bluuebunny/crossref_metadata_2025 huggingface dataset:
Tutorial
Authors: Taft S. Tucker
Published: September 2014

This tutorial will introduce the attendees to analysis and proof techniques for programs using parallelism and multi-threading. There are no specific prerequisites, but a familiarity with the notions of preconditions and postconditions, aliasing, race conditions, and deadlocks would be of value. The examples will be based on the threading and parallelism models of Java, Ada, and two new parallel languages, one called ParaSail [4] and another, inspired by the verifiable SPARK[1][2] subset of Ada, called Sparkel[3]. We will introduce the distinction between safety and liveness properties, and then focus primarily on techniques for the verification of safety properties, including the absence of race conditions and deadlocks. We will also discuss the issue of determinism vs. non-determinism in parallel and multi-threaded programs.
Engineering domain-specific languages with formula 2.0
Authors: Jackson Ethan K.
Published: September 2014

Domain-specific languages (DSLs) are useful for capturing and reusing engineering expertise. They can formalize industrial patterns and practices while increasing the scalability of verification, because input programs are written at a higher level of abstraction. However, engineering new DSLs with custom verification is a non-trivial task in its own right, and usually requires programming language, formal methods, and automated theorem proving expertise.

In this tutorial we present FORMULA 2.0, which is formal framework for developing DSLs. FORMULA specifications are succinct descriptions of DSLs, and specifications can be immediately connected to state-of-the-art analysis engines without additional expertise. FORMULA provides: (1) succinct specifications of DSLs and compilers, (2) efficient compilation and execution of input programs, (3) program synthesis and compiler verification.

We take a unique approach to provide these features: Specifications are written as strongly-typed open-world logic programs. These specifications are highly declarative and easily express rich synthesis / verification problems. Automated reasoning is enabled by efficient symbolic execution of logic programs into quantifier-free sub-problems, which are dispatched to the state-of-the-art SMT solver Z3. FORMULA has been applied within Microsoft to develop DSLs for verifiable device drivers and protocols. It has been used by the automotive / embedded systems industries for software / hardware co-design and design-space exploration under hard resource allocation constraints. It is being used to develop semantic specifications for complex cyber-physical systems.
Service-oriented architecture (SOA) concepts and implementations
Authors: Boleng Jeff , Sward Ricky
Published: September 2014

This tutorial explains how to implement a Service-Oriented Architecture (SOA) for reliable systems using an Enterprise Service Bus (ESB) and the Ada Web Server (AWS). The first part of the tutorial describes terms of Service-Oriented Architectures (SOA) including service, service registry, service provider, service consumer, Service Oriented Architecture Protocol (SOAP), and Web Service Description Language (WSDL). This tutorial also presents principles of SOA including loose coupling, encapsulation, composability of web services, and statelessness of web services. The tutorial also covers the benefits of SOA and organizations that are supporting SOA infrastructure. The second part of the tutorial covers the Enterprise Service Bus (ESB) including definitions, capabilities, benefits and drawbacks. The tutorial discusses the difference between SOA and an ESB, as well as some of the commercially available ESB solutions on the market. The Mule ESB is explored in more detail and several examples are given. In the third part, the tutorial covers the Ada Web Server (AWS) built using the Ada programming language. The tutorial covers the capabilities of AWS and explains how to build and install AWS. The tutorial explains how to build an AWS server and include the server in an Ada application. The tutorial demonstrates how to build a call back function in AWS and build a response to a SOAP message. Finally, the tutorial explains how to connect an AWS server to an ESB endpoint. AWS is a key component to building a SOA for a reliable system. This capability allows the developer to expose services in a high-integrity system using the Ada and SPARK programming languages.
Formal methods
Authors: Wing Jeannette M.
Published: September 2014

Formal methods research has made tremendous progress since the 1980s when a proof using a theorem prover was worthy of a Ph.D. thesis and a bug in a VLSI textbook was found using a model checker. Now, with advances in theorem proving, model checking, satisfiability modulo theories (SMT) solvers, and program analysis, the engines of formal methods are more sophisticated and are applicable and scalable: to a wide range of domains, from biology to mathematics; to a wide range of systems, from asynchronous systems to spreadsheets; and for a wide range of properties, from security to program termination. In this talk, I will present a few Microsoft Research stories of advances in formal methods and their application to Microsoft products and services. Formal methods use, however, is not routine?yet?in industrial practice. So, I will close with outstanding challenges and new directions for research in formal methods.
Up and out
Authors: Whalen Michael W.
Published: September 2014

Systems are naturally constructed in hierarchies in which design choices made at higher levels of abstraction ``flow down'' to requirements on system components at lower levels of abstraction. Thus, whether an aspect of the system is a design choice or a requirement depends largely on one's vantage point within the hierarchy of system components. Furthermore, systems are often constructed middle-out rather than top-down; compatibility with existing systems and architectures, or availability of specific components influences high-level requirements. We believe that requirements and architectural design should be more closely aligned: that requirements models must account for hierarchical system construction, and that architectural design notations must better support specification of requirements for system components.

In this presentation, I describe tools supporting iterative development of architecture and verification based on software models. We represent the hierarchical composition of the system in the Architecture Analysis & Design Language (AADL), and use an extension to the AADL language to describe requirements at different levels of abstraction for compositional verification. To describe and verify component-level behavior, we use Simulink and Stateflow and multiple analysis tools.
Practical specification and verification with code contracts
Authors: Logozzo Francesco
Published: September 2014

In this tutorial I will introduce CodeContracts, the .NET solution for contract specifications. CodeContracts consist of a language and compiler-agnostic API to express contracts, and of a set of tools to automatically generate the documentation and to perform dynamic and static verification. The CodeContracts API is part of .NET since v4, the tools are available for download on the Visual Studio Gallery. To date, they have been downloaded more than 100,000 times.
Getting F-bounded polymorphism into shape
Authors: Greenman Ben , Muehlboeck Fabian , Tate Ross
Published: September 2014

We present a way to restrict recursive inheritance without sacrificing the benefits of F-bounded polymorphism. In particular, we distinguish two new concepts,
materials
and
shapes
, and demonstrate through a survey of 13.5 million lines of open-source generic-Java code that these two concepts never actually overlap in practice. With this
Material-Shape Separation
, we prove that even naïve type-checking algorithms are sound and complete, some of which address problems that were unsolvable even under the existing proposals for restricting inheritance. We illustrate how the simplicity of our design reflects the design intuitions employed by programmers and potentially enables new features coming into demand for upcoming programming languages.
Commutativity race detection
Authors: Dimitrov Dimitar , Raychev Veselin , Vechev Martin , Koskinen Eric
Published: September 2014

This paper introduces the concept of a commutativity race. A commutativity race occurs in a given execution when two library method invocations can happen concurrently yet they do not commute. Commutativity races are an elegant concept enabling reasoning about concurrent interaction at the library interface.

We present a dynamic commutativity race detector. Our technique is based on a novel combination of vector clocks and a structural representation automatically obtained from a commutativity specification. Conceptually, our work can be seen as generalizing classical read-write race detection.

We also present a new logical fragment for specifying commutativity conditions. This fragment is expressive, yet guarantees a constant number of comparisons per method invocation rather than linear with unrestricted specifications.

We implemented our analyzer and evaluated it on real-world applications. Experimental results indicate that our analysis is practical: it discovered harmful commutativity races with overhead comparable to state-of-the-art, low-level race detectors.
Verification modulo versions
Authors: Logozzo Francesco , Lahiri Shuvendu K. , Fähndrich Manuel , Blackshear Sam
Published: September 2014

We introduce Verification Modulo Versions (VMV), a new static analysis technique for reducing the number of alarms reported by static verifiers while providing sound semantic guarantees. First, VMV extracts semantic environment conditions from a base program P. Environmental conditions can either be sufficient conditions (implying the safety of P) or necessary conditions (implied by the safety of P). Then, VMV instruments a new version of the program, P', with the inferred conditions. We prove that we can use (i) sufficient conditions to identify abstract regressions of P' w.r.t. P; and (ii) necessary conditions to prove the relative correctness of P' w.r.t. P. We show that the extraction of environmental conditions can be performed at a hierarchy of abstraction levels (history, state, or call conditions) with each subsequent level requiring a less sophisticated matching of the syntactic changes between P' and P. Call conditions are particularly useful because they only require the syntactic matching of entry points and callee names across program versions. We have implemented VMV in a widely used static analysis and verification tool. We report our experience on two large code bases and demonstrate a substantial reduction in alarms while additionally providing relative correctness guarantees.
What exactly is inexact computation good for?
Authors: Palem Krishna
Published: September 2014

Our willingness to deliberately trade accuracy of computing systems for significant resource savings, notably energy consumption, got a boost from two directions. First, energy (or power, the more popularly used measure) consumption started emerging as a serious hurdle to our ability to continue scaling the complexity of processors, and thus enable ever richer computing applications. This "energy hurdle" spanned the gamut from large data-centers to portable embedded computing systems. Second, many believed that an engine of growth that supported scaling, captured by Gordon Moore's remarkable prophecy (Moore's law), was headed towards an irrevocable cliff edge - when this happens, our ability to produce computing systems whose hardware would support precise or exact computing would diminish greatly. In this talk which emphasizes the physical and hardware layers of abstraction where all of these troubles start (after all energy is rooted in thermodynamics), I will first review reasons that compelled and encouraged us to consider trading accuracy for energy savings deliberately resulting in inexact computing.
Laws of concurrent programming
Authors: Hoare Tony
Published: September 2014

The talk extends the Laws of Programming [1] by four laws governing concurrent composition of programs. This operator is associative and commutative and distributive through union; and it has the same unit (do nothing) as sequential composition. Furthermore, sequential and concurrent composition distribute through each other, in accordance with an exchange law; this permits an implementation of concurrency by partial interleaving.
A personal perspective on concurrency
Authors: Misra Jayadev
Published: September 2014

This talk will describe a view of concurrency, the author's own, as it has evolved since the late 1970s. Early notions of concurrency were intimately tied with physical hardware and speeding up of computations, which proved to be an impediment to the development of a logical theory of concurrency. In collaboration with K. Mani Chandy, the author developed a theory called UNITY that combined a programming notation with a verification logic to describe a large class of fundamental concurrent algorithms arising in operating systems, communication protocols and distributed systems. Several model checkers, including Murphi, developed by David Dill, are based on UNITY.

A limitation of UNITY was a lack of adequate structuring mechanism. While this was not a major problem in low-level applications, the current wide-spread use of concurrency requires theories that go beyond managing infrastructure to the level of massive applications. Our current research, a programming model called Orc, introduces mechanisms to organize the communication, synchronization and coordination in programs that run on wide-area networks. Orc includes constructs to orchestrate the concurrent invocation of services to achieve a goal -- while managing time-outs, priorities, and failure of sites or communication.
Efficient code generation in a region-based dynamic binary translator
Authors: Spink Tom , Wagstaff Harry , Franke Björn , Topham Nigel
Published: September 2014

Region-based JIT compilation operates on translation units comprising multiple basic blocks and, possibly cyclic or conditional, control flow between these. It promises to reconcile aggressive code optimisation and low compilation latency in performance-critical dynamic binary translators. Whilst various region selection schemes and isolated code optimisation techniques have been investigated it remains unclear how to best exploit such regions for efficient code generation. Complex interactions with indirect branch tables and translation caches can have adverse effects on performance if not considered carefully. In this paper we present a complete code generation strategy for a region-based dynamic binary translator, which exploits branch type and control flow profiling information to improve code quality for the common case. We demonstrate that using our code generation strategy a competitive region-based dynamic compiler can be built on top of the LLVM JIT compilation framework. For the ARM-V5T target ISA and SPEC CPU 2006 benchmarks we achieve execution rates of, on average, 867 MIPS and up to 1323 MIPS on a standard X86 host machine, outperforming state-of-the-art QEMU-ARM by delivering a speedup of 264%.
Exploiting function similarity for code size reduction
Authors: Edler von Koch Tobias J.K. , Franke Björn , Bhandarkar Pranav , Dasgupta Anshuman
Published: September 2014

For cost-sensitive or memory constrained embedded systems, code size is at least as important as performance. Consequently, compact code generation has become a major focus of attention within the compiler community. In this paper we develop a pragmatic, yet effective code size reduction technique, which exploits structural similarity of functions. It avoids code duplication through merging of similar functions and targeted insertion of control flow to resolve small differences. We have implemented our purely software based and platform-independent technique in the LLVM compiler frame work and evaluated it against the SPEC CPU2006 benchmarks and three target platforms: Intel x86, ARM based Qualcomm Krait(TM), and Qualcomm Hexagon(TM) DSP. We demonstrate that code size for SPEC CPU2006 can be reduced by more than 550KB on x86. This corresponds to an overall code size reduction of 4%, and up to 11.5% for individual programs. Overhead introduced by additional control flow is compensated for by better I-cache performance of the compacted programs. We also show that identifying suitable candidates and subsequent merging of functions can be implemented efficiently.
WCET
Authors: Zheng Wenguang , Wu Hui
Published: September 2014

Caches are widely used in embedded systems to bridge the increasing speed gap between processors and off-chip memory. However, caches make it significantly harder to compute the WCET(Worst Case Execution Time) of a task. To alleviate this problem, cache locking has been proposed. We investigate the I-cache locking problem, and propose a WCET-aware, min-cut based dynamic instruction cache locking approach for reducing the WCET of a single task. We have implemented our approach and compared it with the two state-of-the-art cache locking approaches by using a set of benchmarks from the MRTC benchmark suite. The experimental results show that our approach achieves the average improvements of 41%, 15% and 7% over the partial locking approach for the 256B, 512B and 1KB caches, respectively, and 7%, 18% and 17% over the longest path based dynamic locking approach for the 256B, 512B and 1KB caches, respectively.
Partitioning data-parallel programs for heterogeneous MPSoCs
Authors: Chandramohan Kiran , O'Boyle Michael F.P.
Published: September 2014

Multiprocessor System-on-Chips(MPSoCs) are now widely used in embedded devices. MPSoCs typically contain a range of specialised processors. Alongside the CPU, there are microcontrollers, DSPs and other hardware accelerators. Programming these MPSoCs is difficult because of the difference in instruction-set architecture (ISA) and disjoint address spaces. In this paper we consider MPSoCs as a target for individual benchmarks. We examine how data-parallel programs can be optimally mapped to heterogeneous multicores for different criteria such as performance, power and energy. We investigate the partitioning of seven benchmarks taken from DSPstone, UTDSP and Polybench suites. Based on design space exploration we show that the best partition depends on compiler optimization level, program, input size and crucially optimization criteria. We develop a straightforward approach that attempts to select the best partitioning for a given program. On average it achieves speedups of 2.2x and energy improvements of 1.45x on the OMAP 4430 platform.
Random walk based biased sampling for data collection on communication networks
Authors: Shioda Shigeo
Published: September 2014

Sampling via random walks is the first choice for collecting random samples of online-social networks, peer-to-peer networks, and the World Wide Web. This paper proposes an algorithm for random-walk sampling, which allows us to collect a biased (non-random) sample, depending on which nodes are to be investigated in detail. Since the stationary distribution of a random walker under the proposed algorithm can be analytically derived, the bias involved in a collected sample can be removed using the notion of change of measure in probability theory, which is also presented in this paper. The effectiveness of the proposals is verified using simulation experiments based on the data of real networks.
On competitive provisioning of cloud services
Authors: Nair Jayakrishnan , Subramanian Vijay G. , Wierman Adam
Published: September 2014

Motivated by cloud services, we consider the interplay of network effects, congestion, and competition in ad-supported services. We study the strategic interactions between competing service providers and a user base, modeling congestion sensitivity and two forms of positive network effects: "firm-specific" versus "industry-wide." Our analysis reveals that users are generally no better off due to the competition in a marketplace of ad-supported services. Further, our analysis highlights an important contrast between firm-specific and industry-wide network effects: firms can coexist in a marketplace with industry-wide network effects, but near-monopolies tend to emerge in marketplaces with firm-specific network effects.
A cooperative sequential adsorption model for wireless gossiping
Authors: Meyfroyt Thomas M.M.
Published: September 2014

Wireless sensor networks require communication protocols for efficiently maintaining data in a distributed fashion. The Trickle algorithm is a popular protocol serving as the basis for many of the current standard communication protocols. In this paper we develop a mathematical model describing how Trickle maintains data, establish a relationship with a class of spatial stochastic models known as Cooperative Sequential Adsorption (CSA). We derive asymptotic results for the coverage ratio for a specific class of CSA models and investigate the scalability of the Trickle algorithm.
Scaling of capacity and reliability in data center networks
Authors: Bradonjić Milan , Saniee Iraj , Widjaja Indra
Published: September 2014

The traditional connectivity model within the data center is that of a hierarchical tree with redundant connections (\fat tree") and with a top node consisting of one or more routers that bring in (and send out completed) requests for processing. In this paper we examine alternative connectivity models for large-scale data centers. In the first model, we examine hypergrids as the structure connecting switches and routers to the edge server racks. In the second model, we examine random graphs as the interconnecting network. We compare and contrast the capacity, congestion and reliability requirements for these relative to fat-trees. We show that, as the system size increases and for uniform switch-end-to- switch-end demand, the fat-tree configuration emerges as an expensive option demanding higher port density switches but has low congestion and high reliability. In contrast, the random graph model shows the same low level of congestion, lower cost due to fewer ports and reasonable reliability, whereas the hypergrid model does not require scaling of switch ports, provides high reliability but exhibits higher congestion.
Modeling D2D communications with LTE and WiFi
Authors: Asadi Arash , Jacko Peter , Mancuso Vincenzo
Published: September 2014

In this work we propose a roadmap towards the analytical understanding of Device-to-Device (D2D) communications in LTE-A networks. Various D2D solutions have been proposed, which include inband and outband D2D transmission modes, each of which exhibits different pros and cons in terms of complexity, interference, and spectral efficiency achieved. We go beyond traditional mode optimization and mode-selection schemes. Specifically, we formulate a general problem for the joint per-user mode selection, connection activation and resource scheduling of connections using both LTE and WiFi resources.
Asymptotic optimality of BestFit for stochastic bin packing
Authors: Ghaderi Javad , Zhong Yuan , Srikant R.
Published: September 2014

In the static bin packing problem, items of diffierent sizes must be packed into bins or servers with unit capacity in a way that minimizes the number of bins used, and it is well-known to be a hard combinatorial problem. Best-Fit is among the simplest online heuristics for this problem. Motivated by the problem of packing virtual machines in servers in the cloud, we consider the dynamic version of this problem, when jobs arrive randomly over time and leave the system after completion of their service. We analyze the uid limits of the system under an asymptotic Best-Fit algorithm and show that it asymptotically minimizes the number of servers used in steady state (on the uid scale). The significance of the result is due to the fact that Best-Fit seems to achieve the best performance in practice.
On the impact of subgraph insertion or removal on Moore-Penrose Laplacian and resistance distance
Authors: Tizghadam Ali , Leon-Garcia Alberto
Published: September 2014

A large body of network-related problems can be formulated or explained by Moore-Penrose inverse of the graph Laplacian matrix of the network. This paper studies the impact of overlaying or removing a subgraph (inserting / removing a group of links, or modifying a set of link weights) on Moore-Penrose inverse of the Laplacian matrix of an existing network topology. Moreover, an iterative method is proposed to find point-to-point resistance distance (effective resistance) and network criticality of a graph as key performance measures to study the robustness of a network at the presence of subgraph insertion and/or subgraph removal.
The expression profile of acid-sensing ion channel (ASIC) subunits ASIC1a, ASIC1b, ASIC2a, ASIC2b, and ASIC3 in the esophageal vagal afferent nerve subtypes
Authors: Dusenkova Svetlana , Ru Fei , Surdenikova Lenka , Nassenstein Christina , Hatok Jozef , Dusenka Robert , Banovcin Peter , Kliment Jan , Tatar Milos , Kollarik Marian
Published: September 2014

Acid-sensing ion channels (ASICs) have been implicated in esophageal acid sensing and mechanotransduction. However, insufficient knowledge of ASIC subunit expression profile in esophageal afferent nerves hampers the understanding of their role. This knowledge is essential because ASIC subunits form heteromultimeric channels with distinct functional properties. We hypothesized that the esophageal putative nociceptive C-fiber nerves (transient receptor potential vanilloid 1, TRPV1-positive) express multiple ASIC subunits and that the ASIC expression profile differs between the nodose TRPV1-positive subtype developmentally derived from placodes and the jugular TRPV1-positive subtype derived from neural crest. We performed single cell RT-PCR on the vagal afferent neurons retrogradely labeled from the esophagus. In the guinea pig, nearly all (90%–95%) nodose and jugular esophageal TRPV1-positive neurons expressed ASICs, most often in a combination (65–75%). ASIC1, ASIC2, and ASIC3 were expressed in 65–75%, 55–70%, and 70%, respectively, of both nodose and jugular TRPV1-positive neurons. The ASIC1 splice variants ASIC1a and ASIC1b and the ASIC2 splice variant ASIC2b were similarly expressed in both nodose and jugular TRPV1-positive neurons. However, ASIC2a was found exclusively in the nodose neurons. In contrast to guinea pig, ASIC3 was almost absent from the mouse vagal esophageal TRPV1-positive neurons. However, ASIC3 was similarly expressed in the nonnociceptive TRPV1-negative (tension mechanoreceptors) neurons in both species. We conclude that the majority of esophageal vagal nociceptive neurons express multiple ASIC subunits. The placode-derived nodose neurons selectively express ASIC2a, known to substantially reduce acid sensitivity of ASIC heteromultimers. ASIC3 is expressed in the guinea pig but not in the mouse vagal esophageal TRPV1-positive neurons, indicating species differences in ASIC expression.
The Effect on Treatment Adherence of Administering Drugs as Fixed-Dose Combinations versus as Separate Pills: Systematic Review and Meta-Analysis
Authors: van Galen Katy A. , Nellen Jeannine F. , Nieuwkerk Pythia T.
Published: September 2014

Administering drugs as fixed-dose combinations (FDCs) versus the same active drugs administered as separate pills is assumed to enhance treatment adherence. We synthesized evidence from randomized controlled trials (RCTs) about the effect of FDCs versus separate pills on adherence. We searched PubMed for RCTs comparing a FDC with the same active drugs administered as separate pills, including a quantitative estimate of treatment adherence, without restriction to medical condition. The odds ratio (OR) of optimal adherence with FDCs versus separate pills was used as common effect size and aggregated into a pooled effect estimate using a random effect model with inverse variance weights. Out of 1258 articles screened, only six studies fulfilled inclusion criteria. Across medical conditions, administering drugs as FDC significantly increased the likelihood of optimal adherence (OR 1.33 (95% CI, 1.03–1.71)). Within subgroups of specific medical conditions, the favourable effect of FDCs on adherence was of borderline statistical significance for HIV infection only (OR 1.46 (95% CI, 1.00–2.13)). We observed a remarkable paucity of RCTs comparing the effect on adherence of administering drugs as FDC versus as separate pills. Administering drugs as FDC improved medication adherence. However, this conclusion is based on a limited number of RCTs only.
From Bench to Bedside: Immunotherapy for Prostate Cancer
Authors: Tse Brian Wan-Chi , Jovanovic Lidija , Nelson Colleen Coyne , de Souza Paul , Power Carl Andrew , Russell Pamela Joan
Published: September 2014

The mainstay therapeutic strategy for metastatic castrate-resistant prostate cancer (CRPC) continues to be androgen deprivation therapy usually in combination with chemotherapy or androgen receptor targeting therapy in either sequence, or recently approved novel agents such as Radium 223. However, immunotherapy has also emerged as an option for the treatment of this disease following the approval of sipuleucel-T by the FDA in 2010. Immunotherapy is a rational approach for prostate cancer based on a body of evidence suggesting these cancers are inherently immunogenic and, most importantly, that immunological interventions can induce protective antitumour responses. Various forms of immunotherapy are currently being explored clinically, with the most common being cancer vaccines (dendritic-cell, viral, and whole tumour cell-based) and immune checkpoint inhibition. This review will discuss recent clinical developments of immune-based therapies for prostate cancer that have reached the phase III clinical trial stage. A perspective of how immunotherapy could be best employed within current treatment regimes to achieve most clinical benefits is also provided.
Loss of Keratinocytic RXRα Combined with Activated CDK4 or Oncogenic NRAS Generates UVB-Induced Melanomas via Loss of p53 and PTEN in the Tumor Microenvironment
Authors: Coleman Daniel J. , Chagani Sharmeen , Hyter Stephen , Sherman Anna M. , Löhr Christiane V. , Liang Xiaobo , Ganguli-Indra Gitali , Indra Arup K.
Published: September 2014

Understanding the molecular mechanisms behind formation of melanoma, the deadliest form of skin cancer, is crucial for improved diagnosis and treatment. One key is to better understand the cross-talk between epidermal keratinocytes and pigment-producing melanocytes. Here, using a bigenic mouse model system combining mutant oncogenic NRASQ61K (constitutively active RAS) or mutant activated CDK4R24C/R24C (prevents binding of CDK4 by kinase inhibitor p16INK4A) with an epidermis-specific knockout of the nuclear retinoid X receptor alpha (RXRαep−/−) results in increased melanoma formation after chronic ultraviolet-B (UVB) irradiation compared with control mice with functional RXRα. Melanomas from both groups of bigenic RXRαep−/− mice are larger in size with higher proliferative capacity, and exhibit enhanced angiogenic properties and increased expression of malignant melanoma markers. Analysis of tumor adjacent normal skin from these mice revealed altered expression of several biomarkers indicative of enhanced melanoma susceptibility, including reduced expression of tumor suppressor p53 and loss of PTEN, with concomitant increase in activated AKT. Loss of epidermal RXRα in combination with UVB significantly enhances invasion of melanocytic cells to draining lymph nodes in bigenic mice expressing oncogenic NRASQ61K compared with controls with functional RXRα. These results suggest a crucial role of keratinocytic RXRα to suppress formation of UVB-induced melanomas and their progression to malignant cancers in the context of driver mutations such as activated CDK4R24C/R24C or oncogenic NRASQ61K.

Implications: These findings suggest that RXRα may serve as a clinical diagnostic marker and therapeutic target in melanoma progression and metastasis. Mol Cancer Res; 13(1); 186–96. ©2014 AACR.
RSK Promotes Prostate Cancer Progression in Bone through ING3, CKAP2, and PTK6-Mediated Cell Survival
Authors: Yu Guoyu , Lee Yu-Chen , Cheng Chien-Jui , Wu Chuan-Fen , Song Jian H. , Gallick Gary E. , Yu-Lee Li-Yuan , Kuang Jian , Lin Sue-Hwa
Published: September 2014

Prostate cancer has a proclivity to metastasize to bone. The mechanism by which prostate cancer cells are able to survive and progress in the bone microenvironment is not clear. Identification of molecules that play critical roles in the progression of prostate cancer in bone will provide essential targets for therapy. Ribosomal S6 protein kinases (RSK) have been shown to mediate many cellular functions critical for cancer progression. Whether RSK plays a role in the progression of prostate cancer in bone is unknown. IHC analysis of human prostate cancer specimens showed increased phosphorylation of RSK in the nucleus of prostate cancer cells in a significant fraction of human prostate cancer bone metastasis specimens, compared with the primary site or lymph node metastasis. Expression of constitutively active myristylated RSK in C4-2B4 cells (C4-2B4/RSK) increased their survival and anchorage-independent growth compared with C4-2B4/vector cells. Using an orthotopic bone injection model, it was determined that injecting C4-2B4/RSK cells into mouse femurs enhanced their progression in bone compared with control cells. In PC3-mm2 cells, knockdown of RSK1 (RPS6KA1), the predominant RSK isoform, but not RSK2 (RPS6KA2) alone, decreased anchorage-independent growth in vitro and reduced tumor progression in bone and tumor-induced bone remodeling in vivo. Mechanistic studies showed that RSK regulates anchorage-independent growth through transcriptional regulation of factors that modulate cell survival, including ING3, CKAP2, and PTK6. Together, these data provide strong evidence that RSK is an important driver in prostate cancer progression in bone.

Implications: RSK, an important driver in prostate cancer progression in bone, has promising potential as a therapeutic target for prostate cancer bone metastasis. Mol Cancer Res; 13(2); 348–57. ©2014 AACR.
INTERVENÇÃO TERAPÊUTICA OCUPACIONAL EM UMA CRECHE DA CIDADE DO RECIFE
Authors: Almeida Bruna Chagas , Marcelino Juliana Fonsêca de Queiroz
Published: September 2014

A atuação do terapeuta ocupacional na Educação se iniciou no sistema de educação especial, restringindo-se à criança com defi ciência. Com a expansão dos campos de atuação da Terapia Ocupacional, o objetivo de intervenção passou a ser a promoção do desenvolvimento integral, atendendo qualquer criança inserida neste contexto, de forma a incluir todos os atores do processo de aprendizagem. O objetivo deste artigo é descrever o processo terapêutico ocupacional de crianças com difi culdade na aprendizagem em idade pré-escolar, atendidas em uma creche da cidade do Recife, a partir da análise de documentos registrados de março a dezembro de 2011. A análise dos documentos inclusos na pesquisa mostrou que as ações envolveram intervenção com as crianças, individualmente e em grupo, e orientação aos familiares e educadores, buscando maior envolvimento de todos a fi m de alcançar um melhor desempenho escolar das crianças. Foram percebidas melhora no desempenho das crianças nos diversos aspectos que abrangem o contexto escolar, sendo observados, também, pelos próprios educadores, afi rmando a inclusão deste profissional na área da Educação como agente promotor do desenvolvimento integral da criança.
A utilização do brincar nas práticas de terapeutas ocupacionais da Baixada Santista
Authors: Silva Carla Cilene Baptista da , Pontes Fernando Vicente de
Published: September 2014

O presente estudo teve por objetivo identificar e caracterizar as práticas desenvolvidas pelos terapeutas ocupacionais que atuam na região metropolitana da Baixada Santista, quanto à utilização do brincar. Para tanto, foi aplicado um questionário estruturado com 36 terapeutas ocupacionais que atuam na área da infância. Os principais referenciais teóricos utilizados pelos profissionais são a Terapia de Integração Sensorial e o Método Neuroevolutivo Bobath. Os profi ssionais caracterizam a utilização do brincar como um recurso facilitador do processo terapêutico ocupacional, utilizando-o durante todos os momentos do atendimento. Portanto, o brincar é visto como recurso terapêutico utilizado para a promoção do desenvolvimento infantil como um dos principais objetivos da clínica em Terapia Ocupacional. O estudo procurou contribuir na caracterização da prática profi ssional quanto à utilização do brincar.
Reflexões sobre a prática do residente Terapeuta Ocupacional na Estratégia Saúde da Família no município de São Carlos
Authors: Manho Flávia , Soares Léa Beatriz Teixeira , Nicolau Stella Maris
Published: September 2014

O olhar dos residentes egressos de Terapia Ocupacional sobre suas práticas na Residência Multiprofissional em Saúde da Família e Comunidade da UFSCar foi o objetivo deste estudo. Durante o programa de pós-graduação “lato sensu”, de ensino em serviço, os residentes desenvolvem competências de cuidado individual e coletivo, gestão, educação permanente e pesquisa, na lógica do apoio matricial, inseridos em Unidades de Saúde da Família do município. Responderam a um questionário on-line, sete dos oito residentes formados de 2007 a 2011. O material empírico foi agrupado em blocos a partir de um entendimento da hermenêutica dialética em diálogo com o referencial teórico e o projeto pedagógico da residência. Embora com diferenças, todos os residentes puderam reconhecer, de forma ampliada, as práticas e os preceitos da Estratégia Saúde da Família. Nos relatos, associaram o cuidado individual e coletivo ao núcleo de saber da Terapia Ocupacional, e associaram as ações coletivas, de gestão e de educação permanente, ao campo de saber da Saúde Coletiva. Os egressos reconheceram a residência como fundamental para sua formação pessoal e profissional.
Respostas agudas da frequência cardíaca e da pressão arterial em uma sessão de jogos de vídeo game ativos em adultos saudáveis: um estudo piloto.
Authors: Melo Raphael José Perrier , Gomes Jorge Luiz Brito , Oliveira Saulo Fernandes Melo , Costa Manoel da Cunha
Published: September 2014

Objetivos: analisar as respostas da frequência cardíaca e da pressão arterial durante e após uma sessão de vídeo games ativos (VGA’s). Procedimento Metodológico:oito sujeitos do gênero masculino (idade: 21±1,6 anos; peso: 71,0±4,2; estatura:1,77±4 cm; % de gordura: 23±5,78). A sessão: 72 minutos com o VGA Xbox360º Kinect® em 4 diferentes jogos (Dance Central 3 e Kinect Sports: boxe, vôlei e tênis de mesa). Resultados: as respostas da frequência cardíaca e pressão arterial em VGA´s, mostram que os jogos são capazes de alterar o sistema cardiovascular. Conclusão: Através da FCmáx, os VGA’s atingiram níveis de intensidade moderada.
Revisão das propriedades psicométricas de testes de coordenação motora dos membros superiores em hemiparéticos
Authors: Avelino Patrick Roberto , Kiefer Kênia , Cesinando Augusto , Hirochi Tânia Lúcia , Fuscaldi Luci
Published: September 2014

Objetivo: Sumarisar as propriedades psicométricas e a utilidade clínica de instrumentos de coordenação motora (CM) dos membros superiores, que consideram a velocidade e aqualidade dos movimentos, para hemiparéticos. Procedimentos Metodológicos: Foi realizada uma busca computadorizada nas bases de dados Medline, EMBASE, PsynINFO, CINAHL, Web of Science, LILACS, SciELO, PEDro, Cochrane e OT Seeker e uma busca manual. Dois autores independentes realizaram a extração dos dados. Resultados: A estratégia de busca inicial retornou 2.152 estudos, sendo que 2.116 foram excluídos. A busca manual retornou sete estudos e assim, o número total de estudos incluídos foi 43. As propriedades psicométricas dos 16 instrumentos encontrados apresentaram, no geral, valores adequados, no entanto somente seis reportaram valores para todas. A utilidade clínica revelou que nem todos os testes são rápidos, baratos e práticos para serem utilizados. Conclusões: A deficiência na literatura deestudos que investiguem as propriedades psicométricas de teste de CM dos MMSS pode limitar a interpretação e utilização destes intrumentos na prática clínica e pesquisa. Além disso, a utilidade é um importante fator que deve interferir na escolha do instrumento.
NADPH Oxidase Deficiency Exacerbates Angiotensin II–Induced Abdominal Aortic Aneurysms in Mice
Authors: Kigawa Yasuyoshi , Miyazaki Takuro , Lei Xiao-Feng , Nakamachi Tomoya , Oguchi Tatsunori , Kim-Kaneyama Joo-ri , Taniyama Matsuo , Tsunawaki Shohko , Shioda Seiji , Miyazaki Akira
Published: September 2014

Objective—

Although nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) is reportedly essential for phagocyte host defenses, it has been found to aggravate atherosclerosis in apolipoprotein E (
Apoe
)-null mice through excess production of superoxide. We therefore assessed the role of NOX2 in an experimental model of abdominal aortic aneurysm (AAA) and assessed the mechanism of NOX2 action in AAA.

Approach and Results—

AAA was induced in low-density lipoprotein receptor-null (
Ldlr
–/–
) mice by infusing angiotensin II.
Nox2
expression was elevated in the abdominal aortae of these mice during infusion of angiotensin II, with enhanced
Nox2
expression mainly because of the recruitment of NOX2-enriched macrophages into AAA lesions. Unexpectedly, systemic
Nox2
deficiency promoted AAA development but reduced the level of reactive oxygen species in AAA lesions.
Nox2
deficiency stimulated macrophage conversion toward the M1 subset, enhancing expression of interleukin (IL)-1β and matrix metalloproteinase-9/12 mRNA. Administration of neutralizing antibody against IL-1β abolished AAA development in
Nox2
-deficient mice. Bone marrow transplantation experiments revealed that AAA aggravation by
Nox2
deficiency is because of bone marrow–derived cells. Isolated bone marrow–derived macrophages from
Nox2
-null mice could not generate reactive oxygen species. In contrast, IL-1β expression in peritoneal and bone marrow–derived macrophages, but not in peritoneal neutrophils, was substantially enhanced by
Nox2
deficiency. Pharmacological inhibition of Janus kinase/signal transducers and activators of transcription signaling inhibited excess IL-1β expression in
Nox2
-deficient macrophages, whereas matrix metalloproteinase-9 secretion was constitutively stimulated via nuclear factor-κB signals.

Conclusions—

Nox2
deficiency enhances macrophage secretion of IL-1β and matrix metalloproteinase-9, disrupting tissue-remodeling functions in AAA lesions. These actions are unfavorable if NOX2 is to serve as a molecular target for AAA.
Patient Access and 1-Year Outcomes of Percutaneous Coronary Intervention Facilities With and Without On-Site Cardiothoracic Surgery
Authors: Maddox Thomas M. , Stanislawski Maggie A. , O’Donnell Colin , Plomondon Mary E. , Bradley Steven M. , Ho P. Michael , Tsai Thomas T. , Shroff Adhir R. , Speiser Bernadette , Jesse Robert J. , Rumsfeld John S.
Published: September 2014

Background—

The safety of percutaneous coronary intervention (PCI) at medical facilities without on-site cardiothoracic (CT) surgery has been established in clinical trials. However, the comparative effectiveness of this strategy in real-world practice, including impact on patient access and outcomes, is uncertain. The Veterans Affairs (VA) health care system has used this strategy, with strict quality oversight, since 2005, and can provide insight into this question.

Methods and Results—

Among 24 387 patients receiving PCI at VA facilities between October 2007 and September 2010, 6616 (27.1%) patients underwent PCI at facilities (n=18) without on-site CT surgery. Patient drive time (as a proxy for access), procedural complications, 1-year mortality, myocardial infarction, and rates of subsequent revascularization procedures were compared by facility. Results were stratified by procedural indication (ST–segment-elevation myocardial infarction versus non–ST–segment-elevation myocardial infarction/unstable angina versus elective) and PCI volume. With the inclusion of PCI facilities without on-site CT surgery, median drive time for patients treated at those facilities decreased by 90.8 minutes (
P
<0.001). Procedural need for emergent coronary artery bypass graft and mortality rates were low and similar between facilities. Adjusted 1-year mortality and myocardial infarction rates were similar between facilities (hazard ratio in PCI facilities without relative to those with on-site CT surgery, 1.02; 95% confidence interval, 0.87–1.2), and not modified by either PCI indication or PCI volume. Subsequent revascularization rates were higher at sites without on-site CT surgery facilities (hazard ratio, 1.21; 95% confidence interval, 1.03–1.42).

Conclusions—

This study suggests that providing PCI facilities without on-site CT surgery in an integrated health care system with quality oversight improves patient access without compromising procedural or 1-year outcomes.
Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial
Authors: Scirica Benjamin M. , Braunwald Eugene , Raz Itamar , Cavender Matthew A. , Morrow David A. , Jarolim Petr , Udell Jacob A. , Mosenzon Ofri , Im KyungAh , Umez-Eronini Amarachi A. , Pollack Pia S. , Hirshberg Boaz , Frederich Robert , Lewis Basil S. , McGuire Darren K. , Davidson Jaime , Steg Ph. Gabriel , Bhatt Deepak L.
Published: September 2014

Background—

Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point.

Methods and Results—

A total of 16 492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07–1.51;
P
=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15–1.88;
P
=0.002), with no significant difference thereafter (time-varying interaction,
P
=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ≤60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (
P
for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups.

Conclusions—

In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01107886.