bluuebunny/crossref_metadata_2025 huggingface dataset:
Spacecraft Actuator Diagnosis with Principal Component Analysis: Application to the Rendez-Vous Phase of the Mars Sample Return Mission
Authors: Nasri Othman , Gueddi Imen , Dague Philippe , Benothman Kamal
Published: May 2015

This paper presents a fault detection and isolation (FDI) approach in order to detect and isolate actuators (thrusters and reaction wheels) faults of an autonomous spacecraft involved in the rendez-vous phase of the Mars Sample Return (MSR) mission. The principal component analysis (PCA) has been adopted to estimate the relationships between the various variables of the process. To ensure the feasibility of the proposed FDI approach, a set of data provided by the industrial “high-fidelity” simulator of the MSR and representing the opening (resp., the rotation) rates of the spacecraft thrusters (resp., reaction wheels) has been considered. The test results demonstrate that the fault detection and isolation are successfully accomplished.
Health Care Consumption during Pregnancy in relation to Maternal Body Mass Index: A Swedish Population Based Observational Study
Authors: Lindholm Elisabeth S. , Altman Daniel , Norman Margareta , Blomberg Marie
Published: May 2015

Objective. To assess whether antenatal health care consumption is associated with maternal body mass index (BMI).Design. A register based observational study.Methods. The Swedish Medical Birth Register, the Maternal Health Care Register, and the Inpatient Register were used to determine antenatal health care consumption according to BMI categories for primiparous women with singleton pregnancies, from 2006 to 2008,n=71,638. Pairwise comparisons among BMI groups are obtained post hoc by Tukey HSD test.Result. Obese women were more often admitted for in-patient care (p<0.001), had longer antenatal hospital stays (p<0.001), and were more often sick-listed by an obstetrician (p<0.001) during their pregnancy, compared to women with normal weight women. Preeclampsia was more than four times as common, hypertension five times as common, and gestational diabetes 11 times as common when comparing in-patient care, obese to normal weight women (p<0.001for all comparisons). Underweight mothers had longer stay in hospitals (p<0.05) and hydronephrosis and hyperemesis gravidarum were more than twice as common (bothp<0.001).Conclusion. Obese and underweight mothers consumed significantly more health care resources and obese women were significantly more often sick-listed during their pregnancy when compared to pregnant women of normal weight.
Primitive Neuroectodermal Tumor of the Pancreas: A Case Report and Review of the Literature
Authors: Teixeira Uirá , Goldoni Marcos , Unterleider Michelle , Diedrich João , Balbinot Diogo , Rodrigues Pablo , Monteiro Rodolfo , Gomes Daniel , Sampaio José , Fontes Paulo , Waechter Fábio
Published: May 2015

Primitive neuroectodermal tumors (PNETs) are presented as rare malignant neoplasms. In unusual cases, those neoplasms may arise in solid organs containing neuroendocrine cells, such as the pancreas. Herein the case of a 28-year-old patient that underwent gastroduodenopancreatectomy after the diagnosis of a huge mass (PNET) located in both head and body of the pancreas is reported. This is the 19th case of pancreatic PNET reported in literature.
Simultaneous Bilateral Femoral Neck Stress Fracture in a Young Stone Mason
Authors: Khadabadi Nikhil A. , Patil Kiran S.
Published: May 2015

Unilateral stress fractures of the femoral neck are very uncommon and bilateral involvement is even rarer. They commonly occur in athletes, military recruits, older persons, or individuals with underlying metabolic disorders and very seldom in normal individuals. We present a rare case of simultaneous bilateral fracture neck of femur in a 25-year-old man who came with complaints of pain in bilateral groin for 1 month. There was no history of trauma or history suggestive of excessive activity prior to the onset of pain, but there was history of lifting heavy weights daily. On evaluation with MRI scan bilateral fracture of the femur neck was diagnosed and patient was operated on bilaterally with internal fixation done using dynamic hip screw. Patient then regained his routine activity over a period of 6 months and on follow-up at 1 year no avascular necrosis changes were seen in the femur head. We presented this case because of its unusual presentation and the diagnostic challenge it poses.
Improving ELM-Based Service Quality Prediction by Concise Feature Extraction
Authors: Zhao Yuhai , Yin Ying , Sheng Gang , Zhang Bin , Wang Guoren
Published: May 2015

Web services often run on highly dynamic and changing environments, which generate huge volumes of data. Thus, it is impractical to monitor the change of every QoS parameter for the timely trigger precaution due to high computational costs associated with the process. To address the problem, this paper proposes an active service quality prediction method based on extreme learning machine. First, we extract web service trace logs and QoS information from the service log and convert them into feature vectors. Second, by the proposed EC rules, we are enabled to trigger the precaution of QoS as soon as possible with high confidence. An efficient prefix tree based mining algorithm together with some effective pruning rules is developed to mine such rules. Finally, we study how to extract a set of diversified features as the representative of all mined results. The problem is proved to be NP-hard. A greedy algorithm is presented to approximate the optimal solution. Experimental results show that ELM trained by the selected feature subsets can efficiently improve the reliability and the earliness of service quality prediction.
Posterior Reversible Encephalopathy Syndrome due to High Dose Corticosteroids for an MS Relapse
Authors: Morrow Sarah A. , Rana Robina , Lee Donald , Paul Terri , Mahon Jeffrey L.
Published: May 2015

Increased blood pressure is a known adverse effect associated with corticosteroids but little is published regarding the risk with the high doses used in multiple sclerosis (MS). A 53-year-old female with known relapsing remitting MS presented with a new brainstem relapse. Standard of care treatment for an acute MS relapse, 1250 mg of oral prednisone for 5 days, was initiated. She developed an occipital headache and dizziness and felt generally unwell. These symptoms persisted after treatment was complete. On presentation to medical attention, her blood pressure was 199/110 mmHg, although she had no history of hypertension. MRI changes were consistent with posterior reversible encephalopathy syndrome (PRES), demonstrating abnormal T2 signal in both thalami, the posterior occipital and posterior parietal white matter with mild sulcal effacement. As her pressure normalized with medication, her symptoms resolved and the MRI changes improved. No secondary cause of hypertension was found. This is the first reported case of PRES secondary to high dose corticosteroid use for an MS relapse without a history of hypertension and with no other secondary cause of hypertension identified. This rare complication should be considered in MS patients presenting with a headache or other neurological symptoms during treatment for a relapse.
Effects of the Junction Functionality and Chain Entanglements in Chemomechanical Behavior of Polyelectrolyte Gels
Authors: Ma Lianhua , Yang Qingsheng , Yang Chunhui
Published: May 2015

By considering the functionality of junctions and entanglements of polymer chains for polyelectrolyte gels, a new free energy density function is presented via combining Edwards-Vilgis slip-link model with Flory-Huggins theory. On this basis, the effects of the functionality of network junctions and entanglements of polymer chains are systematically analyzed for free swelling of a cubic polyelectrolyte gel and constrained swelling of a blanket layer of the gel. Analytical results show that the functionality of junctions and chains entanglements plays an important role in the coupled chemomechanical deformation of polyelectrolyte gels.
Expression and Characterization of the Novel Genefr47during Freezing in the Wood Frog,Rana sylvatica
Authors: Sullivan Katrina J. , Biggar Kyle K. , Storey Kenneth B.
Published: May 2015

The wood frog,Rana sylvatica, has numerous adaptations that allow it to survive freezing of up to 65% of its total body water during the winter. Such adaptations have been found to include the expression of novel freeze responsive genes that are thought to be important for adaptation and survival. In this study, the tissue-specific stress responsive expression of one novel gene,fr47, was assessed in seven wood frog tissues. In response to freezing, the transcript expression offr47increased significantly in six tissues: heart, lung, liver, skeletal muscle, kidney, and testes. The expression offr47was also strongly upregulated by component stresses of freezing, namely, anoxia and dehydration. A dynamic change infr47expression was also observed during tadpole development, with expression low in embryonic stages (Gosner stages 14–20), increasing through intermediate (stages 26–43) and transformation phases (stages 44-45). These results indicated thatfr47potentially has a role to play in development and metamorphosis, in addition to freeze, anoxia, and dehydration tolerance.De novoanalysis of FR47 protein structure revealed a likelihood of membrane associated function and possible GRB2 association. It is hypothesized that this interaction may influence inositol 1,4,5-trisphosphate production, known to increase during wood frog freezing.
Subjective Visual Vertical during Caloric Stimulation in Healthy Subjects: Implications to Research and Neurorehabilitation
Authors: Funabashi Martha , Flores Aline I. , Vicentino Amanda , Barros Camila G. C. , Pontes-Neto Octavio M. , Leite João P. , Santos-Pontelli Taiza E. G.
Published: May 2015

Background. The subjective visual vertical (SVV) is a perception often impaired in patients with neurologic disorders and is considered a sensitive tool to detect otolithic dysfunctions. However, it remains unclear whether the semicircular canals (SCCs) are also involved in the visual vertical perception.Objective. The aim of this study was to analyze the influence of horizontal SCCs on SVV by caloric stimulation in healthy subjects.Methods. SVV was performed before and during the ice-cold caloric stimulation (4°C, right ear) in 30 healthy subjects.Results. The mean SVV tilts before and during the caloric stimulation were 0.31° ± 0.39 and −0.28° ± 0.40, respectively. There was no significant difference between the mean SVV tilts before and during stimulationp=0.113.Conclusion. These results suggest that horizontal SCCs do not influence SVV. Therefore, investigations and rehabilitation approaches for SVV misperceptions should be focused on otolithic and cognitive strategies.
Dynamical Behaviors of a Stage-Structured Predator-Prey Model with Harvesting Effort and Impulsive Diffusion
Authors: Huang Lingzhi , Yang Zhichun
Published: May 2015

We consider a delayed predator-prey model with harvesting effort and impulsive diffusion between two patches. By the impulsive comparison theorem and the discrete dynamical system determined by the stroboscopic map, we obtain some sufficient conditions on the existence and global attractiveness of predator-eradicated periodic solution for the system. Furthermore, the permanence of the system is derived. The obtained results will modify and improve the ones in some existing publications and give the estimate for the ultimately low and upper boundedness of the systems.
Surgical Extirpation of Apical Left Ventricular Thrombus in Takotsubo Cardiomyopathy
Authors: Niino Tetsuya , Unosawa Satoshi
Published: May 2015

We report a patient with takotsubo cardiomyopathy who underwent surgical resection of apical left ventricular thrombus. A 59-year-old woman was transferred to our hospital in shock with hypothermia and diabetic ketoacidosis. The electrocardiogram showed ST segment elevation, while echocardiography revealed a reduced ejection fraction with apical and midventricular akinesis. Emergency coronary angiography showed normal coronary arteries, so takotsubo cardiomyopathy was diagnosed. Follow-up echocardiography revealed improvement of the ejection fraction. A mobile apical thrombus was also detected. Thrombectomy was performed via a left apical incision and postoperative recovery was uneventful.
On the Performance of a Secure Storage Mechanism for Key Distribution Architectures in Wireless Sensor Networks
Authors: Kazienko Juliano F. , Silva Filho Paulo R. S. , Moraes Igor M. , Albuquerque Célio V. N.
Published: May 2015

Security in wireless sensor networks (WSNs) demands efficient key management schemes. In particular, one of the main research challenges is to ensure secure key storage by sensors due to their constrained resources and high exposure to tampering attempts. To address this issue, we have proposed SENSORLock, a secure key storage mechanism which can be applied to different key distribution architectures for WSNs. In this work, we evaluate SENSORLock through different study cases considering three key distribution architectures: TinySec, SPINS, and NCD. Our goal is to demonstrate its feasibility in large-scale sensor networks. Simulation results indicate that our mechanism introduces an average overhead of 1.9% in terms of end to end delay and provides a similar estimated power consumption compared to the aforementioned architectures. Hence, we argue that it is feasible to use SENSORLock (i) in large-scale sensor networks and (ii) under different key distribution schemes.
One-Class Classification with Extreme Learning Machine
Authors: Leng Qian , Qi Honggang , Miao Jun , Zhu Wentao , Su Guiping
Published: May 2015

One-class classification problem has been investigated thoroughly for past decades. Among one of the most effective neural network approaches for one-class classification, autoencoder has been successfully applied for many applications. However, this classifier relies on traditional learning algorithms such as backpropagation to train the network, which is quite time-consuming. To tackle the slow learning speed in autoencoder neural network, we propose a simple and efficient one-class classifier based on extreme learning machine (ELM). The essence of ELM is that the hidden layer need not be tuned and the output weights can be analytically determined, which leads to much faster learning speed. The experimental evaluation conducted on several real-world benchmarks shows that the ELM based one-class classifier can learn hundreds of times faster than autoencoder and it is competitive over a variety of one-class classification methods.
Generating Multibillion Element Unstructured Meshes on Distributed Memory Parallel Machines
Authors: Soner Seren , Ozturan Can
Published: May 2015

We present a parallel mesh generator called PMSH that is developed as a wrapper code around the open source sequential Netgen mesh generator. Parallelization of the mesh generator is carried out in five stages: (i) generation of a coarse volume mesh; (ii) partitioning of the coarse mesh; (iii) refinement of coarse surface mesh to produce fine surface submeshes; (iv) remeshing of each fine surface submesh to get a final fine mesh; (v) matching of partition boundary vertices followed by global vertex numbering. A new integer based barycentric coordinate method is developed for matching distributed partition boundary vertices. This method does not have precision related problems of floating point coordinate based vertex matching. Test results obtained on an SGI Altix ICE X system with 8192 cores confirm that our approach does indeed enable us to generate multibillion element meshes in a scalable way.
Usage and Limitation of Standard Mobility Models for TCAD Simulation of Nanoscaled FD-SOI MOSFETs
Authors: Ciprut A. , Chelly A. , Karsenty A.
Published: May 2015

TCAD tools have been largely improved in the last decades in order to support both process and device complementary simulations which are usually based on continuously developed models following the technology progress. In this paper, we compare between experimental and TCAD simulated results of two kinds of nanoscale devices: ultrathin body (UTB) and nanoscale Body (NSB) SOI-MOSFET devices, sharing the sameW/Lratio but having a channel thickness ratio of 10 : 1 (46 nm and 4.6 nm, resp.). The experimental transferI-Vcharacteristics were found to be surprisingly different by several orders of magnitude. We analyzed this result by considering the severe mobility degradation and the influence of a large gate voltage dependent series resistance (RSD). TCAD tools do not usually considerRSDto be either channel thickness or gate voltage dependent. After observing a clear discrepancy between the mobility values extracted from our measurements and those modeled by the available TCAD models, we propose a new semiempirical approach to model the transfer characteristics.
A Review of the Application and Performance of Carbon Nanotubes in Fuel Cells
Authors: Luo Chong , Xie Hui , Wang Qin , Luo Geng , Liu Chao
Published: May 2015

The fuel cell has
the nature of high energy conversion efficiency
and low pollutant emission. Carbon nanotubes
used for fuel cells can decrease the needs of
noble metals which are used for catalyst and
improve the performance of fuel cells. The
application of carbon nanotubes in fuel cells is
summarized and discussed. The following aspects
are described in this paper: the method used to
reduce the platinum, the effect of carbon
nanotubes on the fuel cell, improving the
performance of fuel cell catalysts, the
interaction between catalyst and carbon nanotube
support, and the synthetic conditions of carbon
nanotube supported catalyst. We summarize some
of the results of previous studies and raise
expectations for the microscopic state study of
carbon nanotubes in the future.
Plasma Fatty Acids in Zambian Adults with HIV/AIDS: Relation to Dietary Intake and Cardiovascular Risk Factors
Authors: Nyirenda Christopher K. , Kabagambe Edmond K. , Koethe John R. , Kiage James N. , Chi Benjamin H. , Musonda Patrick , Blevins Meridith , Bosire Claire N. , Tsai Michael Y. , Heimburger Douglas C.
Published: May 2015

Objective. To determine whether 24 hr dietary recalls (DR) are a good measure of polyunsaturated fatty acid (PUFA) intake when compared to plasma levels, and whether plasma PUFA is associated with markers of HIV/AIDS progression and cardiovascular disease (CVD) risk.Methods. In a cross-sectional study among 210 antiretroviral therapy-naïve HIV-infected adults from Lusaka, Zambia, we collected data on medical history and dietary intake using 24 hr DR. We measured fatty acids and markers of AIDS progression and CVD risk in fasting plasma collected at baseline.Results. PUFA intakes showed modest correlations with corresponding plasma levels; Spearman correlations were 0.36(p<0.01)for eicosapentaenoic acid and 0.21(p=0.005)for docosahexaenoic acid. While there were no significant associations(p>0.05)between total plasma PUFA and C-reactive protein (CRP) or lipid levels, plasma arachidonic acid was inversely associated with CRP and triglycerides and positively associated with HDL-C, CD4+ T-cell count, and plasma albumin(p<0.05). Plasma saturated fatty acids (SFA) were positively associated with CRP (β= 0.24; 95% CI: 0.08 to 0.40,p=0.003) and triglycerides (β= 0.08; 95% CI: 0.03 to 0.12,p<0.01).Conclusions. Our data suggest that a single DR is inadequate for assessing PUFA intake and that plasma arachidonic acid levels may modulate HIV/AIDS progression and CVD risk.
Applications of Nanostructured Carbon Materials in Constructions: The State of the Art
Authors: Lu Shu-Nan , Xie Ning , Feng Li-Chao , Zhong Jing
Published: May 2015

The most recent studies on the applications of nanostructured carbon materials, including carbon nanotubes, carbon nanofibers, and graphene oxides, in constructions are presented. First, the preparation of nanostructured carbon/infrastructure material composites is summarized. This part is mainly focused on how the nanostructured carbon materials were mixed with cementitious or asphalt matrix to realize a good dispersion condition. Several methods, including high speed melting mixing, surface treatment, and aqueous solution with surfactants and sonication, were introduced. Second, the applications of the carbon nanostructured materials in constructions such as mechanical reinforcement, self‐sensing detectors, self‐heating element for deicing, and electromagnetic shielding component were systematically reviewed. This paper not only helps the readers understand the preparation process of the carbon nanostructured materials/infrastructure material composites but also sheds some light on the state‐of‐the‐art applications of carbon nanostructured materials in constructions.
From Heuristic to Mathematical Modeling of Drugs Dissolution Profiles: Application of Artificial Neural Networks and Genetic Programming
Authors: Mendyk Aleksander , Güres Sinan , Jachowicz Renata , Szlęk Jakub , Polak Sebastian , Wiśniowska Barbara , Kleinebudde Peter
Published: May 2015

The purpose of this work was to develop a mathematical model of the drug dissolution (Q) from the solid lipid extrudates based on the empirical approach. Artificial neural networks (ANNs) and genetic programming (GP) tools were used. Sensitivity analysis of ANNs provided reduction of the original input vector. GP allowed creation of the mathematical equation in two major approaches: (1) direct modeling ofQversus extrudate diameter (d) and the time variable (t) and (2) indirect modeling through Weibull equation. ANNs provided also information about minimum achievable generalization error and the way to enhance the original dataset used for adjustment of the equations’ parameters. Two inputs were found important for the drug dissolution:dandt. The extrudates length (L) was found not important. Both GP modeling approaches allowed creation of relatively simple equations with their predictive performance comparable to the ANNs (root mean squared error (RMSE) from 2.19 to 2.33). The direct mode of GP modeling ofQversusdandtresulted in the most robust model. The idea of how to combine ANNs and GP in order to escape ANNs’ black-box drawback without losing their superior predictive performance was demonstrated. Open Source software was used to deliver the state-of-the-art models and modeling strategies.
Analysis of Nonpoint Source Pollution and Water Environmental Quality Variation Trends in the Nansi Lake Basin from 2002 to 2012
Authors: Wang Weiliang , Ju Tiantian , Dong Wenping , Liu Xiaohui , Yang Chuanxi , Wang Yufan , Huang Lihui , Ren Zongming , Qi Li , Wang Hongyan
Published: May 2015

Based on the data analysis of economic development and the water environmental quality from 2002 to 2012 in the Nansi Lake Basin in China, the correlation between economic development and the water environmental quality was researched. Analysis shows that the GDP of the Nansi Lake Basin had an average annual growth of 7.3% in 2012, and the COD andCODMnhad the average annual decrease of 7.69% and 6.79%, respectively, compared to 2002. Basin water environmental quality overall improved, reaching Class III of the “Environmental quality standards for surface water (GB3838-2002).” The pollution of the water environment was analyzed from three aspects: agricultural fertilizers and pesticides, livestock, and aquaculture. Results indicated that the water pollution of the Nansi Lake Basin mainly came from nonpoint source pollution, accounting for more than 80% of the overall pollution. The contributions of both agricultural fertilizers and pesticides account for more than 85% of the overall nonpoint source, followed by livestock and aquaculture. According to the water pollution characteristics of the Nansi Lake Basin, the basin pollution treatment strategy and prevention and treatment system were dissected, to solve the pollution problem of the Nansi Lake Basin.
Systems Pharmacology Dissecting Holistic Medicine for Treatment of Complex Diseases: An Example Using Cardiocerebrovascular Diseases Treated by TCM
Authors: Wang Yonghua , Zheng Chunli , Huang Chao , Li Yan , Chen Xuetong , Wu Ziyin , Wang Zhenzhong , Xiao Wei , Zhang Boli
Published: May 2015

Holistic medicine is an interdisciplinary field of study that integrates all types of biological information (protein, small molecules, tissues, organs, external environmental signals, etc.) to lead to predictive and actionable models for health care and disease treatment. Despite the global and integrative character of this discipline, a comprehensive picture of holistic medicine for the treatment of complex diseases is still lacking. In this study, we develop a novel systems pharmacology approach to dissect holistic medicine in treating cardiocerebrovascular diseases (CCDs) by TCM (traditional Chinese medicine). Firstly, by applying the TCM active ingredients screened out by a systems-ADME process, we explored and experimentalized the signed drug-target interactions for revealing the pharmacological actions of drugs at a molecule level. Then, at a/an tissue/organ level, the drug therapeutic mechanisms were further investigated by a target-organ location method. Finally, a translational integrating pathway approach was applied to extract the diseases-therapeutic modules for understanding the complex disease and its therapy at systems level. For the first time, the feature of the drug-target-pathway-organ-cooperations for treatment of multiple organ diseases in holistic medicine was revealed, facilitating the development of novel treatment paradigm for complex diseases in the future.
Intratubular Antibacterial Effect of Polyethyleneimine Nanoparticles: An Ex Vivo Study in Human Teeth
Authors: Abramovitz Itzhak , Wisblech Dekel , Zaltsman Natan , Weiss Ervin I. , Beyth Nurit
Published: May 2015

Enterococcus faecalis is a facultative gram positive bacterium which can remain in the teeth root canals and cause refractory or persistent periapical diseases. E. faecalis bacteria that penetrate the dentinal tubules can be the source of intracanal infection and endodontic disease. Quaternary ammonium polyethyleneimine (QPEI) nanopolymers were shown to have long lasting antibacterial activity against gram positive and gram negative bacteria. The present study evaluated the intratubular antibacterial effect of an epoxy resin sealer incorporating 1% QPEI against E. faecalis in a human dentin model. Root canals of extracted teeth were inoculated with E. faecalis for 7 days prior to standard endodontic treatment. The antibacterial effect of an epoxy‐amine resin endodontic sealer was tested at concentration of 0% or 1% (wt/wt) added QPEI nanoparticles. Reduction in bacterial viability (p < 0.01) was depicted in the dentinal tubules of the root canals obturated with the sealer incorporating QPEI nanoparticles. In conclusion, QPEI nanoparticles when incorporated in a small percentage into epoxy‐resin based sealer may target E. faecalis in the dentinal tubules, producing a potent antibacterial effect that reduces significantly bacterial viability.
Nicotine Metabolite Ratio (3-Hydroxycotinine/Cotinine) in Plasma and Urine by Different Analytical Methods and Laboratories: Implications for Clinical Implementation
Authors: Tanner Julie-Anne , Novalen Maria , Jatlow Peter , Huestis Marilyn A. , Murphy Sharon E. , Kaprio Jaakko , Kankaanpää Aino , Galanti Laurence , Stefan Cristiana , George Tony P. , Benowitz Neal L. , Lerman Caryn , Tyndale Rachel F.
Published: May 2015

Background: The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3′-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers.

Methods: Plasma (n = 35) and urine (n = 35) samples were sent to eight different laboratories, which used similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland–Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods.

Results: Measures of plasma NMR were in strong agreement between methods according to Bland–Altman analysis (ratios, 0.82–1.16) and were highly correlated (all Pearson r > 0.96, P < 0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62–1.71) and less strongly correlated (Pearson r values of 0.66–0.98, P < 0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than that in urine, as was observed for NMR.

Conclusions: Plasma is a very reliable biologic source for the determination of NMR, robust to differences in these analytical protocols or assessment site.

Impact: Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies. Cancer Epidemiol Biomarkers Prev; 24(8); 1239–46. ©2015 AACR.
Integrated Genomic Analysis Suggests MLL3 Is a Novel Candidate Susceptibility Gene for Familial Nasopharyngeal Carcinoma
Authors: Sasaki Mark M. , Skol Andrew D. , Bao Riyue , Rhodes Lindsay V. , Chambers Rachelle , Vokes Everett E. , Cohen Ezra E.W. , Onel Kenan
Published: May 2015

Background: Little is known about genetic factors associated with nasopharyngeal carcinoma (NPC). To gain insight into NPC etiology, we performed whole exome sequencing on germline and tumor DNA from three closely related family members with NPC.

Methods: The family was ascertained through the Pediatric Familial Cancer Clinic at The University of Chicago (Chicago, IL). The diagnosis of NPC was confirmed pathologically for each individual. For each sample sequenced, 97.3% of the exome was covered at 5×, with an average depth of 44×. Candidate germline and somatic variants associated with NPC were identified and prioritized using a custom pipeline.

Results: We discovered 72 rare deleterious germline variants in 56 genes shared by all three individuals. Of these, only three are in previously identified NPC-associated genes, all of which are located within MLL3, a gene known to be somatically altered in NPC. One variant introduces an early stop codon in MLL3, which predicts complete loss-of-function. Tumor DNA analysis revealed somatic mutations and Epstein–Barr virus (EBV) integration events; none, however, were shared among all three individuals.

Conclusions: These data suggest that inherited mutations in MLL3 may have predisposed these three individuals from a single family to develop NPC, and may cooperate with individually acquired somatic mutations or EBV integration events in NPC etiology.

Impact: Our finding is the first instance of a plausible candidate high penetrance inherited mutation predisposing to NPC. Cancer Epidemiol Biomarkers Prev; 24(8); 1222–8. ©2015 AACR.
Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy
Authors: Giuliano Mario , Hu Huizhong , Wang Yen-Chao , Fu Xiaoyong , Nardone Agostina , Herrera Sabrina , Mao Sufeng , Contreras Alejandro , Gutierrez Carolina , Wang Tao , Hilsenbeck Susan G. , De Angelis Carmine , Wang Nicholas J. , Heiser Laura M. , Gray Joe W. , Lopez-Tarruella Sara , Pavlick Anne C. , Trivedi Meghana V. , Chamness Gary C. , Chang Jenny C. , Osborne C. Kent , Rimawi Mothaffar F. , Schiff Rachel
Published: May 2015

Purpose: To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples.

Experimental design: Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 posttreatment) were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and Western blot analysis. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant, respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro.

Results: Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy compared with untreated tumors in both preclinical models (UACC812: ER P = 0.0014; Bcl2 P < 0.001 and MCF7/HER2-18: ER P = 0.0007; Bcl2 P = 0.0306). In the neoadjuvant clinical study, lapatinib treatment for 2 weeks was associated with parallel upregulation of ER and Bcl2 (Spearman coefficient: 0.70; P = 0.0002). Importantly, 18% of tumors originally ER-negative (ER−) converted to ER+ upon anti-HER2 therapy. In ER−/HER2+ MCF7/HER2-18 xenografts, ER reexpression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (P = 0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti–HER2-resistant growth (P < 0.0001).

Conclusions: HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance. Clin Cancer Res; 21(17); 3995–4003. ©2015 AACR.
MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor
Authors: Xiao Yu , Nimmer Paul , Sheppard George S. , Bruncko Milan , Hessler Paul , Lu Xin , Roberts-Rapp Lisa , Pappano William N. , Elmore Steven W. , Souers Andrew J. , Leverson Joel D. , Phillips Darren C.
Published: May 2015

Hyperexpression of antiapoptotic BCL-2 family proteins allows cells to survive despite the receipt of signals that would ordinarily induce their deletion, a facet frequently exploited by tumors. Tumors addicted to the BCL-2 family proteins for survival are now being targeted therapeutically. For example, navitoclax, a BCL-2/BCL-XL/BCL-W inhibitor, is currently in phase I/II clinical trials in numerous malignancies. However, the related family member, MCL-1, limits the efficacy of navitoclax and other chemotherapeutic agents. In the present study, we identify breast cancer cell lines that depend upon MCL-1 for survival and subsequently determine the mechanism of apoptosis mediated by the MCL-1 selective inhibitor A-1210477. We demonstrate that apoptosis resulting from a loss in MCL-1 function requires expression of the proapoptotic protein BAK. However, expression of BCL-XL can limit apoptosis resulting from loss in MCL-1 function through sequestration of free BIM. Finally, we demonstrate substantial synergy between navitoclax and MCL-1 siRNA, the direct MCL-1 inhibitor A-1210477, or the indirect MCL-1 inhibitor flavopiridol, highlighting the therapeutic potential for inhibiting BCL-XL and MCL-1 in breast cancer. Mol Cancer Ther; 14(8); 1837–47. ©2015 AACR.
PTK6 Potentiates Gemcitabine-Induced Apoptosis by Prolonging S-phase and Enhancing DNA Damage in Pancreatic Cancer
Authors: Ono Hiroaki , Basson Marc D. , Ito Hiromichi
Published: May 2015

Protein Tyrosine Kinase 6 (PTK6) is a non-receptor–type tyrosine kinase known to be expressed in various cancers, including pancreatic cancer. The role of PTK6 in cancer chemoresistance remains unclear. Therefore, it was hypothesized that PTK6 mechanistically regulates gemcitabine resistance in pancreatic cancer. Gemcitabine treatment stimulated endogenous PTK6 overexpression in MIAPaCa2 and Panc1 cells. PTK6 gene silencing increased cell survival after gemcitabine treatment and decreased apoptosis, whereas PTK6 overexpression decreased cell survival and increased apoptosis. Selection for gemcitabine resistance revealed substantially lower PTK6 expression in the gemcitabine-resistant subclones compared with the parental lines, while restoring PTK6 rescued gemcitabine sensitivity. Gemcitabine induced phosphorylation of H2AX (γ-H2AX) and ataxia-telangiectasia mutated kinase (pATM), specific markers for DNA double-strand breaks. Both gemcitabine-induced phosphorylation of H2AX and ATM were reduced by PTK6 knockdown and increased by PTK6 overexpression. PTK6 overexpression also increased the S-phase fraction 48 hours after gemcitabine treatment. Although gemcitabine activated both caspase-8 (CASP8) and caspase-9 (CASP9), the effect of PTK6 on gemcitabine-induced apoptosis required CASP8 but not CASP9. In mouse xenografts, PTK6 overexpression in subcutaneous tumors attenuated tumor growth after gemcitabine treatment. In conclusion, PTK6 prolongs S-phase and increases the ability of gemcitabine to cause DNA damage in vitro and in vivo.

Implications: PTK6 affects cell cycle and DNA damage, thus making it an important therapeutic target to improve the outcomes of patients with pancreatic cancer. Mol Cancer Res; 13(8); 1174–84. ©2015 AACR.
Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma
Authors: Liu Xian-De , Hoang Anh , Zhou Lijun , Kalra Sarathi , Yetil Alper , Sun Mianen , Ding Zhiyong , Zhang Xuesong , Bai Shanshan , German Peter , Tamboli Pheroze , Rao Priya , Karam Jose A. , Wood Christopher , Matin Surena , Zurita Amado , Bex Axel , Griffioen Arjan W. , Gao Jianjun , Sharma Padmanee , Tannir Nizar , Sircar Kanishka , Jonasch Eric
Published: May 2015

Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and antiangiogenic therapy is the current mainstay of treatment. Patients with RCC develop innate or adaptive resistance to antiangiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy. We assessed the interaction between antiangiogenic therapy and the tumor immune microenvironment and determined their impact on clinical outcome. We found that antiangiogenic therapy–treated RCC primary tumors showed increased infiltration of CD4+ and CD8+ T lymphocytes, which was inversely related to patient overall survival and progression-free survival. Furthermore, specimens from patients treated with antiangiogenic therapy showed higher infiltration of CD4+FOXP3+ regulatory T cells and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T-lymphocyte infiltration and were negatively related to patient survival. Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Results from this study indicate that antiangiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy and will guide the development of combination therapy with PD-1/PD-L1–blocking agents. Cancer Immunol Res; 3(9); 1017–29. ©2015 AACR.
Differential Expression of PD-L1 between Primary and Metastatic Sites in Clear-Cell Renal Cell Carcinoma
Authors: Callea Marcella , Albiges Laurence , Gupta Mamta , Cheng Su-Chun , Genega Elizabeth M. , Fay André P. , Song Jiaxi , Carvo Ingrid , Bhatt Rupal S. , Atkins Michael B. , Hodi F. Stephen , Choueiri Toni K. , McDermott David F. , Freeman Gordon J. , Signoretti Sabina
Published: May 2015

PD-L1 expression in primary clear-cell renal cell carcinoma (ccRCC) increases the likelihood of response to anti–PD-1 inhibition, but fails to identify all responders. We hypothesized that PD-L1 levels assessed in randomly selected areas of the primary tumors may not accurately reflect expression levels in metastatic lesions, which are the target of systemic therapy. Therefore, we compared PD-L1 expression in a series of primary ccRCC and their metastases. Tissue blocks from 53 primary ccRCCs and 76 corresponding metastases were retrieved. Areas with predominant and highest nuclear grade were selected. Slides were immunostained with a validated anti–PD-L1 antibody (405.9A11). Membranous expression in tumor cells was quantified using H-score. Expression in tumor-infiltrating mononuclear cells (TIMC) was quantified using a combined score. Discordant tumor cell PD-L1 staining between primary tumors and metastases was observed in 11 of 53 cases (20.8%). Overall, tumor cell PD-L1 levels were not different in primary tumors and metastases (P = 0.51). Tumor cell PD-L1 positivity was associated with higher T stage (P = 0.03) and higher Fuhrman nuclear grade (P < 0.01). Within individual lesions, PD-L1 positivity was heterogeneous and almost exclusively detected in high nuclear grade areas (P < 0.001). No difference was found in PD-L1 levels in TIMCs between primary tumors and metastases (P = 0.82). The heterogeneity of PD-L1 expression in ccRCC suggests that its assessment as a predictive biomarker for PD-1 blockade may require analysis of metastatic lesions. Notably, because PD-L1 expression was mostly detected in high nuclear grade areas, to avoid false-negative results, these areas should be specifically selected for assessment. Cancer Immunol Res; 3(10); 1158–64. ©2015 AACR.
Influence of Hormonal Profile on Resting Metabolic Rate in Normal, Overweight and Obese Individuals
Authors: Wright Thomas G. , Dawson Brian , Jalleh Geoffrey , Guelfi Kym J.
Published: May 2015

Aims: To investigate whether blood thyroid stimulating hormone (TSH), cortisol, insulin and glucose concentrations (plus glucose:insulin ratio; GIR) could improve the accuracy of resting metabolic rate (RMR) prediction in normal, overweight and obese persons. Methods: Predictive equations were developed and compared against indirect calorimetry measures for RMR in 217 weight-control clinic participants (n = 128 males and n = 89 females: ∼24% normal weight, ∼39% overweight and ∼37% obese). Results: Using the common accuracy criteria of the proportion of predicted RMR within ±10% of measured RMR, our equations (using age, height, weight and gender, plus the blood factors, both independently and in combination) were accurate ∼36-44% of the time, for the whole sample, and when separated by gender and weight class. Specifically, the addition of the blood hormone and glucose concentrations improved the accuracy of predicted RMR by only 1-8% (NS). Conclusions: Including blood TSH, cortisol, insulin, glucose and GIR into RMR prediction equations did not significantly improve estimation accuracy, which in any case only met a criterion of ±10% of the measured RMR ∼40% of the time. Further work to refine the prediction of RMR is still needed, and at present, direct measurements should be made wherever possible.
Performance of T1 and T2 Mapping Cardiovascular Magnetic Resonance to Detect Active Myocarditis in Patients With Recent-Onset Heart Failure
Authors: Bohnen Sebastian , Radunski Ulf K. , Lund Gunnar K. , Kandolf Reinhard , Stehning Christian , Schnackenburg Bernhard , Adam Gerhard , Blankenberg Stefan , Muellerleile Kai
Published: May 2015

Background—

This study evaluated the performance of novel quantitative T1 and T2 mapping cardiovascular magnetic resonance (CMR) techniques to identify active myocarditis in patients with recent-onset heart failure.

Methods and Results—

Thirty-one consecutive patients with recent-onset heart failure, reduced left ventricular function and clinically suspected myocarditis underwent endomyocardial biopsy and CMR at 1.5 Tesla. The CMR protocol included standard Lake-Louise parameters as well as T1 mapping using a modified Look-Locker inversion recovery sequence and T2 mapping using a hybrid gradient and spin-echo sequence. Short-axis maps were generated using an OsiriX plug-in to calculate global myocardial T1, T2, and extracellular volume fraction. Active myocarditis was defined by ongoing inflammation on endomyocardial biopsy. Endomyocardial biopsy revealed active myocarditis in 16 (52%) of 31 patients. Neither clinical characteristics, standard Lake-Louise CMR parameters, global myocardial T1 nor extracellular volume fraction differed significantly between patients with and without active myocarditis. However, median global myocardial T2 was significantly higher in patients with active myocarditis (65 ms [Q1–Q3, 61–70 ms]) than in patients without active myocarditis (59 ms [Q1–Q3, 55–64 ms];
P
<0.01). A cutoff value for global myocardial T2 of ≥60 ms provided a sensitivity, specificity, accuracy, negative and positive predictive value of 94% (70%–100%), 60% (32%–84%), 77% (60%–89%), 90% (56%–100%), and 71% (48%–89%) for active myocarditis, respectively.

Conclusions—

T2 mapping seems to be superior when compared with standard CMR parameters, global myocardial T1, and extracellular volume fraction values for assessing the activity of myocarditis in patients with recent-onset heart failure and reduced left ventricular function.
Wave Separation, Wave Intensity, the Reservoir-Wave Concept, and the Instantaneous Wave-Free Ratio
Authors: Westerhof Nico , Segers Patrick , Westerhof Berend E.
Published: May 2015

Wave separation analysis and wave intensity analysis (WIA) use (aortic) pressure and flow to separate them in their forward and backward (reflected) waves. While wave separation analysis uses measured pressure and flow, WIA uses their derivatives. Because differentiation emphasizes rapid changes, WIA suppresses slow (diastolic) fluctuations of the waves and renders diastole a seemingly wave-free period. However, integration of the WIA-obtained forward and backward waves is equal to the wave separation analysis–obtained waves. Both the methods thus give similar results including backward waves spanning systole and diastole. Nevertheless, this seemingly wave-free period in diastole formed the basis of both the reservoir-wave concept and the Instantaneous wave-Free Ratio of (iFR) pressure and flow. The reservoir-wave concept introduces a reservoir pressure,
P
res
, (Frank Windkessel) as a wave-less phenomenon. Because this Windkessel model falls short in systole an excess pressure,
P
exc
, is introduced, which is assumed to have wave properties. The reservoir-wave concept, however, is internally inconsistent. The presumed wave-less
P
res
equals twice the backward pressure wave and travels, arriving later in the distal aorta. Hence, in contrast,
P
exc
is minimally affected by wave reflections. Taken together,
P
res
seems to behave as a wave, rather than
P
exc
. The iFR is also not without flaws, as easily demonstrated when applied to the aorta. The ratio of diastolic aortic pressure and flow implies division by zero giving nonsensical results. In conclusion, presumptions based on WIA have led to misconceptions that violate physical principles, and reservoir-wave concept and iFR should be abandoned.