bluuebunny/crossref_metadata_2025 huggingface dataset:
Aero Engine Component Fault Diagnosis Using Multi-Hidden-Layer Extreme Learning Machine with Optimized Structure
Authors: Pang Shan , Yang Xinyi , Zhang Xiaofeng
Published: August 2016

A new aero gas turbine engine gas path component fault diagnosis method based on multi-hidden-layer extreme learning machine with optimized structure (OM-ELM) was proposed. OM-ELM employs quantum-behaved particle swarm optimization to automatically obtain the optimal network structure according to both the root mean square error on training data set and the norm of output weights. The proposed method is applied to handwritten recognition data set and a gas turbine engine diagnostic application and is compared with basic ELM, multi-hidden-layer ELM, and two state-of-the-art deep learning algorithms: deep belief network and the stacked denoising autoencoder. Results show that, with optimized network structure, OM-ELM obtains better test accuracy in both applications and is more robust to sensor noise. Meanwhile it controls the model complexity and needs far less hidden nodes than multi-hidden-layer ELM, thus saving computer memory and making it more efficient to implement. All these advantages make our method an effective and reliable tool for engine component fault diagnosis tool.
Securing SDN Southbound and Data Plane Communication with IBC
Authors: Lam JunHuy , Lee Sang-Gon , Lee Hoon-Jae , Oktian Yustus Eko
Published: August 2016

In software-defined network (SDN), the southbound protocol defines the communication between the control plane and the data plane. The agreed protocol, OpenFlow, suggests securing the southbound communication with Transport Layer Security (TLS). However, most current SDN projects do not implement the security segment, with only a few exceptions such as OpenDayLight, HP VAN SDN, and ONOS implementing TLS in the southbound communication. From the telecommunication providers’ perspective, one of the major SDN consumers besides data centers, the data plane becomes much more complicated with the addition of wireless data plane as it involves numerous wireless technologies. Therefore, the complicated resource management along with the security of such a data plane can hinder the migration to SDN. In this paper, we propose securing the distributed SDN communication with a multidomain capable Identity-Based Cryptography (IBC) protocol, particularly for the southbound and wireless data plane communication. We also analyze the TLS-secured Message Queuing Telemetry Transport (MQTT) message exchanges to find out the possible bandwidth saved with IBC.
Leaf Growth and Canopy Development of Three Sugarcane Genotypes under High Temperature Rainfed Conditions in Northeastern Mexico
Authors: Castro-Nava Sergio , Huerta Alfredo J. , Plácido-de la Cruz José Manuel , Mireles-Rodríguez Epifanio
Published: August 2016

The aim of this study was to compare sugarcane (Saccharumspp.) canopy developmental components of three commercial varieties (CP 72-2086, Mex 79-431, and Mex 68-P-23) in a subtropical environment under rainfed and high temperature conditions, a poorly described topic in the literature. A field experiment was carried out in southern Tamaulipas, Mexico, throughout November 2011–January 2013 crop cycle, during which 111 of the days had daily maximum temperatures at or above 35°C. Number of leaves, leaf area, leaf appearance rate, and leaf area index (LAI) were determined. Thermal time exposure, °Cd (°C day−1), was determined based on total number of green ligulate leaves using 10°C as the base temperature. At 5000°Cd the number of leaves per plant ranged from 32 to 40 and the dependence of leaf emergence rate as a function of temperature was confirmed. The leaf emergence rate of CP 72-2086 was significantly greater than that of the other two varieties. Cultivars did not differ with respect to leaf length but differed for all other parameters measured. These results show the potential importance of considering sugarcane varietal differences in leaf phenology and canopy development for breeding programs focusing on rainfed and high temperature conditions.
Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus
Authors: Tse Gary , Lai Eric Tsz Him , Tse Vivian , Yeo Jie Ming
Published: August 2016

Diabetes is a common endocrine disorder with an ever increasing prevalence globally, placing significant burdens on our healthcare systems. It is associated with significant cardiovascular morbidities. One of the mechanisms by which it causes death is increasing the risk of cardiac arrhythmias. The aim of this article is to review the cardiac (ion channel abnormalities, electrophysiological and structural remodelling) and extracardiac factors (neural pathway remodelling) responsible for cardiac arrhythmogenesis in diabetes. It is concluded by an outline of molecular targets for future antiarrhythmic therapy for the diabetic population.
Some Fixed Points Results of Quadratic Functions in Split Quaternions
Authors: Kwun Young Chel , Munir Mobeen , Nazeer Waqas , Kang Shin Min
Published: August 2016

We attempt to find fixed points of a general quadratic polynomial in the algebra of split quaternion. In some cases, we characterize fixed points in terms of the coefficients of these polynomials and also give the cardinality of these points. As a consequence, we give some simple examples to strengthen the infinitude of these points in these cases. We also find the roots of quadratic polynomials as simple consequences.
Prevalence and Antimicrobial Resistance inSalmonellaandShigellaSpecies Isolated from Outpatients, Jimma University Specialized Hospital, Southwest Ethiopia
Authors: Lamboro Tesfahun , Ketema Tsige , Bacha Ketema
Published: August 2016

This study was designed to investigate the prevalence ofSalmonellaandShigellaamong outpatients in Jimma University Specialized Hospital, Southwest Ethiopia. Cross-sectional study was conducted involving a total of 176 outpatients. Stool specimens from both adult and pediatric outpatients were collected and analyzed for the presence of presumptiveSalmonellaandShigellacolonies followed by confirmation by biochemical tests. Pure cultures ofSalmonellaandShigellaspecies were further subjected to test for antibiotic resistance against the commonly used antibiotics. Furthermore, growth potential of the isolates in selected foods items was assessed following standard procedures. The result indicated that the prevalence ofSalmonellaandShigellaamong outpatients in the study area was 19 (10.8%) and 2 (1.1%), respectively. In addition,Salmonellaspecies were resistant to ampicillin (100%) followed by tetracycline (47.4%) and nalidixic acid (26.3%) whileShigellaspecies were highly resistant to ampicillin and tetracycline (100%, each). Multidrug resistance towards maximum of four drugs was observed in both pathogens. The pathogens were observed growing to their infective dose within 24 hours. In conclusion,SalmonellaandShigellaare still among microbes of public health importance in the study area. Thus, this calls for frequent monitory and evaluation of their prevalence and drug resistance patterns besides awareness development on water sanitation and hygienic food handling practices to the public at large.
Acute Kidney Injury and Atypical Features during Pediatric Poststreptococcal Glomerulonephritis
Authors: Ayoob Rose M. , Schwaderer Andrew L.
Published: August 2016

The most common acute glomerulonephritis in children is poststreptococcal glomerulonephritis (PSGN) usually occurring between 3 and 12 years old. Hypertension and gross hematuria are common presenting symptoms. Most PSGN patients do not experience complications, but rapidly progressive glomerulonephritis and hypertensive encephalopathy have been reported. This paper reports 17 patients seen in 1 year for PSGN including 4 with atypical PSGN, at a pediatric tertiary care center. Seventeen children (11 males), mean age of 8 years, were analyzed. Ninety-four percent had elevated serum BUN levels and decreased GFR. Four of the hospitalized patients had complex presentations that included AKI along with positive ANA or ANCAs. Three patients required renal replacement therapy and two were thrombocytopenic. PSGN usually does not occur as a severe nephritis. Over the 12-month study period, 17 cases associated with low serum albumin in 53%, acute kidney injury in 94%, and thrombocytopenia in 18% were treated. The presentation of PSGN may be severe and in a small subset have associations similar to SLE nephritis findings including AKI, positive ANA, and hematological anomalies.
A Predictive Neural Network-Based Cascade Control for pH Reactors
Authors: AlDhaifallah Mujahed , Alsabbah Shebel , Mujtaba Iqbal
Published: August 2016

This paper is concerned with the development of predictive neural network-based cascade control for pH reactors. The cascade structure consists of a master control loop (fuzzy proportional-integral) and a slave one (predictive neural network). The master loop is chosen to be more accurate but slower than the slave one. The strong features found in cascade structure have been added to the inherent features in model predictive neural network. The neural network is used to alleviate modeling difficulties found with pH reactor and to predict its behavior. The parameters of predictive algorithm are determined using an optimization algorithm. The effectiveness and feasibility of the proposed design have been demonstrated using MatLab.
A Mass Spectrometric Analysis Method Based on PPCA and SVM for Early Detection of Ovarian Cancer
Authors: Wu Jiang , Ji Yanju , Zhao Ling , Ji Mengying , Ye Zhuang , Li Suyi
Published: August 2016

Background. Surfaced-enhanced laser desorption-ionization-time of flight mass spectrometry (SELDI-TOF-MS) technology plays an important role in the early diagnosis of ovarian cancer. However, the raw MS data is highly dimensional and redundant. Therefore, it is necessary to study rapid and accurate detection methods from the massive MS data.Methods. The clinical data set used in the experiments for early cancer detection consisted of 216 SELDI-TOF-MS samples. An MS analysis method based on probabilistic principal components analysis (PPCA) and support vector machine (SVM) was proposed and applied to the ovarian cancer early classification in the data set. Additionally, by the same data set, we also established a traditional PCA-SVM model. Finally we compared the two models in detection accuracy, specificity, and sensitivity.Results. Using independent training and testing experiments 10 times to evaluate the ovarian cancer detection models, the average prediction accuracy, sensitivity, and specificity of the PCA-SVM model were 83.34%, 82.70%, and 83.88%, respectively. In contrast, those of the PPCA-SVM model were 90.80%, 92.98%, and 88.97%, respectively.Conclusions. The PPCA-SVM model had better detection performance. And the model combined with the SELDI-TOF-MS technology had a prospect in early clinical detection and diagnosis of ovarian cancer.
Growing Menace of Antibacterial Resistance in Clinical Isolates ofPseudomonas aeruginosain Nepal: An Insight of Beta-Lactamase Production
Authors: Ansari Shamshul , Dhital Rabindra , Shrestha Sony , Thapa Sangita , Puri Ram , Chaudhary Niraj , Khatiwada Suresh , Gautam Rajendra
Published: August 2016

Introduction. Pseudomonas aeruginosais the most frequently isolated organism as it acts as the opportunistic pathogen and can cause infections in immunosuppressed patients. The production of different types of beta-lactamases renders this organism resistant to many commonly used antimicrobials. Therefore, the aim of this study was to document the antibiotic resistance rate inPseudomonas aeruginosaisolated from different clinical specimens.Methods. Pseudomonas aeruginosarecovered was identified by standard microbiological methods. Antibiotic susceptibility testing was performed by modified Kirby-Bauer disc diffusion method following Clinical and Laboratory Standard Institute (CLSI) guidelines and all the suspected isolates were tested for the production of ESBLs, MBLs, and AmpC.Results.Out of total (178) isolates, 83.1% were recovered from the inpatient department (IPD). Majority of the isolates mediated resistance towards the beta-lactam antibiotics, while nearly half of the isolates were resistant to ciprofloxacin. Most of the aminoglycosides used showed resistance rate up to 75% but amikacin proved to be better option. No resistance to polymyxin was observed. ESBLs, MBLs, and AmpC mediated resistance was seen in 33.1%, 30.9%, and 15.7% isolates, respectively.Conclusions. Antibiotic resistance rate and beta-lactamase mediated resistance were high. Thus, regular surveillance of drug resistance is of utmost importance.
Optimal Tracking Performance of MIMO Discrete-Time Systems with Network Parameters
Authors: Chen Chao-Yang , Gui Weihua , Guan Zhi-Hong , Zhou Shaowu , Huang Cailun
Published: August 2016

The optimal regulation properties of multi-input and multioutput (MIMO) discrete-time networked control systems (NCSs), over additive white Gaussian noise (AWGN) fading channels, based on state space representation, are investigated. The average performance index is introduced. Moreover, the regulation performance is measured by the control energy and the error energy of the system, and fundamental limitations are obtained. Two kinds of network parameters, fading and the additive white Gaussian noise, are considered. The best attainable regulation performance limitations can be obtained by the limiting steady state solution of the corresponding algebraic Riccati equation (ARE). The simulation results are given to demonstrate the main results of the theoretical development.
Study on Strength and Microstructure of Cement-Based Materials Containing Combination Mineral Admixtures
Authors: Rao Meijuan , Wei Jianpeng , Gao Zhiyang , Zhou Wei , Li Qiaoling , Liu Shuhua
Published: August 2016

The compressive strength of complex binders containing two or three blended mineral admixtures in terms of glass powder (GP), limestone powder (LP), and steel slag powder (SP) was determined by a battery solution type compressive testing machine. The morphology and microstructure characteristics of complex binder hydration products were also studied by microscopic analysis methods, such as XRD, TG-DTA, and SEM. The mechanical properties of the cement-based materials were analyzed to reveal the most appropriate mineral admixture type and content. The early sample strength development with GP was very slow, but it rapidly grew at later stages. The micro aggregate effect and pozzolanic reaction mutually occurred in the mineral admixture. In the early stage, the micro aggregate effect reduced paste porosity and the small particles connected with the cement hydration products to enhance its strength. In the later stage, the pozzolanic reaction of some components in the complex powder occurred and consumed part of the calcium hydroxide to form C-S-H gel, thus improving the hydration environment. Also, the produced C-S-H gel made the structure more compact, which improved the structure’s strength.
Energy Efficiency of Ultra-Low-Power Bicycle Wireless Sensor Networks Based on a Combination of Power Reduction Techniques
Authors: Gharghan Sadik Kamel , Nordin Rosdiadee , Ismail Mahamod
Published: August 2016

In most wireless sensor network (WSN) applications, the sensor nodes (SNs) are battery powered and the amount of energy consumed by the nodes in the network determines the network lifespan. For future Internet of Things (IoT) applications, reducing energy consumption of SNs has become mandatory. In this paper, an ultra-low-power nRF24L01 wireless protocol is considered for a bicycle WSN. The power consumption of the mobile node on the cycle track was modified by combining adjustable data rate, sleep/wake, and transmission power control (TPC) based on two algorithms. The first algorithm was a TPC-based distance estimation, which adopted a novel hybrid particle swarm optimization-artificial neural network (PSO-ANN) using the received signal strength indicator (RSSI), while the second algorithm was a novel TPC-based accelerometer using inclination angle of the bicycle on the cycle track. Based on the second algorithm, the power consumption of the mobile and master nodes can be improved compared with the first algorithm and constant transmitted power level. In addition, an analytical model is derived to correlate the power consumption and data rate of the mobile node. The results indicate that the power savings based on the two algorithms outperformed the conventional operation (i.e., without power reduction algorithm) by 78%.
Effect of Different Light Qualities on Growth, Pigment Content, Chlorophyll Fluorescence, and Antioxidant Enzyme Activity in the Red AlgaPyropia haitanensis(Bangiales, Rhodophyta)
Authors: Wu Huanyang
Published: August 2016

Spectral light changes evoke different morphogenetic and photosynthetic responses that can vary among different algae species. The aim of this study is to investigate the photosynthetic characteristics of the red macroalgae grown under different spectrum environments. In this study,Pyropia haitanensiswere cultured under blue, red, and green LED and fluorescent tubes light. The growth rate, photopigment composition, chlorophyll fluorescence, and antioxidative enzymes activities in different light spectrums were investigated. The results revealed that growth rate was significantly higher in the thalli grown under blue, green, and fluorescent tubes light. Contents of Chl a and phycobiliprotein in red light were lower among all the growth conditions. Furthermore, a striking increase in SOD and CAT activity was observed in red light treatment along with the NPQ increase. The results revealed that the photosynthetic efficiency and increased growth rate ofP. haitanensisbenefitted from light spectrums such as blue, green, and fluorescent tubes light by pigment composition and photochemical efficiency manipulation, whereas red light has disadvantageous effects. Accordingly, the results for improving quality and the economic yield of algae species in some extent and the combination of different wavelengths could allow better economic resource exploitation.
A Risk-Based Interval Two-Stage Programming Model for Agricultural System Management under Uncertainty
Authors: Xu Ye , Huang Guohe
Published: August 2016

Nonpoint source (NPS) pollution caused by agricultural activities is main reason that water quality in watershed becomes worse, even leading to deterioration. Moreover, pollution control is accompanied with revenue’s fall for agricultural system. How to design and generate a cost-effective and environmentally friendly agricultural production pattern is a critical issue for local managers. In this study, a risk-based interval two-stage programming model (RBITSP) was developed. Compared to general ITSP model, significant contribution made by RBITSP model was that it emphasized importance of financial risk under various probabilistic levels, rather than only being concentrated on expected economic benefit, where risk is expressed as the probability of not meeting target profit under each individual scenario realization. This way effectively avoided solutions’ inaccuracy caused by traditional expected objective function and generated a variety of solutions through adjusting weight coefficients, which reflected trade-off between system economy and reliability. A case study of agricultural production management with the Tai Lake watershed was used to demonstrate superiority of proposed model. Obtained results could be a base for designing land-structure adjustment patterns and farmland retirement schemes and realizing balance of system benefit, system-failure risk, and water-body protection.
Applying Cost-Sensitive Extreme Learning Machine and Dissimilarity Integration to Gene Expression Data Classification
Authors: Liu Yanqiu , Lu Huijuan , Yan Ke , Xia Haixia , An Chunlin
Published: August 2016

Embedding cost-sensitive factors into the classifiers increases the classification stability and reduces the classification costs for classifying high-scale, redundant, and imbalanced datasets, such as the gene expression data. In this study, we extend our previous work, that is, Dissimilar ELM (D-ELM), by introducing misclassification costs into the classifier. We name the proposed algorithm as the cost-sensitive D-ELM (CS-D-ELM). Furthermore, we embed rejection cost into the CS-D-ELM to increase the classification stability of the proposed algorithm. Experimental results show that the rejection cost embedded CS-D-ELM algorithm effectively reduces the average and overall cost of the classification process, while the classification accuracy still remains competitive. The proposed method can be extended to classification problems of other redundant and imbalanced data.
Hydrogen Sulfide Improves Endothelial Dysfunction via Downregulating BMP4/COX‐2 Pathway in Rats with Hypertension
Authors: Xiao Lin , Dong Jing-Hui , Jin Sheng , Xue Hong-Mei , Guo Qi , Teng Xu , Wu Yu-Ming
Published: August 2016

Aims. We object to elucidate that protective effect of H2S on endothelium is mediated by downregulating BMP4 (bone morphogenetic protein 4)/cyclooxygenase‐ (COX‐) 2 pathway in rats with hypertension. Methods and Results. The hypertensive rat model induced by two‐kidney one‐clip (2K1C) model was used. Exogenous NaHS administration (56 μmol/kg/day, intraperitoneally once a day) reduced mean arterial pressure (MAP) of 2K1C rats from 199.9 ± 3.312 mmHg to 159.4 ± 5.434 mmHg, while NaHS did not affect the blood pressure in the Sham rats and ameliorated endothelium‐dependent contractions (EDCs) of renal artery in 2K1C rats. 2K1C reduced CSE level twofold, decreased plasma levels of H2S about 6‐fold, increased BMP4, Nox2, and Nox4 levels 2‐fold and increased markers of oxidative stress MDA and nitrotyrosine 1.5‐fold, upregulated the expression of phosphorylation‐p38 MAPK 2‐fold, and increased protein levels of COX‐2 1.5‐fold, which were abolished by NaHS treatment. Conclusions. Our results demonstrate that H2S prevents activation of BMP4/COX‐2 pathway in hypertension, which may be involved in the ameliorative effect of H2S on endothelial impairment. These results throw light on endothelial protective effect of H2S and provide new target for prevention and therapy of hypertension.
Connexin’s Connection in Breast Cancer Growth and Progression
Authors: Banerjee Debarshi
Published: August 2016

Gap junctions are cell-to-cell junctions that are located in the basolateral surface of two adjoining cells. A gap junction channel is composed of a family of proteins called connexins. Gap junction channels maintain intercellular communication between two cells through the exchange of ions, small metabolites, and electrical signals. Gap junction channels or connexins are widespread in terms of their expression and function in maintaining the development, differentiation, and homeostasis of vertebrate tissues. Gap junction connexins play a major role in maintaining intercellular communication among different cell types of normal mammary gland for proper development and homeostasis. Connexins have also been implicated in the pathogenesis of breast cancer. Differential expression pattern of connexins and their gap junction dependent or independent functions provide pivotal cross talk of breast tumor cells with the surrounding stromal cell in the microenvironment. Substantial research from the last 20 years has accumulated ample evidences that allow us a better understanding of the roles that connexins play in the tumorigenesis of primary breast tumor and its metastatic progression. This review will summarize the knowledge about the connexins and gap junction activities in breast cancer highlighting the differential expression and functional dynamics of connexins in the pathogenesis of the disease.
Silver-Coated Hip Megaprosthesis in Oncological Limb Savage Surgery
Authors: Donati F. , Di Giacomo G. , D’Adamio S. , Ziranu A. , Careri S. , Rosa MA. , Maccauro G.
Published: August 2016

Silver coating has demonstrated good antimicrobial activity and low toxicity. Silver-coated megaprostheses have been introduced in oncological musculoskeletal surgery considering the high rate of infection. We conducted a retrospective analysis on 68 cases of primary or metastatic bone tumors, affecting the proximal femur, treated between 2005 and 2016 with wide margins resection and tumor implants reconstruction. All patients were treated by the same surgeon, with antibiotic prophylaxis according to a standard protocol. In 55.9% of patients silver-coated hip hemiarthroplasty was implanted; in the remaining 44.1% uncoated megaprostheses were implanted. Patients were reevaluated recording the complications and focusing the analysis on infective complications. The average follow-up was 46.5 months. No patient has shown any sign of local or general silver toxicity. A SEM analysis was conducted on the 3-silver-coated hip hemiarthroplasty explanted confirming a severe degradation with a small amount of residual silver on the coating surface. Silver-coated hip prostheses have a lower rate of early infection than traditional implants but showed a reduction of antimicrobial activity for silver coating wear. We recommend using silver-coated prosthesis as primary implants for limb salvage surgery, in primary or metastatic bone tumors affecting the proximal femur, considering the absence of signs of toxicity and the lower rate of early infection.
Multiple Model-Based Synchronization Approaches for Time Delayed Slaving Data in a Space Launch Vehicle Tracking System
Authors: Song Haryong , Choi Yongtae
Published: August 2016

Due to the inherent characteristics of the flight mission of a space launch vehicle (SLV), which is required to fly over very large distances and have very high fault tolerances, in general, SLV tracking systems (TSs) comprise multiple heterogeneous sensors such as radars, GPS, INS, and electrooptical targeting systems installed over widespread areas. To track an SLV without interruption and to hand over the measurement coverage between TSs properly, the mission control system (MCS) transfers slaving data to each TS through mission networks. When serious network delays occur, however, the slaving data from the MCS can lead to the failure of the TS. To address this problem, in this paper, we propose multiple model-based synchronization (MMS) approaches, which take advantage of the multiple motion models of an SLV. Cubic spline extrapolation, prediction through anα-β-γfilter, and a single model Kalman filter are presented as benchmark approaches. We demonstrate the synchronization accuracy and effectiveness of the proposed MMS approaches using the Monte Carlo simulation with the nominal trajectory data of Korea Space Launch Vehicle-I.
Batch and Continuous Flow Adsorption of Phenolic Compounds from Olive Mill Wastewater: A Comparison between Nonionic and Ion Exchange Resins
Authors: Pinelli Davide , Molina Bacca Aurora Esther , Kaushik Ankita , Basu Subhankar , Nocentini Massimo , Bertin Lorenzo , Frascari Dario
Published: August 2016

The goals of this work were (i) to compare two anion ion exchange resins (IRA958 Cl and IRA67) and a nonionic resin (XAD16) in terms of phenolic compounds adsorption capacity from olive mill wastewater and (ii) to compare the adsorption capacity of the best resin on columns of different length. The ion exchange resins performed worse than nonionic XAD16 in terms of resin utilization efficiency (20% versus 43%) and phenolic compounds/COD enrichment factor (1.0 versus 2.5). The addition of volatile fatty acids did not hinder phenolic compounds adsorption on either resin, suggesting a noncompetitive adsorption mechanism. A pH increase from 4.9 to 7.2 did not affect the result of this comparison. For the best performing resin (XAD16), an increase in column length from 0.5 to 1.8 m determined an increase in resin utilization efficiency (from 12% to 43%), resin productivity (from 3.4 to 7.6 gsorbed  phenolics/kgresin), and phenolics/COD enrichment factor (from 1.2 to 2.5). An axial dispersion model with nonequilibrium adsorption accurately interpreted the phenolic compounds and COD experimental curves.
Ultrasonic-Assisted Synthesis of Twot-Butoxycarbonylamino Cephalosporin Intermediates on SiO2
Authors: Xue Feng , Wei Yibin , Ju Shengui , Xing Weihong
Published: August 2016

Herein, we describe a facile and high efficient strategy for the synthesis of two forms of the 7β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylates using ultrasonic irradiation. By SiO2as weak Lewis acid catalyst, 4-methoxybenzyl 7β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-carboxylate (Boc-ACLE) and benzhydryl 7β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylate (Boc-ACLH) were successfully synthesized through the efficient protection of theN-t-butoxycarbonyl (N-Boc), and the reactions occurred at low temperature requiring short reaction times and exhibiting excellent isolated yields (96% and 96.2%, resp.). The advantages of this reaction route including the usage of economical reagents and mild reaction conditions and high isolated yield make the two significantt-butoxycarbonylamino cephalosporin intermediates possible in large-scale production.
INT6/EIF3E Controls the RNF8-Dependent Ubiquitylation Pathway and Facilitates DNA Double-Strand Break Repair in Human Cells
Authors: Morris Christelle , Tomimatsu Nozomi , Burma Sandeep , Jalinot Pierre
Published: August 2016

Unrepaired DNA double-strand breaks (DSB) are the most destructive chromosomal lesions driving genomic instability, a core hallmark of cancer. Here, we identify the antioncogenic breast cancer factor INT6/EIF3E as an essential regulator of DSB repair that promotes homologous recombination (HR)–mediated repair and, to a lesser extent, nonhomologous end-joining repair. INT6 silencing impaired the accrual of the ubiquitin ligase RNF8 at DSBs and the formation of ubiquitin conjugates at DSB sites, especially Lys63-linked polyubiquitin chains, resulting in impaired recruitment of BRCA1, BRCA2, and RAD51, which are all involved in HR repair. In contrast, INT6 deficiency did not affect the accumulation of RNF168, 53BP1, or RPA at DSBs. In INT6-silenced cells, there was also an alteration in DNA damage-induced localization of MDC1, a key target for ATM phosphorylation, which is a prerequisite for RNF8 recruitment. The attenuated DNA damage localization of RNF8 resulting from INT6 depletion could be attributed to the defective retention of ATM previously reported by us. Our findings deepen insights into how INT6 protects against breast cancer by showing how it functions in DSB repair, with potential clinical implications for cancer therapy. Cancer Res; 76(20); 6054–65. ©2016 AACR.
Traditional Breast Cancer Risk Factors in Filipina Americans Compared with Chinese and Japanese Americans in Los Angeles County
Authors: Wu Anna H. , Vigen Cheryl , Lee Eunjung , Tseng Chiu-Chen , Butler Lesley M.
Published: August 2016

Background: Filipina Americans have one of the highest breast cancer incidence rates among Asian Americans for poorly understood reasons.

Methods: Breast cancer risk factors were investigated in a population-based study of Filipina (790 cases, 587 controls), Japanese (543 cases, 510 controls), and Chinese (913 cases, 904 controls) Americans. Cases were identified by the Los Angeles County Cancer Surveillance Program, and controls were matched to cases on age, ethnicity, and neighborhood. Multivariable conditional logistic regression was performed by Asian ethnicity.

Results: In Filipina, Chinese, and Japanese Americans, breast cancer risk decreased significantly with increasing parity (all Ptrend < 0.0001). Breast cancer risk increased with increasing quartiles of cumulative menstrual months in premenopausal (Ptrend = 0.019) and postmenopausal Filipina (Ptrend = 0.008), in premenopausal (Ptrend = 0.0003) but not postmenopausal Chinese (Ptrend = 0.79), and in neither premenopausal (Ptrend = 0.092) nor postmenopausal (Ptrend = 0.75) Japanese Americans. For postmenopausal Filipina and Japanese, greater weight gain since age 18 (Ptrend = 0.019 and 0.053, respectively), high current body mass index (both Ptrend < 0.01), and greater waist circumferences (both Ptrend < 0.04) were statistically significant; these associations were weaker for postmenopausal Chinese women.

Conclusions: Cumulative menstrual months and body size factors were statistically significant risk factors for Filipina. Total menstrual months were associated with breast cancer among Chinese but not for Japanese, while body size factors were significantly associated with risk among Japanese but not among Chinese.

Impact: Characterization of breast cancer risk factors in Filipina will help to generate hypotheses for their high breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 25(12); 1572–86. ©2016 AACR.
Therapeutic Inhibition of the MDM2–p53 Interaction Prevents Recurrence of Adenoid Cystic Carcinomas
Authors: Nör Felipe , Warner Kristy A. , Zhang Zhaocheng , Acasigua Gerson A. , Pearson Alexander T. , Kerk Samuel A. , Helman Joseph I. , Sant'Ana Filho Manoel , Wang Shaomeng , Nör Jacques E.
Published: August 2016

Purpose: Conventional chemotherapy has modest efficacy in advanced adenoid cystic carcinomas (ACC). Tumor recurrence is a major challenge in the management of ACC patients. Here, we evaluated the antitumor effect of a novel small-molecule inhibitor of the MDM2–p53 interaction (MI-773) combined with cisplatin in patient-derived xenograft (PDX) ACC tumors.

Experimental Design: Therapeutic strategies with MI-773 and/or cisplatin were evaluated in SCID mice harboring PDX ACC tumors (UM-PDX-HACC-5) and in low passage primary human ACC cells (UM-HACC-2A, -2B, -5, -6) in vitro. The effect of therapy on the fraction of cancer stem cells (CSC) was determined by flow cytometry for ALDH activity and CD44 expression.

Results: Combined therapy with MI-773 with cisplatin caused p53 activation, induction of apoptosis, and regression of ACC PDX tumors. Western blots revealed induction of MDM2, p53 and downstream p21 expression, and regulation of apoptosis-related proteins PUMA, BAX, Bcl-2, Bcl-xL, and active caspase-9 upon MI-773 treatment. Both single-agent MI-773 and MI-773 combined with cisplatin decreased the fraction of CSCs in PDX ACC tumors. Notably, neoadjuvant MI-773 and surgery eliminated tumor recurrences during a postsurgical follow-up of more than 300 days. In contrast, 62.5% of mice that received vehicle control presented with palpable tumor recurrences within this time period (P = 0.0097).

Conclusions: Collectively, these data demonstrate that therapeutic inhibition of MDM2–p53 interaction by MI-773 decreased the CSC fraction, sensitized ACC xenograft tumors to cisplatin, and eliminated tumor recurrence. These results suggest that patients with ACC might benefit from the therapeutic inhibition of the MDM2–p53 interaction. Clin Cancer Res; 23(4); 1036–48. ©2016 AACR.
A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia
Authors: Pratz Keith W. , Rudek Michelle A. , Gojo Ivana , Litzow Mark R. , McDevitt Michael A. , Ji Jiuping , Karnitz Larry M. , Herman James G. , Kinders Robert J. , Smith B. Douglas , Gore Steven D. , Carraway Hetty E. , Showel Margaret M. , Gladstone Douglas E. , Levis Mark J. , Tsai Hua-Ling , Rosner Gary , Chen Alice , Kaufmann Scott H. , Karp Judith E.
Published: August 2016

Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone.

Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML).

Results: A total of 99 patients received veliparib 10–100 mg orally twice daily on days 1–8, 1–14, or 1–21 along with continuous infusion topotecan 1.0–1.2 mg/m2/d + carboplatin 120–150 mg/m2/d on days 3–7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage–induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27–0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater phosphorylation in cells from responders.

Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias. Clin Cancer Res; 23(4); 899–907. ©2016 AACR.
Dinaciclib Induces Anaphase Catastrophe in Lung Cancer Cells via Inhibition of Cyclin-Dependent Kinases 1 and 2
Authors: Danilov Alexey V. , Hu Shanhu , Orr Bernardo , Godek Kristina , Mustachio Lisa Maria , Sekula David , Liu Xi , Kawakami Masanori , Johnson Faye M. , Compton Duane A. , Freemantle Sarah J. , Dmitrovsky Ethan
Published: August 2016

Despite advances in targeted therapy, lung cancer remains the most common cause of cancer-related mortality in the United States. Chromosomal instability is a prominent feature in lung cancer and, because it rarely occurs in normal cells, it represents a potential therapeutic target. Our prior work discovered that lung cancer cells undergo anaphase catastrophe in response to inhibition of cyclin-dependent kinase 2 (CDK2), followed by apoptosis and reduced growth. In this study, the effects and mechanisms of the multi-CDK inhibitor dinaciclib on lung cancer cells were investigated. We sought to determine the specificity of CDK-dependent induction of anaphase catastrophe. Live cell imaging provided direct evidence that dinaciclib caused multipolar cell divisions resulting in extensive chromosome missegregation. Genetic knockdown of dinaciclib CDK targets revealed that repression of CDK2 and CDK1, but not CDK5 or CDK9, triggered anaphase catastrophe in lung cancer cells. Overexpression of CP110, which is a mediator of CDK2 inhibitor–induced anaphase catastrophe (and a CDK1 and 2 phosphorylation substrate), antagonized anaphase catastrophe and apoptosis following dinaciclib treatment. Consistent with our previous findings, acquisition of activated KRAS sensitized lung cancer cells to dinaciclib-mediated anaphase catastrophe and cell death. Combining dinaciclib with the mitotic inhibitor taxol augmented anaphase catastrophe induction and reduced cell viability of lung cancer cells. Thus, the multi-CDK inhibitor dinaciclib causes anaphase catastrophe in lung cancer cells and should be investigated as a potential therapeutic for wild-type and KRAS-mutant lung cancer, individually or in combination with taxanes. Mol Cancer Ther; 15(11); 2758–66. ©2016 AACR.
A Novel Polyphenol Conjugate Sensitizes Cisplatin-Resistant Head and Neck Cancer Cells to Cisplatin via Nrf2 Inhibition
Authors: Kim Eun Hye , Jang Hyejin , Roh Jong-Lyel
Published: August 2016

Many cancer cells show acquired resistance to chemotherapeutic agents, such as cisplatin. This is a major cause of cancer treatment failure, and novel agents to overcome resistance are thus urgently required. A novel synthetic polyphenol conjugate, (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP-23), selectively kills tumor cells via the reactive oxygen species (ROS)–mediated unfolded protein response. We investigated the ability of DPP-23 to overcome cisplatin resistance in head and neck cancer (HNC) cells and further clarified its molecular mechanisms of action. Cisplatin-resistant HNC cell lines and their parental and other HNC cell lines were used. The effects of cisplatin and DPP-23 were assessed alone and in combination in HNC and normal cells using cell viability, cell cycle, and cell death assays, by measuring glutathione (GSH), ROS, and protein levels, and via preclinical mouse studies. DPP-23 induced selective cell death in HNC cells, including cisplatin-resistant HNC cells, but spared normal cells, via cellular GSH depletion and ROS accumulation. The effect was blocked by the antioxidant N-acetyl-L-cysteine. DPP-23 activated p53 and its related cell death pathways via a robust accumulation of cellular ROS that involved inhibition of nuclear factor erythroid 2–related factor 2 antioxidant defense mechanisms. Thus, DPP-23 significantly overcame cisplatin resistance in HNC cells in vitro and in vivo. As a promising anticancer strategy, ROS generation and subsequent selective cancer cell killing by DPP-23 might help to overcome cisplatin resistance in HNC. Mol Cancer Ther; 15(11); 2620–9. ©2016 AACR.
Association between Urine Creatinine Excretion and Arterial Stiffness in Chronic Kidney Disease: Data from the KNOW-CKD Study
Authors: Hyun Young Youl , Kim Hyang , Sung Su-Ah , Kim Soo Wan , Chae Dong Wan , Kim Yong-Soo , Choi Kyu Hun , Ahn Curie , Lee Kyu-Beck
Published: August 2016

Background/Aims: Previous studies have shown that low muscle mass is associated with arterial stiffness, as measured by pulse wave velocity (PWV), in a population without chronic kidney disease (CKD). This link between low muscle mass and arterial stiffness may explain why patients with CKD have poor cardiovascular outcomes. However, the association between muscle mass and arterial stiffness in CKD patients is not well known. Methods: Between 2011 and 2013, 1,529 CKD patients were enrolled in the prospective Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD). We analyzed 888 participants from this cohort who underwent measurements of 24-hr urinary creatinine excretion (UCr) and brachial-ankle PWV (baPWV) at baseline examination. The mean of the right and left baPWV (mPWV) was used as a marker of arterial stiffness. Results: The baPWV values varied according to the UCr quartile (1,630±412, 1,544±387, 1,527±282 and 1,406±246 for the 1st to 4th quartiles of UCr, respectively, P<0.001). For each 100 mg/d increase in UCr, baPWV decreased by 6m/sec in a multivariable linear regression model fully adjusted for traditional and renal cardiovascular risk factors. The odds ratio of the 1st quartile for high baPWV (highest quintile of mPWV) compared with the 4th quartile was 2.62 (1.24-5.54, P=0.011) in a logistic model fully adjusted for traditional and renal cardiovascular risk factors. Conclusion: Low muscle mass estimated by low UCr was associated high baPWV in pre-dialysis CKD patients in Korea. Further studies are needed to confirm the causal relationship between UCR and baPWV, and the role of muscle mass in the development of cardiovascular disease in CKD.
L-Carnitine Protects Renal Tubular Cells Against Calcium Oxalate Monohydrate Crystals Adhesion Through Preventing Cells From Dedifferentiation
Authors: Li Shujue , Wu Wenqi , Wu Wenzheng , Duan Xiaolu , Kong Zhenzhen , Zeng Guohua
Published: August 2016

Background/Aims: The interactions between calcium oxalate monohydrate (COM) crystals and renal tubular epithelial cells are important for renal stone formation but still unclear. This study aimed to investigate changes of epithelial cell phenotype after COM attachment and whether L-carnitine could protect cells against subsequent COM crystals adhesion. Methods: Cultured MDCK cells were employed and E-cadherin and Vimentin were used as markers to estimate the differentiate state. AlexaFluor-488-tagged COM crystals were used in crystals adhesion experiment to distinguish from the previous COM attachment, and adhesive crystals were counted under fluorescence microscope, which were also dissolved and the calcium concentration was assessed by flame atomic absorption spectrophotometry. Results: Dedifferentiated MDCK cells induced by transforming growth factor β1 (TGF-β1) shown higher affinity to COM crystals. After exposure to COM for 48 hours, cell dedifferentiation were observed and more subsequent COM crystals could bind onto, mediated by Akt/GSK-3β/Snail signaling. L-carnitine attenuated this signaling, resulted in inhibition of cell dedifferentiation and reduction of subsequent COM crystals adhesion. Conclusions: COM attachment promotes subsequent COM crystals adhesion, by inducing cell dedifferentiation via Akt/GSK-3β/Snail signaling. L-carnitine partially abolishes cell dedifferentiation and resists COM crystals adhesion. L-carnitine, may be used as a potential therapeutic strategy against recurrence of urolithiasis.
Serum Anti-Müllerian Hormone Concentration in Young Women with Chronic Kidney Disease on Hemodialysis, and After Successful Kidney Transplantation
Authors: Sikora-Grabka Ewelina , Adamczak Marcin , Kuczera Piotr , Szotowska Magdalena , Madej Paweł , Wiecek Andrzej
Published: August 2016

Background/Aims: In women with chronic kidney disease (CKD) fertility abnormalities occur frequently. Anti-Müllerian hormone (AMH) inhibits excessive recruitment of primordial follicles. The aim of the study was to evaluate the serum AMH concentration in women on hemodialysis and after kidney transplantation (KTx). Methods: 46 hemodialysed women and 14 with CKD about to undergo kidney transplantation were enrolled into the study. The control group consisted of 40 healthy women. In all subjects serum concentration of AMH was determined (in chronic hemodialysis women and in control group once, and in women after KTx immediately before surgery, and 3 times after the transplantation). Results: Serum AMH concentration in hemodialysed women and in the control group did not differ significantly, while in hemodialysed women with regular menstrual cycles it was significantly lower than in the control group: 2.20 (1.08-3.55ng/ml) and 3.30 (1.80-6.10ng/ml) respectively, (p=0.02). In the KTx group, a significant decrease in serum AMH concentration was found from 3.30ng/ml (2.20-6.50ng/ml) at baseline to 1.90ng/ml (1.30-2.40ng/ml) at 6 months after KTx (p=0.007). Conclusions: 1. Significantly lower serum AMH concentration was found in the regularly menstruating CKD women on hemodialysis in comparison with the healthy controls. 2. Serum AMH decreased significantly after successful KTx.
Efficacy of Intravenous and Oral Sotalol in Pharmacologic Conversion of Atrial Fibrillation: A Systematic Review and Meta-Analysis
Authors: Milan David J. , Saul J. Philip , Somberg John C. , Molnar Janos
Published: August 2016

Objectives: The role of sotalol is well established for the maintenance of sinus rhythm after successful conversion of atrial fibrillation (AF). However, its role in pharmacologic conversion of AF is poorly defined. The purpose of this study is to compare the efficacy of sotalol to that of other antiarrhythmic agents for AF conversion. Methods: Standard methods of meta-analysis were employed. Full-text publications of clinical trials in English that compared the efficacy of sotalol to that of other antiarrhythmics or placebo/no treatment were eligible for inclusion. Results: A systematic review revealed 10 eligible publications. Sotalol was superior to placebo and/or no antiarrhythmic therapy in AF conversion, with a relative success of 24 (95% CI 4.7-119, p < 0.001). Sotalol was not significantly different from class IA antiarrhythmic drugs. Similarly, sotalol was not different from class IC antiarrhythmic drugs or amiodarone in terms of conversion efficacy. In one study, sotalol was less effective than high-dose ibutilide (2 mg), with a relative success of 0.248 (95% CI 0.128-0.481, p < 0.001). Ibutilide caused more proarrhythmia. Conclusions: Sotalol is as effective as class IA and class IC antiarrhythmic agents, and it is also as effective as amiodarone for pharmacologic conversion of AF. Only ibutilide at a high dose showed a greater conversion rate of AF.