bluuebunny/crossref_metadata_2025 huggingface dataset:
A unifying look at zero-sum invariants
Authors: Gao Weidong , Li Yuanlin , Peng Jiangtao , Wang Guoqing
Published: September 2017

The purpose of the paper is to provide a unified way to formulate zero-sum invariants. Let [Formula: see text] be a finite additive abelian group. Let [Formula: see text] denote the monoid of all zero-sum sequences over [Formula: see text]. For [Formula: see text], let [Formula: see text] be the smallest integer [Formula: see text] such that every sequence [Formula: see text] over [Formula: see text] of length [Formula: see text] has a subsequence in [Formula: see text]. We provide some first results and open problems on [Formula: see text].
PGL2(𝔽ℓ) number fields with rational companion forms
Authors: Roberts David P.
Published: September 2017

We give a list of [Formula: see text] number fields for [Formula: see text] which have rational companion forms. Our list has 53 fields and seems likely to be complete. Some of the fields on our list are very lightly ramified for their Galois group.
Non-vanishing of the first derivative of GL(3) ×GL(2) L-functions
Authors: Chen Guohua , Yan Xiaofei
Published: September 2017

Let [Formula: see text] be a fixed self-dual Hecke–Maass cusp form for [Formula: see text] and [Formula: see text] be an orthogonal basis of odd Hecke–Maass cusp forms for [Formula: see text]. We prove an asymptotic formula for the average of the first derivative of the Rankin–Selberg [Formula: see text]-function of [Formula: see text] and [Formula: see text] at the center point [Formula: see text]. This implies the non-vanishing results for the first derivative of these [Formula: see text]-functions at the center point [Formula: see text].
A Novel User-Friendly Image Analysis Technique for Determination of Electrospun Nanofibrous Mats Thickness
Authors: Moghadam Bentolhoda Hadavi , Kasaei Shohreh , Haghi A. K.
Published: September 2017

In this study, a novel technique for measuring the thickness of electrospun nanofibrous mat based on image analysis techniques is proposed. The thicknesses of electrospun polyacrylonitrile (PAN), polyvinyl alcohol (PVA), and polyurethane (PU) nanofibrous mats are calculated using depth estimation in different views. The images are captured by a fixed scanning electron microscope (SEM) where the mat sample is rotated by 15[Formula: see text], 30[Formula: see text], and 45[Formula: see text] angles. By calculating the disparity value (the distance between two corresponding points in two images), the relative depth of images and consequently the thickness of nanofibrous mat are obtained. Furthermore, the thickness of three electrospun mats are measured from the cross-section view of the nanofibrous mat by scanning the electron microscopy. A close agreement between results obtained by this method at low angle views (15[Formula: see text]) and the direct thickness measurement obtained from the cross-section view is achieved. Comparison of the average thickness from the direct measurement and the proposed method for different samples exhibits a linear relationship with the high regression coefficient of 0.96. By using the proposed method, the quantitative evaluation of the thickness measurement becomes feasible over the entire surface of electrospun mats.
Blood–brain barrier and laser technology for drug brain delivery
Authors: Semyachkina-Glushkovskaya Oxana V. , Abdurashitov Arkady S. , Saranceva Elena I. , Borisova Eketerina G. , Shirokov Alexander A. , Navolokin Nikita V.
Published: September 2017

Here, we discuss an important problem in medicine as development of effective strategies for brain drug delivery. This problem is related to the blood–brain barrier (BBB), which is a “customs” controlling the entrance of different molecules from blood into the brain protecting the normal function of central nervous system (CNS). We show three interfaces of anatomical side of BBB and two functional types of BBB — physical and transporter barriers. Although this protective mechanism is essential for health of CNS, it also creates a hindrance to the entry of drugs into the brain. The BBB was discovered over 100 years ago but till now, there is no effective methods for brain drug delivery. There are more than 70 approaches for overcoming BBB including physical, chemical and biological techniques but all of these tools have limitation to be widely used in clinical practice due to invasiveness, challenge in performing, very costly or limitation of drug concentration.

Photodynamic therapy (PDT) is usual clinical method of surgical navigation for the resection of brain tumor and anti-cancer therapy. Nowadays, the application of PDT is considered as a potential promising tool for brain drug delivery via opening of BBB. Here, we show the first successful experimental results in this field discussing the adventures and disadvantages of PDT-related BBB disruption as well as alternatives to overcome these limitations and possible mechanisms with new pathways for brain clearance via glymphatic and lymphatic systems.
Performance Implications of Extended Page Tables on Virtualized x86 Processors
Authors: Merrifield Timothy , Taheri H. Reza
Published: September 2017

Managing virtual memory is an expensive operation, and becomes even more expensive on virtualized servers. Processing TLB misses on a virtualized x86 server requires a twodimensional page walk that can have 6x more page table lookups, hence 6x more memory references, than a native page table walk. Thus much of the recent research on the subject starts from the assumption that TLB miss processing in virtual environments is significantly more expensive than on native servers. However, we will show that with the latest software stack on modern x86 processors, most of these page table lookups are satisfied by internal paging structure caches and the L1/L2 data caches, and the actual virtualization overhead of TLB miss processing is a modest fraction of the overall time spent processing TLB misses.

We show that even for the heaviest workloads, a welltuned application that uses large pages on a recent OS release with a modern hypervisor running on the latest x86 processors sees only minimal degradation from the additional overhead of the two-dimensional page walks in a virtualized server.
Hybrid Cloud Storage
Authors: Gupta Abhishek , Spillane Rick , Wang Wenguang , Austruy Maxime , Fereydouny Vahid , Karamanolis Christos
Published: September 2017

Thanks to the compelling economics of public cloud storage, the trend in the IT industry is to move the bulk of analytics and application data to services such as AWS S3 and Google Cloud Storage. At the same time, customers want to continue accessing and analyzing much of that data using applications that run on compute clusters that may reside either on public clouds or on-premise. For VMware customers, those clusters run vSphere (sometimes with vSAN) on-premise and in the future may utilize SDDCaaS. Cloud storage exhibits high latencies and it is not appropriate for direct use by applications. A key challenge for these use cases is determining the subset of the typically huge data sets that need to be moved into the primary storage tier of the compute clusters.

This paper introduces a novel approach for creating a hybrid cloud storage that allows customers to utilize the fast primary storage of their compute clusters as a caching tier in front of a slow secondary storage tier. This approach can be completely transparent requiring no changes to the application. To achieve this, we extended VDFS [16], a POSIX-compliant scale-out filesystem, with the concept of caching-tier volumes.

VDFS caching-tier volumes resemble regular file system volumes, but they fault-in data from a cloud storage back-end on first access. Cached data are persisted on fast primary storage, close to the compute cluster, like VMware's vSAN.

Caching-tier volumes use a write-back approach. The enterprise features of the primary storage ensure the persistence and fault tolerance of new or updated data. Write-back from the primary to cloud storage is managed using an efficient change-tracking mechanism built into VDFS called exo-clones [18].

This paper outlines the architecture and implementation of caching tier volumes on VDFS and reports on an initial evaluation of the current prototype.
Optical Tests on a Curve Fresnel Lens as Secondary Optics for Solar Troughs
Authors: Fontani D. , Sansoni P. , Francini F. , DeLucia M. , Pierucci G. , Jafrancesco D.
Published: September 2017

A curve Fresnel lens is developed as secondary concentrator for solar parabolic troughs to reduce the number of photovoltaic cells. Specific measurements and optical tests are used to evaluate the optical features of manufactured samples. The cylindrical Fresnel lens transforms the focal line, produced by the primary mirror, into a series of focal points. The execution of special laboratory tests on some secondary concentrator samples is discussed in detail, illustrating the methodologies tailored to the specific case. Focusing tests are performed, illuminating different areas of the lens with solar divergence light and acquiring images on the plane of the photocell using a CMOS camera. Concentration measurements are carried out to select the best performing samples of curve Fresnel lens. The insertion of the secondary optics within the concentrating photovoltaic (CPV) trough doubles the solar concentration of the system. The mean concentration ratio is 1.73, 2.13, and 2.09 for the three tested lenses. The concentration ratio of the solar trough is 140 and approaches 300 after the introduction of the secondary lens.
Identifying Novel Glioma-Associated Noncoding RNAs by Their Expression Profiles
Authors: Matjašič Alenka , Tajnik Mojca , Boštjančič Emanuela , Popović Mara , Matos Boštjan , Glavač Damjan
Published: September 2017

Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play a significant role in cancer development as regulators of protein-coding genes. Their dysregulation was in some extent already associated with glioma, the most aggressive primary brain tumours in adults. The correct diagnosis and treatment selection due to high tumour heterogeneity might be difficult and inadequate, resulting in poor prognosis. Studies of expression patterns of noncoding RNAs (ncRNAs) could provide useful insight in glioma molecular development. We used the qPCR approach to screen and investigate the expression of lncRNAs that were previously deregulated in other cancer types. The study showed altered expression levels for numerous lncRNAs across histologically different glioma samples. Validation of few lncRNAs showed association of expression levels with histological subtype and/or malignancy grade. We also observed deregulated and subtype-distinctive expression for four lncRNA-associated miRNAs. Expression of few lncRNAs and miRNA was also associated with patients’ survival, showing potential prognostic value. Several ncRNAs, some already related to glioma and some, to the best of our knowledge, investigated for the first time, might be of greater importance in glioma molecular development and progression. Finding the subtype-specific lncRNA and/or miRNA expression patterns may contribute additional information for a more objective classification.
Oxidative Stress in Hemodialysis Patients: A Review of the Literature
Authors: Liakopoulos Vassilios , Roumeliotis Stefanos , Gorny Xenia , Dounousi Evangelia , Mertens Peter R.
Published: September 2017

Hemodialysis (HD) patients are at high risk for all‐cause mortality and cardiovascular events. In addition to traditional risk factors, excessive oxidative stress (OS) and chronic inflammation emerge as novel and major contributors to accelerated atherosclerosis and elevated mortality. OS is defined as the imbalance between antioxidant defense mechanisms and oxidant products, the latter overwhelming the former. OS appears in early stages of chronic kidney disease (CKD), advances along with worsening of renal failure, and is further exacerbated by the HD process per se. HD patients manifest excessive OS status due to retention of a plethora of toxins, subsidized under uremia, nutrition lacking antioxidants and turn‐over of antioxidants, loss of antioxidants during renal replacement therapy, and leukocyte activation that leads to accumulation of oxidative products. Duration of dialysis therapy, iron infusion, anemia, presence of central venous catheter, and bioincompatible dialyzers are several factors triggering the development of OS. Antioxidant supplementation may take an overall protective role, even at early stages of CKD, to halt the deterioration of kidney function and antagonize systemic inflammation. Unfortunately, clinical studies have not yielded unequivocal positive outcomes when antioxidants have been administered to hemodialysis patients, likely due to their heterogeneous clinical conditions and underlying risk profile.
Management of Psychosis in Parkinson’s Disease: Emphasizing Clinical Subtypes and Pathophysiological Mechanisms of the Condition
Authors: Taddei Raquel N. , Cankaya Seyda , Dhaliwal Sandeep , Chaudhuri K. Ray
Published: September 2017

Investigation into neuropsychiatric symptoms in Parkinson’s disease (PD) is sparse and current drug development is mainly focused on the motor aspect of PD. The tight association of psychosis with an impaired quality of life in PD, together with an important underreporting of this comorbid condition, contributes to its actual insufficient assessment and management. Furthermore, the withdrawal from access to readily available treatment interventions is unacceptable and has an impact on PD prognosis. Despite its impact, to date no standardized guidelines to the adequate management of PD psychosis are available and they are therefore highly needed. Readily available knowledge on distinct clinical features as well as early biomarkers of psychosis in PD justifies the potential for its timely diagnosis and for early intervention strategies. Also, its specific characterisation opens up the possibility of further understanding the underlying pathophysiological mechanisms giving rise to more targeted therapeutic developments in the nearer future. A literature review on the most recent knowledge with special focus on specific clinical subtypes and pathophysiological mechanisms will not only contribute to an up to date practical approach of this condition for the health care providers, but furthermore open up new ideas for research in the near future.
Effect of Surface Charge and Hydrophobicity Modulation on the Antibacterial and Antibiofilm Potential of Magnetic Iron Nanoparticles
Authors: Shebl Rania Ibrahim , Farouk Faten , Azzazy Hassan Mohamed El-Said
Published: September 2017

Unmodified magnetic nanoparticles (MNPs) lack antibacterial potential. We investigated MNPs surface modifications that can impart antibacterial activity. Six MNPs species were prepared and characterized. Their antibacterial and antibiofilm potentials, surface affinity, and cytotoxicity were evaluated. Prepared MNPs were functionalized with citric acid, amine group, amino-propyl trimethoxy silane (APTMS), arginine, or oleic acid (OA) to give hydrophilic and hydrophobic MNPs with surface charge ranging from −30 to +30 mV. Prepared MNPs were spherical in shape with an average size of 6–15 nm. Hydrophobic (OA-MNPs) and positively charged MNPs (APTMS-MNPs) had significant concentration dependent antibacterial effect. OA-MNPs showed higher inhibitory potential againstS. aureusandE. coli(80%) than APTMS-MNPs (70%). Both particles exhibited surface affinity toS. aureusandE. coli.Different concentrations of OA-MNPs decreasedS. aureusandE. colibiofilm formation by 50–90%, while APTMS-MNPs reduced it by 30–90%, respectively. Up to 90% of preformed biofilms ofS. aureusandE. coliwere destroyed by OA-MNPs and APTMS-MNPs. In conclusion, surface positivity and hydrophobicity enhance antibacterial and antibiofilm properties of MNPs.
Information-Balance-Aware Approximated Summarization of Data Provenance
Authors: Pei Jisheng , Ye Xiaojun
Published: September 2017

Extracting useful knowledge from data provenance information has been challenging because provenance information is often overwhelmingly enormous for users to understand. Recently, it has been proposed that we may summarize data provenance items by grouping semantically related provenance annotations so as to achieve concise provenance representation. Users may provide their intended use of the provenance data in terms of provisioning, and the quality of provenance summarization could be optimized for smaller size and closer distance between the provisioning results derived from the summarization and those from the original provenance. However, apart from the intended provisioning use, we notice that more dedicated and diverse user requirements can be expressed and considered in the summarization process by assigning importance weights to provenance elements. Moreover, we introduce information balance index (IBI), an entropy based measurement, to dynamically evaluate the amount of information retained by the summary to check how it suits user requirements. An alternative provenance summarization algorithm that supports manipulation of information balance is presented. Case studies and experiments show that, in summarization process, information balance can be effectively steered towards user-defined goals and requirement-driven variants of the provenance summarizations can be achieved to support a series of interesting scenarios.
Expression of MicroRNA-29a Regulated by Yes-Associated Protein Modulates the Neurite Outgrowth in N2a Cells
Authors: Tan Chunye , Yu Changlin , Song Zhiwen , Zou Hongjun , Xu Xu , Liu Jinbo
Published: September 2017

Yes-associated protein (YAP) is proved to increase miR-29a in the present study, but the relevant molecular mechanism is not clear. Also, growing evidence indicates that the high-level miR-29a promotes the neurite outgrowth by decreasing PTEN (phosphatase and tensin homologue deleted on chromosome 10). Results show that the expression of miR-29a increases but the PTEN decreases during transfecting the N2a cells with the YAP plasmid. Meanwhile, the advancement of neurite outgrowth is presented via using multiple methods to detect the expression of GAP-43 and NF-200, which have a strong association with neurite outgrowth. The expression of miR-29a, GAP-43, and NF-200 shows an opposite tendency compared to the PTEN when YAP is downregulated. By treating N2a cells with miR-29a mimic and inhibitor, we also find the same conclusion. For in silico analysis of miR-29a, its promoter may have a binding site for YAP. Based on a luciferase reporter assay and a chromatin immunoprecipitation (ChIP) experiment, we demonstrate that YAP could increase the expression of miR-29a by targeting the promoter of miR-29a. In conclusion, the results identify that YAP promotes the neurite outgrowth via targeting the promoter of miR-29a, and it may be an effective therapeutic medicine for the neural disease.
Naturally Acquired Antibody Responses to a Synthetic Malaria Antigen AS202.11
Authors: Nazareth Rebeka , Horumpende Pius , Sonda Tolbert , Ndaro Arnold , Mollel Edson , Paul Eliakim , Athanase Emmanuel , Chilongola Jaffu
Published: September 2017

Background. A major challenge to malaria vaccine development is identification of protective epitopes and respective protective immune responses. Objective. To characterize naturally acquired Immunoglobulin G (IgG) responses to the synthetic peptide AS202.11, a malaria vaccine candidate. Methodology. This community based cross-sectional study enrolled 320 participants aged 1 year and above. Demographic information was recorded through interviews. Detection of P. falciparum infection was done by microscopy, malaria rapid diagnostic test, and polymerase chain reaction. ELISA was used to detect IgG antibody. Data was analyzed using STATA. Results. The overall AS202.11 IgG seropositivity was 78.8% (73.9–82.9). Seropositivity by age categories was ≤12 years [74.3% (67.4–80.2)], 13–40 years [85.3% (76.5–91.1)], and >40 years [82.6% (68.7–91.1)]. Compared to the ≤ 12-year-old group, aORs for the other groups were 2.22 (1.14–4.32), p=0.019, and 1.87 (0.81–4.35), p=0.143, for the 13–40-year-old and >40-year-old groups, respectively. The 13–40-year-old group had more seropositive individuals compared to the ≤ 12-year-old group. Conclusion. We report a high degree of recognition of AS202.11 by IgG elicited by field P. falciparum strains, suggesting its close similarity to native P. falciparum antigens and possible suitability of the peptide as a future malaria vaccine candidate.
Ubiquitin-Specific Protease 2 Modulates the Lipopolysaccharide-Elicited Expression of Proinflammatory Cytokines in Macrophage-like HL-60 Cells
Authors: Kitamura Hiroshi , Ishino Takeshi , Shimamoto Yoshinori , Okabe Jun , Miyamoto Tomomi , Takahashi Eiki , Miyoshi Ichiro
Published: September 2017

We investigated the regulatory roles of USP2 in mRNA accumulation of proinflammatory cytokines in macrophage-like cells after stimulation with a toll-like receptor (TLR) 4 ligand, lipopolysaccharide (LPS). Human macrophage-like HL-60 cells, mouse macrophage-like J774.1 cells, and mouse peritoneal macrophages demonstrated negative feedback to USP2 mRNA levels after LPS stimulation, suggesting that USP2 plays a significant role in LPS-stimulated macrophages.USP2knockdown (KD) by short hairpin RNA in HL-60 cells promoted the accumulation of transcripts for 25 of 104 cytokines after LPS stimulation. In contrast, limited induction of cytokines was observed in cells forcibly expressing the longer splice variant of USP2 (USP2A), or in peritoneal macrophages isolated fromUsp2atransgenic mice. An ubiquitin isopeptidase-deficient USP2A mutant failed to suppress LPS-induced cytokine expression, suggesting that protein ubiquitination contributes to USP2-mediated cytokine repression. Although USP2 deficiency did not accelerate TNF receptor-associated factor (TRAF) 6-nuclear factor-κB (NF-κB) signaling, it increased the DNA binding ratio of the octamer binding transcription factor (Oct)-1 to Oct-2 inTNF,CXCL8,CCL4, andIL6promoters. USP2 decreased nuclear Oct-2 protein levels in addition to decreasing the polyubiquitination of Oct-1. In summary, USP2 modulates proinflammatory cytokine induction, possibly through modification of Oct proteins, in macrophages following TLR4 activation.
A Degree Theory for Compact Perturbations of Monotone Type Operators and Application to Nonlinear Parabolic Problem
Authors: Asfaw Teffera M.
Published: September 2017

Let X be a real locally uniformly convex reflexive Banach space with locally uniformly convex dual space X⁎. Let T:X⊇D(T)→2X⁎ be maximal monotone, S:X→2X⁎ be bounded and of type (S+), and C:D(C)→X⁎ be compact with D(T)⊆D(C) such that C lies in Γστ (i.e., there exist σ≥0 and τ≥0 such that Cx≤τx+σ for all x∈D(C)). A new topological degree theory is developed for operators of the type T+S+C. The theory is essential because no degree theory and/or existence result is available to address solvability of operator inclusions involving operators of the type T+S+C, where C is not defined everywhere. Consequently, new existence theorems are provided. The existence theorem due to Asfaw and Kartsatos is improved. The theory is applied to prove existence of weak solution (s) for a nonlinear parabolic problem in appropriate Sobolev spaces.
Effects of Jiawei Shaoyao‐Gancao Decoction and Its Drug‐Containing Serum on Proliferation, Apoptosis, and Ultrastructure of Human Adenomyosis Foci Cells
Authors: Zeng Yu-yan , Li Kun-yin
Published: September 2017

Objective. The present study aimed to investigate the effects of Jiawei Shaoyao‐Gancao Decoction (JSGD) and its drug‐containing serum (CDS) on the proliferation, apoptosis, and ultrastructure of human adenomyosis foci cells. Methods. Primary cultures of human adenomyosis foci cells were prepared from hard uterine lesions of adenomyosis patients. The cells were treated with JSGD (10 and 20 mg/ml), CDS, and mifepristone (MIF) for 24 or 48 h. Cell proliferation was detected using CCK‐8 assay, cell apoptosis was measured by flow cytometry, and the cell ultrastructure was observed by transmission electron microscopy (TEM). Results. JSGD and CDS significantly induced cell apoptosis and inhibited cell proliferation for 24 h or 48 h, in which the effects of JSGD were in a dose‐dependent manner. The effect of CDS for 24 h was higher than that of CDS for 48 h. Moreover, JSGD and CDS treatments induced marked apoptosis in adenomyosis foci cells, characterized by nucleus chromatin, condensation, fragmentation, mitochondria and endoplasmic swelling, and autophagy‐lysosome. Conclusions. JSGD and CDS can suppress proliferation and induce apoptosis in adenomyosis foci cells, through altering their ultrastructure. The results provided support for JSGD and CDS in the treatment of adenomyosis and gained further insight into the effect of this prescription.
Effect on Chest Deformation of Simultaneous Correction of Pectus Excavatum with Scoliosis
Authors: Ye Jin-Duo , Lu Guang-Pu , Feng Jing-Jing , Zhong Wei-Hong
Published: September 2017

Objective. This paper is to understand the effect of simultaneous correction of pectus excavatum with scoliosis and to provide some useful information for clinical orthopedic surgery design. Methods. The method of a three-dimensional reconstruction has been used to the reconstruction of the chest model of pectus excavatum with scoliosis, and the numerical stimulation has been conducted to the process of minimally invasive correction. Three kinds of correction methods have been considered in the numerical simulation, stretch spine, stretch spine and minimally invasive correction at the same time, and release stretch spine after stretch spine and minimally invasive correction of pectus excavatum at the same time. Results. It is found that stretch spine may help to correction of scoliosis but aggravate the sternum collapse, and release stretch spine after stretch spine and minimally invasive correction at the same time could not only be good at scoliosis but also improve the collapse of the sternum, which could help to improve the heartbeat and breath of the patients. Conclusion. Among the three kinds of correction methods, release stretch spine after stretch spine and minimally invasive correction at the same time could help to improve both the scoliosis and the collapse of the sternum.
Modeling and Control for HIV/AIDS Transmission in China Based on Data from 2004 to 2016
Authors: Li Zhiming , Teng Zhidong , Miao Hui
Published: September 2017

HIV is one of the major life-threatening viruses that are spreading in the People’s Republic of China (China for short). A susceptible-exposed in the latent stage-infectious (SEI) model is established to sketch the evolution of epidemic. The basic reproduction number is defined. By constructing Lyapunov function, globally asymptotical stabilities of the disease-free and endemic equilibria are given. Then, optimal control theory is applied in HIV/AIDS epidemic. Precaution, screening, and treatment of control variables are introduced and a new model with control is established. Through the HIV/AIDS data in China, all parameters involved in SEI model are analyzed and parts of them are estimated. Further, by control model, optimal strategy is obtained. Results show that the precaution and treatment are the major contributors to preventing and controlling HIV/AIDS epidemic.
The Evaluation of Oxidative Stress Parameters in Serum Patients with Relapsing‐Remitting Multiple Sclerosis Treated with II‐Line Immunomodulatory Therapy
Authors: Adamczyk Bożena , Wawrzyniak Sławomir , Kasperczyk Sławomir , Adamczyk-Sowa Monika
Published: September 2017

Objectives. The assessment of oxidative stress (OS) in serum relapsing‐remitting multiple sclerosis patients treated with II‐line immunomodulatory therapy (fingolimod, natalizumab) compared to newly diagnosed patients (de novo group) treated with interferon (IFN) beta and controls. The relationship between OS parameters and gender, age, disease duration, Expanded Disability Status Scale, annualized relapse rate, MRI lesions in patients treated with II‐line. Materials and Methods. One hundred and twenty‐one patients with RRMS were enrolled in the study. Patients were divided into groups: de novo group, IFN, fingolimod (FG), natalizumab (NT), and controls. Lipid hydroperoxides (LHP), malondialdehyde (MDA), lipofuscin (LPS), and total oxidative status (TOS) were determined. Results. LHP, MDA, and TOS were lower in NT and FG groups compared to the de novo group. Levels of OS were different between NT and FG patients and the IFN group. Women treated with FG and NT had lower MDA, LPH, and TOS than women who were not treated while in men only LPH was lowered. Positive correlations were found between MDA, LHP, TOS, and ARR in the NT group. Conclusion. The II‐line immunomodulatory treatment decreased OS particularly among women. No difference in OS levels was observed between II‐line therapy and IFN beta.
VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma
Authors: Yao Xiaosai , Tan Jing , Lim Kevin Junliang , Koh Joanna , Ooi Wen Fong , Li Zhimei , Huang Dachuan , Xing Manjie , Chan Yang Sun , Qu James Zhengzhong , Tay Su Ting , Wijaya Giovani , Lam Yue Ning , Hong Jing Han , Lee-Lim Ai Ping , Guan Peiyong , Ng Michelle Shu Wen , He Cassandra Zhengxuan , Lin Joyce Suling , Nandi Tannistha , Qamra Aditi , Xu Chang , Myint Swe Swe , Davies James O. J. , Goh Jian Yuan , Loh Gary , Tan Bryan C. , Rozen Steven G. , Yu Qiang , Tan Iain Bee Huat , Cheng Christopher Wai Sam , Li Shang , Chang Kenneth Tou En , Tan Puay Hoon , Silver David Lawrence , Lezhava Alexander , Steger Gertrud , Hughes Jim R. , Teh Bin Tean , Tan Patrick
Published: September 2017

Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel–Lindau (VHL) tumor suppressor. Roles for noncoding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Superenhancer profiling identified ZNF395 as a ccRCC-specific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo. VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α–HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter–enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression.

Significance: Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered cis-regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL, a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter–enhancer complexes. Cancer Discov; 7(11); 1284–305. ©2017 AACR.

See related commentary by Ricketts and Linehan, p. 1221.

This article is highlighted in the In This Issue feature, p. 1201
Chrysotile Causes Human Bronchial Epithelial Cell Apoptosis in Response to the Fas-Mediated Apoptosis Pathway
Authors: Zhang Min , Chen Junqiang , Jiang Zhaoqiang , Zhu Lijin , Wu Wei , Xiao Yun , Chen Kun
Published: September 2017

Aims: Asbestos is harmful to human health. However, the pathogenicity of chrysotile is a controversial matter. This study aimed to investigate the apoptosis of a human bronchial epithelial cell line (BEAS-2B) exposed to chrysotile that may function in part through the Fas death receptor pathway. Methods: Cultured human BEAS-2B cells were treated with chrysotile and cell viability was evaluated by CCK-8 assay. The induction of cell apoptosis was evaluated by FACS analysis. mRNA expression levels of Fas, caspase-3, and caspase-8 were evaluated quantitatively by real-time PCR. The expression of Fas, caspase-3, and caspase-8 proteins were evaluated by Western blot. Meanwhile, cells were preincubated with various concentrations of anti-Fas antibody (CH11) and antagonistic anti-Fas antibody (ZB4). Results: Chrysotile inhibits proliferation, induces apoptosis, and upregulates the expression of Fas, caspase-3, and caspase-8. The role of Fas as a regulator of chrysotile-induced apoptosis in BEAS-2B cells was tested by the prominent increase in and partial blockade of the apoptotic rate with CH11 and ZB4. When CH11 was pretreated, a synergistic effect was apparent on chrysotile-induced apoptosis and the mRNA and protein expression levels of Fas and cleaved caspase-3. Conclusion: Chrysotile causes the apoptosis of BEAS-2B cells via the Fas death receptor pathway. The Fas-mediated apoptosis pathway plays an important role in chrysotile-induced apoptosis of BEAS-2B cells in vitro.
Einsatzerlebnisse, moralische Verletzungen, Werte und psychische Erkrankungen bei Einsatzsoldaten der Bundeswehr
Authors: Hellenthal Andrea , Zimmermann Peter , Willmund Gerd , Lovinusz Alexander , Fiebig Rüdiger , Bozoyan Christiane , Maercker Andreas , Alliger-Horn Christina
Published: September 2017

Hintergrund: Soldaten sind in militärischen Auslandseinsätzen vielfältigen belastenden Erlebnissen ausgesetzt, die zu erhöhten Raten an psychischen Erkrankungen führen. Moralische Verletzungen und Wertorientierungen scheinen in der Pathogenese dieser Erkrankungen eine Rolle zu spielen. Patienten und Methode: 191 Bundeswehrsoldaten erhielten zum Ende eines Einsatzes in Afghanistan eine Skala zu Einsatzerfahrungen (MHAT), die Posttraumatic Stress Diagnostic Scale (PDS), den Patient Health Questionnaire (PHQ-D), die Moral Injury Events Scale sowie den Portrait Values Questionnaire (PVQ). In Regressionsanalysen wurden direkte Assoziationen von Einsatzstressoren und Wertorientierungen mit psychischen Syndromen untersucht. In einer Mediationsanalyse wurden moralische Verletzungen als Mediator zwischen Einsatzerleben und psychischen Erkrankungen betrachtet. Ergebnisse: Der einsatzbezogene Stressor «Konfrontation mit Not, Leid, Gewalt in der Bevölkerung» zeigte einen direkten signifikanten Einfluss auf psychische Erkrankungen. Moralische Verletzungen stellten eine differenziell vermittelnde Variable zwischen dem Stressor «Konfrontation mit Not, Leid, Gewalt in der Bevölkerung» und den psychischen Syndromen «posttraumatische Belastungsstörung» und «Depressivität» einerseits und Alkoholmissbrauch andererseits dar. Keine signifikanten Zusammenhänge ergaben sich zwischen traditionellen Werthaltungen und psychischen Erkrankungen sowie zwischen traditionellen Werthaltungen und moralischen Verletzungen. Schlussfolgerung: Einsatzerlebnisse mit moralischer Dimension scheinen eine besonders starke Rolle in Bezug auf psychische Erkrankungen bei Bundeswehrsoldaten zu spielen. Der Effekt wird über das Konstrukt moralischer Verletzungen vermittelt. Diese Ergebnisse können zur Weiterentwicklung präventiver und therapeutischer Maßnahmen beitragen.
Anti-Inflammatory Nutrition and Successful Ageing in Elderly Individuals: The Multinational MEDIS Study
Authors: Tyrovolas Stefanos , Haro Josep Maria , Foscolou Alexandra , Tyrovola Dimitra , Mariolis Anargiros , Bountziouka Vassiliki , Piscopo Suzanne , Valacchi Giuseppe , Anastasiou Foteini , Gotsis Efthimios , Metallinos George , Papairakleous Natassa , Polychronopoulos Evangelos , Matalas Antonia-Leda , Lionis Christos , Zeimbekis Akis , Tur Josep-Antoni , Sidossis Labros S. , Panagiotakos Demosthenes B. ,   for the MEDIS Study Group
Published: September 2017

Background: The role of diet and inflammation in successful ageing is not transparent, and as such, is still being investigated. The aim of the present work was to evaluate the inflammatory potential of dietary habits in the successful ageing of a random sample of older adults living in the Mediterranean basin and who participated in the MEDIS (MEDiterranean ISlands) study. Methods: During 2005-2016, 3,128 older adults (aged 65-100 years) from 24 Mediterranean islands and the rural Mani region (Peloponnesus) of Greece were enrolled in the study. A multidimensional successful ageing index consisting of 10 components was employed. A validated and reproducible Food Frequency Questionnaire (FFQ) was used to evaluate the dietary habits of the older adults. A nutrition anti-inflammatory (NAI) score based on the participants' specific dietary habits was assessed. Results: Participants with high NAI scores (proinflammatory nutrition) had a higher prevalence of hypercholesterolemia and lower levels of successful ageing. After adjusting for several confounders, the NAI score was associated with successful ageing (-0.03, 95% CI -0.5 to -0.006). Stratified analysis by gender and advanced age revealed heterogeneity in the NAI score, predicting successful ageing. Conclusions: The inflammatory potential of nutrition was reported as an important factor for successful ageing, suggesting that further research is needed on the role of anti- and proinflammatory dietary habits in healthy and successful ageing.
Placental Component and Pregnancy Outcome in Singleton versus Twin Pregnancies Complicated by Preeclampsia
Authors: Weiner Eran , Feldstein Ohad , Schreiber Letizia , Grinstein Ehud , Barber Elad , Dekalo Ann , Bar Jacob , Kovo Michal
Published: September 2017

Objective: To compare placental histopathological lesions and pregnancy outcomes in singleton and twin pregnancies complicated by preeclampsia (PE). Methods: Maternal characteristics, neonatal outcomes, and placental histopathology reports of pregnancies complicated by PE between January 2008 and October 2016 were reviewed. Results were compared between singletons (singleton group) and dichorionic-diamniotic twins (twin group). Placental lesions were classified into maternal and fetal vascular supply lesions. Small for gestational age (SGA) was defined as birth weight ≤10th percentile. Composite adverse neonatal outcome was defined as one or more early neonatal complications. Results: Compared to the twin group (n = 67), the singleton group (n = 275) was characterized by lower maternal age (p = 0.003), higher gestational age (p < 0.001), higher rates of previous PE (p = 0.017), chronic hypertension (p = 0.036), and severe features (p < 0.001). Placentas from the singleton group were characterized by higher rates of maternal vascular malperfusion lesions (p < 0.001) and fetal vascular supply lesions (p = 0.002). Using multivariable regression analysis, composite maternal and fetal vascular malperfusion lesions were independently associated with singletons (aOR = 2.7, 95% CI = 1.2-7.8, p < 0.001, and aOR = 1.2, 95% CI = 1.2-5.6, p = 0.025, respectively). SGA was more common in the singleton group (p = 0.002). Neonatal outcome did not differ between the groups. Conclusion: Placentas from singleton pregnancies complicated by PE were characterized by higher rates of maternal and fetal vascular lesions compared to those from twin pregnancies, suggesting that different mechanisms participate in the development of PE in these two groups.
Performance of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for the Diagnosis of Isolated Mediastinal and Hilar Lymphadenopathy
Authors: Tyan Chung-Chun , Machuca Tiago , Czarnecka Kasia , Ko Hyang Mi , da Cunha Santos Gilda , Boerner Scott L. , Pierre Andrew , Cypel Marcelo , Waddell Tom , Darling Gail , de Perrot Marc , Keshavjee Shaf , Geddie William , Yasufuku Kazuhiro
Published: September 2017

Background: Although many studies have assessed the diagnostic utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the context of a specific disease, few studies have assessed the overall diagnostic yield, sensitivity, and negative predictive value in patients with isolated mediastinal and hilar lymphadenopathy (IMHL). Objective: We evaluated the performance of EBUS-TBNA for diagnosing IMHL in a population with a high prevalence of concurrent or preexisting non-pulmonary malignancy. Methods: A retrospective chart review of patients who underwent EBUS-TBNA from October 2008 to April 2014 was performed to identify patients with IMHL. Patients with known or suspected primary pulmonary malignancy were excluded. When available, EBUS-TBNA results were cross-referenced with further diagnostic investigation or clinical diagnosis based on follow-up. Results: EBUS-TBNA was used to sample 765 lymph nodes from 350 patients. One hundred and fourteen (33.3%) patients had a concurrent or preexisting non-pulmonary malignancy. The overall yield of EBUS-TBNA for specific diagnosis was 300/350 (86%). The diagnostic yield for sarcoidosis, lymphoproliferative disease, metastatic lymphadenopathy from extrathoracic malignancy, and necrotizing granuloma was 123/149 (83%), 27/33 (82%), 20/25 (80%), and 13/19 (68%), respectively. Amongst 50 patients with non-diagnostic EBUS-TBNA, 25 yielded an insufficient sample and another 25 yielded only benign lymphoid material which was not representative of the underlying pathology. Overall, EBUS-TBNA had a sensitivity of 89%, a diagnostic yield of 86%, and a negative predictive value of 79%. Conclusion: For patients with isolated hilar or mediastinal lymphadenopathy and a high background prevalence of concurrent and preexisting non-pulmonary malignancy, EBUS-TBNA is a reliable first-line diagnostic investigation.
Filing Sources after Oral P2Y12 Platelet Inhibitors to the Food and Drug Administration Adverse Event Reporting System (FAERS)
Authors: Serebruany Victor L. , Cherepanov Vasily , Kim Moo Hyun , Litvinov Oleg , Cabrera-Fuentes Hector A. , Marciniak Thomas A.
Published: September 2017

Background: The US Food and Drug Administration Adverse Event Reporting System (FAERS) is a global passive surveillance database that relies on voluntary reporting by health care professionals and consumers as well as required mandatory reporting by pharmaceutical manufacturers. However, the initial filers and comparative patterns for oral P2Y12 platelet inhibitor reporting are unknown. We assessed who generated original FAERS reports for clopidogrel, prasugrel, and ticagrelor in 2015. Methods: From the FAERS database we extracted and examined adverse event cases coreported with oral P2Y12 platelet inhibitors. All adverse event filing originating sources were dichotomized into consumers, lawyers, pharmacists, physicians, other health care professionals, and unknown. Results: Overall, 2015 annual adverse events were more commonly coreported with clopidogrel (n = 13,234) with known source filers (n = 12,818, or 96.9%) than with prasugrel (2,896; 98.9% out of 2,927 cases) or ticagrelor (2,163, or 82.3%, out of 2,627 cases, respectively). Overall, most adverse events were filed by consumers (8,336, or 44.4%), followed by physicians (5,290, or 28.2%), other health care professionals (2,997, or 16.0%), pharmacists (1,125, or 6.0%), and finally by lawyers (129, or 0.7%). The origin of 811 (4.7%) initial reports remains unknown. The adverse event filing sources differ among drugs. While adverse events coreported with clopidogrel and prasugrel were commonly originated by patients (40.4 and 84.3%, respectively), most frequently ticagrelor reports (42.5%) were filed by physicians. Conclusion: The reporting quality and initial sources differ among oral P2Y12 platelet inhibitors in FAERS. The ticagrelor surveillance in 2015 was inadequate when compared to clopidogrel and prasugrel. Patients filed most adverse events for clopidogrel and prasugrel, while physicians originated most ticagrelor complaints. These differences justify stricter compliance control for ticagrelor manufacturers and may be attributed to the confusion of treating physicians with unexpected fatal, cardiac, and thrombotic adverse events linked to ticagrelor.
New Insights into the Natural History of Congenital Zika Virus Syndrome
Authors: Lovagnini Frutos María Guadalupe , Ochoa José Héctor , Barbás María Gabriela , Lucchini Héctor Dante , Moya Martín , Malinger Gustavo
Published: September 2017

We describe the prenatal evolution of the brain findings in a patient with proved Zika virus infection at 8 weeks of gestation showing the very early appearance at 17 weeks of ventriculomegaly and signs of brain parenchymal involvement without microcephaly. The involvement of the brain becomes more evident at 22 and 27 weeks with the apparition of calcifications and microcephaly. Interestingly, the postnatal findings failed to show significant worsening when compared to these prenatal findings.
Two-Year Outcomes of a Treat-and-Extend Regimen Using Intravitreal Aflibercept Injections for Typical Age-Related Macular Degeneration
Authors: Ito Arisa , Matsumoto Hidetaka , Morimoto Masahiro , Mimura Kensuke , Akiyama Hideo
Published: September 2017

Purpose: The aim of this study was to evaluate the efficacy of a treat-and-extend (TAE) regimen using intravitreal injection of aflibercept (IVA) for typical age-related macular degeneration (tAMD). Methods: We retrospectively studied 61 treatment-naïve eyes with tAMD. Best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), number of injections, and complications during 2 years were evaluated. Results: BCVA significantly improved by on average 0.13 logMAR units, and CMT and CCT significantly decreased after 2 years. The number of injections was on average 13.6. In the second year, eyes with classic choroidal neovascularization (CNV) needed significantly fewer treatments than eyes with occult CNV. Fourteen eyes, which developed subfoveal fibrosis, showed significantly poorer BCVA after 2 years. Subfoveal fibrosis was significantly common in classic CNV. Conclusion: A TAE regimen using IVA for tAMD might be effective for improving BCVA and exudative changes. The exudation may be suppressed with fewer treatments in classic CNV compared to occult CNV.
Angelman Syndrome due to a Maternally Inherited Intragenic Deletion Encompassing Exons 7 and 8 of the UBE3A Gene
Authors: Ververi Athina , Islam Lily , Bewes Beverley , Busby Louise , Sullivan Caroline , Canham Natalie
Published: September 2017

Angelman syndrome (AS) is characterised by developmental delay, lack of speech, seizures, a characteristic behavioural profile with a happy demeanour, microcephaly, and ataxia. More than two-thirds of cases are due to an approximately 5-Mb interstitial deletion of the imprinted region 15q11.2q13, which is usually de novo. The rest are associated with point mutations in the UBE3A gene, imprinting defects, and paternal uniparental disomy. Small intragenic UBE3A deletions have rarely been described. They are usually maternally inherited, increasing the recurrence risk to 50%, and may be missed by conventional testing (methylation studies and UBE3A gene sequencing). We describe a boy with AS due to an 11.7-kb intragenic deletion. The deletion was identified by array-CGH and was subsequently detected in his affected first cousin and unaffected maternal grandfather, mother, and aunt, confirming the silencing of the paternal allele. The patient had developmental delay, speech impairment, a happy demeanour, microcephaly, and an abnormal EEG, but no seizures by the age of 4 years. Delineation of the underlying genetic mechanism is of utmost importance for reasons of genetic counselling, as well as appropriate management and prognosis. Alternative techniques, such as array-CGH and MLPA, are necessary when conventional testing for AS has failed to identify the underlying genetic mechanism.