithms called BPX and DBS that are able to provide the cloud customer with the abstraction of buying bulk capacity. These algorithms dynamically allocate the bulk capacity purchased by a customer between its VMs based on their individual demands and user-set importance. Our algorithms are highly scalable and are designed to work in a large-scale distributed environment. We implemented a prototype of BPX as part of VMware's management software and showed that BPX is able to closely mimic the behavior of a centralized allocator in a distributed manner.
Designing large-scale nudge engines
Authors: Prabhakar Balaji
Published: June 2013

In many of the challenges faced by the modern world, from overcrowded transportation systems to overstretched healthcare systems, large benefits for society come about from small changes by very many individuals. We survey the problems and the cost they impose on society, and describe a framework for designing "nudge engines"---algorithms, incentives and technology for influencing human behavior. We present a model for analyzing their effectiveness and results from transportation pilots conducted in Bangalore, at Stanford and in Singapore, and a wellness program for the employees of Accenture-USA.
Challenges in cloud scale data centers
Authors: Maltz David A.
Published: June 2013

Data centers are fascinating places, where the massive scale required to deliver on-line services like web search and cloud hosting turns minor issues into major challenges that must be addressed in the design of the physical infrastructure and the software platform. In this talk, I'll briefly overview the kinds of applications that run in mega-data centers and the workloads they place on the infrastructure. I'll then describe a number of challenges seen in Microsoft's data centers, with the goals of posing questions more than describing solutions and explaining how economic factors, technology issues, and software design interact when creating low-latency, low-cost, high availability services.
Tutorial on geo-replication in data center applications
Authors: Aguilera Marcos K.
Published: June 2013

Data center applications increasingly require a *geo-replicated* storage system, that is, a storage system replicated across many geographic locations. Geo-replication can reduce access latency, improve availability, and provide disaster tolerance. It turns out there are many techniques for geo-replication with different trade-offs. In this tutorial, we give an overview of these techniques, organized according to two orthogonal dimensions: level of synchrony (synchronous and asynchronous) and type of storage service (read-write, state machine, transaction). We explain the basic idea of these techniques, together with their applicability and trade-offs.
Multipath TCP algorithms
Authors: Peng Qiuyu , Walid Anwar , Low Steven H.
Published: June 2013

Multi-path TCP (MP-TCP) has the potential to greatly improve application performance by using multiple paths transparently. We propose a fluid model for a large class of MP-TCP algorithms and identify design criteria that guarantee the existence, uniqueness, and stability of system equilibrium. We characterize algorithm parameters for TCP-friendliness and prove an inevitable tradeoff between responsiveness and friendliness. We discuss the implications of these properties on the behavior of existing algorithms and motivate a new design that generalizes existing algorithms. We use ns2 simulations to evaluate the proposed algorithm and illustrate its superior overall performance.
Characterizing and modeling the impact of wireless signal strength on smartphone battery drain
Authors: Ding Ning , Wagner Daniel , Chen Xiaomeng , Pathak Abhinav , Hu Y. Charlie , Rice Andrew
Published: June 2013

Despite the tremendous market penetration of smartphones, their utility has been and will remain severely limited by their battery life. A major source of smartphone battery drain is accessing the Internet over cellular or WiFi connection when running various apps and services. Despite much anecdotal evidence of smartphone users experiencing quicker battery drain in poor signal strength, there has been limited understanding of how often smartphone users experience poor signal strength and the quantitative impact of poor signal strength on the phone battery drain. The answers to such questions are essential for diagnosing and improving cellular network services and smartphone battery life and help to build more accurate online power models for smartphones, which are building blocks for energy profiling and optimization of smartphone apps. In this paper, we conduct the first measurement and modeling study of the impact of wireless signal strength on smartphone energy consumption. Our study makes four contributions. First, through analyzing traces collected on 3785 smartphones for at least one month, we show that poor signal strength of both 3G and WiFi is routinely experienced by smartphone users, both spatially and temporally. Second, we quantify the extra energy consumption on data transfer induced by poor wireless signal strength. Third, we develop a new power model for WiFi and 3G that incorporates the signal strength factor and significantly improves the modeling accuracy over the previous state of the art. Finally, we perform what-if analysis to quantify the potential energy savings from opportunistically delaying network traffic by exploring the dynamics of signal strength experienced by users.
Elastic paging
Authors: Peserico Enoch
Published: June 2013

We study a generalization of the classic paging problem where memory capacity can vary over time - a property of many modern computing realities, from cloud computing to multi-core and energy-optimized processors. We show that good performance in the "classic" case provides no performance guarantees when memory capacity fluctuates: roughly speaking, moving from static to dynamic capacity can mean the difference between optimality within a factor 2 in space, time and energy, and suboptimality by an arbitrarily large factor. Surprisingly, several classic paging algorithms still perform remarkably well, maintaining that factor 2 optimality even if faced with adversarial capacity fluctuations - without taking those fluctuations into explicit account!
Microbial Contributions to Phosphorus Cycling in Eutrophic Lakes and Wastewater
Authors: McMahon Katherine D. , Read Emily K.
Published: June 2013

Phosphorus is a key element controlling the productivity of freshwater ecosystems, and microbes drive most of its relevant biogeochemistry. Eutrophic lakes are generally dominated by cyanobacteria that compete fiercely with algae and heterotrophs for the element. In wastewater treatment, engineers select for specialized bacteria capable of sequestering phosphorus from the water, to protect surface waters from further loading. The intracellular storage molecule polyphosphate plays an important role in both systems, allowing key taxa to control phosphorus availability. The importance of dissolved organic phosphorus in eutrophic lakes and mineralization mechanisms is still underappreciated and understudied. The need for functional redundancy through biological diversity in wastewater treatment plants is also clear. In both systems, a holistic ecosystems biology approach is needed to understand the molecular mechanisms controlling phosphorus metabolism and the ecological interactions and factors controlling ecosystem-level process rates.
Leaf Epidermis of the Rheophyte Dyckia brevifolia Baker (Bromeliaceae)
Authors: Lobo Ghislaine Maria , de Souza Thaysi Ventura , Voltolini Caroline Heinig , Reis Ademir , Santos Marisa
Published: June 2013

Some species of Dyckia Schult. f., including Dyckia brevifolia Baker, are rheophytes that live in the fast‐moving water currents of streams and rivers which are subject to frequent flooding, but also period of low water. This study aimed to analyze the leaf epidermis of D. brevifolia in the context of epidermal adaptation to this aquatic plant’s rheophytic habitat. The epidermis is uniseriate, and the cuticle is thickened. The inner periclinal and anticlinal walls of the epidermal cells are thickened and lignified. Stomata are tetracytic, located in the depressions in relation to the surrounding epidermal cells, and covered by peltate trichomes. While the epidermal characteristics of D. brevifolia are similar to those of Bromeliaceae species, this species has made particular adaptations of leaf epidermis in response to its rheophytic environment.
Observability of Nonlinear Fractional Dynamical Systems
Authors: Balachandran K. , Govindaraj V. , Rivero M. , Tenreiro Machado J. A. , Trujillo J. J.
Published: June 2013

We study the observability of linear and nonlinear fractional differential systems of order0<α<1by using the Mittag-Leffler matrix function and the application of Banach’s contraction mapping theorem. Several examples illustrate the concepts.
Amniotic Fluid or Its Fatty Acids Produce Actions Similar to Diazepam on Lateral Septal Neurons Firing Rate
Authors: Gutiérrez-García Ana G. , Contreras Carlos M. , Vásquez-Hernández Diana Idania
Published: June 2013

Human amniotic fluid (AF) contains eight fatty acids (FATs), and both produce anxiolytic‐like effects in adult rats and appetitive responses in human newborns. The medial amygdala and lateral septal nucleus function are related to social behavior, but the action of AF or its FATs in this circuit is known. We obtained 267 single‐unit extracellular recordings in Wistar rats treated with vehicle (1 mL, s.c.; n = 12), human AF (1 mL, s.c.; n = 12), a FAT mixture (1 mL, s.c.; n = 13), diazepam (1 mg/kg, i.p.; n = 11), and fluoxetine (1 mg/kg, p.o.; n = 12). Compared with the vehicle group, the spontaneous septal firing rate in the AF, FAT mixture, and diazepam groups was the lowest and in the fluoxetine group the highest. Cumulative peristimulus histograms indicated that the significant change in septal firing occurred only in the AF and FAT mixture groups and exclusively in those neurons that increased their firing rate during amygdala stimulation. We conclude that human AF and its FATs produce actions comparable to anxiolytic drugs and are able to modify the responsivity of a circuit involved in social behavior, suggesting facilitation of social recognition processes by maternal‐fetal fluids.
Solvent‐Dependent Self‐Assembly of 4,7‐Dibromo‐5,6‐bis(octyloxy)benzo[c][1,2,5] Thiadiazole on Graphite Surface by Scanning Tunneling Microscopy
Authors: Zha Bao , Miao Xinrui , Li Yijing , Liu Pei , Miao Kai , Deng Wenli
Published: June 2013

Solvent effect on self‐assembly of 4,7‐dibromo‐5,6‐bis(octyloxy)benzo[c][1,2,5] thiadiazole (DBT) on a highly oriented graphite (HOPG) surface was investigated by scanning tunneling microscopy (STM) by using 1‐phenyloctane, 1‐octanoic acid, and 1‐octanol as the solvents. Two different patterns were obtained in 1‐phenyloctane and 1‐octanoic acid, suggesting that the self‐assembly of DBT was solvent dependent. At the 1‐phenyloctane/HOPG interface, a linear structure was revealed due to the intermolecular halogen bonding. When 1‐octanoic acid and 1‐octanol are used as the solvents, the coadsorption of solvent molecules resulting from the hydrogen bonding between DBT and solvent made an important contribution to the formation of a lamellar structure. The results demonstrate that solvents could affect the molecular self‐assembly according to the variational intermolecular interactions.
Intraocular Microsurgical Forceps (20, 23, and 25 gauge) Membrane Peeling Forces Assessment
Authors: Velez-Montoya Raul , Patel Chirag , Oliver Scott C. N. , Quiroz-Mercado Hugo , Mandava Naresh , Olson Jeffrey L.
Published: June 2013

Background. To assess the peeling forces exerted by different calibers of microsurgical forceps on an experimental model of epiretinal membrane.Methods. A model of epiretinal membrane was constructed using thin cellulose paper and heptanes-isopropyl alcohol 1% mixture. The model was mounted on a force censoring device. Subsequently, flaps were created with three different microsurgical forceps of different calibers. We recorded the number of attempts, the duration of the event, and the pushing and the pulling forces during the peeling. The results were compared by a one-way ANOVA and a Fisher unprotected least significant difference test with an alpha value of 0.05 for statistically significance.Results. There was a statistical significant difference on the pulling and pushing forces between the 25 gauge (13.79 mN; −13.27 mN) and the 23 (6.63 mN; −5.76 mN) and 20 (5.02 mN; −5.30 mN) gauge, being greater in the first (P<0.001). There were no differences in the duration of all events, meaning that all the forces were measured within the same period of time.Conclusions. The 25 gauge microsurgical forceps exerted the greatest mechanical stress over our simulated epiretinal membrane model and required more attempts to create a surgical suitable flap. The clinical implication of this finding is still to be determined.
Noninvasive Strategies to Promote Functional Recovery after Stroke
Authors: Faralli Alessio , Bigoni Matteo , Mauro Alessandro , Rossi Ferdinando , Carulli Daniela
Published: June 2013

Stroke is a common and disabling global health-care problem, which is the third most common cause of death and one of the main causes of acquired adult disability in many countries. Rehabilitation interventions are a major component of patient care. In the last few years, brain stimulation, mirror therapy, action observation, or mental practice with motor imagery has emerged as interesting options as add-on interventions to standard physical therapies. The neural bases for poststroke recovery rely on the concept of plasticity, namely, the ability of central nervous system cells to modify their structure and function in response to external stimuli. In this review, we will discuss recent noninvasive strategies employed to enhance functional recovery in stroke patients and we will provide an overview of neural plastic events associated with rehabilitation in preclinical models of stroke.
Hemiparesis after Operation of Astrocytoma Grade II in Adults: Effects of Acupuncture on Sensory-Motor Behavior and Quality of Life
Authors: Yu Haibo , Schröder Sven , Liu Yongfeng , Li Zhifeng , Yang Ying , Chen Yu , Huang Xingxian
Published: June 2013

To evaluate the effect of acupuncture on hemiparesis and quality of life for adults with brain astrocytoma grade II, we conducted a randomized, observer-blinded clinical trial. Fifty-eight patients were randomized tostandard rehabilitation (SR) therapy without acupuncture(n=20),SR plus standard acupuncture (SA)(n=19), andSR plus individualized acupuncture (IA)(n=19). SA points werePC6,SP6,HT1,LU5,BL40, andST36, while a special concept called “connecting and regulation Ren and Du” and “Jin-3-needling” served as IA. This treatment was individualized according to the clinical syndrome. The outcome was measured by the Barthel Index (BI), the Fugl-Meyer scale (FM), and the EORTC Core Quality of Life Questionnaire (QLQ-C30) with the Brain Cancer Module (BCM20). IA + SR reached significantly higher BI scores than SA + SR, which reached significantly higher BI scores than SR. IA + SR was significantly superior to SA + SR and to SR at the 8th week for the scores of FM motor and sensory assessments and most QLQ-C30-BCM20 items. In conclusion, the individualized acupuncture concept of “connecting and regulating Ren and Du” combined with “Jin-3-needling” offers a promising possibility for the treatment of hemiparesis due to astrocytoma, but further evaluation is mandatory.
A Sequence Polymorphism in miR-608 Predicts Recurrence after Radiotherapy for Nasopharyngeal Carcinoma
Authors: Zheng Jian , Deng Jieqiong , Xiao Mang , Yang Lei , Zhang Liyuan , You Yonghe , Hu Min , Li Na , Wu Hongchun , Li Wei , Lu Jiachun , Zhou Yifeng
Published: June 2013

Nasopharyngeal carcinoma is treated with radiotherapy and other modalities, but there is little information on individual genetic factors to help predict and improve patient outcomes. Single-nucleotide polymorphisms (SNP) in mature microRNA (miRNA) sequences have the potential to exert broad impact as miRNAs target many mRNAs. The aim of this study was to evaluate the effects of SNPs in mature miRNA sequences on clinical outcome in patients with nasopharyngeal carcinoma receiving radiotherapy. In particular, we analyzed associations between seven SNPs and nasopharyngeal carcinoma locoregional recurrence (LRR) in 837 patients from eastern China, validating the findings in an additional 828 patients from southern China. We found that miR-608 rs4919510C>G exhibited a consistent association with LRR in the discovery set [HR, 2.05; 95% confidence interval (CI), 1.35–3.21], the validation set (HR, 2.24; 95% CI, 1.45–3.38), and the combined dataset (HR, 2.08; 95% CI, 1.41–3.26). Biochemical investigations showed that rs4919510C>G affects expression of miR-608 target genes along with nasopharyngeal carcinoma cell growth after irradiation in vivo and in vitro. Notably, X-ray radiation induced more chromatid breaks in lymphocyte cells from rs4919510CC carriers than in those from subjects with other genotypes (P = 0.0024). Our findings reveal rs4919510C>G in miR-608 as a simple marker to predict LRR in patients with radiotherapy-treated nasopharyngeal carcinoma. Cancer Res; 73(16); 5151–62. ©2013 AACR.
Colorectal Cancer Screening with Blood-Based Biomarkers: Cost-Effectiveness of Methylated Septin 9 DNA versus Current Strategies
Authors: Ladabaum Uri , Allen John , Wandell Michael , Ramsey Scott
Published: June 2013

Background: Screening reduces colorectal cancer mortality, but many persons remain unscreened. Screening with a blood test could improve screening rates. We estimated the comparative effectiveness and cost-effectiveness of colorectal cancer screening with emerging biomarkers, illustrated by a methylated Septin 9 DNA plasma assay (mSEPT9), versus established strategies.

Methods: We conducted a cost-utility analysis using a validated decision analytic model comparing mSEPT9, fecal occult blood testing (FOBT), fecal immunochemical testing (FIT), sigmoidoscopy, and colonoscopy, projecting lifetime benefits and costs.

Results: In the base case, mSEPT9 decreased colorectal cancer incidence by 35% to 41% and colorectal cancer mortality by 53% to 61% at costs of $8,400 to $11,500/quality-adjusted life year gained versus no screening. All established screening strategies were more effective than mSEPT9. FIT was cost saving, dominated mSEPT9, and was preferred among all the alternatives. Screening uptake and longitudinal adherence rates over time strongly influenced the comparisons between strategies. At the population level, mSEPT9 yielded incremental benefit at acceptable costs when it increased the fraction of the population screened more than it was substituted for other strategies.

Conclusions: m SEPT9 seems to be effective and cost-effective compared with no screening. To be cost-effective compared with established strategies, mSEPT9 or blood-based biomarkers with similar test performance characteristics would need to achieve substantially higher uptake and adherence rates than the alternatives. It remains to be proven whether colorectal cancer screening with a blood test can improve screening uptake or long-term adherence compared with established strategies.

Impact: Our study offers insights into the potential role of colorectal cancer screening with blood-based biomarkers. Cancer Epidemiol Biomarkers Prev; 22(9); 1567–76. ©2013 AACR.
Molecular Pathways: YAP and TAZ Take Center Stage in Organ Growth and Tumorigenesis
Authors: Piccolo Stefano , Cordenonsi Michelangelo , Dupont Sirio
Published: June 2013

The evolution of a solid tumor is fueled by genetic aberrations. Yet, the tumor environment often dominates over the effects of genetics: normal tissues have powerful tumor-suppressive properties that constantly tame or eliminate cells carrying transforming mutations. Critical elements of such a suppressive microenvironment are structural characteristics of normal cells and tissues, such as cell polarity, attachment to the extracellular matrix (ECM), and epithelial organization. Once these tissue-level checkpoints have been overcome, tumor growth is enhanced by recruitment of stromal cells and remodeling of the ECM. Genetic inactivation in mouse models indicates the Hippo pathway as a fundamental inhibitor of organ growth during development and as a critical tumor suppressor in epithelial tissues, such as the liver, skin, and ovaries, and soft tissues. At the centerpiece of this pathway lie two related transcriptional coactivators, YAP and TAZ, that promote tissue proliferation and the self-renewal of normal and cancer stem cells, and incite metastasis. Strikingly, YAP and TAZ are controlled by the same architectural features that first inhibit and then foster cancer growth, such as ECM elasticity, cell shape, and epithelial-to-mesenchymal transition. These findings open unexpected opportunities for the development of new cancer therapeutics targeting key YAP/TAZ regulatory inputs such as Wnt signaling, cytoskeletal contractility, G-protein–coupled receptors, or YAP/TAZ-regulated transcription. Clin Cancer Res; 19(18); 4925–30. ©2013 AACR.
Identification of Circulating MicroRNA Signatures for Breast Cancer Detection
Authors: Chan Maurice , Liaw Chiew Suan , Ji Shen Mo , Tan Hwee Huang , Wong Chow Yin , Thike Aye Aye , Tan Puay Hoon , Ho Gay Hui , Lee Ann Siew-Gek
Published: June 2013

Purpose: There is a quest for novel noninvasive diagnostic markers for the detection of breast cancer. The goal of this study is to identify circulating microRNA (miRNA) signatures using a cohort of Asian Chinese patients with breast cancer, and to compare miRNA profiles between tumor and serum samples.

Experimental Design: miRNA from paired breast cancer tumors, normal tissue, and serum samples derived from 32 patients were comprehensively profiled using microarrays or locked nucleic acid real-time PCR panels. Serum samples from healthy individuals (n = 22) were also used as normal controls. Significant serum miRNAs, identified by logistic regression, were validated in an independent set of serum samples from patients (n = 132) and healthy controls (n = 101).

Results: The 20 most significant miRNAs differentially expressed in breast cancer tumors included miRNA (miR)-21, miR-10b, and miR-145, previously shown to be dysregulated in breast cancer. Only 7 miRNAs were overexpressed in both tumors and serum, suggesting that miRNAs may be released into the serum selectively. Interestingly, 16 of the 20 most significant miRNAs differentially expressed in serum samples were novel. MiR-1, miR-92a, miR-133a, and miR-133b were identified as the most important diagnostic markers, and were successfully validated; receiver operating characteristic curves derived from combinations of these miRNAs exhibited areas under the curves of 0.90 to 0.91.

Conclusion: The clinical use of miRNA signatures as a noninvasive diagnostic strategy is promising, but should be further validated for different subtypes of breast cancers. Clin Cancer Res; 19(16); 4477–87. ©2013 AACR.
Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities
Authors: Cairns Rob A. , Mak Tak W.
Published: June 2013

Heterozygous mutations in catalytic arginine residues of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are common in glioma, acute myeloid leukemia, chondrosarcoma, cholangiocarcinoma, and angioimmunoblastic T-cell lymphoma. The mutant enzymes acquire a neomorphic activity that converts α-ketoglutarate (α-KG) to D-2-hydroxyglutarate (D2HG), a rare metabolite. In cells and tissues expressing mutant IDH, D2HG concentrations are highly elevated. D2HG may act as an “oncometabolite” by inhibiting a class of α-KG–dependent enzymes involved in epigenetic regulation, collagen synthesis, and cell signaling. Knock-in mouse models of IDH1 mutations have shed light on these mechanisms and will provide valuable animal models for further investigation.

Significance: Mutations in IDH1 and IDH2 promote the development of a number of malignancies. These active site mutations cause a gain-of-function leading to the accumulation of the rare metabolite D2HG. Mouse models of these mutations should provide insights into the mechanisms driving tumorigenesis and facilitate evaluation of new treatments. Cancer Discov; 3(7); 730–41. ©2013 AACR.
A Pilot Study of Training and Compensation Interventions for Mild Cognitive Impairment
Authors: Konsztowicz Susanna , Anton Jerine , Crane Joelle , Moafmashhadi Parastoo , Koski Lisa
Published: June 2013

Background: This pilot clinical trial sought to estimate the feasibility and efficacy of two interventions aimed at improving memory performance in geriatric clinic patients with mild cognitive impairment. Methods: Fifteen participants were randomized to either a memory training group or a memory compensation group. Results: Recruitment rates were low, whereas adherence and retention rates were acceptable. The memory training group improved in self-reported memory abilities and satisfaction with memory. The memory compensation group improved on one objective memory test but showed no consistent changes on any other outcomes. Conclusion: Effect size estimates will inform the design of larger clinical trials.
Computed Tomography and Echocardiography together Reveal More High-Risk Findings than Echocardiography Alone in the Diagnostics of Stroke Etiology
Authors: Sipola Petri , Hedman Marja , Onatsu Juha , Turpeinen Anu , Halinen Matti , Jäkälä Pekka , Vanninen Ritva
Published: June 2013

Background: Cardioembolic stroke carries a major risk of stroke recurrence, which can be markedly reduced by early initiation of appropriate secondary prevention. We investigate whether combined examination of the heart, aorta, and cervicocranial arteries with computed tomography (CACC-CT) may improve the diagnosis of stroke etiology. Methods: Patients with suspected cardiogenic ischemic stroke or transient ischemic attack (n = 140; mean age 60 ± 10 years; 95 males) underwent CACC-CT and standard diagnostics including transthoracic and transesophageal echocardiography (TTE/TEE). Patients with atrial fibrillation were excluded because cardiac imaging will not affect to anticoagulant treatment. Imaging findings with a potential cardioembolic source were analyzed. Aortic and cardiac risk findings were evaluated independently. Consensus reading of 2 experts using the findings of both approaches and complemented by cardiac MRI when needed served as the reference standard. Results: In 101 patients (72%) the clinical diagnosis was stroke, and transient ischemic attack was confirmed in the remaining patients. Imaging findings associated with highly increased cardioembolic risk were detected in 22 patients (16%). Nine high-risk findings in 140 patients were found by TTE/TEE and this number rose to 25 high after performing both echocardiography and CACC-CT. No difference was found between CACC-CT and TTE/TEE in detecting patients with of at least one high-risk findings (sensitivity 68 vs. 41%, p = 0.052; specificity 98 vs. 99%; overall accuracy 94 vs. 90%). Combined use of CACC-CT and TTE/TEE was more sensitive than TTE/TEE alone for detecting patients with at least one cardiac or aortic high-risk finding (sensitivity 91 vs. 41%, p < 0.001; specificity 98 vs. 99%; overall accuracy 97 vs. 90%). TTE/TEE was insufficient for diagnosing myocardial infarction with left ventricular aneurysm, whereas the accuracy of CACC-CT was high. In 9 patients (6%) with normal or mild hypokinesia in TTE/TEE, CACC-CT and MRI showed myocardial infarction large enough to indicate anticoagulant therapy. In contrast, CACC-CT was not suitable for diagnosing small left artrial thrombi, patent foramen ovale or to measure left ventricular ejection fraction. Conclusion: CACC-CT and TTE/TEE alone show limited accuracy for the diagnostics of stroke etiology. Therefore, CACC-CT could be a valuable tool in patients with cryptogenic stroke despite standard stroke diagnostics.
Hyperperfusion Syndrome after Carotid Endarterectomy and Carotid Stenting
Authors: Buczek Julia , Karliński Michał , Kobayashi Adam , Białek Paweł , Członkowska Anna
Published: June 2013

Background: Hyperperfusion syndrome (HS) is a relatively rare but possibly serious complication of carotid revascularization procedures. Impaired cerebral autoregulation and postrevascularization changes in cerebral blood flow are the main mechanisms involved in the development of HS. Most up-to-date studies addressing this issue are retrospective and tend to concentrate on carotid endarterectomy (CEA), neglecting carotid stenting (CAS). Our aim was to compare the frequency of clinical signs of HS and hyperperfusion detected by transcranial Doppler (TCD) in patients undergoing CAS or CEA due to carotid stenosis. Methods: In this prospective observational study, we evaluated 61 patients scheduled for routine CAS or CEA. Each patient was examined by a neurologist before and after the revascularization procedure to assess the clinical status. Severe headache, ocular or facial pain, confusion, visual disturbances, epileptic seizures or any focal deficits not caused by cerebral ischemia were considered clinical signs of HS. Peak systolic velocity (PSV), end-diastolic velocity, mean velocity (MV), and pulsatility index were measured by TCD once before and twice after the intervention (within 6 h after and 2-5 days after the procedure). Hyperperfusion was defined as a >100% increase in the middle cerebral artery (MCA) blood velocity, evaluated separately for PSV and MV after the procedure compared with the baseline value. Cerebrovascular reactivity (CVR) was evaluated with a TCD acetazolamide test before the intervention. Results: CAS (n = 33) and CEA (n = 28) patients were included in the study. There was no difference between the groups in the frequency of clinical signs of HS (21.2 vs. 21.4%) and ratio of TCD hyperperfusion (12.1 vs. 14.3%). In the CAS group, ipsilateral MCA velocity significantly increased directly after the intervention and 2-5 days later, while it increased in the CEA group only 2-5 days after the intervention. The sensitivity and specificity of hyperperfusion, defined by MV, for HS signs were 38.5 and 93.8%, respectively, whereas those defined by PSV were 30.8 and 89.6%, respectively. The sensitivity and specificity of impaired CVR (<25%) for HS signs were 63.6 and 73.5%, respectively. Conclusions: There is no difference in the frequency of HS clinical signs and hyperperfusion detected by TCD between patients after CAE and CAS. Clinical signs suggested HS does not always correspond with TCD hyperperfusion. However, both the CVR test and TCD measurements of MCA velocity can help identify patients at high risk for HS.
Conservative Approach in the Treatment of Renal Trauma in Children
Authors: Pirinççi Necip , Kaba Mehmet , Geçit İlhan , Güneş Mustafa , Tanik Serhat , Ceylan Kadir
Published: June 2013

Objective: Our aim was to evaluate the role of a conservative approach in the treatment of renal trauma in the pediatric age group. Materials and Methods: A total of 31 pediatric patients with renal trauma (male = 25, female = 6) in whom we used a conservative approach in our clinic between the years 2002 and 2010 were included in the study. Patients were assessed according to the type of trauma, type of treatment, findings of radiological imaging, concomitant other organ injuries and complications occurring during follow-up. Results: Surgery was required in just 4 of 31 pediatric patients who were treated with the conservative approach. Of the patients who underwent surgery, only one child needed nephrectomy. No complications were detected in the clinical and radiological follow-up of the patients who received the conservative approach. Conclusions: The main objective in the treatment of renal trauma occurring in childhood is to protect the kidneys. If the hemodynamic findings are stable, a conservative approach should be the first preferred method of treatment in every grade of renal trauma that can occur in childhood.
Efficacy and Safety of Tadalafil Monotherapy for Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: A Meta-Analysis
Authors: Dong Yang , Hao Lin , Shi Zhenduo , Wang Gang , Zhang Zhiguo , Han Conghui
Published: June 2013

Objective: To evaluate the efficacy and safety of tadalafil monotherapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). Methods: A comprehensive search was done to identify randomized controlled trials comparing the efficacy and safety of tadalafil for LUTS/BPH with placebos. Meta-analytical techniques were applied to evaluate the differences in the study results. Results: Eight studies were identified and analyzed. Compared with placebo, tadalafil was associated with significant improvements in the International Prostate Symptom Score (IPSS) (mean difference = -2.19, p < 0.00001) and the International Index of Erectile Function (IIEF) score (mean difference = +4.66, p < 0.00001), despite the concomitant presence of erectile dysfunction. Significant differences were also observed in the IPSS irritative and obstructive subscores, IPSS quality of life index and BPH impact index. After pooling four doses (2.5, 5, 10 and 20 mg), tadalafil failed to produce a significant outcome in maximal urinary flow rate (Qmax) (mean difference = +0.26 ml/s, p = 0.14), but 5 mg of tadalafil significantly improved Qmax (mean difference = +0.63 ml/s, p = 0.04). No significant difference was detected in the incidence of serious adverse events (risk ratio = 1.00, p = 1.00) after tadalafil treatment. Conclusions: Tadalafil showed good efficacy and safety for improving LUTS and erectile dysfunction in men with BPH, and 5 mg of tadalafil significantly improved Qmax.