bluuebunny/crossref_metadata_2025 huggingface dataset:
Sickle-Cell Disease Healthcare Cost in Africa: Experience of the Congo
Authors: Ngolet L. O. , Moyen Engoba M. , Kocko Innocent , Elira Dokekias Alexis , Mombouli Jean-Vivien , Moyen Georges Marius
Published: February 2016

Background. Lack of medical coverage in Africa leads to inappropriate care that has an impact on the mortality rate. In this study, we aimed to evaluate the cost of severe acute sickle-cell related complications in Brazzaville.Methods. A retrospective study was conducted in 2014 in the Paediatric Intensive Care Unit. It concerned 94 homozygote sickle-cell children that developed severe acute sickle-cell disease related complications (average age 69 months). For each patient, we calculated the cost of care complication.Results. The household income was estimated as low (<XAF 90,000/<USD 158.40) in 27.7%. The overall median cost for hospitalization for sickle-cell related acute complications was XAF 65,460/USD 115.21. Costs were fluctuating depending on the generating factors of the severe acute complications (p=0.041). They were higher in case of complications generated by bacterial infections (ranging from XAF 66,765/USD 117.50 to XAF 135,271.50/USD 238.07) and lower in case of complications associated with malaria (ranging from XAF 28,305/49.82 to XAF 64,891.63/USD 114.21). The mortality rate was 17% and was associated with the cost of the case management (p=0.006).Conclusion. The case management cost of severe acute complications of sickle-cell disease in children is high in Congo.
Hydroxyapatite Whiskers Based Resin Composite versus Commercial Dental Composites: Mechanical and Biocompatibility Characterization
Authors: Calabrese L. , Fabiano F. , Currò M. , Borsellino C. , Bonaccorsi L. M. , Fabiano V. , Ientile R. , Proverbio E.
Published: February 2016

A systematic evaluation of mechanical and biocompatibility properties of different volume fractions of hydroxyapatite whiskers in comparison with three commercial dental composites filled with micro- and nanosilica particles was carried out. Six groups with different hydroxyapatite whiskers mass fractions were taken into account in order to be compared with the performances of silica particles based composites group. Flexural properties were evaluated via a universal testing machine (2.5 kN Zwick Line) with a 2 kN load-cell (sensitivity 0.001 N). The test was replicated 10 times for the seven experimental groups to better identify statically the significance of the mechanical performances data. MTT quantitative colorimetric assay was performed in order to evaluate the mitochondrial activity of living cells exposed to different resin composites. Data obtained show better interfacial interaction with filler/matrix until 20 wt% of hydroxyapatite whiskers partially replaced silica particles filler. After this threshold, the mechanical performances decrease dramatically due to both the hydroxyapatite agglomerates formation and the low degree of resin conversion. In addition, biocompatibility test showed less cytotoxic effect with the addition of 20 wt% of hydroxyapatite in comparison with higher rates.
Behavior of Photovoltaic System during Solar Eclipse in Prague
Authors: Libra Martin , Kouřím Pavel , Poulek Vladislav
Published: February 2016

PV power plants have been recently installed in very large scale. So the effects of the solar eclipse are of big importance especially for grid connected photovoltaic (PV) systems. There was a partial solar eclipse in Prague on 20th March 2015. We have evaluated the data from our facility in order to monitor the impact of this natural phenomenon on the behavior of PV system, and these results are presented in the paper. The behavior of PV system corresponds with the theoretical assumption. The power decrease of the PV array corresponds with the relative size of the solar eclipse.I-Vcharacteristics of the PV panel correspond to the theoretical model presented in our previous work.
Improving Accuracy and Simplifying Training in Fingerprinting-Based Indoor Location Algorithms at Room Level
Authors: Muñoz-Organero Mario , Brito-Pacheco Claudia
Published: February 2016

Fingerprinting-based algorithms are popular in indoor location systems based on mobile devices. Comparing the RSSI (Received Signal Strength Indicator) from different radio wave transmitters, such as Wi-Fi access points, with prerecorded fingerprints from located points (using different artificial intelligence algorithms), fingerprinting-based systems can locate unknown points with a few meters resolution. However, training the system with already located fingerprints tends to be an expensive task both in time and in resources, especially if large areas are to be considered. Moreover, the decision algorithms tend to be of high memory and CPU consuming in such cases and so does the required time for obtaining the estimated location for a new fingerprint. In this paper, we study, propose, and validate a way to select the locations for the training fingerprints which reduces the amount of required points while improving the accuracy of the algorithms when locating points at room level resolution. We present a comparison of different artificial intelligence decision algorithms and select those with better results. We do a comparison with other systems in the literature and draw conclusions about the improvements obtained in our proposal. Moreover, some techniques such as filtering nonstable access points for improving accuracy are introduced, studied, and validated.
A New Concept for Carotid Artery Stenting: Coating the Atherosclerotic Plaque by Covered Stent before Bare Stent Implantation
Authors: Akgul Erol
Published: February 2016

In carotid artery stenting (CAS) procedures, distal embolism, periprocedural stent thrombosis, and 30-day stroke due to the plaque fragmentation and protrusion caused by stent implantation and balloon dilation are frequent complications. In this technical case report, a case is presented of extracranial carotid artery stenosis treated with a covered stent and subsequent implantation of a bare stent. In addition, the possibility is discussed that this new technique prevents the distal microembolic complications, periprocedural stent thrombosis, and 30-day stroke of extracranial CAS.
Determinants of Mean Blood Pressure and Hypertension among Workers in West Africa
Authors: Bosu William K.
Published: February 2016

Background. This review was undertaken to estimate the mean blood pressure and evaluate its determinants as well as the determinants of hypertension among workers in West Africa.Methods. In a follow-up to an earlier study, a systematic search for articles published between 1980 and August 2015 was undertaken using major databases.Results. A total of 55 articles involving 34,919 different cadres of workers from six countries were retrieved. The mean systolic blood pressure (BP) ranged from116.6±1.3 mmHg to151.7±13.6 mmHg while the mean diastolic BP ranged from69.6±11.0 mmHg to97.1±9.1 mmHg. Population-wide prehypertension was common. The major determinants of mean BP and hypertension were similar and included male sex, older age group, higher socioeconomic status, obesity, alcohol consumption, plasma glucose, and sodium excretion. Ethnicity and educational level were inconsistently associated with hypertension. Workers at higher risk of cardiovascular event did not perceive themselves as such.Conclusion. The prevailing mean prehypertensive BP, low perception of risk, and clustering of risk factors call for interventions such as healthy diets, improved physical activity, and a favourable work environment. Successful models for improving the cardiovascular health of sedentary informal sector workers in Africa are urgently needed.
The Comparative Evaluation of the Antimicrobial Effect of Propolis with Chlorhexidine against Oral Pathogens: An In Vitro Study
Authors: Akca A. Eralp , Akca Gülçin , Topçu Fulya Toksoy , Macit Enis , Pikdöken Levent , Özgen I. Şerif
Published: February 2016

This study aimed to compare the antimicrobial effectiveness of ethanolic extract of propolis (EEP) to chlorhexidine gluconate (CHX) on planktonicStreptococcus mutans,Streptococcus sobrinus,Lactobacillus acidophilus,Lactobacillus salivariussubsp.salivarius,Aggregatibacter actinomycetemcomitans,Prevotella intermedia,Porphyromonas gingivalis,Staphylococcus aureus,Enterococcus faecalis,Actinomyces israelii,Candida albicans, and their single-species biofilms by agar dilution and broth microdilution test methods. Both agents inhibited the growth of all planktonic species. On the other hand, CHX exhibited lower minimum bactericidal concentrations than EEP against biofilms ofA. actinomycetemcomitans,S. aureus, andE. faecaliswhereas EEP yielded a better result against Lactobacilli andP. intermedia. The bactericidal and fungicidal concentrations of both agents were found to be equal against biofilms of Streptecocci,P. gingivalis,A. israelii, andC. albicans. The results of this study revealed that propolis was more effective in inhibiting Gram-positive bacteria than the Gram-negative bacteria in their planktonic state and it was suggested that EEP could be as effective as CHX on oral microorganisms in their biofilm state.
Influence of Oxidative Stress on Stored Platelets
Authors: Manasa K. , Vani R.
Published: February 2016

Platelet storage and its availability for transfusion are limited to 5-6 days. Oxidative stress (OS) is one of the causes for reduced efficacy and shelf-life of platelets. The studies on platelet storage have focused on improving the storage conditions by altering platelet storage solutions, temperature, and materials. Nevertheless, the role of OS on platelet survival during storage is still unclear. Hence, this study was conducted to investigate the influence of storage on platelets. Platelets were stored for 12 days at 22°C. OS markers such as aggregation, superoxides, reactive oxygen species, glucose, pH, lipid peroxidation, protein oxidation, and antioxidant enzymes were assessed. OS increased during storage as indicated by increments in aggregation, superoxides, pH, conjugate dienes, and superoxide dismutase and decrements in glucose and catalase. Thus, platelets could endure OS till 6 days during storage, due to the antioxidant defense system. An evident increase in OS was observed from day 8 of storage, which can diminish the platelet efficacy. The present study provides an insight into the gradual changes occurring during platelet storage. This lays the foundation towards new possibilities of employing various antioxidants as additives in storage solutions.
Neutrophil-to-Lymphocyte Ratio Predicts Early Mortality in Patients with HBV-Related Decompensated Cirrhosis
Authors: Zhang Honggang , Sun Qinqin , Mao Weilin , Fan Jian , Ye Bo
Published: February 2016

Background. The neutrophil-to-lymphocyte ratio (NLR) is an inflammation index that has been shown to independently predict poor clinical outcomes. We aimed to evaluate the clinical value of NLR in the prediction of 30-day mortality in patients with HBV-related decompensated cirrhosis (HBV-DeCi).Methods. This was a retrospective cohort study that included 148 patients with HBV-DeCi.Results. An elevated NLR was associated with increased severity of liver disease and mortality within 30 days. Multivariate analysis suggested that NLR, similar to the model for end-stage liver disease (MELD) score, is an additional independent predictor of 30-day mortality (P<0.01).Conclusion. Our results suggest that a high NLR can be considered a new independent biomarker for predicting 30-day mortality in patients with HBV-DeCi.
Does the Degree of Hepatocellular Carcinoma Tumor Necrosis following Transarterial Chemoembolization Impact Patient Survival?
Authors: Haywood Nathan , Gennaro Kyle , Obert John , Sauer Paul F. , Redden David T. , Zarzour Jessica , Smith J. Kevin , Bolus David , Saddekni Souheil , Aal Ahmed Kamel Abdel , Gray Stephen , White Jared , Eckhoff Devin E. , DuBay Derek A.
Published: February 2016

Purpose. The association between transarterial chemoembolization- (TACE-) induced HCC tumor necrosis measured by the modified Response Evaluation Criteria In Solid Tumors (mRECIST) and patient survival is poorly defined. We hypothesize that survival will be superior in HCC patients with increased TACE-induced tumor necrosis.Materials and Methods. TACE interventions were retrospectively reviewed. Tumor response was quantified via dichotomized (responders and nonresponders) and the four defined mRECIST categories.Results. Median survival following TACE was significantly greater in responders compared to nonresponders (20.8 months versus 14.9 months,p=0.011). Survival outcomes also significantly varied among the four mRECIST categories (p=0.0003): complete, 21.4 months; partial, 20.8; stable, 16.8; and progressive, 7.73. Only progressive disease demonstrated significantly worse survival when compared to complete response. Multivariable analysis showed that progressive disease, increasing total tumor diameter, and non-Child-Pugh class A were independent predictors of post-TACE mortality.Conclusions. Both dichotomized (responders and nonresponders) and the four defined mRECIST responses to TACE in patients with HCC were predictive of survival. The main driver of the survival analysis was poor survival in the progressive disease group. Surprisingly, there was small nonsignificant survival benefit between complete, partial, and stable disease groups. These findings may inform HCC treatment decisions following first TACE.
Polymorphisms of the PPAR-γ(rs1801282) and Its Coactivator (rs8192673) Have a Minor Effect on Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus
Authors: Pleskovič Aleš , Šantl Letonja Marija , Cokan Vujkovac Andreja , Starćević Jovana Nikolajević , Petrovič Danijel
Published: February 2016

Background. The present study was designed to clarify whether common single nucleotide polymorphisms (SNPs) of the Peroxisome Proliferator-Activated Receptor-γ(PPAR-γ) gene (rs1801282) and the Peroxisome Proliferator-Activated Receptor-γCoactivator-1 (PGC-1α) gene (rs8192673) are associated with markers of carotid and coronary atherosclerosis in Caucasians with type 2 diabetes mellitus (T2DM).Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled in the cross-sectional study. Markers of carotid atherosclerosis were assessed ultrasonographically. In 215 out of 595 subjects with T2DM, a coronary computed tomography angiography (CCTA) was performed for diagnostic purposes. Genotyping of either rs1801282 or rs8192673 was performed using KASPar assays.Results. In our study, we demonstrated an effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM in univariate and in multivariable linear regression analyses. Finally, we did not demonstrate any association between either rs1801282 or rs8192673 and markers of coronary atherosclerosis.Conclusions. In our study, we demonstrated a minor effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM. Moreover, we demonstrated a minor effect of the rs8192673 on CIMT progression in the 3.8-year follow-up in Caucasians with T2DM.
Correlation betweenTrichomonas vaginalisand Concurrency: An Ecological Study
Authors: Kenyon Chris R. , Hamilton Deven T.
Published: February 2016

Objective. There is a large variation in the prevalence ofTrichomonas vaginalis(TV) between different countries and between racial groups within countries. Sexual partner concurrency may play a role. We investigate the correlation between the prevalence of sexual partner concurrency and TV prevalence.Methods. Spearman’s correlation to assess relationship between TV prevalence in women and point prevalence of concurrency in men in (1) 11 countries with comparable data (concurrency data from WHO Survey and TV prevalence data from Global Burden of Disease estimates) and (2) three racial groups in the United States (Add Health Study).Results. The prevalence of TV and concurrency was positively correlated in the international (rho = 0.84,P=0.001) and USA study (rho = 1.0,P<0.001).Conclusion. Prospective longitudinal studies that include measures of partner behavior are required to definitively establish the role of concurrency in the spread of TV.
Optimal Bounds for Neuman Mean Using Arithmetic and Centroidal Means
Authors: Song Ying-Qing , Qian Wei-Mao , Chu Yu-Ming
Published: February 2016

We present the best possible parametersα1,α2,β1,β2∈Randα3,β3∈(1/2,1)such that the double inequalitiesα1A(a,b)+(1-α1)C(a,b)<NQA(a,b)<β1A(a,b)+(1-β1)C(a,b),Aα2(a,b)C1-α2(a,b)<NQA(a,b)<Aβ2(a,b)C1-β2(a,b),andC[α3a+(1-α3)b,α3b+(1-α3)a]<NQA(a,b)0witha≠band give several sharp inequalities involving the hyperbolic and inverse hyperbolic functions. Here,N(a,b),A(a,b),Q(a,b), andC(a,b)are, respectively, the Neuman, arithmetic, quadratic, and centroidal means ofaandb, andNQA(a,b)=N[Q(a,b),A(a,b)].
The First Observation of Metallic Behaviour in Nd3.5Sm0.5Ni3O8
Authors: Nakata Akitoshi , Yano Syunsuke , Yamamoto Hiroki , Sakura Syunsuke , Kimishima Yoshihide , Uehara Masatomo
Published: February 2016

In Nd3.5Sm0.5Ni3O8which has basically the same crystal structure and the similar electrical configuration (Ni+3d9/Ni2+3d8mix valence state) with high-Tccuprate, it has been found that this material shows metallic behaviour down to about 20 K by intercalation and subsequent deintercalation with sulfur. This is the first observation of the metallic state in this system. It is unclear why sulfur-intercalation and deintercalation induce the metallic state. We speculate that sulfur works as an effective getter for removing the interstitial apical oxygen which impedes the metallic conduction. However, the weak localization of carriers in the NiO2planes still remains below 20 K and the localization may be one of the obstacles to occurrence of possible superconductivity.
An Unusual Case of Spontaneous Esophageal Rupture after Swallowing a Boneless Chicken Nugget
Authors: Aga Zeenia , Avelino Jackie , Darling Gail E. , Leung Jo Jo
Published: February 2016

A 25-year-old previously healthy man presented to our Emergency Department with shortness of breath and epigastric pain after swallowing a boneless chicken nugget one hour prior to presentation. Physical examination revealed epigastric rigidity and tenderness. Serology was normal except for mildly elevated bilirubin and amylase. Computed tomography (CT) scan of the chest revealed a distal esophageal rupture with accompanying pneumomediastinum and left-sided pleural effusion. Treatment was initiated with administration of intravenous fluids and broad-spectrum antibiotics. Subsequently, an esophageal stent was inserted endoscopically in addition to VATS (Video-Assisted Thoracoscopic Surgery) drainage of the left-sided pleural space. This case illustrates an unusual presentation of Boerhaave’s syndrome: a rare and life-threatening form of noniatrogenic esophageal rupture most often preceded by forceful vomiting. Our case demonstrates that physicians should maintain an index of suspicion for spontaneous esophageal rupture in patients presenting with shortness of breath and epigastric pain even in the absence of preceding vomiting, cough, or seizure. Additionally, ingestion of boneless, shell-less foods may be sufficient to cause rupture in individuals without underlying esophageal pathology. CT scan of the thorax and upper abdomen should be performed in these patients to rule out this rare and life-threatening diagnosis.
Recombinant Brain Natriuretic Peptide for the Prevention of Contrast-Induced Nephropathy in Patients with Chronic Kidney Disease Undergoing Nonemergent Percutaneous Coronary Intervention or Coronary Angiography: A Randomized Controlled Trial
Authors: Liu Jinming , Xie Yanan , He Fang , Gao Zihan , Hao Yuming , Zu Xiuguang , Chang Liang , Li Yongjun
Published: February 2016

The role of brain natriuretic peptide (BNP) in the prevention of contrast-induced nephropathy (CIN) is unknown. This study aimed to investigate BNP’s effect on CIN in chronic kidney disease (CKD) patients undergoing elective percutaneous coronary intervention (PCI) or coronary angiography (CAG). The patients were randomized to BNP (0.005 μg/kg/min before contrast media (CM) exposure and saline hydration,n=106) or saline hydration alone (n=103). Cystatin C, serum creatinine (SCr) levels, and estimated glomerular filtration rates (eGFR) were assessed at several time points. The primary endpoint was CIN incidence; secondary endpoint included changes in cystatin C, SCr, and eGFR. CIN incidence was significantly lower in the BNP group compared to controls (6.6% versus 16.5%,P=0.025). In addition, a more significant deterioration of eGFR, cystatin C, and SCr from 48 h to 1 week (P<0.05) was observed in controls compared to the BNP group. Although eGFR gradually deteriorated in both groups, a faster recovery was achieved in the BNP group. Multivariate logistic regression revealed that using >100 mL of CM (odds ratio: 4.36,P=0.004) and BNP administration (odds ratio: 0.21,P=0.006) were independently associated with CIN. Combined with hydration, exogenous BNP administration before CM effectively decreases CIN incidence in CKD patients.
Relationships among the Microstructure, Mechanical Properties, and Fatigue Behavior in Thin Ti6Al4V
Authors: Fan Y. , Tian W. , Guo Y. , Sun Z. , Xu J.
Published: February 2016

The microstructures of Ti6Al4V are complex and strongly affect its mechanical properties and fatigue behavior. This paper investigates the role of microstructure on mechanical and fatigue properties of thin-section Ti6Al4V sheets, with the aim of reviewing the effects of microstructure on fatigue properties where suboptimal microstructures might result following heat treatment of assemblies that may not be suited to further annealing, for example, following laser welding. Samples of Ti6Al4V sheet were subjected to a range of heat treatments, including annealing and water quenching from temperatures ranging from 650°C to 1050°C. Micrographs of these samples were inspected for microstructure, and hardness, 0.2% proof stress, elongation, and fracture strength were measured and attributed back to microstructure. Fractography was used to support the findings from microstructure and mechanical analyses. The strength ranking from high to low for the microstructures of thin Ti6Al4V sheets observed in this study is as follows: acicularα′martensite, Widmanstätten, bimodal, and equiaxed microstructure. The fatigue strength ranking from high to low is as follows: equiaxed, bimodal, Widmanstätten, and acicularα′martensite microstructure.
The Synthesis and Evaluations of the68Ga-Lissamine Rhodamine B (LRB) as a New Radiotracer for Imaging Tumors by Positron Emission Tomography
Authors: Li Xuena , Yin Yafu , Du Bulin , Li Na , Li Yaming
Published: February 2016

Purpose. The aim of this study is to synthesize and evaluate68Ga-labeled Lissamine Rhodamine B (LRB) as a new radiotracer for imaging MDA-MB-231 and MCF-7 cells induced tumor mice by positron emission tomography (PET).Methods. Firstly, we performed the radio synthesis and microPET imaging of68Ga(DOTA-LRB) in athymic nude mice bearing MDA-MB-231 and MCF-7 human breast cancer xenografts. Additionally, the evaluations of18F-fluorodeoxyglucose (FDG), as a glucose metabolism radiotracer for imaging tumors in the same xenografts, have been conducted as a comparison.Results. The radiochemical purity of68Ga(DOTA-LRB) was >95%. MicroPET dynamic imaging revealed that the uptake of68Ga(DOTA-LRB) was mainly in normal organs, such as kidney, heart, liver, and brain and mainly excreted from kidney. The MDA-MB-231 and MCF-7 tumors were not clearly visible in PET images at 5, 15, 30, 40, 50, and 60 min after injection of68Ga(DOTA-LRB). The tumor uptake values of18F-FDG were3.79±0.57and1.93±0.48%ID/g in MDA-MB-231 and MCF-7 tumor xenografts, respectively.Conclusions.68Ga(DOTA-LRB) can be easily synthesized with high radiochemical purity and stability; however, it may be not an ideal PET radiotracer for imaging of MDR-positive tumors.
Joint Degradation in a Monkey Model of Collagen-Induced Arthritis: Role of Cathepsin K Based on Biochemical Markers and Histological Evaluation
Authors: Tanaka Makoto , Yamada Hiroyuki , Nishikawa Satoshi , Mori Hiroshi , Ochi Yasuo , Horai Naoto , Li Minqi , Amizuka Norio
Published: February 2016

The role of cathepsin K in joint degradation in a model of collagen-induced arthritis (CIA) in cynomolgus monkey was examined using biochemical markers and histology. Joint swelling, urinary C-telopeptide of type II collagen (CTX-II), deoxypyridinoline (DPD), and N- and C-telopeptides of type I collagen (NTX and CTX-I, resp.) were analyzed. Immunohistochemistry of type II collagen, cathepsin K, and CTX-II were performed using joints. Joint swelling reached peak on day 42 and continued at this level. The CTX-II level peaked on day 28 and declined thereafter, while CTX-I, NTX, and DPD reached plateau on day 43. Joint swelling was positively correlated with CTX-II increases on days 20 and 42/43, with increases in CTX-I and NTX/Cr on days 42/43 and 84, and with DPD increases throughout the study period. Intense cathepsin K staining was observed in osteoclasts and in articular cartilage and synovial tissue in arthritic joints. CTX-II was present in the superficial layer of articular cartilage in CIA monkeys. Evidence from biochemical markers suggests that matrix degradation in the CIA model starts with degradation of cartilage, rather than bone resorption. Cathepsin K expressed in osteoclasts, articular cartilage, and synovial tissue may contribute to degradation of cartilage.
Short-Term Speed Prediction Using Remote Microwave Sensor Data: Machine Learning versus Statistical Model
Authors: Jiang Han , Zou Yajie , Zhang Shen , Tang Jinjun , Wang Yinhai
Published: February 2016

Recently, a number of short-term speed prediction approaches have been developed, in which most algorithms are based on machine learning and statistical theory. This paper examined the multistep ahead prediction performance of eight different models using the 2-minute travel speed data collected from three Remote Traffic Microwave Sensors located on a southbound segment of 4th ring road in Beijing City. Specifically, we consider five machine learning methods: Back Propagation Neural Network (BPNN), nonlinear autoregressive model with exogenous inputs neural network (NARXNN), support vector machine with radial basis function as kernel function (SVM-RBF), Support Vector Machine with Linear Function (SVM-LIN), and Multilinear Regression (MLR) as candidate. Three statistical models are also selected: Autoregressive Integrated Moving Average (ARIMA), Vector Autoregression (VAR), and Space-Time (ST) model. From the prediction results, we find the following meaningful results: (1) the prediction accuracy of speed deteriorates as the prediction time steps increase for all models; (2) the BPNN, NARXNN, and SVM-RBF can clearly outperform two traditional statistical models: ARIMA and VAR; (3) the prediction performance of ANN is superior to that of SVM and MLR; (4) as time step increases, the ST model can consistently provide the lowest MAE comparing with ARIMA and VAR.
The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer
Authors: Youngblood Victoria M. , Kim Laura C. , Edwards Deanna N. , Hwang Yoonha , Santapuram Pranav R. , Stirdivant Steven M. , Lu Pengcheng , Ye Fei , Brantley-Sieders Dana M. , Chen Jin
Published: February 2016

Dysregulation of receptor tyrosine kinases (RTK) contributes to cellular transformation and cancer progression by disrupting key metabolic signaling pathways. The EPHA2 RTK is overexpressed in aggressive forms of breast cancer, including the HER2+ subtype, and correlates with poor prognosis. However, the role of EPHA2 in tumor metabolism remains unexplored. In this study, we used in vivo and in vitro models of HER2-overexpressing breast cancer to investigate the mechanisms by which EPHA2 ligand–independent signaling promotes tumorigenesis in the absence of its prototypic ligand, ephrin-A1. We demonstrate that ephrin-A1 loss leads to upregulated glutamine metabolism and lipid accumulation that enhanced tumor growth. Global metabolic profiling of ephrin-A1–null, HER2-overexpressing mammary tumors revealed a significant increase in glutaminolysis, a critical metabolic pathway that generates intermediates for lipogenesis. Pharmacologic inhibition of glutaminase activity reduced tumor growth in both ephrin-A1–depleted and EPHA2-overexpressing tumor allografts in vivo. Mechanistically, we show that the enhanced proliferation and glutaminolysis in the absence of ephrin-A1 were attributed to increased RhoA-dependent glutaminase activity. EPHA2 depletion or pharmacologic inhibition of Rho, glutaminase, or fatty acid synthase abrogated the increased lipid content and proliferative effects of ephrin-A1 knockdown. Together, these findings highlight a novel, unsuspected connection between the EPHA2/ephrin-A1 signaling axis and tumor metabolism, and suggest potential new therapeutic targets in cancer subtypes exhibiting glutamine dependency. Cancer Res; 76(7); 1825–36. ©2016 AACR.
Abscopal Benefits of Localized Radiotherapy Depend on Activated T-cell Trafficking and Distribution between Metastatic Lesions
Authors: Poleszczuk Jan T. , Luddy Kimberly A. , Prokopiou Sotiris , Robertson-Tessi Mark , Moros Eduardo G. , Fishman Mayer , Djeu Julie Y. , Finkelstein Steven E. , Enderling Heiko
Published: February 2016

It remains unclear how localized radiotherapy for cancer metastases can occasionally elicit a systemic antitumor effect, known as the abscopal effect, but historically, it has been speculated to reflect the generation of a host immunotherapeutic response. The ability to purposefully and reliably induce abscopal effects in metastatic tumors could meet many unmet clinical needs. Here, we describe a mathematical model that incorporates physiologic information about T-cell trafficking to estimate the distribution of focal therapy–activated T cells between metastatic lesions. We integrated a dynamic model of tumor–immune interactions with systemic T-cell trafficking patterns to simulate the development of metastases. In virtual case studies, we found that the dissemination of activated T cells among multiple metastatic sites is complex and not intuitively predictable. Furthermore, we show that not all metastatic sites participate in systemic immune surveillance equally, and therefore the success in triggering the abscopal effect depends, at least in part, on which metastatic site is selected for localized therapy. Moreover, simulations revealed that seeding new metastatic sites may accelerate the growth of the primary tumor, because T-cell responses are partially diverted to the developing metastases, but the removal of the primary tumor can also favor the rapid growth of preexisting metastatic lesions. Collectively, our work provides the framework to prospectively identify anatomically defined focal therapy targets that are most likely to trigger an immune-mediated abscopal response and therefore may inform personalized treatment strategies in patients with metastatic disease. Cancer Res; 76(5); 1009–18. ©2016 AACR.
HER2 Signaling Drives DNA Anabolism and Proliferation through SRC-3 Phosphorylation and E2F1-Regulated Genes
Authors: Nikolai Bryan C. , Lanz Rainer B. , York Brian , Dasgupta Subhamoy , Mitsiades Nicholas , Creighton Chad J. , Tsimelzon Anna , Hilsenbeck Susan G. , Lonard David M. , Smith Carolyn L. , O'Malley Bert W.
Published: February 2016

Approximately 20% of early-stage breast cancers display amplification or overexpression of the ErbB2/HER2 oncogene, conferring poor prognosis and resistance to endocrine therapy. Targeting HER2+ tumors with trastuzumab or the receptor tyrosine kinase (RTK) inhibitor lapatinib significantly improves survival, yet tumor resistance and progression of metastatic disease still develop over time. Although the mechanisms of cytosolic HER2 signaling are well studied, nuclear signaling components and gene regulatory networks that bestow therapeutic resistance and limitless proliferative potential are incompletely understood. Here, we use biochemical and bioinformatic approaches to identify effectors and targets of HER2 transcriptional signaling in human breast cancer. Phosphorylation and activity of the Steroid Receptor Coactivator-3 (SRC-3) is reduced upon HER2 inhibition, and recruitment of SRC-3 to regulatory elements of endogenous genes is impaired. Transcripts regulated by HER2 signaling are highly enriched with E2F1 binding sites and define a gene signature associated with proliferative breast tumor subtypes, cell-cycle progression, and DNA replication. We show that HER2 signaling promotes breast cancer cell proliferation through regulation of E2F1-driven DNA metabolism and replication genes together with phosphorylation and activity of the transcriptional coactivator SRC-3. Furthermore, our analyses identified a cyclin-dependent kinase (CDK) signaling node that, when targeted using the CDK4/6 inhibitor palbociclib, defines overlap and divergence of adjuvant pharmacologic targeting. Importantly, lapatinib and palbociclib strictly block de novo synthesis of DNA, mostly through disruption of E2F1 and its target genes. These results have implications for rational discovery of pharmacologic combinations in preclinical models of adjuvant treatment and therapeutic resistance. Cancer Res; 76(6); 1463–75. ©2016 AACR.
IgG Glycome in Colorectal Cancer
Authors: Vučković Frano , Theodoratou Evropi , Thaçi Kujtim , Timofeeva Maria , Vojta Aleksandar , Štambuk Jerko , Pučić-Baković Maja , Rudd Pauline M. , Đerek Lovorka , Servis Dražen , Wennerström Annika , Farrington Susan M. , Perola Markus , Aulchenko Yurii , Dunlop Malcolm G. , Campbell Harry , Lauc Gordan
Published: February 2016

Purpose: Alternative glycosylation has significant structural and functional consequences on IgG and consequently also on cancer immunosurveillance. Because of technological limitations, the effects of highly heritable individual variations and the differences in the dynamics of changes in IgG glycosylation on colorectal cancer were never investigated before.

Experimental Design: Using recently developed high-throughput UPLC technology for IgG glycosylation analysis, we analyzed IgG glycome composition in 760 patients with colorectal cancer and 538 matching controls. Effects of surgery were evaluated in 28 patients sampled before and three times after surgery. A predictive model was built using regularized logistic regression and evaluated using a 10-cross validation procedure. Furthermore, IgG glycome composition was analyzed in 39 plasma samples collected before initial diagnosis of colorectal cancer.

Results: We have found that colorectal cancer associates with decrease in IgG galactosylation, IgG sialylation and increase in core-fucosylation of neutral glycans with concurrent decrease of core-fucosylation of sialylated glycans. Although a model based on age and sex did not show discriminative power (AUC = 0.499), the addition of glycan variables into the model considerably increased the discriminative power of the model (AUC = 0.755). However, none of these differences were significant in the small set of samples collected before the initial diagnosis.

Conclusions: Considering the functional relevance of IgG glycosylation for both tumor immunosurveillance and clinical efficacy of therapy with mAbs, individual variation in IgG glycosylation may turn out to be important for prediction of disease course or the choice of therapy, thus warranting further, more detailed studies of IgG glycosylation in colorectal cancer. Clin Cancer Res; 22(12); 3078–86. ©2016 AACR.
Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic
Authors: van der Watt Pauline J. , Chi Alicia , Stelma Tamara , Stowell Catherine , Strydom Erin , Carden Sarah , Angus Liselotte , Hadley Kate , Lang Dirk , Wei Wei , Birrer Michael J. , Trent John O. , Leaner Virna D.
Published: February 2016

Karyopherin beta 1 (Kpnβ1) is a nuclear transport receptor that imports cargoes into the nucleus. Recently, elevated Kpnβ1 expression was found in certain cancers and Kpnβ1 silencing with siRNA was shown to induce cancer cell death. This study aimed to identify novel small molecule inhibitors of Kpnβ1, and determine their anticancer activity. An in silico screen identified molecules that potentially bind Kpnβ1 and Inhibitor of Nuclear Import-43, INI-43 (3-(1H-benzimidazol-2-yl)-1-(3-dimethylaminopropyl)pyrrolo[5,4-b]quinoxalin-2-amine) was investigated further as it interfered with the nuclear localization of Kpnβ1 and known Kpnβ1 cargoes NFAT, NFκB, AP-1, and NFY and inhibited the proliferation of cancer cells of different tissue origins. Minimum effect on the proliferation of noncancer cells was observed at the concentration of INI-43 that showed a significant cytotoxic effect on various cervical and esophageal cancer cell lines. A rescue experiment confirmed that INI-43 exerted its cell killing effects, in part, by targeting Kpnβ1. INI-43 treatment elicited a G2–M cell-cycle arrest in cancer cells and induced the intrinsic apoptotic pathway. Intraperitoneal administration of INI-43 significantly inhibited the growth of subcutaneously xenografted esophageal and cervical tumor cells. We propose that Kpnβ1 inhibitors could have therapeutic potential for the treatment of cancer. Mol Cancer Ther; 15(4); 560–73. ©2016 AACR.
Dissecting Therapeutic Resistance to ERK Inhibition
Authors: Jha Sharda , Morris Erick J. , Hruza Alan , Mansueto My Sam , Schroeder Gottfried K. , Arbanas Jaren , McMasters Daniel , Restaino Clifford R. , Dayananth Priya , Black Stuart , Elsen Nathaniel L. , Mannarino Anthony , Cooper Alan , Fawell Stephen , Zawel Leigh , Jayaraman Lata , Samatar Ahmed A.
Published: February 2016

The MAPK pathway is frequently activated in many human cancers, particularly melanomas. A single-nucleotide mutation in BRAF resulting in the substitution of glutamic acid for valine (V600E) causes constitutive activation of the downstream MAPK pathway. Selective BRAF and MEK inhibitor therapies have demonstrated remarkable antitumor responses in BRAFV600E-mutant melanoma patients. However, initial tumor shrinkage is transient and the vast majority of patients develop resistance. We previously reported that SCH772984, an ERK 1/2 inhibitor, effectively suppressed MAPK pathway signaling and cell proliferation in BRAF, MEK, and concurrent BRAF/MEK inhibitor-resistant tumor models. ERK inhibitors are currently being evaluated in clinical trials and, in anticipation of the likelihood of clinical resistance, we sought to prospectively model acquired resistance to SCH772984. Our data show that long-term exposure of cells to SCH772984 leads to acquired resistance, attributable to a mutation of glycine to aspartic acid (G186D) in the DFG motif of ERK1. Structural and biophysical studies demonstrated specific defects in SCH772984 binding to mutant ERK. Taken together, these studies describe the interaction of SCH772984 with ERK and identify a novel mechanism of ERK inhibitor resistance through mutation of a single residue within the DFG motif. Mol Cancer Ther; 15(4); 548–59. ©2016 AACR.
Novel Mps1 Kinase Inhibitors with Potent Antitumor Activity
Authors: Wengner Antje M. , Siemeister Gerhard , Koppitz Marcus , Schulze Volker , Kosemund Dirk , Klar Ulrich , Stoeckigt Detlef , Neuhaus Roland , Lienau Philip , Bader Benjamin , Prechtl Stefan , Raschke Marian , Frisk Anna-Lena , von Ahsen Oliver , Michels Martin , Kreft Bertolt , von Nussbaum Franz , Brands Michael , Mumberg Dominik , Ziegelbauer Karl
Published: February 2016

Monopolar spindle 1 (Mps1) has been shown to function as the key kinase that activates the spindle assembly checkpoint (SAC) to secure proper distribution of chromosomes to daughter cells. Here, we report the structure and functional characterization of two novel selective Mps1 inhibitors, BAY 1161909 and BAY 1217389, derived from structurally distinct chemical classes. BAY 1161909 and BAY 1217389 inhibited Mps1 kinase activity with IC50 values below 10 nmol/L while showing an excellent selectivity profile. In cellular mechanistic assays, both Mps1 inhibitors abrogated nocodazole-induced SAC activity and induced premature exit from mitosis (“mitotic breakthrough”), resulting in multinuclearity and tumor cell death. Both compounds efficiently inhibited tumor cell proliferation in vitro (IC50 nmol/L range). In vivo, BAY 1161909 and BAY 1217389 achieved moderate efficacy in monotherapy in tumor xenograft studies. However, in line with its unique mode of action, when combined with paclitaxel, low doses of Mps1 inhibitor reduced paclitaxel-induced mitotic arrest by the weakening of SAC activity. As a result, combination therapy strongly improved efficacy over paclitaxel or Mps1 inhibitor monotreatment at the respective MTDs in a broad range of xenograft models, including those showing acquired or intrinsic paclitaxel resistance. Both Mps1 inhibitors showed good tolerability without adding toxicity to paclitaxel monotherapy. These preclinical findings validate the innovative concept of SAC abrogation for cancer therapy and justify clinical proof-of-concept studies evaluating the Mps1 inhibitors BAY 1161909 and BAY 1217389 in combination with antimitotic cancer drugs to enhance their efficacy and potentially overcome resistance. Mol Cancer Ther; 15(4); 583–92. ©2016 AACR.
Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner
Authors: Esfandiari Arman , Hawthorne Thomas A. , Nakjang Sirintra , Lunec John
Published: February 2016

Sensitivity to MDM2 inhibitors is widely different among responsive TP53 wild-type cell lines and tumors. Understanding the determinants of MDM2 inhibitor sensitivity is pertinent for their optimal clinical application. Wild-type p53-inducible phosphatase-1 (WIP1) encoded by PPM1D, is activated, gained/amplified in a range of TP53 wild-type malignancies, and is involved in p53 stress response homeostasis. We investigated cellular growth/proliferation of TP53 wild-type and matched mutant/null cell line pairs, differing in PPM1D genetic status, in response to Nutlin-3/RG7388 ± a highly selective WIP1 inhibitor, GSK2830371. We also assessed the effects of GSK2830371 on MDM2 inhibitor-induced p53Ser15 phosphorylation, p53-mediated global transcriptional activity, and apoptosis. The investigated cell line pairs were relatively insensitive to single-agent GSK2830371. However, a non–growth-inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harboring PPM1D-activating mutations or copy number gain (up to 5.8-fold decrease in GI50). Potentiation also correlated with significant increase in MDM2 inhibitor–induced cell death endpoints that were preceded by a marked increase in a WIP1 negatively regulated substrate, phosphorylated p53Ser15, known to increase p53 transcriptional activity. Microarray-based gene expression analysis showed that the combination treatment increases the subset of early RG7388-induced p53 transcriptional target genes. These findings demonstrate that potent and selective WIP1 inhibition potentiates the response to MDM2 inhibitors in TP53 wild-type cells, particularly those with PPM1D activation or gain, while highlighting the mechanistic importance of p53Ser15 and its potential use as a biomarker for response to this combination regimen. Mol Cancer Ther; 15(3); 379–91. ©2016 AACR.
The Role of CD44 in Glucose Metabolism in Prostatic Small Cell Neuroendocrine Carcinoma
Authors: Li Wei , Cohen Alexa , Sun Yin , Squires Jill , Braas Daniel , Graeber Thomas G. , Du Lin , Li Gang , Li Zhen , Xu Xiang , Chen Xufeng , Huang Jiaoti
Published: February 2016

While prostatic adenocarcinomas are relatively indolent, some patients with advanced adenocarcinomas recur with small cell neuroendocrine carcinoma which is highly aggressive and lethal. Because glycolysis is a feature of malignancy and the degree of glycolysis generally correlates with tumor aggressiveness, we wanted to compare the metabolic differences and the molecular mechanisms involved between the two tumor types. In this study, and based on previous characterization, LNCaP and PC-3 prostate cancer cell lines were selected as models of prostatic adenocarcinoma and small cell neuroendocrine carcinoma, respectively. In addition to measuring glucose consumption, lactate secretion, and reactive oxygen species (ROS) levels, we performed metabolic profiling in these two model systems. The role of CD44 was studied by RNAi and lentivirus-mediated overexpression. Expression of key enzymes in glycolysis was studied using human tissue microarrays containing benign prostate, adenocarcinoma, and small cell neuroendocrine carcinoma. Results showed that glycolytic features of PC-3 cells were higher than that of LNCaP cells. PFKFB4 was overexpressed in human small cell carcinoma tissue versus adenocarcinoma tissue. CD44 regulated glucose metabolism, intracellular ROS, and cell proliferation in PC-3 cells. Inhibition of CD44 also sensitized PC-3 cells to carboplatin. In conclusion, this study suggests different pathways of glucose metabolism contribute to the disparate biologic behaviors of these two tumor types.

Implications: CD44 is an important regulator of glucose metabolism in small cell neuroendocrine carcinoma and may be an important therapeutic target. Mol Cancer Res; 14(4); 344–53. ©2016 AACR.
The Complex Role of Neutrophils in Tumor Angiogenesis and Metastasis
Authors: Liang Wei , Ferrara Napoleone
Published: February 2016

Chronic inflammation fosters cancer development and progression and also modulates tumor responses to anticancer therapies. Neutrophils are key effector cells in innate immunity and are known to play a critical role in various inflammatory disorders. However, the functions of neutrophils in cancer pathogenesis have been largely neglected until recently and still remain poorly characterized compared with other immune cells in the tumor microenvironment. We highlight recent findings on the mechanisms by which tumor cells, in cooperation with tumor-associated stromal cells, induce expansion, recruitment, and polarization of neutrophils. We also review the multifaceted roles that neutrophils play in different aspects of cancer development and progression, with an emphasis on tumor angiogenesis and metastasis. Cancer Immunol Res; 4(2); 83–91. ©2016 AACR.
Comparison of the Estimated Glomerular Filtration Rate (eGFR) in Diabetic Patients, Non-Diabetic Patients and Living Kidney Donors
Authors: Tsuda Akihiro , Ishimura Eiji , Uedono Hideki , Yasumoto Mari , Ichii Mitsuru , Nakatani Shinya , Mori Katsuhito , Uchida Junji , Emoto Masanori , Nakatani Tatsuya , Inaba Masaaki
Published: February 2016

Background/Aims: We have reported that the eGFR overestimates renal function when glycemic control is poor. It has been reported that eGFR calculated by serum creatinine underestimates GFR in living kidney donors. We compared the utility of the eGFR in diabetic patients, non-diabetic patients and living kidney donors. Forty diabetic patients, 40 non-diabetic patients, and 40 living kidney donors were enrolled. Methods: GFR was measured by inulin clearance (Cin). eGFR was calculated based on serum creatinine (eGFRcr) or serum cystatin C (eGFRcys). We compared the agreements between each of the eGFR and Cin in each group. Results: There were significant and positive correlations between each eGFR and Cin in diabetic patients and non-diabetic patients. However, the intraclass correlation coefficients (ICC) between each eGFR and Cin in diabetic patients (ICC: eGFRcr 0.699, eGFRcys 0.604) were weaker than those in non-diabetic patients (ICC: eGFRcr 0.865, eGFRcys 0.803). The correlation coefficients between each eGFR and Cin (eGFRcr; r = 0.422, p = 0.0067 and eGFRcys; r = 0.358, p = 0.0522) in living kidney donors were significantly weaker than those in non-diabetic patients. The ICCs between each eGFR and Cin (ICC: eGFRcr 0.340, eGFRcys 0.345) in living kidney donors were significantly weaker than those in non-diabetic patients. Conclusions: Based on Cin, eGFR was accurate in non-diabetic patients. However, eGFR was inaccurate in living kidney donors and relatively inaccurate in diabetic patients.