bluuebunny/crossref_metadata_2025 huggingface dataset:
Regular projections of the knot 62
Authors: Takimura Yusuke
Published: October 2018

A knot [Formula: see text] is a minor of a knot [Formula: see text] if any regular projection of [Formula: see text] is also a regular projection of [Formula: see text]. This defines a pre-ordering on the set of all knots. For each knot of five or less crossings, the set of all regular projections of it is determined by Taniyama [A partial order of knots, Tokyo J. Math. 12(1) (1989) 205–229]. Thus, the pre-ordering is determined up to five crossing knots. In this paper, we determine the set of all regular projections of the knot [Formula: see text].
The total zero-divisor graph of a commutative ring
Authors: Ðurić Alen , Jevđenić Sara , Oblak Polona , Stopar Nik
Published: October 2018

In this paper, we initiate the study of the total zero-divisor graph over a commutative ring with unity. This graph is constructed by both relations that arise from the zero-divisor graph and from the total graph of a ring and give a joint insight of the structure of zero-divisors in a ring. We characterize Artinian rings with the connected total zero-divisor graphs and give their diameters. Moreover, we compute major characteristics of the total zero-divisor graph of the ring [Formula: see text] of integers modulo [Formula: see text] and prove that the total zero-divisor graphs of [Formula: see text] and [Formula: see text] are isomorphic if and only if [Formula: see text].
An invitation to singular symplectic geometry
Authors: Braddell Roisin , Delshams Amadeu , Miranda Eva , Oms Cédric , Planas Arnau
Published: October 2018

In this paper, we analyze in detail a collection of motivating examples to consider [Formula: see text]-symplectic forms and folded-type symplectic structures. In particular, we provide models in Celestial Mechanics for every [Formula: see text]-symplectic structure. At the end of the paper, we introduce the odd-dimensional analogue to [Formula: see text]-symplectic manifolds: [Formula: see text]-contact manifolds.
Imprinted Graphene-Starch Nanocomposite Matrix-Anchored EQCM Platform for Highly Selective Sensing of Epinephrine
Authors: Srivastava Juhi , Kushwaha Archana , Singh Meenakshi
Published: October 2018

In this paper, an electrochemical sensor for epinephrine (EP), a neurotransmitter was developed by anchoring molecularly imprinted polymeric matrix (MIP) on the surface of gold-coated quartz crystal electrode of electrochemical quartz crystal microbalance (EQCM) using starch nanoparticles (Starch NP) — reduced graphene oxide (RGO) nanocomposite as polymeric format for the first time. Use of EP in therapeutic treatment requires proper dose and route of administration. Proper follow-up of neurological disorders and timely diagnosis of them has been found to depend on EP level. The MIP sensor was developed by electrodeposition of starch NP-RGO composite on EQCM electrode in presence of template EP. As the imprinted sites are located on the surface, high specific surface area enables good accessibility and high binding affinity to template molecule. Differential pulse voltammetry (DPV) and piezoelectrogravimmetry were used for monitoring binding/release, rebinding of template to imprinted cavities. MIP-coated EQCM electrode were characterized by contact angle measurements, AFM images, piezoelectric responses including viscoelasticity of imprinted films, and other voltammetric measurements including direct (DPV) and indirect (using a redox probe) measurements. Selectivity was assessed by imprinting factor (IF) as high as 3.26 (DPV) and 3.88 (EQCM). Sensor was rigorously checked for selectivity in presence of other structurally close analogues, real matrix (blood plasma), reproducibility, repeatability, etc. Under optimized conditions, the EQCM-MIP sensor showed linear dynamic ranges (1–10[Formula: see text][Formula: see text]M). The limit of detection 40 ppb (DPV) and 290 ppb (EQCM) was achieved without any cross reactivity and matrix effect indicating high sensitivity and selectivity for EP. Hence, an eco-friendly MIP-sensor with high sensitivity and good selectivity was fabricated which could be applied in “real” matrices in a facile manner.
Applicability of Mass-Spring Models for Seismically Isolated Liquid Storage Tanks
Authors: Kalantari Afshin , Nikoomanesh Mohammad Reza , Goudarzi Mohammad Ali
Published: October 2018

Employing base isolation technique for reduction of seismic response of liquid storage tanks has been proved to be quite effective. The main purpose of this paper is to quantitatively clarify, the contribution of convective and impulsive parts of the contained liquid in seismic behavior of an isolated liquid tank. Moreover, the accuracy of the simplified model which is generally used for the prediction of seismic behavior of conventional tanks is examined for isolated liquid tanks. For these purposes, the seismic response of the isolated cylindrical liquid storage tanks is considered using both the exact finite element model and simplified mass-spring model. The fluid–structure interaction is considered in finite element model. The comparison of the results obtained from two models shows that unlike conventionally constructed tanks, the contribution of convective mass cannot be neglected for seismically isolated tanks. Moreover, the accuracy of the simplified model for evaluating the main design parameters including base shear, global overturning moment, and sloshing height is examined for various tank dimensions and earthquake ground motions. The difference between the base shear and overturning moment results in the FE model and the simplified model of an isolated tank limited to 10%. It approves that the simplified mechanical models can be used with confidence for evaluating the seismic design parameters of various isolated tanks. However, the free surface displacement cannot be accurately predicted by simplified models, especially for medium and broad tanks.
Electronic Structure for Europium Chalcogenides with Modified Becke–Johnson Potential Plus an On-Site Coulomb U (mBJ+U)
Authors: Belhachi S.
Published: October 2018

The full potential linearized-augmented-plane-wave (FP-LAPW) method is generalized to a case of an all-electron fully-relativistic spin-polarized self-consistent band calculation based on the relativistic spin-density functional theory and the modified Becke–Johnson potential (TB-mBJ) plus an on-site coulomb U employed for greater generation of the band gap. The results show that these materials are semiconducting materials. The indirect energy gap obtained in this calculation is 1.63[Formula: see text]eV, 1.79[Formula: see text]eV and 1.96[Formula: see text]eV for EuS, EuSe and EuTe, respectively. It is clear from the plots that LSDA[Formula: see text][Formula: see text][Formula: see text]U is a poor technique for the calculation of the band gaps of chalcogenides (EuX). The calculated results for EuX (S, Se and Te) by mBJ[Formula: see text][Formula: see text][Formula: see text]U are in good agreement with the experimental values as compared to the other calculated results.
Rule-of-Law Ethnography
Authors: Cheesman Nick
Published: October 2018

This review outlines an emerging agenda for ethnographic interpretation of the rule of law. From a survey of studies done on the rule of law in Africa, Asia, Europe, and the Americas, the review identifies four general characteristics of this mode of inquiry, namely, that it is located, relational, and comparative and has extrinsic value. It offers three nonexhaustive reasons for interpreting the rule of law ethnographically, which are as a counterhegemonic practice, in response to counterintuitive observations, and as a means to do constitutive theorizing. Contending that ethnographic work on the rule of law involves some kind of stance toward both research subjects and object of inquiry, the review advocates for the exercise of passionate humility: a conviction about the rule of law tempered by willingness to be proven wrong through inquiries in critical proximity with socially and politically mediated facts. Rule-of-law ethnography's possibility lies in its attending to the relationship between what is claimed in the rule of law's name and what is realized, not to make the idea look foolish, but to show how it emerges and why it persists through struggle.
Implementation of Black Box Models for Internal Ballistics Optimization Using an Artificial Neural Network
Authors: Chen Jie , Li JingYin , Li ShuangXi , You YunXiang
Published: October 2018

The process of UUV delivery is a typical nonlinear transient dynamic phenomenon, which is generally described by the internal ballistic model. Evaluation of optimal internal ballistics parameters is a key step for promoting ballistic weapon performance under given launch constraints. Hence, accurate and efficient optimization techniques are required in ballistics technology. In this study, an artificial neural network (ANN) is used to simplify the process of regression analysis. To this end, an internal ballistics model is built in this study as a black box for a classic underwater launching system, such as a torpedo launcher, based on ANN parameter identification. The established black box models are mainly employed to calculate the velocity of a ballistic body and the torque of a launching pump. Typical internal ballistics test data are adopted as samples for training the ANN. Comparative results demonstrate that the developed black box models can accurately reflect changes in internal ballistics parameters according to rotational speed variations. Therefore, the proposed approach can be fruitfully applied to the task of internal ballistics optimization. The optimization of internal ballistics precision control, optimal control of the launching pump, and optimal low-energy launch control were, respectively, realized in conjunction with the established model using the SHERPA search algorithm. The results demonstrate that the optimized internal ballistics rotational speed curve can achieve the optimization objectives of low-energy launch and peak power while meeting the requirements of optimization constraints.
Phase Synchronization Dynamics of Neural Network during Seizures
Authors: Liu Hao , Zhang Puming
Published: October 2018

Epilepsy has been considered as a network-level disorder characterized by recurrent seizures, which result from network reorganization with evolution of synchronization. In this study, the brain networks were established by calculating phase synchronization based on electrocorticogram (ECoG) signals from eleven refractory epilepsy patients. Results showed that there was a significant increase of synchronization prior to seizure termination and no significant difference of the transitions of network states among the preseizure, seizure, and postseizure periods. Those results indicated that synchronization might participate in termination of seizures, and the network states transitions might not dominate the seizure evolution.
Improving Earth’s Magnetic Field Measurements by Numerical Corrections of Thermal Drifts and Man-Made Disturbances
Authors: Janošek Michal , Butta Mattia , Vlk Michal , Bayer Tomáš
Published: October 2018

This contribution deals with challenges encountered in real-world geomagnetic measurements and is focused on improving the performance of two variometer stations of Kelčany and Polom, which have been recently established in the Czech Republic. It is shown that a carefully designed full-field instrument, despite lacking temperature stabilization, can provide vectorial and scalar data accurate to a few nT, if the raw data were postprocessed by compensating for gain temperature coefficients—we show how this can be obtained by a precise calibration and long-term scalar measurements. We also show a method for suppressing nT-level spikes in the data due to nearby car traffic, by utilizing gradiometric measurement for detecting the car occurrences and by employing a linear optimization problem in order to find the parameters of the moving magnetic dipole and compensate for it. In this manner, we were able to reduce the anthropogenous noise due to car traffic while keeping as much original information as possible.
Combined Use of Trisodium Citrate and Transglutaminase to Enhance the Stiffness and Water-Holding Capacity of Acidified Yak Milk Gels
Authors: Yang Lin
Published: October 2018

In this research, the synergistic effect of trisodium citrate (TSC) and microbial transglutaminase (TGase) treatment on the textural properties of acidified yak skim milk gels was investigated. TSC was added to yak skim milk to concentrations of 0, 20, and 40 mmol/L, followed by adjusting the pH to 6.7. The samples were incubated with TGase for the cross-linking reaction, after which the samples were acidified with 1.4% (w/v) gluconodelta-lactone (GDL) at 42°C for 4 h to form gels. The stiffness and water holding capacity (WHC) of gels exhibited higher values at 20 or 40 mmol/L than without TSC. The final storage modulus (G′) of yak milk gels was positively related to the concentration of TSC prior to TGase treatment. Cryoscanning electron microscopy observations showed that the gel networks were more rigid with higher TSC concentrations. Overall, TSC dissociated particles in yak milk into smaller ones. The newly formed particles in yak skim milk could form acid-induced gels with greater stiffness and higher WHC in the presence of TGase.
Interstitial Pregnancy: From Medical to Surgical Approach—Report of Three Cases
Authors: Di Tizio L. , Spina M. R. , Gustapane S. , D’Antonio F. , Liberati M.
Published: October 2018

Background.Interstitial pregnancy is a rare form of ectopic pregnancy that usually leads to uterine rupture resulting in sudden life-threatening haemorrhage, need for blood transfusion, and admission to intensive care unit. Mortality rate is 6–7 times higher than that in classical ectopic pregnancy. Uterine rupture has been typically reported to occur at more advanced gestational ages compared to tubal pregnancy although several recent reports have shown a high risk of rupture before 12 weeks of gestation.Cases Presentation.We report three cases of women affected by interstitial pregnancy, with different clinical symptoms, and managed to be treated with surgery or medical therapy. An emergency laparotomy was performed in the first case by the general surgeon, while in the second case laparoscopy was made by a gynecologist; last case shows the success of systemic administration of methotrexate.Conclusion.Interstitial pregnancy is still a challenging condition to diagnose and treat; early diagnosis may help to choose the proper management.
A Multiscale Differential Evolution Algorithm‐Based Maintenance Plan Optimization for Building Energy Retrofitting
Authors: Wang Bo , Wu Zhou , Liu Lei
Published: October 2018

This paper addresses a maintenance plan optimization problem for building energy retrofitting with a novel differential evolution‐based algorithm. The problem manifests substantial complexity due to the parallel optimization of the maintenance time scale, maintenance instants, and maintenance rates, with multiple objectives and time scales. The problem is formulated based on an impulsive and switched phenomenon, with objectives of maximizing the energy performances and economic indicators for the retrofitting project over a finite horizon. A multiscale differential evolution algorithm is accordingly proposed to be the numerical solver. The proposed algorithm is able to optimize the decision variables simultaneously, especially the maintenance time scale that can influence the number of other decision variables. Simulation results illustrate the effectiveness of the proposed approach.
Privacy Preserving k-Nearest Neighbor for Medical Diagnosis in e-Health Cloud
Authors: Park Jeongsu , Lee Dong Hoon
Published: October 2018

Cloud computing is highly suitable for medical diagnosis in e-health services where strong computing ability is required. However, in spite of the huge benefits of adopting the cloud computing, the medical diagnosis field is not yet ready to adopt the cloud computing because it contains sensitive data and hence using the cloud computing might cause a great concern in privacy infringement. For instance, a compromised e-health cloud server might expose the medical dataset outsourced from multiple medical data owners or infringe on the privacy of a patient inquirer by leaking his/her symptom or diagnosis result. In this paper, we propose a medical diagnosis system using e-health cloud servers in a privacy preserving manner when medical datasets are owned by multiple data owners. The proposed system is the first one that achieves the privacy of medical dataset, symptoms, and diagnosis results and hides the data access pattern even from e-health cloud servers performing computations using the data while it is still robust against collusion of the entities. As a building block of the proposed diagnosis system, we design a novel privacy preserving protocol for finding the k data with the highest similarity (PE-FTK) to a given symptom. The protocol reduces the average running time by 35% compared to that of a previous work in the literature. Moreover, the result of the previous work is probabilistic, i.e., the result can contain some error, while the result of our PE-FTK is deterministic, i.e., the result is correct without any error probability.
An Ensemble Learning Method for Wireless Multimedia Device Identification
Authors: Zhang Zhen , Li Yibing , Wang Chao , Wang Meiyu , Tu Ya , Wang Jin
Published: October 2018

In the last decade, wireless multimedia device is widely used in many fields, which leads to efficiency improvement, reliability, security, and economic benefits in our daily life. However, with the rapid development of new technologies, the wireless multimedia data transmission security is confronted with a series of new threats and challenges. In physical layer, Radio Frequency Fingerprinting (RFF) is a unique characteristic of IoT devices themselves, which can difficultly be tampered. The wireless multimedia device identification via Radio Frequency Fingerprinting (RFF) extracted from radio signals is a physical-layer method for data transmission security. Just as people’s unique fingerprinting, different Internet of Things (IoT) devices exhibit different RFF which can be used for identification and authentication. In this paper, a wireless multimedia device identification system based on Ensemble Learning is proposed. The key technologies such as signal detection, RFF extraction, and classification model are discussed. According to the theoretical modeling and experiment validation, the reliability and the differentiability of the RFFs are evaluated and the classification results are shown under the real wireless multimedia device environments.
Antiperiodic Solutions for Quaternion‐Valued Shunting Inhibitory Cellular Neural Networks with Distributed Delays and Impulses
Authors: Huo Nina , Li Yongkun
Published: October 2018

This paper is concerned with quaternion‐valued shunting inhibitory cellular neural networks (QVSICNNs) with distributed delays and impulses. By using a new continuation theorem of the coincidence degree theory, the existence of antiperiodic solutions for QVSICNNs is obtained. By constructing a suitable Lyapunov function, some sufficient conditions are derived to guarantee the global exponential stability of antiperiodic solutions for QVSICNNs. Finally, an example is given to show the feasibility of obtained results.
Cytotoxic and Bactericidal Effect of Silver Nanoparticles Obtained by Green Synthesis Method Using Annona muricata Aqueous Extract and Functionalized with 5-Fluorouracil
Authors: Sánchez-Navarro María del Carmen , Ruiz-Torres Claudio Adrian , Niño-Martínez Nereyda , Sánchez-Sánchez Roberto , Martínez-Castañón Gabriel Alejandro , DeAlba-Montero I. , Ruiz Facundo
Published: October 2018

Nanomaterials obtained by green synthesis technologies have been widely studied in recent years owing to constitute cost-effective and environmental-friendly methods. In addition, there are several works that report the simultaneous performance of the reducer agent as a functionalizing agent, modifying the properties of the nanomaterial. As a simple and economical synthesis methodology, this work presents a method to synthesize silver nanoparticles (AgNPs) using Annona muricata aqueous extract and functionalized with 5-fluorouracil (5-FU). The processes of reduction, nucleation, and functionalization of the nanoparticles were analyzed by UV-Vis absorption spectroscopy, and it was found that they are the function of the contact time of the metal ions with the extract. The structural characterization was carried out by transmission electron microscopy (TEM) and X-ray diffraction patterns (XRD). The antibacterial properties of the synthetized nanomaterials were tested using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Enterococcus faecalis, Staphylococcus aureus, and Escherichia coli growth.
Numerical Study of the Zero Velocity Surface and Transfer Trajectory of a Circular Restricted Five-Body Problem
Authors: Wang R. F. , Gao F. B.
Published: October 2018

We focus on a type of circular restricted five-body problem in which four primaries with equal masses form a regular tetrahedron configuration and circulate uniformly around the center of mass of the system. The fifth particle, which can be regarded as a small celestial body or probe, obeys the law of gravity determined by the four primaries. The geometric configuration of zero-velocity surfaces of the fifth particle in the three-dimensional space is numerically simulated and addressed. Furthermore, a transfer trajectory of the fifth particle skimming over four primaries then is designed.
Diagnostic Value of lncRNAs as Biomarker in Hepatocellular Carcinoma: An Updated Meta-Analysis
Authors: Chen Shilian , Zhang Yaqin , Wu Xuan , Zhang Chaoyang , Li Guancheng
Published: October 2018

Some long noncoding RNAs (lncRNAs) display aberrantly high or low expression in hepatocellular carcinoma (HCC) and have the potential to serve as diagnostic biomarkers. Here, we accomplished a meta-analysis based on current studies to assess the diagnostic value of lncRNAs in HCC. Eligible literatures were systematically selected from PubMed, Web of Science, and Embase (up to January 20, 2018) according to defined inclusion and exclusion criteria. QUADAS scale was applied to the quality assessment of the included studies. Statistical analysis was performed through bivariate random-effects models based on R software. Publication bias was evaluated by funnel plot and Begg’s and Egger’s tests. 16 articles containing 2,268 cancer patients and 2,574 controls were selected for the final meta-analysis. Random effect model was used for the meta-analysis due to significant between-study heterogeneity. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were 0.87(0.838-0.897), 0.829(0.794-0.86), 23.085(20.575-25.901), 4.533(4.239-4.847), and 0.176(0.166-0.186), respectively. Summary receiver operating characteristic curve (SROC) was conducted to estimate the diagnostic accuracy of lncRNAs in HCC with the area under curve (AUC) of 0.915. Subgroups analysis showed that lncRNA profiling, sample size, specimen types, and ethnicity might be the sources of heterogeneity. No publication bias existed according to funnel plot symmetry and Begg’s (P= 0.187) and Egger’s (P= 0.477) tests. In conclusion, lncRNAs can serve as potential diagnostic biomarkers of HCC with high sensitivity and specificity. In addition, lncRNAs panel from serum and plasma has a relatively high diagnostic value for HCC patients from Asia.
Experimental Study on Nonlinear Seepage Characteristics and Particle Size Gradation Effect of Fractured Sandstones
Authors: Shi Xuyang , Zhou Wei , Cai Qingxiang , Lu Xiang
Published: October 2018

Seepage mutation of fractured rock mass is one of the main inducements of dump slide and other disasters. Pore structure is a significant factor affecting the seepage characteristics of fractured rock mass, while particle size gradation has an important effect on the distribution of pore structure. Through the self‐developed experimental system, the nonlinear seepage test on the fractured sandstones of the coalseam roof was conducted to investigate the influence of seepage pressure, porosity, and fractal dimension. Besides, the nonlinear seepage model was established by Barree–Conway theory. The results showed that, during the seepage process of fractured sandstone, there were significant nonlinear characteristics, which increased with the increase of the seepage pressure. With the increasing porosity, there was greater average pore size of fractured sandstone, stronger permeability, and weaker nonlinear seepage. The seepage characteristics approximated to that of Darcy model. However, with increasing grading fractal dimension, there were smaller average pore size of fractured sandstone, weaker permeability, and stronger nonlinear seepage. The seepage characteristics approximated to that of Forchheimer model.
A Comparative Study of Regularization Method in Structure Load Identification
Authors: Miao Bingrong , Zhou Feng , Jiang Chuanying , Chen Xiangyu , Yang Shuwang
Published: October 2018

This study aims to correlate the vibration data with quantitative indicators of structural health by comparing and validating the feasibility of identifying unknown excitation forces using output vibration responses. First, numerical analysis was performed to investigate the accuracy, convergence, and robustness of the load identification results for different noise levels, sensors numbers, and initial estimates of structural parameters. Then, the laboratory beam structure experiments were conducted. The results show that using the two identification methods Tikhonov (L‐curve) and TSVD (GCV‐curve) can successfully and accurately identify the different excitation forces of the external hammer. The TSVD based on GCV method has more advantages than the Tikhonov based on L‐curve method. The proposed two kinds of load identification procedure based on vibration response can be applied to the safety performance evaluation of the railway track structure in future inverse problems research.
Serum- and Glucocorticoid-induced Kinase Sgk1 Directly Promotes the Differentiation of Colorectal Cancer Cells and Restrains Metastasis
Authors: Lee Lennard Y.W. , Woolley Connor , Starkey Thomas , Biswas Sujata , Mirshahi Tia , Bardella Chiara , Segditsas Stefania , Irshad Shazia , Tomlinson Ian
Published: October 2018

Purpose:

The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, because in colorectal cancer, the degree of differentiation of a tumor is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer, there is marked downregulation of SGK1 compared with normal tissue.

Experimental Design: An inducible SGK1 viral overexpression system was utilized to induce reexpression of SGK1 in colorectal cancer cell lines. Transcriptomic and phenotypic analyses of these colorectal cancer lines was performed and validation in mouse and human cohorts was performed.

Results:

We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Reexpression of SGK1 in colorectal cancer cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated, in part, by SGK1-induced PKP3 expression and increased degradation of MYC.

Conclusions:

Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit colorectal cancer metastasis.
The Number of Screening Cycles Needed to Reduce Prostate Cancer Mortality in the Finnish Section of the European Randomized Study of Prostate Cancer (ERSPC)
Authors: Pakarainen Tomi , Nevalainen Jaakko , Talala Kirsi , Taari Kimmo , Raitanen Jani , Kujala Paula , Stenman Ulf-Håkan , Tammela Teuvo L.J. , Auvinen Anssi
Published: October 2018

Purpose:

The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer mortality by PSA-based screening. The aim of the study is to evaluate screening effect on prostate cancer incidence and mortality in relation to number of screening rounds attended.

Experimental Design: The participants in the screening arm of the Finnish trial (31,867 men) were classified according to screening attendance in a time-dependent fashion. Initially, all men in the screening arm were regarded as nonattenders until the first screening attendance, then remained among the once-screened until the second screen and similarly for the possible third round. The control arm was the reference. Follow-up started at randomization and ended at death, emigration, or end of 2013. Prostate cancer incidence and mortality, as well lung cancer and overall mortality were evaluated.

Results:

Prostate cancer incidence was increased among screened men, but was not directly related to the number of screening rounds. Prostate cancer mortality was decreased in men screened twice or three times, but did not materially differ in those who did not attend the screening, and in men screened once compared with the control arm. The largest mortality reduction was in men screened three times [HR 0.17; 95% confidence interval (CI), 0.09–0.33]. However, a reduction was also seen in lung cancer (HR 0.59; 95% CI, 0.47–0.73) and overall mortality (HR 0.56; 95% CI, 0.52–0.60).

Conclusions:

Assuming a similar relative reduction being due to selection bias and screening in prostate cancer as other causes of death (40% reduction), approximately half of the observed prostate cancer mortality reduction by repeated screening is likely to be noncausal and a real screening effect may account for up to 40% reduction in men screened three times. Prostate cancer mortality reduction can only be achieved by repeated screening cycles.
Enhanced Antitumor Efficacy of Oncolytic Adenovirus–loaded Menstrual Blood–derived Mesenchymal Stem Cells in Combination with Peripheral Blood Mononuclear Cells
Authors: Moreno Rafael , Fajardo Carlos Alberto , Farrera-Sal Marti , Perisé-Barrios Ana Judith , Morales-Molina Alvaro , Al-Zaher Ahmed Abdullah , García-Castro Javier , Alemany Ramon
Published: October 2018

Several studies have evaluated the efficacy of using human oncolytic adenovirus (OAdv)–loaded mesenchymal stem cells (MSC) for cancer treatment. For example, we have described the antitumor efficacy of CELYVIR, autologous bone marrow–mesenchymal stem cells infected with the OAdv ICOVIR-5, for treatment of patients with neuroblastoma. Results from this clinical trial point out the role of the immune system in the clinical outcome. In this context, a better understanding of the immunophenotypic changes of human MSCs upon adenoviral infection and how these changes affect human autologous or allogeneic peripheral blood mononuclear cells (PBMC) could guide strategies to improve the antitumor efficacy of infected MSCs. In this work, we show how infection by an OAdv induces toll-like receptor 9 overexpression and activation of the NFĸB pathway in menstrual blood–derived MSCs, leading to a specific cytokine secretion profile. Moreover, a proinflammatory environment, mainly mediated by monocyte activation that leads to the activation of both T cells and natural killer cells (NK cell), is generated when OAdv-loaded MSCs are cocultured with allogeneic PBMCs. This combination of allogeneic PBMCs and OAdv-loaded MSCs enhances antitumor efficacy both in vitro and in vivo, an effect partially mediated by monocytes and NK cells. Altogether our results demonstrate not only the importance of the immune system for the OAdv-loaded MSCs antitumor efficacy, but in particular the benefits of using allogeneic MSCs for this therapy.
Multiplex Three-Dimensional Mapping of Macromolecular Drug Distribution in the Tumor Microenvironment
Authors: Lee Steve Seung-Young , Bindokas Vytautas P. , Kron Stephen J.
Published: October 2018

Macromolecular cancer drugs such as therapeutic antibodies and nanoparticles are well known to display slow extravasation and incomplete penetration into tumors, potentially protecting cancer cells from therapeutic effects. Conventional assays to track macromolecular drug delivery are poorly matched to the heterogeneous tumor microenvironment, but recent progress on optical tissue clearing and three-dimensional (3D) tumor imaging offers a path to quantitative assays with cellular resolution. Here, we apply transparent tissue tomography (T3) as a tool to track perfusion and delivery in the tumor and to evaluate target binding and vascular permeability. Using T3, we mapped anti–programmed cell death protein-ligand 1 (PD-L1) antibody distribution in whole mouse tumors. By measuring 3D penetration distances of the antibody drug out from the blood vessel boundaries into the tumor parenchyma, we determined spatial pharmacokinetics of anti–PD-L1 antibody drugs in mouse tumors. With multiplex imaging of tumor components, we determined the distinct distribution of anti–PD-L1 antibody drug in the tumor microenvironment with different PD-L1 expression patterns. T3 imaging revealed CD31+ capillaries are more permeable to anti–PD-L1 antibody transport compared with the blood vessels composed of endothelium supported by vascular fibroblasts and smooth muscle cells. T3 analysis also confirmed that isotype IgG antibody penetrates more deeply into tumor parenchyma than anti-Her2 or anti-EGFR antibody, which were restrained by binding to their respective antigens on tumor cells. Thus, T3 offers simple and rapid access to 3D, quantitative maps of macromolecular drug distribution in the tumor microenvironment, offering a new tool for development of macromolecular cancer therapeutics.
UNC-45A Is a Novel Microtubule-Associated Protein and Regulator of Paclitaxel Sensitivity in Ovarian Cancer Cells
Authors: Mooneyham Ashley , Iizuka Yoshie , Yang Qing , Coombes Courtney , McClellan Mark , Shridhar Vijayalakshmi , Emmings Edith , Shetty Mihir , Chen Liqiang , Ai Teng , Meints Joyce , Lee Michael K. , Gardner Melissa , Bazzaro Martina
Published: October 2018

UNC-45A, a highly conserved member of the UCS (UNC45A/CRO1/SHE4P) protein family of cochaperones, plays an important role in regulating cytoskeletal-associated functions in invertebrates and mammalian cells, including cytokinesis, exocytosis, cell motility, and neuronal development. Here, for the first time, UNC-45A is demonstrated to function as a mitotic spindle-associated protein that destabilizes microtubules (MT) activity. Using in vitro biophysical reconstitution and total internal reflection fluorescence microscopy analysis, we reveal that UNC-45A directly binds to taxol-stabilized MTs in the absence of any additional cellular cofactors or other MT-associated proteins and acts as an ATP-independent MT destabilizer. In cells, UNC-45A binds to and destabilizes mitotic spindles, and its depletion causes severe defects in chromosome congression and segregation. UNC-45A is overexpressed in human clinical specimens from chemoresistant ovarian cancer and that UNC-45A–overexpressing cells resist chromosome missegregation and aneuploidy when treated with clinically relevant concentrations of paclitaxel. Lastly, UNC-45A depletion exacerbates paclitaxel-mediated stabilizing effects on mitotic spindles and restores sensitivity to paclitaxel.

Implications:

These findings reveal novel and significant roles for UNC-45A in regulation of cytoskeletal dynamics, broadening our understanding of the basic mechanisms regulating MT stability and human cancer susceptibility to paclitaxel, one of the most widely used chemotherapy agents for the treatment of human cancers.
Single-Nucleotide Polymorphism of the
MLX
Gene Is Associated With Takayasu Arteritis
Authors: Tamura Natsuko , Maejima Yasuhiro , Matsumura Takayoshi , Vega Rick B. , Amiya Eisuke , Ito Yusuke , Shiheido-Watanabe Yuka , Ashikaga Takashi , Komuro Issei , Kelly Daniel P. , Hirao Kenzo , Isobe Mitsuaki
Published: October 2018

Background:

Takayasu arteritis (TAK) is an autoimmune systemic arteritis of unknown pathogenesis. Genome-wide association studies revealed that single-nucleotide polymorphisms in the
MLX
gene encoding the MLX (Max-like protein X) transcription factor are significantly associated with TAK in Japanese patients.
MLX
single-nucleotide polymorphism rs665268 is a missense mutation causing the Q139R substitution in the DNA-binding site of MLX.

Methods:

To elucidate the hypothesis that the single-nucleotide polymorphism of the
MLX
gene plays a critical role in the development of TAK, we conducted clinical and laboratory analyses.

Results:

We show that rs665268 significantly correlated with the severity of TAK, including the number of arterial lesions and morbidity of aortic regurgitation; the latter may be attributed to the fact that
MLX
mRNA expression was mostly detected in the aortic valve. Furthermore, the Q139R mutation caused structural changes in MLX, which resulted in enhanced formation of a heterodimer with MondoA, upregulation of TXNIP (thioredoxin-interacting protein) expression, and increase in the activity of the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome and cellular oxidative stress. Furthermore, autophagy, which negatively regulates inflammasome activation, was suppressed by the Q139R mutation in MLX. The MLX-Q139R mutant significantly induced macrophage proliferation and macrophage–endothelium interaction, which was abolished by the treatment with SBI-477, an inhibitor of MondoA nuclear translocation. Our findings suggest that the Q139R substitution in MLX plays a crucial role in the pathogenesis of TAK.

Conclusions:

MLX-Q139R mutation plays a crucial role in the pathogenesis of TAK through promoting inflammasome formation.
Clinical Outcome of Patients With Inducible Capillary Blood Flow Abnormalities During Demand Stress in the Presence or Absence of Angiographic Coronary Disease
Authors: Kutty Shelby , Bisselou Moukagna Karl Stessy , Craft Mary , Shostrom Valerie , Xie Feng , Porter Thomas R.
Published: October 2018

Background:

Our aim was to determine the cardiovascular outcome of patients with capillary blood flow (CBF) abnormalities detected during demand stress in the absence of obstructive coronary artery disease.

Methods and Results:

We identified 380 consecutive patients referred for coronary angiography (CA) after dobutamine or exercise stress echocardiography (SE) between 2008 and 2013 performed with real-time perfusion imaging to examine myocardial CBF with a continuous ultrasound contrast infusion. Patients with left ventricular ejection fraction <40% were excluded. There were 3 groups based on results: positive SE/negative CA, patients who had abnormal regional CBF but no significant angiographic disease; positive SE/positive CA, those with abnormal CBF and significant disease on subsequent CA; and negative SE/negative CA, patients with normal CBF and negative CA. Event-free survival examining death and nonfatal myocardial infarction was compared. Median follow-up was 4 years. There were 91 positive SE/negative CA, 189 positive SE/positive CA, and 100 negative SE/negative CA patients over the study period. The positive SE/negative CA patients were more frequently women and had a lower prevalence of hypertension and hyperlipidemia (all
P
<0.001). Analysis of event-free survival with Cox regression demonstrated that death/nonfatal myocardial infarction rates were higher in the positive SE/positive CA (hazard ratio, 2.10; CI, 1.02–4.29) and positive SE/negative CA (hazard ratio, 2.02; CI, 0.99–4.31) groups when compared with negative SE/negative CA groups.

Conclusions:

Patients with inducible CBF abnormalities in the absence of significant obstructive disease at CA still have similar death/nonfatal myocardial infarction rates as those with significant disease at CA.
Prognostic Importance of Left Ventricular Mechanical Dyssynchrony in Predicting Cardiovascular Death in the General Population
Authors: Modin Daniel , Biering-Sørensen Sofie Reumert , Møgelvang Rasmus , Jensen Jan Skov , Biering-Sørensen Tor
Published: October 2018

Background:

Cardiovascular death (CVD) is a leading cause of death and constitutes a major burden on society. Left ventricular mechanical dyssynchrony (LVMD), evaluated as SD of time to peak regional longitudinal strain, is a capable predictor of many cardiovascular outcomes related to CVD, including ventricular arrhythmias, but the prognostic utility of LVMD in the general population is unknown. Hence, this study sought to determine the prognostic value of LVMD in the general population in predicting CVD.

Methods and Results:

A total of 1138 participants underwent a general health examination and an echocardiographic examination including speckle tracking analysis with subsequent calculation of LVMD from time-to-peak regional strain. Primary end point was CVD, and secondary end point was noncardiovascular death. Follow-up was 100%. During a median follow-up of 11.1 years (interquartile range: 10.2–11.3 years), 62 participants suffered CVD (5.5%) while 131 participants experienced noncardiovascular death (11.5%). LVMD was an independent predictor of CVD (subdistribution hazard ratio, 1.04; 95% CI, 1.01–1.06;
P
=0.004, per 10-ms increase) in competing risk regression treating noncardiovascular death as a competing risk and retained prognostic capability after extensive multivariable adjustment. LVMD was not a significant predictor of noncardiovascular death. LVMD added incremental prognostic information in predicting CVD beyond the Systematic Coronary Risk Evaluation risk chart and a modified version of the American College of Cardiology/American Heart Association Pooled Cohort Equation.

Conclusions:

Left ventricular mechanical dyssynchrony adds incremental prognostic information in addition to established risk factors in prediction of CVD in individuals from the general population without atrial fibrillation and significant valvular disease.
Clinical Benefit of Treatment of Stage-1, Low-Risk Hypertension
Authors: Lee Chan Joo , Ryu Jiin , Kim Hyeon-Chang , Ryu Dong-Ryeol , Ihm Sang-Hyun , Kim Yong-Jin , Shin Jin-Ho , Pyun Wook Bum , Kang Hyoung-Soo , Park Jong-Heon , Hwang Jinseub , Park Sungha
Published: October 2018

Evidence about the benefits of treating uncomplicated, low-risk, stage-1 hypertension is lacking. The study aimed to investigate the association between mean blood pressure (BP) and clinical outcomes, and to determine optimal BPs in treated, low-risk, stage-1 hypertension. From the National Health Insurance Service Health Examination Database, patients with stage-1 hypertension between 2005 and 2006 were selected. They had a systolic BP of 140 to 159 mm Hg or diastolic BP of 90 to 99 mm Hg. Patients were grouped as controlled (mean BP <140/90 mm Hg; n=99 301) and uncontrolled (mean BP ≥140/90 mm Hg; n=49 460) according to their mean BP recorded during the follow-up health examination. All-cause mortality and cardiovascular outcomes were examined. Mean BPs in the controlled and uncontrolled groups were 131.1/80.9 and 144.6/86.8 mm Hg, respectively. Controlled BP was associated with significantly lower risks of all-cause mortality, all stroke, hemorrhagic stroke, ischemic stroke, and end-stage renal disease. Subgroup analysis demonstrated benefits of controlled BP in hypertensive patients aged <50 years for all-cause mortality, all stroke, hemorrhagic stroke, ischemic stroke, and end-stage renal disease, with no significant interaction according to age. The BP associated with the lowest risk of all-cause mortality was 120 to <130 mm Hg (systolic BP) and 70 to <80 mm Hg (diastolic BP). There was an increased risk of myocardial infarction in patients with mean systolic BP <120 mm Hg and diastolic BP <80 mm Hg. BP <140/90 mm Hg was associated with a significant reduction in the risk of mortality, stroke, and end-stage renal disease, with the lowest mortality risk at BP ranges of 120 to <130 and 70 to <80 mm Hg.
Predictors of Unexpected Early Reocclusion After Successful Mechanical Thrombectomy in Acute Ischemic Stroke Patients
Authors: Mosimann Pascal J. , Kaesmacher Johannes , Gautschi Dominic , Bellwald Sebastian , Panos Leonidas , Piechowiak Eike , Dobrocky Tomas , Zibold Felix , Mordasini Pasquale , El-Koussy Marwan , Wiest Roland , Bervini David , Wagner Franca , Arnold Marcel , Jung Simon , Galimanis Aikaterini , Gralla Jan , Fischer Urs
Published: October 2018

Background and Purpose—

Sustained successful reperfusion is an important prognostic factor for good clinical outcome in acute ischemic stroke. We aimed to identify the prevalence, clinical impact, and predictors of early reocclusion after initially successful thrombectomies within a prospective cohort.

Methods—

A total of 711 stroke patients with successful reperfusion (modified Thrombolysis in Cerebral Infarction, 2b/3) followed with magnetic resonance or computed tomographic angiography at 24 to 48 hours were included. Multivariable logistic regression analysis was used to evaluate associated factors and clinical impact. Results are displayed as adjusted odds ratio (aOR) and 95% CI. Improvement in accuracy of additional imaging findings on angiography control runs after the intervention was evaluated by area under the curve.

Results—

Early reocclusion was observed in 16 of 711 successfully reperfused patients (2.3%; 95% CI, 1.1–3.3; median delay: 20 hours). Suggestive predictors were higher platelets on admission (aOR, 1.01; 95% CI, 1.01–1.02), prestroke functional dependence (aOR, 7.12; 95% CI, 1.49–34.03), and stroke of undetermined or other specified pathogenesis in the TOAST classification (aOR, 7.19; 95% CI, 1.10–47.05 and aOR, 36.50; 95% CI, 4.47–298.11, respectively). When implementing residual embolic fragments or stenosis at the thrombectomy site into the logistic regression model, discrimination between patients with and without reocclusion improved significantly (area under the curve, 0.955 versus 0.854;
P
=0.023). Early reocclusion was an independent predictor of unfavorable outcome at 90 days (aOR for modified Rankin Scale ≤2, 0.13; 95% CI, 0.03–0.57).

Conclusions—

Early reocclusion within 48 hours after successful mechanical thrombectomy is rare but associated with poor outcome. Patients with high platelets on admission and residual embolic fragments or stenosis at the thrombectomy site are at high risk for reocclusion, which may be prevented or corrected after carefully re-evaluating the last angiographic run.