bluuebunny/crossref_metadata_2025 huggingface dataset:
MARINE
Authors: Delicato Flávia C. , Portocarrero Jesús M.T. , Silva José R. , Pires Paulo F. , de Araújo Rodrigo P.M. , Batista Thais
Published: July 2013

Wireless sensor networks (WSNs) operate in a highly heterogeneous and dynamic scenario. On one hand, there is a wide range of potential applications for WSNs, each one with different features and requirements and defining a different mission for the sensor nodes to accomplish. On the other hand, the execution context regarding the devices, networks and the physical environment around is subject to frequent changes. In order to achieve the best network performance while meeting requirements of different application missions and contexts, it is crucial to endow the WSN with customization and adaptation capabilities. Such capabilities should be preferably provided by a middleware layer that translates application missions to network configuration in a transparent way for the final users and client applications. This middleware should also provide facilities to program the WSN nodes, to access sensor generated data and to promote interoperability among different applications and networks. To tackle these challenges, we propose MARINE (MiddlewAre for Resource and mIssion-oriented sensor NEtworks), a WSN middleware built on REST and microkernel architectural patterns. MARINE tailors the WSN to requirements of each application mission while saving the overall resource consumption in sensor nodes.
Ripple-2
Authors: Silva Agnelo R. , Liu Mingyan , Moghaddam Mahta
Published: July 2013

The design of Ripple-2, a wireless in-situ soil moisture sensing system is presented in this paper. The main objective of such system is to collect high fidelity and fine grained data both spatially and temporally compared to radar remote sensing, which is the more traditional way of capturing soil moisture, and to use the former to validate and calibrate the latter. To do so, the in-site sensor network must cover a sufficiently large area, on the order of at least a few square kilometers. At the same time, cost constraints (both in deployment and in maintenance) puts a limit on the total number of sensor nodes, resulting in a very sparse (on average) network. The main challenge in designing the system lies in achieving reliability and energy efficiency in such a sparse network. For instance, in our pilot deployment, a 200mx400m area is covered by 22 nodes (average inter-node distance > 50m). Traditional WSN technology typically calls for many more nodes to be deployed in such an area. Ripple-2 is introduced as a non-traditional WSN architecture where (1) the network is physically and logically segmented into isolated clusters, (2) a regular node (or end device, ED) only communicates with the cluster head (CH) of its segment, and (3) the ED-CH communication is distinct from the CH-sink (or CH-Data Server) and both links can use virtually any kind of point-to-point wireless technology. We use both simulated and empirical results to demonstrate the effectiveness of Ripple-2; it proves to be ideal for low duty-cycle data collection applications due to its exceptional small network overhead (typically smaller than 1%) and its robustness to the size of the network.
WiFi access point deployment for efficient mobile data offloading
Authors: Bulut Eyuphan , Szymanski Boleslaw K.
Published: July 2013

Recently, there has been a tremendous increase in mobile data usage with the wide-spread proliferation of smartphone like devices. However, this increased demand from users has caused severe traffic overloading in cellular networks. Offloading the traffic through several other devices (femtocells, WiFi access points) have been considered to be immediate remedy for such a problem. Thus, in this paper, we study the deployment of WiFi access points (AP) in a metropolitan area for efficient offloading of mobile data traffic. We analyze a large scale real user mobility traces and propose a deployment algorithm based on the density of user data request frequency. In simulations, we present offloading ratio that our algorithm can accomplish with different number of APs. The results demonstrate that our algorithm can achieve close to optimal offloading ratio that is higher than offloading ratios that existing algorithms can achieve with the same number of APs.
Abstracts of recent doctoral dissertations in computer algebra
Authors: Johnson Jeremy
Published: July 2013

Each month we are pleased to present abstracts of recent doctoral dissertations in Computer Algebra and Symbolic Computation. We encourage all recent Ph.D. graduates (and their supervisors), who have defended in the past two years, to submit their abstracts for publication in CCA. Please send abstracts to the CCA editors editors_SIGSAM@acm.org for consideration.
Simplifying products of fractional powers of powers
Authors: Stoutemyer David R.
Published: July 2013

Most computer algebra systems incorrectly simplify
z
--
z
/√
w
2
1/
w
3
--
w
√
w
2
to 0 rather than to 0/0. The reasons for this are:

The default simplification does not succeed in simplifying the denominator to 0.

There is a rule that 0 is the result of 0 divided by anything that does not simplify to either 0 or 0/0.

.

Many of these systems have more powerful optional transformation and general purpose simplification functions. However that is unlikely to help this example even if one of those functions can simplify the denominator to 0, because the input to those functions is the result of
default
simplification, which has already incorrectly simplified the overall ratio to 0. Try it on your computer algebra systems!

This article describes how to simplify products of the form
w
α
(
w
β1
)
λ1
... (
w

β
n

)

λ
n

correctly and well, where
w
is any real or complex expression and the exponents are rational numbers.

It might seem that correct good simplification of such a restrictive expression class must already be published and/or built into at least one widely used computer-algebra system, but apparently this issue has been overlooked. Default and relevant optional simplification was tested with 86 examples on 5 systems with
n
= 1. Using a spectrum from the most serious flaw being a result that is not equivalent to the input somewhere to the least serious being not rationalizing a denominator when that does not cause a more serious flaw, the overall percentage of most flaw types is alarming.
MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet
Authors: Gadang Vidya , Kohli Rohit , Myronovych Andriy , Hui David Y. , Perez-Tilve Diego , Jaeschke Anja
Published: July 2013

Saturated fatty acids activate the c-Jun NH2-terminal kinase (JNK) pathway, resulting in chronic low-grade inflammation and the development of insulin resistance. Mixed-lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that mediates JNK activation in response to saturated fatty acids in vitro; however, the exact mechanism for diet-induced JNK activation in vivo is not known. Here, we have used MLK3-deficient mice to examine the role of MLK3 in a saturated-fat diet model of obesity. MLK3-KO mice fed a high-fat diet enriched in medium-chain saturated fatty acids for 16 wk had decreased body fat compared with wild-type (WT) mice due to increased energy expenditure independently of food consumption and physical activity. Moreover, MLK3 deficiency attenuated palmitate-induced JNK activation and M1 polarization in bone marrow-derived macrophages in vitro, and obesity induced JNK activation, macrophage infiltration into adipose tissue, and expression of proinflammatory cytokines in vivo. In addition, loss of MLK3 improved insulin resistance and decreased hepatic steatosis. Together, these data demonstrate that MLK3 promotes saturated fatty acid-induced JNK activation in vivo and diet-induced metabolic dysfunction.
Nitroxyl donors retain their depressor effects in hypertension
Authors: Irvine Jennifer C. , Ravi Ravina M. , Kemp-Harper Barbara K. , Widdop Robert E.
Published: July 2013

Nitroxyl (HNO), the redox congener of nitric oxide, has numerous vasoprotective actions including an ability to induce vasodilation and inhibit platelet aggregation. Given HNO is resistant to scavenging by superoxide and does not develop tolerance, we hypothesised that HNO would retain its in vivo vasodilatory action in the setting of hypertension. The in vitro and in vivo vasodilator properties of the HNO donors Angeli's salt (AS) and isopropylamine/NONOate (IPA/NO) were compared with the NO˙ donor diethylamine/NONOate (DEA/NO) in spontaneously hypertensive rats (SHR) and normotensive [Wistar-Kyoto (WKY) rats]. AS (10, 50, and 200 μg/kg), IPA/NO (10, 50, and 200 μg/kg), and DEA/NO (1, 5, and 20 μg/kg) caused dose-dependent depressor responses in conscious WKY rats of similar magnitude. Depressor responses to AS and IPA/NO were significantly attenuated ( P < 0.01) after infusion of the HNO scavenger N-acetyl-l-cysteine (NAC), confirming that AS and IPA/NO function as HNO donors in vivo. In contrast, responses to DEA/NO were unchanged following NAC infusion. Depressor responses to AS and IPA/NO in conscious SHR retained their sensitivity to the inhibitory effects of NAC ( P < 0.01), yet those to DEA/NO in SHR were significantly ( P < 0.05) enhanced following NAC infusion. Importantly, depressor responses to AS, IPA/NO, and DEA/NO were preserved in hypertension and vasorelaxation to AS and DEA/NO, in isolated aorta, unchanged in SHR as compared with WKY rats. This study has shown for the first time that HNO donors exert antihypertensive effects in vivo and may, therefore, offer a therapeutic alternative to traditional nitrovasodilators in the treatment of cardiovascular disorders such as hypertension.
On the Estimations of the Small Periodic Eigenvalues
Authors: Dinibütün Seza , Veliev O. A.
Published: July 2013

We estimate the small periodic and semiperiodic eigenvalues of Hill's operator with sufficiently differentiable potential by two different methods. Then using it we give the high precision approximations for the length of th gap in the spectrum of Hill-Sehrodinger operator and for the length of th instability interval of Hill's equation for small values of Finally we illustrate and compare the results obtained by two different ways for some examples.
Non-Newtonian Natural Convection Flow along a Horizontal Circular Cylinder with Uniform Surface Heat Flux
Authors: Bhowmick Sidhartha , Molla Md. Mamun , Hossain Md. Anwar
Published: July 2013

Laminar two-dimensional natural convection boundary-layer flow of non-Newtonian fluids along a horizontal circular cylinder with uniform surface heat flux has been studied using a modified power-law viscosity model. In this model, there are no unrealistic limits of zero or infinite viscosity; consequently, no irremovable singularities are introduced into boundary-layer formulation for such fluids. Therefore, the boundary-layer equations can be solved numerically by using marching order implicit finite difference method with double sweep technique. Numerical results are presented for the case of shear thinning as well as shear thickening fluids in terms of the fluid velocity and temperature distributions, shear stresses, and rate of heat transfer in terms of the local skin friction coefficient and local Nusselt number, respectively.
Personnel's Health Surveillance at Work: Effect of Age, Body Mass Index, and Shift Work on Mental Workload and Work Ability Index
Authors: Safari Shahram , Akbari Jafar , Kazemi Meghdad , Mououdi Mohammad Amin , Mahaki Behzad
Published: July 2013

Introduction.Two great changes in developed countries are taking place: populations are ageing and becoming increasingly overweight. Combination of these factors with shift work is a risk factor for work ability and mental workload that are dynamic processes which change greatly throughout an individual's work life. The aim of this study was to investigate mental workload and work ability in textile workers and to identify factors which affect work ability and mental workload.Methods.This cross-sectional study was carried out among 194 male workers in textile industry. Employees based on their job group and work conditions have been divided into 6 categories. They completed work ability index and mental workload questionnaires during three work shifts. Body mass index (BMI) and demographic details were recorded.Results.All of the participants rated their work ability as moderate with high mental workload. The mean WAI and mental workload in age group were significant. The mean BMI was 25.5 kg/m2(standard deviation 4.1) and the mean age was 40.22 years. There was a statistically significant correlation between work ability index and shift work.Conclusions.Unlike the previous study, a decrease point in WAI started in early age that may be due to life-style work and another psychological factor; on the other hand, NASA-TLX revealed high score in six subscales that can be another reason for low WAI.
Neural Network for WGDOP Approximation and Mobile Location
Authors: Chen Chien-Sheng , Lin Jium-Ming , Lee Chin-Tan
Published: July 2013

This paper considers location methods that are applicable in global positioning systems (GPS), wireless sensor networks (WSN), and cellular communication systems. The approach is to employ the resilient backpropagation (Rprop), an artificial neural network learning algorithm, to compute weighted geometric dilution of precision (WGDOP), which represents the geometric effect on the relationship between measurement error and positioning error. The original four kinds of input-output mapping based on BPNN for GDOP calculation are extended to WGDOP based on Rprop. In addition, we propose two novel Rprop–based architectures to approximate WGDOP. To further reduce the complexity of our approach, the first is to select the serving BS and then combines it with three other measurements to estimate MS location. As such, the number of subsets is reduced greatly without compromising the location estimation accuracy. We further employed another Rprop that takes the higher precision MS locations of the first several minimum WGDOPs as the inputs into consideration to determine the final MS location estimation. This method can not only eliminate the poor geometry effects but also significantly improve the location accuracy.
Application of Optimal Homotopy Asymptotic Method to Burger Equations
Authors: Nawaz R. , Ullah H. , Islam S. , Idrees M.
Published: July 2013

We apply optimal homotopy asymptotic method (OHAM) for finding approximate solutions of the Burger's-Huxley and Burger's-Fisher equations. The results obtained by proposed method are compared to those of Adomian decomposition method (ADM) (Ismail et al., (2004)). As a result it is concluded that the method is explicit, effective, and simple to use.
A Class of Fractionalp-Laplacian Integrodifferential Equations in Banach Spaces
Authors: Liu Yiliang , Lu Liang
Published: July 2013

We study a class of nonlinear fractional integrodifferential equations withp-Laplacian operator in Banach space. Some new existence results are obtained via fixed point theorems for nonlocal boundary value problems of fractionalp-Laplacian equations. An illustrative example is also discussed.
Self-Consistent Green Function Method in Nuclear Matter
Authors: Hassaneen Khaled S. A.
Published: July 2013

Symmetric nuclear matter is studied within the Brueckner-Hartree-Fock (BHF) approach and is extending to the self-consistent Green’s function (SCGF) approach. Both approximations are based on realistic nucleon-nucleon interaction; that is, CD-Bonn potential is chosen. The single-particle energy and the equation of state (EOS) are studied. The Fermi energy at the saturation point fulfills the Hugenholtz-Van Hove theorem. In comparison to the BHF approach, the binding energy is reduced and the EOS is stiffer. Both the SCGF and BHF approaches do not reproduce the correct saturation point. A simple contact interaction should be added to SCGF and BHF approaches to reproduce the empirical saturation point.
Recent Developments of Electrochemical Promotion of Catalysis in the Techniques of DeNOx
Authors: Tang Xiaolong , Xu Xianmang , Yi Honghong , Chen Chen , Wang Chuan
Published: July 2013

Electrochemical promotion of catalysis reactions (EPOC) is one of the most significant discoveries in the field of catalytic and environmental protection. The work presented in this paper focuses on the aspects of reaction mechanism, influencing factors, and recent positive results. It has been shown with more than 80 different catalytic systems that the catalytic activity and selectivity of conductive catalysts deposited on solid electrolytes can be altered in the last 30 years. The active ingredient of catalyst can be activated by applying constant voltage or constant current to the catalysts/electrolyte interface. The effect of EPOC can improve greatly the conversion rate of NOx. And it can also improve the lifetime of catalyst by inhibiting its poisoning.
Positive Periodic Solution of Second-Order Coupled Systems with Singularities
Authors: Ma Tiantian
Published: July 2013

This paper establishes the existence of periodic solution for a kind of second-order singular nonautonomous coupled systems. Our approach is based on fixed point theorem in cones. Examples are given to illustrate the main result.
Role of Magnetic Interaction in Dense Plasma
Authors: Sarkar S. , Pal K. , Dutt-Mazumder A. K.
Published: July 2013

Quasiparticle excitations and associated phenomena of energy and momentum transfer rates have been calculated in terms of the drag and the diffusion coefficients exposing clearly the dominance of the magnetic interaction over its electric counterpart. The results have been compared with the finite temperature results highlighting the similarities and dissimilarities in the two extreme regimes of temperature and density. Non-Fermi-liquid behavior of various physical quantities like neutrino mean free path and thermal relaxation time due to the inclusion of magnetic interaction has clearly been revealed. All the results presented in the current review are pertinent to the degenerate and ultradegenerate plasma.
Protein Homeostasis Defects of Alanine-Glyoxylate Aminotransferase: New Therapeutic Strategies in Primary Hyperoxaluria Type I
Authors: Pey Angel L. , Albert Armando , Salido Eduardo
Published: July 2013

Alanine-glyoxylate aminotransferase catalyzes the transamination between L-alanine and glyoxylate to produce pyruvate and glycine using pyridoxal 5′-phosphate (PLP) as cofactor. Human alanine-glyoxylate aminotransferase is a peroxisomal enzyme expressed in the hepatocytes, the main site of glyoxylate detoxification. Its deficit causes primary hyperoxaluria type I, a rare but severe inborn error of metabolism. Single amino acid changes are the main type of mutation causing this disease, and considerable effort has been dedicated to the understanding of the molecular consequences of such missense mutations. In this review, we summarize the role of protein homeostasis in the basic mechanisms of primary hyperoxaluria. Intrinsic physicochemical properties of polypeptide chains such as thermodynamic stability, folding, unfolding, and misfolding rates as well as the interaction of different folding states with protein homeostasis networks are essential to understand this disease. The view presented has important implications for the development of new therapeutic strategies based on targeting specific elements of alanine-glyoxylate aminotransferase homeostasis.
Responses of Green Leaves and Green Pseudobulbs of CAM OrchidCattleya laeliocattleyaAloha Case to Drought Stress
Authors: He Jie , Norhafis Hazelman , Qin Lin
Published: July 2013

This study examined the responses of green leaves (GL) and green pseudobulbs (GPSB) of CAM orchidCattleya laeliocattleyaAloha Case to drought stress. After being subjected to drought stress, the decrease in water content (WC) was much greater in GPSB than in GL, indicating that GPSB facilitated a slow reduction in the WC of GL. This finding was further supported by the result of relative water content (RWC) of GL, which started to decrease only after 3 weeks of drought stress. Decreases of middayFv/Fmratios of GL occurred in all plants. However, the degrees of decrease were much greater in drought-stressed GL than in well-watered GL. ReducedFv/Fmratio (<0.8) at early morning was observed in drought-stressed GL after 3 weeks of treatments. Decreases in total chlorophyll (Chl) content, electron transport rate (ETR), photochemical quenching, qP, and nonphotochemical quenching, qN, were severer in GPSB than in GL after drought treatment. CAM acidity was significantly lower in both GL and GPSB after 2 weeks of drought treatment compared to well-watered plants. However, decrease of CAM acidity was smaller in GL than in GPSB. These results suggest that both GL and GPSB of CAM orchidCattleyaplantswere susceptible to drought stress.
miR-1279, miR-548j, miR-548m, and miR-548d-5p Binding Sites in CDSs of Paralogous and OrthologousPTPN12,MSH6, andZEB1Genes
Authors: Ivashchenko Anatoliy T. , Issabekova Assel S. , Berillo Olga A.
Published: July 2013

OnlyPTPN12, MSH6, andZEB1have significant miR-1279 binding sites among paralogous genes of human tyrosine phosphatase family, DNA mismatch repair family, and zinc finger family, respectively. All miRNA binding sites are located within CDSs of studied mRNAs. Nucleotide sequences of hsa-miR-1279 binding sites with mRNAs of humanPTPN12, MSH6, andZEB1genes encode TKEQYE, EGSSDE, and GEKPYE oligopeptides, respectively. The conservation of miRNA binding sites encoding oligopeptides has been revealed. MRNAs of many paralogs of zinc finger gene family have from 1 to 12 binding sites coding the same GEKPYE hexapeptide. MRNAs ofPTPN12, MSH6, andZEB1orthologous genes from different animal species have binding sites for hsa-miR-1279 which consist of homologous oligonucleotides encoding similar human oligopeptides TKEQYE, EGSSDE, and GEKPYE. MiR-548j, miR-548m, and miR-548d-5p have homologous binding sites in the mRNA ofPTPN12orthologous genes which encode PRTRSC, TEATDI, and STASAT oligopeptides, respectively. All regions of miRNA are important for binding with the mRNA.
Battery-Less 6LoWPAN-Based Wireless Home Automation by Use of Energy Harvesting
Authors: Efendi Ardiansyah Musa , Oh Seungkyo , Negara Ali Fahmi Perwira , Choi Deokjai
Published: July 2013

Being one of the current main technologies, wireless sensor network (WSN) is absolutely critical and plays an increasingly important role in the development of a wide range of data acquisition, processing, and control applications. One interesting challenge application of the WSNs is Internet-based home automation system. The rapid expansion of IPv6, moreover, after IETF defined 6LoWPAN as a technique to apply IPv6 into WSNs standard, added potential for Internet paradigm communication, control, and monitoring of home automation devices from anywhere on the globe. The use of 6LoWPAN communications technology also helps lower expense of the system and decreases complexity of the home automation architecture. When implementing 6LoWPAN-based home automation system, the important feature is long periods of life to support full automation without the need for periodically replacing its batteries. To have this, 6LoWPAN home devices with total energy independence are needed. By using additional components for power management and the implementation of 3 V, 70 mA small polycrystalline silicon solar cell for solar energy harvesting, we can have home automation node for an indefinite amount of life time.
Thiol Redox Sensitivity of Two Key Enzymes of Heme Biosynthesis and Pentose Phosphate Pathways: Uroporphyrinogen Decarboxylase and Transketolase
Authors: McDonagh Brian , Pedrajas José Rafael , Padilla C. Alicia , Bárcena José Antonio
Published: July 2013

Uroporphyrinogen decarboxylase (Hem12p) and transketolase (Tkl1p) are key mediators of two critical processes within the cell, heme biosynthesis, and the nonoxidative part of the pentose phosphate pathway (PPP). The redox properties of both Hem12p and Tkl1p fromSaccharomyces cerevisiaewere investigated using proteomic techniques (SRM and label-free quantification) and biochemical assays in cell extracts andin vitrowith recombinant proteins. Thein vivoanalysis revealed an increase in oxidized Cys-peptides in the absence of Grx2p, and also after treatment with H2O2in the case of Tkl1p, without corresponding changes in total protein, demonstrating a true redox response. Out of three detectable Cys residues in Hem12p, only the conserved residue Cys52 could be modified by glutathione and efficiently deglutathionylated by Grx2p, suggesting a possible redox control mechanism for heme biosynthesis. On the other hand, Tkl1p activity was sensitive to thiol redox modification and although Cys622 could be glutathionylated to a limited extent, it was not a natural substrate of Grx2p. The human orthologues of both enzymes have been involved in certain cancers and possess Cys residues equivalent to those identified as redox sensitive in yeast. The possible implication for redox regulation in the context of tumour progression is put forward.
Effects ofNigella sativaandLepidium sativumon Cyclosporine Pharmacokinetics
Authors: Al-Jenoobi F. I. , Al-Suwayeh S. A. , Muzaffar Iqbal , Alam Mohd Aftab , Al-Kharfy Khalid M. , Korashy Hesham M. , Al-Mohizea Abdullah M. , Ahad Abdul , Raish Mohd
Published: July 2013

The present study was conducted to investigate the effects ofNigella sativaandLepidium sativumon the pharmacokinetics of cyclosporine in rabbits. Two groups of animals were treated separately withNigella sativa(200 mg/kg p.o.) orLepidium sativum(150 mg/kg p.o.) for eight consecutive days. On the 8th day, cyclosporine (30 mg/kg p.o.) was administered to each group one hour after herbal treatment. Blood samples were withdrawn at different time intervals (0.0, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12, and 24 hrs) from marginal ear vein. Cyclosporine was analyzed using UPLC/MS method. The coadministration ofNigella sativasignificantly decreased theCmaxandAUC0-∞of cyclosporine; the change was observed by 35.5% and 55.9%, respectively (P≤0.05).Lepidium sativumdid not produce any significant change inCmaxof cyclosporine, although its absorption was significantly delayed compared with control group. A remarkable change was observed inTmaxandAUC0-tofLepidium sativumtreated group. Our findings suggest that concurrent consumption ofNigella sativaandLepidium sativumcould alter the pharmacokinetics of cyclosporine at various levels.
The Exomes of the NCI-60 Panel: A Genomic Resource for Cancer Biology and Systems Pharmacology
Authors: Abaan Ogan D. , Polley Eric C. , Davis Sean R. , Zhu Yuelin J. , Bilke Sven , Walker Robert L. , Pineda Marbin , Gindin Yevgeniy , Jiang Yuan , Reinhold William C. , Holbeck Susan L. , Simon Richard M. , Doroshow James H. , Pommier Yves , Meltzer Paul S.
Published: July 2013

The NCI-60 cell lines are the most frequently studied human tumor cell lines in cancer research. This panel has generated the most extensive cancer pharmacology database worldwide. In addition, these cell lines have been intensely investigated, providing a unique platform for hypothesis-driven research focused on enhancing our understanding of tumor biology. Here, we report a comprehensive analysis of coding variants in the NCI-60 panel of cell lines identified by whole exome sequencing, providing a list of possible cancer specific variants for the community. Furthermore, we identify pharmacogenomic correlations between specific variants in genes such as TP53, BRAF, ERBBs, and ATAD5 and anticancer agents such as nutlin, vemurafenib, erlotinib, and bleomycin showing one of many ways the data could be used to validate and generate novel hypotheses for further investigation. As new cancer genes are identified through large-scale sequencing studies, the data presented here for the NCI-60 will be an invaluable resource for identifying cell lines with mutations in such genes for hypothesis-driven research. To enhance the utility of the data for the greater research community, the genomic variants are freely available in different formats and from multiple sources including the CellMiner and Ingenuity websites. Cancer Res; 73(14); 4372–82. ©2013 AACR.
Stromally Derived Lysyl Oxidase Promotes Metastasis of Transforming Growth Factor-β–Deficient Mouse Mammary Carcinomas
Authors: Pickup Michael W. , Laklai Hanane , Acerbi Irene , Owens Philip , Gorska Agnieszka E. , Chytil Anna , Aakre Mary , Weaver Valerie M. , Moses Harold L.
Published: July 2013

The tumor stromal environment can dictate many aspects of tumor progression. A complete understanding of factors driving stromal activation and their role in tumor metastasis is critical to furthering research with the goal of therapeutic intervention. Polyoma middle T-induced mammary carcinomas lacking the type II TGF-β receptor (PyMTmgko) are highly metastatic compared with control PyMT-induced carcinomas (PyMTfl/fl). We hypothesized that the PyMTmgko-activated stroma interacts with carcinoma cells to promote invasion and metastasis. We show that the extracellular matrix associated with PyMTmgko tumors is stiffer and has more fibrillar collagen and increased expression of the collagen crosslinking enzyme lysyl oxidase (LOX) compared with PyMTfl/fl mammary carcinomas. Inhibition of LOX activity in PyMTmgko mice had no effect on tumor latency and size, but significantly decreased tumor metastasis through inhibition of tumor cell intravasation. This phenotype was associated with a decrease in keratin 14–positive myoepithelial cells in PyMTmgko tumors following LOX inhibition as well as a decrease in focal adhesion formation. Interestingly, the primary source of LOX was found to be activated fibroblasts. LOX expression in these fibroblasts can be driven by myeloid cell-derived TGF-β, which is significantly linked to human breast cancer. Overall, stromal expansion in PyMTmgko tumors is likely caused through the modulation of immune cell infiltrates to promote fibroblast activation. This feeds back to the epithelium to promote metastasis by modulating phenotypic characteristics of basal cells. Our data indicate that epithelial induction of microenvironmental changes can play a significant role in tumorigenesis and attenuating these changes can inhibit metastasis. Cancer Res; 73(17); 5336–46. ©2013 AACR.
Intestinal Bacteria Modify Lymphoma Incidence and Latency by Affecting Systemic Inflammatory State, Oxidative Stress, and Leukocyte Genotoxicity
Authors: Yamamoto Mitsuko L. , Maier Irene , Dang Angeline Tilly , Berry David , Liu Jared , Ruegger Paul M. , Yang Jiue-in , Soto Phillip A. , Presley Laura L. , Reliene Ramune , Westbrook Aya M. , Wei Bo , Loy Alexander , Chang Christopher , Braun Jonathan , Borneman James , Schiestl Robert H.
Published: July 2013

Ataxia-telangiectasia is a genetic disorder associated with high incidence of B-cell lymphoma. Using an ataxia-telangiectasia mouse model, we compared lymphoma incidence in several isogenic mouse colonies harboring different bacterial communities, finding that intestinal microbiota are a major contributor to disease penetrance and latency, lifespan, molecular oxidative stress, and systemic leukocyte genotoxicity. High-throughput sequence analysis of rRNA genes identified mucosa-associated bacterial phylotypes that were colony-specific. Lactobacillus johnsonii, which was deficient in the more cancer-prone mouse colony, was causally tested for its capacity to confer reduced genotoxicity when restored by short-term oral transfer. This intervention decreased systemic genotoxicity, a response associated with reduced basal leukocytes and the cytokine-mediated inflammatory state, and mechanistically linked to the host cell biology of systemic genotoxicity. Our results suggest that intestinal microbiota are a potentially modifiable trait for translational intervention in individuals at risk for B-cell lymphoma, or for other diseases that are driven by genotoxicity or the molecular response to oxidative stress. Cancer Res; 73(14); 4222–32. ©2013 AACR.
PTK6 Activation at the Membrane Regulates Epithelial–Mesenchymal Transition in Prostate Cancer
Authors: Zheng Yu , Wang Zebin , Bie Wenjun , Brauer Patrick M. , Perez White Bethany E. , Li Jing , Nogueira Veronique , Raychaudhuri Pradip , Hay Nissim , Tonetti Debra A. , Macias Virgilia , Kajdacsy-Balla André , Tyner Angela L.
Published: July 2013

The intracellular tyrosine kinase protein tyrosine kinase 6 (PTK6) lacks a membrane-targeting SH4 domain and localizes to the nuclei of normal prostate epithelial cells. However, PTK6 translocates from the nucleus to the cytoplasm in human prostate tumor cells. Here, we show that while PTK6 is located primarily within the cytoplasm, the pool of active PTK6 in prostate cancer cells localizes to membranes. Ectopic expression of membrane-targeted active PTK6 promoted epithelial–mesenchymal transition in part by enhancing activation of AKT, thereby stimulating cancer cell migration and metastases in xenograft models of prostate cancer. Conversely, siRNA-mediated silencing of endogenous PTK6 promoted an epithelial phenotype and impaired tumor xenograft growth. In mice, PTEN deficiency caused endogenous active PTK6 to localize at membranes in association with decreased E-cadherin expression. Active PTK6 was detected at membranes in some high-grade human prostate tumors, and PTK6 and E-cadherin expression levels were inversely correlated in human prostate cancers. In addition, high levels of PTK6 expression predicted poor prognosis in patients with prostate cancer. Our findings reveal novel functions for PTK6 in the pathophysiology of prostate cancer, and they define this kinase as a candidate therapeutic target. Cancer Res; 73(17); 5426–37. ©2013 AACR.
The Functionalized Human Serine Protease Granzyme B/VEGF121 Targets Tumor Vasculature and Ablates Tumor Growth
Authors: Mohamedali Khalid A. , Cao Yu , Cheung Lawrence H. , Hittelman Walter N. , Rosenblum Michael G.
Published: July 2013

The serine protease granzyme B (GrB) induces apoptosis through both caspase-dependent and -independent multiple-cascade mechanisms. VEGF121 binds to both VEGF receptor (VEGFR)-1 and VEGFR-2 receptors. We engineered a unique GrB/VEGF121 fusion protein and characterized its properties in vitro and in vivo. Endothelial and tumor cell lines showed varying levels of sensitivity to GrB/VEGF121 that correlated closely to total VEGFR-2 expression. GrB/VEGF121 localized efficiently into VEGFR-2–expressing cells, whereas the internalization into VEGFR-1–expressing cells was significantly reduced. Treatment of VEGFR-2+ cells caused mitochondrial depolarization in 48% of cells by 48 hours. Exposure to GrB/VEGF121 induced apoptosis in VEGFR-2+, but not in VEGFR-1+, cells and rapid caspase activation was observed that could not be inhibited by treatment with a pan-caspase inhibitor. In vivo, GrB/VEGF121 localized in perivascular tumor areas adjacent to microvessels and in other areas in the tumor less well vascularized, whereas free GrB did not specifically localize to tumor tissue. Administration (intravenous) of GrB/VEGF121 to mice at doses up to 40 mg/kg showed no toxicity. Treatment of mice bearing established PC-3 tumor xenografts with GrB/VEGF121 showed significant antitumor effect versus treatment with GrB or saline. Treatment with GrB/VEGF121 at 27 mg/kg resulted in the regression of four of five tumors in this group. Tumors showed a two-fold lower Ki-67–labeling index compared with controls. Our results show that targeted delivery of GrB to tumor vascular endothelial cells or to tumor cells activates apoptotic cascades and this completely human construct may have significant therapeutic potential. Mol Cancer Ther; 12(10); 2055–66. ©2013 AACR.
Mutual Exclusivity Analysis of Genetic and Epigenetic Drivers in Melanoma Identifies a Link Between p14ARF and RARβ Signaling
Authors: Dahl Christina , Christensen Claus , Jönsson Göran , Lorentzen Anders , Skjødt Mette Louise , Borg Åke , Pawelec Graham , Guldberg Per
Published: July 2013

Melanoma genomes contain thousands of alterations including: mutations, copy number alterations, structural aberrations, and methylation changes. The bulk of this variation is stochastic and functionally neutral, with only a small minority representing “drivers” that contribute to the genesis and maintenance of tumors. Drivers are often directly or inversely correlated across tumors, reflecting the molecular and regulatory signaling pathways in which they operate. Here, a profile of genetic and epigenetic drivers in 110 human melanoma cell lines was generated and searched for non-random distribution patterns. Statistically significant mutual exclusivity was revealed among components of each of the p16INK4A-CDK4-RB, RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways. In addition, an inverse correlation was observed between promoter hypermethylation of retinoic acid receptor β (RARB) and CDKN2A alterations affecting p14ARF (P < 0.0001), suggesting a functional link between RARβ signaling and the melanoma-suppressive activities of p14ARF. Mechanistically, all-trans retinoic acid (ATRA) treatment increased the expression of p14ARF in primary human melanocytes and the steady-state levels of p14ARF in these cells were shown to be regulated via RARβ. Furthermore, the ability of ATRA to induce senescence is reduced in p14ARF-depleted melanocytes, and we provide proof-of-concept that ATRA can induce irreversible growth arrest in melanoma cells with an intact RARβ-p14ARF signaling axis, independent of p16INK4A and p53 status.

Implications: These data highlight the power of mutual exclusivity analysis of cancer drivers to unravel molecular pathways and establish a previously unrecognized cross-talk between RARβ and p14ARF with potential implications for melanoma treatment. Mol Cancer Res; 11(10); 1166–78. ©2013 AACR.
53BP1 Is Limiting for NHEJ Repair in ATM-deficient Model Systems That Are Subjected to Oncogenic Stress or Radiation
Authors: Rybanska-Spaeder Ivana , Reynolds Taylor L. , Chou Jeremy , Prakash Mansi , Jefferson Tameca , Huso David L. , Desiderio Stephen , Franco Sonia
Published: July 2013

The DNA damage response (DDR) factors ataxia telangiectasia mutated (ATM) and p53 binding protein 1 (53BP1) function as tumor suppressors in humans and mice, but the significance of their mutual interaction to the suppression of oncogenic translocations in vivo has not been investigated. To address this question, the phenotypes of compound mutant mice lacking 53BP1 and ATM (Trp53bp1−/−/Atm−/−), relative to single mutants, were examined. These analyses revealed that loss of 53BP1 markedly decreased the latency of T-lineage lymphomas driven by RAG-dependent oncogenic translocations in Atm−/− mice (average survival, 14 and 23 weeks for Trp53bp1−/−/Atm−/− and Atm−/− mice, respectively). Mechanistically, 53BP1 deficiency aggravated the deleterious effect of ATM deficiency on nonhomologous end-joining (NHEJ)—mediated double-strand break repair. Analysis of V(D)J recombinase-mediated coding joints and signal joints in Trp53bp1−/−/Atm−/− primary thymocytes is, however, consistent with canonical NHEJ-mediated repair. Together, these findings indicate that the greater NHEJ defect in the double mutant mice resulted from decreased efficiency of rejoining rather than switching to an alternative NHEJ-mediated repair mechanism. Complementary analyses of irradiated primary cells indicated that defects in cell-cycle checkpoints subsequently function to amplify the NHEJ defect, resulting in more frequent chromosomal breaks and translocations in double mutant cells throughout the cell cycle. Finally, it was determined that 53BP1 is dispensable for the formation of RAG-mediated hybrid joints in Atm−/− thymocytes but is required to suppress large deletions in a subset of hybrid joints.

Implications: The current study uncovers novel ATM-independent functions for 53BP1 in the suppression of oncogenic translocations and in radioprotection.

Visual Overview: http://mcr.aacrjournals.org/content/11/10/1223/F1.large.jpg.

Mol Cancer Res; 11(10); 1223–34. ©2013 AACR.
Platelet-Derived Growth Factor Receptor Beta Serum Concentrations during First-Line Therapy in Ovarian Cancer
Authors: Mathey Sabrina , Graeser Monika Karla , zu Eulenburg Christine , Woelber Linn , Trillsch Fabian , Jaenicke Fritz , Müller Volkmar , Milde-Langosch Karin , Mahner Sven
Published: July 2013

Objectives: Angiogenesis plays an important role in ovarian cancer. The interaction of platelet-derived growth factor receptor-beta (PDGFR-β) with vascular endothelial growth factor (VEGF) in the process of angiogenesis may represent an essential feature in the progression of the disease. Methods: Patients with epithelial ovarian cancer, who underwent primary surgery and platinum-based first-line chemotherapy, were included. A total of 133 serum samples from 39 patients were analyzed. Samples were prospectively collected at 4 time points: (1) before surgery, (2) after surgery and before chemotherapy, (3) during chemotherapy and (4) after chemotherapy. Serum PDGFR-β was quantified by ELISA. We analyzed the correlation of serum levels to chemotherapy response, progression-free and overall survival (PFS and OS) and the serum markers CA-125 and VEGF-165. Results: Serum concentration of PDGFR-β ranged between 4 and 72 ng/ml and increased significantly during first-line chemotherapy (p = 0.019). PDGFR-β serum concentrations showed an inverse correlation with CA-125 and VEGF-165 after chemotherapy (r = -0.495, p = 0.003 and r = -0.345, p = 0.04, respectively). Increased PDGFR-β serum levels after chemotherapy were significantly correlated with better PFS (p = 0.026) and OS (p = 0.013) in a univariate analysis. Conclusion: PDGFR-β might be a useful biomarker in terms of prognosis and could be important as antiangiogenic agents become a component of standard treatment in ovarian cancer.
Validation of RiskCheck Bladder Cancer ©, Version 5.0 for Risk-Adapted Screening of Bladder Cancer
Authors: Martini T. , Mayr R. , Lodde M. , Seitz C. , Trenti E. , Comploj E. , Palermo S. , Pycha A. , Mian C. , Zywica M. , Weidner W. , Lüdecke G.
Published: July 2013

Introduction: The aim of the study was to assess the strength of the online tool RiskCheck Bladder Cancer©, version 5.0 (RCBC) for early detection of bladder cancer (BC). Materials and Methods: RCBC was evaluated retrospectively based on the data of 241 patients, of which 141 were suffering from BC. Statistical analysis was performed by descriptive statistics, nonparametric group comparison, classification tree analysis and ROC analysis. Results: ROC analysis of the risk classification showed a sensitivity of 71.6%, a specificity of 56.5%, a positive predictive value of 67.8%, a negative predictive value of 52% and an accuracy of 63.5%. BC risk factors ranked by importance are time of smoking (p < 0.0001), gender (within the nonsmoking group: p < 0.009), occupational toxin exposure (within the group <35 years of smoking: p < 0.048) and amount of consumed cigarettes resulting in a 95% association with BC (within the group >35 years of smoking: p < 0.0001). Conclusions: The high predictive power of RCBC for the identification of asymptomatic patients living under risk could be demonstrated.
Comparison of Immunosuppressive and Cytotoxic Cells in Angiosarcoma: Development of a Possible Supportive Therapy for Angiosarcoma
Authors: Kambayashi Yumi , Fujimura Taku , Furudate Sadanori , Hashimoto Akira , Haga Takahiro , Aiba Setsuya
Published: July 2013

An imbalance of immunosuppressive and cytotoxic cells plays an important role in inhibiting the anti-tumor immune response of the tumor-bearing host. The purpose of this study was to elucidate the involvement of immunosuppressive cells, such as regulatory T cells and CD163+ M2 macrophages as well as cytotoxic cells, such as granulysin-bearing cells and TIA-1+ cells in cutaneous angiosarcoma (AS) by immunohistochemical staining. In addition we evaluated the potencies of bisphosphonate, which was previously reported to suppress the expression of matrix metalloproteinase 9 (MMP-9), as a supportive therapy for AS together with docetaxel in 6 cases of cutaneous AS. These findings suggest that a high number of immunosuppressive cells might be related to the prognosis of AS, and that a combination of docetaxel with bisphosphonate risedronate sodium might be effective for MMP-9-expressing AS.
Vemurafenib-Induced Eccrine Squamous Syringometaplasia
Authors: Lescoat A. , Droitcourt C. , Stock N. , Le Gall F. , Dupuy A.
Published: July 2013

We report herein a patient treated with vemurafenib for a stage IV melanoma who developed an eruption related to eccrine squamous syringometaplasia (ESS). This entity is a well-described side effect of cytostatic therapies used for malignant neoplasia and is clinically characterized by a symmetric cutaneous eruption composed of papules and vesicles preferentially located on fold and intertriginous areas. It is histologically defined by a squamous metaplasia of eccrine ductal epithelium. ESS represents another skin eruption to be added to the list of cutaneous adverse events associated with vemurafenib, a selective BRAF inhibitor used to treat patients with metastatic melanoma harboring the V600E mutation. The discussion focuses on the pathogenesis of ESS secondary to vemurafenib and on alternative diagnoses.
Comparative Study of High-Resolution Multifrequency Ultrasound of the Plantar Skin in Patients with Various Types of Hereditary Palmoplantar Keratoderma
Authors: Goldberg I. , Sprecher E. , Schwartz M.E. , Gaitini D.
Published: July 2013

Background: High-variable-frequency ultrasound is used as an imaging tool for various cutaneous disorders. We utilized this tool in pachyonychia congenita (PC) patients, who typically present with plantar hyperkeratosis and often severely debilitating pain, compared to patients with epidermolytic palmoplantar keratoderma (EPPK) and mal de Meleda (MDM). Objective: To ascertain the feasibility of ultrasound technology for the diagnosis of PC. Methods: The study included a total of 16 patients, 7 with PC, 5 with EPPK and 4 with MDM, who underwent ultrasound examination of the plantar skin with high-resolution multifrequency ultrasound equipment. Results: Ultrasound scans performed over the proximal and distal plantar foot calluses in PC patients demonstrated hyperechoic dots and lines within the epidermis compatible with hyperkeratosis, engorged varicose veins in the dermis and an anechoic layer interposed between the epidermis and the dermis, corresponding to blister fluid below the calluses. In contrast to PC patients, patients with MDM and EPPK demonstrated no blisters. Conclusion: PC patients, as opposed to a group of patients with MDM and EPPK, displayed subepidermal blistering beneath their calluses. This finding may help in the diagnosis of PC and in partially explaining plantar pain as part of PC symptomatology.