bluuebunny/crossref_metadata_2025 huggingface dataset:
Digital Image Steganography Using Eight-Directional PVD against RS Analysis and PDH Analysis
Authors: Swain Gandharba
Published: September 2018

The least significant bit (LSB) substitution techniques are detected by RS analysis and the traditional pixel value differencing (PVD) approaches are detected by pixel difference histogram (PDH) analysis. The PVD steganography can escape from PDH analysis by using the edges in multiple directions. This paper proposes a steganography technique by exploiting the edges in eight directions and also using LSB substitution to resist from both RS analysis and PDH analysis. For every 3×3 pixel block the central pixel is embedded with 3 or 4 bits of data by modified LSB substitution technique. Then this new value of the central pixel is utilized to calculate eight difference values with eight neighboring pixels. These eight difference values are used to hide the data. There are two types with regard to two different range tables. Type 1 uses 3 bit modified LSB substitution and range table 1. Type 2 uses 4 bit modified LSB substitution and range table 2. Type 1 and type 2 are also known as variant 1 and variant 2, respectively. Type 1 possesses higher PSNR and type 2 possesses higher hiding capacity.
The Calculation of Coal Rock Fracture Conductivity with Different Arrangements of Proppants
Authors: Li Yuwei , Meng Wannong , Rui Ray , Wang Jinghui , Jia Dan , Chen Gang , Patil Shirish , Dandekar Abhijit
Published: September 2018

An accurate evaluation of coal rock fracture conductivity is an important prerequisite for predicting the productivity of CBM wells. Coal rock is soft and fragile, with low elastic modulus and high Poisson ratio. In the process of fracturing flowback, the contact deformation between proppant and fracture wall will affect the fracture conductivity when the proppant is embedded in the coal rock; thus the calculation method of plate fracture conductivity is no longer suitable for the evaluation of coal rock. Based on the contact deformation theory of elastic mechanics, a method for calculating contact deformation of proppant in fracture is proposed. Considering the effect of the deformation and embedded depth of proppant and the tortuosity of pore flow channel between proppant particles on fracture conductivity, a model for calculating fracture conductivity of coal rock fractures under three kinds of proppant arrangement (Model 4-1, Model 3-1, and Model 2-1) is established. Comparison of calculation results of theoretical model and experiments confirmed that the arrangement of proppant in coal rock fracture is closest to Model 3-1, and the influence of mechanical parameters of coal rock and proppant on fracture conductivity is calculated and analyzed by this theoretical model. The study shows that the coal rock fracture conductivity is affected little by Poisson’s ratio of coal rock and proppant, which is greatly influenced by the elastic modulus of them, and the effect of particle size of proppant is especially significant.
Update on Vertigo in Autoimmune Disorders, from Diagnosis to Treatment
Authors: Girasoli Laura , Cazzador Diego , Padoan Roberto , Nardello Ennio , Felicetti Mara , Zanoletti Elisabetta , Schiavon Franco , Bovo Roberto
Published: September 2018

The prevalence of autoimmune diseases has been increasing over the last 20 years. The clinical presentation of this large and heterogeneous group of disorders depends on whether the involvement is organ-specific or non-organ-specific. Dizziness, vertigo, and disequilibrium are common symptoms reported by patients with vestibulocochlear involvement. The association of vertigo and autoimmune diseases has been largely documented, suggesting that autoimmune disorders could be overrepresented in patients with vertigo in comparison to the general population. The aim of this review is to present the recent literature findings in the field of autoimmune-mediated diseases with cochleovestibular involvement, focusing on the clinical presentation, diagnosis, and treatment of immune-mediated inner ear diseases including autoimmune inner ear disease (AIED), Meniere’s disease, and bilateral vestibulopathy, as well as of systemic autoimmune diseases with audiovestibular disorders, namely, Behçet’s disease, Cogan’s syndrome, sarcoidosis, autoimmune thyroid disease, Vogt-Koyanagi-Harada syndrome, relapsing polychondritis, systemic lupus erythematosus, antiphospholipid syndrome, IgG4-related disease, and ANCA-associated vasculitides.
A New and Simple Risk Predictor of Contrast-Induced Nephropathy in Patients Undergoing Primary Percutaneous Coronary Intervention: TIMI Risk Index
Authors: Kaya Ahmet , Karataş Ahmet , Kaya Yasemin , Düğeroğlu Harun , Dereli Seçkin , Bayramoğlu Adil
Published: September 2018

Background. The thrombolysis in myocardial infarction risk index (TRI) was developed to estimate prognosis at the initial contact of the healthcare provider in coronary artery disease patients without laboratory parameters. In this study, we aimed to investigate the relationship of the baseline TRI and contrast-induced nephropathy (CIN) in patients with ST-elevation myocardial infarction (STEMI).Methods. A total of 963 consecutive STEMI diagnosed patients who underwent primary percutaneous intervention were included in the study. TRI was calculated using the formula “heart rate × (age/10) 2/SBP” on admission. CIN was defined as an increase in serum creatinine concentration ≥25%, 48 hours later over the baseline.Results. Of the total of 963 patients, CIN was observed in 13% (n=128). TRI was significantly higher in the CIN (+) group compared with the CIN (−) group (32.9 ± 18.8 vs 19.9 ± 9.9,P<0.001). There was a stronger correlation between CIN and age, diastolic blood pressure, heart rate, Killip class, left ventricular ejection fraction, amount of contrast media, and diabetes mellitus. The amount of contrast media (OR 1.010, 95% CI 1.007–1.012,P<0.001) and TRI (OR 1.047, 95% CI 1.020–1.075,P=001) were independent predictors of CIN. The best threshold TRI for predicting CIN was ≥25.8, with a 67.1% sensitivity and 80.4% specificity (area under the curve (AUC): 0.740, 95% CI: 0.711–0.768,P<0.001).Conclusion. TRI is an independent predictor of CIN, and it may be used as a simple and reliable risk assessment of CIN in STEMI patients without the need for laboratory parameters.
Macrophage Activation Syndrome, Glomerulonephritis, Pericarditis, and Retinal Vasculitis as Initial Presentation of Systemic Lupus Erythematosus
Authors: Luo Yiming , Wen Yumeng , Arevalo Molina Ana Belen , Dahal Punya , Leuprecht Lorenz , Bsrat Makda
Published: September 2018

Macrophage activation syndrome (MAS) is a rare manifestation of systemic lupus erythematosus (SLE) with potentially life-threatening consequences. To the best of our knowledge, this is the first case reported in literature for a constellation of MAS, glomerulonephritis, pericarditis, and retinal vasculitis as initial presentation of SLE. Despite extensive multisystem involvement of his disease, the patient responded well to initial steroid treatment, with mycophenolate mofetil successfully added as a steroid-sparing agent. Our case highlights the importance of multispecialty collaboration in the diagnosis and management of SLE with multisystem involvement.
Task Allocation in Distributed Software Development: A Systematic Literature Review
Authors: Simão Filho Marum , Pinheiro Plácido R. , Albuquerque Adriano B. , Rodrigues Joel J. P. C.
Published: September 2018

Distributed development is a constant need in the software industry. The allocation of tasks, in turn, is a critical activity for any project, especially in a distributed setting. Assigning a task to an individual or team can be done in a rigorous manner, taking into account a number of factors. In this scenario, the more data on factors that influence task assignment are available to support the assignment decision, the more likely the project will succeed. As a result, companies have been looking to build their big data with historical project data, aiming to better their chances of success. Some studies about task allocation in distributed software development (DSD) have been carried out along the years aiming at mapping this topic and its features. Also, some approaches, models, and frameworks to task allocation in DSD have been proposed. This paper presents a systematic review of the literature whose objective is to identify works based on multicriteria models for assigning tasks in DDS projects, especially those based on qualitative decision‐making methods, considering the cognitive validity present in some of these methods. The review results allowed identifying several interesting aspects and classifying the works according to a set of questions. In addition, it has made some important findings that may be very useful for those who intend to conduct research with qualitative multicriteria methods, since some of them employ techniques considered psychologically valid to address the complexity of the decision about the task allocation in distributed projects.
Development of a HPLC‐MS/MS Method to Determine 11 Bioactive Compounds in Tongmai Yangxin Pill and Application to a Pharmacokinetic Study in Rats
Authors: Shen Jiayuan , Wei Juan , Li Li , Ouyang Huizi , Chang Yanxu , Chen Xiaopeng , He Jun
Published: September 2018

A sensitive and reliable HPLC‐MS/MS method has been developed and validated for simultaneous determination of eleven bioactive compounds (rhein, emodin, stilbene glycoside, liquiritin, ononin, verbascoside, gallic acid, schisandrin, liquiritigenin, glycyrrhizic acid, and isoliquiritigenin) in rat plasma after oral administration of Tongmai Yangxin Pill. The collected plasma samples were prepared by liquid‐liquid extraction with ethyl acetate after acidification. Eleven compounds were separated on a CORTECS™ C18 column with mobile phases consisting of 0.1% formic acid in deionized water and acetonitrile. The flow rate was 0.3 mL/min. The detection was performed on a tandem mass system with an electrospray ionization (ESI) source in both positive and negative ionization using multiple‐reaction monitoring (MRM) mode. The calibration curves were linear over the range of 8‐2000 ng/mL for glycyrrhizic acid; 4‐1000 ng/mL for liquiritin; 0.8‐200 ng/mL for emodin, gallic acid, ononin, schisandrin, and stilbene glycoside; 0.4‐100 ng/mL for isoliquiritigenin, liquiritigenin, rhein, and verbascoside, respectively. The intra‐ and interday precision of the analytes were less than 9.3% and 8.5%. The intra‐ and interday accuracy were in the range of ‐14.0% to 10.3% and ‐6.5% to 9.6%. Meanwhile, the extraction recovery of the analytes in plasma samples ranged from 85.2% to 109.1% and matrix effect from 89.2% to 113.4%. The developed method was successfully applied to the pharmacokinetics of eleven bioactive compounds in rat plasma after oral administration of Tongmai Yangxin Pill prescription.
Closing the Equity Gap of Access to Emergency Departments of Private Hospitals in Thailand
Authors: Suriyawongpaisal Paibul , Atiksawedparit Pongsakorn , Srithamrongsawad Samrit , Thongtan Thanita
Published: September 2018

Background. Previous policy implementation in 2012 to incentivize private hospitals in Thailand, a country with universal health coverage, to provide free-of-charge emergency care using DRG-based payment resulted in an equity gap of access and copayment. To bridge the gap, strategic policies involving financial and legal interventions were implemented in 2017. This study aims to assess whether this new approach would be able to fill the gap. Methods. We analyzed an administrative dataset of over 20,206 patients visiting private hospital EDs from April 2017 to October 2017 requested for the preauthorization of access to emergency care in the first 72 hours free of charge. The association between types of insurance and the approval status was explored using logistic regression equation adjusting for age, modes of access, systolic blood pressure, respiratory rate, and Glasgow coma scores. Results and Discussion. The strategic policies implementation resulted in reversing ED payer mix from the most privileged scheme, having the major share of ED visit, to the least privileged scheme. The data showed an increasing trend of ED visits to private hospitals indicates the acceptance of the financial incentive. Obvious differences in degrees of urgency between authorized and unauthorized patients suggested the role of preauthorization as a barrier to the noncritical patient visiting the ED. Furthermore, our study depicted the gender disparity between authorized and unauthorized patients which might indicate a delay in care seeking among critical female patients. Lessons learned for policymakers in low-and-middle income countries attempting to close the equity gap of access to private hospital EDs are discussed.
Can Deep Learning Identify Tomato Leaf Disease?
Authors: Zhang Keke , Wu Qiufeng , Liu Anwang , Meng Xiangyan
Published: September 2018

This paper applies deep convolutional neural network (CNN) to identify tomato leaf disease by transfer learning. AlexNet, GoogLeNet, and ResNet were used as backbone of the CNN. The best combined model was utilized to change the structure, aiming at exploring the performance of full training and fine-tuning of CNN. The highest accuracy of 97.28% for identifying tomato leaf disease is achieved by the optimal model ResNet with stochastic gradient descent (SGD), the number of batch size of 16, the number of iterations of 4992, and the training layers from the 37 layer to the fully connected layer (denote as “fc”). The experimental results show that the proposed technique is effective in identifying tomato leaf disease and could be generalized to identify other plant diseases.
Application of Hierarchical Facility Location-Routing Problem with Optimization of an Underground Logistic System: A Case Study in China
Authors: Hu Yingpeng , Zhang Kaixi , Yang Jing , Wu Yanghui
Published: September 2018

Facility location problem (FLP) and vehicle routing problem (VRP) are two of the most challenging issues in logistics. This paper presents an exploration of the multinode facility location-routing problem with realistic conditions. The disposal centers, transfer stations, connected collection sites, and unconnected collection sites are built into a new hierarchical model which is solved by Generate Algorithm (GA). Model costs include node construction cost, pipeline construction cost, transport cost, and transfer cost. This paper considers that the transportation is a bidirectional flow not a single flow; each pairs node in the area needs transportation; the dynamic routing selection method is used to determine the routes of unconnected collection sites. FLP and VRP can be both solved in this model. To illustrate the applicability of the model, a case study is presented and the results are discussed. The model in this paper can reduce the cost of the traditional underground logistics system by 6%~8% in experiments.
A Hybrid Forecasting Model Based on EMD-GASVM-RBFNN for Power Grid Investment Demand
Authors: Li Jinchao , Zhu Shaowen , Wu Qianqian , Zhang Pengfei
Published: September 2018

Power grid as an important infrastructure which ensures the healthy development of economy and society and accurate and reasonable prediction of the power grid investment demand has always been the focus problem of the power planning department and the power grid enterprises. In view of the complex nonlinear and nonstationary characteristics of the power grid investment demand sequence, a novel hybrid EMD-GASVM-RBFNN forecasting model based on empirical mode decomposition (EMD) method, support vector machines optimized by genetic algorithm (GA-SVM) model, and radial basis function neural network (RBFNN) model is proposed. Firstly, the EMD method is used to decompose the original power grid investment data sequence into a series of IMF components and a residual component which have stronger regularity compared with the original data. Then, according to the different characteristics of each subsequence, the GA-SVM and RBFNN model will be used to forecast different subsequences, respectively. Next, the prediction results of different subsequences are aggregated to obtain the final prediction results of the power grid investment. Finally, this paper dynamically simulates China’s power grid investment from 2018 to 2020 based on the EMD-GASVM-RBFNN hybrid forecasting model and Monte Carlo method.
Application of X‐Ray Computed Tomography in Monitoring Chloride Ion Penetration Paths in Recycled Aggregate Concrete
Authors: Zuo Yuan , Qi Bing , Gao Jianming , Li Weibin
Published: September 2018

The penetration paths of chloride ions in recycled aggregate concrete (RAC) are of significant interest and have not been well studied previously. This study used X‐ray computed tomography (X‐CT) as a novel approach to investigate chloride ion penetration paths in RAC. The results indicate that X‐CT can be used for the constant monitoring of chloride ion penetration paths in RAC, and the influence of mix proportions on the chloride ion penetration can be understood through the X‐CT visualization.
Achieving the Optimal k-Anonymity for Content Privacy in Interactive Cyberphysical Systems
Authors: Wang Jinbao , Tian Ling , Huang Yan , Yang Donghua , Gao Hong
Published: September 2018

Modern applications and services leveraged by interactive cyberphysical systems (CPS) are providing significant convenience to our daily life in various aspects at present. Clients submit their requests including query contents to CPS servers to enjoy diverse services such as health care, automatic driving, and location-based services. However, privacy concerns arise at the same time. Content privacy is recognized and a lot of efforts have been made in the literature of privacy preserving in interactive cyberphysical systems such as location-based services. Nevertheless, neither the cloaking based solutions nor existing client based solutions have achieved effective content privacy by optimizing proper content privacy metrics. In this paper we formulate the problem of achieving the optimal content privacy in interactive cyberphysical systems using k-anonymity solutions based on two content privacy metrics, which are defined using the concepts of entropy and differential privacy. Then we propose an algorithm, Multilayer Alignment (MLA), to establish k-anonymity mechanisms for preserving content privacy in interactive cyberphysical systems. Our proposed MLA is theoretically proved to achieve the optimal content privacy in terms of both the entropy based and the differential privacy mannered content privacy metrics. Evaluation based on real-life datasets is conducted, and the evaluation results validate the effectiveness of our proposed algorithm.
Stationary Gas Networks with Compressor Control and Random Loads: Optimization with Probabilistic Constraints
Authors: Gugat Martin , Schuster Michael
Published: September 2018

We introduce a stationary model for gas flow based on simplified isothermal Euler equations in a non-cycled pipeline network. Especially the problem of the feasibility of a random load vector is analyzed. Feasibility in this context means the existence of a flow vector meeting these loads, which satisfies the physical conservation laws with box constraints for the pressure. An important aspect of the model is the support of compressor stations, which counteract the pressure loss caused by friction in the pipes. The network is assumed to have only one influx node; all other nodes are efflux nodes. With these assumptions the set of feasible loads can be characterized analytically. In addition we show the existence of optimal solutions for some optimization problems with probabilistic constraints. A numerical example based on real data completes this paper.
Development of Novel Protocol to Al3+ Stress Tolerance at Germination Stage in Indica Rice through Statistical Approaches
Authors: Jahan Nusrat , Abd Manan Fazilah , Mansoor Arsala , Zaidi Mudassir Asrar , Shahwani Muhammad Naeem , Javed Muhammad Arshad
Published: September 2018

Rice production is decreasing by abiotic stresses like heavy metals. In such circumstances, producing food for growing human population is a challenge for plant breeders. Excess of Al3+ in soil has become threat for high yield of rice. Improvement of crop is one of potential solution for high production. The aim of this study was to develop the new method for optimization of Al3+ toxicity tolerance in indica rice at germination stag using two-way ANOVA and Duncan’s multiple-range test (DMRT). Seeds of two indica rice cultivars (Pokkali and Pak Basmati) were exposed in different concentrations (control, 5 mM, 15 mM, and 20 mM) of Al3+ toxicity at pH 4 ±0.2 for two weeks. Germination traits such as final germination percentage (FG%), germination energy (GE), germination speed (GS), germination index (GI), mean time of germination (MGT), germination value (GV), germination velocity (GVe), peak value of germination (GPV), and germination capacity (GC) and growth traits such as root length (RL), shoot length (SL), total dry biomass (TDB), and germination vigour index (GVI) were measured. To obtain the maximum number of significance (≤ 0.01%) parameters in each concentration of Al3+ toxicity with control, two-way ANOVA was established and comparison of mean was done using DMRT. The results showed that 5 mM, 10 mM, and 15 mM have less significant effects on the above-mentioned parameters. However, 20 mM concentration of Al3+ produced significant effects (≤ 0.01%). Therefore, 20 mM of Al3+ is considered optimized limit for indica cultivars (Pokkali and Pak Basmati).
The Epidemiology of Hepatitis D Virus in North Africa: A Systematic Review and Meta-Analysis
Authors: Daw Mohamed A. , Daw Amina M. , Sifennasr Nadia E. M. , Draha Aisha M. , Daw Ahmed M. , Daw Ali M. , Ahmed Mohamed O. , Mokhtar Ebtisam S. , El-Bouzedi Abdallah , Daw Ibrahem M.
Published: September 2018

Background. Hepatitis D virus (HDV) infection has been considered a serious neglected pandemic, particularly in developing countries. The virus causes a more severe disease than mono infection with hepatitis B virus (HBV). The epidemiology of HDV is not well documented in North Africa, which is known to be endemic for HBV. In this study, we explored the prevalence of HDV infection and also attempted to identify factors associated with hepatitis D positive status among chronic hepatitis B patients in North Africa.Methods. The electronic databases PubMed, Embase, Scopus, Science Direct, Web of Science, and Google Scholar were comprehensively searched for all papers published between January 1, 1998, and December 31, 2017, using appropriate strategies containing all related keywords, including North Africa, names of countries in the region, and all permutations of hepatitis D virus. The estimated prevalence of HDV in North Africa was calculated as an average of the pooled infection prevalence in each country weighted by the ratio of the country’s hepatitis D virus population to the study’s sample size in the survey data analysis.Findings. A total of 312 studies were identified and 32 were included in this study, with a total sample of 4907 individuals screened for HDV. There was considerable variability in the prevalence estimates of HDV within the countries of the region. The overall prevalence of HDV in the general population of North Africa was 5·01% (95% CI: 1·25–8·27) and in liver disease patients it was 20.7% (95% CI:9.87–44.53). Genotype-1 was the most prominent genotype reported in five published studies. Ten studies reported on HDV RNA in participants who were seropositive for HDV, and four studies highlighted the impact of demographic factors (sex and age). No study showed the impact of risk factors on the prevalence of HDV in North Africa.Interpretation. This review provides a comprehensive assessment of the burden of HDV in Northern Africa. There were significant differences in seroprevalence, study population, and diagnostic testing between the countries in the region. The results presented here will alert health professionals to implement clear policies based on evidence to diminish the burden of HDV infection. Such measures may include but are not restricted to improving the laboratory diagnostic tests and initiating patient data registries and blood screening. Further epidemiological and research studies are needed to explore the risk factors, coinfections, and approaches to increase testing for HDV, particularly in high-risk subpopulations, such as intravenous drug users and immigrants, and to define the consequences of HDV infection in North Africa.
Pregnancy Complicated by Maternal MODY 3 and Paternal MODY 2 Diabetes and Subsequent Rapidly Falling Insulin Requirement
Authors: Mikuscheva Anastasia , Mekhail Adel , Wheeler Benjamin J.
Published: September 2018

Background. ‘Maturity-Onset Diabetes of the Young’ (MODY) or monogenic diabetes accounts for approximately 1–2% of diabetes and is frequently misdiagnosed as type 1 or type 2 diabetes. Here we report a case of a 19-year-old pregnant woman with a MODY 3 diabetes expecting a child to a father with MODY 2 diabetes. Possible inheritance scenarios are described and the implications of these scenarios on the pregnancy and infant are discussed. In addition, the pregnancy was complicated by drastically falling insulin requirements in the mother in the 3rd trimester as well as preterm labour and delivery at 33+4 weeks of gestation.
Investigation on Smoke Suppression Mechanism of Hydrated Lime in Asphalt Combustion
Authors: Zhu Kai , Wang Yunhe , Zhou Qi , Tang Daquan , Gu Lingzhu , Wu Ke
Published: September 2018

In this study, cone calorimeter and thermogravimetric analyses were used to simulate the asphalt combustion process under the conditions of fire radiation and programmed temperature increase. The gaseous compositions and release rules were analyzed by infrared spectroscopy to investigate the influence of hydrated lime on the smoke suppression mechanism in the asphalt combustion process. The experimental results show that hydrated lime can promote the asphalt mastic surface to form a barrier layer during the combustion process. This barrier layer can reduce the burning intensity of asphalt. Although the compositions of gaseous products do not change much, the rates of CO production and smoke release are decreased. In addition, hydrated lime is alkaline and can thus neutralize acidic gases such as SO2 and reduce the toxicity of gaseous products. With the addition of 40 wt.% hydrated lime, the total smoke release and the CO release rate both decrease by more than 20% relative to the addition of the same amount of limestone fillers and decrease by more than 10% relative to the addition of the same amount of magnesium hydroxide flame retardant.
Four-miRNA Signature to Identify Asbestos-Related Lung Malignancies
Authors: Santarelli Lory , Gaetani Simona , Monaco Federica , Bracci Massimo , Valentino Matteo , Amati Monica , Rubini Corrado , Sabbatini Armando , Pasquini Ernesto , Zanotta Nunzia , Comar Manola , Neuzil Jiri , Tomasetti Marco , Bovenzi Massimo
Published: September 2018

Background:

Altered miRNA expression is an early event upon exposure to occupational/environmental carcinogens; thus, identification of a novel asbestos-related profile of miRNAs able to distinguish asbestos-induced cancer from cancer with different etiology can be useful for diagnosis. We therefore performed a study to identify miRNAs associated with asbestos-induced malignancies.

Methods:

Four groups of patients were included in the study, including patients with asbestos-related (NSCLCAsb) and asbestos-unrelated non–small cell lung cancer (NSCLC) or with malignant pleural mesothelioma (MPM), and disease-free subjects (CTRL). The selected miRNAs were evaluated in asbestos-exposed population.

Results:

Four serum miRNAs, that is miR-126, miR-205, miR-222, and miR-520g, were found to be implicated in asbestos-related malignant diseases. Notably, increased expression of miR-126 and miR-222 were found in asbestos-exposed subjects, and both miRNAs are involved in major pathways linked to cancer development. Epigenetic changes and cancer-stroma cross-talk could induce repression of miR-126 to facilitate tumor formation, angiogenesis, and invasion.

Conclusions:

This study indicates that miRNAs are potentially involved in asbestos-related malignancies, and their expression outlines mechanism(s) whereby miRNAs may be involved in an asbestos-induced pathogenesis.

Impact:

The discovery of a miRNA panel for asbestos-related malignancies would impact on occupational compensation and may be utilized for screening asbestos-exposed populations.
RB1 Heterogeneity in Advanced Metastatic Castration-Resistant Prostate Cancer
Authors: Nava Rodrigues Daniel , Casiraghi Nicola , Romanel Alessandro , Crespo Mateus , Miranda Susana , Rescigno Pasquale , Figueiredo Ines , Riisnaes Ruth , Carreira Suzanne , Sumanasuriya Semini , Gasperini Paola , Sharp Adam , Mateo Joaquin , Makay Alan , McNair Christopher , Schiewer Matthew , Knudsen Karen , Boysen Gunther , Demichelis Francesca , de Bono Johann S.
Published: September 2018

Purpose:

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal but clinically heterogeneous disease, with patients having variable benefit from endocrine and cytotoxic treatments. Intrapatient genomic heterogeneity could be a contributing factor to this clinical heterogeneity. Here, we used whole-genome sequencing (WGS) to investigate genomic heterogeneity in 21 previously treated CRPC metastases from 10 patients to investigate intrapatient molecular heterogeneity (IPMH).

Experimental Design: WGS was performed on topographically separate metastases from patients with advanced metastatic prostate cancer. IPMH of the RB1 gene was identified and further evaluated by FISH and IHC assays.

Results:

WGS identified limited IPMH for putative driver events. However, heterogeneous genomic aberrations of RB1 were detected. We confirmed the presence of these RB1 somatic copy-number aberrations, initially identified by WGS, with FISH, and identified novel structural variants involving RB1 in 6 samples from 3 of these 10 patients (30%; 3/10). WGS uncovered a novel deleterious RB1 structural lesion constituted of an intragenic tandem duplication involving multiple exons and associating with protein loss. Using RB1 IHC in a large series of mCRPC biopsies, we identified heterogeneous expression in approximately 28% of mCRPCs.

Conclusions:

mCRPCs have a high prevalence of RB1 genomic aberrations, with structural variants, including rearrangements, being common. Intrapatient genomic and expression heterogeneity favors RB1 aberrations as late, subclonal events that increase in prevalence due to treatment-selective pressures.
Oncogenic STRAP Supports Hepatocellular Carcinoma Growth by Enhancing Wnt/β-Catenin Signaling
Authors: Wang Wenhui , Li Shan , Liu Pengyu , Sideras Kostandinos , van de Werken Harmen J.G. , van der Heide Marieke , Cao Wanlu , Lavrijsen Marla , Peppelenbosch Maikel P. , Bruno Marco , Pan Qiuwei , Smits Ron
Published: September 2018

Aberrant activation of Wnt/β-catenin signaling plays a key role in the onset and development of hepatocellular carcinomas (HCC), with about half of them acquiring mutations in either CTNNB1 or AXIN1. The serine/threonine kinase receptor-associated protein (STRAP), a scaffold protein, was recently shown to facilitate the aberrant activation of Wnt/β-catenin signaling in colorectal cancers. However, the function of STRAP in HCC remains completely unknown. Here, increased levels of STRAP were observed in human and mouse HCCs. RNA sequencing of STRAP knockout clones generated by gene editing of Huh6 and Huh7 HCC cells revealed a significant reduction in expression of various metabolic and cell-cycle–related transcripts, in line with their general slower growth observed during culture. Importantly, Wnt/β-catenin signaling was impaired in all STRAP knockout/down cell lines tested, regardless of the underlying CTNNB1 or AXIN1 mutation. In accordance with β-catenin's role in (cancer) stem cell maintenance, the expressions of various stem cell markers, such as AXIN2 and LGR5, were reduced and concomitantly differentiation-associated genes were increased. Together, these results show that the increased STRAP protein levels observed in HCC provide growth advantage among others by enhancing Wnt/β-catenin signaling. These observations also identify STRAP as a new player in regulating β-catenin signaling in hepatocellular cancers.

Implications:

Elevated STRAP levels in hepatocellular cancers provide a growth advantage by enhancing Wnt/β-catenin signaling.
Targeting of SGK1 by miR-576-3p Inhibits Lung Adenocarcinoma Migration and Invasion
Authors: Greenawalt Evan J. , Edmonds Mick D. , Jain Neha , Adams Clare M. , Mitra Ramkrishna , Eischen Christine M.
Published: September 2018

Metastatic lung cancer is common in patients with lung adenocarcinoma, but the molecular mechanisms of metastasis remain incompletely resolved. miRNA regulate gene expression and contribute to cancer development and progression. This report identifies miR-576-3p and its mechanism of action in lung cancer progression. miR-576-3p was determined to be significantly decreased in clinical specimens of late-stage lung adenocarcinoma. Overexpression of miR-576-3p in lung adenocarcinoma cells decreased mesenchymal marker expression and inhibited migration and invasion. Inhibition of miR-576-3p in nonmalignant lung epithelial cells increased migration and invasion as well as mesenchymal markers. Serum/glucocorticoid–regulated kinase 1 (SGK1) was a direct target of miR-576-3p, and modulation of miR-576-3p levels led to alterations in SGK1 protein and mRNA as well as changes in activation of its downstream target linked to metastasis, N-myc downstream regulated 1 (NDRG1). Loss of the ability of miR-576-3p to bind the 3′-UTR of SGK1 rescued the inhibition in migration and invasion observed with miR-576-3p overexpression. In addition, increased SGK1 levels were detected in lung adenocarcinoma patient samples expressing mesenchymal markers, and pharmacologic inhibition of SGK1 resulted in a similar inhibition of migration and invasion of lung adenocarcinoma cells as observed with miR-576-3p overexpression. Together, these results reveal miR-576-3p downregulation is selected for in late-stage lung adenocarcinoma due to its ability to inhibit migration and invasion by targeting SGK1. Furthermore, these results also support targeting SGK1 as a potential therapeutic for lung adenocarcinoma.

Implications:

This study reveals SGK1 inhibition with miR-576-3p or pharmacologically inhibits migration and invasion of lung adenocarcinoma, providing mechanistic insights into late-stage lung adenocarcinoma and a potential new treatment avenue.
The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT
Authors: Ryan Molly R. , Sohl Christal D. , Luo BeiBei , Anderson Karen S.
Published: September 2018

FGFR1 has been implicated in numerous cancer types including squamous cell lung cancer, a subset of non–small cell lung cancer with a dismal 5-year survival rate. Small-molecule inhibitors targeting FGFR1 are currently in clinical trials, with AZD4547 being one of the furthest along; however, the development of drug resistance is a major challenge for targeted therapies. A prevalent mechanism of drug resistance in kinases occurs through mutation of the gatekeeper residue, V561M in FGFR1; however, mechanisms underlying V561M resistance to AZD4547 are not fully understood. Here, the cellular consequences of the V561M gatekeeper mutation were characterized, and it was found that although AZD4547 maintains nanomolar affinity for V561M FGFR1, based on in vitro binding assays, cells expressing V561M demonstrate dramatic resistance to AZD4547 driven by increased STAT3 activation downstream of V561M FGFR1. The data reveal that the V561M mutation biases cells toward a more mesenchymal phenotype, including increased levels of proliferation, migration, invasion, and anchorage-independent growth, which was confirmed using CyTOF, a novel single-cell analysis tool. Using shRNA knockdown, loss of STAT3 restored sensitivity of cancer cells expressing V561M FGFR1 to AZD4547. Thus, the data demonstrate that combination therapies including FGFR and STAT3 may overcome V561M FGFR1–driven drug resistance in the clinic.

Implications:

The V561M FGFR1 gatekeeper mutation leads to devastating drug resistance through activation of STAT3 and the epithelial–mesenchymal transition; this study demonstrates that FGFR1 inhibitor sensitivity can be restored upon STAT3 knockdown.
TGFβ1 Cell Cycle Arrest Is Mediated by Inhibition of MCM Assembly in Rb-Deficient Conditions
Authors: Nepon-Sixt Brook S. , Alexandrow Mark G.
Published: September 2018

Transforming growth factor β1 (TGFβ1) is a potent inhibitor of cell growth that targets gene-regulatory events, but also inhibits the function of CDC45-MCM-GINS helicases (CMG; MCM, Mini-Chromosome Maintenance; GINS, Go-Ichi-Ni-San) through multiple mechanisms to achieve cell-cycle arrest. Early in G1, TGFβ1 blocks MCM subunit expression and suppresses Myc and Cyclin E/Cdk2 activity required for CMG assembly, should MCMs be expressed. Once CMGs are assembled in late-G1, TGFβ1 blocks CMG activation using a direct mechanism involving the retinoblastoma (Rb) tumor suppressor. Here, in cells lacking Rb, TGFβ1 does not suppress Myc, Cyclin E/Cdk2 activity, or MCM expression, yet growth arrest remains intact and Smad2/3/4-dependent. Such arrest occurs due to inhibition of MCM hexamer assembly by TGFβ1, which is not seen when Rb is present and MCM subunit expression is normally blocked by TGFβ1. Loss of Smad expression prevents TGFβ1 suppression of MCM assembly. Mechanistically, TGFβ1 blocks a Cyclin E–Mcm7 molecular interaction required for MCM hexamer assembly upstream of CDC10-dependent transcript-1 (CDT1) function. Accordingly, overexpression of CDT1 with an intact MCM-binding domain abrogates TGFβ1 arrest and rescues MCM assembly. The ability of CDT1 to restore MCM assembly and allow S-phase entry indicates that, in the absence of Rb and other canonical mediators, TGFβ1 relies on inhibition of Cyclin E-MCM7 and MCM assembly to achieve cell cycle arrest.

Implications:

These results demonstrate that the MCM assembly process is a pivotal target of TGFβ1 in eliciting cell cycle arrest, and provide evidence for a novel oncogenic role for CDT1 in abrogating TGFβ1 inhibition of MCM assembly.
Expanding Neutrophil Horizons: New Concepts in Inflammation
Authors: Chatfield Simon M. , Thieblemont Nathalie , Witko-Sarsat Véronique
Published: September 2018

Research into neutrophil biology in the last 10 years has uncovered a number of unexpected aspects of this still mysterious innate immune cell. Advances in technology have allowed visualisation of neutrophil trafficking to sites of inflammation, and, remarkably, neutrophils have been observed to depart from the scene in what has been termed reverse migration. There has also been increasing appreciation of the heterogeneity of neutrophils with ongoing categorisation of neutrophil subsets, including myeloid-derived suppressor cells and low-density granulocytes. Newly recognised neutrophil functions include the ability to release novel immune mediators such as extracellular DNA and microvesicles. Finally, studies of neutrophil cell death, both apoptotic and non-apoptotic, have revealed remarkable differences compared to other cell types. This review will highlight important discoveries in these facets of neutrophil biology and how the new findings will inform treatment of diseases where neutrophils are implicated.
Propofol Inhibits Proliferation, Migration, Invasion and Promotes Apoptosis Through Down-Regulating miR-374a in Hepatocarcinoma Cell Lines
Authors: Liu Sheng-Qun , Zhang Jing-Liang , Li Zhan-Wen , Hu Zhen-Hua , Liu Zhe , Li Yi
Published: September 2018

Background: Propofol is a commonly used anaesthetic with controversial effects on cancer cells. We aimed to explore the functional roles of propofol in hepatocellular carcinoma (HCC) cells as well as the underlying mechanisms. Methods: HepG2 and SMMC-7721 cells were used in this study. Firstly, the effects of propofol on cell viability, migration, invasion, apoptosis, and involved proteins were assessed by Cell Counting Kit-8 assay, Transwell assay, flow cytometry assay and Western blot analysis, respectively. Subsequently, alteration of miR-374a after stimulation of propofol was analyzed by qRT-PCR. miR-374a was overexpressed and the alteration of proteins in the Wnt/β-catenin and PI3K/AKT pathways was detected by Western blot analysis. The downstream factor of miR-374a was finally studied. Results: Propofol inhibited cell viability, migration and invasion but promoted apoptosis of HepG2 and SMMC-7721 cells. Meanwhile, cyclinD1, matrix metalloproteinase (MMP)-2 and MMP-9 were down-regulated while Bax/Bcl-2, cleaved caspase-3 and cleaved caspase-9 were up-regulated by propofol. Then, miR-374a level was reduced by propofol. Expression of Wnt3a, β-catenin, p-PI3K and p-AKT was decreased by propofol, whereas these decreases were reversed by miR-374a overexpression. Finally, TP53 was proven to be target of miR-374a in HepG2 cells. Conclusion: Propofol inhibited cell proliferation, migration and invasion while promoted cell apoptosis of HepG2 and SMMC-7721 cells through inhibiting the Wnt/β-catenin and PI3K/ AKT pathways via down-regulation of miR-374a. Besides, miR-374a affected propofol-treated HepG2 cells by targeting TP53.
Fangjifuling Ameliorates Lipopolysaccharide-Induced Renal Injury via Inhibition of Inflammatory and Apoptotic Response in Mice
Authors: Su Zhonghao , Yu Ping , Sheng Lanyue , Ye Jin , Qin Zhenxia
Published: September 2018

Background/Aims: Acute kidney injury (AKI) is a frequent and serious complication of sepsis; however, there is no effective treatment for it. FangJiFuling (FF) decoction is widely used to treat acute glomerulonephritis and nephritic syndrome in the clinical setting. Methods: On the basis of its anti-inflammatory properties, the renoprotective effect of FF on a mouse model of lipopolysaccharide (LPS)-induced AKI was investigated. Major compounds were identified in FF with high-performance liquid chromatography. A bioinformatics analysis tool was used to predict target genes. Quantitative real-time PCR and western blot analyses were performed to validate the targets. Furthermore, the expression of a target gene was silenced by small interfering RNA-mediated knockdown in vitro. Results: Bioinformatics analysis indicated that inflammation, apoptosis, and cell junction were closely related to the renoprotective effects of FF. Validation was confirmed by an in vivo test. A reduction of inflammatory cell infiltration and inflammatory cytokine mRNA expression (iNOS, NF-κB, MCP-1, and TNF-α) following the administration of FF (50 mg/kg) was observed in LPS-treated renal tissue. In addition, FF treatment suppressed mitochondrial-mediated apoptosis by regulating the Bax/Bcl-2 ratio in LPS-induced renal injury. Silencing Cx43, a cell-to-cell junction protein, was found to enhance the protective effect of FF against LPS-induced renal injury. Conclusion: Our study suggests that FF exhibits a renoprotective effect against LPS-induced inflammatory and apoptotic responses. In addition, Cx43 might be involved in these processes. These findings indicate the potential role of FF as a natural renoprotective product.
miR-128 Targets the SIRT1/ROS/DR5 Pathway to Sensitize Colorectal Cancer to TRAIL-Induced Apoptosis
Authors: Lian Bo , Yang Dongxiang , Liu Yanlong , Shi Gang , Li Jibin , Yan Xiaofei , Jin Keer , Liu Xin , Zhao Jianfeng , Shang Wen , Zhang Rui
Published: September 2018

Background/Aims: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an ideal anti-tumor drug because it exhibits selective cytotoxicity against cancer cells. However, certain cancer cells are resistant to TRAIL, and the potential mechanisms are still unclear. The aim of this study was to reduce the resistance of colorectal cancer (CRC) cells to TRAIL. Methods: Quantitative real-time PCR analysis was performed to detect the expression of microRNA-128 (miR-128) in tissues from patients with CRC and CRC cell lines. MTT assays were used to evaluate the effect of miR-128 on TRAIL-induced cytotoxicity against CRC cell lines. The distribution of death receptor 5 (DR5) and the production of reactive oxygen species (ROS) were detected by flow cytometry analysis. Western blot, flow cytometry, and luciferase reporter assays were performed to evaluate the potential mechanism and pathway of miR-128-promoted apoptosis in TRAIL-treated CRC cells. Results: MiR-128 expression was downregulated in tumor tissues from patients with CRC as well as in CRC cell lines in vitro. The enforced expression of miR-128 sensitized CRC cells to TRAIL-induced cytotoxicity by inducing apoptosis. Mechanistically, bioinformatics, western blot analysis, and luciferase reporter assays showed that miR-128 directly targeted sirtuin 1 (SIRT1) in CRC cells. miR-128 overexpression suppressed SIRT1 expression, which promoted the production of ROS in TRAIL-treated CRC cells. This increase of ROS subsequently induced DR5 expression, and thus increased TRAIL-induced apoptosis in CRC cells. Conclusion: The combination of miR-128 with TRAIL may represent a novel approach for the treatment of CRC.
Association of Polymorphisms of the Matrix Metalloproteinase 9 Gene with Ischaemic Stroke in a Southern Chinese Population
Authors: Li You , Chen Linfa , Yao Shaoyu , Chen Jianya , Hu Weidong , Wang Mengxu , Chen Shaofeng , Chen Xinglan , Li Shengnan , Gu Xuefeng , Ma Guoda , Zhao Bin , Zhong Wangtao , Li Keshen
Published: September 2018

Background/Aims: Matrix metalloproteinase 9 (MMP9), a potent endopeptidase degrading extracellular matrix, plays a pivotal role in the pathogenesis of ischaemic stroke (IS). The present study was undertaken to determine the association of MMP9 gene polymorphisms and the risk of IS in a southern Chinese population. Methods: A cohort of 1274 patients and 1258 age-matched healthy controls were genotyped to detect the four MMP9 polymorphisms (rs17156, rs3787268, rs3918241 and rs3918242) using SNaPshot. Results: Our study demonstrated a significant difference in the genotype and allele frequencies of the MMP9 rs3918242 polymorphism between the IS patients and the controls (P = 0.012 for the genotype and P = 0.0092 for the allele). Stratification by smoking status showed statistically significant differences in the frequency and allele of the rs3918242 polymorphism between IS patients and the controls (P = 0.0052 for the genotype and P = 0.0019 for the allele). Further stratification by IS subtypes revealed that the presence of the T allele of the MMP9 rs3918242 polymorphism confers a higher risk of the large artery atherosclerosis subtype of IS (P = 0.017). Moreover, IS patients with the rs3918242 T allele of MMP9 presented with increased serum MMP9 production, and this increase was more significant in smokers with IS (P = 0.022). Patients carrying the variant T allele of the MMP9 rs3918242 polymorphism exhibited significantly higher infarct volumes than those with the major CC genotype (P = 0.036). Conclusion: Our study provides preliminary evidence that the MMP9 rs3918242 polymorphism is linked to a higher risk of IS, confirming the role of MMP9 in the pathophysiology of IS, with potentially important therapeutic implications.