bluuebunny/crossref_metadata_2025 huggingface dataset:
How to compute worst-case execution time by optimization modulo theory and a clever encoding of program semantics
Authors: Henry Julien , Asavoae Mihail , Monniaux David , Maïza Claire
Published: September 2014

In systems with hard real-time constraints, it is necessary to compute upper bounds on the worst-case execution time (WCET) of programs; the closer the bound to the real WCET, the better. This is especially the case of synchronous reactive control loops with a fixed clock; the WCET of the loop body must not exceed the clock period.

We compute the WCET (or at least a close upper bound thereof) as the solution of an optimization modulo theory problem that takes into account the semantics of the program, in contrast to other methods that compute the longest path whether or not it is feasible according to these semantics. Optimization modulo theory extends satisfiability modulo theory (SMT) to maximization problems.

Immediate encodings of WCET problems into SMT yield formulas intractable for all current production-grade solvers --- this is inherent to the DPLL(T) approach to SMT implemented in these solvers. By conjoining some appropriate "cuts" to these formulas, we considerably reduce the computation time of the SMT-solver.

We experimented our approach on a variety of control programs, using the OTAWA analyzer both as baseline and as underlying microarchitectural analysis for our analysis, and show notable improvement on the WCET bound on a variety of benchmarks and control programs.
em-SPADE
Authors: Chaudhary Sandeep , Fischmeister Sebastian , Tan Lin
Published: September 2014

Traditional compilers ignore processor specifications, thousands of pages of which are available for modern processors. To bridge this gap, em-SPADE analyzes processor specifications and creates processor-specific rules to reduce low-level programming errors. This work shows the potential of automatically analyzing processor- and other hardware specifications to detect low-level programming errors at compile time.

em-SPADE is a compiler extension to automatically detect software bugs in low-level programs. From processor specifications, a preprocessor extracts target-specific rules such as register use and read-only or reserved registers. A special LLVM pass then uses these rules to detect incorrect register assignments. Our experiments with em-SPADE have correctly extracted 652 rules from 15 specifications and consequently found 20 bugs in ten software projects. The work is generalizable to other types of specifications and shows the clear prospects of using hardware specifications to enhance compilers.
Lightweight and block-level concurrent sweeping for javascript garbage collection
Authors: Kim Hongjune , Bak Seonmyeong , Lee Jaejin
Published: September 2014

JavaScript is a dynamic-typed language originally developed for the purpose of giving dynamic client-side behaviors to web pages. It is mainly used in web application development and because of its popularity and rapid development style it is now also used in other types of applications. Increasing data processing requirements and growing usage in more resource-limited environments, such as mobile devices, has given demands for JavaScript implementations to handle memory more efficiently through garbage collection.

Since aggressive use of time consuming operations in garbage collection can slow down the JavaScript application, there is a trade-off relationship between the effectiveness and the execution time of garbage collection.

In this paper, we present a lightweight, block-level concurrent sweeping mechanism for a mark-and-sweep garbage collector. The sweeping process is detached to an additional thread to eagerly collect free memory blocks and recycle it. To minimize the overhead that comes from the synchronization between the mutator thread and the new sweeping thread, we have chosen a course grained block-level collecting scheme for sweeping. To avoid contention that comes from object destruction, we execute the object destruction phase concurrently with the foreground marking phase.

We have implemented our algorithm in JavaScript Core (JSC) engine embedded in the WebKit browser that uses a variant of mark-and-sweep algorithm to manage JavaScript objects. The original garbage collection implementation performs lazy sweeping that cannot reuse the free blocks. We evaluate our implementation on an ARM-based mobile system and show that memory utilization of the system is significantly improved without performance degradation.
Improving performance of loops on DIAM-based VLIW architectures
Authors: Lee Jinyong , Lee Jongwon , Lee Jongeun , Paek Yunheung
Published: September 2014

Recent studies show that very long instruction word (VLIW) architectures, which inherently have wide datapath (e.g. 128 or 256 bits for one VLIW instruction word), can benefit from dynamic implied addressing mode (DIAM) and can achieve lower power consumption and smaller code size with a small performance overhead. Such overhead, which is claimed to be small, is mainly caused by the execution of additionally generated special instructions for conveying information that cannot be encoded in reduced instruction bit-width. In this paper, however, we show that the performance impact of applying DIAM on VLIW architecture cannot be overlooked expecially when applications possess high level of instruction level parallelism (ILP), which is mostly the case for loops because of the result of aggressive code scheduling. We also propose a way to relieve the performance degradation especially focusing on loops since loops spend almost 90% of total execution time in programs and tend to have high ILP. We first implement the original DIAM compilation technique in a compiler, and augment it with the proposed loop optimization scheme to show that ours can clearly alleviate the performance loss caused by the excessive number of additional instructions, with the help of slightly modified hardware. Moreover, the well-known loop unrolling scheme, which would produce denser code in loops at the cost of substantial code size bloating, is integrated into our compiler. The experiment result shows that the loop unrolling technique, combined with our augmented DIAM scheme, produces far better code in terms of performance with quite an acceptable amount of code increase.
Energy efficient data access techniques
Authors: Whalley David
Published: September 2014

Energy has become a first class design constraint for all types of processors. Data accesses contribute to processor energy usage and can account for up to 25% of the total energy used in embedded processors. Using a set-associative level-one data cache (L1 DC) organization is particularly energy inefficient as load operations access all L1 DC tag and data arrays in parallel to reduce access latency, but the data can reside in at most one way. Techniques that reduce L1 DC energy usage at the expense of degrading performance, such as filter caches, have not been adopted. In this presentation I will describe various techniques we have developed to reduce the energy usage for L1 DC accesses without adversely affecting performance. These techniques include avoiding unnecessary loads from L1 DC data arrays and a practical data filter cache design that not only significantly reduces data access energy usage, but also avoids the traditional execution time penalty associated with data filter caches.
Efficient resource placement in cloud computing and network applications
Authors: Rochman Yuval , Levy Hanoch , Brosh Eli
Published: September 2014

We address the problem of resource placement in general networking applications, in particular cloud computing. We consider a large-scale service faced by regionally distributed demands for various resources. The service aims at placing the resources across regions to maximize profit, accounting for demand granting revenues minus resource placement costs. Cloud computing and online services, utilizing regional datacenters and facing the problem of where and how much to place various servers, naturally fall under this paradigm.

The main challenge posed by this setting is the need to deal with arbitrary multi-dimensional stochastic demands. We show that, despite the challenging stochastic combinatorial complexity, one can optimize the system operation using fairly efficient algorithms.
Probiotics normalize the gut-brain-microbiota axis in immunodeficient mice
Authors: Smith Carli J. , Emge Jacob R. , Berzins Katrina , Lung Lydia , Khamishon Rebecca , Shah Paarth , Rodrigues David M. , Sousa Andrew J. , Reardon Colin , Sherman Philip M. , Barrett Kim E. , Gareau Mélanie G.
Published: September 2014

The gut-brain-microbiota axis is increasingly recognized as an important regulator of intestinal physiology. Exposure to psychological stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis and causes altered intestinal barrier function, intestinal dysbiosis, and behavioral changes. The primary aim of this study was to determine whether the effects of psychological stress on intestinal physiology and behavior, including anxiety and memory, are mediated by the adaptive immune system. Furthermore, we wanted to determine whether treatment with probiotics would normalize these effects. Here we demonstrate that B and T cell-deficient Rag1 −/− mice displayed altered baseline behaviors, including memory and anxiety, accompanied by an overactive HPA axis, increased intestinal secretory state, dysbiosis, and decreased hippocampal c-Fos expression. Both local (intestinal physiology and microbiota) and central (behavioral and hippocampal c-Fos) changes were normalized by pretreatment with probiotics, indicating an overall benefit on health conferred by changes in the microbiota, independent of lymphocytes. Taken together, these findings indicate a role for adaptive immune cells in maintaining normal intestinal and brain health in mice and show that probiotics can overcome this immune-mediated deficit in the gut-brain-microbiota axis.
Earl Wood–A research career noted for development of novel instruments driven by the power of the indicator dilution concept
Authors: Ritman Erik L.
Published: September 2014

During World War 2, Earl Wood was charged with elucidating the biomedical factors in acceleration-induced loss of consciousness experienced by pilots in high-performance aircraft. For this, he developed devices for measurement and recording of blood pressure and tissue blood content. Those data lead to the design and fabrication of successful countermeasures to acceleration-induced loss of consciousness with an inflatable “G-suit” and “M1” breath-holding maneuver. After World War 2, he utilized and modified these instruments and made use of indicator dilution techniques by continuous intracardiac blood sampling to greatly increase the specificity and sensitivity of diagnosis of intracardiac anatomic and functional abnormalities in patients with congenital heart disease. This contributed to the greatly increased success rate of open-heart surgery in the 1950s. In the 1960s, he built on the then recently available video-coupled electronic X-ray image intensifier to develop X-ray fluoroscopy-based recording of indicator dilution signals in all cardiac chambers and surrounding great vessels without the need for placing catheter tips at those locations for blood sampling. However, these blood flow-related data were of limited value, as they were not measured concurrent with myocardial functional demand for perfusion. In the 1970s, he overcame this limitation by developing a high-speed multislice X-ray imaging scanner to provide tomographic images of concurrent dynamic cardiac anatomy and the indicator dilution-based estimates of blood flow distributions. On his retirement at age 70 in 1982, he had accomplished his 2 decade-old goal of the ability to make accurate concurrent, minimally invasive, and indicator dilution-based measurement of cardiovascular structure to function relationships.
Macroscopic Ensembles of Aligned Carbon Nanotubes in Bubble Imprints Studied by Polarized Raman Microscopy
Authors: Ushiba Shota , Hoyt Jordan , Masui Kyoko , Kono Junichiro , Kawata Satoshi , Shoji Satoru
Published: September 2014

We study the alignment of single‐wall carbon nanotubes (SWCNTs) in bubble imprints through polarized Raman microscopy. A hemispherical bubble containing SWCNTs is pressed against a glass substrate, resulting in an imprint of the bubble membrane with a coffee ring on the substrate. We find that macroscopic ensembles of aligned SWCNTs are obtained in the imprints, in which there are three patterns of orientations: (i) azimuthal alignment on the coffee ring, (ii) radial alignment at the edge of the membrane, and (iii) random orientation at the center of the membrane. We also find that the alignment of SWCNTs in the imprints can be manipulated by spinning bubbles. The orientation of SWCNTs on the coffee ring is directed radially, which is orthogonal to the case of unspun bubbles. This approach enables one to align SWCNTs in large quantities and in a short time, potentially opening up a wide range of CNT‐based electronic and optical applications.
Simplified Pedestrian Tracking Filters with Positioning and Foot-Mounted Inertial Sensors
Authors: Martin Henar , Besada Juan A. , Bernardos Ana M. , Metola Eduardo , Casar José R.
Published: September 2014

Pedestrian tracking is one of the bases for many ubiquitous context-aware services, but it is still an open issue in indoor environments or when GPS estimations are not optimal. In this paper, we propose two novel different data fusion algorithms to track a pedestrian using current positioning technologies (i.e., GPS, received signal strength localization from Wi-Fi or Bluetooth networks, etc.) and low cost inertial sensors. In particular, the algorithms rely, respectively, on an extended Kalman filter (EKF) and a simplified complementary Kalman filter (KF). Both approaches have been tested with real data, showing clear accuracy improvement with respect to raw positioning data, with much reduced computational cost with respect to previous high performance solutions in literature. The fusion of both inputs is done in a loosely coupled way, so the system can adapt to the infrastructure that is available at a specific moment, delivering both outdoors and indoors solutions.
Robust Adaptive Fault-Tolerant Tracking Control of Three-Phase Induction Motor
Authors: Tohidi Hossein , Erenturk Koksal
Published: September 2014

This paper deals with the problem of induction motor tracking control against actuator faults and external disturbances using the linear matrix inequalities (LMIs) method and the adaptive method. A direct adaptive fault-tolerant tracking controller design method is developed based on Lyapunov stability theory and a constructive algorithm based on linear matrix inequalities for online tuning of adaptive and state feedback gains to stabilize the closed-loop system in order to reduce the fault effect with disturbance attenuation. Simulation results reveal the merits of proposed robust adaptive fault-tolerant tracking control scheme on an induction motor subjected to actuator faults.
Network Modeling of TGFβ Signaling in Hepatocellular Carcinoma Epithelial-to-Mesenchymal Transition Reveals Joint Sonic Hedgehog and Wnt Pathway Activation
Authors: Steinway Steven Nathaniel , Zañudo Jorge G.T. , Ding Wei , Rountree Carl Bart , Feith David J. , Loughran Thomas P. , Albert Reka
Published: September 2014

Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to leave the primary tumor site, invade surrounding tissue, and establish distant metastases. A hallmark of EMT is the loss of E-cadherin expression, and one major signal for the induction of EMT is TGFβ, which is dysregulated in up to 40% of hepatocellular carcinoma (HCC). We have constructed an EMT network of 70 nodes and 135 edges by integrating the signaling pathways involved in developmental EMT and known dysregulations in invasive HCC. We then used discrete dynamic modeling to understand the dynamics of the EMT network driven by TGFβ. Our network model recapitulates known dysregulations during the induction of EMT and predicts the activation of the Wnt and Sonic hedgehog (SHH) signaling pathways during this process. We show, across multiple murine (P2E and P2M) and human HCC cell lines (Huh7, PLC/PRF/5, HLE, and HLF), that the TGFβ signaling axis is a conserved driver of mesenchymal phenotype HCC and confirm that Wnt and SHH signaling are induced in these cell lines. Furthermore, we identify by network analysis eight regulatory feedback motifs that stabilize the EMT process and show that these motifs involve cross-talk among multiple major pathways. Our model will be useful in identifying potential therapeutic targets for the suppression of EMT, invasion, and metastasis in HCC. Cancer Res; 74(21); 5963–77. ©2014 AACR.
Targeting the Oncogenic MUC1-C Protein Inhibits Mutant EGFR-Mediated Signaling and Survival in Non–Small Cell Lung Cancer Cells
Authors: Kharbanda Akriti , Rajabi Hasan , Jin Caining , Tchaicha Jeremy , Kikuchi Eiki , Wong Kwok-Kin , Kufe Donald
Published: September 2014

Purpose: Non–small cell lung cancers (NSCLC) that express EGF receptor with activating mutations frequently develop resistance to EGFR kinase inhibitors. The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in NSCLC cells and confers a poor prognosis; however, the functional involvement of MUC1 in mutant EGFR signaling is not known.

Experimental Design: Targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in NSCLC cells harboring mutant EGFR was studied for effects on signaling, growth, clonogenic survival, and tumorigenicity.

Results: Stable silencing of MUC1-C in H1975/EGFR(L858R/T790M) cells resulted in downregulation of AKT signaling and inhibition of growth, colony formation, and tumorigenicity. Similar findings were obtained when MUC1-C was silenced in gefitinib-resistant PC9GR cells expressing EGFR(delE746_A750/T790M). The results further show that expression of a MUC1-C(CQC→AQA) mutant, which blocks MUC1-C homodimerization, suppresses EGFR(T790M), AKT and MEK→ERK activation, colony formation, and tumorigenicity. In concert with these results, treatment of H1975 and PC9GR cells with GO-203, a cell-penetrating peptide that blocks MUC1-C homodimerization, resulted in inhibition of EGFR, AKT, and MEK→ERK signaling and in loss of survival. Combination studies of GO-203 and afatinib, an irreversible inhibitor of EGFR, further demonstrate that these agents are synergistic in inhibiting growth of NSCLC cells harboring the activating EGFR(T790M) or EGFR(delE746-A750) mutants.

Conclusions: These findings indicate that targeting MUC1-C inhibits mutant EGFR signaling and survival, and thus represents a potential approach alone and in combination for the treatment of NSCLCs resistant to EGFR kinase inhibitors. Clin Cancer Res; 20(21); 5423–34. ©2014 AACR.
Lung Squamous Cell Carcinomas with Basaloid Histology Represent a Specific Molecular Entity
Authors: Brambilla Christian , Laffaire Julien , Lantuejoul Sylvie , Moro-Sibilot Denis , Mignotte Hélène , Arbib François , Toffart Anne-Claire , Petel Fabien , Hainaut Pierre , Rousseaux Sophie , Khochbin Saadi , de Reyniès Aurélien , Brambilla Elisabeth
Published: September 2014

Purpose: The basaloid carcinoma (pure) and the (mixed) basaloid variant of lung squamous cell carcinoma (SCC) have a dismal prognosis but their underlying specific molecular characteristics remain obscure and no therapy has proven to be efficient.

Experimental Design: To assess their molecular specificity among other lung SCCs we analyzed DNA copy number aberrations and mRNA expression pangenomic profiles of 93 SCCs, including 42 basaloid samples (24 pure, 18 mixed).

Results: Supervised analyses reveal that pure basaloid tumors display a specific mRNA expression profile, encoding factors controlling the cell cycle, transcription, chromatin, and splicing, with prevalent expression in germline and stem cells, while genes related to squamous differentiation are underexpressed. From this signature, we derived a 2-genes (SOX4, IVL) immunohistochemistry-based predictor that discriminated basaloid tumors (pure and mixed) from non-basaloid tumors with 94% accuracy in an independent series. The pure basaloid tumors are also distinguished through unsupervised analyses. Using a centroid-based predictor, the corresponding molecular subtype was found in 8 independent public datasets (n = 58/533), and was shown to be associated with a very poor survival as compared with other SCCs (adjusted HR = 2.45; P = 0.000001).

Conclusion: This study enlightens the heterogeneity of SCCs that can be subclassified in mRNA expression subtypes. This study demonstrates for the first time that basaloid SCCs constitute a distinct histomolecular entity, which justifies its recognition and distinction from non-basaloid SCCs. In addition, their characteristic molecular profile highlights their intrinsic resistance to cytotoxic chemotherapy and could serve as a guide for targeted therapies. Clin Cancer Res; 20(22); 5777–86. ©2014 AACR.
A Phase I/II Trial of Belinostat in Combination with Cisplatin, Doxorubicin, and Cyclophosphamide in Thymic Epithelial Tumors: A Clinical and Translational Study
Authors: Thomas Anish , Rajan Arun , Szabo Eva , Tomita Yusuke , Carter Corey A. , Scepura Barbara , Lopez-Chavez Ariel , Lee Min-Jung , Redon Christophe E. , Frosch Ari , Peer Cody J. , Chen Yuanbin , Piekarz Richard , Steinberg Seth M. , Trepel Jane B. , Figg William D. , Schrump David S. , Giaccone Giuseppe
Published: September 2014

Purpose: This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed.

Experimental Design: Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48 hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used.

Results: Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m2 belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. Twenty-four patients were treated at the MTD of 1,000 mg/m2 with chemotherapy (P, 50 mg/m2 on day 2; A, 25 mg/m2 on days 2 and 3; C, 500 mg/m2 on day 3). Objective response rates in thymoma and thymic carcinoma were 64% (95% confidence interval, 30.8%-89.1%) and 21% (4.7%–50.8%), respectively. Modulation of pharmacodynamic markers of HDAC inhibition and declines in regulatory T cell (Treg) and exhausted CD8+ T-cell populations were observed. Decline in Tregs was associated with response (P = 0.0041) and progression-free survival (P = 0.021). Declines in TIM3+ CD8+ T cells were larger in responders than nonresponders (P = 0.049).

Conclusion: This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3+ CD8+ T cells warrant further study. Clin Cancer Res; 20(21); 5392–402. ©2014 AACR.
Galectin-1 Mediates Radiation-Related Lymphopenia and Attenuates NSCLC Radiation Response
Authors: Kuo Peiwen , Bratman Scott V. , Shultz David B. , von Eyben Rie , Chan Cato , Wang Ziwei , Say Carmen , Gupta Aparna , Loo Bill W. , Giaccia Amato J. , Koong Albert C. , Diehn Maximilian , Le Quynh-Thu
Published: September 2014

Purpose: Radiotherapy can result in lymphopenia, which has been linked to poorer survival. Here, we test the hypothesis that radiotherapy-induced lymphopenia is mediated by a tumor-secreted factor, Galectin-1 (Gal-1), which possesses T-cell proapoptotic activities.

Experimental Design: Matched Gal-1 wild-type (WT) or null mice were implanted with Lewis lung carcinoma (LLC-1) that either expressed Gal-1 or had Gal-1 stably downregulated. Tumors were irradiated locally and circulating Gal-1 and T cells were measured. Tumor growth, lung metastasis, intratumoral T-cell apoptosis, and microvessel density count were quantified. Thiodigalactoside (TDG), a Gal-1 inhibitor, was used to inhibit Gal-1 function in another group of mice to validate the observations noted with Gal-1 downregulation. Lymphocyte counts, survival, and plasma Gal-1 were analyzed in cohorts of radiotherapy-treated lung [non–small cell lung cancer (NSCLC)] and head and neck cancer patients.

Results: LLC irradiation increased Gal-1 secretion and decreased circulating T cells in mice, regardless of host Gal-1 expression. Inhibition of tumor Gal-1 with either shRNA or thiodigalactoside ablated radiotherapy-induced lymphopenia. Irradiated shGal-1 tumors showed significantly less intratumoral CD8+ T-cell apoptosis and microvessel density, which led to marked tumor growth delay and reduced lung metastasis compared with controls. Similar observations were made after thiodigalactoside treatment. Radiotherapy-induced lymphopenia was associated with poorer overall survival in patients with NSCLC treated with hypofractionated radiotherapy. Plasma Gal-1 increased whereas T-cell decreased after radiation in another group of patients.

Conclusions: Radiotherapy-related systemic lymphopenia appeared to be mediated by radiotherapy-induced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis. Clin Cancer Res; 20(21); 5558–69. ©2014 AACR.
Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform
Authors: Dokter Wim , Ubink Ruud , van der Lee Miranda , van der Vleuten Monique , van Achterberg Tanja , Jacobs Danielle , Loosveld Eline , van den Dobbelsteen Diels , Egging David , Mattaar Ellen , Groothuis Patrick , Beusker Patrick , Coumans Ruud , Elgersma Ronald , Menge Wiro , Joosten John , Spijker Henri , Huijbregts Tijl , de Groot Vincent , Eppink Michel , de Roo Guy , Verheijden Gijs , Timmers Marco
Published: September 2014

A linker-drug platform was built on the basis of a cleavable linker-duocarmycin payload for the development of new-generation antibody–drug conjugates (ADC). A leading ADC originating from that platform is SYD983, a HER2-targeting ADC based on trastuzumab. HER2-binding, antibody-dependent cell-mediated cytotoxicity and HER2-mediated internalization are similar for SYD983 as compared with trastuzumab. HER2-expressing cells in vitro are very potently killed by SYD983, but SYD983 is inactive in cells that do not express HER2. SYD983 dose dependently reduces tumor growth in a BT-474 mouse xenograft in vivo. The ADC is stable in human and cynomolgus monkey plasma in vitro but shows relatively poor stability in mouse plasma due to mouse-specific carboxylesterase. SYD983 could be dosed up to 30 mg/kg in cynomolgus monkeys with high exposure, excellent stability in blood, and without severe toxic effects. The monkey safety study showed no SYD983-induced thrombocytopenia and no induction of peripheral sensory neuropathy, both commonly observed in trials and studies with ADCs based on tubulin inhibitors. Finally, to improve homogeneity, SYD983 was further purified by hydrophobic interaction chromatography resulting in an ADC (designated SYD985) predominantly containing DAR2 and DAR4 species. SYD985 showed high antitumor activity in two patient-derived xenograft models of HER2-positive metastatic breast cancers. In conclusion, the data obtained indicate great potential for this new HER2-targeting ADC to become an effective drug for patients with HER2-positive cancers with a favorable safety profile. More generally, this new-generation duocarmycin-based linker-drug technology could be used with other mAbs to serve more indications in oncology. Mol Cancer Ther; 13(11); 2618–29. ©2014 AACR.
Identification of Kinase Inhibitor Targets in the Lung Cancer Microenvironment by Chemical and Phosphoproteomics
Authors: Gridling Manuela , Ficarro Scott B. , Breitwieser Florian P. , Song Lanxi , Parapatics Katja , Colinge Jacques , Haura Eric B. , Marto Jarrod A. , Superti-Furga Giulio , Bennett Keiryn L. , Rix Uwe
Published: September 2014

A growing number of gene mutations, which are recognized as cancer drivers, can be successfully targeted with drugs. The redundant and dynamic nature of oncogenic signaling networks and complex interactions between cancer cells and the microenvironment, however, can cause drug resistance. While these challenges can be addressed by developing drug combinations or polypharmacology drugs, this benefits greatly from a detailed understanding of the proteome-wide target profiles. Using mass spectrometry-based chemical proteomics, we report the comprehensive characterization of the drug–protein interaction networks for the multikinase inhibitors dasatinib and sunitinib in primary lung cancer tissue specimens derived from patients. We observed in excess of 100 protein kinase targets plus various protein complexes involving, for instance, AMPK, TBK1 (sunitinib), and ILK (dasatinib). Importantly, comparison with lung cancer cell lines and mouse xenografts thereof showed that most targets were shared between cell lines and tissues. Several targets, however, were only present in tumor tissues. In xenografts, most of these proteins were of mouse origin suggesting that they originate from the tumor microenvironment. Furthermore, intersection with subsequent global phosphoproteomic analysis identified several activated signaling pathways. These included MAPK, immune, and integrin signaling, which were affected by these drugs in both cancer cells and the microenvironment. Thus, the combination of chemical and phosphoproteomics can generate a systems view of proteins, complexes, and signaling pathways that are simultaneously engaged by multitargeted drugs in cancer cells and the tumor microenvironment. This may allow for the design of novel anticancer therapies that concurrently target multiple tumor compartments. Mol Cancer Ther; 13(11); 2751–62. ©2014 AACR.
As redes sociais na perspectiva de pessoas com o diagnóstico de esquizofrenia em tratamento em um CAPS de Campinas e as implicações no recovery
Authors: Montanher Monica Krieck , Leal Erotildes Maria
Published: September 2014

O modelo de assistência preconizado pela Reforma Psiquiátrica introduz um cuidado em saúde mental baseado em estratégias de reabilitação psicossocial das pessoas com transtornos mentais. Nesse sentido, as redes sociais podem ajudar os sujeitos a lidarem com a doença. Assim, a análise das redes sociais, a partir da experiência dos sujeitos, pode indicar de que forma essas redes contribuem (ou não) para o processo de recovery. Este artigo apresenta os resultados de uma pesquisa qualitativa informada pelo referencial da Análise Fenomenológica Interpretativa. Teve como objetivo conhecer como as pessoas com diagnóstico de esquizofrenia em tratamento em um CAPS da cidade de Campinas compõem e experimentam as suas redes sociais e que implicações as redes sociais tem no seu processo de recovery. Resultou-se da análise a identificação de categorias temáticas referentes aos vínculos e tipos de interação estabelecidos pelos participantes. Concluiu-se a partir das narrativas que as redes são positivas para a experiência de recovery, se vivenciadas com alguma capacidade de proporcionar esperança, incentivo e suporte. Uma relação será experiência da positivamente se for capaz de minimizar ou ressignificar uma relação ruim ou a própria relação garantindo-lhe plasticidade.
AVALIAÇÃO DAS ATIVIDADES DE VIDA DIÁRIA EM CONTEXTOS INFANTIS: UMA REVISÃO DA LITERATURA
Authors: Vasconcelos Thamires Bezerra de , Cavalcante Lília Iêda Chaves
Published: September 2014

Objetivo: Identifi car e caracterizar os principais métodos utilizados para a avaliação do desempenho de crianças nas rotinas de autocuidado encontrados na literatura sobre Atividades de Vida Diária (AVD), assim como os contextos em que foram realizadas. Método: A busca foi realizada nas bases de dados eletrônicas BVS, CINAHL e Web of Science. Resultados: a partir dos artigos encontrados no período de 1991 a 2012 (n=2.386), foram selecionados 58 estudos, seguindo os critérios de inclusão e exclusão. Foi observado um aumento nos últimos anos da produção científica sobre o tema, e o uso de métodos padronizados de avaliação (n=50). A maioria dos estudos avaliou populações infantis portadoras de patologias neurológicas (n=31). Em relação ao contexto de avaliação, a maior parte dos trabalhos não descreveu os ambientes de sua realização como fator relevante na discussão dos resultados encontrados. Conclusões: Considera-se que os métodos de avaliação das AVD de crianças podem seguir orientando pesquisas que sirvam não apenas à avaliação funcional para fins terapêuticos, como também à realização de estudos sobre o desenvolvimento em contextos ecológicos de populações infantis em risco social.
Calcific Aortic Valve Disease
Authors: Yutzey Katherine E. , Demer Linda L. , Body Simon C. , Huggins Gordon S. , Towler Dwight A. , Giachelli Cecilia M. , Hofmann-Bowman Marion A. , Mortlock Douglas P. , Rogers Melissa B. , Sadeghi Mehran M. , Aikawa Elena
Published: September 2014

Calcific aortic valve disease (CAVD) is increasingly prevalent worldwide with significant morbidity and mortality. Therapeutic options beyond surgical valve replacement are currently limited. In 2011, the National Heart Lung and Blood Institute assembled a working group on aortic stenosis. This group identified CAVD as an actively regulated disease process in need of further study. As a result, the Alliance of Investigators on CAVD was formed to coordinate and promote CAVD research, with the goals of identifying individuals at risk, developing new therapeutic approaches, and improving diagnostic methods. The group is composed of cardiologists, geneticists, imaging specialists, and basic science researchers. This report reviews the current status of CAVD research and treatment strategies with identification of areas in need of additional investigation for optimal management of this patient population.
Elevated Circulating Lipocalin-2 Levels Independently Predict Incident Cardiovascular Events in Men in a Population-Based Cohort
Authors: Wu Guangyu , Li Huating , Fang Qichen , Jiang Shan , Zhang Lei , Zhang Jing , Hou Xuhong , Lu Junxi , Bao Yuqian , Xu Aimin , Jia Weiping
Published: September 2014

Objective—

Adipose tissue inflammation and perturbation of adipokine secretion may contribute to the pathogenesis of cardiovascular diseases (CVD). Lipocalin-2 (LCN2), mainly released from adipocytes, has been shown to be positively associated with CVD in cross-sectional studies. We aimed to evaluate the association of LCN2 with CVD involving a population-based cohort recruited from the Shanghai Diabetes Study.

Approach and Results—

Serum LCN2 levels were measured using ELISA. Independent predictors of CVD development were identified using Cox proportion hazards regression. The predictive performances of the various models were assessed by Kaplan–Meier analysis. At baseline, circulating LCN2 was significantly associated with a cluster of traditional cardiovascular risk factors. Baseline LCN2 levels in male subjects who developed CVD events during follow-up were significantly higher than those who did not develop CVD events (
P
=0.012). However, such difference was not significant in female subjects. LCN2 was a predictor of CVD in men, which remained statistically significant after adjustment for traditional cardiovascular risk factors (hazard ratio, 1.038 [95% confidence interval, 1.017–1.060]). LCN2 remained significantly associated with incident CVD even after adjustment for renal function, adiponectin, and high-sensitivity C-reactive protein levels. Kaplan–Meier analysis suggested combination of LCN2 and high-sensitivity C-reactive protein might improve the prediction of CVD events in male subjects.

Conclusions—

Elevated circulating LCN2 level is an independent predictor of CVD events in men in a population-based cohort and adds to the prognostic value of high-sensitivity C-reactive protein, which is currently the most extensively studied biomarker of CVD. Measurement of serum LCN2 might be useful for early detection and intervention of CVD.
Homoarginine and Cardiovascular Outcome in the Population-Based Dallas Heart Study
Authors: Atzler Dorothee , Gore M. Odette , Ayers Colby R. , Choe Chi-un , Böger Rainer H. , de Lemos James A. , McGuire Darren K. , Schwedhelm Edzard
Published: September 2014

Objective—

The nonproteinogenic amino acid homoarginine has been postulated to have antiatherosclerotic effects as a weak substrate of nitric oxide synthase. This investigation in the population-based Dallas Heart Study (DHS) aimed to evaluate the association of homoarginine with clinical and subclinical cardiovascular outcomes.

Approach and Results—

Plasma homoarginine was measured in 3514 participants of the DHS using liquid chromatography-tandem mass spectrometry. Associations between homoarginine and major adverse cardiovascular events and all-cause mortality were analyzed using Cox proportional hazard models adjusting for cardiovascular risk factors. Linear regression was used to assess cross-sectional associations between homoarginine and subclinical cardiovascular disease, including coronary artery calcium measured by electron beam-computed tomography, and aortic plaque burden and aortic wall thickness by MRI. Median age was 43 (interquartile range, 36–52) years, with 56% women and 52% black participants. Median follow-up was 9.4 (9.0–9.8) years. Median plasma homoarginine was 2.80 (2.14–3.54) μmol/L. In multivariable models, higher homoarginine was associated with lower rate of major adverse cardiovascular events (hazard ratio, 0.86; 95% confidence interval, 0.75–0.98) and lower all-cause mortality (hazard ratio, 0.82; 0.73–0.92; per 1 log SD increase in homoarginine). Homoarginine was inversely and independently associated with aortic wall thickness (β-estimate, −0.04;
P
<0.01) but not with aortic plaque burden and coronary artery calcium.

Conclusions—

Homoarginine is inversely associated with subclinical vascular disease and with risk for cardiovascular disease events. Additional studies are needed to evaluate whether the regulation of plasma homoarginine could emerge as a novel therapeutic option to improve outcomes in cardiovascular disease.
The Hemodynamic Basis of Exercise Intolerance in Tricuspid Regurgitation
Authors: Andersen Mads J. , Nishimura Rick A. , Borlaug Barry A.
Published: September 2014

Background—

Patients with severe tricuspid regurgitation (TR) frequently present with exertional fatigue and dyspnea, but the hemodynamic basis for exercise limitation in people with TR remains unclear.

Methods and Results—

Twelve subjects with normal left ventricular (LV) ejection fraction and grade ≥3 TR underwent high-fidelity invasive hemodynamic exercise testing with simultaneous expired gas analysis and were compared with 13 age- and sex-matched controls. At rest, TR subjects had lower pulmonary blood flow (3.6±0.4 versus 5.1±1.9 L/min;
P
=0.01), increased right atrial pressure (12±5 versus 4±1 mm Hg;
P
=0.0002), and higher pulmonary capillary wedge pressure (17±5 versus 9±3 mm Hg;
P
=0.0001). However, LV transmural pressure (pulmonary capillary wedge pressure−right atrial pressure), which reflects LV preload independent of right heart congestion and pericardial restraint, was similar in TR and controls (6±3 versus 4±2 mm Hg;
P
=0.3). With exercise, TR subjects displayed lower peak V
O
2
(10.3±2.8 versus 13.8±4.2 mL/min per kg;
P
=0.02), lower pulmonary blood flow (6.4±1.3 versus 10.3±3.3 L/min;
P
=0.001), and less increase in pulmonary blood flow relative to V
O
2
(+4.6±1.1vs +6.2±0.7;
P
=0.001). TR subjects displayed higher pulmonary capillary wedge pressure with exercise, but this was solely because of RA hypertension (27±9 versus 8±3 mm Hg;
P
<0.0001), because LV transmural pressure dropped with exercise in subjects with TR (−5±6 versus +3±3 mm Hg;
P
=0.0007), suggesting inadequate LV diastolic filling, despite high pulmonary capillary wedge pressure.

Conclusions—

Impaired exercise capacity in people with severe TR is related to low cardiac output reserve relative to metabolic needs, coupled with elevated systemic and pulmonary venous pressures. Left heart pressures are elevated with exercise in subjects with TR, despite low LV preload, secondary to enhanced ventricular interaction.
Tbx1 Coordinates Addition of Posterior Second Heart Field Progenitor Cells to the Arterial and Venous Poles of the Heart
Authors: Rana M. Sameer , Théveniau-Ruissy Magali , De Bono Christopher , Mesbah Karim , Francou Alexandre , Rammah Mayyasa , Domínguez Jorge N. , Roux Marine , Laforest Brigitte , Anderson Robert H. , Mohun Timothy , Zaffran Stephane , Christoffels Vincent M. , Kelly Robert G.
Published: September 2014

Rationale:

Cardiac progenitor cells from the second heart field (SHF) contribute to rapid growth of the embryonic heart, giving rise to right ventricular and outflow tract (OFT) myocardium at the arterial pole of the heart, and atrial myocardium at the venous pole. Recent clonal analysis and cell-tracing experiments indicate that a common progenitor pool in the posterior region of the SHF gives rise to both OFT and atrial myocytes. The mechanisms regulating deployment of this progenitor pool remain unknown.

Objective:

To evaluate the role of
TBX1
, the major gene implicated in congenital heart defects in 22q11.2 deletion syndrome patients, in posterior SHF development.

Methods and Results:

Using transcriptome analysis, genetic tracing, and fluorescent dye-labeling experiments, we show that
Tbx1
-dependent OFT myocardium originates in
Hox
-expressing cells in the posterior SHF. In
Tbx1
null embryos, OFT progenitor cells fail to segregate from this progenitor cell pool, leading to failure to expand the dorsal pericardial wall and altered positioning of the cardiac poles. Unexpectedly, addition of SHF cells to the venous pole of the heart is also impaired, resulting in abnormal development of the dorsal mesenchymal protrusion, and partially penetrant atrioventricular septal defects, including ostium primum defects.

Conclusions:

Tbx1
is required for inflow as well as OFT morphogenesis by regulating the segregation and deployment of progenitor cells in the posterior SHF. Our results provide new insights into the pathogenesis of congenital heart defects and 22q11.2 deletion syndrome phenotypes.
Validity of Hospital Discharge Diagnosis Codes for Stroke
Authors: Jones Sydney A. , Gottesman Rebecca F. , Shahar Eyal , Wruck Lisa , Rosamond Wayne D.
Published: September 2014

Background and Purpose—

Characterizing International Classification of Disease 9th Revision, Clinical Modification (ICD-9-CM) code validity is essential given widespread use of hospital discharge databases in research. Using the Atherosclerosis Risk in Communities (ARIC) Study, we estimated the accuracy of ICD-9-CM stroke codes.

Methods—

Hospitalizations with ICD-9-CM codes 430 to 438 or stroke keywords in the discharge summary were abstracted for ARIC cohort members (1987–2010). A computer algorithm and physician reviewer classified definite and probable ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Using ARIC classification as a gold standard, we calculated the positive predictive value (PPV) and sensitivity of ICD-9-CM codes grouped according to the American Heart Association/American Stroke Association (AHA/ASA) 2013 categories and an alternative code grouping for comparison.

Results—

Thirty-three percent of 4260 hospitalizations were validated as strokes (1251 ischemic, 120 intracerebral hemorrhage, 46 subarachnoid hemorrhage). The AHA/ASA code groups had PPV 76% and 68% sensitivity compared with PPV 72% and 83% sensitivity for the alternative code groups.

The PPV of the AHA/ASA code group for ischemic stroke was slightly higher among blacks, individuals <65 years, and at teaching hospitals. Sensitivity was higher among older individuals and increased over time. The PPV of the AHA/ASA code group for intracerebral hemorrhage was higher among blacks, women, and younger individuals. PPV and sensitivity varied across study sites.

Conclusions—

A new AHA/ASA discharge code grouping to identify stroke had similar PPV and lower sensitivity compared with an alternative code grouping. Accuracy varied by patient characteristics and study sites.
Hormone Replacement Therapy and Adverse Outcomes in Women With Atrial Fibrillation
Authors: Apostolakis Stavros , Sullivan Renee M. , Olshansky Brian , Lip Gregory Y.H.
Published: September 2014

Background and Purpose—

Hormone replacement therapy (HRT) use has been related to thromboembolism, but whether HRT increases adverse outcomes in females with atrial fibrillation is uncertain.

Methods—

We used the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial data set that included 1594 women (39.3% of the population, mean age 71±8), of whom 376 (23.6%) were taking HRT at baseline. The primary end point, a composite of all-cause death, stroke, systemic/pulmonary embolism, and myocardial infarction, and secondary outcomes (ie, each individual end point) and major bleeding, were considered.

Results—

HRT was not independently associated with the primary end point (hazard ratio=0.894; 95% confidence interval, 0.658–1.214;
P
=0.473) or any secondary outcome. Age (
P
<0.001), diabetes mellitus (
P
<0.001), previous stroke (
P
=0.011), and heart failure (
P
<0.001) predicted the primary end point. Lack of association between HRT and the primary end point was confirmed in a propensity score–matched control group (hazard ratio=0.966; 95% confidence interval, 0.663–1.409;
P
=0.858).

Conclusions—

HRT does not independently predict mortality, thromboembolism, or bleeding in a large cohort of women with atrial fibrillation.
Steinernema huense sp. n., a new entomopathogenic nematode (Nematoda: Steinernematidae) from Vietnam
Authors: Phan Ke Long , Mráček Zdeněk , Půža Vladimír , Nermut Jiří , Jarošová Andrea
Published: September 2014

A new entomopathogenic nematode,Steinernema huensesp. n., belonging to thecarpocapsaegroup, was recovered in Bach Ma National Park (Thua Thien Hue province) Vietnam.Steinernema huensesp. n. infective juveniles are characterised by short body length of 527 (444-571) μm, distance from anterior end to excretory pore of 43 (38-46) μm, anterior end to end of pharynx of 116 (103-129) μm; tail length of 50 (43-56) μm, D% = 37 (34-39) and E% = 85 (79-93), H% = 44 (39-52) and in having six ridges (i.e., seven lines) in the lateral field. For first generation males, the diagnostic characters include the spicule length of 67 (60-72) μm; D% = 48 (41-61); SW% = 195 (168-238) and GS% = 76 (68-81). Both generations possess a minute filamentous mucron, which can be rudimentary in the first generation, and 23 genital papillae. Spicules are finely curved, brownish and slender with a prominent rostrum. First generation females have a non-protruding, symmetrical vulva, with double flapped epiptygma. The tail of mature females is obese with a short conical tip (peg) lacking minute protuberances, and post-anal swelling not developed. The new species is further characterised by sequences of ITS and D2-D3 regions of the ribosomal DNA. According to molecular data, the symbiotic bacterium ofS. huensesp. n. is closely related toXenorhabdus stockiae.