bluuebunny/crossref_metadata_2025 huggingface dataset:
Reducing System Power Consumption Using Check-Pointing on Nonvolatile Embedded Magnetic Random Access Memories
Authors: Layer Christophe , Becker Laurent , Jabeur Kotb , Claireux Sylvain , Dieny Bernard , Prenat Guillaume , Pendina Gregory Di , Gros Stephane , Paoli Pierre , Javerliac Virgile , Bernard-Granger Fabrice , Decloedt Loic
Published: May 2016

The most widely used embedded memory technology, static random access memory (SRAM), is heading toward scaling problems in advanced technology nodes due to the leakage currents caused by the quantum tunneling effect. As an alternative, spin-transfer torque magnetic RAM (STT-MRAM) technology shows comparable performance in terms of speed and power consumption and much better performance in terms of density and leakage. Moreover, MRAM brings up new paradigms in system design thanks to its inherent nonvolatility, which allows the definition of new instant-on/off policies and leakage current optimization. Based on our compact model, we have developed a fully characterized system-on-chip from the basic cell up to the system architecture in a 40nm LP hybrid CMOS/magnetic process. Through simulations, first we demonstrate that STT-MRAM is a candidate for the memory part of embedded systems, and second we implement a check-pointing methodology based on the regular interrupt routines of a processor to enable a fast power on and off functionality. Using a synthetic benchmark developed in high-level programming languages intended to be representative of integer system performance, our method shows that having MRAM instead of SRAM in an embedded design brings up important energy savings. The influence of the check-pointing routine on power consumption is finally evaluated with regard to various shutdown and restart behaviors.
The To-and-Fro of Sense Making
Authors: Hornecker Eva
Published: May 2016

Based on case studies from a heritage/museum context, I present and illustrate the notion of “spatio-contextual embedding,” which conceptualizes installation designs that augment real objects and environments while keeping these primary focuses of attention. Key for this “embeddedness” is that interaction is contextualized within a meaningful setting, creating relationships between system and environment. While retaining a focus on original objects or environments, it supports user's active engagement and sense making by inviting, enticing, or forcing them to draw connections. At the heart of this is “indexing”: mindful acts of referencing back-and-forth between here and there, connecting objects or representations. Analysis of case studies provides a repertoire of examples of “indexing,” and examples for high- and low-tech installation designs that foster drawing of connections.

Two core values for design underpin the argument: (1) primacy of real objects and environments and (2) supporting human agency. The case examples highlight how technological arrangements may support or hinder indexing activity. This is condensed into potential design strategies. This article contributes to design knowledge on design for human agency, sense making, and mindful engagement with our environment. “Indexing” is relevant beyond the heritage setting domain, as part of HCI design in support of human agency.
The Exact Complexity of the First-Order Logic Definability Problem
Authors: Arenas Marcelo , Diaz Gonzalo I.
Published: May 2016

We study the
definability problem
for first-order logic, denoted by FO-D
ef
. The input of FO-D
ef
is a relational database instance
I
and a relation
R
; the question to answer is whether there exists a first-order query
Q
(or, equivalently, a relational algebra expression
Q
) such that
Q
evaluated on
I
gives
R
as an answer.

Although the study of FO-D
ef
dates back to 1978, when the decidability of this problem was shown, the exact complexity of FO-D
ef
remains as a fundamental open problem. In this article, we provide a polynomial-time algorithm for solving FO-D
ef
that uses calls to a graph-isomorphism subroutine (or oracle). As a consequence, the first-order definability problem is found to be complete for the class
GI
of all problems that are polynomial-time Turing reducible to the graph isomorphism problem, thus closing the open question about the exact complexity of this problem. The technique used is also applied to a generalized version of the problem that accepts a finite set of relation pairs, and whose exact complexity was also open; this version is also found to be
GI
-complete.
An Effective Chemical Mechanical Polishing Fill Insertion Approach
Authors: Liu Chuangwen , Tu Peishan , Wu Pangbo , Tang Haomo , Jiang Yande , Kuang Jian , Young Evangeline F. Y.
Published: May 2016

To reduce chip-scale topography variation, dummy fill is commonly used to improve the layout density uniformity. Previous works either sought the most uniform density distribution or sought to minimize the inserted dummy fills while satisfying certain density uniformity constraint. However, due to more stringent manufacturing challenges, more criteria, like line deviation and outlier, emerge at newer technology nodes. This article presents a joint optimization scheme to consider variation, total fill, line deviation, outlier, overlap, and running time simultaneously. More specifically, first we decompose the rectilinear polygons and partition fillable regions into rectangles for easier processing. After decomposition, we insert dummy fills into the fillable rectangular regions optimizing the fill metrics simultaneously. We propose three approaches,
Fast Median
approach,
LP
approach, and
Iterative
approach, which are much faster with better quality, compared with the results of the top three contestants in the ICCAD Contest 2014.
DC Characteristics and Variability on 90nm CMOS Transistor Array-Style Analog Layout
Authors: Chen Gong , Fujimura Toru , Dong Qing , Nakatake Shigetoshi , Yang Bo
Published: May 2016

In the MOS analog layout, variability suppression is becoming a major issue, as is layout efficiency. Introducing a transistor array (TA) style to analog layout, this article addresses the layout-dependent variability based on the measurement results of test chips on 90nm CMOS process. In TA style, a large transistor is decomposed into a set of unified subtransistors, which are connected in series or parallel. Focusing on one row layout of diffusion sharing for the multiple gates, we analyze the current direction-dependent variability and the leakage current via off-gates for the electrical isolation. Furthermore, we present several analog design cases on TA including analysis of the impact on the DC characteristics caused by the transistor channel decomposition.
People Do Not Feel Guilty About Exploiting Machines
Authors: Melo Celso De , Marsella Stacy , Gratch Jonathan
Published: May 2016

Guilt and envy play an important role in social interaction. Guilt occurs when individuals cause harm to others or break social norms. Envy occurs when individuals compare themselves unfavorably to others and desire to benefit from the others’ advantage. In both cases, these emotions motivate people to act and change the status quo: following guilt, people try to make amends for the perceived transgression, and following envy, people try to harm envied others. In this article, we present two experiments that study participants’ experience of guilt and envy when engaging in social decision making with machines and humans. The results showed that, though experiencing the same level of envy, people felt considerably less guilt with machines than with humans. These effects occurred both with subjective and behavioral measures of guilt and envy, and in three different economic games: public goods, ultimatum, and dictator game. This poses an important challenge for human-computer interaction because, as shown here, it leads people to systematically exploit machines, when compared to humans. We discuss theoretical and practical implications for the design of human-machine interaction systems that hope to achieve the kind of efficiency -- cooperation, fairness, reciprocity, etc. -- we see in human-human interaction.
SmartLMK
Authors: Kim Sang-Hoon , Jeong Jinkyu , Kim Jin-Soo , Maeng Seungryoul
Published: May 2016

As the mobile computing environment evolves, users demand high-quality apps and better user experience. Consequently, memory demand in mobile devices has soared. Device manufacturers have fulfilled the demand by equipping devices with more RAM. However, such a hardware approach is only a temporary solution and does not scale well in the resource-constrained mobile environment.

Meanwhile, mobile systems adopt a new app life cycle and a memory reclamation scheme tailored for the life cycle. When a user leaves an app, the app is not terminated but cached in memory as long as there is enough free memory. If the free memory gets low, a victim app is terminated and the associated memory to the app is reclaimed. This process-level approach has worked well in the mobile environment. However, user experience can be impaired severely because the victim selection policy does not consider the user experience.

In this article, we propose a novel memory reclamation scheme called
SmartLMK
. SmartLMK minimizes the impact of the process-level reclamation on user experience. The worthiness to keep an app in memory is modeled by means of user-perceived app launch time and app usage statistics. The memory footprint and impending memory demand are estimated from the history of the memory usage. Using these values and memory models, SmartLMK picks up the least valuable apps and terminates them at once. Our evaluation on a real Android-based smartphone shows that SmartLMK efficiently distinguishes the valuable apps among cached apps and keeps those valuable apps in memory. As a result, the user-perceived app launch time can be improved by up to 13.2%.
A Graph-Based Dynamic Slicing of Distributed Aspect-Oriented Software
Authors: Singh Jagannath , Panda Subhrakanta , Khilar P. M. , Mohapatra D. P.
Published: May 2016

Distributed computing has become very popular these days due to its speed, accuracy and fault tolerance capability. In this pa-per, we have considered the distributed Aspect-Oriented Programs (AOPs) where message passing and synchronization are handled by Aspects. In this paper, we present a parallel dynamic slicing algorithm for distributed AOPs. We introduce parallelism into our slicing algorithm to make the slice computation process much faster. Our algorithm is implemented on our developed tool, called DDG generator, to generate the required intermediate graphs for distributed AOPs. The proposed slicing technique is compared with one related existing technique using three case studies. The experimental results show that our proposed slicing algorithm generates precise slices in less time as compared to the existing algorithm.
Notes On Agile and Safety-Critical Development
Authors: Axelsson Jakob , Papatheocharous Efi , Nyfjord Jaana , Törngren Martin
Published: May 2016

Agile approaches have been highly influential to the software engineering practices in many organizations, and are increasingly being applied in larger companies, and for developing systems outside the pure software domain. To understand more about the current state of agile, its applications to safety-critical systems, and the consequences on innovation and large organizations, a seminar was organized in Stockholm in 2014. This paper gives an overview of the topics discussed at that seminar, a summary of the main results and suggestions for future work as input to a research agenda for agile development of safety-critical software.
Plan Bouquets
Authors: Dutt Anshuman , Haritsa Jayant R.
Published: May 2016

Identifying efficient execution plans for declarative OLAP queries typically entails estimation of several predicate selectivities. In practice, these estimates often differ significantly from the values actually encountered during query execution, leading to poor plan choices and grossly inflated response times. We propose here a conceptually new approach to address this classical problem, wherein the compile-time estimation process is completely eschewed for error-prone selectivities. Instead, from the set of optimal plans in the query’s selectivity error space, a limited subset, called the “plan bouquet,” is selected such that at least one of the bouquet plans is 2-optimal at each location in the space. Then, at run time, a sequence of cost-budgeted executions from the plan bouquet is carried out, eventually finding a plan that executes to completion within its assigned budget. The duration and switching of these executions is controlled by a graded progression of isosurfaces projected onto the optimal performance profile. We prove that this construction results, for the first time, in guarantees on worst-case performance sub-optimality. Moreover, it ensures repeatable execution strategies across different invocations of a query.

We then present a suite of enhancements to the basic plan bouquet algorithm, including randomized variants, that result in significantly stronger performance guarantees. An efficient isosurface identification algorithm is also introduced to curtail the bouquet construction overheads.

The plan bouquet approach has been empirically evaluated on both PostgreSQL and a commercial DBMS, over the TPC-H and TPC-DS benchmark environments. Our experimental results indicate that it delivers substantial improvements in the worst-case behavior, without impairing the average-case performance, as compared to the native optimizers of these systems. Moreover, it can be implemented using existing optimizer infrastructure, making it relatively easy to incorporate in current database engines.

Overall, the plan bouquet approach provides novel performance guarantees that open up new possibilities for robust query processing.
From APIs to languages: generalising method names
Authors: Homer Michael , Jones Timothy , Noble James
Published: May 2016

Method names with multiple separate parts are a feature of many dynamic languages derived from Smalltalk. Generalising the syntax of method names to allow parts to be repeated, optional, or alternatives, means a single definition can respond to a whole family of method requests. We show how generalising method names can support flexible APIs for domain-specific languages, complex initialisation tasks, and control structures defined in libraries. We describe how we have extended Grace to support generalised method names, and prove that such an extension can be integrated into a gradually-typed language while preserving type soundness.
Control-flow analysis of dynamic languages via pointer analysis
Authors: Lyde Steven , Byrd William E. , Might Matthew
Published: May 2016

We demonstrate how to map a control-flow analysis for a higher-order language (dynamic languages are typically higher-order) into a pointer analysis for a first-order language, such as C. This allows us to use existing pointer analysis tools to perform a control-flow analysis, exploiting their technical advancements and the engineering effort that went into developing them. We compare the results of two recent parallel pointer analysis tools with a parallel control-flow analysis tool. While it has been known that a control-flow analysis of higher-order languages and a pointer analysis of first-order languages are very similar, we demonstrate that these two analyses are actually more similar than previously thought. We present the first mapping between a high-order control-flow analysis and a pointer analysis.
Server-side type profiling for optimizing client-side JavaScript engines
Authors: Kedlaya Madhukar N. , Robatmili Behnam , Hardekopf Ben
Published: May 2016

Modern JavaScript engines optimize hot functions using a JIT compiler along with type information gathered by an online profiler. However, the profiler's information can be unsound and when unexpected types are encountered the engine must recover using an expensive mechanism called deoptimization. In this paper we describe a method to significantly reduce the number of deoptimizations observed by client-side JavaScript engines by using ahead-of-time profiling on the server-side. Unlike previous work on ahead-of-time profiling for statically-typed languages such as Java, our technique must operate on a dynamically-typed language, which significantly changes the required insights and methods to make the technique effective. We implement our proposed technique using the SpiderMonkey JavaScript engine, and we evaluate our implementation using three different kinds of benchmarks: the industry-standard Octane benchmark suite, a set of JavaScript physics engines, and a set of real-world websites from the Membench50 benchmark suite. We show that using ahead-of-time profiling provides significant performance benefits over the baseline vanilla SpiderMonkey engine.
An empirical investigation of the effects of type systems and code completion on API usability using TypeScript and JavaScript in MS visual studio
Authors: Fischer Lars , Hanenberg Stefan
Published: May 2016

Recent empirical studies that compared static and dynamic type systems on API usability showed a positive impact of static type systems on developer productivity in most cases. Nevertheless, it is unclear how large this effect is in comparison to other factors. One obvious factor in programming is tooling: It is commonly accepted that modern IDEs have a large positive impact on developers, although it is not clear which parts of modern IDEs are responsible for that. One possible---and for most developers obvious candidate---is code completion. This paper describes a 2x2 randomized trial that compares JavaScript and Microsoft's statically typed alternative TypeScript with and without code completion in MS Visual Studio. While the experiment shows (in correspondence to previous experiments) a large positive effect of the statically typed language TypeScript, the code completion effect is not only marginal, but also just approaching statistical significance. This seems to be an indicator that the effect of static type systems is larger than often assumed, at least in comparison to code completion.
Access control to reflection with object ownership
Authors: Teruel Camille , Ducasse Stéphane , Cassou Damien , Denker Marcus
Published: May 2016

Reflection is a powerful programming language feature that enables language extensions, generic code, dynamic analyses, development tools, etc. However, uncontrolled reflection breaks object encapsulation and considerably increases the attack surface of programs e.g., malicious libraries can use reflection to attack their client applications. To bring reflection and object encapsulation back together, we use dynamic object ownership to design an access control policy to reflective operations. This policy grants objects full reflective power over the objects they own but limited reflective power over other objects. Code is still able to use advanced reflective operations but reflection cannot be used as an attack vector anymore.
CLOP: a multi-stage compiler to seamlessly embed heterogeneous code
Authors: Makarov Dmitri , Hauswirth Matthias
Published: May 2016

Heterogeneous programming complicates software development. We present CLOP, a platform that embeds code targeting heterogeneous compute devices in a convenient and clean way, allowing unobstructed data flow between the host code and the devices, reducing the amount of source code by an order of magnitude. The CLOP compiler uses the standard facilities of the D programming language to generate code strictly at compile-time. In this paper we describe the CLOP language and the CLOP compiler implementation.
Generative software product line development using variability-aware design patterns
Authors: Seidl Christoph , Schuster Sven , Schaefer Ina
Published: May 2016

Software Product Lines (SPLs) are an approach to reuse in-the-large that models a set of closely related software systems in terms of commonalities and variabilities. Design patterns are best practices for addressing recurring design problems in object-oriented source code. In the practice of implementing an SPL, instances of certain design patterns are employed to handle variability, which makes these "variability-aware design patterns" a best practice for SPL design. However, there currently is no dedicated method for proactively developing SPL using design patterns suitable for realizing variable functionality. In this paper, we present a method to perform generative SPL development with design patterns. We use role models to capture design patterns and their relation to a variability model. We further allow mapping of individual design pattern roles to elements of realization artifacts to be generated (e.g., classes, methods) and check the conformance of the realization with the specification of the pattern. With this method, we support proactive development of SPL using design patterns to apply best practices for the realization of variability. We present an implementation of our approach within the Eclipse IDE and demonstrate it within a case study.
Inverse macro in Scala
Authors: Yamaguchi Hiroshi , Chiba Shigeru
Published: May 2016

We propose a new variant of typed syntactic macro systems named inverse macro, which improves the expressiveness of macro systems. The inverse macro system enables to implement operators with complex side-effects, such as lazy operators and delimited continuation operators, which are beyond the power of existing macro systems. We have implemented the inverse macro system as an extension to Scala 2.11. We also show the expressiveness of the inverse macro system by comparing two versions of shift/reset, bundled in Scala 2.11 and implemented with the inverse macro system.
Contract-based general-purpose GPU programming
Authors: Kolesnichenko Alexey , Poskitt Christopher M. , Nanz Sebastian , Meyer Bertrand
Published: May 2016

Using GPUs as general-purpose processors has revolutionized parallel computing by offering, for a large and growing set of algorithms, massive data-parallelization on desktop machines. An obstacle to widespread adoption, however, is the difficulty of programming them and the low-level control of the hardware required to achieve good performance. This paper suggests a programming library, SafeGPU, that aims at striking a balance between programmer productivity and performance, by making GPU data-parallel operations accessible from within a classical object-oriented programming language. The solution is integrated with the design-by-contract approach, which increases confidence in functional program correctness by embedding executable program specifications into the program text. We show that our library leads to modular and maintainable code that is accessible to GPGPU non-experts, while providing performance that is comparable with hand-written CUDA code. Furthermore, runtime contract checking turns out to be feasible, as the contracts can be executed on the GPU.
Orchestrating masses of sensors: a design-driven development Approach
Authors: Kabáč Milan , Consel Charles
Published: May 2016

This paper proposes a design-driven development approach that is dedicated to the domain of orchestration of masses of sensors. The developer declares what an application does using a domain-specific language (DSL). Our compiler processes domain-specific declarations to generate a customized programming framework that guides and supports the programming phase.
The New Organizational Learning: A Review of Teaming
Authors: Quinn Clark
Published: May 2016

Amy Edmondson's new book, Teaming, points the way to the future of organizations. She makes a strong case that learning in organizations, the source of innovation, comes from people in teams. Professor Edmondson lays out the need for new structures, new processes, and new approaches for leadership. This review provides an overview and points out the contributions.
Relationship between pancreatic hormones and glucose metabolism: A cross-sectional study in patients after acute pancreatitis
Authors: Pendharkar Sayali A. , Asrani Varsha M. , Xiao Amy Y. , Yoon Harry D. , Murphy Rinki , Windsor John A. , Petrov Maxim S.
Published: May 2016

Abnormal glucose metabolism is present in almost 40% of patients after acute pancreatitis, but its pathophysiology has been poorly investigated. Pancreatic hormone derangements have been sparingly studied to date, and their relationship with abnormal glucose metabolism is largely unknown. The aim was to investigate the associations between pancreatic hormones and glucose metabolism after acute pancreatitis, including the effect of potential confounders. This was a cross-sectional study of 83 adult patients after acute pancreatitis. Fasting venous blood was collected from all patients and used for analysis of insulin, glucagon, pancreatic polypeptide, amylin, somatostatin, C-peptide, glucose, and hemoglobin A1c. Statistical analyses were conducted using the modified Poisson regression, multivariable linear regression, and Spearman's correlation. Age, sex, body mass index, recurrence of acute pancreatitis, duration from first attack, severity, and etiology were adjusted for. Increased insulin was significantly associated with abnormal glucose metabolism after acute pancreatitis, in both unadjusted ( P = 0.038) and adjusted ( P = 0.001) analyses. Patients with abnormal glucose metabolism also had significantly decreased pancreatic polypeptide ( P = 0.001) and increased amylin ( P = 0.047) in adjusted analyses. Somatostatin, C-peptide, and glucagon were not changed significantly in both unadjusted and adjusted analyses. Increased insulin resistance and reduced insulin clearance may be important components of hyperinsulinemic compensation in patients after acute pancreatitis. Increased amylin and reduced pancreatic polypeptide fasting levels characterize impaired glucose homeostasis. Clinical studies investigating islet-cell hormonal responses to mixed-nutrient meal testing and euglycemic-hyperinsulinemic clamps are now warranted for further insights into the role of pancreatic hormones in glucose metabolism derangements secondary to pancreatic diseases.
Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance ofNippostrongylus brasiliensisthrough induction of TH2 cytokines
Authors: McLean Leon P. , Smith Allen , Cheung Lumei , Urban Joseph F. , Sun Rex , Grinchuk Viktoriya , Desai Neemesh , Zhao Aiping , Raufman Jean-Pierre , Shea-Donohue Terez
Published: May 2016

Despite increased appreciation for the role of nicotinic receptors in the modulation of and response to inflammation, the contribution of muscarinic receptors to mucosal homeostasis, clearance of enteric pathogens, and modulation of immune cell function remains relatively undefined. Uninfected and Nippostrongylus brasiliensis-infected wild-type and type 3 muscarinic receptor (M3R)-deficient ( Chrm3−/−) mice were studied to determine the contribution of M3R to mucosal homeostasis as well as host defense against the TH2-eliciting enteric nematode N. brasiliensis. Intestinal permeability and expression of TH1/TH17 cytokines were increased in uninfected Chrm3−/−small intestine. Notably, in Chrm3−/−mice infected with N. brasiliensis, small intestinal upregulation of TH2 cytokines was attenuated and nematode clearance was delayed. In Chrm3−/−mice, TH2-dependent changes in small intestinal function including smooth muscle hypercontractility, increased epithelial permeability, decreased epithelial secretion and absorption, and goblet cell expansion were absent despite N. brasiliensis infection. These findings identify an important role for M3R in host defense and clearance of N. brasiliensis, and support the expanding role of cholinergic muscarinic receptors in maintaining mucosal homeostasis.
Association between Body Powder Use and Ovarian Cancer: The African American Cancer Epidemiology Study (AACES)
Authors: Schildkraut Joellen M. , Abbott Sarah E. , Alberg Anthony J. , Bandera Elisa V. , Barnholtz-Sloan Jill S. , Bondy Melissa L. , Cote Michele L. , Funkhouser Ellen , Peres Lauren C. , Peters Edward S. , Schwartz Ann G. , Terry Paul , Crankshaw Sydnee , Camacho Fabian , Wang Frances , Moorman Patricia G.
Published: May 2016

Background: Epidemiologic studies indicate increased ovarian cancer risk among women who use genital powder, but this has not been thoroughly investigated in African American (AA) women, a group with a high prevalence of use. We evaluate the relationship between use of genital powder and nongenital powder in invasive epithelial ovarian cancer (EOC).

Methods: Subjects are 584 cases and 745 controls enrolled in the African American Cancer Epidemiology Study (AACES), an ongoing, population-based case–control study of EOC in AA women in 11 geographic locations in the United States. AA controls were frequency matched to cases on residence and age. Logistic regression was used to calculate ORs and 95% confidence intervals (CI) for associations between genital and nongenital powder exposure and EOC risk, controlling for potential confounders.

Results: Powder use was common (62.8% of cases and 52.9% of controls). Genital powder was associated with an increased risk of EOC (OR = 1.44; 95% CI, 1.11–1.86) and a dose–response relationship was found for duration of use and number of lifetime applications (P < 0.05). Nongenital use was also associated with EOC risk, particularly among nonserous EOC cases (OR = 2.28; 95% CI, 1.39–3.74). An association between powder use and upper respiratory conditions suggests an enhanced inflammatory response may explain the association between body powder and EOC.

Conclusions: In a study of AA women, body powder use was significantly associated with EOC risk.

Impact: The results support that body powder is a modifiable risk factor for EOC among AA women. Cancer Epidemiol Biomarkers Prev; 25(10); 1411–7. ©2016 AACR.

See related commentary by Trabert, p. 1369
Loss of ARID1A Activates ANXA1, which Serves as a Predictive Biomarker for Trastuzumab Resistance
Authors: Berns Katrien , Sonnenblick Amir , Gennissen Annemiek , Brohée Sylvain , Hijmans E. Marielle , Evers Bastiaan , Fumagalli Debora , Desmedt Christine , Loibl Sibylle , Denkert Carsten , Neven Patrick , Guo Wei , Zhang Fan , Knijnenburg Theo A. , Bosse Tjalling , van der Heijden Michiel S. , Hindriksen Sanne , Nijkamp Wouter , Wessels Lodewyk F.A. , Joensuu Heikki , Mills Gordon B. , Beijersbergen Roderick L. , Sotiriou Christos , Bernards René
Published: May 2016

Purpose: Despite the substantial progress in the development of targeted anticancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment.

Experimental Design: Genome-wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTOR targeting agents in HER2+ breast cancer cell lines. Expression and adjuvant trastuzumab response data from the HER2+ breast cancer trials FinHer and Responsify were used to validate our findings in patient series.

Results: We find that reduced ARID1A expression confers resistance to several drugs that inhibit the HER2/PI3K/mTOR signaling cascade at different levels. We demonstrate that ARID1A loss activates annexin A1 (ANXA1) expression, which is required for drug resistance through its activation of AKT. We find that the AKT inhibitor MK2206 restores sensitivity of ARID1A knockdown breast cancer cells to both the mTOR kinase inhibitor AZD8055 and trastuzumab. Consistent with these in vitro data, we find in two independent HER2+ breast cancer patient series that high ANXA1 expression is associated with resistance to adjuvant trastuzumab–based therapy.

Conclusions: Our findings provide a rationale for why tumors accumulate ARID1A mutations and identify high ANXA1 expression as a predictive biomarker for trastuzumab-based treatment. Our findings also suggest strategies to treat breast cancers with elevated ANXA1 expression. Clin Cancer Res; 22(21); 5238–48. ©2016 AACR.
Zukunftsperspektiven auf dem Gebiet der pulmonal-arteriellen Hypertonie
Authors: Rubin Lewis
Published: May 2016

In einem bemerkenswert kurzen Zeitraum hat sich die pulmonal-arteriellen Hypertonie (PAH) von einer Krankheit unbekannter Pathogenese ohne wirksame Therapie zu einem pathologischen Zustand entwickelt, dessen zelluläre und molekulare Grundlagen immer besser bekannt sind und für den mittlerweile drei Therapieklassen zur Verfügung stehen. Dennoch bleibt die PAH unheilbar und ist oft refraktär gegenüber medikamentöser Therapie, was die Notwendigkeit weiterer Forschung unterstreicht. In diesem Bei- trag werden einige der meistbeachteten Forschungsansätze zur Pathogenese, Diagnose und Überwachung sowie neue Therapieansätze vorgestellt, die hoffentlich künftig Einzug in die klinische Praxis halten.
Referenzwerte für statische Lungenvolumina und TLCO einer Populationsstichprobe in Nordgriechenland
Authors: Preisser Alexandra M.
Published: May 2016

Hintergrund: Die am häufigsten verwendeten Referenzgleichungen zur Messung statischer Lungenvolumina/-kapazitäten und des CO-Transferfaktors der Lunge (TLCO) gehen auf rund 30-40 Jahre alte Studien zurück, die erhebliche Einschränkungen aufweisen. Ziele: Unser Ziel war es, (1) Referenzgleichungen für statische Lungenvolumina und TLCO unter Verwendung der aktuellen Leitlinien der American Thoracic Society / European Respiratory Society zu entwickeln und (2) diese Gleichungen mit denen abzustimmen, die am häufigsten angewendet werden. Methoden: Es wurden gesunde Probanden kaukasischen Ursprungs (234 männlich und 233 weiblich) im Alter von 18 bis 91 Jahren rekrutiert. Alle waren gesund, mit unauffälligem Röntgenbefund des Thorax, und hatten nie geraucht. Statische Lungenvolumina und TLCO wurden gemäß den aktuellen Leitlinien mittels Single-Breath-Methode ermittelt. Ergebnisse: Kurvilineare Regressions-Vorhersagegleichungen, die aus der vorliegenden Studie abgeleitet wurden, wurden mit den derzeit gebräuchlichsten Gleichungen verglichen. Unsere Referenzgleichungen auf der Grundlage der neuesten Studien ergaben niedrigere Werte für alle statischen Lungenvolumenparameter und TLCO sowie eine andere Art der Abweichung dieser Parameter (nämlich mit dem Alter abnehmende Gesamtlungenkapazität sowie sinkender TLCO bei beiden Geschlechtern, außerdem Anstieg der funktionellen Residualkapazität bei Männern). Schlussfolgerungen: Wir schlagen vor, die alten Referenzwerte für statische Lungenvolumina und TLCO zu aktualisieren; zudem sollte die Interpretation von Abweichungen bei verschiedenen spirometrischen Parametern geändert werden. Unsere neuen kurvilinearen Referenzgleichungen, die gemäß den aktuellen Leitlinien entwickelt wurden, könnten zur Aktualisierung der alten, bestehenden Referenzwerte durch die Fachgesellschaften und damit zur besseren Einschätzung der Lungenfunktion von Populationen beitragen, deren Merkmale mit denen der hier untersuchten Population kaukasischen Ursprungs vergleichbar sind.Übersetzung aus Respiration 2015; 89:226-234 (DOI:10.1159/000371469)
Quality of the Patient Experience during Radiosurgery: Measurement toward Improvement
Authors: Kondziolka Douglas , LoPresti Melissa , Tyburczy Amy , Golden Cassandra , Seto Timmy , Boulio Lynda , Doody Caitlyn , Yeh Brian , Silverman Joshua
Published: May 2016

Background: All physicians seek to improve the patient experience. In an awake surgical procedure, the patient has a unique opportunity to comment on all aspects of care. The provision of a positive experience is part of quality health care. Our purpose was to define this experience to determine areas for improvement. Methods: We evaluated 125 patients who underwent stereotactic radiosurgery using a frame-based, gamma knife technique. Patients were surveyed by a nurse practitioner across all elements of their procedural experience prior to same-day discharge. Results: The radiosurgery was completed in all patients with same-day discharge. In an initial 100-patient cohort, 89 patients said they had received adequate oral and/or intravenous sedation before the procedure. All 100 patients said that they felt comfortable before stereotactic frame application, and all patients later remembered frame application. These patients described frame application as very or adequately comfortable (n = 73), minimally uncomfortable (n = 18), or very uncomfortable (n = 9). Neuroimaging was described as very or adequately comfortable (n = 93), minimally uncomfortable (n = 3), or very uncomfortable (n = 4). Radiosurgery in the gamma knife unit was found to be very or adequately comfortable (n = 99) or very uncomfortable (n = 1). We evaluated how 8 separate factors may have contributed to survey responses related to procedural comfort. These factors included intravenous line placement, delivery of sedation medications, application of the head frame, having the MRI, having radiosurgery on the gamma knife bed, removal of the stereotactic frame, communication with caregivers, and knowing what to expect beforehand. We asked the patients to rate their nursing care during the radiosurgery experience, and ‘excellent' was chosen by all initial 100 patients. Other elements of the procedure were also studied as well as suggestions for improvement. As a secondary objective, we then modified our protocol to include sodium bicarbonate added to the local anesthetic for frame application and evaluated an additional cohort of 25 patients. Conclusions: Utilizing a system of physician and nursing education, together with pharmacological sedation and efficient procedural steps, patients said that intravenous line placement (91%), stereotactic frame application (74%), MRI (93%), receiving radiosurgery in the unit (99%), frame removal (84%), communication with caregivers (100%), and knowing what to expect beforehand (97%) were either very or adequately comfortable. Specific evaluations of care processes can lead to care improvement.
Improving the Accuracy of Diagnosing Placenta Previa on Transvaginal Ultrasound by Distinguishing between the Uterine Isthmus and Cervix: A Prospective Multicenter Observational Study
Authors: Hasegawa Junichi , Kawabata Ikuno , Takeda Yoshiharu , Aoki Hiroaki , Fukami Takehiko , Tajima Atsushi , Miyakoshi Kei , Otsuki Katsufumi , Shinozuka Norio , Matsuda Yoshio , Iwashita Mitsutoshi , Okai Takashi , Nakai Akihito ,   Japanese Organization of Prevention of Preterm delivery (JOPP)
Published: May 2016

Objective: To clarify whether distinguishing between the uterine isthmus and cervix can improve the accuracy of diagnosing placenta previa at term. Methods: A multicenter prospective observational study was conducted among pregnant women with suspected placenta previa at 20-24 weeks' gestation. Subjects were divided into the open isthmus group and closed isthmus group. The accuracy of diagnosing placenta previa at term was compared between the 2 groups. Results: We screened 9,341 patients, and 53 (0.6%) met the inclusion criteria. Nineteen cases with an open isthmus and 34 with a closed isthmus were followed. The accuracy for diagnosing placenta previa or a low-lying placenta at term was 94.7% in the open isthmus group and 26.5% in the closed isthmus group (p < 0.001). Elective or emergency Cesarean section was required in 100% of cases in the open isthmus group and 20.6% in the closed isthmus group (p < 0.001). Conclusion: A high prediction rate of placenta previa was obtained by using transvaginal ultrasound at 20-24 weeks' gestation after the isthmus opened by carefully distinguishing between the cervix and isthmus.
Current Challenges in the Evaluation and Management of Hyponatremia
Authors: McGreal Kerri , Budhiraja Pooja , Jain Nishank , Yu Alan S.L.
Published: May 2016

Background: Hyponatremia is a common electrolyte imbalance that clinicians face on a regular basis. Summary: This review aims to discuss four current challenges that can arise when diagnosing and treating hyponatremia: low solute intake, heart failure, exercise-associated hyponatremia, and mild chronic hyponatremia. Low solute intake in a person who already has a urinary concentrating defect will lead to increased retention of free water. The free water retention will cause or worsen hyponatremia that is already present. Low solute intake is overlooked in patients with other disease processes that can cause hyponatremia, such as liver disease or heart failure. Heart failure and hyponatremia present their own set of challenges specifically with treatment as there are limited options. The newer class of aquaretics allows for the short-term treatment of hyponatremia. Exercise-associated hyponatremia is a phenomenon that has been described in ultra-endurance athletes. This happens when a person drinks a significant amount of water while exercising in the setting of antidiuretic hormone production from prolonged exercise. This acute drop in sodium must be treated with hypertonic saline. The term asymptomatic mild chronic hyponatremia is no longer valid. Mild chronic hyponatremia carries an increased risk of falls and fractures, specifically in the elderly populations. Key Message: In summary, hyponatremia is a multifaceted disease and presents many challenges for physicians treating it.
Different Pathophysiology of Gastritis in East and West? A Western Perspective
Authors: Wirth Hans-Peter , Yang Manqiao
Published: May 2016

Background: Gastritis results from multifactorial gastric mucosal injury. Helicobacter pylori(Hp) is the main cause, and associated diseases have typical underlying patterns of gastritis. Gastric ulcer and gastric cancer (GC) develop from chronic atrophic corpus gastritis (CAG) which therefore represents the most important pattern. GC incidences in East Asia are substantially higher than elsewhere, and this should be also reflected by higher prevalences of CAG and characteristic differences in pathophysiology compared to the West. Summary: The few available comparative studies of gastritis in Eastern and Western patients are summarized. The main pathogenic factors of gastritis are discussed together with their limitations to explain local differences in disease outcome. Emphasis was put to also include less well-established pathogenic host and environmental factors of possible impact. Conclusions: CAG is more prevalent in East Asian areas with high GC incidences than the West. Geographic heterogeneity of associated diseases is due to differences in Hp prevalence and virulence as well as modulating host and environmental factors. The following may contribute to the higher burden of CAG in the East: ABD type of CagA with vacA s1 and babA2 alleles of Hp, host Lewis(b) expression in sej/sej nonsecretors, H. heilmannii, low parietal cell mass, high sodium and nitrate intake, preferences in vegetable and fruit consumption, cigarette smoking, air pollution, alcohol. Conversely, green tea, nonfermented soy products and rice may confer protective effects. Hp is on the decline, but also in a world cleared from this bacterium, differences in host genetics will continue to modify gastric disease outcome together with maintained customs as part of cultural diversity.
Hypothalamic-Pituitary-Gonadal Axis in Aging Men and Women: Increasing Total Testosterone in Aging Men
Authors: Xia Fangzhen , Wang Ningjian , Han Bing , Li Qin , Chen Yi , Zhu Chunfang , Chen Yingchao , Pu Xiaoqi , Cang Zhen , Zhu Chaoxia , Lu Meng , Meng Ying , Guo Hui , Chen Chi , Lin Dongping , Zheng Junke , Kuang Lin , Tu Weiping , Li Bin , Hu Lin , Shen Zhoujun , Lu Yingli
Published: May 2016

Background: Aging is associated with variations in hypothalamic-pituitary-gonadal (HPG) axis hormones. However, it is not clear how aging changes these hormones. This study examined the natural alterations in the HPG axis in aging men and women in China. Methods: Data were obtained from our cross-sectional study (SPECT-China) in 16 areas of three provinces in East China between February and June 2014. There were 6,825 subjects selected, including 2,908 men and 3,917 women aged 25-93 years who had no diseases affecting HPG hormones and did not take exogenous supplements. Total testosterone (TT), estradiol (E2), free testosterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured. Results: In men, the ranges of the 10-90th percentiles for each hormone were as follows: TT, 9.9-23.4 nmol/l; SHBG, 20.6-79.54 nmol/l; E2, 34.84-187 pmol/l. TT values were higher in men aged 25-30 years than in those aged 31-35 years and began to increase progressively at the age of 41-50 years until men reached their eighties. The unadjusted annual age trend (β) was 0.079 nmol/l/year (p < 0.001). A linear regression analysis, after full adjustment for demographic variables, metabolic factors, other hormones, lifestyle and co-morbidities, showed that higher TT levels were still associated with aging (p < 0.05). However, the ratio of TT to LH decreased with age (β = -0.272/year, p < 0.001). E2 and SHBG increased with age (β = 1.774 pmol/l/year and 1.118 nmol/l/year, respectively, p < 0.001). In women, the 10-90th percentile range of E2 was 32.79-565.8 pmol/l. E2 began to decrease at the age of 46-50 years, declined sharply at the age of 51-55 years (β = -5.73 pmol/l/year, p < 0.001) and then stabilized at a low concentration after the age of 55 years. The 10-90th percentile ranges of LH and FSH in men were 2.4-9.2 and 3.4-15.5 IU/l, and in women they were 3-36.6 and 4-89.28 IU/l, respectively. FSH increased by 7.11% per annum in men and by 12.76% per annum in women, but LH increased by only approximately 4.00% per annum in both sexes. Conclusions: The influence of aging on the HPG axis is sex dependent. The pattern of age-related TT was different in Chinese Han men when compared with previous studies in Western populations. TT values increased in aging men, so it is not suitable to estimate the life quality of older Chinese men just based on TT.
A novel thromboxane receptor antagonist, nstpbp5185, inhibits platelet aggregation and thrombus formation in animal models
Authors: Huang Shiu-Wen , Kuo Heng-Lan , Hsu Ming-Tsung , Tseng Yufeng Jane , Lin Shu-Wha , Kuo Sheng-Chu , Peng Hui-Chin , Lien Jin-Cherng , Huang Tur-Fu
Published: May 2016

A novel benzimidazole derivative, nstpbp5185, was discovered through in vitro and in vivo evaluations for antiplatelet activity. Thro-maboxane receptor (TP) is important in vascular physiology, haemostasis and pathophysiological thrombosis. Nstpbp5185 concentration-dependently inhibited human platelet aggregation caused by collagen, arachidonic acid and U46619. Nstpbp5185 caused a right-shift of the concentration-response curve of U46619 and competitively inhibited the binding of 3H-SQ-29548 to TP receptor expressed on HEK-293 cells, with an IC50 of 0.1 μM, indicating that nstpbp5185 is a TP antagonist. In murine thrombosis models, nstpbp5185 significantly prolonged the latent period in triggering platelet plug formation in mesenteric and FeCl3-induced thrombi formation, and increased the survival rate in pulmonary embolism model with less bleeding than aspirin. This study suggests nstpbp5185, an orally selective antithrombotic agent, acting through blockade of TXA2 receptor, may be efficacious for prevention or treatment of pathologic thrombosis.

Supplementary Material to this article is available online at www.thrombosis-online.com.