bluuebunny/crossref_metadata_2025 huggingface dataset:
An iterative scheme for the generalized Peierls–Nabarro model based on the inverse Hilbert transform
Authors: Ramabathiran Amuthan A.
Published: November 2019

A new and efficient semi-analytical iterative scheme is proposed in this work for solving the generalized Peierls–Nabarro model. The numerical method developed here exploits certain basic properties of the Hilbert transform to achieve a reduction of the nonlocal and nonlinear equations characterizing the generalized Peierls–Nabarro model to a local model which is then solved using a fixed point iteration scheme. This is in sharp contrast to existing schemes for solving the generalized Peierls–Nabarro model like the semi-discrete variational Peierls–Nabarro model, or methods involving the fitting of the slip distribution to a linear combination of predefined elementary slip distributions, all of which involve the solution of nonlinear and nonlocal equations using gradient-based optimization tools. The key idea behind the proposed technique is to transform the nonlocal Peierls–Nabarro model into an equivalent local model, called the inverse Peierls–Nabarro model. From a computational viewpoint, the resulting local model is attractive since it can be solved without recourse to any gradient based algorithms; combined with appropriate acceleration schemes, the proposed algorithm provides a computationally expedient alternative to solving the generalized Peierls–Nabarro model. Further, the fixed point iterative scheme developed here easily lends itself to parallelization, unlike iterative methods for the fully nonlocal and nonlinear models currently in use. The proposed numerical scheme is validated both with simple examples involving the 1D Peierls–Nabarro model corresponding to a sinusoidal stacking fault energy, and with realistic examples involving calculations of the core structure of both edge and screw dislocations on the close-packed [Formula: see text] planes in Aluminum. An approximate technique to incorporate external stresses within the framework of the proposed iterative scheme is also discussed with applications to the equilibration of a dislocation dipole. Finally, the advantages, limitations and avenues for future extension of the proposed method are discussed.
Human-in-the-loop Learning for Personalized Diet Monitoring from Unstructured Mobile Data
Authors: Hezarjaribi Niloofar , Mazrouee Sepideh , Hemati Saied , Chaytor Naomi S. , Perrigue Martine , Ghasemzadeh Hassan
Published: November 2019

Lifestyle interventions with the focus on diet are crucial in self-management and prevention of many chronic conditions, such as obesity, cardiovascular disease, diabetes, and cancer. Such interventions require a diet monitoring approach to estimate overall dietary composition and energy intake. Although wearable sensors have been used to estimate eating context (e.g., food type and eating time), accurate monitoring of dietary intake has remained a challenging problem. In particular, because monitoring dietary intake is a self-administered task that involves the end-user to record or report their nutrition intake, current diet monitoring technologies are prone to measurement errors related to challenges of human memory, estimation, and bias. New approaches based on mobile devices have been proposed to facilitate the process of dietary intake recording. These technologies require individuals to use mobile devices such as smartphones to record nutrition intake by either entering text or taking images of the food. Such approaches, however, suffer from errors due to low adherence to technology adoption and time sensitivity to the dietary intake context.

In this article, we introduce
EZNutriPal
,
1
an interactive diet monitoring system that operates on unstructured mobile data such as speech and free-text to facilitate dietary recording, real-time prompting, and personalized nutrition monitoring. EZNutriPal features a natural language processing unit that learns incrementally to add user-specific nutrition data and rules to the system. To prevent missing data that are required for dietary monitoring (e.g., calorie intake estimation), EZNutriPal devises an interactive operating mode that prompts the end-user to complete missing data in real-time. Additionally, we propose a combinatorial optimization approach to identify the most appropriate pairs of food names and food quantities in complex input sentences. We evaluate the performance of EZNutriPal using real data collected from 23 human subjects who participated in two user studies conducted in 13 days each. The results demonstrate that EZNutriPal achieves an accuracy of 89.7% in calorie intake estimation. We also assess the impacts of the incremental training and interactive prompting technologies on the accuracy of nutrient intake estimation and show that incremental training and interactive prompting improve the performance of diet monitoring by 49.6% and 29.1%, respectively, compared to a system without such computing units.
A Trust Computing-based Security Routing Scheme for Cyber Physical Systems
Authors: Liu Yuxin , Liu Xiao , Liu Anfeng , Xiong Neal N. , Liu Fang
Published: November 2019

Security is a pivotal issue for the development of Cyber Physical Systems (CPS). The trusted computing of CPS includes the complete protection mechanisms, such as hardware, firmware, and software, the combination of which is responsible for enforcing a system security policy. A Trust Detection-based Secured Routing (TDSR) scheme is proposed to establish security routes from source nodes to the data center under malicious environment to ensure network security. In the TDSR scheme, sensor nodes in the routing path send detection routing to identify relay nodes’ trust. And then, data packets are routed through trustworthy nodes to sink securely. In the TDSR scheme, the detection routing is executed in those nodes that have abundant energy; thus, the network lifetime cannot be affected. Performance evaluation through simulation is carried out for success of routing ratio, compromised node detection ratio, and detection routing overhead. The experiment results show that the performance can be improved in the TDSR scheme compared to previous schemes.
Continuous Data-driven Software Engineering - Towards a Research Agenda
Authors: Gerostathopoulos Ilias , Konersmann Marco , Krusche Stephan , Mattos David I. , Bosch Jan , Bures Tomas , Fitzgerald Brian , Goedicke Michael , Muccini Henry , Olsson Helena H. , Brand Thomas , Chatley Robert , Diamantopoulos Nikolaos , Friedman Arik , Jiménez Miguel , Johanssen Jan Ole , Manggala Putra , Koseki Masumi , Melegati Jorge , Munaiah Nuthan , Tamura Gabriel , Theodorou Vasileios , Wong Jeffrey , Figalist Iris
Published: November 2019

The rapid pace with which software needs to be built, together with the increasing need to evaluate changes for end users both quantitatively and qualitatively calls for novel software engineering approaches that focus on short release cycles, continuous deployment and delivery, experiment-driven feature development, feedback from users, and rapid tool-assisted feedback to developers. To realize these approaches there is a need for research and innovation with respect to automation and tooling, and furthermore for research into the organizational changes that support flexible data-driven decision-making in the development lifecycle. Most importantly, deep synergies are needed between software engineers, managers, and data scientists. This paper reports on the results of the joint 5th International Workshop on Rapid Continuous Software Engineering (RCoSE 2019) and the 1st International Workshop on Data-Driven Decisions, Experimentation and Evolution (DDrEE 2019), which focuses on the challenges and potential solutions in the area of continuous data-driven software engineering.
Implications of Resurgence in Artificial Intelligence for Research Collaborations in Software Engineering
Authors: Marijan Dusica , Shang Weiyi , Shukla Rakesh
Published: November 2019

Challenges of implementing successful research collaborations between industry and academia in software engineering are varied and many. Differing timelines, metrics, expectations, and perceptions of these two communities are some common obstacles, which need be analyzed and discussed, to discover synergies and strengthen collaborations between researchers and practitioners. In this report, we present insights from the 6th International Workshop on Software Engineering Research and Industrial Practice held at the International Conference on Software Engineering 2019. Specifically, one particular topic dominated the discussion - the resurgence of artificial intelligence and machine learning algorithms in software engineering research and industry practice, and its implications for the collaboration between these two communities. We present takeaways from keynote talks on this subject, insights from paper presentations, and findings from the discussion session.
The Struggle for Recognition in Advanced Dementia
Authors: Foley Sarah , McCarthy John , Pantidi Nadia
Published: November 2019

Focusing on the person with advanced dementia as a social being presents a new opportunity for Experience-Centered Design (ECD), opening design to appreciate the agency and intentional actions of the person with advanced dementia. If Human-Computer Interaction is to shift from the predominantly assistive approach to a focus on experience, a theoretical framing that emphasizes the relational nature of selfhood is needed. In this article, we present Recognition Theory—a social theory based on an inter-subjectivist account of the struggle for recognition—to extend ECD approaches for advanced dementia. Focusing on people with advanced dementia, we examine recognition as a social and ethical perspective for establishing and maintaining self. We present a framework for design based on research with people with advanced dementia, experience-centered engagement and social identity, that will support designers to craft opportunities for mutual recognition in the design process and the practice of making.
Applications of Distributed Ledger Technologies to the Internet of Things
Authors: Zhu Qingyi , Loke Seng W. , Trujillo-Rasua Rolando , Jiang Frank , Xiang Yong
Published: November 2019

Distributed Ledger Technologies (DLTs) and blockchain systems have received enormous academic, government, and commercial interest in recent years. This article surveys the integration of DLTs within another life-changing technology, the Internet of Things (IoT). IoT-based applications, such as smart home, smart transport, supply chain, smart healthcare, and smart energy, promise to boost the efficiency of existing infrastructures and change every facet of our daily life. This article looks into the challenges faced by such applications and reviews a comprehensive selection of existing DLT solutions to those challenges. We also identify issues for future research, including DLT security and scalability, multi-DLT applications, and survival of DLT in the post-quantum world.
Rebuilding Social Capital in Refugees and Asylum Seekers
Authors: Almohamed Asam , Vyas Dhaval
Published: November 2019

Displacement caused by war, conflict and persecution affects refugees and asylum seekers in more ways than we can imagine. This article investigates refugees and asylum seekers’ experiences associated with displacement and the effects it has on their social capital. We present findings from a qualitative study that involved a mix of 24 participants, including refugees, asylum seekers, community workers and activists. Cultural probes and semi-structured interviews were adopted in this study. We discuss our findings in four themes: displacement related stressors, acceptance in the host community, access to social resources and technology use by refugees. We discuss examples from our study and offer practical, theoretical and technological design implications that can foster social capital for refugees and asylum seekers.
Understanding Affective Dynamics of Learning Toward a Ubiquitous Learning System
Authors: Mandalapu Varun , Gong Jiaqi
Published: November 2019

Understanding student learning behaviors is of prime importance for educational research. Many complex factors influence learning processes, but one collective impact of all these factors is how they affect learning and the degree of motivation. In this study, we discuss the current state of human affect detection in education, our proposed affect change model and its implications. This study adopts dataset from ASSISTments online learning platform, which consists of student interaction data, and ground truth labels for affect states coded by Baker Rodrigo Ocumpaugh Monitoring Protocol (BROMP) certified coders to develop and validate the affect change model. We show that the proposed affect change model in combination with the adoption of machine learning algorithms will support the development of a ubiquitous learning system that tracks the student learning process within the context of contributing factors and provide interventions when needed.
InvisibleEye
Authors: Steil Julian , Tonsen Marc , Sugano Yusuke , Bulling Andreas
Published: November 2019

Despite their potential for a range of exciting new applications, mobile eye trackers suffer from several fundamental usability problems. InvisibleEye is an innovative approach for mobile eye tracking that uses millimeter-size RGB cameras, which can be fully embedded into normal glasses frames, as well as appearancebased gaze estimation to directly estimate gaze from the eye images. Through evaluation on three large-scale, increasingly realistic datasets, we show that InvisibleEye can achieve a person-specific gaze estimation accuracy of up to 2.04° using three camera pairs with a resolution of only 3x3 pixels.
Superpower Glass
Authors: Kline Aaron , Voss Catalin , Washington Peter , Haber Nick , Schwartz Hessey , Tariq Qandeel , Winograd Terry , Feinstein Carl , Wall Dennis P.
Published: November 2019

Autism Spectrum Disorder (ASD) is quickly becoming a global health crisis estimated to affect one in 40 children in the United States [8]. ASD consists of social deficiencies, such as impaired communication, eye contact, facial expression recognition, and social interaction. The current standard of care, applied behavioral analysis (ABA), relies on teaching these skills primarily in clinical environments with tools such as static flashcards. Such tools are largely removed from real world emotional contexts. While ABA can lead to improvements [1, 2], the therapy often generalizes poorly to situations that extend beyond the routines practiced in clinical contexts [3]. Furthermore, access to such treatment is constrained by the availability of therapists, who struggle to keep up with the increasing demand for care.
On the Economic Sustainability of Cloud Sharing Systems Are Dynamic Single Resource Sharing Markets Stable?
Authors: Pal Ranjan , Ahuja Aditya , Lin Sung-Han , Kumar Abhishek , Golubchik Leana , Jagadeesan Nachikethas A.
Published: November 2019

The recent emergence of the small cloud (SC), both in concept and in practice, has been driven mainly by issues related to service cost and complexity of commercial cloud providers (e.g., Amazon) employing massive data centers. However, the resource inelasticity problem [29] faced by the SCs due to their relatively scarce resources might lead to a potential degradation of customer QoS and loss of revenue. A proposed solution to this problem recommends the sharing of resources between competing SCs to alleviate the resource inelasticity issues that might arise. Based on this idea, a recent e?ort ([18]) proposed SC-Share, a performance-driven static market model for competitive small cloud environments that results in an e?cient market equilibrium jointly optimizing customer QoS satisfaction and SC revenue generation. However, an important question with a non-obvious answer still remains to be answered, without which SC sharing markets may not be guaranteed to sustain in the long-run - is it still possible to achieve a stable market e?cient state when the supply of SC resources is dynamic in nature?. In this paper, we take a? rst step to addressing the problem of e?cient market design for single SC resource sharing in dynamic environments. We answer our previous question in the a?rmative through the use of Arrow and Hurwicz's disequilibrium process [9, 10] in economics, and the gradient play technique in game theory that allows us to iteratively converge upon e?cient and stable market equilibria.
Muscle alterations in the development and progression of cancer-induced muscle atrophy: a review
Authors: Rosa-Caldwell Megan E. , Fix Dennis K. , Washington Tyrone A. , Greene Nicholas P.
Published: November 2019

Cancer cachexia—cancer-associated body weight and muscle loss—is a significant predictor of mortality and morbidity in cancer patients across a variety of cancer types. However, despite the negative prognosis associated with cachexia onset, there are no clinical therapies approved to treat or prevent cachexia. This lack of treatment may be partially due to the relative dearth of literature on mechanisms occurring within the muscle before the onset of muscle wasting. Therefore, the purpose of this review is to compile the current scientific literature on mechanisms contributing to the development and progression of cancer cachexia, including protein turnover, inflammatory signaling, and mitochondrial dysfunction. We define “development” as changes in cell function occurring before the onset of cachexia and “progression” as alterations to cell function that coincide with the exacerbation of muscle wasting. Overall, the current literature suggests that multiple aspects of cellular function, such as protein turnover, inflammatory signaling, and mitochondrial quality, are altered before the onset of muscle loss during cancer cachexia and clearly highlights the need to study more thoroughly the developmental stages of cachexia. The studying of these early aberrations will allow for the development of effective therapeutics to prevent the onset of cachexia and improve health outcomes in cancer patients.
Intracortical Administration of the Complement C3 Receptor Antagonist Trifluoroacetate Modulates Microglia Reaction after Brain Injury
Authors: Surugiu Roxana , Catalin Bogdan , Dumbrava Danut , Gresita Andrei , Olaru Denisa Greta , Hermann Dirk M. , Popa-Wagner Aurel
Published: November 2019

Worldwide, millions of individuals suffer an ischemic stroke each year, causing major disability, especially in the elderly, where stroke is the number one cause of disability. However, to date, no effective therapy exists that targets the functional recovery after stroke. After necrosis, neuroinflammation is a common feature of the acute stroke and a major obstacle to tissue restoration. In the lesioned area, the dying neurons release chemotactic signals, such as fractalkine/CX3CL1, which evoke “eat-me” signals that are recognized by microglia expressing complement C3a receptor (C3aR), resulting in phagocytosis of the dying but still viable neurons, known as secondary phagocytosis. Using a mouse model of stroke and two-photon microscopy, we aimed to attenuate poststroke phagocytosis of the dying but still viable neurons by using SB 290157, an antagonist of C3aR. We found that intracortical administration of SB 290157 reduced the number of inflammatory microglial cells expressing ED1 and Iba1 antigens at the lesion site. We could show, in vivo, that two days after a needle-induced cortical lesion there were less microglial cells present around the injury site, displaying less high-order branches and an increase in the lower order ones, suggesting an attenuated phagocytic phenotype in treated animals as compared with controls. We conclude that the C3aR antagonist, SB 290157, may be used in the future to limit the neuronal death by limiting secondary phagocytosis after stroke.
Laser Doppler Signal Denoising Based on Wavelet Packet Thresholding Method
Authors: Zhang Da , Liu Ranglei
Published: November 2019

In laser Doppler velocimeter (LDV), calculation precision of Doppler shift is affected by noise contained in Doppler signal. In order to restrain the noise interference and improve the precision of signal processing, wavelet packet threshold denoising methods are proposed. Based on the analysis of Doppler signal, appropriate threshold function and decomposition layer number are selected. Heursure, sqtwolog, rigrsure, and minimaxi rules are adopted to get the thresholds. Processing results indicate that signal-to-noise ratio (SNR) and root mean square error (RMSE) of simulated signals with original SNR of 0 dB, 5 dB, and 10 dB in both low- and high-frequency ranges are significantly improved by wavelet packet threshold denoising. A double-beam and double-scattering LDV system is built in our laboratory. For measured signals obtained from the experimental system, the minimum relative error of denoised signal is only 0.079% (using minimaxi rule). The denoised waveforms of simulated and experimental signals are much more smooth and clear than that of original signals. Generally speaking, denoising effects of minimaxi and saqtwolog rules are better than those of heursure and rigrsure rules. As shown in the processing and analysis of simulated and experimental signals, denoising methods based on wavelet packet threshold have ability to depress the noise in laser Doppler signal and improve the precision of signal processing. Owing to its effectiveness and practicability, wavelet packet threshold denoising is a practical method for LDV signal processing.
The Intracellular Growth ofM. tuberculosisIs More Associated with High Glucose Levels Than with Impaired Responses of Monocytes from T2D Patients
Authors: Torres Martha , Herrera María Teresa , Fabián-San-Miguel Guadalupe , Gonzalez Yolanda
Published: November 2019

Diabetes mellitus, a metabolic disease characterized by hyperglycemia and poor glucose control, is a risk factor forMycobacterium tuberculosis(M. tuberculosis) infection and the development of active tuberculosis. To evaluate whetherM. tuberculosisinfection susceptibility is associated with an intrinsic factor in monocytes from type 2 diabetes (T2D) patients or it is associated with hyperglycemiaper se, we analyzed TLR-2 and TLR-4 expression by flow cytometry and the cytokines IL-1β, IL-6, IL-8, IL-10, and TNF-αby cytometric bead array assays, either stimulated with TLR-2 and TLR-4 ligands or infected withM. tuberculosisin the whole blood from T2D patients (n=43) and healthy subjects (n=26) or in CD14+ monocytes from healthy subjects cultured in high glucose (HG) (30 mM). The intracellular growth ofM. tuberculosiswas evaluated by CFU counts at 0, 1, and 3 days in both monocytes from T2D patients and monocytes from healthy subjects cultured in HG. We did not find significant differences in TLR expression, cytokine production, or growth ofM. tuberculosisin monocytes from T2D patients compared with those in monocytes from healthy subjects. Despite these results,in vitroassays of monocytes cultured with 30 mM glucose led to significantly increased TLR-2 and TLR-4 basal expression compared to those of monocytes cultured with 11 mM glucose (P<0.05). Conversely, the production of IL-6 by TLR-2 ligand stimulation, of IL-1β, IL-6, and IL-8 by TLR-4 ligand stimulation, and of IL-8 byM. tuberculosisinfection significantly decreased in monocytes cultured in HG (P<0.05). Additionally, the intracellular survival ofM. tuberculosisincreased in monocytes in HG after day 3 of culture (P<0.05). In conclusion, HG decreased IL-8 production and the intracellular growth control ofM. tuberculosisby monocytes, supporting the hypothesis that hyperglycemia plays an important role in the impaired immune responses toM. tuberculosisin patients with T2D.
Laboratory Risk Indicator for Necrotizing Fasciitis of the Oro-Cervical Region (LRINEC-OC): A Possible Diagnostic Tool for Emergencies of the Oro-Cervical Region
Authors: Ogawa Masaru , Yokoo Satoshi , Takayama Yu , Kurihara Jun , Makiguchi Takaya , Shimizu Takahiro
Published: November 2019

Aim. Oro-cervical necrotizing fasciitis (OCNF) treatment requires early surgical debridement and opening of the wound, and therefore, early diagnosis is very important. The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score based on blood test data has recently been proposed as an auxiliary diagnostic tool. However, in some cases, it is difficult to diagnose OCNF. We performed a pooled analysis of patients with OCNF at Gunma University Hospital and literature cases, with the goal of designing a new auxiliary diagnostic tool for OCNF by adding physical characteristics of the oro-cervical region to blood test data in the first examination. Methods. Univariate and multivariate logistic regression was used to select predictors of OCNF. The LRINEC-Oro-Cervical (OC) score was then designed using correlation coefficients of items selected in logistic regression analysis. A cutoff value for the LRINEC-OC score was determined using receiver operating characteristic (ROC) curve analysis. Results. CRP, WBC, Cr, and skin flare in the cervical and precordial regions were extracted as independent factors (p<0.05) and evaluated as predictors of OCNF. The LRINEC-OC score for the prediction of OCNF was designed using the regression coefficients in logistic analysis. The cutoff value for the LRINEC-OC score was 6 points with a sensitivity of 88.5% and a specificity of 93.4%, and the AUC was 0.909. Conclusion. Delays in diagnosis and surgical treatment for OCNF led to a fatal prognosis, and the potential utility of the LRINEC-OC score for improving the prognosis was shown in this study.
Thrombin Induces Secretion of Multiple Cytokines and Expression of Protease-Activated Receptors in Mouse Mast Cell Line
Authors: Fang Xiaobin , Liao Ren , Yu Yingyan , Li Jingyi , Guo Zaipei , Zhu Tao
Published: November 2019

Background. Thrombin could elicit degranulation of mast cells involved in numerous physiologic and pathologic processes; however, the detailed scrutiny of this procedure and further research of possible cell signaling pathways are lacking.Methods. P815 mouse mast cells were exposed to various concentrations of thrombin for 16 h. Expression of protease-activated receptor (PAR)1, PAR2, PAR3, and PAR4 mRNA in P815 was analyzed by quantitative real-time PCR (qRT-PCR) and the fittest concentration of thrombin was decided. Then, secretions of mediators from P815 stimulated by thrombin 0.2 U/ml were determined using enzyme-linked immunosorbent assay (ELISA) and Luminex liquichip; the possible cell signaling pathways were measured by immunoblotting. Furthermore, inhibition of thrombin inhibitor (hirudin), PAR1 inhibitor (SCH79797), and MAPK inhibitors (SB203580, PD98059, and SP600125) on the mediator section was evaluated by ELISA and Luminex liquichip.Results. Thrombin 0.2 U/ml induced the elevated expression of PAR1, PAR2, PAR3, and PAR4, as well as the increasing level of phospho-IκBα, phospho-SAPK/JNK MAPK, phospho-P38 MAPK (Thr180/Tyr182), and phospho-ERK1/2 MAPK (p44/42) in P815. Secretion of vascular endothelial growth factor (VEGF), tumor necrosis factor-α(TNF-α), interleukin- (IL-) 2, IL-6, chemokine ligand- (CCL-) 2, chemokine (C-X-C motif) ligand- (CXCL-) 1, and CXCL-5 from P815 increased apparently; this effect could be diminished by hirudin, whereas SCH79797 and MAPK inhibitors (SB203580, PD98059, and SP600125) diminish the secretions with weaker effect.Conclusion. We found the expression of PAR mRNA in P815, activation of signaling pathways of nuclear factor-kappaB (NF-κB), and mitogen-activated protein kinases (MAPKs) including C-Jun NH2-terminal kinase (JNK), P38, and extracellular signal-regulated kinase 1/2 (ERK1/2), and the release of multiple inflammatory mediators stimulated by thrombin, as well as the inhibition of the inflammatory releases by hirudin, SCH79797, and MAPK inhibitors including SB203580, PD98059, and SP600125.
miR-221 Augments TRAIL-Mediated Apoptosis in Prostate Cancer Cells by Inducing Endogenous TRAIL Expression and Targeting the Functional Repressors SOCS3 and PIK3R1
Authors: Krebs Markus , Behrmann Christoph , Kalogirou Charis , Sokolakis Ioannis , Kneitz Susanne , Kruithof-de Julio Marianna , Zoni Eugenio , Rech Anne , Schilling Bastian , Kübler Hubert , Spahn Martin , Kneitz Burkhard
Published: November 2019

miR-221 is regarded as an oncogene in many malignancies, and miR-221-mediated resistance towards TRAIL was one of the first oncogenic roles shown for this small noncoding RNA. In contrast, miR-221 is downregulated in prostate cancer (PCa), thereby implying a tumour suppressive function. By using proliferation and apoptosis assays, we show a novel feature of miR-221 in PCa cells: instead of inducing TRAIL resistance, miR-221 sensitized cells towards TRAIL-induced proliferation inhibition and apoptosis induction. Partially responsible for this effect was the interferon-mediated gene signature, which among other things contained an endogenous overexpression of the TRAIL encoding gene TNFSF10. This TRAIL-friendly environment was provoked by downregulation of the established miR-221 target gene SOCS3. Moreover, we introduced PIK3R1 as a target gene of miR-221 in PCa cells. Proliferation assays showed that siRNA-mediated downregulation of SOCS3 and PIK3R1 mimicked the effect of miR-221 on TRAIL sensitivity. Finally, Western blotting experiments confirmed lower amounts of phospho-Akt after siRNA-mediated downregulation of PIK3R1 in PC3 cells. Our results further support the tumour suppressing role of miR-221 in PCa, since it sensitises PCa cells towards TRAIL by regulating the expression of the oncogenes SOCS3 and PIK3R1. Given the TRAIL-inhibiting effect of miR-221 in various cancer entities, our results suggest that the influence of miR-221 on TRAIL-mediated apoptosis is highly context- and entity-dependent.
Optical Coherence Tomography Angiography Assessed Retinal and Choroidal Microvasculature Features in Patients with Retinitis Pigmentosa: A Meta-Analysis
Authors: Ling Ling , Gao Feifei , Zhang Qinglin , He Tao , Zhao Yi , Xing Yiqiao , Yu Yifeng , Ji Kaibao
Published: November 2019

Background. The aim of this study was to assess the retinal and choroidal microvasculature features using optical coherence tomography angiography (OCTA) in patients with retinitis pigmentosa (RP). Methods. This study was a meta-analysis of relevant published studies that were included after a comprehensive search of PubMed, Embase, Cochrane Library, and Web of Science databases. Mean difference (MD) with a 95% confidence interval was used to assess continuous variable outcomes. Heterogeneity was evaluated using the chi-squared test based on the values of P and I2. Results. Seven studies were included in this meta-analysis. The vessel density values measured in the superficial and deep foveal zones of RP patients using OCTA were significantly lower than the recorded values in the control groups (MD = −3.58, P=0.04; MD = −4.93, P=0.02, respectively). The superficial and deep parafoveal vessel density values measured with OCTA were also significantly lower in RP patients than in control groups (MD = −9.09, P<0.00001; MD = −10.74, P<0.00001, respectively); for choriocapillaris vessel density, there was no statistically significant difference between RP patients and controls (MD = −1.33, P=0.09). The deep foveal avascular zone (FAZ) was significantly larger in RP patients than in controls (MD = 0.15, P=0.01), whereas there was no significant difference in the superficial foveal avascular zones in the two groups (MD = 0.08, P=0.11). Conclusions. We showed that retinal and choroidal vessels were attenuated in RP patients. Additionally, we revealed that the FAZ was larger in RP patients, especially the deep FAZ. OCTA may become a useful modality in the diagnosis and monitoring of patients with RP.
Experimental Study on Electrode Wear of Diamond-Nickel Coated Electrode in EDM Small Hole Machining
Authors: Liu Yu , Wang Wenjian , Zhang Wenchao , Ma Fujian , Yang Dapeng , Sha Zhihua , Zhang Shengfang
Published: November 2019

Aiming at the problem of obvious tool length wear and side wear in the small hole processing of EDM, the nickel-coated composite electrode and diamond-nickel-coated composite electrode were prepared by chemical composite coating using brass, copper, molybdenum, and copper-tungsten alloy materials as the matrix material. Comparative experiments of EDM small hole machining using composite tools were carried out on die steel. The effects of nickel-coated composite electrode and diamond-nickel-coated composite electrode on tool length wear, tool side wear, and tool shape change were analyzed. The results show that the diamond-nickel-coated composite electrode can effectively reduce both the length wear and side wear of the electrodes.
A Combination of Peppermint Oil and Caraway Oil for the Treatment of Functional Dyspepsia: A Systematic Review and Meta-Analysis
Authors: Li Juanjuan , Lv Lin , Zhang Jiaqi , Xu Lin , Zeng Enjin , Zhang Zedan , Wang Fengyun , Tang Xudong
Published: November 2019

A combination of peppermint oil and caraway oil (POCO) with its unique properties has been shown clinical benefits for FD. However, the potent statistical data to confirm its effects are lacking. This meta-analysis thus aimed at evaluating the efficacy and safety of POCO compared with placebo in treating patients with FD. We searched CENTRAL, PubMed, EMBASE (Ovid), Web of Science, Google Scholar, China National Knowledge Infrastructure database, Wanfang, and VIP databases for randomized clinical trials (RCTs) up to June 2019. Dichotomous data were shown as a risk ratio (RR) with 95% confidence intervals (CIs). All data were analyzed by Review Manager 5.2 software. The search identified 382 citations, and 5 RCTs (578 participants) were included. POCO showed a statistically significant effect in global improvement of FD symptoms (RR for not much or very much improvement 0.59, 95% CI: 0.49 to 0.71,P<0.00001,I236%, NNT 3) and improvement in epigastric pain (RR 1.61, 95% CI: 1.28 to 2.03,P<0.0001,I20%, NNT 3). There were no significant differences in the total number of adverse events between POCO and placebo (NNH 40). In conclusion, this is the first meta-analysis to assess the effects of POCO in FD. POCO is an effective and safe short-term treatment for FD. However, current findings are based on smaller sample sizes and low/very low quality of the evidence. More well-designed RCTs with large sample sizes of FD patients are required.
Alteration of Extracellular Matrix Molecules and Perineuronal Nets in the Hippocampus of Pentylenetetrazol-Kindled Mice
Authors: Ueno Hiroshi , Suemitsu Shunsuke , Murakami Shinji , Kitamura Naoya , Wani Kenta , Takahashi Yu , Matsumoto Yosuke , Okamoto Motoi , Ishihara Takeshi
Published: November 2019

The pathophysiological processes leading to epilepsy are poorly understood. Understanding the molecular and cellular mechanisms involved in the onset of epilepsy is crucial for drug development. Epileptogenicity is thought to be associated with changes in synaptic plasticity; however, whether extracellular matrix molecules—known regulators of synaptic plasticity—are altered during epileptogenesis is unknown. To test this, we used a pentylenetetrazole- (PTZ-) kindling model mouse to investigate changes to hippocampal parvalbumin- (PV-) positive neurons, extracellular matrix molecules, and perineuronal nets (PNNs) after the last kindled seizure. We found an increase in Wisteria floribunda agglutinin- (WFA-) and Cat-315-positive PNNs and a decrease in PV-positive neurons not surrounded by PNNs, in the hippocampus of PTZ-kindled mice compared to control mice. Furthermore, the expression of WFA- and Cat-315-positive molecules increased in the extracellular space of PTZ-kindled mice. In addition, consistent with previous studies, astrocytes were activated in PTZ-kindled mice. We propose that the increase in PNNs after kindling decreases neuroplasticity in the hippocampus and helps maintain the neural circuit for recurrent seizures. This study shows that possibility of changes in extracellular matrix molecules due to astrocyte activation is associated with epilepticus in PTZ-kindled mice.
Prophylactic In Vivo Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models
Authors: Li Chang , Course Meredith M. , McNeish Iain A. , Drescher Charles W. , Valdmanis Paul N. , Lieber André
Published: November 2019

Population-wide testing for cancer-associated mutations has established that more than one-fifth of ovarian and breast carcinomas are associated with inherited risk. Salpingo-oophorectomy and/or mastectomy are currently the only effective options offered to women with high-risk germline mutations. Our goal here is to develop a long-lasting approach that provides immunoprophylaxis for mutation carriers. Our approach leverages the fact that at early stages, tumors recruit hematopoietic stem/progenitor cells (HSPC) from the bone marrow and differentiate them into tumor-supporting cells. We developed a technically simple technology to genetically modify HSPCs in vivo. The technology involves HSPC mobilization and intravenous injection of an integrating HDAd5/35++ vector. In vivo HSPC transduction with a GFP-expressing vector and subsequent implantation of syngeneic tumor cells showed >80% GFP marking in tumor-infiltrating leukocytes. To control expression of transgenes, we developed a miRNA regulation system that is activated only when HSPCs are recruited to and differentiated by the tumor. We tested our approach using the immune checkpoint inhibitor anti-PD-L1-γ1 as an effector gene. In in vivo HSPC-transduced mice with implanted mouse mammary carcinoma (MMC) tumors, after initial tumor growth, tumors regressed and did not recur. Conventional treatment with an anti-PD-L1 mAb had no significant antitumor effect, indicating that early, self-activating expression of anti-PD-L1-γ1 can overcome the immunosuppressive environment in MMC tumors. The efficacy and safety of this approach was further validated in an ovarian cancer model with typical germline mutations (ID8 p53−/− brca2−/−), both in a prophylactic and therapeutic setting. This HSPC gene therapy approach has potential for clinical translation.

Significance:

Considering the limited prophylactic options that are currently offered to women with high-risk germ-line mutations, the in vivo HSPC gene therapy approach is a promising strategy that addresses a major medical problem.
HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma
Authors: Courtney Kevin D. , Ma Yuanqing , Diaz de Leon Alberto , Christie Alana , Xie Zhiqun , Woolford Layton , Singla Nirmish , Joyce Allison , Hill Haley , Madhuranthakam Ananth J. , Yuan Qing , Xi Yin , Zhang Yue , Chang Jenny , Fatunde Oluwatomilade , Arriaga Yull , Frankel Arthur E. , Kalva Sanjeeva , Zhang Song , McKenzie Tiffani , Reig Torras Oscar , Figlin Robert A. , Rini Brian I. , McKay Renée M. , Kapur Payal , Wang Tao , Pedrosa Ivan , Brugarolas James
Published: November 2019

Purpose:

The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1β, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients.

Patients and Methods:

We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies.

Results:

PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance.

Conclusions:

These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).
A Potent Blood–Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model
Authors: Machida Yukino , Nakagawa Makoto , Matsunaga Hironori , Yamaguchi Masayuki , Ogawara Yoko , Shima Yutaka , Yamagata Kazutsune , Katsumoto Takuo , Hattori Ayuna , Itoh Masato , Seki Takahiko , Nishiya Yumi , Nakamura Koichi , Suzuki Kanae , Imaoka Tomoki , Baba Daichi , Suzuki Makoto , Sampetrean Oltea , Saya Hideyuki , Ichimura Koichi , Kitabayashi Issay
Published: November 2019

Gliomas are the second most common primary brain tumors in adults. They are treated with combination therapies, including surgery, radiotherapy, and chemotherapy. There are currently limited treatment options for recurrent gliomas, and new targeted therapies need to be identified, especially in glioblastomas, which have poor prognosis. Isocitrate dehydrogenase (IDH) mutations are detected in various tumors, including gliomas. Most patients with IDH mutant glioma harbor the IDH1R132H subtype. Mutant IDH catalyzes the conversion of α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), which induces aberrant epigenetic status and contributes to malignant progression, and is therefore a potential therapeutic target for IDH mutant tumors. The present study describes a novel, orally bioavailable selective mutant IDH1 inhibitor, DS-1001b. The drug has high blood–brain barrier (BBB) permeability and inhibits IDH1R132H. Continuous administration of DS-1001b impaired tumor growth and decreased 2-HG levels in subcutaneous and intracranial xenograft models derived from a patient with glioblastoma with IDH1 mutation. Moreover, the expression of glial fibrillary acidic protein was strongly induced by DS-1001b, suggesting that inhibition of mutant IDH1 promotes glial differentiation. These results reveal the efficacy of BBB-permeable DS-1001b in orthotopic patient-derived xenograft models and provide a preclinical rationale for the clinical testing of DS-1001b in recurrent gliomas.
Estrogen Receptor Pathway Activity Score to Predict Clinical Response or Resistance to Neoadjuvant Endocrine Therapy in Primary Breast Cancer
Authors: Inda Márcia A. , Blok Erik J. , Kuppen Peter J.K. , Charehbili Ayoub , den Biezen-Timmermans Eveline C. , van Brussel Anne , Fruytier Sevgi E. , Meershoek-Klein Kranenbarg Elma , Kloet Susan , van der Burg Bart , Martens John W.M. , Sims Andrew H. , Turnbull Arran K. , Dixon J. Michael , Verhaegh Wim , Kroep Judith R. , van de Velde Cornelis J.H. , van de Stolpe Anja
Published: November 2019

Endocrine therapy is important for management of patients with estrogen receptor (ER)–positive breast cancer; however, positive ER staining does not reliably predict therapy response. We assessed the potential to improve prediction of response to endocrine treatment of a novel test that quantifies functional ER pathway activity from mRNA levels of ER pathway–specific target genes. ER pathway activity was assessed on datasets from three neoadjuvant-treated ER-positive breast cancer patient cohorts: Edinburgh: 3-month letrozole, 55 pre-/2-week/posttreatment matched samples; TEAM IIa: 3- to 6-month exemestane, 49 pre-/28 posttreatment paired samples; and NEWEST: 16-week fulvestrant, 39 pretreatment samples. ER target gene mRNA levels were measured in fresh-frozen tissue (Edinburgh, NEWEST) with Affymetrix microarrays, and in formalin-fixed paraffin-embedded samples (TEAM IIa) with qRT-PCR. Approximately one third of ER-positive patients had a functionally inactive ER pathway activity score (ERPAS), which was associated with a nonresponding status. Quantitative ERPAS decreased significantly upon therapy (P < 0.001 Edinburgh and TEAM IIa). Responders had a higher pretreatment ERPAS and a larger 2-week decrease in activity (P = 0.02 Edinburgh). Progressive disease was associated with low baseline ERPAS (P = 0.03 TEAM IIa; P = 0.02 NEWEST), which did not decrease further during treatment (P = 0.003 TEAM IIa). In contrast, the staining-based ER Allred score was not significantly associated with therapy response (P = 0.2). The ERPAS identified a subgroup of ER-positive patients with a functionally inactive ER pathway associated with primary endocrine resistance. Results confirm the potential of measuring functional ER pathway activity to improve prediction of response and resistance to endocrine therapy.
A Phase 4 Study of Everolimus to Evaluate Efficacy and Safety in Patients with Metastatic Renal-Cell Carcinoma after Failure of First-Line Sunitinib or Pazopanib (SUNPAZ)
Authors: Schostak Martin , de Geeter Patrick , Decker Thomas , Resch Anna , Quiering Claudia , Schmitz Stephan
Published: November 2019

Introduction: Sunitinib and pazopanib are both standard first-line therapies for clear-cell metastatic renal-cell carcinoma (mRCC). Everolimus is a well-established second-line treatment. Objective: To estimate the efficacy and safety of second-line everolimus following pazopanib or sunitinib. Methods: SUNPAZ was an open-label, phase 4 clinical trial of everolimus in patients with clear-cell mRCC progressing after first-line sunitinib or pazopanib. The primary end point was the number of patients without progression 6 months after starting everolimus. Secondary end points included progression-free survival (PFS), overall survival (OS), and overall response rate. Enrollment was terminated early due to slow recruitment; all analyses are descriptive. Results: Patients who received prior sunitinib (n = 16) or pazopanib (n = 13) were enrolled. One of 12 patients in the sunitinib group and 6/13 patients in the pazopanib group were progression-free by month 6 in the full analysis set. Median PFS in the sunitinib and pazopanib groups was 2.8 and 8.0 months, and median OS was 14.8 months and 20.4 months, respectively. Fifteen patients in the sunitinib group and 13 in the pazopanib group experienced adverse events. Conclusions: Safety and efficacy results confirm the second-line everolimus profile. However, baseline differences in patient populations should be taken into consideration.