bluuebunny/crossref_metadata_2025 huggingface dataset:
Dark solitons for a variable-coefficient higher-order nonlinear Schrödinger equation in the inhomogeneous optical fiber
Authors: Sun Yan , Tian Bo , Wu Xiao-Yu , Liu Lei , Yuan Yu-Qiang
Published: May 2017

Under investigation in this paper is a variable-coefficient higher-order nonlinear Schrödinger equation, which has certain applications in the inhomogeneous optical fiber communication. Through the Hirota method, bilinear forms, dark one- and two-soliton solutions for such an equation are obtained. We graphically study the solitons with [Formula: see text], [Formula: see text] and [Formula: see text], which represent the variable coefficients of the group-velocity dispersion, third-order dispersion and fourth-order dispersion, respectively. With the different choices of the variable coefficients, we obtain the parabolic, periodic and V-shaped dark solitons. Head-on and overtaking collisions are depicted via the dark two soliton solutions. Velocities of the dark solitons are linearly related to [Formula: see text], [Formula: see text] and [Formula: see text], respectively, while the amplitudes of the dark solitons are not related to such variable coefficients.
Quantum Key Recycling with 8-state encoding (The Quantum One-Time Pad is more interesting than we thought)
Authors: Škorić Boris , de Vries Manon
Published: May 2017

Perfect encryption of quantum states using the Quantum One-Time Pad (QOTP) requires two classical key bits per qubit. Almost-perfect encryption, with information-theoretic security, requires only slightly more than 1. We slightly improve lower bounds on the key length. We show that key length [Formula: see text] suffices to encrypt [Formula: see text] qubits in such a way that the cipherstate’s [Formula: see text]-distance from uniformity is upperbounded by [Formula: see text]. For a stricter security definition involving the [Formula: see text]-norm, we prove sufficient key length [Formula: see text], where [Formula: see text] is a small probability of failure. Our proof uses Pauli operators, whereas previous results on the [Formula: see text]-norm needed Haar measure sampling. We show how to QOTP-encrypt classical plaintext in a nontrivial way: we encode a plaintext bit as the vector [Formula: see text] on the Bloch sphere. Applying the Pauli encryption operators results in eight possible cipherstates which are equally spread out on the Bloch sphere. This encoding, especially when combined with the half-keylength option of QOTP, has advantages over 4-state and 6-state encoding in applications such as Quantum Key Recycling (QKR) and Unclonable Encryption (UE). We propose a key recycling scheme that is more efficient and can tolerate more noise than a recent scheme by Fehr and Salvail. For 8-state QOTP encryption with pseudorandom keys, we do a statistical analysis of the cipherstate eigenvalues. We present numerics up to nine qubits.
Theory of a Time Domain Boundary Element Development for the Dynamic Analysis of Coupled Multiphase Porous Media
Authors: Maghoul Pooneh , Gatmiri Behrouz
Published: May 2017

This paper presents an advanced formulation of the time-domain two-dimensional (2D) boundary element method (BEM) for an elastic, homogeneous unsaturated soil subjected to dynamic loadings. Unlike the usual time-domain BEM, the present formulation applies a convolution quadrature which requires only the Laplace-domain instead of the time-domain fundamental solutions. The coupled equations governing the dynamic behavior of unsaturated soils ignoring contributions of the inertia effects of the fluids (water and air) are derived based on the poromechanics theory within the framework of a suction-based mathematical model. In this formulation, the solid skeleton displacements [Formula: see text], water pressure [Formula: see text] and air pressure [Formula: see text] are presumed to be independent variables. The fundamental solutions in Laplace transformed-domain for such a dynamic [Formula: see text] theory have been obtained previously by authors. Then, the BE formulation in time is derived after regularization by partial integrations and time and spatial discretizations. Thereafter, the BE formulation is implemented in a 2D boundary element code (PORO-BEM) for the numerical solution. To verify the accuracy of this implementation, the displacement response obtained by the boundary element formulation is verified by comparison with the elastodynamics problem.
The Use of SPARK in a Complex Spacecraft
Authors: Brandon Carl , Chapin Peter
Published: May 2017

Building on our previous experience of constructing and operating a successful Earth orbiting satellite, in which the software was primarily written in SPARK, we now describe our new project: writing the flight software for a complex, lunar orbiting spacecraft called Lunar IceCube (LIC). We continue with our use of SPARK for this new mission, extending and enhancing the techniques used in our previous mission. Although this work is ongoing, we have found SPARK to be a manageable technology for us, even in our student-centered development environment.
When Does Globalization Help the Poor?
Authors: Rudra Nita , Tobin Jennifer
Published: May 2017

What is the relationship between globalization and poverty? Developing economies have long turned to international trade and finance as a solution for development, yet 35% of the world's population still lives below the international poverty line. Economists and political scientists explore this relationship but are far from reaching a conclusion. We review this literature and argue that to understand the relationship between globalization and poverty, we must ultimately understand the political motivations underlying the policies directed at the poorest. Specifically, we contend that scholars need to identify the ideological positions of developing country governments, an identification that moves beyond the conventional left–right divide that prevails in developed nations. We provide theoretical guidance on how scholars might begin to operationalize ideology on a global basis and why this is necessary to evaluate the globalization–poverty linkage. Further, we provide some preliminary quantitative and qualitative tests of our argument. Ultimately, scholars from both disciplines must begin to evaluate government commitment to pro-poor redistribution (rather than the extent to which policy is beholden to vested elite interest groups) in order to assess the relationship between trade and poverty.
The Electoral Consequences of Corruption
Authors: De Vries Catherine E. , Solaz Hector
Published: May 2017

Democratic elections have been assumed to play a crucial role in curbing corruption among public officials. Voters, due to their general distaste for corruption, are expected to sanction politicians who misuse public office for private gains. Yet, empirical evidence to date is mixed, and it often suggests that the electoral punishment of corruption is rather mild. Recently, political scientists have made great strides in understanding why corruption might be tolerated by voters. In this review, we identify three key stages—information acquisition, blame attribution, and behavioral response—that underlie a retrospective vote based on corruption. A breakdown of one or more of these stages may lead to a lack of electoral punishment of corruption. We also outline some areas for future progress, particularly highlighting the importance of voter coordination for understanding the extent to which corruption is punished at the ballot box.
Combining new tools to assess renal function and morphology: a holistic approach to study the effects of aging and a congenital nephron deficit
Authors: Geraci Stefania , Chacon-Caldera Jorge , Cullen-McEwen Luise , Schad Lothar R. , Sticht Carsten , Puelles Victor G. , Bertram John F. , Gretz Norbert
Published: May 2017

Recently, new methods for assessing renal function in conscious mice (transcutaneous assessment) and for counting and sizing all glomeruli in whole kidneys (MRI) have been described. In the present study, these methods were used to assess renal structure and function in aging mice, and in mice born with a congenital low-nephron endowment. Age-related nephron loss was analyzed in adult C57BL/6 mice (10–50 wk of age), and congenital nephron deficit was assessed in glial cell line-derived neurotrophic factor heterozygous (GDNF HET)-null mutant mice. Renal function was measured through the transcutaneous quantitation of fluorescein isothiocyanate-sinistrin half-life ( t1/2) in conscious mice. MRI was used to image, count, and size cationic-ferritin labeled glomeruli in whole kidneys ex vivo. Design-based stereology was used to validate the MRI measurements of glomerular number and mean volume. In adult C57BL/6 mice, older age was associated with fewer and larger glomeruli, and a rightward shift in the glomerular size distribution. These changes coincided with a decrease in renal function. GNDF HET mice had a congenital nephron deficit that was associated with glomerular hypertrophy and exacerbated by aging. These findings suggest that glomerular hypertrophy and hyperfiltration are compensatory processes that can occur in conjunction with both age-related nephron loss and congenital nephron deficiency. The combination of measurement of renal function in conscious animals and quantitation of glomerular number, volume, and volume distribution provides a powerful new tool for investigating aspects of renal aging and functional changes.
Kinematic Design of a Seven‐Bar Linkage with Optimized Centrodes for Pure‐Rolling Cutting
Authors: Liu Biao , Ma Yali , Wang Delun , Bai Shaoping , Li Yangyang , Li Kangkang
Published: May 2017

A novel method for designing a seven‐bar linkage based on the optimization of centrodes is presented in this paper. The proposed method is applied to the design of a pure‐rolling cutting mechanism, wherein close interrelation between the contacting lines and centrodes of two pure‐rolling bodies is formulated and the genetic optimization algorithm is adopted for the dimensional synthesis of the mechanism. The optimization is conducted to minimize the error between mechanism centrodes and the expected trajectories, subject to the design requirements of the opening distance, the maximum amount of overlap error, and peak value of shearing force. An optimal solution is obtained and the analysis results show that the horizontal slipping and standard deviation of the lowest moving points of the upper shear blade have been reduced by 78.0% and 80.1% and the peak value of shear stress decreases by 29%, which indicate better cutting performance and long service life.
Chemical Composition and Hypotensive Effect of Campomanesia xanthocarpa
Authors: Sant’Anna Liane Santariano , Merlugo Liara , Ehle Catrine Santos , Limberger Jessica , Fernandes Maquelen Blanco , Santos Marí Castro , Mendez Andreas Sebastian Loureiro , Paula Fávero Reisdorfer , Moreira Cleci Menezes
Published: May 2017

Campomanesia xanthocarpa is known in Brazil as Guabiroba and is popularly used for various diseases, such as inflammatory, renal, and digestive diseases and dyslipidemia. The aim of the study was to analyze the chemical composition and investigate the effects of aqueous extract of C. xanthocarpa on the blood pressure of normotensive rats, analyzing the possible action mechanism using experimental and in silico procedures. The extract was evaluated for total phenolic compounds and total flavonoid content. The chemical components were determined by HPLC analyses. Systolic and diastolic blood pressure and heart rate were measured with extract and drugs administration. The leaves of C. xanthocarpa presented the relevant content of phenolics and flavonoids, and we suggested the presence of chlorogenic acid, gallic acid, quercetin, and theobromine. The acute administration of aqueous extract of C. xanthocarpa has a dose‐dependent hypotensive effect in normotensive rats, suggesting that the action mechanism may be mediated through the renin‐angiotensin system by AT1 receptor blockade and sympathetic autonomic response. Docking studies showed models that indicated an interaction between chlorogenic acid and quercetin with the AT1 receptor (AT1R) active site. The findings of these docking studies suggest the potential of C. xanthocarpa constituents for use as preventive agents for blood pressure.
Physicochemical and Luminescent Properties of Copolymers Composed of Three Monomers: Polythiophenes Based on 3-Hexylthiophene and 3,4-Ethylenedioxythiophene
Authors: Ramírez-Gómez Marco Antonio , Guzmán-Rabadán Karla Karina , González-Juárez Edgar , Güizado-Rodríguez Marisol , Ramos-Ortiz Gabriel , Alba-Rosales Jorge Enrique , Panzo-Medrano Huehueteotl , Barba Victor , Rodríguez Mario , Maldonado José Luis , Basurto-Pensado Miguel Ángel
Published: May 2017

The chemical synthesis and physicochemical and luminescent characterizations of polymers based on 3-HT, EDOT, and 2,2′-(9,9-dioctyl-9H-fluorene-2,7-diyl) bisthiophene (fluorene) or (E)-2-(ethyl(4-((4-nitrophenyl)diazenyl)phenyl)amino)ethyl 2-(thiophen-3-yl)acetate (TDR1) are reported. The fluorene unit was bound to the conjugate backbone, while the Disperse Red 1 (DR1) chromophore was present as a pendant group. Characterizations by 1H NMR, FT-IR, DSC-TGA, GPC, UV-vis, cyclic voltammetry, fluorescence quantum yield, excited state lifetime, and two-photon absorption cross-section were carried out. These polymers combined the physicochemical properties of EDOT and 3-HT, such as high electron density, high charge mobility, low oxidation potential, and good processability. The optical properties of these copolymers were highly dependent on the presence of EDOT, the molecular weight, and the regioregularity rather than the presence of the third component (fluorene or TDR1). The good nonlinear absorption and luminescent properties exhibited by these copolymers were exploited to fabricate nanoparticles used as fluorescent tags for the imaging of microstructures.
Schisandrae Fructus Reduces Symptoms of 4‐Vinylcyclohexene Diepoxide‐Induced Ovarian Failure in Mice
Authors: Shin Dasom , Ha Jinhee , Hong Seong Bin , Kang Geun-Hyung , Hwang Deok-Sang , Bae Hyunsu
Published: May 2017

Menopause is associated with a decrease in the level of sex hormones such as ovarian estradiol and progesterone and can cause various symptoms such as depression, hot flash, fatigue, heart palpitations, and headache. Furthermore, there is a risk of developing complications such as osteoporosis, cardiovascular diseases, Alzheimer’s disease, and ovarian cancer. Schisandrae Fructus (SF) is widely used in Korean medicine as a cure for such complications. This study was conducted to evaluate the therapeutic effects of SF against menopause symptoms associated with follicle depletion caused by the industrial chemical 4‐vinylcyclohexene diepoxide (VCD) in mice. VCD directly targets the preantral follicles. Mice were injected with VCD (160 mg/kg intraperitoneally) daily for 15 days and then with SF dosage 3 times/week for six weeks. To evaluate the effects of SF, body weight, tail skin temperature, uterine weight, lipid profile, and osteocalcin levels were measured. A decrease in body weight and tail skin temperature and an increase in uterine weight were observed upon SF treatment. Moreover, SF treatment significantly decreased total cholesterol, triglyceride, osteocalcin, and low‐density lipoprotein levels and low‐density/high‐density lipoprotein ratio. These results suggest the potential use of SF in the treatment of menopausal symptoms in women.
Experimental Investigation of Isothermal Section of the B-Cr-Fe Phase Diagram at 1353 K
Authors: Homolová Viera , Čiripová Lucia
Published: May 2017

The isothermal section of the B-Cr-Fe ternary system was studied experimentally at 1353 K. X-ray diffraction and scanning electron microscopy equipped with EDX analyzer were used for determination of phase equilibria and composition of the coexisting phases in the B-Cr-Fe model alloys after long-term annealing (1500–2205 h). Two iron borides FeB and Fe2B, six chromium borides Cr2B, Cr5B3, CrB, Cr3B4, CrB2, and CrB4 and also iron and chromium solid solutions (α(Fe,Cr), α(Cr,Fe), γ(Fe,Cr)) and β-rhombohedral B were observed in the alloys. High solubilities of the third element in binary borides and no ternary phase were found. Based on the experimental results, isothermal section of the B-Cr-Fe system at 1353 K was determined.
Lightweight Data Aggregation Scheme against Internal Attackers in Smart Grid Using Elliptic Curve Cryptography
Authors: He Debiao , Zeadally Sherali , Wang Huaqun , Liu Qin
Published: May 2017

Recent advances of Internet and microelectronics technologies have led to the concept of smart grid which has been a widespread concern for industry, governments, and academia. The openness of communications in the smart grid environment makes the system vulnerable to different types of attacks. The implementation of secure communication and the protection of consumers’ privacy have become challenging issues. The data aggregation scheme is an important technique for preserving consumers’ privacy because it can stop the leakage of a specific consumer’s data. To satisfy the security requirements of practical applications, a lot of data aggregation schemes were presented over the last several years. However, most of them suffer from security weaknesses or have poor performances. To reduce computation cost and achieve better security, we construct a lightweight data aggregation scheme against internal attackers in the smart grid environment using Elliptic Curve Cryptography (ECC). Security analysis of our proposed approach shows that it is provably secure and can provide confidentiality, authentication, and integrity. Performance analysis of the proposed scheme demonstrates that both computation and communication costs of the proposed scheme are much lower than the three previous schemes. As a result of these aforementioned benefits, the proposed lightweight data aggregation scheme is more practical for deployment in the smart grid environment.
An Invocation Cost Optimization Method for Web Services in Cloud Environment
Authors: Qi Lianyong , Yu Jiguo , Zhou Zhili
Published: May 2017

The advent of cloud computing technology has enabled users to invoke various web services in a “pay-as-you-go” manner. However, due to the flexible pricing model of web services in cloud environment, a cloud user’ service invocation cost may be influenced by many factors (e.g., service invocation time), which brings a great challenge for cloud users’ cost-effective web service invocation. In view of this challenge, in this paper, we first investigate the multiple factors that influence the invocation cost of a cloud service, for example, user’s job size, service invocation time, and service quality level; and afterwards, a novel Cloud Service Cost Optimization Method named CS-COM is put forward, by considering the above multiple impact factors. Finally, a set of experiments are designed, deployed, and tested to validate the feasibility of our proposal in terms of cost optimization. The experiment results show that our proposed CS-COM method outperforms other related methods.
Astragalus Extract Mixture HT042 Improves Bone Growth, Mass, and Microarchitecture in Prepubertal Female Rats: A Microcomputed Tomographic Study
Authors: Song Jungbin , Lee Sung Hyun , Lee Donghun , Kim Hocheol
Published: May 2017

Astragalus extract mixture HT042 is a standardized multiherbal mixture comprising Astragalus membranaceus, Eleutherococcus senticosus, and Phlomis umbrosa, which has proven to promote children’s height growth. The aim of this study was to investigate the effects of HT042 on longitudinal bone growth, bone mass, and bone microstructure in growing rats using a high‐resolution microcomputed tomography system. Four‐week‐old female rats were fed an HT042‐containing diet for 2 weeks. Tibial length was measured at baseline and weekly in vivo. At the end of the study, volumetric bone mineral density (vBMD) and microarchitectural parameters were estimated in the trabecular and cortical bone of the tibia. Tibial length gain was significantly increased by HT042 compared to that reported with the control diet. In the proximal tibial metaphysis, HT042‐treated rats had significantly higher trabecular vBMD, bone volume fraction, and trabecular number and lower trabecular separation, trabecular pattern factor, and structure model index values than control rats did. Total cross‐sectional area and bone area of the cortical bone in the tibial diaphysis also increased. These findings suggest that HT042 increases longitudinal bone growth rate, improves trabecular bone mass, and enhances the microarchitecture of trabecular and cortical bone during growth.
Applied Gaussian Process in Optimizing Unburned Carbon Content in Fly Ash for Boiler Combustion
Authors: Wang Chunlin , Liu Yang , Everson Richard M. , Rahat A. A. M. , Zheng Song
Published: May 2017

Recently, Gaussian Process (GP) has attracted generous attention from industry. This article focuses on the application of coal fired boiler combustion and uses GP to design a strategy for reducing Unburned Carbon Content in Fly Ash (UCC‐FA) which is the most important indicator of boiler combustion efficiency. With getting rid of the complicated physical mechanisms, building a data‐driven model as GP is an effective way for the proposed issue. Firstly, GP is used to model the relationship between the UCC‐FA and boiler combustion operation parameters. The hyperparameters of GP model are optimized via Genetic Algorithm (GA). Then, served as the objective of another GA framework, the predicted UCC‐FA from GP model is utilized in searching the optimal operation plan for the boiler combustion. Based on 670 sets of real data from a high capacity tangentially fired boiler, two GP models with 21 and 13 inputs, respectively, are developed. In the experimental results, the model with 21 inputs provides better prediction performance than that of the other. Choosing the results from 21‐input model, the UCC‐FA decreases from 2.7% to 1.7% via optimizing some of the operational parameters, which is a reasonable achievement for the boiler combustion.
Locally Advanced Thyroglossal Duct Cyst Carcinoma Presenting as a Neck Mass
Authors: Tachamo Niranjan , Le Brian , Driben Jeffrey , Magaji Vasudev
Published: May 2017

Thyroglossal duct cyst carcinoma is rare and occurs in just 1% of cases with thyroglossal duct cysts. It is not always possible to distinguish a thyroglossal cyst harboring malignancy from its benign counterparts unless biopsied, thus posing the dilemma. Currently there is no clear consensus on the optimal management of thyroglossal duct cyst carcinoma. Here we present the case of a 69-year-old female who presented with a midline neck mass and dysphagia and was found to have papillary thyroid cancer in the biopsy specimen of the neck mass. She underwent excision of the mass and the thyroglossal duct cyst along with total thyroidectomy; however, the thyroidectomy specimen showed no malignancy. Her lymph node mapping was negative and she is awaiting radioactive iodine treatment.
The Efficacy of Acupuncture for the Treatment of Cervical Vertigo: A Systematic Review and Meta‐Analysis
Authors: Hou Zhuanzhuan , Xu Shibing , Li Qinglin , Cai Libing , Wu Weigang , Yu Huida , Chen Huade
Published: May 2017

Objective. This study aims to evaluate the efficacy and safety of acupuncture for the treatment of cervical vertigo (CV). Methods. Randomized controlled trials (RCTs) regarding effectiveness of acupuncture for treating CV were searched in 7 comprehensive databases prior to April 2016. The data analysis was performed by using RevMan version 5.3. Results. A total of 10 studies with 914 participants were included. Results showed that acupuncture was more effective than conventional medicine therapy (CMT) in effectiveness, improvement rate of vertigo and headache, and increased average blood flow velocity of vertebral‐basilar artery. In the subgroup analysis, the results did not change in different acupuncture methods and drug categories substantially. Sensitivity analysis demonstrated that the results of this meta‐analysis were stable. Meanwhile, the long‐term safety of acupuncture for CV still remains uncertain. GRADE analysis indicated that the quality of evidence for all outcomes was from very low to low which limited the value of the meta‐analysis. Conclusion. Based on the systematic review, acupuncture appeared to be a promising therapeutic approach for CV based on low or very low quality of evidence. However, large‐scale and high‐quality trials are required to provide stronger evidence for the conclusion.
Putting Continuous Metaheuristics to Work in Binary Search Spaces
Authors: Crawford Broderick , Soto Ricardo , Astorga Gino , García José , Castro Carlos , Paredes Fernando
Published: May 2017

In the real world, there are a number of optimization problems whose search space is restricted to take binary values; however, there are many continuous metaheuristics with good results in continuous search spaces. These algorithms must be adapted to solve binary problems. This paper surveys articles focused on the binarization of metaheuristics designed for continuous optimization.
Phase Noise Suppression Algorithm Based on Modified LLR Metric in SC-FDMA System
Authors: Xu Zijie , Ren Guangliang
Published: May 2017

In single-carrier frequency-division multiple-access (SC-FDMA) receivers in the long-term evolution uplink, phase noise is one of the major radio-frequency front-end impairments that degrade system performance. To address this issue, we propose a new log-likelihood ratio (LLR) computation algorithm. A signal model with residual phase noise is considered in the algorithm. Based on this model, we derive a closed-form expression of the likelihood function of the received symbol and calculate more accurate LLR information. Thus the accuracy of the decoder is increased and the performance of the SC-FDMA system is improved. Simulation results show that our proposed algorithm achieves superior bit error rate (BER) performance compared with the existing LLR calculation algorithms in high-order quadrature amplitude modulations (QAM).
TWIST1-WDR5-Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis
Authors: Malek Reem , Gajula Rajendra P. , Williams Russell D. , Nghiem Belinda , Simons Brian W. , Nugent Katriana , Wang Hailun , Taparra Kekoa , Lemtiri-Chlieh Ghali , Yoon Arum R. , True Lawrence , An Steven S. , DeWeese Theodore L. , Ross Ashley E. , Schaeffer Edward M. , Pienta Kenneth J. , Hurley Paula J. , Morrissey Colm , Tran Phuoc T.
Published: May 2017

TWIST1 is a transcription factor critical for development that can promote prostate cancer metastasis. During embryonic development, TWIST1 and HOXA9 are coexpressed in mouse prostate and then silenced postnatally. Here we report that TWIST1 and HOXA9 coexpression are reactivated in mouse and human primary prostate tumors and are further enriched in human metastases, correlating with survival. TWIST1 formed a complex with WDR5 and the lncRNA Hottip/HOTTIP, members of the MLL/COMPASS–like H3K4 methylases, which regulate chromatin in the Hox/HOX cluster during development. TWIST1 overexpression led to coenrichment of TWIST1 and WDR5 as well as increased H3K4me3 chromatin at the Hoxa9/HOXA9 promoter, which was dependent on WDR5. Expression of WDR5 and Hottip/HOTTIP was also required for TWIST1-induced upregulation of HOXA9 and aggressive cellular phenotypes such as invasion and migration. Pharmacologic inhibition of HOXA9 prevented TWIST1-induced aggressive prostate cancer cellular phenotypes in vitro and metastasis in vivo. This study demonstrates a novel mechanism by which TWIST1 regulates chromatin and gene expression by cooperating with the COMPASS-like complex to increase H3K4 trimethylation at target gene promoters. Our findings highlight a TWIST1–HOXA9 embryonic prostate developmental program that is reactivated during prostate cancer metastasis and is therapeutically targetable. Cancer Res; 77(12); 3181–93. ©2017 AACR.
Genome-wide DNA Methylation Analysis Reveals GABBR2 as a Novel Epigenetic Target for EGFR 19 Deletion Lung Adenocarcinoma with Induction Erlotinib Treatment
Authors: Niu Xiaomin , Liu Fatao , Zhou Yi , Zhou Zhen , Zhou Daizhan , Wang Ting , Li Ziming , Ye Xiangyun , Yu Yongfeng , Weng Xiaoling , Zhang Hong , Ye Junyi , Liao Meilin , Liu Yun , Chen Zhiwei , Lu Shun
Published: May 2017

Purpose: The past decade has witnessed the rapid development of personalized targeted therapies in lung cancer. It is still unclear whether epigenetic changes are involved in the response to tyrosine kinase inhibitor (TKI) treatment in epidermal growth factor receptor (EGFR)-mutated lung cancer.

Experimental Design: Methyl-sensitive cut counting sequencing (MSCC) was applied to investigate the methylation changes in paired tissues before and after erlotinib treatment for 42 days with partial response (PR) from stage IIIa (N2) lung adenocarcinoma patients (N = 2) with EGFR 19 deletion. The Sequenom EpiTYPER assay was used to validate the changed methylated candidate genes. Up- or downregulation of the candidate gene was performed to elucidate the potential mechanism in the regulation of erlotinib treatment response.

Results: Sixty aberrant methylated genes were screened using MSCC sequencing. Two aberrant methylated genes, CBFA2T3 and GABBR2, were clearly validated. A same differential methylated region (DMR) between exon 2 and exon 3 of GABBR2 gene was confirmed consistently in both patients. GABBR2 was significantly downregulated in EGFR 19 deletion cells, HCC4006 and HCC827, but remained conserved in EGFR wild-type A549 cells after erlotinib treatment. Upregulation of GABBR2 expression significantly rescued erlotinib-induced apoptosis in HCC827 cells. GABBR2 was significantly downregulated, along with the reduction of S6, p-p70 S6, and p-ERK1/2, demonstrating that GABBR2 may play an important role in EGFR signaling through the ERK1/2 pathway.

Conclusions: We demonstrated that GABBR2 gene might be a novel potential epigenetic treatment target with induction erlotinib treatment for stage IIIa (N2) EGFR 19 deletion lung adenocarcinoma. Clin Cancer Res; 23(17); 5003–14. ©2017 AACR.
High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer
Authors: Sokolowska-Wedzina Aleksandra , Chodaczek Grzegorz , Chudzian Julia , Borek Aleksandra , Zakrzewska Malgorzata , Otlewski Jacek
Published: May 2017

Targeted delivery of anticancer drugs using antibodies specific for tumor-associated antigens represents one of the most important approaches in current immuno-oncology research. Fibroblast growth factor receptor 1 (FGFR1) has been demonstrated to be a high-frequency targetable oncogene specific for smoking-associated lung cancers, present in over 20% of lung squamous cell carcinoma cases. This report describes the generation of a potent, fully human antibody fragment in scFv-Fc format efficiently targeting FGFR1. Antibody phage display was used to select high-affinity scFv antibody fragments against the extracellular domain of FGFR1(IIIc). Enzyme immunoassay (ELISA) and surface plasmon resonance (SPR) analysis were used for antibody screening and characterization. The best binder (named D2) was cloned to diabody and Fc fusion formats. All D2 antibodies demonstrated high affinity for FGFR1 with dissociation constants of 18 nmol/L (scFvD2), 0.82 nmol/L (scFvD2 diabody), and 0.59 nmol/L (scFvD2-Fc). scFvD2 was found to be exquisitely selective for FGFR1 versus other FGFR family members and bound FGFR1 even in the presence of its natural ligand FGF2, as shown by competitive analysis. Confocal microscopy revealed that scFvD2-Fc was specifically and rapidly internalized by a panel of cell lines overexpressing FGFR1. Finally, it was demonstrated that scFvD2-Fc mediated specific delivery of a cytotoxic payload into lung cancer cells harboring oncogenic FGFR1 gene amplifications.

Implications: This study reports a highly specific internalizing antibody fragment that can serve as a therapeutic targeting agent for efficient delivery of cytotoxic drugs into FGFR1-positive lung cancer cells. Mol Cancer Res; 15(8); 1040–50. ©2017 AACR.
Fusobacterium Nucleatum Subspecies Animalis Influences Proinflammatory Cytokine Expression and Monocyte Activation in Human Colorectal Tumors
Authors: Ye Xiangcang , Wang Rui , Bhattacharya Rajat , Boulbes Delphine R. , Fan Fan , Xia Ling , Adoni Harish , Ajami Nadim J. , Wong Matthew C. , Smith Daniel P. , Petrosino Joseph F. , Venable Susan , Qiao Wei , Baladandayuthapani Veera , Maru Dipen , Ellis Lee M.
Published: May 2017

Chronic infection and associated inflammation have long been suspected to promote human carcinogenesis. Recently, certain gut bacteria, including some in the Fusobacterium genus, have been implicated in playing a role in human colorectal cancer development. However, the Fusobacterium species and subspecies involved and their oncogenic mechanisms remain to be determined. We sought to identify the specific Fusobacterium spp. and ssp. in clinical colorectal cancer specimens by targeted sequencing of Fusobacterium 16S ribosomal RNA gene. Five Fusobacterium spp. were identified in clinical colorectal cancer specimens. Additional analyses confirmed that Fusobacterium nucleatum ssp. animalis was the most prevalent F. nucleatum subspecies in human colorectal cancers. We also assessed inflammatory cytokines in colorectal cancer specimens using immunoassays and found that expression of the cytokines IL17A and TNFα was markedly increased but IL21 decreased in the colorectal tumors. Furthermore, the chemokine (C-C motif) ligand 20 was differentially expressed in colorectal tumors at all stages. In in vitro co-culture assays, F. nucleatum ssp. animalis induced CCL20 protein expression in colorectal cancer cells and monocytes. It also stimulated the monocyte/macrophage activation and migration. Our observations suggested that infection with F. nucleatum ssp. animalis in colorectal tissue could induce inflammatory response and promote colorectal cancer development. Further studies are warranted to determine if F. nucleatum ssp. animalis could be a novel target for colorectal cancer prevention and treatment. Cancer Prev Res; 10(7); 398–409. ©2017 AACR.
A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice
Authors: Foote Jeremy B. , Kok Marleen , Leatherman James M. , Armstrong Todd D. , Marcinkowski Bridget C. , Ojalvo Laureen S. , Kanne David B. , Jaffee Elizabeth M. , Dubensky Thomas W. , Emens Leisha A.
Published: May 2017

Stimulator of interferon genes (STING) signaling induces IFNβ production by intratumoral dendritic cells (DC), driving T-cell priming and recruitment into the tumor microenvironment (TME). We examined to what extent preexisting antigen-specific tolerance influenced the efficacy of in situ delivery of a potent STING-activating cyclic dinucleotide (CDN), ADU S-100, against established HER-2+ breast tumors. ADU S-100 induced HER-2–specific CD8+ T-cell priming and durable tumor clearance in 100% of nontolerant parental FVB/N mice. In contrast, ADU S-100 did not sufficiently prime HER-2–specific CD8+ T cells in tolerant neu/N mice, resulting in only delayed tumor growth and tumor clearance in 10% of the mice. No differences in IFNβ production, DC priming, or HER-2–specific CD8+ T-cell trafficking were detected between FVB/N and neu/N mice. However, activation and expansion of HER-2–specific CD8+ T cells were defective in neu/N mice. Immune cell infiltrates of untreated tumor-bearing neu/N mice expressed high numbers of PD1 and OX40 receptors on their CD8+ T cells, and PD-L1 was highly expressed on both myeloid and tumor cells. Modulating PD-L1 and OX40 receptor signaling combined with intratumoral ADU S-100 administration enhanced HER-2–specific CD8+ T-cell activity, clearing tumors in 40% of neu/N mice. Thus, intratumoral STING agonists could potently prime tumor antigen–specific CD8+ T-cell responses, and adding PD-L1 blockade and OX40 receptor activation can overcome antigen-enforced immune tolerance to induce tumor regression. Cancer Immunol Res; 5(6); 468–79. ©2017 AACR.
The Peptidoglycan Recognition Proteins PGRPLA and PGRPLB Regulate Anopheles Immunity to Bacteria and Affect Infection by Plasmodium
Authors: Gendrin Mathilde , Turlure Fanny , Rodgers Faye H. , Cohuet Anna , Morlais Isabelle , Christophides George K.
Published: May 2017

Peptidoglycan recognition proteins (PGRPs) form a family of immune regulators that is conserved from insects to mammals. In the malaria vector mosquito Anophelescoluzzii, the peptidoglycan receptor PGRPLC activates the immune-deficiency (Imd) pathway limiting both the microbiota load and Plasmodium infection. Here, we carried out an RNA interference screen to examine the role of all 7 Anopheles PGRPs in infections with Plasmodium berghei and P. falciparum. We show that, in addition to PGRPLC, PGRPLA and PGRPS2/PGRPS3 also participate in antiparasitic defenses, and that PGRPLB promotes mosquito permissiveness to P. falciparum. We also demonstrate that following a mosquito blood feeding, which promotes growth of the gut microbiota, PGRPLA and PGRPLB positively and negatively regulate the activation of the Imd pathway, respectively. Our data demonstrate that PGRPs are important regulators of the mosquito epithelial immunity and vector competence.
A Systematic Review of the Clinimetric Properties of the 6-Item Version of the Hamilton Depression Rating Scale (HAM-D6)
Authors: Timmerby N. , Andersen J.H. , Søndergaard S. , Østergaard S.D. , Bech Per
Published: May 2017

Background: In a study aimed at identifying the items carrying information regarding the global severity of depression, the 6-item Hamilton Depression Rating Scale (HAM-D6) was derived from the original 17-item version of the scale (HAM-D17). Since then, the HAM-D6 has been used in a wide range of clinical studies. We now provide a systematic review of the clinimetric properties of HAM-D6 in comparison with those of HAM-D17 and the Montgomery Asberg Depression Rating Scale (MADRS). Methods: We conducted a systematic search of the literature in PubMed, PsycInfo, and EMBASE databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Studies reporting data on the clinimetric validity of the HAM-D6 and either the HAM-D17 or MADRS in non-psychotic unipolar or bipolar depression were included in the synthesis. Results: The search identified 681 unique records, of which 51 articles met the inclusion criteria. According to the published literature, HAM-D6 has proven to be superior to both HAM-D17 and MADRS in terms of scalability (each item contains unique information regarding syndrome severity), transferability (scalability is constant over time and irrespective of sex, age, and depressive subtypes), and responsiveness (sensitivity to change in severity during treatment). Conclusions: According to the published literature, the clinimetric properties of HAM-D6 are superior to those of both the HAM-D17 and MADRS. Since the validity of HAM-D6 has been demonstrated in both research and clinical practice, using the scale more consistently would facilitate translation of results from one setting to the other.
Evaluation of Clinical Application and Dosimetric Comparison of Treatment Plans of Gamma Knife and CyberKnife in Treating Arteriovenous Malformations
Authors: Kuo Chun-Yuan , Tsai Yi-Chieh , Shiau An-Cheng , Cheng Hao-Wen , Yu Hsiao-Wei , Su Yu-Kai , Tsai Jo-Ting
Published: May 2017

Purpose: To analyze and compare the characteristics of dose distributions for Leksell Gamma Knife Perfexion (LGK-PFX) and CyberKnife (CK) in treating arteriovenous malformations (AVMs). Subjects and Methods: Twenty-four patients with AVMs who received CK radiosurgery at a prescribed dose (PD) of 16-25 Gy in a single fraction were selected. A LGK-PFX treatment plan with the same PD was designed for each patient. Dosimetric values for both systems were compared with respect to the conformity index (CI); selectivity index (SI); gradient index (GI) of 75, 50, and 25% of the PD; heterogeneity index; volume of the brain tissue covered by doses of 10 and 12 Gy; maximum dose delivered to the brainstem; and beam-on time. Results: The CIs of LGK-PFX and CK were 0.744 ± 0.075 and 0.759 ± 0.071 (p = 0.385), respectively. The SIs of LGK-PFX and CK were 0.764 ± 0.081 and 0.780 ± 0.076 (p = 0.424), respectively. The GI75%, GI50%, and GI25% values of LGK-PFX and CK were 1.028 ± 0.123 and 2.439 ± 0.338 (p < 0.001), 3.169 ± 0.265 and 4.972 ± 0.852 (p < 0.001), and 8.650 ± 0.914 and 14.261 ± 2.476 (p < 0.001), respectively. Volumes of the brain tissue covered by 10 Gy and 12 Gy for LGK-PFX and CK (p < 0.001) exhibited a significant difference. Conclusions: LGK-PFX and CK exhibited similar dose conformity. LGK-PFX showed superior normal tissue sparing.
Nuclear Architecture of Mouse Spermatocytes: Chromosome Topology, Heterochromatin, and Nucleolus
Authors: Berrios Soledad
Published: May 2017

The nuclear organization of spermatocytes in meiotic prophase I is primarily determined by the synaptic organization of the bivalents that are bound by their telomeres to the nuclear envelope and described as arc-shaped trajectories through the 3D nuclear space. However, over this basic meiotic organization, a spermatocyte nuclear architecture arises that is based on higher-ordered patterns of spatial associations among chromosomal domains from different bivalents that are conditioned by the individual characteristics of chromosomes and the opportunity for interactions between their domains. Consequently, the nuclear architecture is species-specific and prone to modification by chromosomal rearrangements. This model is valid for the localization of any chromosomal domain in the meiotic prophase nucleus. However, constitutive heterochromatin plays a leading role in shaping nuclear territories. Thus, the nuclear localization of nucleoli depends on the position of NORs in nucleolar bivalents, but the association among nucleolar chromosomes mainly depends on the presence of constitutive heterochromatin that does not affect the expression of the ribosomal genes. Constitutive heterochromatin and nucleoli form complex nuclear territories whose distribution in the nuclear space is nonrandom, supporting the hypothesis regarding the existence of a species-specific nuclear architecture in first meiotic prophase spermatocytes.
Low Plasma Protein Levels at Birth Are Associated with Poor Cardiovascular Adaptation and Serious Adverse Outcome in Infants with Gestational Age <32 Weeks: The ProHémie Study
Authors: Bonsante Francesco , Ramful Duksha , Samperiz Sylvain , Daniel Sandrine , Godeluck Anais , Robillard Pierre-Yves , Jamal-Bey Karim , Gouyon Jean-Bernard , Binquet Christine , Iacobelli Silvia
Published: May 2017

Background: Retrospective studies suggest that early hypoproteinemia has prognostic value for adverse outcome in preemies, but the underlying pathophysiology is unknown. We hypothesized that the prognostic relevance of hypoproteinemia could be related to its association with impaired cardiovascular function and organ perfusion during transition. Objectives: To describe the plasma protein status and the measures of cardiovascular function according to the outcome in infants <32 weeks' gestation. Methods: One hundred and twenty-eight infants were prospectively included from birth to discharge. During the first 24 h of life, we assessed the cardiovascular function and systemic and organ blood flow by Doppler ultrasound, and monitored cerebral and renal regional oxygen saturation (cRSO2, rRSO2) using near-infrared spectroscopy. These measures were analyzed in relationship to hypoproteinemia (total plasma protein level <40 g/L at 12 h of life) and severe adverse outcome (death or survival with severe neurological injury). Results: Hypoproteinemia was associated with a higher risk of a severe adverse outcome after adjustment of confounding variables (adjusted OR = 6.8; 95% CI 1.3-34). Compared to normoproteinemic infants and after adjustment for gestational age, hypoproteinemic ones had more significantly: hypotension (7 vs. 13%, p = 0.03), abnormal capillary refilling time (20 vs. 36%, p < 0.001), abnormal renal blood flow (resistive index 0.78 ± 0.11 vs. 0.85 ± 0.09, p = 0.04), lower rRSO2 (82.9 ± 9.2 vs. 73.6 ± 10.5%, p = 0.04), and lower systemic vascular resistance (0.155 ± 0.058 vs. 0.108 ± 0.037 mm Hg/L/kg; p = 0.04). The cRSO2 patterns were significantly decreased in infants with severe adverse outcome and independent from protein status. Conclusion: Hypoproteinemia is associated with impaired cardiovascular function. Further studies are required to elucidate the interplay between changes in protein levels, postnatal hemodynamics and clinical outcome.
Cytarabine Induced Acute Cerebellar Syndrome during Hyper-CVAD Treatment for B-Cell Acute Lymphoblastic Leukemia
Authors: Tran Phu Ngoc , Kong Xiao-Tang
Published: May 2017

Acute cerebellar syndrome can be caused by high doses of cytarabine, but it has not been described in patients with acute lymphoblastic leukemia (ALL) who received hyper-CVAD chemotherapy. Herein, we report two cases with histories of positive Philadelphia chromosome B-cell ALL who developed acute cerebellar syndrome after the exposure to relatively low doses of cytarabine in the second cycle of hyper-CVAD regimen. The cerebellar symptoms were attenuated by cytarabine discontinuation and administration of steroids. This case report provides detailed discussions on the treatments, the potential role of methotrexate in cytarabine-induced cerebellar syndrome, and the importance of carefully monitoring renal function during hyper-CVAD treatment.