bluuebunny/crossref_metadata_2025 huggingface dataset:
Achieving compliance with pool fencing legislation in New Zealand: a survey of regulatory authorities
Authors: Morrison Luke , Chalmers David J , Langley John D , Alsop Jonathan C , McBean Catriona
Published: December 2008

Objectives—To identify the status of compliance and enforcement of New Zealand's Fencing of Swimming Pools Act (FOSP Act), 10 years after its introduction, and to identify methods for improving both compliance with the act and the process of enforcement.

Methods—A postal questionnaire was sent to all 74 authorities in New Zealand in which they were asked questions about their enforcement of the FOSP Act. Semistructured telephone interviews were conducted with 12 authorities to supplement the data obtained in the postal survey.

Results—Based on responses to the survey, it was estimated that there are over 59 000 domestic swimming pools in New Zealand, giving rates of 46 pools/1000 dwellings and 16 pools/1000 persons. The authorities reported that 44% of pools complied with the act, and a further 4% had been granted exemptions. Nineteen per cent of pools were reported to not comply with the act, and the compliance status of a further 33% was not known, or not stated by the authority. Only 9% of authorities had procedures for locating and inspecting pools, while 28% had a programme of reinspection to ensure that pools continued to comply. Pool owner resistance was considered to be the main difficulty with enforcing the act, and nearly half of the authorities believed publicity or education was needed to overcome these barriers. Fifty two per cent of authorities had publicised the act during the 12 months preceding the survey.

Conclusions—Due to ambiguities within the legislation, and differing levels of commitment by authorities to locate pools and monitor compliance, compliance with the FOSP Act is not consistent nationally. If the act were less ambiguous, there would be greater consistency and more enforcement.
Unintentional childhood injury mortality in Europe 1984–93: a report from the EURORISC Working Group
Authors: Morrison Anita , Stone David H
Published: December 2008

Objective—To examine recent trends in unintentional childhood injury mortality in Europe, and to identify the contribution of specific causes.

Setting—The 15 current member countries of the European Union.

Methods—Analysis of mortality data (1984–93) obtained from the World Health Organisation and national government agencies.

Results—Injuries continue to be the leading cause of childhood death in all study countries, with more than 4500 fatalities annually, accounting for over 30% of all child mortality. The major causes of death in all countries were injuries due to motor vehicle traffic accidents, drownings, fire and flames, and falls. Portugal experienced mortality rates double those of most other countries, with the differentials particularly stark early in the study period. Although a decrease in age standardised mortality rates was observed in all countries over the decade, the extent of the decrease varied widely, from −47% in the UK to −11% in Finland.

Conclusion—The pattern of childhood injury in Europe is similar to that observed elsewhere in the world. None the less, differences in rates of childhood injury mortality persist between countries. Identifying the reasons for these variations between countries may hold the key to the reduction injury rates in Europe as a whole.
Urban and rural patterns of bicycle helmet use: factors predicting usage
Authors: Harlos Sande , Warda Lynne , Buchan Norma , Klassen Terry P , Koop Virginia L , Moffatt Michael E K
Published: December 2008

Objectives—To document current bicycle helmet use in Winnipeg, Manitoba and nearby rural communities, and to identify target groups for a helmet promotion campaign.

Methods—Cyclist helmet use was observed between 28 May and 20 August 1996 at a sample of urban and rural locations. Age, gender, helmet use, riding companion(s), location type, correct helmet use, and use of headphones were recorded. Univariate and multivariate analyses were performed. Adjusted odds ratios with 95% confidence intervals were calculated from the final models.

Results—Altogether 2629 cyclists (70% male, 30% female) were observed: 2316 at 183 urban locations and 313 at 25 rural locations, with nearly equal numbers of children and adults observed. Overall helmet use was 21.3%, with lower use in males (18.9%) than females (26.3%), despite gender only being a significant variable on multivariate analysis for children under 8 years and adults. Urban helmet use was considerably higher (22.9%) than rural use (8.9%). Helmet use increased linearly as mean neighbourhood income increased, with a nearly fourfold difference in use between the highest and lowest income neighbourhoods. Children less than 8 years old and adults had the highest, and teenagers the lowest, use. Significant predictive variables were identified separately by age category to inform targeted programming.

Conclusions—We documented low helmet use in our region, emphasizing the need for a regional helmet promotion campaign as well as future helmet legislation. A marked urban-rural difference in helmet use that has not been previously reported was also identified. Target groups for a future campaign include adolescents, males, rural cyclists, and those in lower income neighbourhoods.
Coding the circumstances of injury: ICD-10 a step forward or backwards?
Authors: Langley John D , Chalmers David J
Published: December 2008

TheInternational Classification of Diseases(ICD) E codes are the most widely used coding frame for categorising the circumstances of injury and poisoning. In 1992 major revisions to the E codes were released. The aim of this paper was to consider whether the changes made are a step forward or backwards in terms of facilitating injury prevention.

The approach taken was to reflect on some former injury prevention research needs and the challenges they presented using data coded according to ICD-9, and then to consider how, if at all, ICD-10 has addressed these difficulties.

As with ICD-9, there are essentially two axes associated with each cause: intent and mechanism of injury, and these are captured by one code. This approach can have the unintended effect of hiding the significance of some mechanisms of injury. While there have been significant improvements in some areas, such as falls, in others, such as injuries due to firearms, ICD-10 has taken a step backward. In addition the failure to produce mutually exclusive codes presents problems for determining the incidence of downing events.

A welcome addition are “optional” activity codes which enable the identification of work related and sport related injury for the first time. Nevertheless, the limited range of codes and absence of coding guides limits their utility. The revised place of occurrence codes do not represent a significant improvement on ICD-9 in that they are limited to 10, they are not mutually exclusive, and they do not adequately cover a range of specific places of occurrence.

In summary, relative to its predecessor, ICD-10 represents a significant improvement in many areas. Unfortunately, it still falls far short of the mark for many injury prevention needs.
Child death reviews: a gold mine for injury prevention and control
Authors: Onwuachi-Saunders Chukwudi , Forjuoh Samuel N , West Patricia , Brooks Cimon
Published: December 2008

Objectives—The purpose of this study was to demonstrate how child death review teams can be used to prevent future deaths through retrospective, multiagency case analysis and recommendations for educational programs and policy change.

Methods—A listing of all deaths to persons ages 21 years and younger in Philadelphia that occurred in 1995 was compiled by the Philadelphia Interdisciplinary Youth Fatality Review Team (PIYFRT), a multiagency, multidisciplinary, community based group created in 1993 with the mission to prevent future deaths through review, analysis, and initiation of corrective actions. Data were collected on demographic variables, as well as the circumstantial variables on injuries such as weapon type, alcohol and drug use, and contact with the criminal justice system, among others. Each case was reviewed thoroughly to determine whether or not the death was preventable. Selected injury related death cases were analyzed further by demographic and circumstantial variables.

Results—In 1995, 607 children ages 21 years and younger died in Philadelphia from natural causes (61.6%), unintentional injuries (16.3%), homicide (18.6%), suicide (2.3%), and undetermined causes (1.2%). More than a third (37.2%) of all deaths were considered preventable. Of the injury deaths (n=224), 95% were judged to be preventable. Preventable fire/burn injury deaths (n=29) were associated with lack of a smoke detector, non-supervision of children, and faulty home appliances. Violent deaths were associated with substance abuse, gang involvement, chronic truancy, academic failure, and access to weapons.

Conclusions—Relevant policies for these preventable or intervenable deaths are discussed such as use of non-battery powered smoke detectors.
USING SCATTERED MOBILE AGENTS TO LOCATE A BLACK HOLE IN AN UN-ORIENTED RING WITH TOKENS
Authors: DOBREV STEFAN , SANTORO NICOLA , SHI WEI
Published: January 2009

A black hole in a network is a highly harmful host that disposes of any incoming agents upon their arrival. Determining the location of a black hole in a ring network has been studied when each node is equipped with a whiteboard. Recently, the Black Hole Search problem was solved in a less demanding and less expensive token model with co-located agents. Whether the problem can be solved with scattered agents in a token model remains an open problem.

In this paper, we show not only that a black hole can be located in a ring using tokens with scattered agents, but also that the problem is solvable even if the ring is un-oriented. More precisely, first we prove that the black hole search problem can be solved using only three scattered agents. We then show that, with K (K ⩾ 4) scattered agents, the black hole can be located in O(kn + n log n) moves. Moreover, when K (K ⩾ K) is a constant number, the move cost can be reduced to O(n log n), which is optimal. These results hold even if both agents and nodes are anonymous.
LHC SIGNATURES FOR Z' MODELS WITH CONTINUOUSLY DISTRIBUTED MASS
Authors: KRASNIKOV N. V.
Published: December 2008

We discuss phenomenological consequences of renormalizable Z' models with continuously distributed mass. We point out that one of the possible LHC signatures for such model is the existence of broad resonance in Drell–Yan reaction pp →Z' →l+l-.
AN ITERATIVE PROCEDURE FOR OPTIMAL POLLUTION CONTROL UNDER INCOMPLETE INFORMATION
Authors: QUEROU NICOLAS
Published: December 2008

We consider a repeated regulation model in an oligopoly under asymmetric information with pollution. An iterative procedure is proposed where the regulator designs stationary taxes, and firms are not required to be perfectly rational. They can form and update simple beliefs about their competitors' aggregate output at each period. Two versions of the mechanism are provided depending on whether firms behave adaptively or with perfect foresight. Conditions under which the procedure converges to a unique steady state are provided. It is proved that there exists a suitable stationary tax policy that enables the firms to adjust to socially optimal choices in the long run. The tax rates of both versions are typically strictly less than the ones that result from a full information, Nash implementation. Moreover, in the myopic case, the tax rate decreases as the number of firms increases. We discuss problems relating to the potential implementation of the procedure.
FISHERY MANAGEMENT GAMES: HOW TO ADMIT NEW MEMBERS AND REDUCE HARVESTING LEVELS
Authors: PHAM DO KIM HANG , FOLMER HENK , NORDE HENK
Published: December 2008

This paper applies game theory to address the problem of allocating profits among fishing nations, once the countries concerned have expressed an interest in achieving an agreement through a Regional Fishery Management Organization (RFMO). Proposing the population monotonic allocation scheme as management rule for division of profits, we argue that existing RFMOs can be expanded by means of the Shapley value. We also show that adjustment from the Nash equilibrium to sustainable or more efficient can be achieved by means of the proportional rule without harming any of the countries involved.
The genetics of neutral lipid biosynthesis: an evolutionary perspective
Authors: Turkish Aaron R. , Sturley Stephen L.
Published: December 2008

The storage of fatty acids and fatty alcohols in the form of neutral lipids such as triacylglycerol (TAG), cholesteryl ester (CE), and wax ester (WE) serves to provide reservoirs for membrane formation and maintenance, lipoprotein trafficking, lipid detoxification, evaporation barriers, and fuel in times of stress or nutrient deprivation. This ancient process likely originated in actinomycetes and has persisted in eukaryotes, albeit by different molecular mechanisms. A surfeit of neutral lipids is strongly, perhaps causally, related to several human diseases such as diabetes mellitus, obesity, atherosclerosis and nonalcoholic fatty liver disease. Therefore, understanding the metabolic pathways of neutral lipid synthesis and the roles of the enzymes involved may facilitate the development of new therapeutic interventions for these syndromes.
Beyond triglyceride synthesis: the dynamic functional roles of MGAT and DGAT enzymes in energy metabolism
Authors: Shi Yuguang , Cheng Dong
Published: December 2008

Monoacyglycerol acyltransferases (MGATs) and diacylglycerol acyltransferases (DGATs) catalyze two consecutive steps of enzyme reactions in the synthesis of triacylglycerols (TAGs). The metabolic complexity of TAG synthesis is reflected by the presence of multiple isoforms of MGAT and DGAT enzymes that differ in catalytic properties, subcellular localization, tissue distribution, and physiological functions. MGAT and DGAT enzymes play fundamental roles in the metabolism of monoacylglycerol (MAG), diacylglycerol (DAG), and triacylglycerol (TAG) that are involved in many aspects of physiological functions, such as intestinal fat absorption, lipoprotein assembly, adipose tissue formation, signal transduction, satiety, and lactation. The recent progress in the phenotypic characterization of mice deficient in MGAT and DGAT enzymes and the development of chemical inhibitors have revealed important roles of these enzymes in the regulation of energy homeostasis and insulin sensitivity. Consequently, selective inhibition of MGAT or DGAT enzymes by synthetic compounds may provide novel treatment for obesity and its related metabolic complications.
Early response of gene clusters is associated with mouse lung resistance or sensitivity to cigarette smoke
Authors: Cavarra Eleonora , Fardin Paolo , Fineschi Silvia , Ricciardi Annamaria , De Cunto Giovanna , Sallustio Fabio , Zorzetto Michele , Luisetti Maurizio , Pfeffer Ulrich , Lungarella Giuseppe , Varesio Luigi
Published: December 2008

We have investigated the effects of cigarette smoke exposure in three different strains of mice. DBA/2 and C57BL/6J are susceptible to smoke and develop different lung changes in response to chronic exposure, whereas ICR mice are resistant to smoke and do not develop emphysema. The present study was carried out to determine early changes in the gene expression profile of mice exposed to cigarette smoke with either a susceptible or resistant phenotype. The three strains of mice were exposed to smoke from three cigarettes per day, 5 days/wk, for 4 wk. Microarray analysis was carried out on total RNA extracted from the lung using the Affymetrix platform. Cigarette smoke modulates several clusters of genes (i.e., proemphysematous, acute phase response, and cell adhesion) in smoke-sensitive DBA/2 or C57BL/6J strains, but the same genes are not altered by smoke in ICR resistant mice. Only a few genes were commonly modulated by smoke in the three strains of mice. This pattern of gene expression suggests that the response to smoke is strain-dependent and may involve different molecular signaling pathways. Real-time quantitative PCR was used to verify the pattern of modulation of selected genes and their potential biological relevance. We conclude that gene expression response to smoke is highly dependent on the mouse genetic background. We speculate that the definition of gene clusters associated, to various degrees, with mouse susceptibility or resistance to smoke may be instrumental in defining the molecular basis of the individual response to smoke-induced lung injury in humans.
Protein synthesis and the expression of growth-related genes are altered by running in human vastus lateralis and soleus muscles
Authors: Harber Matthew P. , Crane Justin D. , Dickinson Jared M. , Jemiolo Bozena , Raue Ulrika , Trappe Todd A. , Trappe Scott W.
Published: December 2008

Recent evidence suggests aerobic exercise may help preserve soleus muscle mass during unloading. The purpose of this investigation was to examine the muscle-specific metabolic response to running as it relates to muscle growth. Mixed-muscle protein synthesis [fractional synthetic rate (FSR)] and gene expression (GE) were examined in the vastus lateralis (VL) and soleus (SOL) muscles from eight men (26 ± 2 yr; V̇o2max 63 ± 2 ml·kg−1·min−1) before and after a 45-min level-grade treadmill run at 77 ± 1% intensity. Muscle glycogen utilization was similar between muscles. Resting FSR was similar between the VL (0.080 ± 0.007 %/h) and SOL (0.086 ± 0.008 %/h) and was higher ( P < 0.05) 24 h postexercise compared with rest for both muscles. The absolute change in FSR was not different between muscles (0.030 ± 0.007 vs. 0.037 ± 0.012 %/h for VL and SOL). At baseline, myostatin GE was approximately twofold higher ( P < 0.05) in SOL compared with VL, while no other muscle-specific differences in GE were present. After running, myostatin GE was suppressed ( P < 0.05) in both muscles at 4 h and was higher ( P < 0.05) than baseline at 24 h for VL only. Muscle regulatory factor 4 mRNA was elevated ( P < 0.05) at 4 h in both SOL and VL; MyoD and peroxisome-proliferator-activated receptor-gamma coactivator-1α (PGC-1α) were higher ( P < 0.05) at 4 h, and forkhead box [FOXO]3A was higher at 24 h in SOL only, while muscle-RING-finger protein-1 (MuRF-1) was higher ( P < 0.05) at 4 h in VL only. Myogenin and atrogin-1 GE were unaltered. The similar increases between muscles in FSR support running as part of the exercise countermeasure to preserve soleus mass during unloading. The subtle differences in GE suggest a potential mechanism for muscle-specific adaptations to chronic run training.
Theta and Gamma Coherence Along the Septotemporal Axis of the Hippocampus
Authors: Sabolek Helen R. , Penley Stephanie C. , Hinman James R. , Bunce Jamie G. , Markus Etan J. , Escabi Monty , Chrobak James J.
Published: December 2008

Theta and gamma rhythms synchronize neurons within and across brain structures. Both rhythms are widespread within the hippocampus during exploratory behavior and rapid-eye-movement (REM) sleep. How synchronous are these rhythms throughout the hippocampus? The present study examined theta and gamma coherence along the septotemporal (long) axis of the hippocampus in rats during REM sleep, a behavioral state during which theta signals are unaffected by external sensory input or ongoing behavior. Unilateral entorhinal cortical inputs are thought to play a prominent role in the current generation of theta, whereas current generation of gamma is primarily due to local GABAergic neurons. The septal 50% (4–5 mm) of the dentate gyrus (DG) receives a highly divergent, unilateral projection from any focal point along a lateral band of entorhinal neurons near the rhinal sulcus. We hypothesized that theta coherence in the target zone (septal DG) of this divergent entorhinal input would not vary, while gamma coherence would significantly decline with distance in this zone. However, both theta and gamma coherence decreased significantly along the long axis in the septal 50% of the hippocampus across both DG and CA1 electrode sites. In contrast, theta coherence between homotypic (e.g., DG to DG) sites in the contralateral hemisphere (∼3–5 mm distant) were quite high (∼0.7–0.9), much greater than theta coherence between homotypic sites 3–5 mm distant (∼0.4–0.6) along the long axis. These findings define anatomic variation in both rhythms along the longitudinal axis of the hippocampus, indicate the bilateral CA3/mossy cell projections are the major determinant of theta coherence during REM, and demonstrate that theta coherence varies as a function of anatomical connectivity rather than physical distance. We suggest CA3 and entorhinal inputs interact dynamically to generate theta field potentials and advance the utility of theta and gamma coherence as indicators of hippocampal dynamics.
Transcriptional profiling of human mesenchymal stem cells transduced with reporter genes for imaging
Authors: Wang Fangjing , Dennis James E. , Awadallah Amad , Solchaga Luis A. , Molter Joseph , Kuang Yu , Salem Nicolas , Lin Yuan , Tian Haibin , Kolthammer Jeffery A. , Kim Yunhui , Love Zachary B. , Gerson Stanton L. , Lee Zhenghong
Published: December 2008

Mesenchymal stem cells (MSCs) can differentiate into osteogenic, adipogenic, chondrogenic, myocardial, or neural lineages when exposed to specific stimuli, making them attractive for tissue repair and regeneration. We have used reporter gene-based imaging technology to track MSC transplantation or implantation in vivo. However, the effects of lentiviral transduction with the fluc-mrfp-ttk triple-fusion vector on the transcriptional profiles of MSCs remain unknown. In this study, gene expression differences between wild-type and transduced hMSCs were evaluated using an oligonucleotide human microarray. Significance Analysis of Microarray identified differential genes with high accuracy; RT-PCR validated the microarray results. Annotation analysis showed that transduced hMSCs upregulated cell differentiation and antiapoptosis genes while downregulating cell cycle, proliferation genes. Despite transcriptional changes associated with bone and cartilage remodeling, their random pattern indicates no systematic change of crucial genes that are associated with osteogenic, adipogenic, or chondrogenic differentiation. This correlates with the experimental results that lentiviral transduction did not cause the transduced MSCs to lose their basic stem cell identity as demonstrated by osteogenic, chondrogenic, and adipogenic differentiation assays with both transduced and wild-type MSCs, although a certain degree of alterations occurred. Histological analysis demonstrated osteogenic differentiation in MSC-loaded ceramic cubes in vivo. In conclusion, transduction of reporter genes into MSCs preserved the basic properties of stem cells while enabling noninvasive imaging in living animals to study the biodistribution and other biological activities of the cells.
Experimental Investigation of Innovative Internal Trailing Edge Cooling Configurations with Pentagonal Arrangement and Elliptic Pin Fin
Authors: Tarchi L. , Facchini B. , Zecchi S.
Published: December 2008

This paper describes a heat transfer experimental study
of four different internal trailing edge cooling configurations
based on pin fin schemes. The aim of the study is the
comparison between innovative configurations and standard
ones. So, a circular pin fin configuration with an innovative
pentagonal scheme is compared to a standard staggered
scheme, while two elliptic pin fin configurations are compared
to each other turning the ellipse from the streamwise
to the spanwise direction. For each configuration, heat transfer
and pressure loss measurements were made keeping the
Mach number fixed at 0.3 and varying the Reynolds number
from 9000 to 27000. In order to investigate the overall behavior
of both endwall and pedestals, heat transfer measurements
are performed using a combined transient technique.
Over the endwall surface, the classic transient technique
with thermochromic liquid crystals allows the measurement
of a detailed heat transfer coefficient (HTC) map. Pin fins
are made of high thermal conductivity material, and an inverse
data reduction method based on a finite element code
allows to evaluate the mean HTC of each pin fin. Results
show that the pentagonal arrangement generates a nonuniform
HTC distribution over the endwall surface, while, in
terms of average values, it is equivalent to the staggered
configuration. On the contrary, the HTC map of the two
elliptic configurations is similar, but the spanwise arrangement
generates higher heat transfer coefficients and pressure
losses.
Strong Convergence of Viscosity Methods for Continuous Pseudocontractions in Banach Spaces
Authors: Cianciaruso Filomena , Marino Giuseppe , Muglia Luigi , Zhou Haiyun
Published: December 2008

We define a viscosity method for continuous pseudocontractive
mappings defined on closed and convex subsets of reflexive Banach spaces with
a uniformly Gâteaux differentiable norm. We prove the convergence of these
schemes improving the main theorems in the work by Y. Yao et al. (2007) and H. Zhou (2008).
A Low‐Overhead Cooperative Retransmission Scheme for IR‐UWB Networks
Authors: Naddafzadeh Shirazi Ghasem , Kong Peng-Yong , Tham Chen-Khong
Published: December 2008

The UWB unique properties such as fine ranging and immunity to small scale fading are utilized in order to exploit the multiuser diversity in UWB networks. The optimal
cooperation strategies in the absence of control packet overhead
are analyzed in the proactive and reactive settings. It is shown
that the proposed method achieves a considerable diversity gain
while minimizing the overhead of control packet exchange that
is required for coordination among the relays.
Performance Evaluation of an Enhanced Uplink 3.5G System for Mobile Healthcare Applications
Authors: Komnakos Dimitris , Vouyioukas Demosthenes , Maglogiannis Ilias , Constantinou Philip
Published: December 2008

The present paper studies the prospective and the performance of a forthcoming high-speed third generation (3.5G) networking technology, called enhanced uplink, for delivering mobile health (m-health) applications. The performance of 3.5G networks is a critical factor for successful development of m-health services perceived by end users. In this paper, we propose a methodology for performance assessment based on the joint uplink transmission of voice, real-time video, biological data (such as electrocardiogram, vital signals, and heart sounds), and healthcare records file transfer. Various scenarios were concerned in terms of real-time, nonreal-time, and emergency applications in random locations, where no other system but 3.5G is available. The accomplishment of quality of service (QoS) was explored through a step-by-step improvement of enhanced uplink system's parameters, attributing the network system for the best performance in the context of the desired m-health services.
Performance Analysis of IEEE 802.11 DCF under Nonsaturation Condition
Authors: Lee Yutae , Chung Min Young , Lee Tae-Jin
Published: December 2008

Carrier sense multiple access with collision avoidance (CSMA/CA) methods are considered to be attractive MAC protocols for wireless LANs. IEEE 802.11 distributed coordination function (DCF) is a random channel access scheme based on CSMA/CA method and the binary slotted exponential backoff procedure to reduce the packet collision. In this paper, we propose a new analytical model for a nonsaturated IEEE 802.11 DCF network and evaluate its performance. We verify our model using simulations and show that our results agree with the simulations.
Strong Expression of Chemokine ReceptorCXCR4 by Renal Cell Carcinoma Correlates with Advanced Disease
Authors: Wehler Thomas C. , Graf Claudine , Biesterfeld Stefan , Brenner Walburgis , Schadt Jörg , Gockel Ines , Berger Martin R. , Thüroff Joachim W. , Galle Peter R. , Moehler Markus , Schimanski Carl C.
Published: December 2008

Diverse chemokines and their receptors have been associated with tumor growth, tumor dissemination, and local immune escape. In different tumor entities, the level of chemokine receptorCXCR4 expression has been linked with tumor progression and decreased survival. The aim of this study was to evaluate the influence ofCXCR4 expression on the progression of human renal cell carcinoma.CXCR4 expression of renal cell carcinoma was assessed by immunohistochemistry in 113 patients. Intensity ofCXCR4 expression was correlated with both tumor and patient characteristics. Human renal cell carcinoma revealed variable intensities ofCXCR4 expression. StrongCXCR4 expression of renal cell carcinoma was significantly associated with advanced T-status (P=.039), tumor dedifferentiation (P= .0005), and low hemoglobin (P= .039). In summary, strongCXCR4 expression was significantly associated with advanced dedifferentiated renal cell carcinoma.
Design of a Mathematical Unit in FPGA for the Implementation of the Control of a Magnetic Levitation System
Authors: Raygoza-Panduro Juan José , Ortega-Cisneros Susana , Rivera Jorge , de la Mora Alberto
Published: December 2008

This paper presents the design and implementation of an automatically generated mathematical unit, from a program developed in Java that describes the VHDL circuit, ready to be synthesized with the Xilinx ISE tool. The core contains diverse complex operations such as mathematical functions including sine and cosine, among others. The proposed unit is used to synthesize a sliding mode controller for a magnetic levitation system. This kind of systems is used in industrial applications requiring high level of mathematical calculations in small time periods. The core is designed to calculate trigonometric and arithmetic operations in such a way that each function is performed in a clock cycle. In this paper, the results of the mathematical core are shown in terms of implementation, utilization, and application to control a magnetic levitation system.
A Nonstandard Dynamically Consistent Numerical Scheme Applied to Obesity Dynamics
Authors: Villanueva Rafael J. , Arenas Abraham J. , González-Parra Gilberto
Published: December 2008

The obesity epidemic is considered a health concern of paramount importance
in modern society. In this work, a nonstandard finite difference
scheme has been developed with the aim to solve numerically a mathematical
model for obesity population dynamics. This interacting population
model represented as a system of coupled nonlinear ordinary differential
equations is used to analyze, understand, and predict the dynamics of obesity
populations. The construction of the proposed discrete scheme is developed
such that it is dynamically consistent with the original differential
equations model. Since the total population in this mathematical model
is assumed constant, the proposed scheme has been constructed to satisfy
the associated conservation law and positivity condition. Numerical
comparisons between the competitive nonstandard scheme developed here
and Euler′s method show the effectiveness of the proposed nonstandard
numerical scheme. Numerical examples show that the nonstandard difference
scheme methodology is a good option to solve numerically different
mathematical models where essential properties of the populations need to
be satisfied in order to simulate the real world.
A New 3D Simulation Method for the Construction of Optical Phase Contrast Images of Gold Nanoparticle Clusters in Biological Cells
Authors: Tanev Stoyan , Pond James , Paddon Paul , Tuchin Valery V.
Published: December 2008

A new 3D simulation method based on the finite‐difference time domain (FDTD) approach in combination with Fourier optic techniques is applied to the modeling of optical phase contrast microscope (OPCM) imaging of gold nanoparticles (NPs) in singe biological cells. We consider a realistic size 3D cell model at optical immersion conditions, that is, when the refractive index values of the cytoplasm and of the extracellular medium are equal. For the first time, an FDTD‐based OPCM model is applied to visualize the presence of a cluster of gold NPs in the cytoplasm at both resonant and nonresonant conditions. The results demonstrate the capability to model OPCM image enhancement by optically controlling the resonant properties of the NPs. Our research study extends the applicability of the FDTD modeling approach into a new biomedical optics research area.
Antiretroviral‐Related Adipocyte Dysfunction and Lipodystrophy in HIV‐Infected Patients: Alteration of the PPARγ‐Dependent Pathways
Authors: Caron Martine , Vigouroux Corinne , Bastard Jean-Philippe , Capeau Jacqueline
Published: December 2008

Lipodystrophy and metabolic alterations are major complications of antiretroviral therapy in HIV‐infected patients. In vitro studies using cultured murine and human adipocytes revealed that some protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) were implicated to a different extent in adipose cell dysfunction and that a chronic incubation with some PIs decreased mRNA and protein expression of PPARγ. Defective lamin A maturation linked to PI inhibitory activity could impede the nuclear translocation of SREBP1c, therefore, reducing PPARγ expression. Adipose cell function was partially restored by the PPARγ agonists, thiazolidinediones. Adverse effects of PIs and NRTIs have also been reported in macrophages, a cell type that coexists with, and modulates, adipocyte function in fat tissue. In HIV‐infected patients under ART, a decreased expression of PPARγ and of PPARγ‐related genes was observed in adipose tissue, these anomalies being more severe in patients with ART‐induced lipoatrophy. Altered PPARγ expression was reversed in patients stopping PIs. Treatment of patients with agonists of PPARγ could improve, at least partially, the subcutaneous lipoatrophy. These data indicate that decreased PPARγ expression and PPARγ‐related function, resulting from ART‐induced adipose tissue toxicity, play a central role in HIV‐related lipoatrophy and metabolic consequences.
Impaired Bub1 Function In vivo Compromises Tension-Dependent Checkpoint Function Leading to Aneuploidy and Tumorigenesis
Authors: Schliekelman Mark , Cowley Dale O. , O'Quinn Ryan , Oliver Trudy G. , Lu Lucy , Salmon E.D. , Van Dyke Terry
Published: December 2008

Bub1 is a serine/threonine kinase originally described as a core component of the spindle assembly checkpoint (SAC) mechanism in yeast. Bub1 binding at kinetochores has been reported to be required for SAC function and localization of other SAC components. A proper SAC is believed to be essential for murine embryonic development, as all previously described null mutations in SAC components in mice cause embryonic lethality. We produced mice harboring a Bub1 mutant allele lacking exons 2 and 3, resulting in a hypomorphic mutant expressed at <5% of wild-type levels. Despite this significant reduction, homozygous mutant animals are viable on a mixed 129P2/B6 or FVB background but display increased tumorigenesis with aging, whereas mice with a C57Bl/6J background die perinatally. Bub1 mutant murine embryonic fibroblasts (MEFs) display defects in chromosome congression to the metaphase plate, severe chromosome missegregation, and aneuploidy accompanied by high levels of premature senescence. Mutant MEFs have a robust SAC in response to nocodazole treatment but an impaired response to Taxol. Mutant MEFs also show reduced kinetochore localization of BubR1, but not of Mad2. The significant reduction in SAC response to Taxol, but not nocodazole, coupled with the reduced binding of BubR1, but not Mad2, indicates that Bub1 is particularly critical for the SAC response to a lack of tension on kinetochores. Thus, Bub1 is essential for proper chromosome segregation, a defect that can lead to severe phenotypes, including perinatal lethality and a predisposition to cancer. [Cancer Res 2009;69(1):45–54]
Mutations in the Phosphatidylinositol-3-Kinase Pathway Predict for Antitumor Activity of the Inhibitor PX-866 whereas Oncogenic Ras Is a Dominant Predictor for Resistance
Authors: Ihle Nathan T. , Lemos Robert , Wipf Peter , Yacoub Adly , Mitchell Clint , Siwak Doris , Mills Gordon B. , Dent Paul , Kirkpatrick D. Lynn , Powis Garth
Published: December 2008

The novel phosphatidylinositol-3-kinase (PI3K) inhibitor PX-866 was tested against 13 experimental human tumor xenografts derived from cell lines of various tissue origins. Mutant PI3K (PIK3CA) and loss of PTEN activity were sufficient, but not necessary, as predictors of sensitivity to the antitumor activity of the PI3K inhibitor PX-866 in the presence of wild-type Ras, whereas mutant oncogenic Ras was a dominant determinant of resistance, even in tumors with coexisting mutations in PIK3CA. The level of activation of PI3K signaling measured by tumor phosphorylated Ser473-Akt was insufficient to predict in vivo antitumor response to PX-866. Reverse-phase protein array revealed that the Ras-dependent downstream targets c-Myc and cyclin B were elevated in cell lines resistant to PX-866 in vivo. Studies using an H-Ras construct to constitutively and preferentially activate the three best-defined downstream targets of Ras, i.e., Raf, RalGDS, and PI3K, showed that mutant Ras mediates resistance through its ability to use multiple pathways for tumorigenesis. The identification of Ras and downstream signaling pathways driving resistance to PI3K inhibition might serve as an important guide for patient selection as inhibitors enter clinical trials and for the development of rational combinations with other molecularly targeted agents. [Cancer Res 2009;69(1):143–50]
Human Multidrug Resistance Protein 7 (ABCC10) Is a Resistance Factor for Nucleoside Analogues and Epothilone B
Authors: Hopper-Borge Elizabeth , Xu Xiu , Shen Tong , Shi Zhi , Chen Zhe-Sheng , Kruh Gary D.
Published: December 2008

Multidrug resistance protein 7 (MRP7; ABCC10) is an ATP-binding cassette transporter which is able to transport amphipathic anions and confer resistance to docetaxel and, to a lesser extent, vincristine and paclitaxel. Whereas some detail on the resistance profile of MRP7 is known, the activities of the pump have not been completely determined. Here, it is shown by the analysis of MRP7-transfected HEK293 cells that, in addition to natural product agents, MRP7 is also able to confer resistance to nucleoside-based agents, such as the anticancer agents cytarabine (Ara-C) and gemcitabine, and the antiviral agents 2′,3′-dideoxycytidine and PMEA. Consistent with the operation of an efflux pump, expression of MRP7 reduced the accumulation of Ara-C and PMEA. In addition, MRP7 is also able to confer resistance to the microtubule-stabilizing agent epothilone B. Ectopic expression of MRP7 in mouse embryo fibroblasts deficient in P-glycoprotein and Mrp1 revealed that MRP7 has a broad resistance profile for natural product agents. In this drug-sensitive cellular background, MRP7 conferred high levels of resistance to docetaxel (46-fold), paclitaxel (116-fold), SN-38 (65-fold), daunorubicin (7.5-fold), etoposide (11-fold), and vincristine (56-fold). Buthionine sulfoximine did not attenuate MRP7-conferred resistance to docetaxel or Ara-C. These experiments indicate that the resistance capabilities of MRP7 include nucleoside-based agents and a range of natural product anticancer agents that includes nontaxane antimicrotubule agents that are not susceptible to P-glycoprotein–mediated transport and that, unlike MRP1 and MRP2, MRP7-mediated drug transport does not involve glutathione. [Cancer Res 2009;69(1):178–84]
Vascular Endothelial Growth Factor-C and C-C Chemokine Receptor 7 in Tumor Cell–Lymphatic Cross-talk Promote Invasive Phenotype
Authors: Issa Amine , Le Thomas X. , Shoushtari Alexander N. , Shields Jacqueline D. , Swartz Melody A.
Published: December 2008

Most carcinomas spread to distant sites through lymphatic vessels. Several preclinical and clinical studies have shown a positive correlation between the incidence of lymph node metastasis and secretion of the lymphatic growth factor vascular endothelial growth factor-C (VEGF-C) by tumor cells, suggesting tumor lymphangiogenesis as an escape mechanism. However, recent evidence has shown VEGF receptor-3 (VEGFR-3) expression on tumor cells and autocrine signaling, which increase metastatic potential. Furthermore, there is growing evidence implicating lymphatic-homing chemokine receptors, particularly C-C chemokine receptor 7 (CCR7), in lymph node metastasis. We report here that expressions of VEGF-C and CCR7 by tumor cells act synergistically to promote their invasion toward lymphatics. First, VEGF-C acts to increase lymphatic secretion of CCL21, which in turn drives CCR7-dependent tumor chemoinvasion toward lymphatics. Second, VEGF-C acts in an autocrine fashion to increase tumor invasiveness by increasing the proteolytic activity and motility of tumor cells in a three-dimensional matrix. Both of these effects are VEGFR-3 dependent and evident only in three-dimensional environments. We further verified that VEGF-C induces lymphatic CCL21 up-regulation in vivo by direct injection of VEGF-C protein intradermally in the mouse. Taken together, these results bridge the prometastatic functions of CCR7 and VEGF-C in tumors and show that, beyond lymphangiogenesis, VEGF-C promotes tumor invasion toward lymphatics by both autocrine and CCR7-dependent paracrine signaling mechanisms, which may be a significant cause of lymph node metastasis. [Cancer Res 2009;69(1):349–57]
Identification of Novel Alternative Splice Isoforms of Circulating Proteins in a Mouse Model of Human Pancreatic Cancer
Authors: Menon Rajasree , Zhang Qing , Zhang Yan , Fermin Damian , Bardeesy Nabeel , DePinho Ronald A. , Lu Chunxia , Hanash Samir M. , Omenn Gilbert S. , States David J.
Published: December 2008

To assess the potential of tumor-associated, alternatively spliced gene products as a source of biomarkers in biological fluids, we have analyzed a large data set of mass spectra derived from the plasma proteome of a mouse model of human pancreatic ductal adenocarcinoma. MS/MS spectra were interrogated for novel splice isoforms using a nonredundant database containing an exhaustive three-frame translation of Ensembl transcripts and gene models from ECgene. This integrated analysis identified 420 distinct splice isoforms, of which 92 did not match any previously annotated mouse protein sequence. We chose seven of those novel variants for validation by reverse transcription–PCR. The results were concordant with the proteomic analysis. All seven novel peptides were successfully amplified in pancreas specimens from both wild-type and mutant mice. Isotopic labeling of cysteine-containing peptides from tumor-bearing mice and wild-type controls enabled relative quantification of the proteins. Differential expression between tumor-bearing and control mice was notable for peptides from novel variants of muscle pyruvate kinase, malate dehydrogenase 1, glyceraldehyde-3-phosphate dehydrogenase, proteoglycan 4, minichromosome maintenance, complex component 9, high mobility group box 2, and hepatocyte growth factor activator. Our results show that, in a mouse model for human pancreatic cancer, novel and differentially expressed alternative splice isoforms are detectable in plasma and may be a source of candidate biomarkers. [Cancer Res 2009;69(1):300–9]
Tumor Protein 53–Induced Nuclear Protein 1 Is a Major Mediator of p53 Antioxidant Function
Authors: Cano Carla E. , Gommeaux Julien , Pietri Sylvia , Culcasi Marcel , Garcia Stéphane , Seux Mylène , Barelier Sarah , Vasseur Sophie , Spoto Rose P. , Pébusque Marie-Josèphe , Dusetti Nelson J. , Iovanna Juan L. , Carrier Alice
Published: December 2008

p53 exerts its tumor suppressor function mainly through transcriptional induction of target genes involved in several processes, including cell cycle checkpoints, apoptosis, and regulation of cell redox status. p53 antioxidant function is dependent on its transcriptional activity and proceeds by sequential induction of antioxidant and proapoptotic targets. However, none of the thus far renowned p53 targets have proved able to abolish on their own the intracellular reactive oxygen species (ROS) accumulation caused by p53 deficiency, therefore pointing to the existence of other prominent and yet unknown p53 antioxidant targets. Here, we show that TP53INP1 represents such a target. Indeed, TP53INP1 transcript induction on oxidative stress is strictly dependent on p53. Mouse embryonic fibroblasts (MEF) and splenocytes derived from TP53INP1-deficient (inp1−/−) mice accumulate intracellular ROS, whereas overexpression of TP53INP1 in p53-deficient MEFs rescues ROS levels to those of p53-proficient cells, indicating that TP53INP1 antioxidant function is p53 independent. Furthermore, accumulation of ROS in inp1−/− cells on oxidant challenge is associated with decreased expression of p53 targets p21/Cdkn1a, Sesn2, TAp73, Puma, and Bax. Mutation of p53 Ser58 (equivalent to human p53 Ser46) abrogates transcription of these genes, indicating that TP53INP1-mediated p53 Ser58 phosphorylation is implicated in this process. In addition, TP53INP1 deficiency results in an antioxidant (N-acetylcysteine)-sensitive acceleration of cell proliferation. Finally, TP53INP1 deficiency increases oxidative stress–related lymphoma incidence and decreases survival of p53+/− mice. In conclusion, our data show that TP53INP1 is a major actor of p53-driven oxidative stress response that possesses both a p53-independent intracellular ROS regulatory function and a p53-dependent transcription regulatory function. [Cancer Res 2009;69(1):219–26]
Hypoxia-Inducible Carbonic Anhydrase IX and XII Promote Tumor Cell Growth by Counteracting Acidosis through the Regulation of the Intracellular pH
Authors: Chiche Johanna , Ilc Karine , Laferrière Julie , Trottier Eric , Dayan Frédéric , Mazure Nathalie M. , Brahimi-Horn M. Christiane , Pouysségur Jacques
Published: December 2008

Acidosis of the tumor microenvironment is typical of a malignant phenotype, particularly in hypoxic tumors. All cells express multiple isoforms of carbonic anhydrase (CA), enzymes catalyzing the reversible hydration of carbon dioxide into bicarbonate and protons. Tumor cells express membrane-bound CAIX and CAXII that are controlled via the hypoxia-inducible factor (HIF). Despite the recognition that tumor expression of HIF-1α and CAIX correlates with poor patient survival, the role of CAIX and CAXII in tumor growth is not fully resolved. To understand the advantage that tumor cells derive from expression of both CAIX and CAXII, we set up experiments to either force or invalidate the expression of these enzymes. In hypoxic LS174Tr tumor cells expressing either one or both CA isoforms, we show that (a) in response to a “CO2 load,” both CAs contribute to extracellular acidification and (b) both contribute to maintain a more alkaline resting intracellular pH (pHi), an action that preserves ATP levels and cell survival in a range of acidic outside pH (6.0–6.8) and low bicarbonate medium. In vivo experiments show that ca9 silencing alone leads to a 40% reduction in xenograft tumor volume with up-regulation of ca12 mRNA levels, whereas invalidation of both CAIX and CAXII gives an impressive 85% reduction. Thus, hypoxia-induced CAIX and CAXII are major tumor prosurvival pHi-regulating enzymes, and their combined targeting shows that they hold potential as anticancer targets. [Cancer Res 2009;69(1):358–68]