bluuebunny/crossref_metadata_2025 huggingface dataset:
Asthma and Seroconversion fromToxocaraspp. Infection: Which Comes First?
Authors: Fialho Paula Mayara Matos , Correa Carlos Roberto Silveira , Lescano Susana Zevallos
Published: May 2018

The aim of this study was to estimate the incidence of seroconversion ofToxocaraspp. infection and related variables. We conducted a cohort study of 77 children aged 2–12 years who had negative serology in a previous cross-sectional study. Univariate and bivariate analyses were performed to describe the cohort, using socioeconomic, behavioral, and health conditions as variables. Logistic regression analysis was performed using seroconversion as the dependent variable, and the remaining variables are treated as independent variables. Asthma was the only independent variable that showed an association with seroconversion, with an odds ratio = 3.57 (1.01–12.6). The incidence of seroconversion fromToxocaraspp. infection in the children followed was 10.4 per 100 per year. Previous studies reporting an association of asthma with toxocariasis have only been carried out using cross-sectional studies. Therefore, this study is one of only a few describing the incidence of seroconversion fromToxocaraspp. infection, which is relevant for understanding the burden of this parasite.
Research Progress in the Effect of Traditional Chinese Medicine for Invigoration on Neurotransmitter Related Diseases
Authors: Zhang Xiting , Li Lin , Chen Ting , Sun Zuoyan , Tang Weiwei , Wang Shuang , Wang Tianqi , Wang Yi , Zhang Han
Published: May 2018

Tonic traditional Chinese medicine is widely used in clinical practice and is categorized into four main drugs, namely, Qi‐supplementing, Blood‐enriching, Yin‐nourishing, and Yang‐tonifying. Neurotransmitters play a coordinating role in the nervous system, visceral function, and stress response. The excitation or suppression of the central nervous system is closely related to various diseases, such as insomnia, depression, Alzheimer’s disease, Parkinson’s disease, and perimenopausal syndrome. An increasing amount of evidence shows that Chinese tonic herb and its active ingredients can delay the occurrence and development of these diseases by modulating related neurotransmitters and their receptors, including norepinephrine (NE), serotonin (5‐HT), dopamine (DA), acetylcholine (ACh), and γ‐aminobutyric acid (GABA). In the present report, studies on the treatment of these neurotransmitter related diseases in relation to the application of tonic Chinese medicine are reviewed.
Preparation and Coloration of Colored Ceramics Derived from the Vanadium‐Titanium Slags
Authors: Deng Yi , Zhou Yang , Yang Yuanyi , Shi Xiuyuan , Zhang Kewei , Zhang Ping , Yang Weizhong
Published: May 2018

Vanadium‐titanium slag is a type of industrial solid waste from vanadium‐titanium magnetite, and the resource utilization of vanadium‐titanium slag is of great significance. The chemical composition of vanadium‐titanium slag is similar to ceramic raw materials. Besides, the Fe, Ti, and Mn elements in vanadium‐titanium slags possess strong color rendering ability. In the present study, we explored the influence of Fe, Ti, and Mn in vanadium‐titanium slags on the coloration of ceramics. Besides, the crystal structures and chemical constituents of the sintered ceramics were studied by XRD, SEM, EDS, XPS, and ultraviolet‐visible near‐infrared spectrophotometer, and the color‐rendering ability (L∗a∗b∗ values) of the ceramics was investigated. The results showed that the main crystal phases of the ceramics were quartz and anorthite. In addition, the color of the ceramics with the addition of vanadium‐titanium slags was significantly affected by Fe and Mn ions, which decreased their L∗ and a∗ values. Meanwhile, Ti ion alone had no apparent coloring effect but strengthened the coloring effects of Fe and Mn ions. This work could provide the feasibility for preparation of colored ceramics based on vanadium‐titanium slag, which could be used in the fields of high‐value added building decoration, infrared‐emission ceramic, and artwork.
Analytical Solution of Tunnel Surrounding Rock for Stress and Displacement Based on Lade–Duncan Criterion
Authors: Zhu MingZheng , Yang Yugui , Gao Feng , Liu Juan
Published: May 2018

The deformation and failure of tunnel surrounding rock is the result of tunnel excavation disturbance and rock stress release. When the local stress of surrounding rock exceeds the elastic limit of rock mass, the plastic analysis of surrounding rock must be carried out to judge the stability of tunnel. In this study, the Lade–Duncan yield criterion is used to calculate the analytic solutions for the surrounding rock in a tunnel, and the radius and displacement of the plastic zone are deduced using an equilibrium equation. The plastic zone radius and displacement based on Lade–Duncan criterion and Mohr–Coulomb criterion were compared by using single‐factor analysis method under the different internal friction angles, in situ stresses, and support resistances. The results show that the solutions of the radius and displacement of plastic zone calculated by the Lade–Duncan criterion are close to those of Mohr–Coulomb criterion under the high internal friction angle and support resistance or low in situ rock stress; however, the radius and displacement of the plastic zone calculated by the Lade–Duncan criterion are larger under normal circumstances, and the Lade–Duncan criterion is more applicable to the stability analysis of the surrounding rock in a tunnel.
The Protective Effects of Glycyrrhetinic Acid and Chrysin against Ischemia-Reperfusion Injury in Rat Ovaries
Authors: Melekoglu Rauf , Ciftci Osman , Eraslan Sevil , Alan Saadet , Basak Nese
Published: May 2018

Objective. To evaluate the protective effects of glycyrrhetinic acid (GA) and chrysin (CH) on experimental ischemia-reperfusion (I/R) injury in rat ovaries using tissue oxidative stress marker levels, hormone levels, and histopathological scores.Methods. Sixty healthy rats were randomly divided into six equal groups: control, I/R, I/R + CH (50 mg/kg/day), I/R + GA (100 mg/kg/day), CH (50 mg/kg/day), and GA (100 mg/kg/day). Biochemical, hormonal, and histopathological evaluations were performed on blood and tissue samples 14 days after CH and GA treatment.Results. The antioxidant defense system parameters were significantly higher in the ovarian tissues of the I/R + CH and I/R + GA groups than in those of the I/R group. Serum follicle-stimulating hormone levels were significantly reduced, and serum anti-Müllerian hormone levels were significantly increased in rats treated with CH and GA compared with those in the I/R group. Additionally, the histopathological scores of the I/R + CH and I/R + GA groups were significantly improved compared with those of the I/R group.Conclusions. The significant improvements in tissue oxidative stress parameters, serum hormone levels, and histological scores observed in this study indicate that treatment with CH or GA may be a conservative approach to prevent I/R injury in adnexal torsion cases after the ovarian detorsion procedure.
A Modified Bayesian Trustworthiness Evaluation Method to Mitigate the Effect of Unfair Ratings
Authors: Anakpa Manawa , Yuan Yuyu , Barseghyan Ghazaros
Published: May 2018

The choice of trustworthy interaction partners is one of the key factors for successful transactions in online communities. To choose the most trustworthy sellers to interact with, buyers rely on trust and reputation models. Therefore, online systems must be able to accurately assess peers’ trustworthiness. The Beta distribution function provides a sound mathematical basis for combining feedback and deriving users’ trustworthiness. But the Beta reputation system suffers from many forms of cheating behavior such as the proliferation of unfair positive ratings, leading a poor service provider to build a good reputation, and the proliferation of unfair negative feedback, leading a good service provider to end up with a bad reputation. In this paper, we propose a new and coherent method for computing users’ trustworthiness by combining the Beta trustworthiness expectation function with the credibility function. This novel combination mechanism mitigates the impact of unfair ratings. In comparison with Bayesian trust model, we quantitatively show that our approach provides significantly more accurate estimation of peers’ trustworthiness through feedback gathered from multiple sources. Furthermore, we propose an extension of Bayesian trustworthiness expectation function by introducing the initial trust propensity to allow assessing individuals’ initial trust.
Context Adaptation of Fuzzy Inference System-Based Construction Labor Productivity Models
Authors: Tsehayae Abraham Assefa , Fayek Aminah Robinson
Published: May 2018

Construction labor productivity (CLP) is one of the most studied areas in the construction research field, and several context-specific predictive models have been developed. However, CLP model development remains a challenge, as the complex impact of multiple subjective and objective influencing variables have to be examined in various project contexts while dealing with limited data availability. On the other hand, lack of a framework for adapting existing or original models from one context to other contexts limits the possibility of reusing existing models. Such challenges are addressed in this paper through the development of a context adaptation framework. The framework is used to transfer the knowledge represented in fuzzy inference (FIS) based CLP models from one context to another, by using linear and nonlinear evolutionary based transformation of the membership functions combined with sensitivity analysis of fuzzy operators and defuzzification methods. Using four context-specific CLP models developed for concreting activity under industrial, warehouse, high-rise, and institutional building project contexts, the framework was implemented, and the prediction capability of the adapted models was evaluated based on their prediction similarity with the original models. The results showed that linearly adapted CLP models for industrial and institutional contexts and nonlinearly adapted CLP models for warehouse and high-rise contexts provide a similar prediction capability with the original models. The proposed context adaptation framework and findings from this paper address the limitations in past context adaptation research by examining a practical context-sensitive application problem and further examining the role of fuzzy operators and defuzzification methods. The findings assist researchers and industry practitioners to take full advantage of existing FIS-based models in the study of new contexts, for which data availability might be limited.
Investigating the Hybrid Textures of Neutrino Mass Matrix for Near Maximal Atmospheric Neutrino Mixing
Authors: Singh Madan
Published: May 2018

We have studied that the implication of a large value of the effective Majorana neutrino mass in case of neutrino mass matrices has either two equal elements and one zero element (popularly known as hybrid texture) or two equal cofactors and one zero minor (popularly known as inverse hybrid texture) in the flavor basis. In each of these cases, four out of sixty phenomenologically possible patterns predict near maximal atmospheric neutrino mixing angle in the limit of large effective Majorana neutrino mass. This feature remains irrespective of the experimental data on solar and reactor mixing angles. In addition, we have also performed the comparative study of all the viable cases of hybrid and inverse hybrid textures at 3σ CL.
Analysis of Spatially Doped Fused Silica Fiber Optic by Means of a Hamiltonian Formulation of the Helmholtz Equation
Authors: Jiménez-Mejía Raúl E. , Acuna Herrera Rodrigo , Torres Pedro
Published: May 2018

This paper discusses an alternative method for calculating modal parameters in optical fibers such as propagation constants, transverse distributions, and anisotropy, due to linear and nonlinear phenomena acting as perturbations caused by doped silica regions. This method is based on a Hamiltonian formulation of the Helmholtz equation and the stationary perturbation theory, which allows a full‐vectorial description of the electric field components when linear anisotropic inhomogeneities and Kerr nonlinearity are included. Linear and nonlinear parameters can be found for each propagating mode, and its accuracy has been successfully tested when compared to numerical calculations from the vector finite element method, and the results are published in the literature. This method facilitates the calculation of the spatial‐distributed perturbation effects on individual electric field components for each propagating mode.
Why Are FGM Copulas Successful? A Simple Explanation
Authors: Sriboonchitta Songsak , Kreinovich Vladik
Published: May 2018

One of the most computationally convenient nonredundant ways to describe the dependence between two variables is by describing the corresponding copula. In many applications, a special class of copulas—known as FGM copulas—turned out to be most successful in describing the dependence between quantities. The main result of this paper is that these copulas are the fastest to compute, and this explains their empirical success. As an auxiliary result, we also show that a similar explanation can be given in terms of fuzzy logic.
Toll-Like Receptors and RIG-I-Like Receptors Play Important Roles in Resisting Flavivirus
Authors: Guo Hong-Yan , Zhang Xing-Cui , Jia Ren-Yong
Published: May 2018

Flaviviridae family is a class of single-stranded RNA virus, which is fatal to human and animals and mainly prevalent in subtropic and tropic countries. Even though people and animals are barraged with flavivirus infection every year, we have not invented either vaccines or antiviral for most flavivirus infections yet. Innate immunity is the first line of defense in resisting pathogen invasion, serving an important role in a resisting virus. Toll-like receptors (TLRs) and retinoic acid-inducible gene I- (RIG-I-) like receptors (RLRs) are crucial pattern recognition receptors (PRRs) that play essential roles in recognizing and clearing pathogens, including resisting flavivirus. In the present review, we provide a significant reference for further research on the function of innate immunity in resisting flavivirus.
Free Vibration Analysis of Rings via Wave Approach
Authors: Zhipeng Wang , Wei Liu , Yunbo Yuan , Zhijun Shuai , Yibin Guo , Donghua Wang
Published: May 2018

Free vibration of rings is presented via wave approach theoretically. Firstly, based on the solutions of out‐of‐plane vibration, propagation, reflection, and coordination matrices are derived for the case of a fixed boundary at inner surface and a free boundary at outer surface. Then, assembling these matrices, characteristic equation of natural frequency is obtained. Wave approach is employed to study the free vibration of these ring structures. Natural frequencies calculated by wave approach are compared with those obtained by classical method and Finite Element Method (FEM). Afterwards natural frequencies of four type boundaries are calculated. Transverse vibration transmissibility of rings propagating from outer to inner and from inner to outer is investigated. Finally, the effects of structural and material parameters on free vibration are discussed in detail.
Comparison of Diagnostic Cytomorphology of Natural Killer/T-Cell Lymphoma (Nasal Type) in Conventional Smears, Liquid-Based Preparations, and Histopathology
Authors: Liu Chih-Yi , Tsai Hui-Chih
Published: May 2018

Natural killer (NK)/T-cell lymphoma is formally referred to as extranodal NK/T-cell lymphoma, nasal type (ENKTCL), in the 2008 and 2016 World Health Organization (WHO) classifications. NK/T-cell lymphoma, nasal type, is a rare but clinically important lymphoid neoplasm. It is the predominant type of extranodal lymphoma associated with the Epstein–Barr virus (EBV). NK/T-cell lymphoma is marked by a wide cytomorphological spectrum. The cytological findings may be so subtle that NK/T-cell lymphoma could possibly be easily overlooked. Here, we report a case of NK/T-cell lymphoma involving the sinonasal region with lymph node involvement. Fine needle aspiration of the neck lymph node and punch biopsy of the nasal mucosa were performed. The diagnosis of NK/T-cell lymphoma was confirmed based on pathological and immunohistochemical analyses, as well as in situ hybridization for EBV-encoded mRNA (EBER). The present case report underlines the importance of prompt clinicopathological assessment in suspected cases. The comparison of cytomorphologic features of NK/T-cell lymphoma in various specimens is presented.
Epstein Barr Virus Infection Affects Function of Cytotoxic T Lymphocytes in Patients with Severe Aplastic Anemia
Authors: Zhang Tian , Liu Chunyan , Liu Hui , Li Lijuan , Wang Ting , Fu Rong
Published: May 2018

Severe aplastic anemia (SAA) is characterized by pancytopenia and failure of hematopoietic function and is caused by excessive functioning of cytotoxic T lymphocytes (CTLs). EBNA-1, a nucleoprotein of the Epstein Barr virus (EBV), can influence the proliferation and function of lymphocytes. We therefore tested the number of EBV copies in the CD8+ T cells of 27 patients with SAA and 10 healthy control subjects and observed the influences of EBNA-1 upon the CD8+ T cells of patients with SAA. The results showed that more EBV copies were found in the CD8+ T cells of patients with untreated SAA than in patients with SAA in remission or in the healthy control subjects. Their copy number was positively correlated with the expression of granzyme B and perforin, the secretion level of interferon-γ in CD8+ T cells, and the viability of CD8+ T cells, whereas no correlation was seen between the copy number and the interleukin 4 secretion level or the apoptosis rate. Meanwhile, the expression of granzyme B and perforin was reduced after EBNA-1 gene knockdown, whereas the interferon-γ secretion level and cell viability declined. Therefore, we infer that EBV infection may be a factor in the activation of CTLs and in damaging the bone marrow hematopoietic function of patients with SAA.
Robust Fully Distributed Minibatch Gradient Descent with Privacy Preservation
Authors: Danner Gábor , Berta Árpád , Hegedűs István , Jelasity Márk
Published: May 2018

Privacy and security are among the highest priorities in data mining approaches over data collected from mobile devices. Fully distributed machine learning is a promising direction in this context. However, it is a hard problem to design protocols that are efficient yet provide sufficient levels of privacy and security. In fully distributed environments, secure multiparty computation (MPC) is often applied to solve these problems. However, in our dynamic and unreliable application domain, known MPC algorithms are not scalable or not robust enough. We propose a light-weight protocol to quickly and securely compute the sum query over a subset of participants assuming a semihonest adversary. During the computation the participants learn no individual values. We apply this protocol to efficiently calculate the sum of gradients as part of a fully distributed minibatch stochastic gradient descent algorithm. The protocol achieves scalability and robustness by exploiting the fact that in this application domain a “quick and dirty” sum computation is acceptable. We utilize the Paillier homomorphic cryptosystem as part of our solution combined with extreme lossy gradient compression to make the cost of the cryptographic algorithms affordable. We demonstrate both theoretically and experimentally, based on churn statistics from a real smartphone trace, that the protocol is indeed practically viable.
A Case of Factitious Hyperglycemia in a Patient on Intravenous Ascorbic Acid
Authors: Sharma Eliza , Resta Christine , Park Patricia
Published: May 2018

Finger stick blood glucose meters are widely used in outpatient and inpatient settings. However, various factors can affect accuracy of readings from these meters. Here we present a patient who had spurious glucose elevation on these meters while being on intravenous ascorbic acid.
Tumor Necrosis Factor and Interleukin-1β Modulate Synaptic Plasticity during Neuroinflammation
Authors: Rizzo Francesca Romana , Musella Alessandra , De Vito Francesca , Fresegna Diego , Bullitta Silvia , Vanni Valentina , Guadalupi Livia , Stampanoni Bassi Mario , Buttari Fabio , Mandolesi Georgia , Centonze Diego , Gentile Antonietta
Published: May 2018

Cytokines are constitutively released in the healthy brain by resident myeloid cells to keep proper synaptic plasticity, either in the form of Hebbian synaptic plasticity or of homeostatic plasticity. However, when cytokines dramatically increase, establishing a status of neuroinflammation, the synaptic action of such molecules remarkably interferes with brain circuits of learning and cognition and contributes to excitotoxicity and neurodegeneration. Among others, interleukin-1β (IL-1β) and tumor necrosis factor (TNF) are the best studied proinflammatory cytokines in both physiological and pathological conditions and have been invariably associated with long-term potentiation (LTP) (Hebbian synaptic plasticity) and synaptic scaling (homeostatic plasticity), respectively. Multiple sclerosis (MS) is the prototypical neuroinflammatory disease, in which inflammation triggers excitotoxic mechanisms contributing to neurodegeneration. IL-β and TNF are increased in the brain of MS patients and contribute to induce the changes in synaptic plasticity occurring in MS patients and its animal model, the experimental autoimmune encephalomyelitis (EAE). This review will introduce and discuss current evidence of the role of IL-1β and TNF in the regulation of synaptic strength at both physiological and pathological levels, in particular speculating on their involvement in the synaptic plasticity changes observed in the EAE brain.
Giant Penile Lymphedema Caused by Chronic Penile Strangulation with Rubber Band: A Case Report and Review of the Literature
Authors: Hori Shunsuke , Mitsui Yozo , Iwai Hidenori , Tai Toshihiro , Kobayashi Hideyuki , Nakajima Koichi , Nagao Koichi
Published: May 2018

We treated a 65-year-old Japanese man with a giant penile lymphedema due to chronic penile strangulation with a rubber band. He was referred to our hospital with progressive penile swelling that had developed over a period of 2 years from chronic use of a rubber band placed around the penile base for prevention of urinary incontinence. Under a diagnosis of giant penile lymphedema, we performed resection of abnormal penile skin weighing 4.8 kg, followed by a penile plasty procedure. To the best of our knowledge, this is only the seventh report of such a case worldwide, with the present giant penile lymphedema the most reported.
Protection of Brass in HCl Solution by L‐Cysteine and Cationic Surfactant
Authors: Radovanovic Milan B. , Tasic Zaklina Z. , Petrovic Mihajlovic Marija B. , Antonijevic Milan M.
Published: May 2018

Electrochemical behavior of brass and inhibitory effect of L‐cysteine in HCl solution are investigated using electrochemical techniques in addition to SEM‐EDS analysis. Results show that inhibition efficiency depends on inhibitor concentration and immersion time of brass electrode in inhibitor solution. Electrochemical test results point to formation of Cu(I)‐cysteine complex on the brass surface in chloride solutions with addition of different amounts of cysteine. The formed complex has an important role in inhibition of the corrosion process in the examined media because Cu(I)‐cysteine significantly reduces dissolution of brass. Curves obtained in acidic solution in the presence of cysteine after pretreatment in sodium dodecyl sulfate (SDS) by cyclic measurements and potentiodynamic polarization measurements indicate intense inhibition of corrosion processes. Efficient inhibition of brass dissolution is result of formation of a stable protective layer on the brass surface after pretreatment of the electrode in SDS solution. The brass surface is modified in sodium dodecyl sulfate solution in order to increase cysteine adsorption on the electrode surface and to improve inhibition efficiency. Inhibition mechanism of cysteine includes adsorption on active sites on the electrode surface, which is confirmed by SEM‐EDS analysis of brass. Adsorption of cysteine in hydrochloric acid solution obeys the Langmuir adsorption isotherm. Also, Gibbs free energy of adsorption has a value of −31.5 kJ/mol and indicates strong adsorption of cysteine on the electrode surface.
Mathematical Modeling Reveals the Role of Hypoxia in the Promotion of Human Mesenchymal Stem Cell Long-Term Expansion
Authors: Gao Shuhua , Xiang Cheng , Qin Kairong , Sun Changkai
Published: May 2018

Many experimental studies have found that human mesenchymal stem cells (MSCs) in long-term culture exhibited enhanced cell proliferation and prolonged lifespan under hypoxia (around 1%–7% oxygen) against the normoxic condition (about 21% oxygen). Inspired by the experimental findings, we aimed to investigate the hypoxic effects on MSC expansion quantitatively through mathematical modeling to elucidate the corresponding biological mechanism. A two-compartment model based on ordinary differential equations (ODEs), which incorporate cellular division and senescence via state transition, was developed to describe the MSC expansion process. Parameters of this model were fitted to experimental data and used to interpret the different proliferative capacities of MSCs under hypoxia and normoxia along with model sensitivity analysis. The proposed model was tested on data from two separate experimental studies, and it could reproduce the observed growth characteristics in both conditions. Overall, this compartmental model with a logistic state transition rate was sufficient to explain the experimental findings and highlighted the promotive role of hypoxia in MSC proliferation. This in silico study suggests that hypoxia can enhance MSC long-term expansion mainly by delaying replicative senescence, which is indicated by the slowdown of the state transition rate in our model. Therefore, this explanatory model may provide theoretical proof for the experimentally observed MSC growth superiority under hypoxia and has the potential to further optimize MSC culture protocols for regenerative medicine applications.
Integration in Orlicz-Bochner Spaces
Authors: Nowak Marian
Published: May 2018

Let (Ω,Σ,μ) be a complete σ-finite measure space, φ be a Young function, and X and Y be Banach spaces. Let Lφ(X) denote the Orlicz-Bochner space, and Tφ∧ denote the finest Lebesgue topology on Lφ(X). We study the problem of integral representation of (Tφ∧,·Y)-continuous linear operators T:Lφ(X)→Y with respect to the representing operator-valued measures. The relationships between (Tφ∧,·Y)-continuous linear operators T:Lφ(X)→Y and the topological properties of their representing operator measures are established.
HER2 Amplification in Tumors Activates PI3K/Akt Signaling Independent of HER3
Authors: Ruiz-Saenz Ana , Dreyer Courtney , Campbell Marcia R. , Steri Veronica , Gulizia Nate , Moasser Mark M.
Published: May 2018

Current evidence suggests that HER2-driven tumorigenesis requires HER3. This is likely due to the unique ability of HER3 to activate PI3K/Akt pathway signaling, which is not directly accessible to HER2. By genetic elimination of HER3 or shRNA knockdown of HER3 in HER2-amplified cancer cells, we find residual HER2-driven activation of PI3K/Akt pathway signaling that is driven by HER2 through direct and indirect mechanisms. Indirect mechanisms involved second messenger pathways, including Ras or Grb2. Direct binding of HER2 to PI3K occurred through p-Tyr1139, which has a weak affinity for PI3K but becomes significant at very high expression and phosphorylation. Mutation of Y1139 impaired the tumorigenic competency of HER2. Total elimination of HER3 expression in HCC1569 HER2-amplified cancer cells significantly impaired tumorigenicity only transiently, overcome by subsequent increases in HER2 expression and phosphorylation with binding and activation of PI3K. In contrast to activation of oncogenes by mutation, activation by overexpression was quantitative in nature: weak intrinsic activities were strengthened by overexpression, with additional gains observed through further increases in expression. Collectively, these data show that progressive functional gains by HER2 can increase its repertoire of activities such as the activation of PI3K and overcome its dependency on HER3.

Significance: The intrinsic ability of HER2 to activate PI3K correlates with increased HER2 expression and can supplant the dependency upon HER3 for growth in HER2-amplified cancers. Cancer Res; 78(13); 3645–58. ©2018 AACR.
Development and Validation of a Prostate Cancer Genomic Signature that Predicts Early ADT Treatment Response Following Radical Prostatectomy
Authors: Karnes R. Jeffrey , Sharma Vidit , Choeurng Voleak , Ashab Hussam Al-Deen , Erho Nicholas , Alshalalfa Mohammed , Trock Bruce , Ross Ashley , Yousefi Kasra , Tsai Harrison , Zhao Shuang G. , Tosoian Jeffrey J. , Haddad Zaid , Takhar Mandeep , Chang S. Laura , Spratt Daniel E. , Abdollah Firas , Jenkins Robert B. , Klein Eric A. , Nguyen Paul L. , Dicker Adam P. , Den Robert B. , Davicioni Elai , Feng Felix Y. , Lotan Tamara L. , Schaeffer Edward M.
Published: May 2018

Purpose: Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT.

Experimental Design: A training set consisting of 284 radical prostatectomy patients was established after 1:1 propensity score matching metastasis between adjuvant-ADT (a-ADT)-treated and no ADT–treated groups. An ADT Response Signature (ADT-RS) was identified from neuroendocrine and AR signaling–related genes. Two independent cohorts were used to form three separate data sets for validation (set I, n = 232; set II, n = 435; set III, n = 612). The primary endpoint of the analysis was postoperative metastasis.

Results: Increases in ADT-RS score were associated with a reduction in risk of metastasis only in a-ADT patients. On multivariable analysis, ADT-RS by ADT treatment interaction term remained associated with metastasis in both validation sets (set I: HR = 0.18, Pinteraction = 0.009; set II: HR = 0.25, Pinteraction = 0.019). In a matched validation set III, patients with Low ADT-RS scores had similar 10-year metastasis rates in the a-ADT and no-ADT groups (30.1% vs. 31.0%, P = 0.989). Among High ADT-RS patients, 10-year metastasis rates were significantly lower for a-ADT versus no-ADT patients (9.4% vs. 29.2%, P = 0.021). The marginal ADT-RS by ADT interaction remained significant in the matched dataset (Pinteraction = 0.035).

Conclusions: Patients with High ADT-RS benefited from a-ADT. In combination with prognostic risk factors, use of ADT-RS may thus allow for identification of ADT-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early ADT after surgery. Clin Cancer Res; 24(16); 3908–16. ©2018 AACR.
Genomic Heterogeneity and the Small Renal Mass
Authors: Ueno Daiki , Xie Zuoquan , Boeke Marta , Syed Jamil , Nguyen Kevin A. , McGillivray Patrick , Adeniran Adebowale , Humphrey Peter , Dancik Garrett M. , Kluger Yuval , Liu Zongzhi , Kluger Harriet , Shuch Brian
Published: May 2018

Purpose: Tumor heterogeneity may represent a barrier to preoperative genomic characterization by needle biopsy in clear cell renal cell carcinoma (ccRCC). The extent of heterogeneity in small renal tumors remains unknown. Therefore, we set out to evaluate heterogeneity in resected large and small renal tumors.

Experimental Design: We conducted a study from 2013 to 2016 that evaluated 47 consecutive ccRCC tumors resected during radical or partial nephrectomy. Cases were designated as small (<4 cm) and large (>7 cm) tumors. Each tumor had three regions sampled. Copy-number variation (CNV) was assessed and gene expression analysis was performed to characterize the clear-cell A and B (ccA/ccB) profile and the cell-cycle progression (CCP) score. Genomic heterogeneity between three regions was evaluated using CNV subclonal events, regional expression profiles, and correlation between gene expression.

Results: Twenty-three small and 24 large tumors were analyzed. Total CNVs and subclonal CNVs events were less frequent in small tumors (P < 0.001). Significant gene expression heterogeneity was observed for both CCP scores and ccA/ccB classifications. Larger tumors had more variance in CCP scores (P = 0.026). The distribution of ccA/ccB differed between small and large tumors with mixed ccA/ccB tumors occurring more frequently in the larger tumors (P = 0.024). Analysis of five mixed tumors (with both ccA/ccB regions) demonstrated the more aggressive ccB phenotype had greater CNV events (P = 0.014).

Conclusions: Small renal tumors have much less genomic complexity and fewer subclonal events. Pretreatment genomic characterization with single-needle biopsy in small tumors may be useful to assess biologic potential and may influence therapy. Clin Cancer Res; 24(17); 4137–44. ©2018 AACR.
Transient Telomerase Inhibition with Imetelstat Impacts DNA Damage Signals and Cell-Cycle Kinetics
Authors: Thompson Connor A.H. , Gu Alice , Yang Sunny Y. , Mathew Veena , Fleisig Helen B , Wong Judy M.Y.
Published: May 2018

Telomerase is the ribonucleoprotein reverse transcriptase that catalyzes the synthesis of telomeres at the ends of linear chromosomes and contributes to proper telomere-loop (T-loop) formation. Formation of the T-loop, an obligate step before cell division can proceed, requires the generation of a 3′-overhang on the G-rich strand of telomeric DNA via telomerase or C-strand specific nucleases. Here, it is discovered that telomerase activity is critical for efficient cell-cycle progression using transient chemical inhibition by the telomerase inhibitor, imetelstat. Telomerase inhibition changed cell cycle kinetics and increased the proportion of cells in G2-phase, suggesting delayed clearance through this checkpoint. Investigating the possible contribution of unstructured telomere ends to these cell-cycle distribution changes, it was observed that imetelstat treatment induced γH2AX DNA damage foci in a subset of telomerase-positive cells but not telomerase-negative primary human fibroblasts. Chromatin-immunoprecipitation with γH2AX antibodies demonstrated imetelstat treatment-dependent enrichment of this DNA damage marker at telomeres. Notably, the effects of telomerase inhibition on cell cycle profile alterations were abrogated by pharmacological inhibition of the DNA-damage-repair transducer, ATM. Also, imetelstat potentiation of etoposide, a DNA-damaging drug that acts preferentially during S–G2 phases of the cell cycle, depends on functional ATM signaling. Thus, telomerase inhibition delays the removal of ATM-dependent DNA damage signals from telomeres in telomerase-positive cancer cells and interferes with cell cycle progression through G2.

Implications: This study demonstrates that telomerase activity directly facilitates the progression of the cell cycle through modulation of transient telomere dysfunction signals. Mol Cancer Res; 16(8); 1215–25. ©2018 AACR.
Surgical Outcome and Hepatic Regeneration after Hepatic Resection for Hepatocellular Carcinoma in Elderly Patients
Authors: Inoue Yoshihiro , Tanaka Ryo , Fujii Kensuke , Kawaguchi Nao , Ishii Masatsugu , Masubuchi Shinsuke , Yamamoto Masashi , Hirokawa Fumitoshi , Hayashi Michihiro , Uchiyama Kazuhisa
Published: May 2018

Introduction: The rising proportion of elderly patients (aged 80 yearsor above) in our population means that more elderly patients are undergoing hepatectomy. Methods: Five-hundred and thirty patients who underwent hepatectomy for hepatocellular carcinoma (HCC) were retrospectively analyzed with respect to their preoperative status and perioperative results, including remnant liver regeneration. The remnant liver volume was postoperatively measured with multidetector CT on postoperative day 7 and 1, 2, 5, and 12 months after surgery. An elderly group (aged 80 or older) was compared with a non-elderly group (aged less than 80 years). Results: Underlying diseases of the cardiovascular system were significantly more common in the elderly group (57.8%, p = 0.0008). The postoperative incidence of Clavien-Dindo Grade IIIa or higher complications was 20.0% in the elderly group and 24.3% in the non-elderly group, and this difference was not significant. As for regeneration of the remnant liver after resection, this was not morphologically delayed compared to the non-elderly group. Conclusions: In this study, we have demonstrated that safe, radical hepatectomy, similar to procedures performed on non-elderly patients, can be performed on patients with HCC aged 80 and older with sufficient perioperative care.
Secondary Prevention Three and Six Years after Stroke Using the French National Insurance Healthcare System Database
Authors: Mechtouff Laura , Haesebaert Julie , Viprey Marie , Tainturier Valérie , Termoz Anne , Porthault-Chatard Sylvie , David Jean-Stéphane , Derex Laurent , Nighoghossian Norbert , Schott Anne-Marie
Published: May 2018

Background: Secondary prevention is inadequate in the first 2 years after stroke but what happens after that is less documented. The aim of this study was to assess the use and the adherence to preventive drugs 3 and 6 years after experiencing a transient ischemic attack (TIA) or an ischemic stroke (IS). Methods: The population study was from the AVC69 cohort (IS or TIA admitted in an emergency or stroke unit in the Rhône area, France, for an IS or a TIA during a 7-month period). Medication use was defined as ≥1 purchase during the studied year and adherence as Continuous Measure of Medication Acquisition ≥0.8 using the French medical insurance health care funding database. Results: The study population consisted of 210 patients at 3 years and 163 patients at 6 years. Medication use at 3 and 6 years was, respectively, 80.9 and 79.8% for antithrombotics, 69.1 and 66.3% for antihypertensives, 60.5 and 55.2% for statins and 48.6 and 46.6% for optimal treatment defined as the treatment achieved by the use of the 3 drugs. Adherence to each class was good at 3 years and tends to decrease at 6 years. Conclusions: More than one patient out of 2 do not use the optimal preventive treatment.
Vitamin D Deficiency in a Portuguese Cohort of Patients with Inflammatory Bowel Disease: Prevalence and Relation to Disease Activity
Authors: Branco Joana C. , Cardoso Mariana F. , Anapaz Vera , Lourenço Luís Carvalho , Oliveira Ana Maria , Rodrigues Catarina Graça , Santos Liliana , Reis Jorge A.
Published: May 2018

Background and Aims: Vitamin D deficiency is more common in inflammatory bowel disease (IBD) patients than in the general population. However, there are conflicting data about predictive factors of vitamin D deficiency and its potential association with disease activity. The aims of this study were to determine the prevalence and predictive factors of vitamin D deficiency and to evaluate a possible association with disease activity. Methods: A prospective observational study was conducted, including patients with IBD from January to July 2016. The Endocrine Society guidelines were considered for defining levels of serum 25-hydroxyvitamin D (25-OH-D) as follows: deficient (< 20 ng/mL, < 10 ng/mL being severe deficiency), insufficient (21–29 ng/mL), and adequate (> 30 ng/mL). Results: A total of 152 patients (52% men; 47.2 ± 17.3 years) were included, of whom 70% had Crohn’s disease (CD). Thirty-seven percent of patients were on immunosuppressors and 17% were on biologics. The majority were outpatients (88.2%). Mean 25-OH-D levels were 17.1 ± 8 ng/mL (CD: 16.7 ± 8 ng/mL vs. ulcerative colitis: 17.6 ± 7 ng/mL, p = 0.1). Inadequate levels were present in 90.8% of patients (deficiency: 68.4%; insufficiency: 22.4%). A significant negative correlation between 25-OH-D levels and age (r = –0.2, p = 0.04), C-reactive protein (CRP) levels (r = –0.22, p = 0.004), and Harvey-Bradshaw index (HBi) (r = –0.32, p = 0.001) was found. Patients with severe deficiency showed a higher CRP (0.6 vs. 1.4 mg/dL, p = 0.03), erythrocyte sedimentation rate (ESR) (22 vs. 31 mm/h, p = 0.03), and HBi (2 vs. 5, p < 0.001) and lower hemoglobin (13.6 vs. 12.7 g/dL, p = 0.02). There was no association between vitamin D deficiency and gender, type, extent, and duration of disease, surgery, and other measures of disease activity, such as ESR, hemoglobin (these 2 items except for severe deficiency), fecal calprotectin, or Truelove and Witts classification. Conclusions: There is a high prevalence of inadequate levels of vitamin D in IBD patients, particularly deficiency (68.4%). There seems to exist an association between lower levels of vitamin D and higher disease activity, especially in CD.
Mild Cognitive Impairment and Dementia Show Contrasting Associations with Risk of Cancer
Authors: van der Willik Kimberly D. , Ruiter Rikje , Wolters Frank J. , Ikram M. Kamran , Stricker Bruno H. , Hauptmann Michael , Compter Annette , Schagen Sanne B. , Ikram M. Arfan
Published: May 2018

Background: To investigate and to compare the relation between dementia and cancer with the association between mild cognitive impairment (MCI) and cancer. Methods: A total of 13,207 persons from the Rotterdam Study were followed between 1990 and 2013 for the onset of dementia and cancer (sample 1). Between 2002 and 2005, a subset of 5,181 persons underwent extensive cognitive testing for MCI and subsequently were followed up for cancer until 2013 (sample 2). We used Cox proportional hazard models to determine the association between dementia and cancer, and MCI and cancer. Results: In sample 1, 1,404 patients were diagnosed with dementia, and 2,316 developed cancer (63 among dementia cases). Dementia was associated with a decreased risk of cancer (hazard ratio [HR] 0.53; 95% CI 0.41–0.68). In sample 2, 513 persons were diagnosed with MCI and 670 persons developed cancer (81 among MCI cases). In contrast to individuals with dementia, those with MCI tended to have an increased risk of cancer (HR 1.25; 95% CI 0.99–1.58). Conclusions: We found that persons with MCI tended to have an increased risk of cancer, whereas those with dementia have a decreased risk. These findings call into question a biological explanation for the inverse link between dementia and cancer, thereby suggesting the presence of methodological bias.
Biallelic WRN Mutations in Newly Identified Japanese Werner Syndrome Patients
Authors: Maezawa Yoshiro , Kato Hisaya , Takemoto Minoru , Watanabe Aki , Koshizaka Masaya , Ishikawa Takahiro , Sargolzaeiaval Forough , Kuzuya Masafumi , Wakabayashi Hiroshi , Kusaka Takashi , Yokote Koutaro , Oshima Junko
Published: May 2018

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by systemic accelerated aging. It is caused by pathogenic variants of the WRN gene that encodes a nuclear helicase. In this report, we describe 4 newly identified WS cases among those referred to the Japanese Werner Consortium, Chiba University, Japan. All 4 cases were compound heterozygotes of the Japanese founder mutation, c.3139-1G>C, and a novel null pathogenic variant, c.1587G>A, c.2448+1G>A, or c.3233+1G>T, or an amino acid substitution variant, c.1720G>A, p.Gly574Arg. These 3 null pathogenic variants were not previously described. The p.Gly574Arg was previously reported in a European patient, and the identification of the second p.Gly574Arg case, with classical WS features, further confirmed the pathogenic nature of this variant. For the case with c.3233+1G>T, we determined the phase of 2 disease-causing mutations and demonstrated that they are on different chromosomes. This assay would be particularly important for those cases with ambiguous clinical diagnosis.
Downregulation of S100A4 Alleviates Cardiac Fibrosis via Wnt/β -Catenin Pathway in Mice
Authors: Qian LiJun , Hong Jian , Zhang YanMei , Zhu MengLin , Wang XinChun , Zhang YanJuan , Chu Ming , Yao Jing , Xu Di
Published: May 2018

Background/Aims: Cardiac fibrosis is a pathological change leading to cardiac remodeling during the progression of myocardial ischemic diseases, and its therapeutic strategy remains to be explored. S100A4, a calcium-binding protein, participates in fibrotic diseases with an unclear mechanism. This study aimed to investigate the role of S100A4 in cardiac fibrosis. Methods: Cardiac fibroblasts from neonatal C57BL/6 mouse hearts were isolated and cultured. Myocardial infarction was induced by ligating the left anterior descending coronary artery (LAD). The ligation was not performed in the sham group. A volume of 5×105pfu/g adenovirus or 5 µM/g ICG-001 was intramyocardially injected into five parts bordering the infarction zone or normal region. We used Western blotting, quantitative RT-PCR, immunofluorescence, immunohistochemistry and Masson’s trichrome staining to explore the function of S100A4. Results: We found significant increases of S100A4 level and cardiac fibrosis markers, and β-catenin signaling activation in vitro and in vivo. In addition, knockdown of S100A4 significantly reduced cardiac fibrosis and β-catenin levels. Moreover, the expression of S100A4 decreased after ICG-001 inhibited β-catenin signal pathway. Conclusion: Downregulation of S100A4 alleviates cardiac fibrosis via Wnt/β -catenin pathway in mice. S100A4 may be a therapeutic target of cardiac fibrosis.
Stromal-Cell-Derived Factor (SDF) 1-Alpha Overexpression Promotes Bone Regeneration by Osteogenesis and Angiogenesis in Osteonecrosis of the Femoral Head
Authors: Yang Fan , Xue Feng , Guan Junjie , Zhang Zeng , Yin Jimin , Kang Qingling
Published: May 2018

Background/Aims: Osteonecrosis of the femoral head (ONFH) is a devastating orthopedic disease. Previous studies suggested that stromal-cell-derived factor (SDF)-1 was involved in osteogenesis and angiogenesis. However, whether SDF-1 potentiates the angiogenesis and osteogenesis of bone marrow-derived stromal stem cells (BMSCs) in ONFH is not clear. Methods: BMSCs were transfected with green fluorescent protein (GFP) or the fusion gene encoding GFP and SDF-1α, and transgenic efficacy was monitored by immunofluorescence. The expression of SDF-1α, runt-related transcription factor 2 (Runx2, osteocalcin (OCN), and alkaline phosphatase (ALP) at the mRNA level was measured by real-time polymerase chain reactions (RT-PCR). The expression of SDF-1α, Runx2, OCN, and p-Smad1/5 were measured at the protein level by Western blot. Transwell migration assay and tube formation assay were utilized to detect the angiogenesis in vitro, whereas the in vivo angiogenesis was monitored by angiography. Immunohistological staining and micro-CT scanning were conducted to assess the histological changes in morphology. Results: In vitro, SDF-1α overexpression in BMSCs promoted osteogenic differentiation and upregulated the expression of osteogenic-related proteins, such as ALP, Runx2, OCN, and p-Smadl/5. In the methylprednisolone induced ONFH rat model used in our investigation, the overexpression of SDF-1α in BMSCs promoted significantly more bone regeneration and the expression of OCN and Runx2 as compared with the effect of vehicle overexpression. Moreover, the morphology of ONFH was ameliorated after the transplantation of BMSCs with SDF-1α overexpression. Furthermore, SDF-1α overexpression in BMSCs significantly increased osteoblastic angiogenesis as indicated by the increased tube formation ability, CD31 expression, and vessel volume. Conclusion: SDF-1α overexpression in BMSCs promotes bone generation as indicated by osteogenesis and angiogenesis, suggesting SDF-1α may serve as a therapeutic drug target for ONFH treatment.