bluuebunny/crossref_metadata_2025 huggingface dataset:
CRYPTANALYSIS OF HYBRID CRYPTOSYSTEMS
Authors: MILLERIOUX G.
Published: October 2013

An essential issue for the validation of ciphers is cryptanalysis, that is, the study of attacks in order to reveal possible weaknesses. In this paper, we propose a systematic and unified methodology for cryptanalyzing known chaos-based cryptosystems borrowed from the open literature, namely shift keying, discrete parameter modulation, switched message-embedding, time-varying delay-based schemes. It is shown that all of them have a hybrid feature. Based on this consideration, the cryptanalysis leads to a specific parameter identification. The method is extended in straightforward way for hybrid cryptosystems defined over finite fields, involving in particular Boolean functions. The complexity of the cryptanalysis is derived regardless of the exhibited dynamics and provides a new quantitative measure for security assessment, thus allowing to show, by the way, that most of the chaos-based cryptosystems proposed so far in the literature are weak.
THE EXOTIC (HIGHER ORDER LÉVY) LAPLACIANS GENERATE THE MARKOV PROCESSES GIVEN BY DISTRIBUTION DERIVATIVES OF WHITE NOISE
Authors: ACCARDI LUIGI , JI UN CIG , SAITÔ KIMIAKI
Published: October 2013

We introduce, for each a ∈ ℝ+, the Brownian motion associated to the distribution derivative of order a of white noise. We prove that the generator of this Markov process is the exotic Laplacian of order 2a, given by the Cesàro mean of order 2a of the second derivatives along the elements of an orthonormal basis of a suitable Hilbert space (the Cesàro space of order 2a). In particular, for a = 1/2 one finds the usual Lévy Laplacian, but also in this case the connection with the 1/2-derivative of white noise is new. The main technical tool, used to achieve these goals, is a generalization of a result due to Accardi and Smolyanov5 extending the well-known Cesàro theorem to higher order arithmetic means. These and other estimates allow to prove existence of the heat semi-group associated to any exotic Laplacian of order ≥ 1/2 and to give its explicit expression in terms of infinite dimensional Fourier transform.
A CLOSER LOOK AT QUANTUM CONTROL LANDSCAPES AND THEIR IMPLICATION FOR CONTROL OPTIMIZATION
Authors: DE FOUQUIERES PIERRE , SCHIRMER SOPHIE G.
Published: October 2013

The control landscape for various canonical quantum control problems is considered. For the class of pure-state transfer problems, analysis of the fidelity as a functional over the unitary group reveals no suboptimal attractive critical points (traps). For the actual optimization problem over controls in L2(0, T), however, there are critical points for which the fidelity can assume any value in (0, 1), critical points for which the second order analysis is inconclusive, and traps. For the class of unitary operator optimization problems analysis of the fidelity over the unitary group shows that while there are no traps over U(N), traps already emerge when the domain is restricted to the special unitary group. The traps on the group can be eliminated by modifying the performance index, corresponding to optimization over the projective unitary group. However, again, the set of critical points for the actual optimization problem for controls in L2(0, T) is larger and includes traps, some of which remain traps even when the target time is allowed to vary.
EFFECT OF ALUMINA ADDITION ON MECHANICAL BEHAVIOR AND FRACTURE PROPERTIES OF ALL-CERAMICS ZIRCONIA DENTAL MATERIALS
Authors: ZHANG DONGJIAO , SONG DAWEI , LIAO YUNMAO , CHEN XINMIN , WANG MIN
Published: October 2013

The influence of alumina addition on mechanical behavior and fracture properties of all-ceramics zirconia dental materials was evaluated. Samples containing 0, 5, 10, 15 wt.% Al 2 O 3 particles were prepared by cold isostatic pressing (200 MPa) and sintered at 1500°C for 5 h. Commercial powders were investigated by bulk density and phase formation using Archimedes principle and X-ray diffraction (XRD). Bending strength and fracture load were determined at room temperature by three-point bending test. In order to study the fracture, we took points on the crack path under microscope, plotted points on coordinates and used software "Origin" to general fitting curves. Scanning electron microscopy (SEM) and atomic force microscope (AFM) were introduced to estimate the particle size of powders and observe the fracture surfaces. No density difference was observed for a given alumina content. The majority phases of ceramics were t-zirconia and α-alumina before breaking while m-zirconia, t-zirconia and α-alumina coexisted on the cross section of cracked samples. Zirconia containing 10% alumina had the best mechanical properties, the most tortuous crack propagation and the least obvious crack distribution. This observation may provide a reference for the materials selection, shape design and production process of all-ceramic crown and bridge.
LINEAR BOUNDS FOR LENGTHS OF GEODESIC SEGMENTS ON RIEMANNIAN 2-SPHERES
Authors: NABUTOVSKY ALEXANDER , ROTMAN REGINA
Published: October 2013

In this paper we will show that for every positive integer k and each pair of points p, q ∈ M, where M is a Riemannian manifold diffeomorphic to the 2-dimensional sphere, there always exist at least k geodesics connecting p and q of length at most 22kd, where d is the diameter of M.
Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes
Authors: Hernandez-Valladares Maria , Rihet Pascal , Iraqi Fuad A.
Published: October 2013

There is growing evidence for human genetic factors controlling the outcome of malaria infection, while molecular basis of this genetic control is still poorly understood. Case-control and family-based studies have been carried out to identify genes underlying host susceptibility to malarial infection. Parasitemia and mild malaria have been genetically linked to human chromosomes 5q31-q33 and 6p21.3, and several immune genes located within those regions have been associated with malaria-related phenotypes. Association and linkage studies of resistance to malaria are not easy to carry out in human populations, because of the difficulty in surveying a significant number of families. Murine models have proven to be an excellent genetic tool for studying host response to malaria; their use allowed mapping 14 resistance loci, eight of them controlling parasitic levels and six controlling cerebral malaria. Once quantitative trait loci or genes have been identified, the human ortholog may then be identified. Comparative mapping studies showed that a couple of human and mouse might share similar genetically controlled mechanisms of resistance. In this way, char8, which controls parasitemia, was mapped on chromosome 11; char8 corresponds to human chromosome 5q31-q33 and contains immune genes, such as Il3, Il4, Il5, Il12b, Il13, Irf1, and Csf2. Nevertheless, part of the genetic factors controlling malaria traits might differ in both hosts because of specific host-pathogen interactions. Finally, novel genetic tools including animal models were recently developed and will offer new opportunities for identifying genetic factors underlying host phenotypic response to malaria, which will help in better therapeutic strategies including vaccine and drug development.
MicroRNA associated with dyslipidemia and coronary disease in humans
Authors: Flowers Elena , Aouizerat Bradley E.
Published: October 2013

MicroRNAs are structural components of an epigenetic mechanism of posttranscriptional regulation of messenger RNA translation. Recently, there has been significant interest in the application of microRNA as a blood-based biomarker of underlying physiological conditions. Dyslipidemia is a complex, heterogeneous condition conferring substantially increased risk for cardiovascular disease. The purpose of this review is to describe the current body of knowledge on the role of microRNA regulation of lipoprotein metabolism in humans and to discuss relevant methodological and study design considerations. We highlight the potential roles for microRNA in gene-environment interactions.
Interleukin-1 Two-Locus Haplotype Is Strongly Associated with Severe Chronic Periodontitis among Yemenis
Authors: Al-hebshi Nezar Noor , Shamsan Amat-alrahman Ahmed , Al-ak'hali Mohammed Sultan
Published: October 2013

Aim. To assess IL-1A C[−889]T and IL-1B C[3954]T genotypes as well as haplotypes in relation to sever chronic periodontitis (SCP) among Yemenis. Materials and Methods. 40 cases with SCP and 40 sex- and age-matched controls were included; all were nonsmokers and free of systemic diseases. Genotyping at each locus was performed using an established PCR-RFLP assay. The Haploview and SimHap software were used to assess data for Hardy-Weinberg's equilibrium (HWE) and linkage disequilibrium (LD) and to obtain subject-level haplotypes. Multiple logistic regression was used to seek for associations in dominant, additive, and recessive models. Results. Mean plaque index (MPI) showed the strongest association with SCP (OR=16). A significant LD was observed in the cases (D'=0.80 and r2=0.47). The genotype at each locus showed significant association with SCP in the recessive model (TT versus TC+CC) even after adjustment for MPI (OR=6.29 & 461, resp.). The C-T haplotype conferred protection against SCP in a dominant manner (OR=0.16). On the other hand, the T-T haplotype in double dose (recessive model) showed strong association with CP (OR=15.6). Conclusions. IL-1 two-locus haplotype is associated with SCP in Yemenis. Haplotype-based analysis may be more suited for use in genetic association studies of periodontitis.
DNA Methylation Changes duringIn VitroPropagation of Human Mesenchymal Stem Cells: Implications for Their Genomic Stability?
Authors: Bentivegna Angela , Miloso Mariarosaria , Riva Gabriele , Foudah Dana , Butta Valentina , Dalprà Leda , Tredici Giovanni
Published: October 2013

Mesenchymal stem cells (MSCs) hold great promise for the treatment of numerous diseases. A major problem for MSC therapeutic use is represented by the very low amount of MSCs which can be isolated from different tissues; thusex vivoexpansion is indispensable. Long-term culture, however, is associated with extensive morphological and functional changes of MSCs. In addition, the concern that they may accumulate stochastic mutations which lead the risk of malignant transformation still remains. Overall, the genome of human MSCs (hMSCs) appears to be apparently stable throughout culture, though transient clonal aneuploidies have been detected. Particular attention should be given to the use of low-oxygen environment in order to increase the proliferative capacity of hMSCs, since data on the effect of hypoxic culture conditions on genomic stability are few and contradictory. Furthermore, specific and reproducible epigenetic changes were acquired by hMSCs duringex vivoexpansion, which may be connected and trigger all the biological changes observed. In this review we address current issues on long-term culture of hMSCs with a 360-degree view, starting from the genomic profiles and back, looking for an epigenetic interpretation of their genetic stability.
Research on Effectiveness Modeling of the Online Chat Group
Authors: Zhang Hua-Fei , Dong Li-Gang , Sun Jia-wei , Li Ying
Published: October 2013

The online chat group is a small-scale multiuser social networking platform, in which users participate in the discussions and send and receive information. Online chat group service providers are concerned about the number of active members because more active members means more advertising revenues. For the group owners and members, efficiency of information acquisition is the concern. So it is of great value to model these two indicators’ impacting factors. This paper deduces the mathematical models of the number of active members and efficiency of information acquisition and then conducts numerical experiment. The experimental results provide evidences about how to improve the number of active members and efficiency of information acquisition.
Effect of Dynamic Center Region on the Flow and Mixing Efficiency in a New Tri-Screw Extruder Using 3D Finite Element Modeling
Authors: Zhu X. Z. , He Y. D. , Wang G.
Published: October 2013

Three-dimensional finite element modeling of polymer melt flowing in a new co-rotating tri-screw extruder was established with mesh superposition technique. Based on the particle tracking technology, three typical particle trajectories in the tri-screw extruder were calculated using a 4th-order-Runge-Kutta method to study the dynamic motions of the particles. Then the flow visualizations in the local center region were carried out. Moreover, the dispersive, distributive and stretching mixing efficiencies of the tri-screw and twin-screw extruders were compared, respectively. The results show that when the particles move from one screw to another, there are great abrupt changes in the velocities and displacements, which induce the abrupt change in the stress magnitude. Most of particles, which are initially distributed in the inlet plane of the center region, fast flow out the outlet and don’t pass through any screw. This special phenomenon induces a series of new characteristics in the residence time distribution (RTD), flow number, segregation scale and time averaged efficiency. In comparison with the twin-screw extruder, the tri-screw extruder has better mixing efficiency.
Near-Zero-Refractive-Index Structure at Optical Frequencies
Authors: Ashour Hassan S.
Published: October 2013

We have used a new class of left-handed materials, which uses 3D nanospheres distributed in loops in the dielectric host material. These 3D nanospheres loops give rise to negative effective permeability and permeability at Terahertz (optical) frequencies. The modal dispersion relation for Terahertz TE surface waves has been derived for a slab waveguide constructed from a dielectric material slab sandwiched between two thick layers of Terahertz left-handed material (LHM). The modal dispersion relation and the power flow were numerically solved for a given set of parameters: dielectric slab thickness, the operating frequency, mode order, and the power flow and extinction in the structure. The real part of the effective refractive index exhibits near-zero values, with small extinction coefficient values. Besides that, the power flow in the dielectric core increased with slab thickness increase and the power attenuation decreased with thickness increase.
PPARgamma-Dependent Control of Renin Expression: Molecular Mechanisms and Pathophysiological Relevance
Authors: Todorov Vladimir T.
Published: October 2013

During the last years accumulating evidence demonstrated that the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates the expression of renin gene and thus the overall renin production. This review summarizes the current knowledge of the transcriptional control of the renin gene by PPARgamma received from variety of models ranging from cell culture to transgenic animals. The molecular mechanisms of the PPARgamma action on renin are particularly interesting because they are featured by two newly described characteristics: one of them is the recently identified PPARgamma target sequence Pal3 which is specific for the human renin gene and mediates exceptionally high sensitivity to transactivation; the other is the potentiating effect of PPARgamma on the cAMP signaling in the renin-producing cells. Furthermore, I discuss the need for generating of additional transgenic animal models which are more appropriate with regard to the role of the PPARgamma-dependent regulation of the renin gene expression in human diseases such as arterial hypertension and metabolic syndrome.
A Ternary Catalytic System for the Room Temperature Suzuki‐Miyaura Reaction in Water
Authors: Silva Aires da Conceição , Senra Jaqueline Dias , de Souza Andréa Luzia Ferreira , Brum Malta Luiz Fernando
Published: October 2013

The formation of Pd(0) in the absence of any classical reducing agent in a medium containing Mg2+/Al3+ layered double hydroxide (LDH) and N,N‐dimethylformamide was evidenced. XRD analysis showed the presence of crystalline phases of palladium in the Pd/LDH composite. Suzuki‐Miyaura reactions in aqueous medium were carried out at room temperature, and good yields were obtained with bromoarenes and iodoarenes using the ternary system LDH‐Pd‐CD (cyclodextrin) as catalyst.
Prediction for Traffic Accident Severity: Comparing the Bayesian Network and Regression Models
Authors: Zong Fang , Xu Hongguo , Zhang Huiyong
Published: October 2013

The paper presents a comparison between two modeling techniques, Bayesian network and Regression models, by employing them in accident severity analysis. Three severity indicators, that is, number of fatalities, number of injuries and property damage, are investigated with the two methods, and the major contribution factors and their effects are identified. The results indicate that the goodness of fit of Bayesian network is higher than that of Regression models in accident severity modeling. This finding facilitates the improvement of accuracy for accident severity prediction. Study results can be applied to the prediction of accident severity, which is one of the essential steps in accident management process. By recognizing the key influences, this research also provides suggestions for government to take effective measures to reduce accident impacts and improve traffic safety.
Criterion for Unbounded Synchronous Region in Complex Networks
Authors: Zhou Jin
Published: October 2013

Synchronization of complex networks has been extensively studied in many fields, where intensive efforts have been devoted to the understanding of its mechanisms. As for discriminating network synchronizability by Master Stability Function method, a dilemma usually encountered is that we have no prior knowledge of the network type that the synchronous region belongs to. In this paper, we investigate a sufficient condition for a general complex dynamical network in the absence of control. A main result is that, when the coupling strength is sufficiently strong, the dynamical network achieves synchronization provided that the symmetric part of the inner-coupling matrix is positive definite. According to our results, synchronous region of the network with positive definite inner-coupling matrix belongs to the unbounded one, and then the eigenvalue of the outer-coupling matrix nearest 0 can be used for judging synchronizability. Even though we cannot gain the necessary and sufficient conditions for synchronizing a network so far, our results constitute a first step toward a better understanding of network synchronization.
Minimum-Cost QoS-Constrained Deployment and Routing Policies for Wireless Relay Networks
Authors: Lin Frank Yeong-Sung , Hsiao Chiu-Han , Chu Kuo-Chung , Liu Yi-Heng
Published: October 2013

With the continued evolution of wireless communication technology, relaying is one of the features proposed for the 4G LTE Advanced (LTE-A) system. The aim of relaying is to enhance both coverage and capacity. The idea of relays is not new, but relaying is being considered to ensure that the optimum performance is achieved to enable the expectations or good quality of service (QoS) of the users to be met while still keeping capital expenditure (CAPEX) within the budgeted bounds of operators. In this paper, we try to stand for an operator to propose a solution that determines where and how many relays should be deployed in the planning stages to minimize the development cost. In the planning stages, we not only derive a multicast tree routing algorithm to both determine and fulfill the QoS requirements to enhance throughput, but we also utilize the Lagrangian relaxation (LR) method in conjunction with optimization-based heuristics and conduct computational experiments to evaluate the performance. Our contribution is utilizing the LR method to propose an optimal solution to minimize the CAPEX of operators to build up a relay network with more efficiency and effectiveness and the QoS can be guaranteed by service level agreement.
Mortality from Diabetes by Hispanic Groups: Evidence from the US National Longitudinal Mortality Study
Authors: Kposowa Augustine J.
Published: October 2013

Diabetes is a leading cause of morbidity and mortality in the United States, especially in minority communities. In mortality research, Hispanics are frequently studied as a homogeneous group. The present study was undertaken to compare diabetes deaths among persons of Hispanic origin by disaggregating groups in order to determine whether the components in the Hispanic label have differential mortality. Data utilized were from the US National Longitudinal Mortality Study. Cox proportional hazards regression models were fitted to the data. Findings showed that individuals in the broader Hispanic label were 28% more likely to die from diabetes mellitus than non-Hispanic whites (ARR = 1.28, CI = 1.05, 1.55). When groups were broken down, it was observed that Mexicans were 50% more likely to die of diabetes than their non-Hispanic white counterparts. No other Hispanic origin group was significantly associated with diabetes mortality risk. Education and family income were strong predictors of mortality, regardless of Hispanic origin grouping. It was concluded from the analysis that future behavioral and social science research would be more informative if the broader Hispanic label was broken down into subcategories. Failure to do so might lead to drawing false inferences as a finding may well hold for one group within the Hispanic label, but not for others.
Damage of Stone Baskets by Endourologic Lithotripters: A Laboratory Study of 5 Lithotripters and 4 Basket Types
Authors: Cordes Jens , Nguyen Felix , Lange Birgit , Brinkmann Ralf , Jocham Dieter
Published: October 2013

Background. In some cases, the ureteral stone is simultaneously stabilized by a stone basket when endourologic lithotripsy is performed. This stabilization can be either on purpose or by accident. By accident means that an impaction in the ureter occurs by an extraction of a stone with a basket. A stabilization on purpose means to avoid a retropulsion of the stone into the kidney during lithotripsy. At this part of the operation, stone baskets have been frequently damaged. This severing of wires can lead to ureteral trauma because of hook formation.Material and Methods. In a laboratory setting, the time and the pulse numbers were measured until breaking the wires from four different nitinol stone baskets by using five different lithotripsy devices. The endpoint was gross visibledamage to the wire and loss of electric conduction.Results. The Ho:YAG laser and the ultrasonic device were able to destroy almost all the wires. The ballistic devices and the electrohydraulic device were able to destroy thin wires.Conclusion. The operating surgeon should know the risk of damagefor every lithotripter. The Ho:YAG-laser and the ultrasonic device should be classified as dangerous for the basket wire with all adverse effects to the patient.
Green Tea Extract Supplementation Induces the Lipolytic Pathway, Attenuates Obesity, and Reduces Low-Grade Inflammation in Mice Fed a High-Fat Diet
Authors: Cunha Cláudio A. , Lira Fábio S. , Rosa Neto José C. , Pimentel Gustavo D. , Souza Gabriel I. H. , da Silva Camila Morais Gonçalves , de Souza Cláudio T. , Ribeiro Eliane B. , Frankland Sawaya Alexandra Christine Helena , Oller do Nascimento Cláudia M. , Rodrigues Bruno , de Oliveira Carvalho Patrícia , Oyama Lila M.
Published: October 2013

The aim of this study was to evaluate the effects of green teaCamellia sinensisextract on proinflammatory molecules and lipolytic protein levels in adipose tissue of diet-induced obese mice. Animals were randomized into four groups: CW (chow diet and water); CG (chow diet and water + green tea extract); HW (high-fat diet and water); HG (high-fat diet and water + green tea extract). The mice were fedad libitumwith chow or high-fat diet and concomitantly supplemented (oral gavage) with 400 mg/kg body weight/day of green tea extract (CG and HG, resp.). The treatments were performed for eight weeks. UPLC showed that in 10 mg/mL green tea extract, there were 15 μg/mg epigallocatechin, 95 μg/mg epigallocatechin gallate, 20.8 μg/mg epicatechin gallate, and 4.9 μg/mg gallocatechin gallate. Green tea administered concomitantly with a high-fat diet increased HSL, ABHD5, and perilipin in mesenteric adipose tissue, and this was associated with reduced body weight and adipose tissue gain. Further, we observed that green tea supplementation reduced inflammatory cytokine TNFαlevels, as well as TLR4, MYD88, and TRAF6 proinflammatory signalling. Our results show that green tea increases the lipolytic pathway and reduces adipose tissue, and this may explain the attenuation of low-grade inflammation in obese mice.
Abacus Training Modulates the Neural Correlates of Exact and Approximate Calculations in Chinese Children: An fMRI Study
Authors: Du Fenglei , Chen Feiyan , Li Yongxin , Hu Yuzheng , Tian Mei , Zhang Hong
Published: October 2013

Exact (EX) and approximate (AP) calculations rely on distinct neural circuits. However, the training effect on the neural correlates of EX and AP calculations is largely unknown, especially for the AP calculation. Abacus-based mental calculation (AMC) is a particular arithmetic skill that can be acquired by long-term abacus training. The present study investigated whether and how the abacus training modulates the neural correlates of EX and AP calculations by functional magnetic resonance imaging (fMRI). Neural activations were measured in 20 abacus-trained and 19 nontrained Chinese children during AP and EX calculation tasks. Our results demonstrated that: (1) in nontrained children, similar neural regions were activated in both tasks, while the size of activated regions was larger in AP than those in the EX; (2) in abacus-trained children, no significant difference was found between these two tasks; (3) more visuospatial areas were activated in abacus-trained children under the EX task compared to the nontrained. These results suggested that more visuospatial strategies were used by the nontrained children in the AP task compared to the EX; abacus-trained children adopted a similar strategy in both tasks; after long-term abacus training, children were more inclined to apply a visuospatial strategy during processing EX calculations.
Tumor Seeding of Percutaneous Nephrostomy Tract from Urothelial Carcinoma of the Kidney
Authors: Sorokin Igor , Welliver R. C. , Elkadi Osama , Nazeer Tipu , Kaufman Ronald P.
Published: October 2013

Urothelial carcinoma (UC) of the renal pelvis has been rarely shown to metastasize to the skin. Tumor seeding from iatrogenic procedures is a source of spreading of UC to the skin. We herein present a case of primary UC of the renal pelvis with spreading to the skin from a percutaneous nephrostomy tract.
YEATS4 Is a Novel Oncogene Amplified in Non–Small Cell Lung Cancer That Regulates the p53 Pathway
Authors: Pikor Larissa A. , Lockwood William W. , Thu Kelsie L. , Vucic Emily A. , Chari Raj , Gazdar Adi F. , Lam Stephen , Lam Wan L.
Published: October 2013

Genetic analyses of lung cancer have helped found new treatments in this disease. We conducted an integrative analysis of gene expression and copy number in 261 non–small cell lung cancers (NSCLC) relative to matched normal tissues to define novel candidate oncogenes, identifying 12q13-15 and more specifically the YEATS4 gene as amplified and overexpressed in ∼20% of the NSCLC cases examined. Overexpression of YEATS4 abrogated senescence in human bronchial epithelial cells. Conversely, RNAi-mediated attenuation of YEATS4 in human lung cancer cells reduced their proliferation and tumor growth, impairing colony formation and inducing cellular senescence. These effects were associated with increased levels of p21WAF1 and p53 and cleavage of PARP, implicating YEATS4 as a negative regulator of the p21-p53 pathway. We also found that YEATS4 expression affected cellular responses to cisplastin, with increased levels associated with resistance and decreased levels with sensitivity. Taken together, our findings reveal YEATS4 as a candidate oncogene amplified in NSCLC, and a novel mechanism contributing to NSCLC pathogenesis. Cancer Res; 73(24); 7301–12. ©2013 AACR.
A Personalized Preclinical Model to Evaluate the Metastatic Potential of Patient-Derived Colon Cancer Initiating Cells
Authors: Puig Isabel , Chicote Irene , Tenbaum Stephan P. , Arqués Oriol , Herance José Raúl , Gispert Juan D. , Jimenez José , Landolfi Stefania , Caci Karina , Allende Helena , Mendizabal Leire , Moreno Debora , Charco Ramón , Espín Eloy , Prat Aleix , Elez Maria Elena , Argilés Guillem , Vivancos Ana , Tabernero Josep , Rojas Santiago , Palmer Héctor G.
Published: October 2013

Purpose: Within the aim of advancing precision oncology, we have generated a collection of patient-derived xenografts (PDX) characterized at the molecular level, and a preclinical model of colon cancer metastasis to evaluate drug-response and tumor progression.

Experimental Design: We derived cells from 32 primary colorectal carcinomas and eight liver metastases and generated PDX annotated for their clinical data, gene expression, mutational, and histopathological traits. Six models were injected orthotopically into the cecum wall of NOD-SCID mice in order to evaluate metastasis. Three of them were treated with chemotherapy (oxaliplatin) and three with API2 to target AKT activity. Tumor growth and metastasis progression were analyzed by positron emission tomography (PET).

Results: Patient-derived cells generated tumor xenografts that recapitulated the same histopathological and genetic features as the original patients' carcinomas. We show an 87.5% tumor take rate that is one of the highest described for implanted cells derived from colorectal cancer patients. Cecal injection generated primary carcinomas and distant metastases. Oxaliplatin treatment prevented metastasis and API2 reduced tumor growth as evaluated by PET.

Conclusions: Our improved protocol for cancer cell engraftment has allowed us to build a rapidly expanding collection of colorectal PDX, annotated for their clinical data, gene expression, mutational, and histopathological statuses. We have also established a mouse model for metastatic colon cancer with patient-derived cells in order to monitor tumor growth, metastasis evolution, and response to treatment by PET. Our PDX models could become the best preclinical approach through which to validate new biomarkers or investigate the metastatic potential and drug-response of individual patients. Clin Cancer Res; 19(24); 6787–801. ©2013 AACR.
Hypoxia-Regulated Overexpression of Soluble VEGFR2 Controls Angiogenesis and Inhibits Tumor Growth
Authors: Collet Guillaume , Lamerant-Fayel Nathalie , Tertil Magdalena , El Hafny-Rahbi Bouchra , Stepniewski Jacek , Guichard Alan , Foucault-Collet Alexandra , Klimkiewicz Krzysztof , Petoud Stéphane , Matejuk Agata , Grillon Catherine , Jozkowicz Alicja , Dulak Jozef , Kieda Claudine
Published: October 2013

VEGFs are found at high levels in hypoxic tumors. As major components directing pathologic neovascularization, they regulate stromal reactions. Consequently, novel strategies targeting and inhibiting VEGF overproduction upon hypoxia offer considerable potential for modern anticancer therapies controlling rather than destroying tumor angiogenesis. Here, we report the design of a vector expressing the soluble form of VEGF receptor-2 (sVEGFR2) driven by a hypoxia-responsive element (HRE)-regulated promoter. To enable in vivo imaging by infrared visualization, mCherry and IFP1.4 coding sequences were built into the vector. Plasmid construction was validated through transfection into embryonic human kidney HEK293 and murine B16F10 melanoma cells. sVEGFR2 was expressed in hypoxic conditions only, confirming that the gene was regulated by the HRE promoter. sVEGFR2 was found to bind efficiently and specifically to murine and human VEGF-A, reducing the growth of tumor and endothelial cells as well as impacting angiogenesis in vitro. The hypoxia-conditioned sVEGFR2 expression was shown to be functional in vivo: Tumor angiogenesis was inhibited and, on stable transfection of B16F10 melanoma cells, tumor growth was reduced. Enhanced expression of sVEGFR2 was accompanied by a modulation in levels of VEGF-A. The resulting balance reflected the effect on tumor growth and on control of angiogenesis. A concomitant increase of intratumor oxygen tension also suggested an influence on vessel normalization. The possibility to express an angiogenesis regulator as sVEGFR2, in a hypoxia-conditioned manner, significantly opens new strategies for tumor vessel–controlled normalization and the design of adjuvants for combined cancer therapies. Mol Cancer Ther; 13(1); 165–78. ©2013 AACR.
The Utility of Special Radiological Signs on Routinely Obtained Supine Anteroposterior Chest Radiographs for the Early Recognition of Neonatal Pneumothorax
Authors: Cizmeci Mehmet Nevzat , Akin Kayihan , Kanburoglu Mehmet Kenan , Akelma Ahmet Zulfikar , Andan Hilal , Erbukucu Onur , Tatli Mustafa Mansur
Published: October 2013

Background: Bedside chest radiographs used for the confirmation of diagnosis of pneumothorax in the neonatal intensive care unit (NICU) are routinely obtained in the supine position. However, pneumothoraces may not appear in the classically described forms on these radiographs, resulting in a delayed diagnosis. Objective: To assess the utility of special radiological signs in the neonatal population for the early recognition of pneumothorax. Methods: A case-control study was conducted at a level III referral center from January 2006 to December 2012. For each neonate with pneumothorax, one infant was selected for the control group. A senior radiologist and neonatologist experienced in reading chest radiographs evaluated each radiograph for the presence of special radiological signs. Results: Of the 1,375 infants admitted to the NICU during the study period, 39 had a pneumothorax. A total of 223 radiographs were scored and 46% of the neonates were found to have occult pneumothoraces before they were clinically diagnosed. Twenty-six percent had a single sign detected on a radiograph, whereas 20% had multiple signs. The time interval between the appearance of these signs and clinical diagnosis ranged between 0.5 and 27 h. Conclusions: The present study shows that the recognition of these signs would assist the physician in identifying occult pneumothorax earlier in its course. Physicians dealing with critically ill infants should ensure that they can recognize these radiological signs.
Post-Stroke Depression and Depression-Executive Dysfunction Syndrome Are Associated with Recurrence of Ischaemic Stroke
Authors: Sibolt Gerli , Curtze Sami , Melkas Susanna , Pohjasvaara Tarja , Kaste Markku , Karhunen Pekka J. , Oksala Niku K.J. , Vataja Risto , Erkinjuntti Timo
Published: October 2013

Background: Depression and depression-executive dysfunction syndrome (DES) are common neuropsychiatric consequences of stroke. We hypothesized that if stroke as a cerebrovascular event causes depression, this so-called post-stroke depression will further increase the risk of recurrent stroke. The objective of the study was to investigate whether patients with post-stroke depression or DES have increased rates of stroke recurrence. Methods: We included 223 patients from the Helsinki Stroke Aging Memory cohort (n = 486) admitted to Helsinki University Central Hospital with a follow-up of 12 years. We included only patients with first-ever ischaemic stroke who were testable for depression and executive dysfunction. For follow-up, national register data were reviewed for all diagnosis codes of ischaemic stroke, survival data and causes of death. Neuropsychological and neuropsychiatric evaluations for depression and executive functions were performed 12-20 weeks after the index stroke. Univariate analysis was performed using χ2, Mantel-Haenszel, ANOVA, and Kaplan-Meier log rank analyses. A Cox multivariable model with forced entry was used to adjust for stroke risk factors (age, gender, smoking, atrial fibrillation, hypertension, diabetes, peripheral arterial disease, hypercholesterolaemia). Results: The mean time to first recurrent stroke was shorter for the depressed patient group (8.15, 95% CI 7.11-9.19 vs. 9.63, 8.89-10.38 years) and even shorter for patients with DES (7.15, 5.55-8.75 vs. 9.75, 9.09-10.41 years) compared to the remaining groups, respectively. The cumulative risk for recurrent ischaemic stroke in the 12-year follow-up was higher for the depression group (log rank p = 0.04) and for the DES group (log rank p = 0.01) compared to the remaining groups, respectively. Cox multivariable analyses revealed that the older age of the patient (1.05; 1.01-1.08/year), the absence of hypercholesterolaemia (0.24; 0.09-0.59), depression (1.68; 1.07-2.63), and DES (1.95; 1.14-3.33) were all associated with recurrent stroke. Conclusions: Depression and especially DES are associated with a shorter interval to recurrence of ischaemic stroke but executive dysfunction alone is not associated with a more rapid stroke recurrence. Diagnosis and treatment of depressive syndromes should be considered as a part of secondary prevention in patients with ischaemic stroke.
Impact and Safety of Adjuvant Chemotherapy on Pulmonary Function in Early Stage Non-Small Cell Lung Cancer
Authors: Kreuter Michael , Vansteenkiste Johan , Herth Felix J.F. , Fischer Jürgen R. , Eberhardt Wilfried , Zuna Ivan , Reinmuth Niels , Griesinger Frank , Thomas Michael ,   on behalf of the TREAT investigators
Published: October 2013

Background: Pulmonary function may decline after induction chemotherapy and predict perioperative complications in non-small cell lung cancer (NSCLC). The influence of adjuvant chemotherapy is largely indeterminate. Objective: To assess whether adjuvant chemotherapy alters pulmonary function and impacts on treatment-related adverse events. Methods: In a trial on adjuvant chemotherapy (the TREAT trial), 132 patients with R0-resected NSCLC were randomised to 4 cycles of cisplatin-vinorelbine (CVb, n = 65) or cisplatin-pemetrexed (CPx, n = 67). Pulmonary function tests (forced expiratory volume in 1 s, FEV1, forced vital capacity, FVC, total lung capacity, TLC, diffusing capacity for carbon monoxide, DLCO, and blood gas analyses, BGA) were analysed before and 30 days after the last chemotherapy, and changes were calculated (Δ = mean differences). Results: Overall, FVC increased significantly (Δ +290 ml, n = 76; p < 0.0001), while TLC did not change (Δ +220 ml, n = 41; p = 0.174). For CPx, FEV1 increased significantly (Δ +150 ml, n = 47; p = 0.0017), but not for CVb (Δ +30 ml, n = 30). DLCO decreased only for CVb (-8%, n = 6) but not for CPx (-0.39%, n = 17; p = 0.58). BGA did not change (p = 0.99). In a Cox regression analysis, baseline pulmonary function did not influence treatment failure. Conclusions: Adjuvant chemotherapy seems not to result in a decrease of pulmonary function parameters. A significant FVC increase was probably due to ongoing postoperative improvement. Decline of DLCO was noted with CVb but not with CPx. Pulmonary function does not impact on treatment failure.
Employing Alzheimer Disease Animal Models for Translational Research: Focus on Dietary Components
Authors: Grossi Cristina , Ed Dami Teresa , Rigacci Stefania , Stefani Massimo , Luccarini Ilaria , Casamenti Fiorella
Published: October 2013

Background: Translational research needs valid animal models of disease to discover new pathogenetic aspects and treatments. In Alzheimer's disease (AD), transgenic models are of great value for AD research and drug testing. Objective: It was the aim of this study to analyze the power of dietary polyphenols against neurodegeneration by investigating the effects of oleuropein aglycone (OLE), the main phenol in the extra virgin olive oil (EVOO), a key component of the Mediterranean diet (MD), in a mouse model of amyloid-β deposition. Methods: TgCRND8 mice (3.5 months old), expressing the mutant KM670/671NL+V717F h-βAPP695 transgene, and wild-type (wt) mice were used to study in vivo the effects of an 8-week dietary supplementation with OLE (50 mg/kg of diet) [Grossi et al: PLoS One 2013;8:e71702], following the European Communities Council Directive 86/609 (DL 116/92) and National Guidelines (permit number: 283/2012-B). Results: OLE administration ameliorates memory dysfunction, raises a significant autophagic response in the cortex and promotes the proliferation of newborn cells in the subgranular zone of the dentate gyrus of the hippocampus. Conclusions: Our findings support the beneficial effects of EVOO and highlight the possibility that continuous intake of high doses of OLE, both as a nutraceutical or as a food integrator, may prevent/delay the appearance of AD and reduce the severity of its symptoms.
Impact of Selection Criteria on Recruitment in an Interventional Stroke Trial
Authors: Hotter Benjamin , Jegzentis Kati , Steinbrink Jens , Schmidt Wolf U. , Endres Matthias , Meisel Andreas , Haverkamp Wilhelm , Jungehulsing Gerhard J.
Published: October 2013

Background: Randomized controlled clinical trials are the gold standard for scientific evaluation of clinical diagnostic and treatment concepts. Frequently, recruitment of participants is slower than expected, especially in acute conditions with a short time frame for inclusion. Simple prediction models have been proposed to extrapolate recruitment rates. We hypothesized a significant overestimation of recruitment when ignoring interdependence of selection criteria, leading to an insufficient representation of reality by available models. We proposed that slight modifications to inclusion criteria might augment recruitment without causing selection bias. Methods: We analyzed recruitment in an acute intervention trial of acute ischemic stroke initiated by our facility. Frequencies of selection criteria were recorded and analyzed individually as well as cumulatively. We then amended the trial protocol by moderate modifications to the selection criteria. The main outcome criterion was the rate of recruited over screened patients, with the goal of increasing recruitment fourfold without adding unacceptable selection bias. A previously presented prediction model was applied to our trial and compared with actual recruitment. Data were compared between screening periods at recruitment prior to and after the implementation of the amendments. Results: The impact of typical as well as novel inclusion criteria such as age limits, imaging-based definition of pathology, time between onset and presentation as well as inability to consent were quantified. Age restriction, definition of index event and late arrival after ictus were identified as the most challenging modifiable selection criteria. Amending those criteria increased recruitment by a factor of 4.1. Inability to consent was a significant exclusion criterion gaining impact with the target population. The selection criteria had a cumulative rather than separate recruitment-limiting impact. A previously presented model did not predict recruitment sufficiently. Conclusion: We describe frequencies of selection criteria in a typical cohort of patients suffering from acute cerebrovascular events, and their cumulative impact. These data may help to better understand recruitment limitations and allow designing future trials more effectively. Ability to consent especially is a major contributor to trial exclusion, strongly interfering with the targeted trial population of ischemic stroke. Tentative prescreening phases before site or trial initiation should be considered. No predictive statistical models of recruitment have been established so far.
Gamma-Secretase Inhibitor Activity of a Pterocarpus erinaceus Extract
Authors: Hage Salim , Marinangeli Claudia , Stanga Serena , Octave Jean-Noël , Quetin-Leclercq Joëlle , Kienlen-Campard Pascal
Published: October 2013

Background: Accumulation of β-amyloid peptides (Aβ) and its progressive deposition into amyloid plaques are key events in the aetiology of Alzheimer's disease (AD). To date, AD treatment is symptomatic and consists of drugs treating the cognitive decline. Objective: Identifying molecules specifically targeting Aβ production or aggregation represents a huge challenge in the development of specific AD treatments. Several molecules reported as γ-secretase inhibitors or modulators have been evaluated, but so far none of them have proven to be selective or fully efficient. We have previously investigated the potential interest of plant extracts and we reported that Pterocarpus erinaceus stem-bark extract was active on Aβ release. Our aim here was to characterize the mechanisms by which this extract reduces Aβ levels. Methods: We tested P. erinaceus extract at non-toxic concentrations on cells expressing the human amyloid precursor protein (APP695) or its amyloidogenic β-cleaved C-terminal fragment (C99), as well as on neuronal cell lines. P. erinaceus extract was found to inhibit Aβ release. We further showed that this extract inhibited γ-secretase activity in cell-free and in vitro assays, strongly suggesting that P. erinaceus extract is a natural γ-secretase inhibitor. Importantly, this extract did not inhibit γ-secretase-dependent Notch intracellular domain release. Conclusion: P. erinaceus extract appears as a new potent γ-secretase inhibitor selective towards APP processing.
Variability in the Internal Wave Field Induced by the Atlantic Deep Western Boundary Current at 16°N
Authors: Köhler Janna , Mertens Christian , Walter Maren , Stöber Uwe , Rhein Monika , Kanzow Torsten
Published: October 2013

Five years of continuous mooring data combined with conductivity–temperature–depth (CTD)/lowered acoustic Doppler current profiler (LADCP) measurements from five cruises are used to investigate the influence of the deep western boundary current (DWBC) on the internal wave field and associated vertical mixing at the continental slope at 16°N in the western Atlantic. The mooring data include 2-hourly rotor current-meter measurements and temperature/conductivity time series with a high temporal resolution of 5–20 min. Thus, the data resolve time scales ranging from the low-frequency variability of the large-scale DWBC that generates internal waves due to interactions with the topography to frequencies greater than that of internal waves that are associated with vertical mixing. Estimates of the vertical mixing induced by the breaking of the observed internal waves show elevated diapycnal diffusivities of up to 10−3 ± 0.4 × 10−3 m2 s−1 in the bottommost 1500 m during times of a strong DWBC (maximum velocities at the mooring site up to 50 cm s−1) whereas vertical mixing rates are about an order of magnitude lower (1.6 × 10−4 ± 0.6 × 10−4 m2 s−1) during weak flow. During periods of a strong DWBC, spectra of horizontal velocity and internal wave available potential energy change substantially at depths below 1200 m and show a strong increase in variance particularly in the near-inertial frequency band. Low-frequency, near-inertial waves generated by topography/DWBC interaction on the slope to the west of the moorings can potentially cause this observed wave intensification; ray paths estimated for these waves agree well with the observed spectral changes at different depths. Variability in the high-frequency range, considered as a proxy for turbulent mixing, is significantly correlated with the DWBC strength above the continental slope.