bluuebunny/crossref_metadata_2025 huggingface dataset:
Methylation Changes of Primary Tumors, Monolayer, and Spheroid Tissue Culture Environments in Malignant Melanoma and Breast Carcinoma
Authors: Şükrüoğlu Erdoğan Özge , Kılıç Erciyas Seda , Bilir Ayhan , Buğra Tunçer Şeref , Akdeniz Ödemiş Demet , Kurul Sıdıka , Karanlık Hasan , Cabıoğlu Neslihan , Yazıcı Hülya
Published: January 2019

Epigenetic changes have major role in the normal development and programming of gene expression. Aberrant methylation results in carcinogenesis. The primary objective of our study is to determine whether primary tumor tissue and cultured tumor cells in 2D and 3D tissue culture systems have the same methylation signature forPAX5,TMPRSS2, andSBDS. These findings will play an important role in developing in vitro model system to understand the effect of methylation inhibitors on primary tumor tissue. In a previous studyPAX5,TMPRSS2, andSBDSgenes that we are investigating were reported to be methylated more than 60% in breast cancer and malignant melanoma cell lines. However, these genes have never been studied in primary tumor tissues. Thus, primary tumor tissues of breast cancer and malignant melanoma were first grown in 2D and 3D cultures. Then these two types of tumor tissues and their 2D and 3D cultures were investigated for changes considering methylation levels inPAX5,TMPRSS2, andSBDSgenes using real-time polymerase chain reaction. No differences were observed in the primary tissues and culture systems for bothPAX5andTMPRSS2in malignant melanoma tissues. We found thatPAX5gene was an efficient marker to measure the effects of methylation inhibitors for in vitro systems for malignant melanoma tissue.
Measurements of Tool Wear Parameters Using Machine Vision System
Authors: Thakre Avinash A. , Lad Aniruddha V. , Mala Kiran
Published: January 2019

Monitoring tool wear is very important in machining industry as it may result in loss of dimensional accuracy and quality of finished product. This work includes the development of machine vision system for the direct measurement of flank wear of carbide cutting tool inserts. This system consists of a digital camera to capture the tool wear image, a good light source to illuminate the tool, and a computer for image processing. A new approach of inline automatic calibration of a pixel is proposed in this work. The captured images of carbide inserts are processed, and the segmented tool wear zone has been obtained by image processing. The vision system extracts tool wear parameters such as average tool wear width, tool wear area, and tool wear perimeter. The results of the average tool wear width obtained from the vision system are experimentally validated with those obtained from the digital microscope. An average error of 3% was found for measurements of all 12 carbide inserts. Scanning electron micrographs of the wear zone indicate the severe abrasion marks and damage to the cutting edge for higher machining time. This study indicates that the efficient and reliable vision system can be developed to measure the tool wear parameters.
HCV Eradication with Direct-Acting Antivirals Does Not Impact HCC Progression on the Waiting List or HCC Recurrence after Liver Transplantation
Authors: Emamaullee Juliet A. , Bral Mariusz , Meeberg Glenda , Montano-Loza Aldo J. , Bain Vincent G. , Burak Kelly Warren , Bigam David , Shapiro A. M. James , Kneteman Norman
Published: January 2019

Background. The introduction of direct-acting antivirals (DAA) for HCV has led to high rates of HCV eradication. Treatment of patients awaiting liver transplantation (LT) has been controversial. Recent data suggests that DAA treatment may accelerate recurrent HCC. The impact of DAA on delisting for HCC progression or recurrent HCC post-LT has not been well characterized. Methods. A retrospective review of both waitlist patients and LT recipients at a single institution was performed. Patient demographics, HCV treatment, HCC features and treatments, biopsy results, and graft and patient survival were evaluated. Patients on the LT waitlist or who were transplanted between January 2014 and December 2015 were included. Data was collected through December 2017 to have a minimum of two years of follow-up. Results. In the study period, 128 adult LT were performed. 44 patients were HCV+, and 68.2% (N=30) also had HCC. 38.6% (N=17) of HCV+ patients received DAA pre-LT, and 94.1% (N=16/17) achieved sustained virologic response (SVR) pre-LT. Among untreated HCV+ patients who underwent LT, 81.5% (N=22/27) received DAA post-LT, with 82.6% achieving SVR post-LT (N=18/22). 82.1% (N=23/28) of untreated post-LT patients underwent liver biopsy prior to therapy, and 52.2% had at least F1 METAVIR fibrosis. 87.5% (N=14/16) of active waitlist patients received DAA and achieved SVR. HCV eradication did not result in higher rates of delisting for HCC progression. Due to local HCC listing criteria of total tumor volume and AFP, 60% (N=18/30) of HCV+/HCC patients were beyond Milan criteria at the time of LT. Despite this, there was no difference in HCC recurrence rates post-LT, whether patients achieved SVR pre- or post-LT. Conclusions. These data suggest that HCV eradication pre-LT does not significantly impact waitlist time for HCV+ patients with HCC. HCV eradication does not impact rates of delisting for HCC progression or rates of HCC recurrence post-LT.
Stress during Lactation Induces Insulin Resistance Associated with an Increase in Type 1 Cannabinoid Receptors in Liver and Adipose Tissue
Authors: Fonseca Liza , Castillo Valeska , Aguirre Carolina , Silva Paulo , Ronco Ana M. , Llanos Miguel
Published: January 2019

Several reports have shown that stress during lactation causes long-term metabolic and hormonal disruptions. In this study, we designed experiments to evaluate the effects of stress during lactation on the abundance of Type 1 cannabinoid/endocannabinoid receptors (CB1R) in epididymal fat and liver and development of insulin resistance in adult mice. During the whole lactation, male mice pups were daily subcutaneously injected (days 1–21) with a saline solution to produce a soft nociceptive stress (NS). Mice body weight and food intake were periodically evaluated. Adult animals were subsequently subjected to an insulin tolerance test and some days later sacrificed to evaluate the amount of epididymal fat and abundance of CB1R and adipophilin in liver and epididymal adipose tissue. Lipoprotein lipase (LPL) activity and circulating levels of leptin, adiponectin, and corticosterone were also evaluated. In this model, NS during lactation significantly increased the amount of epididymal fat and induced insulin resistance in adult mice. In addition, a significantly increased abundance of CB1R and adipophilin in epididymal fat and liver was observed, together with elevated circulating levels of leptin and corticosterone. Adult NS animals also had low plasmatic adiponectin and, although nonsignificant, had a sustained trend to a greater LPL activity associated with epididymal fat. These results indicate that increased abundance of CB1R in liver and epididymal fat alters tissue functionality likely associated with development of systemic metabolic alterations such as insulin resistance in adult mice. All these pathophysiological facts are long-term consequences of nociceptive stress during lactation.
Gaussian Process Regression Tuned by Bayesian Optimization for Seawater Intrusion Prediction
Authors: Kopsiaftis George , Protopapadakis Eftychios , Voulodimos Athanasios , Doulamis Nikolaos , Mantoglou Aristotelis
Published: January 2019

Accurate prediction of the seawater intrusion extent is necessary for many applications, such as groundwater management or protection of coastal aquifers from water quality deterioration. However, most applications require a large number of simulations usually at the expense of prediction accuracy. In this study, the Gaussian process regression method is investigated as a potential surrogate model for the computationally expensive variable density model. Gaussian process regression is a nonparametric kernel-based probabilistic model able to handle complex relations between input and output. In this study, the extent of seawater intrusion is represented by the location of the 0.5 kg/m3 iso-chlore at the bottom of the aquifer (seawater intrusion toe). The initial position of the toe, expressed as the distance of the specific line from a number of observation points across the coastline, along with the pumping rates are the surrogate model inputs, whereas the final position of the toe constitutes the output variable set. The training sample of the surrogate model consists of 4000 variable density simulations, which differ not only in the pumping rate pattern but also in the initial concentration distribution. The Latin hypercube sampling method is used to obtain the pumping rate patterns. For comparison purposes, a number of widely used regression methods are employed, specifically regression trees and Support Vector Machine regression (linear and nonlinear). A Bayesian optimization method is applied to all the regressors, to maximize their efficiency in the prediction of seawater intrusion. The final results indicate that the Gaussian process regression method, albeit more time consuming, proved to be more efficient in terms of the mean absolute error (MAE), the root mean square error (RMSE), and the coefficient of determination (R2).
Gait-Based Diplegia Classification Using LSMT Networks
Authors: Ferrari Alberto , Bergamini Luca , Guerzoni Giorgio , Calderara Simone , Bicocchi Nicola , Vitetta Giorgio , Borghi Corrado , Neviani Rita , Ferrari Adriano
Published: January 2019

Diplegia is a specific subcategory of the wide spectrum of motion disorders gathered under the name of cerebral palsy. Recent works proposed to use gait analysis for diplegia classification paving the way for automated analysis. A clinically established gait-based classification system divides diplegic patients into 4 main forms, each one associated with a peculiar walking pattern. In this work, we apply two different deep learning techniques, namely,multilayer perceptronandrecurrent neural networks, to automatically classify children into the 4 clinical forms. For the analysis, we used a dataset comprising gait data of 174 patients collected by means of an optoelectronic system. The measurements describing walking patterns have been processed to extract 27 angular parameters and then used to train both kinds of neural networks. Classification results are comparable with those provided by experts in 3 out of 4 forms.
A Fast Multiobjective Fuzzy Clustering with Multimeasures Combination
Authors: Liu Cong , Chen Qianqian , Chen Yingxia , Liu Jie
Published: January 2019

Most of the existing clustering algorithms are often based on Euclidean distance measure. However, only using Euclidean distance measure may not be sufficient enough to partition a dataset with different structures. Thus, it is necessary to combine multiple distance measures into clustering. However, the weights for different distance measures are hard to set. Accordingly, it appears natural to keep multiple distance measures separately and to optimize them simultaneously by applying a multiobjective optimization technique. Recently a new clustering algorithm called ‘multiobjective evolutionary clustering based on combining multiple distance measures’ (MOECDM) was proposed to integrate Euclidean and Path distance measures together for partitioning the dataset with different structures. However, it is time‐consuming due to the large‐sized genes. This paper proposes a fast multiobjective fuzzy clustering algorithm for partitioning the dataset with different structures. In this algorithm, a real encoding scheme is adopted to represent the individual. Two fuzzy clustering objective functions are designed based on Euclidean and Path distance measures, respectively, to evaluate the goodness of each individual. An improved evolutionary operator is also introduced accordingly to increase the convergence speed and the diversity of the population. In the final generation, a set of nondominated solutions can be obtained. The best solution and the best distance measure are selected by using a semisupervised method. Afterwards, an updated algorithm is also designed to detect the optimal cluster number automatically. The proposed algorithms are applied to many datasets with different structures, and the results of eight artificial and six real‐life datasets are shown in experiments. Experimental results have shown that the proposed algorithms can not only successfully partition the dataset with different structures, but also reduce the computational cost.
Synthesis of Fluorescent Copper Nanoparticles and Ultrasensitive Free Label Detection of Ag+
Authors: Wang Ning , Ga Lu , Jia Meilin , Ai Jun
Published: January 2019

In recent years, the application of fluorescent copper nanomaterials in environmental detection has attracted much attention. This paper mainly introduces the synthesis of copper nanomaterials and the detection of Ag+. A simple method for the determination of Ag+ in water was established by using fluorescent copper nanoparticles synthesized by using glucose (Glc) as a reducing agent as a fluorescent probe. The experimental mechanism of this experiment is that silver ions can rapidly and effectively quench the fluorescence of Glc-CuNPs. A good linear relationship was observed in the range of Ag+ at 100 mol/L–600 mol/L (R=0.9845); the color is gradually enhanced under visible light and visual colorimetric detection. Moreover, the Glc-CuNP sensor selectively selected Ag+, which was not affected by other metal ions, indicating that Glc-CuNPs had good selectivity for the detection of Ag+. Based on this, Glc-CuNP completes the detection of heavy metal silver ions and has a good application prospect in environmental detection.
Semiquantitative Fire Risk Grade Model and Response Plans on a National Highway Bridge
Authors: Ann Hojune , Choi Youngjin , Lee Jin Hyuk , Jang Young Ik , Kong Jung Sik
Published: January 2019

For the last ten years, the number of cases of large‐scale fires which occur on bridges, tunnels, and underpasses has increased. Such fires cause primary and secondary damage, including loss of human life, traffic congestion, and extensive financial damage. Therefore, a risk grade model and effective response plan need to be established for such cases in order to minimize the social and economic costs of bridge fires. In this study, the hazard factors contributing to bridge fires were selected to apply a risk grade model. A total of 144 bridge fire simulations were performed to calculate a surface temperature based on time by using Fire Dynamics Simulation (FDS). A risk grade in accordance with the degree of surface damage state caused by temperature of bridges was presented, and the mobilization time criteria for fire suppression were proposed. The surface temperatures based on time can be classified according to the vertical clearance and mobilization time criteria for fire suppression. Through the classified maximum surface temperatures based on time for bridges, the risk grade can be estimated according to the degree of surface damage state caused by temperature. In order to evaluate the applicability of the established risk grade model to the actual bridge, the arrival time taken from the bridge to the fire station was calculated through a Geographic Information System (GIS) network analysis, and the grades for actual bridge cases were assessed. The purpose of this bridge fire risk grade model is to establish a disaster prevention strategy based on risk grades and to minimize the subsequent social damage by determining a priori the disaster scale.
Significance of the Differential Peptidome in Multidrug-Resistant Tuberculosis
Authors: Yang Yan , Wu Jianqing
Published: January 2019

Most multidrug-resistant tuberculosis (MDR-TB) patients fail to receive a timely diagnosis and treatment. Therefore, we explored the differentially expressed peptides in MDR-TB compared with drug-susceptible tuberculosis (DS-TB) patients using LC-MS/MS and Ingenuity Pathway Analysis (IPA) to analyse the potential significance of these differentially expressed peptides. A total of 301 peptides were differentially expressed between MDR-TB and DS-TB groups. Of these, 24 and 16 peptides exhibited presented high (fold change ≥ 2.0, P < 0.05) and low (fold change ≤ −2.0, P < 0.05) levels in MDR-TB. Significant canonical pathways included the prothrombin activation system, coagulation system, and complement system. In the network of differentially expressed precursor proteins, lipopolysaccharide (LPS) regulates many precursor proteins, including four proteins correlated with organism survival. These four important differentially expressed proteins are prothrombin (F2), complement receptor type 2 (CR2), collagen alpha-2(V) chain (COL5A2), and inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4). After addition of CR2 peptide, IL-6 mRNA expression in THP-1 cells decreased significantly in dose- and time-dependent manners. Cumulatively, our study proposes potential biomarkers for MDR-TB diagnosis and enables a better understanding of the pathogenesis of MDR-TB. The functions of differentially expressed peptides, especially CR2, in MDR-TB require further investigation.
Polypoidal Choroidal Vasculopathy Complicating Retinal Laser in Quiescent Uveitis
Authors: Burke Tomas R. , Lightman Susan L.
Published: January 2019

A 58-year-old Afro-Caribbean gentleman with a diagnosis of quiescent systemic lupus erythematosus- (SLE-) related occlusive retinal vasculitis was previously treated with sector pan-retinal photocoagulation in his right eye to control temporal retinal neovascularization. At routine review he was found to have a focal area of subretinal fluid in the temporal macula sparing an ischaemic fovea. Fundus fluorescein angiography and indocyanine green angiography confirmed a branching vascular network (BVN) and terminal polys (i.e., polypoidal choroidal vasculopathy (PCV)). Interestingly, the BVN arose within an old laser scar. To our knowledge this is the first report of PCV in uveitis in an Afro-Caribbean patient and of the lesions arising within a laser scar.
Development of a MD-LC-MS/MS Method to Analyze 3 Bioactive Compounds in Huoxuezhitong Rubber Patch and Application to a Pharmacokinetic Study in Rats
Authors: Cui Yahua , Yang Chang , Liang Jun , Zhong Linying , Liu Caifeng , Bai Jie , Du Shouying , Liu Daofang
Published: January 2019

Huoxuezhitong rubber patch, a well-known traditional Chinese medicine (TCM) prescription, is utilized to treat pain and inflammation. In this study, a microdialysis-ultra-high-performance liquid chromatography-tandem mass spectrometry (MD-LC-MS/MS) method was designed for the simultaneous determination of active constituents in the rubber patch, such as paeonol (Pae), eugenol (Eug), and piperine (Pip). A microdialysis probe was implanted in the subcutaneous tissue of a rat, which is intended to detect the subcutaneous concentrations of target components. Saline containing 30% ethanol acted as perfusion fluid. Analytes in the microdialysate were completely separated over an ACQITY UPLC RBEH C18column (2.1mm×100mm, 1.7μm). The mobile phase was composed of 0.01% ammonia aqueous and acetonitrile-0.01% ammonia with gradient elution. The single-run analysis time was 10.0 minutes. The linear regression displayed good linear relationships in the ranges of 0.25–100 ng/mL for paeonol and eugenol and 0.001–5 ng/mL for piperine. The interday and intraday precision of the quality control samples exhibited relative standard deviations (RSD) <13.56%. The accuracy values ranged from −14.92% to 14.00%. The present method was successfully applied in pharmacokinetics studies following dermal administration of Huoxuezhitong rubber patch in rats. Pip’sTmax(488.00±150.73) min was greater than that of Pae (186.67±48.44) min and Eug (240.00±138.56) min, and the rank order of t1/2was Pae > Pip > Eug. The rank order of AUC0-720andCmaxwas both Eug > Pae > Pip. MRT0-∞of Pip was higher than that of Pae and Eug. Eugenol showed a faster elimination and a shorter half-life. Paeonol showed a stronger drug reservoir function after removing the drug source.
Sparse Sensor Placement for Interpolated Data Reconstruction Based on Iterative Four Subregions in Sensor Networks
Authors: Xie Mingshan , Huang Mengxing , Bai Yong , Hu Zhuhua , Deng Yanfang
Published: January 2019

Data acquisition in large areas has issues of cost and data loss. When sensors are sparse in the physical field, it is critical to study the deployment methods to improve the accuracy of reconstructed data set and the precision of the recovery of lost data. It is desirable to place sensors at optimal locations to achieve higher precision of recovery. In this paper, we present a sparse sensor placement scheme for data interpolation reconstruction based on iterative four subregions using fractal theory. The results of our experiments demonstrate that the precision of our algorithm is higher than that with random placement in dispersion degree, coverage rate, and reconstruction accuracy.
Section Plane Effects on Morphometric Values of Microcomputed Tomography
Authors: Park Young-Seok
Published: January 2019

Objectives. Histomorphometry is the established gold standard for inspection of trabecular microstructures in biomaterial research. However, microcomputed tomography can provide images from the perspective of various section planes. The aim of the present study was to evaluate the effects of different section planes, which may cause bias in two-dimensional morphometry, on the morphometric values of microcomputed tomography.Methods. A socket preservation technique was performed on the extracted premolar area of 4 beagle dogs. After an 8-week healing period, a total of 16 specimens were obtained and analyzed with conventional histomorphometry and microtomographic morphometry. Using the original images of the histologic specimens for comparison, the most similar tomographic image was selected by trial and error. Then, the section plane was then moved with ±79 μm parallel offsets and rotated ±10° around the center from the occlusal view. The images were compared in terms of bone, graft, and noncalcified area, and the concordance correlation coefficient (CCC) was calculated.Results. There was a high CCC in the comparison between histomorphometric images and the most similar microtomographic images. However, the CCC value was low in the comparisons with both parallel movement and rotation. Our results demonstrate that the sectioning plane has a significant effect on measurements.Conclusion. Two-dimensional morphometric values for biomaterial research should be interpreted with caution, and the simultaneous use of complementary 3-dimensional tools is recommended.
Numerical Simulation on the Cavitation Flow of High Speed Oblique Water Entry of Revolution Body
Authors: Mu Qing , Lv Yipin , Wang Kangjian , Xiong Tianhong , Yi Wenjun
Published: January 2019

To explore the effects of water entry angle on the cavitation flow field of high‐speed revolution body, based on the finite volume method, VOF (Volume of Fluid) multiphase model, Schnerr‐Sauer cavity model, SST k- ω turbulence model, and dynamic mesh method, numerical simulation for modeling the oblique water entry of revolution body at high speed is performed. The evolution laws of cavity shape, motion characteristics, and hydrodynamic characteristics of revolution body at different water entry angles are analyzed. The results show that the numerical calculation method can effectively simulate the change of cavity shape during the water entry of the revolution body. With the increase of water entry angle, the uplift of liquid level decreases in the positive direction of the open cavity and increases in the negative direction. The angle of water entry has little effect on the velocity of the revolution body. The larger the angle of water entry, the greater the peak pressure and the faster the pressure decay at the moment of water entry.
Analgesic and Antioxidant Activities of 4-Phenyl-1,5-benzodiazepin-2-one and Its Long Carbon Chains Derivatives
Authors: Nguema Ongone Terence , Achour Redouane , El Ghoul Mostafa , El Ouasif Latyfa , El Jemli Meryem , Chemlal Laila , Cherrah Yahia , Alaoui Katim , Zellou Amina
Published: January 2019

The aim of this work is to deepen the pharmacological effect of 4-phenyl-1,5-benzodiazepin-2-one derivatives which have a similar structure to nonionic surfactants: 4-phenyl-1,5-benzodiazepin-2-one is the hydrophilic head, and the carbon chain is hydrophobic tail. The antinociceptive activity of 4-phenyl-1,5-benzodiazepin-2-one derivatives was determined using acetic acid-induced writhing and tail immersion tests. In addition, the in vitro antioxidant activities of the tested derivatives were determined by using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method and ferric reducing power assay. A single oral administration of these compounds at the doses of 50 and 100 mg/kg significantly reduced the number of abdominal writhes induced by acetic acid injection. Acute pretreatment with 4-phenyl-1,5-benzodiazepin-2-one derivatives at the dose of 100 mg/kg caused a significant increase in the tail withdrawal latency in the tail immersion test. Additionally, a significant scavenging activity in DPPH and reducing power was observed in testing antioxidant assays. Finally, we carried out a study of the antioxidant activity of these derivatives. The results of this study reveal that these compounds have a low antioxidant activity compared to the BHT. It decreases with the polarity of the molecule. The present study suggests that 4-phenyl-1,5-benzodiazepin-2-one derivatives possess potent antinociceptive and antioxidant effects, which suggest that the tested compounds may be useful in the treatment of pain and oxidation disorders.
Conventional Treatments plus Acupuncture for Asthma in Adults and Adolescent: A Systematic Review and Meta-Analysis
Authors: Jiang Chunxiang , Jiang Lanlan , Qin Qingwu
Published: January 2019

Objectives. The efficacy of conventional treatments plus acupuncture for asthma in adult and adolescent is uncertain. Literature reports are conflicting; therefore, the aim of this study was to determine the efficacy of conventional treatments plus acupuncture versus conventional treatments alone using a meta-analysis of all published randomized clinical trials (RCTs).Methods. Two reviewers independently performed a comprehensive literature search from multiple electronic sources (1990–2018), including PubMed, EMBASE, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, and WanFang databases. RCTs in which adult and adolescent patients with asthma (age ≥12 years) were divided into conventional treatments plus acupuncture and conventional treatments alone were included.Results. Nine studies were included. The results showed that conventional treatments plus acupuncture as a complementary therapy could improve the symptom response rate (OR = 7.87, 95% CI = [4.13, 14.99], p < 0.00001) and significantly decrease interleukin-6 (IL-6) levels (MD = -11.42; 95% CI = [-15.28, -7.56], p < 0.00001). However, indices of pulmonary function, including the forced expiratory volume in one second (FEV1) (MD = 0.22, 95% CI = [-0.11, 0.56], p = 0.19) and FEV1/forced vital capacity (FVC) (MD = 8.62, 95% CI = [-0.35, 17.59], p = 0.06), failed to be improved with conventional treatments plus acupuncture.Conclusion. Conventional treatments plus acupuncture are associated with significant benefits for adult and adolescent patients with asthma. Therefore, we suggest the use of conventional treatments plus acupuncture for asthma patients.
A Hybrid Approach for Project Crashing Optimization Strategy with Risk Consideration: A Case Study for an EPC Project
Authors: Ou-Yang Chao , Chen Wang-Li
Published: January 2019

This study aims to develop and provide a comprehensive evaluation strategy for schedule‐related variations and time‐cost analysis for an engineering–procurement–construction (EPC) project. Time‐cost analysis is an important aspect of project scheduling, particularly in long‐term and costly EPC projects. In this study, a hybrid method is proposed for the time‐cost optimization strategy evaluation of a project. Monte Carlo simulation is applied to determine contingency plans and realize the effective management of estimated schedule uncertainties. A mathematical integer linear programming optimization model coded using CPLEX is developed to assess appropriate strategies for project execution under time and cost constraints. A set of project evaluation optimization models considering risk and project crash plan and the relationship between crash cost and delay penalty is also developed for assessing project feasibility. The correlation between project risk and crashing strategy has seldom been evaluated simultaneously in previous research. This work fills this research gap by quantifying the feasibility of a project, with combined data on risk, schedule, and cost as evaluation indicators. It allows project managers to consider management issues and strategies before they implement projects. A practical example with numerical applications is presented to illustrate the contribution of the decision‐making support mechanism, and several managerial insights are provided.
Ezrin Promotes Stem Cell Properties in Pancreatic Ductal Adenocarcinoma
Authors: Penchev Vesselin R. , Chang Yu-Tai , Begum Asma , Ewachiw Theodore , Gocke Christian , Li Joey , McMillan Ross H. , Wang Qiuju , Anders Robert , Marchionni Luigi , Maitra Anirban , Uren Aykut , Rasheed Zeshaan , Matsui William
Published: January 2019

Self-renewal maintains the long-term clonogenic growth that is required for cancer relapse and progression, but the cellular processes regulating this property are not fully understood. In many diseases, self-renewal is enhanced in cancer stem cells (CSC), and in pancreatic ductal adenocarcinoma (PDAC), CSCs are characterized by the surface expression of CD44. In addition to cell adhesion, CD44 impacts cell shape and morphology by modulating the actin cytoskeleton via Ezrin, a member of the Ezrin/Radixin/Moesin (ERM) family of linker proteins. We examined the expression of Ezrin in PDAC cells and found higher levels of both total and activated Ezrin in CSCs compared with bulk tumor cells. We also found that the knockdown of Ezrin in PDAC cells decreased clonogenic growth, self-renewal, cell migration, and CSC frequency in vitro as well as tumor initiation in vivo. These effects were associated with cytoskeletal changes that are similar to those occurring during the differentiation of normal stem cells, and the inhibition of actin remodeling reversed the impact of Ezrin loss. Finally, targeting Ezrin using a small-molecule inhibitor limited the self-renewal of clinically derived low-passage PDAC xenografts. Our findings demonstrate that Ezrin modulates CSCs properties and may represent a novel target for the treatment of PDAC.

Implications:

Our findings demonstrate that Ezrin modulates CSCs' properties and may represent a novel target for the treatment of PDAC.
Estrogen-Induced Apoptosis in Breast Cancers Is Phenocopied by Blocking Dephosphorylation of Eukaryotic Initiation Factor 2 Alpha (eIF2α) Protein
Authors: Sengupta Surojeet , Sevigny Catherine M. , Bhattacharya Poulomi , Jordan V. Craig , Clarke Robert
Published: January 2019

Approximately 30% of aromatase-inhibitor–resistant, estrogen receptor–positive patients with breast cancer benefit from treatment with estrogen. This enigmatic estrogen action is not well understood and how it occurs remains elusive. Studies indicate that the unfolded protein response and apoptosis pathways play important roles in mediating estrogen-triggered apoptosis. Using MCF7:5C cells, which mimic aromatase inhibitor resistance, and are hypersensitive to estrogen as evident by induction of apoptosis, we define increased global protein translational load as the trigger for estrogen-induced apoptosis. The protein kinase RNA-like endoplasmic reticulum kinase pathway was activated followed by increased phosphorylation of eukaryotic initiation factor-2 alpha (eIF2α). These actions block global protein translation but preferentially allow high expression of specific transcription factors, such as activating transcription factor 4 and C/EBP homologous protein that facilitate apoptosis. Notably, we recapitulated this phenotype of MCF7:5C in two other endocrine therapy–resistant cell lines (MCF7/LCC9 and T47D:A18/4-OHT) by increasing the levels of phospho-eIF2α using salubrinal to pharmacologically inhibit the enzymes responsible for dephosphorylation of eIF2α, GADD34, and CReP. RNAi-mediated ablation of these genes induced apoptosis that used the same signaling as salubrinal treatment. Moreover, combining 4-hydroxy tamoxifen with salubrinal enhanced apoptotic potency.

Implications:

These results not only elucidate the mechanism of estrogen-induced apoptosis but also identify a drugable target for potential therapeutic intervention that can mimic the beneficial effect of estrogen in some breast cancers.
Interaction Between MUC1 and STAT1 Drives IFITM1 Overexpression in Aromatase Inhibitor–Resistant Breast Cancer Cells and Mediates Estrogen-Induced Apoptosis
Authors: Escher Taylor E. , Lui Asona J. , Geanes Eric S. , Walter Katherine R. , Tawfik Ossama , Hagan Christy R. , Lewis-Wambi Joan
Published: January 2019

The human oncoprotein, mucin 1 (MUC1), drives tumorigenesis in breast carcinomas by promoting epithelial-to-mesenchymal transition (EMT), epigenetic reprogramming, and evasion of immune response. MUC1 interacts with STAT1, through JAK/STAT signaling, and stimulates transcription of IFN-stimulated genes, specifically IFN-induced transmembrane protein 1 (IFITM1). Our laboratory has previously shown that IFITM1 overexpression in aromatase inhibitor (AI)-resistant breast cancer cells promotes aggressiveness. Here, we demonstrate that differential regulation of MUC1 in AI-sensitive (MCF-7 and T-47D) compared with AI-resistant (MCF-7:5C) cells is critical in mediating IFITM1 expression. A tumor microarray of 94 estrogen receptor–positive human breast tumors correlated coexpression of MUC1 and IFITM1 with poor recurrence-free survival, poor overall survival, and AI-resistance. In this study, we investigated the effects of MUC1/IFITM1 on cell survival and proliferation. We knocked down MUC1 levels with siRNA and pharmacologic inhibitors, which abrogated IFITM1 mRNA and protein expression and induced cell death in AI-resistant cells. In vivo, estrogen and ruxolitinib significantly reduced tumor size and decreased expression of MUC1, P-STAT1, and IFITM1.

Implications:

MUC1 and IFITM1 overexpression drives AI resistance and can be targeted with currently available therapies.

Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/5/1180/F1.large.jpg.
Fetuses with Isolated Congenital Heart Defects Show Normal Cerebral and Extracerebral Fluid Volume Growth: A 3D Sonographic Study in the Second and Third Trimester
Authors: Jansen F.A.R. , van Zwet E.W. , Everwijn S.M.P. , Teunissen A.K.K. , Rozendaal L. , van Lith J.M.M , Blom N.A. , Haak M.C.
Published: January 2019

Objective: The aim of our study is to explore whether the cerebral growth is delayed in fetuses with congenital heart defects (CHD) in the second and early third trimester. Methods: A prospective cohort study was conducted in 77 CHD cases, with 75 healthy controls. 3D cerebral volume acquisition was performed sequentially. The volumes of the fetal hemicerebrum and extracerebral fluid were compared by linear regression analysis, and the Sylvian fissure was measured. Results: Between 19 and 32 weeks of gestation, 158 measurements in cases and 183 measurements in controls were performed (mean 2.2/subject). The volume growth of the hemicerebrum (R2 = 0.95 vs. 0.95; p = 0.9) and the extracerebral fluid (R2 = 0.84 vs. 0.82, p = 0.9) were similar. Fetuses with abnormal oxygen delivery to the brain have a slightly smaller brain at 20 weeks of gestation (p = 0.02), but this difference disappeared with advancing gestation. CHD cases demonstrated a slightly shallower Sylvian fissure (mean ratio 0.146 vs. 0.153; p = 0.004). Conclusions: Our study shows no differences in cerebral growth, studied in an unselected cohort, with successive cases of isolated CHD. Even in the severest CHD cases, cerebral size is similar in the early third trimester. The cause and meaning of a shallower Sylvian fissure is unclear; possibly, it is a marker for delayed cerebral maturation or it might be an expression of decreasing amount of extracerebral fluid.
The HPV16 E1 Carboxyl Domain Provides a Helper Function for Adeno-Associated Virus Replication
Authors: Cao Maohua , Bandyopadhyay Sarmistha , Zhu Hongqing , You Hong , Hermonat Paul L.
Published: January 2019

Background/Aims: Recombinant adeno-associated virus (rAAV) is now in the clinic, yet production of rAAV remains problematic. We previously determined that human papillomavirus type 16 (HPV16) E1 protein boosts rAAV yields and E1 enhances AAV Rep78’s replication-related biochemistries. Here, we deletion-mapped the helper domain within E1 to help glean its mechanism of action. Methods: Rep78-E1 interaction was analyzed by Gal4-based yeast two-hybrid (Y2H)-cDNA assay. rAAV DNA replication was studied by AAV/helper plasmid transfection into HEK293 cells and Southern blot. Gene expression analysis was made of AAV and E1 plasmid transfection, cDNA generation, and then quantitative polymerase chain reaction. NCBI protein BLAST was used for the homology analysis. Results: Gal4-Y2H- cDNA assay found in vivo Rep78-E1-binding activity across E1, but the carboxyl-third (amino acids [aa] 421–649) of E1 contained the predominant DNA replication helper domain. The amino-half of E1 (aa 1–337) inhibited transcription of rep (p5 promoter) and cap (p40, trending lower) from non-replicating helper plasmid by quantitative (q)RT-PCR. Conclusions: The aa 421–649 helper domain of HPV16 E1 includes the ATP-binding/helicase region of E1 which boosts rAAV production and has homology with the analogous region of parvovirus NS-1/Rep78 by NCBI protein BLAST, suggesting these biochemistries are responsible for the mechanism of action in E1 helper function.
Structural and Functional Characterization of the Retinal Effects of Hydroxychloroquine Treatment in Healthy Eyes
Authors: Gil Pedro , Nunes André , Farinha Cláudia , Teixeira Dora , Pires Isabel , Silva Rufino
Published: January 2019

Purpose: To evaluate the influence of hydroxychloroquine in visual field and retinal layer thickness. Methods: This is a retrospective cross-sectional study. Patients taking hydroxychloroquine without signs of hydroxychloroquine retinopathy were included. Optical coherence tomography segmentation was used to obtain the ETDRS map thickness of each retinal layer. Groups were divided into short-term (< 5 years) and long-term (≥5 years) drug use. Results: We included 93 eyes of 93 patients (short-term: 25 eyes; long-term: 68 eyes). The inner nuclear layer (INL) was thinner in the long-term group (32.86 ± 2.12 vs. 34.14 ± 2.37 μm; p = 0.014). Considering long-term cases, the parafoveal ganglion cell layer (GCL) showed an inverse correlation with cumulative dose (r = –0.37; p < 0.001). After adjusting for confounders, parafoveal ganglion cell complex thickness was associated with cumulative dose (β = –0.239; p = 0.011). The parafoveal outer retina and visual field indices were similar between groups and did not correlate with cumulative dose. Conclusion: Hydroxychloroquine leads to progressive thinning of the parafoveal inner retina, particularly the INL and GCL. Visual field indices do not reflect the long-term effects of the drug.
CD14 Counterregulates Lipopolysacharide-Induced Tumor Necrosis Factor-α Production in a Macrophage Subset
Authors: Grahnert Anja , Weiss Ronald , Schilling Erik , Stanslowsky Nancy , Sack Ulrich , Hauschildt Sunna
Published: January 2019

In response to GM-CSF or M-CSF, macrophages (MΦ) can acquire pro- or anti-inflammatory properties, respectively. Given the importance of CD14 and Toll-like receptor (TLR) 4 in lipopolysaccharide (LPS)-induced signaling, we studied the effect of anti-CD14 antibody mediated CD14 blockade on LPS-induced cytokine production, signal transduction and on the expression levels of CD14 and TLR4 in GM-MΦ and M-MΦ. We found M-MΦ to express higher levels of both surface antigens and to produce more interferon (IFN)-β and interleukin-10, but less tumor necrosis factor (TNF)-α than GM-MΦ. Blockage of CD14 at high LPS concentrations increased the production of proinflammatory cytokines and decreased that of IFN-β in M-MΦ but not in GM-MΦ. We show that phosphorylation states of signaling molecules of the MyD88 (myeloid differentiation primary response 88), TRIF (TIR-domain-containing adapter-inducing IFN-β) and MAPK (mitogen-activated protein kinase) pathways are not altered in any way that would account for the cytokine overshoot reaction. However, CD14 blockage in M-MΦ decreased TLR4 and CD14 expression levels, regardless of the presence of LPS, indicating that the loss of the surface molecules prevented LPS from initiating TRIF signaling. As TNF-α synthesis was even upregulated under these experimental conditions, we suggest that TRIF is normally involved in restricting LPS-induced TNF-α overproduction. Thus, surface CD14 plays a decisive role in the biological response by determining LPS-induced signaling.
Potential of Liquid Biopsies for Breast Cancer Screening, Diagnosis, and Response to Treatment
Authors: Eigeliene Natalja , Saarenheimo Jatta , Jekunen Antti
Published: January 2019

Cancer therapy decisions are often made according to the histopathological-molecular profile of tumor tissue obtained from surgery or biopsy. It has been shown that tumor profiles change with time and treatment, and that tumor tissue is heterogeneous. Thus, other approaches that are easily accessible and less invasive than surgery or biopsy to monitor responses to treatment and predict relapses are urgently needed. In the last few years, the term “liquid biopsies” has been introduced to represent multifunctional circulating biomarkers in the peripheral blood and other physiological fluids of patients with cancer. Liquid biopsies are a noninvasive alternative to tissue biopsies, but they have not been implemented in routine clinical practice for breast cancer. In addition, liquid biopsies seem to be a promising approach for personalized medicine, which enables the prediction, monitoring, and rational selection of appropriate therapy for individual patients. In this review, we outline recent progress and current challenges with liquid biopsies in clinical practice for breast cancer diagnosis, treatment choices, and responses to therapy from a clinician’s perspective.
The Underlying Structure of Comorbid Mental Health and Substance Use Disorders in Prison Populations
Authors: Ignatyev Yuriy , Baggio Stéphanie , Mundt Adrian P.
Published: January 2019

Background: High rates of mental disorders have been reported for prison populations. Understanding patterns of comorbidity may be essential for the development of adequate treatment interventions. The present study aimed to assess the underlying structure of comorbidity between mental health and substance use disorders in prison populations. Methods: Current mental disorders were assessed using the Mini-International Neuropsychiatric Interview in a cross-sectional observational study of 427 individuals consecutively committed to prison facilities in Santiago, Chile. Five alternative structural models were tested using confirmatory factor analysis (CFA). Latent class analysis of comorbid mental health and substance use disorders was carried out. Results: CFA indicated the best fit for a bifactor model with a general psychopathology P factor and specific internalizing and externalizing factors. Borderline personality disorder loaded highest on the P factor (0.85). The latent comorbidity structure showed a four-class solution representing one class without relevant comorbidities (48% prevalence) and three classes representing the following comorbidities: (1) externalizing disorders including substance use and antisocial personality disorder (31%), (2) internalizing disorders including anxiety disorders (10%), and (3) all types of disorders co-occurring (11%). Major depression and borderline personality disorder were present across all three latent classes of comorbidity. Conclusions: Prison mental health services need to serve a highly comorbid population. Specific approaches may be useful for an externalizing and an internalizing spectrum of disorders. An important group of individuals with all types of mental disorders co-occurring may need new approaches in treatment development.
Coil Extrusion into the Naso- and Oropharynx Ten Years after Internal Carotid Artery Pseudoaneurysm Embolization: A Case Report
Authors: Nasi Davide , Dobran Mauro , di Somma Lucia , Di Rienzo Alessandro , De Nicola Maurizio , Iacoangeli Maurizio
Published: January 2019

Coil migration and extrusion outside the cranial compartment after embolization of cerebral aneurysms represents a very rare complication of the endovascular procedures and few cases are reported in the literature. Instability of the vascular malformation wall and the resolution of the intramural hematoma, especially in pseudoaneurysm, might generate extravascular migration of the coils in the first months after embolization. However, to the best of our knowledge, an extrusion of coil 10 years after embolization has never been reported. We reported the unique case of a patient with coil extrusion into the naso- and oropharynx 10 years after internal carotid artery pseudoaneurysm embolization. The pseudoaneurysm occurred after an internal carotid artery injury during an endoscopic endonasal surgery for a clival giant cell tumor.
Long-Term Impact of Iatrogenic Bile Duct Injury
Authors: Schreuder Anne Marthe , Busch Olivier R. , Besselink Marc G. , Ignatavicius Povilas , Gulbinas Antanas , Barauskas Giedrius , Gouma Dirk J. , van Gulik Thomas M.
Published: January 2019

Background: Bile duct injury (BDI) is a devastating complication following cholecystectomy. After initial management of BDI, patients stay at risk for late complications including anastomotic strictures, recurrent cholangitis, and secondary biliary cirrhosis. Methods: We provide a comprehensive overview of current literature on the long-term outcome of BDI. Considering the availability of only limited data regarding treatment of anastomotic strictures in literature, we also retrospectively analyzed patients with anastomotic strictures following a hepaticojejunostomy (HJ) from a prospectively maintained database of 836 BDI patients. Results: Although clinical outcomes of endoscopic, radiologic, and surgical treatment of BDI are good with success rates of around 90%, quality of life (QoL) may be impaired even after “clinically successful” treatment. Following surgical treatment, the incidence of anastomotic strictures varies from 5 to 69%, with most studies reporting incidences around 10–20%. The median time to stricture formation varies between 11 and 30 months. Long-term BDI-related mortality varies between 1.8 and 4.6%. Of 91 patients treated in our center for anastomotic strictures after HJ, 81 (89%) were treated by percutaneous balloon dilatation, with a long-term success rate of 77%. Twenty-four patients primarily or secondarily underwent surgical revision, with recurrent strictures occurring in 21%. Conclusions: The long-term impact of BDI is considerable, both in terms of clinical outcomes and QoL. Treatment should be performed in tertiary expert centers to optimize outcomes. Patients require a long-term follow-up to detect anastomotic strictures. Strictures should initially be managed by percutaneous dilatation, with surgical revision as a next step in treatment.