bluuebunny/crossref_metadata_2025 huggingface dataset:
Nucleus
Authors: Vougioukas Ilias , Sandberg Andreas , Diestelhorst Stephan , Al-Hashimi Bashir M. , Merrett Geoff V.
Published: September 2017

Heterogeneous multi-processors are designed to bridge the gap between performance and energy efficiency in modern embedded systems. This is achieved by pairing
Out-of-Order (OoO)
cores, yielding performance through aggressive speculation and latency masking, with
In-Order (InO)
cores, that preserve energy through simpler design. By leveraging migrations between them, workloads can therefore select the best setting for any given energy/delay envelope. However, migrations introduce execution overheads that can hurt performance if they happen too frequently. Finding the optimal migration frequency is critical to maximize energy savings while maintaining acceptable performance. We develop a simulation methodology that can 1) isolate the hardware effects of migrations from the software, 2) directly compare the performance of different core types, 3) quantify the performance degradation and 4) calculate the cost of migrations for each case. To showcase our methodology we run mibench, a microbenchmark suite, and show that migrations can happen as fast as every 100k instructions with little performance loss. We also show that, contrary to numerous recent studies, hypothetical designs do not need to share all of their internal components to be able to migrate at that frequency. Instead, we propose a feasible system that shares level 2 caches and a
translation lookaside buffer
that matches performance and efficiency. Our results show that there are phases comprising up to 10% that a migration to the OoO core leads to performance benefits without any additional energy cost when running on the InO core, and up to 6% of phases where a migration to the InO core can save energy without affecting performance. When considering a policy that focuses on improving the energy-delay product, results show that on average 66% of the phases can be migrated to deliver equal or better system operation without having to aggressively share the entire memory system or to revert to migration periods finer than 100k instructions.
CAMsure
Authors: Riazi M. Sadegh , Samragh Mohammad , Koushanfar Farinaz
Published: September 2017

We introduce CAMsure, the first realization of secure Content Addressable Memory (CAM) in the context of approximate search using near-neighbor algorithms. CAMsure provides a lightweight solution for practical secure (approximate) search with a minimal drop in the accuracy of the search results. CAM has traditionally been used as a hardware search engine that explores the entire memory in a single clock cycle. However, there has been little attention to the security of the data stored in CAM. Our approach stores distance-preserving hash embeddings within CAM to ensure data privacy. The hashing method provides data confidentiality while preserving similarity in the sense that a high resemblance in the data domain is translated to a small Hamming distance in the hash domain. Consequently, the objective of near-neighbor search is converted to approximate lookup table search which is compatible with the realizations of emerging content addressable memories. Our methodology delivers on average two orders of magnitude faster response time compared to RAM-based solutions that preserve the privacy of data owners.
Energy-Efficient Run-Time Mapping and Thread Partitioning of Concurrent OpenCL Applications on CPU-GPU MPSoCs
Authors: Singh Amit Kumar , Prakash Alok , Basireddy Karunakar Reddy , Merrett Geoff V. , Al-Hashimi Bashir M.
Published: September 2017

Heterogeneous Multi-Processor Systems-on-Chips (MPSoCs) containing CPU and GPU cores are typically required to execute applications concurrently. However, as will be shown in this paper, existing approaches are not well suited for concurrent applications as they are developed either by considering only a single application or they do not exploit both CPU and GPU cores at the same time. In this paper, we propose an energy-efficient run-time mapping and thread partitioning approach for executing concurrent OpenCL applications on both GPU and GPU cores while satisfying performance requirements. Depending upon the performance requirements, for each concurrently executing application, the mapping process finds the appropriate number of CPU cores and operating frequencies of CPU and GPU cores, and the partitioning process identifies an efficient partitioning of the applications’ threads between CPU and GPU cores. We validate the proposed approach experimentally on the Odroid-XU3 hardware platform with various mixes of applications from the Polybench benchmark suite. Additionally, a case-study is performed with a real-world application SLAMBench. Results show an average energy saving of 32% compared to existing approaches while still satisfying the performance requirements.
RISE
Authors: Rouhani Bita Darvish , Mirhoseini Azalia , Koushanfar Farinaz
Published: September 2017

This paper proposes RISE, an automated Reconfigurable framework for real-time background subtraction applied to Intelligent video SurveillancE. RISE is devised with a new streaming-based methodology that adaptively learns/updates a corresponding dictionary matrix from background pixels as new video frames are captured over time. This dictionary is used to highlight the foreground information in each video frame. A key characteristic of RISE is that it adaptively adjusts its dictionary for diverse lighting conditions and varying camera distances by continuously updating the corresponding dictionary. We evaluate RISE on natural-scene vehicle images of different backgrounds and ambient illuminations. To facilitate automation, we provide an accompanying API that can be used to deploy RISE on FPGA-based system-on-chip platforms. We prototype RISE for end-to-end deployment of three widely-adopted image processing tasks used in intelligent transportation systems: License Plate Recognition (LPR), image denoising/reconstruction, and principal component analysis. Our evaluations demonstrate up to 87-fold higher throughput per energy unit compared to the prior-art software solution executed on ARM Cortex-A15 embedded platform.
Efficient Control-Flow Subgraph Matching for Detecting Hardware Trojans in RTL Models
Authors: Piccolboni Luca , Menon Alessandro , Pravadelli Graziano
Published: September 2017

Only few solutions for Hardware Trojan (HT) detection work at Register-Transfer Level (RTL), thus delaying the identification of possible security issues at lower abstraction levels of the design process. In addition, the most of existing approaches work only for specific kinds of HTs. To overcome these limitations, we present a verification approach that detects different types of HTs in RTL models by exploiting an efficient control-flow subgraph matching algorithm. The prototypes of HTs that can be detected are modelled in a library by using Control-Flow Graphs (CFGs) that can be parametrised and extended to cover several variants of Trojan patterns. Experimental results show that our approach is effective and efficient in comparison with other state-of-the-art solutions.
Response Time Analysis for Sporadic Server Based Budget Scheduling in Real Time Virtualization Environments
Authors: Beckert Matthias , Ernst Rolf
Published: September 2017

Virtualization techniques for embedded real-time systems typically employ TDMA scheduling to achieve temporal isolation among different virtualized applications. Recent work already introduced sporadic server based solutions relying on budgets instead of a fixed TDMA schedule. While providing better average-case response times for IRQs and tasks, a formal response time analysis for the worst-case is still missing. In order to confirm the advantage of a sporadic server based budget scheduling, this paper provides a worst-case response time analysis. To improve the sporadic server based budget scheduling even more, we provide a background scheduling implementation which will also be covered by the formal analysis. We show correctness of the analysis approach and compare it against TDMA based systems. In addition to that, we provide response time measurements from a working hypervisor implementation on an ARM based development board.
Flexible PV-cell Modeling for Energy Harvesting in Wearable IoT Applications
Authors: Park Jaehyun , Joshi Hitesh , Lee Hyung Gyu , Kiaei Sayfe , Ogras Umit Y.
Published: September 2017

Wearable devices with sensing, processing and communication capabilities have become feasible with the advances in internet-of-things (IoT) and low power design technologies. Energy harvesting is extremely important for wearable IoT devices due to size and weight limitations of batteries. One of the most widely used energy harvesting sources is photovoltaic cell (PV-cell) owing to its simplicity and high output power. In particular, flexible PV-cells offer great potential for wearable applications. This paper models,
for the first time
, how bending a PV-cell significantly impacts the harvested energy. Furthermore, we derive an analytical model to quantify the harvested energy as a function of the radius of curvature. We validate the proposed model empirically using a commercial PV-cell under a wide range of bending scenarios, light intensities and elevation angles. Finally, we show that the proposed model can accelerate maximum power point tracking algorithms and increase the harvested energy by up to 25.0%.
Portable device fears show power of social development
Authors: Edwards Chris
Published: September 2017

How do small screens impact young minds?
Barriers to refactoring
Authors: Tempero Ewan , Gorschek Tony , Angelis Lefteris
Published: September 2017

Developers know refactoring improves their software, but many find themselves unable to do so when they want to.
Amazon and whole foods
Authors: Cusumano Michael A.
Published: September 2017

Checking out the recent Amazon acquisition of Whole Foods.
The real risks of artificial intelligence
Authors: Parnas David Lorge
Published: September 2017

Incidents from the early days of AI research are instructive in the current AI environment.
FinTech platforms and strategy
Authors: Dhar Vasant , Stein Roger M.
Published: September 2017

Integrating trust and automation in finance.
What can agile methods bring to high-integrity software development?
Authors: Chapman Roderick , White Neil , Woodcock Jim
Published: September 2017

Considering the issues and opportunities raised by Agile practices in the development of high-integrity software.
Art Scott and Michael Frank on energy-efficient computing
Authors: Lewis Ted G.
Published: September 2017

Clock speeds of computing chips have leveled off dramatically since 2005, and putting more cores in systems on a chip (SoC) has produced more heat, adding a new ceiling to further advances. Leading-edge researchers, like Mike Frank, and dedicated technologists with a wealth of experience, like Art Scott, represent a new vanguard of the leap-forward beyond Dennard scaling and Landauer's limit. Art looks for ways to reduce energy consumption and Mike looks for ways to "architect" future chips according to principles of reversibility. Is the future in reversible, adiabatic computing and simpler architectures using posit arithmetic? My guests think so.
No player is ideal
Authors: Neely Erica L.
Published: September 2017

As video games flourish, designers have a responsibility to treat players and potential players justly. In deontological terms, designers are obliged to treat all of them as having intrinsic worth. Since players are a diverse group, designers must not simply focus on an idealized gamer, who is typically a straight white male. This creates a duty to consider whether design choices place unnecessary barriers to the ability of certain groups of players to achieve their ends in playing a game. I examine the design implication of this for the gameworld, avatar design, and accessibility to players with disabilities. I also consider the limits of designers' control by examining responses to abusive player chat in multiplayer games. Ultimately, a careful balance must be found between what is necessary to create the game a designer envisions and what is necessary for treating all players as having intrinsic worth.
Threats of the internet of things in a techno-regulated society
Authors: Magrani Eduardo
Published: September 2017

Continuous interaction between gadgets, sensors and people points to the rising number of data being produced, stored and processed. On one hand, it may bring benefits to consumers, on the other, growing connectivity, accompanied by data overflow, can also challenge privacy and fundamental rights. This paper approaches some of the challenges faced by the rule of law posed by the advancement of the Internet of Things, which includes a wide variety of actors, most importantly private companies that seek to promote techno-regulation through design, algorithms and market-based contracts.
Editor's introduction
Authors: Fu Hu
Published: September 2017

Issue 16.1 of SIGecom Exchanges experiments with a couple of new forms of contribution, while keeping other by-now time-tested traditions.

Within the established tradition, we have a survey/position paper by Brendan Lucier on an economic view of prophet inequalities, two research letters, and the job candidate profiles this year which Vasilis Gkatzelis and Jason Hartline again volunteered to collect and edit. Besdies these, we have a a mini-survey by Shaddin Dughmi, Jason Hartline, Robert Kleinberg and Rad Niazadeh on black-box reductions in mechanism design, and a letter by Hayden Melton on the recent mechanism refinement on Thomson Reuters Matching (a major interbank electronic trading venue for spot foreign exchange).
Bernoulli factories and black-box reductions in mechanism design
Authors: Dughmi Shaddin , Hartline Jason D. , Kleinberg Robert , Niazadeh Rad
Published: September 2017

In this letter, we report on our work providing a polynomial time reduction from Bayesian incentive compatible mechanism design to Bayesian algorithm design for welfare maximization problems. Unlike prior results, our reduction achieves exact incentive compatibility for problems with multidimensional and continuous type spaces.
Market mechanism refinement on a continuous limit order book venue
Authors: Melton Hayden
Published: September 2017

This letter describes an exercise in market mechanism refinement that was recently undertaken on a major electronic trading venue:
Thomson Reuters Matching.
The exercise sought to address problems associated with continuous markets that have been described in recent literature. To this end, the design of the refinement is described, and its consequences are discussed.
Low-threshold mechanoreceptors play a frequency-dependent dual role in subjective ratings of mechanical allodynia
Authors: Löken Line S. , Duff Eugene P. , Tracey Irene
Published: September 2017

In the setting of injury, myelinated primary afferent fibers that normally signal light touch are thought to switch modality and instead signal pain. In the absence of injury, touch is perceived as more intense when firing rates of Aβ afferents increase. However, it is not known if varying the firing rates of Aβ afferents have any consequence to the perception of dynamic mechanical allodynia (DMA). We hypothesized that, in the setting of injury, the unpleasantness of DMA would be intensified as the firing rates of Aβ afferents increase. Using a stimulus-response protocol established in normal skin, where an increase in brush velocity results in an increase of Aβ afferent firing rates, we tested if brush velocity modulated the unpleasantness of capsaicin-induced DMA. We analyzed how changes in estimated low-threshold mechanoreceptor firing activity influenced perception and brain activity (functional MRI) of DMA. Brushing on normal skin was perceived as pleasant, but brushing on sensitized skin produced both painful and pleasant sensations. Surprisingly, there was an inverse relationship between Aβ firing rates and unpleasantness such that brush stimuli that produced low firing rates were most painful and those that elicited high firing rates were rated as pleasant. Concurrently to this, we found increased cortical activity in response to low Aβ firing rates in regions previously implicated in pain processing during brushing of sensitized skin, but not normal skin. We suggest that Aβ signals do not merely switch modality to signal pain during injury. Instead, they exert a high- and low-frequency-dependent dual role in the injured state, with respectively both pleasant and unpleasant consequences.

NEW & NOTEWORTHY We suggest that Aβ signals do not simply switch modality to signal pain during injury but play a frequency-dependent and dual role in the injured state with both pleasant and unpleasant consequences. These results provide a framework to resolve the apparent paradox of how touch can inhibit pain, as proposed by the Gate Control Theory and the existence of dynamic mechanical allodynia.
Impaired Hemorheology in Exacerbations of COPD
Authors: Ugurlu Erhan , Kilic-Toprak Emine , Can Ilknur , Kilic-Erkek Ozgen , Altinisik Goksel , Bor-Kucukatay Melek
Published: September 2017

Background. Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation. Cardiovascular-related comorbidities are established to contribute to morbidity and mortality especially during exacerbations. The aim of the current study was to determine alterations in hemorheology (erythrocyte aggregation, deformability) in newly diagnosed COPD patients and their response to medical treatment and to compare with values of COPD patients with exacerbations.Materials and Methods. The study comprised 13 COPD patients, 12 controls, and 16 COPD patients with exacerbations. The severity of COPD was determined according toGlobal Initiative for Chronic Obstructive Lung Diseaseguidelines. Red blood cell (RBC) deformability and aggregation were measured by an ektacytometer.Results. RBC deformability of COPD patients with exacerbations was decreased compared to the other groups. Erythrocyte aggregation and plasma fibrinogen of COPD patients determined during exacerbations were higher than control.Conclusion. Decreased RBC deformability and increased aggregation associated with exacerbations of COPD may serve as unfavorable mechanisms to worsen oxygenation and thus clinical symptoms of the patient. Treatment modalities that modify rheological parameters might be beneficial.
Testicular Damage following Testicular Sperm Retrieval: A Ram Model Study
Authors: Fedder Jens , Marcussen Niels , Fedder Maja D. K. , Engvad Birte
Published: September 2017

The aim of this study was to evaluate the possible development of histological abnormalities such as fibrosis and microcalcifications after sperm retrieval in a ram model. Fourteen testicles in nine rams were exposed to open biopsy, multiple TESAs, or TESE, and the remaining four testicles were left unoperated on as controls. Three months after sperm retrieval, the testicles were removed, fixed, and cut into 1/2 cm thick slices and systematically put onto a glass plate exposing macroscopic abnormalities. Tissue from abnormal areas was cut into 3 μm sections and stained for histological evaluation. Pathological abnormalities were observed in testicles exposed to sperm retrieval (≥11 of 14) compared to 0 of 4 control testicles. Testicular damage was found independently of the kind of intervention used. Therefore, cryopreservation of excess sperm should be considered while retrieving sperm.
Analysis of a Predator-Prey Model with Switching and Stage-Structure for Predator
Authors: Suebcharoen T.
Published: September 2017

This paper studies the behavior of a predator-prey model with switching and stage-structure for predator. Bounded positive solution, equilibria, and stabilities are determined for the system of delay differential equation. By choosing the delay as a bifurcation parameter, it is shown that the positive equilibrium can be destabilized through a Hopf bifurcation. Some numerical simulations are also given to illustrate our results.
Platelet Carbonic Anhydrase II, a Forgotten Enzyme, May Be Responsible for Aspirin Resistance
Authors: Jakubowski M. , Dębski J. , Szahidewicz-Krupska E. , Turek-Jakubowska A. , Gawryś J. , Gawryś K. , Skomro R. , Derkacz A. , Doroszko A.
Published: September 2017

Background. Thromboembolic events constitute a major health problem, despite the steadily expanding arsenal of antiplatelet drugs. Hence, there is still a need to optimize the antiplatelet therapy. Objectives. The aim of our study was to verify a hypothesis that there are no differences in platelet proteome between two groups of healthy people representing different acetylsalicylic acid (aspirin) responses as assessed by the liquid chromatography/mass spectrometry (LC/MS) technique. Patients/Methods. A total of 61 healthy volunteers were recruited for the study. Physical examination and blood collection were followed by platelet‐rich plasma aggregation assays and platelet separation for proteomic LC/MS analysis. Arachidonic acid‐ (AA‐) induced aggregation (in the presence of aspirin) allowed to divide study participants into two groups aspirin‐resistant (AR) and aspirin‐sensitive (AS) ones. Subsequently, platelet proteome was compared in groups using the LC/MS analysis. Results. The LC/MS analysis of platelet proteome between groups revealed that out of all identified proteins, the only discriminatory protein, affecting aspirin responsiveness, is platelet carbonic anhydrase II (CA II). Conclusions. CA II is a platelet function modulator and should be taken into consideration as a cardiovascular event risk factor or therapeutic target.
A Clustering Method for Data in Cylindrical Coordinates
Authors: Fujita Kazuhisa
Published: September 2017

We propose a new clustering method for data in cylindrical coordinates based on the k‐means. The goal of the k‐means family is to maximize an optimization function, which requires a similarity. Thus, we need a new similarity to obtain the new clustering method for data in cylindrical coordinates. In this study, we first derive a new similarity for the new clustering method by assuming a particular probabilistic model. A data point in cylindrical coordinates has radius, azimuth, and height. We assume that the azimuth is sampled from a von Mises distribution and the radius and the height are independently generated from isotropic Gaussian distributions. We derive the new similarity from the log likelihood of the assumed probability distribution. Our experiments demonstrate that the proposed method using the new similarity can appropriately partition synthetic data defined in cylindrical coordinates. Furthermore, we apply the proposed method to color image quantization and show that the methods successfully quantize a color image with respect to the hue element.
Impact of Orthognathic Surgery on Quality of Life in Patients with Dentofacial Deformities
Authors: Eslamipour Faezeh , Najimi Arash , Tadayonfard Azade , Azamian Zeinab
Published: September 2017

The aim of this investigation was to determine the impact of orthognathic surgery on quality of life in patients with dentofacial deformities at immediate presurgery and at 3-week, 3-month, and 6-month intervals following the surgery. Subjects included forty-three 18–40-year-old Iranian orthognathic patients who were referred to private offices in Isfahan. Data collection was performed using the 22-item Orthognathic Quality of Life Questionnaire (OQLQ). Participants completed the questionnaire prior to surgery and 3 weeks, 3 months, and 6 months after it. Differences and correlations were calculated by the two-tailedt-test, ANOVA with Repeated Measure test, and the Pearson correlation coefficient. The results showed significant reduction returned to baseline in OQLQ mean scores and aesthetic, awareness, and social subdomains in all 3 intervals after surgery. However oral function domain showed an increase atT2and then a decrease at next intervals. Maximum and minimum effect size were observed in aesthetic (ES = 0.7) and oral function (ES = 0.3) domain, respectively. Based on the finding of this study, in 6-month interval after surgery, orthognathic surgery causes significant improvements in quality of life in patients with dentofacial deformities as assessed in emotional, psychological, oral function, and social domains and maximum changes occurred in emotional domain.
Late Ps. aeruginosa Inguinal Mesh Infection 12 Years after the Initial Operation: Report of the Case and Short Review of the Literature
Authors: Filippou Dimitrios
Published: September 2017

Inguinal hernia mesh repair is one of the most frequent operations performed worldwide. The Lichtenstein technique and its various modifications are the most popular operations for groin hernia repair. The rate of surgical site infection (SSI) following inguinal hernia repair ranges between 0 and 14% in various series. Most of these infections developed early postoperatively. The incidence of late mesh infection following open inguinal hernia repair still remains unclear and highly variable. Late deep mesh infections are relatively rare specially after more than 10 years. The most common pathogens reported in the literature are E. coli and St. aureus. The infection is treated by conservative means initially but in case of failure then the mesh should be removed surgically. A unique case of a patient with very late (chronic) mesh infection is presented. The infection was due to Pseudomonas aeruginosa, which occurred 14 years after the initial operation and presented as subcutaneous fistula.
Stem Cell Research and Clinical Translation: A Roadmap about Good Clinical Practice and Patient Care
Authors: Frati Paola , Scopetti Matteo , Santurro Alessandro , Gatto Vittorio , Fineschi Vittorio
Published: September 2017

The latest research achievements in the field of stem cells led in 2016 to the publication of “Guidelines for Stem Cell Research and Clinical Translation” by the International Society for Stem Cell Research (ISSCR). Updating the topics covered in previous publications, the new recommendations offer interesting ethical and scientific insights. Under the common principles of research integrity, protection of patient’s welfare, respect for the research subjects, transparency and social justice, the centrality of good clinical practice, and informed consent in research and translational medicine is supported. The guidelines implement the abovementioned publications, requiring rigor in all areas of research, promoting the validity of the scientific activity results and emphasizing the need for an accurate and efficient public communication. This paper aims to analyze the aforementioned guidelines in order to provide a valid interpretive tool for experts. In particular, a research activity focused on the bioethical, scientific, and social implications of the new recommendations is carried out in order to provide food for thought. Finally, as an emerging issue of potential impact of current guidelines, an overview on implications of compensation for egg donation is offered.
A New Method for Evaporation Modeling: Dynamic Evolving Neural-Fuzzy Inference System
Authors: Kisi Ozgur , Mansouri Iman , Hu Jong Wan
Published: September 2017

Evaporation estimation is very essential for planning and development of water resources. The study investigates the ability of new method, dynamic evolving neural-fuzzy inference system (DENFIS), in modeling monthly pan evaporation. Monthly maximum and minimum temperatures, solar radiation, wind speed, and relative humidity data obtained from two stations located in Turkey are used as inputs to the models. The results of DENFIS method were compared with the classical adaptive neural-fuzzy inference system (ANFIS) by using root mean square error (RMSE), mean absolute relative error (MARE), and Nash-Sutcliffe Coefficient (NS) statistics. Cross validation was applied for better comparison of the models. The results indicated that DENFIS models increased the accuracy of ANFIS models to some extent. RMSE, MARE, and NS of the ANFIS model were increased by 11.13, 11.45, and 6.83% for the Antalya station and 20.11, 12.94%, and 8.29% for the Antakya station using DENFIS.
Effects of Acupuncture on Alzheimer’s Disease in Animal‐Based Research
Authors: Park Sunjung , Lee Jun-Hwan , Yang Eun Jin
Published: September 2017

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, and severe functional deficits in the brain. The pathogenesis and treatment of AD remain topics of investigation and significant global socioeconomic issues. The effect of complementary medicine has been investigated in managing AD. Acupuncture, a form of therapy practiced for more than 3000 years, has shown positive effects on several neurological disorders including AD. Animal studies have evaluated the specific utility and neuropathological mechanisms addressed by acupoint manipulation; however, no study has summarized the relationships among different acupoints and their therapeutic effects in the context of AD. Therefore, we reviewed the effects of acupuncture at different acupoints in animal models of AD. In general, acupuncture produced therapeutic benefits in rodent models of AD. Studies demonstrate the utility of GV20 as a valuable acupoint for electroacupuncture and manual acupuncture. GV20 stimulation suppresses Aβ generation, improves glucose metabolism, and attenuates neuropathological features in various disease models. However, a lack of sufficient evidence in preclinical and clinical studies makes these results controversial. Additional studies are required to confirm the exact utility of specific acupoints in clinically managing AD.
Clinical Relevance of NGAL/MMP-9 Pathway in Patients with Endometrial Cancer
Authors: Cymbaluk-Płoska Aneta , Chudecka-Głaz Anita , Pius-Sadowska Ewa , Sompolska-Rzechuła Agnieszka , Chudecka Karolina , Bulsa Michał , Machaliński Bogusław , Menkiszak Janusz
Published: September 2017

The objectives of the study were to assess the relationship between the serum levels of MMP-9 and NGAL and the clinical staging and histopathological grade of the tumor. Lipocalin-2/NGAL and MMP-9 concentrations were quantified in serum by multiplex fluorescent bead-based immunoassays (Luminex Corporation, Austin, TX, USA). The AUC values for NGAL and MMP-9 were 0.9 and 0.78, respectively. The diagnostic potential of NGAL and MMP-9 in differentiating high-stage (FIGO III and IV) and low-stage (FIGO I and II) cancer and predicting the cell differentiation grade (G1 versus G3) on the basis of the analyses of AUC values was determined to be 0.91 and 0.79 for NGAL and 0.82 and 0.84 for MMP-9, respectively. Multifactorial logistic regression analysis in the final method revealed that NGAL and MMP-9 variables were independent of the endometrial cancer risk. OR values for NGAL and MMP-9 were 1.23 (95% CI 1.421–3.27; p=0.034) and 1.09 (95% CI: 1.38–4.12; p=0.026), respectively. The NGAL/MMP-9 complex may be useful in the assessment of tumor stage before surgical treatment.
Simulation of Pedestrian Crossing Behaviors at Unmarked Roadways Based on Social Force Model
Authors: Ningbo Cao , Wei Wei , Zhaowei Qu , Liying Zhao , Qiaowen Bai
Published: September 2017

Limited pedestrian microcosmic simulation models focus on the interactions between pedestrians and vehicles at unmarked roadways. Pedestrians tend to head to the destinations directly through the shortest path. So, pedestrians have inclined trajectories pointing destinations. Few simulation models have been established to describe the mechanisms underlying the inclined trajectories when pedestrians cross unmarked roadways. To overcome these shortcomings, achieve solutions for optimal design features before implementation, and help to make the design more rational, the paper establishes a modified social force model for interactions between pedestrians and vehicles at unmarked roadways. To achieve this goal, stop/go decision-making model based on gap acceptance theory and conflict avoidance models were developed to make social force model more appropriate in simulating pedestrian crossing behaviors at unmarked roadways. The extended model enables the understanding and judgment ability of pedestrians about the traffic environment and guides pedestrians to take the best behavior to avoid conflict and keep themselves safe. The comparison results of observed pedestrians’ trajectories and simulated pedestrians’ trajectories at one unmarked roadway indicate that the proposed model can be used to simulate pedestrian crossing behaviors at unmarked roadways effectively. The proposed model can be used to explore pedestrians’ trajectories variation at unmarked roadways and improve pedestrian safety facilities.
Calcium Promotes Human Gastric Cancer via a Novel Coupling of Calcium-Sensing Receptor and TRPV4 Channel
Authors: Xie Rui , Xu Jingyu , Xiao Yufeng , Wu Jilin , Wan Hanxing , Tang Bo , Liu Jingjing , Fan Yahan , Wang Suming , Wu Yuyun , Dong Tobias Xiao , Zhu Michael X. , Carethers John M. , Dong Hui , Yang Shiming
Published: September 2017

Although dietary calcium intake has long been recommended for disease prevention, the influence of calcium in development of cancer in the upper gastrointestinal tract has not been explored. Here, we assess the roles of calcium and calcium-sensing receptor (CaSR) in gastric cancer development. CaSR expression was enhanced in gastric cancer specimens, which positively correlated with serum calcium concentrations, tumor progression, poor survival, and male gender in gastric cancer patients. CaSR and transient receptor potential cation channel subfamily V member 4 (TRPV4) were colocalized in gastric cancer cells, and CaSR activation evoked TRPV4-mediated Ca2+ entry. Both CaSR and TRPV4 were involved in Ca2+-induced proliferation, migration, and invasion of gastric cancer cells through a Ca2+/AKT/β-catenin relay, which occurred only in gastric cancer cells or normal cells overexpressing CaSR. Tumor growth and metastasis of gastric cancer depended on CaSR in nude mice. Overall, our findings indicate that calcium may enhance expression and function of CaSR to potentially promote gastric cancer, and that targeting the novel CaSR/TRPV4/Ca2+ pathway might serve as preventive or therapeutic strategies for gastric cancer. Cancer Res; 77(23); 6499–512. ©2017 AACR.
Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition
Authors: Yaeger Rona , Yao Zhan , Hyman David M. , Hechtman Jaclyn F. , Vakiani Efsevia , Zhao HuiYong , Su Wenjing , Wang Lu , Joelson Andrew , Cercek Andrea , Baselga Jose , de Stanchina Elisa , Saltz Leonard , Berger Michael F. , Solit David B. , Rosen Neal
Published: September 2017

BRAF V600E colorectal cancers are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, but resistance invariably develops through undefined mechanisms. In this study, we determined that colorectal cancer progression specimens invariably harbored lesions in elements of the RAS–RAF–MEK–ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in colorectal cancer patients that was not seen in similarly resistant melanomas. We show that wild-type RAS amplification increases receptor tyrosine kinase-dependent activation of RAS more potently in colorectal cancer than in melanoma and causes resistance only in the former. Currently approved RAF inhibitors inhibit RAF monomers but not dimers. All the drug-resistant lesions we identified activate BRAF V600E dimerization directly or by elevating RAS-GTP. Overall, our results show that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant colorectal cancer. Cancer Res; 77(23); 6513–23. ©2017 AACR.
Modeling Cytostatic and Cytotoxic Responses to New Treatment Regimens for Ovarian Cancer
Authors: Falcetta Francesca , Bizzaro Francesca , D'Agostini Elisa , Bani Maria Rosa , Giavazzi Raffaella , Ubezio Paolo
Published: September 2017

The margin for optimizing polychemotherapy is wide, but a quantitative comparison of current and new protocols is rare even in preclinical settings. In silico reconstruction of the proliferation process and the main perturbations induced by treatment provides insight into the complexity of drug response and grounds for a more objective rationale to treatment schemes. We analyzed 12 treatment groups in trial on an ovarian cancer xenograft, reproducing current therapeutic options for this cancer including one-, two-, and three-drug schemes of cisplatin (DDP), bevacizumab (BEV), and paclitaxel (PTX) with conventional and two levels (“equi” and “high”) of dose-dense schedules. All individual tumor growth curves were decoded via separate measurements of cell death and other antiproliferative effects, gaining fresh insight into the differences between treatment options. Single drug treatments were cytostatic, but only DDP and PTX were also cytotoxic. After treatment, regrowth stabilized with increased propensity to quiescence, particularly with BEV. More cells were killed by PTX dose-dense-equi than with PTX conventional, but with the addition of DDP, cytotoxicity was similar and considerably less than expected from that of individual drugs. In the DDP/PTX dose-dense-high scheme, both cell death and regrowth impairment were intensified enough to achieve complete remission, and addition of BEV increased cell death in all schemes. The results support the option for dose-dense PTX chemotherapy with active single doses, showing the relative additional contribution of BEV, but also indicate negative drug interactions in concomitant DDP/PTX treatments, suggesting that sequential schedules could improve antitumor efficacy. Cancer Res; 77(23); 6759–69. ©2017 AACR.
PHGDH as a Key Enzyme for Serine Biosynthesis in HIF2α-Targeting Therapy for Renal Cell Carcinoma
Authors: Yoshino Hirofumi , Nohata Nijiro , Miyamoto Kazutaka , Yonemori Masaya , Sakaguchi Takashi , Sugita Satoshi , Itesako Toshihiko , Kofuji Satoshi , Nakagawa Masayuki , Dahiya Rajvir , Enokida Hideki
Published: September 2017

Continuous activation of hypoxia-inducible factor (HIF) is important for progression of renal cell carcinoma (RCC) and acquired resistance to antiangiogenic multikinase and mTOR inhibitors. Recently, HIF2α antagonists PT2385 and PT2399 were developed and are being evaluated in a phase I clinical trial for advanced or metastatic clear cell RCC (ccRCC). However, resistance to HIF2α antagonists would be expected to develop. In this study, we identified signals activated by HIF2α deficiency as candidate mediators of resistance to the HIF2α antagonists. We established sunitinib-resistant tumor cells in vivo and created HIF2α-deficient variants of these cells using CRISPR/Cas9 technology. Mechanistic investigations revealed that a regulator of the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), was upregulated commonly in HIF2α-deficient tumor cells along with the serine biosynthesis pathway itself. Accordingly, treatment with a PHGDH inhibitor reduced the growth of HIF2α-deficient tumor cells in vivo and in vitro by inducing apoptosis. Our findings identify the serine biosynthesis pathway as a source of candidate therapeutic targets to eradicate advanced or metastatic ccRCC resistant to HIF2α antagonists. Cancer Res; 77(22); 6321–9. ©2017 AACR.
Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma
Authors: Sivakumar Smruthy , Lucas F. Anthony San , McDowell Tina L. , Lang Wenhua , Xu Li , Fujimoto Junya , Zhang Jianjun , Futreal P. Andrew , Fukuoka Junya , Yatabe Yasushi , Dubinett Steven M. , Spira Avrum E. , Fowler Jerry , Hawk Ernest T. , Wistuba Ignacio I. , Scheet Paul , Kadara Humam
Published: September 2017

There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic BRAF variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in AAHs from 4 of 22 (18%) of patients. KRAS mutations in AAH were only found in ever-smokers and were exclusive to BRAF-mutant cases. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF-mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed antitumor (Th1; IL12A, GZMB) and elevated protumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. Cancer Res; 77(22); 6119–30. ©2017 AACR.
Inflammatory Monocytes Promote Perineural Invasion via CCL2-Mediated Recruitment and Cathepsin B Expression
Authors: Bakst Richard L. , Xiong Huizhong , Chen Chun-Hao , Deborde Sylvie , Lyubchik Anna , Zhou Yi , He Shizhi , McNamara William , Lee Sei-Young , Olson Oakley C. , Leiner Ingrid M. , Marcadis Andrea R. , Keith James W. , Al-Ahmadie Hikmat A. , Katabi Nora , Gil Ziv , Vakiani Efsevia , Joyce Johanna A. , Pamer Eric , Wong Richard J.
Published: September 2017

Perineural invasion (PNI) is an ominous event strongly linked to poor clinical outcome. Cells residing within peripheral nerves collaborate with cancer cells to enable PNI, but the contributing conditions within the tumor microenvironment are not well understood. Here, we show that CCR2-expressing inflammatory monocytes (IM) are preferentially recruited to sites of PNI, where they differentiate into macrophages and potentiate nerve invasion through a cathepsin B–mediated process. A series of adoptive transfer experiments with genetically engineered donors and recipients demonstrated that IM recruitment to nerves was driven by CCL2 released from Schwann cells at the site of PNI, but not CCL7, an alternate ligand for CCR2. Interruption of either CCL2–CCR2 signaling or cathepsin B function significantly impaired PNI in vivo. Correlative studies in human specimens demonstrated that cathepsin B–producing macrophages were enriched in invaded nerves, which was associated with increased local tumor recurrence. These findings deepen our understanding of PNI pathogenesis and illuminate how PNI is driven in part by corruption of a nerve repair program. Further, they support the exploration of inhibiting IM recruitment and function as a targeted therapy for PNI. Cancer Res; 77(22); 6400–14. ©2017 AACR.
Multiscale Modeling of Inflammation-Induced Tumorigenesis Reveals Competing Oncogenic and Oncoprotective Roles for Inflammation
Authors: Guo Yucheng , Nie Qing , MacLean Adam L. , Li Yanda , Lei Jinzhi , Li Shao
Published: September 2017

Chronic inflammation is a serious risk factor for cancer; however, the routes from inflammation to cancer are poorly understood. On the basis of the processes implicated by frequently mutated genes associated with inflammation and cancer in three organs (stomach, colon, and liver) extracted from the Gene Expression Omnibus, The Cancer Genome Atlas, and Gene Ontology databases, we present a multiscale model of the long-term evolutionary dynamics leading from inflammation to tumorigenesis. The model incorporates cross-talk among interactions on several scales, including responses to DNA damage, gene mutation, cell-cycle behavior, population dynamics, inflammation, and metabolism-immune balance. Model simulations revealed two stages of inflammation-induced tumorigenesis: a precancerous state and tumorigenesis. The precancerous state was mainly caused by mutations in the cell proliferation pathway; the transition from the precancerous to tumorigenic states was induced by mutations in pathways associated with apoptosis, differentiation, and metabolism-immune balance. We identified opposing effects of inflammation on tumorigenesis. Mild inflammation removed cells with DNA damage through DNA damage-induced cell death, whereas severe inflammation accelerated accumulation of mutations and hence promoted tumorigenesis. These results provide insight into the evolutionary dynamics of inflammation-induced tumorigenesis and highlight the combinatorial effects of inflammation and metabolism-immune balance. This approach establishes methods for quantifying cancer risk, for the discovery of driver pathways in inflammation-induced tumorigenesis, and has direct relevance for early detection and prevention and development of new treatment regimes. Cancer Res; 77(22); 6429–41. ©2017 AACR.
FGF19 Protects Hepatocellular Carcinoma Cells against Endoplasmic Reticulum Stress via Activation of FGFR4–GSK3β–Nrf2 Signaling
Authors: Teng Yong , Zhao Huakan , Gao Lixia , Zhang Wenfa , Shull Austin Y. , Shay Chloe
Published: September 2017

The tumor microenvironment induces endoplasmic reticulum (ER) stress in tumor cells, an event that can promote progression, but it is unknown how tumor cells adapt to this stress. In this study, we show that the fibroblast growth factor FGF19, a gene frequently amplified in hepatocellular carcinoma (HCC), facilitates a survival response to ER stress. Levels of FGF19 expression were increased in stressed HCC cells in culture and in a mouse xenograft model. Induction of ER stress required the transcription factor ATF4, which directly bound the FGF19 promoter. In cells where ER stress was induced, FGF19 overexpression promoted HCC cell survival and increased resistance to apoptosis, whereas FGF19 silencing counteracted these effects. Mechanistic investigations implicated glycogen synthase kinase-3β (GSK3β) in regulating nuclear accumulation of the stress-regulated transcription factor Nrf2 activated by FGF19. Our findings show how FGF19 provides a cytoprotective role against ER stress by activating a FGFR4–GSK3β–Nrf2 signaling cascade, with implications for targeting this signaling node as a candidate therapeutic regimen for HCC management. Cancer Res; 77(22); 6215–25. ©2017 AACR.