bluuebunny/crossref_metadata_2025 huggingface dataset:
A pyrosequencing-based test for detection and relative quantification of theBCR-ABL1T315I point mutation
Authors: Schumacher Jonathan A , Szankasi Philippe , Bahler David W , Ho Albert K , Kelley Todd W
Published: April 2011

Aims

TheBCR-ABL1T315I mutation imparts resistance to tyrosine kinase inhibitors currently available for treatment of chronic myelogenous leukaemia. Thus, quantitative monitoring of the emergence and expansion of T315I-positive subclones may be clinically useful. The goals of this study were to retrospectively review the authors' experience with Sanger sequencing-basedBCR-ABL1kinase domain mutation testing, paying particular attention to the T315I mutation, and to develop an alternative test for relative quantification of T315I using pyrosequencing.

Methods

The performance of a new T315I pyrosequencing assay was evaluated. Total RNA was isolated from whole blood and reverse-transcribed. The resulting cDNA was subjected to an initial round of PCR across theBCR-ABL1breakpoint followed by a second round to amplify the sequence flankingABL1codon 315. The final PCR product was pyrosequenced to detect and quantify the T315I point mutation. Additional experiments were carried out to determine the effects of background untranslocatedABL1on assay sensitivity in samples with low tumour burden.

Results

The results show that T315I was the most commonly detected kinase domain mutation and was persistent in follow-up testing. All 26 specimens that tested positive by Sanger sequencing for the T315I mutation were also positive using the pyrosequencing test. Relative quantification data derived from pyrosequencing matched the approximate wild-type/mutant ratios found by Sanger sequencing. Serial dilution experiments show sensitivity to 5% mutant allele. The authors also quantitatively assessed the influence of untranslocatedABL1in the sample background on the assay and found that it occurred at levels not likely to influence performance.

Conclusion

The described test is useful for detection and relative quantification of the T315I point mutation in chronic myelogenous leukaemia in a sensitive, specific and reproducible manner.
Evaluation of lateral interpretation criteria for rigid drilled shafts
Authors: Chen Yit-Jin , Lin Song-Wei , Kulhawy Fred H.
Published: April 2011

Representative criteria are examined to evaluate the “interpreted failure load” or “capacity” of rigid drilled shaft foundations under lateral loading. Field lateral load test data are used for this analysis, consisting of both drained and undrained databases. It was found that a hyperbola describes the load–displacement data well and that the normalized undrained curve is stiffer, higher, and more sharply curving than the drained curve. The initial elastic region ends at approximately 1%B (where B is the shaft diameter),which represents serviceability limit state (SLS) conditions. The final region begins at about 4%–5%B, which represents ultimate limit state (ULS) conditions. Also, the QLmethod is most appropriate for interpreting the “failure load” because it is the only method that incorporates actual soil-shaft failure mechanisms as part of the interpretation, is the least variable, and has the lowest coefficient of variation (COV). Further detailed recommendations are given for assessing the load test data.
ANALYSIS OF THE INFLUENCE OF LANE CHANGING ON TRAFFIC-FLOW DYNAMICS BASED ON THE CELLULAR AUTOMATON MODEL
Authors: KUKIDA SHINJI , TANIMOTO JUN , HAGISHIMA AYA
Published: April 2011

Many cellular automaton models (CA models) have been applied to analyze traffic flow. When analyzing multilane traffic flow, it is important how we define lane-changing rules. However, conventional models have used simple lane-changing rules that are dependent only on the distance from neighboring vehicles. We propose a new lane-changing rule considering velocity differences with neighboring vehicles; in addition, we embed the rules into a variant of the Nagel–Schreckenberg (NaSch) model, called the S-NFS model, by considering an open boundary condition. Using numerical simulations, we clarify the basic characteristics resulting from different assumptions with respect to lane changing.
ANALYTIC DARK SOLITON SOLUTIONS FOR A GENERALIZED VARIABLE-COEFFICIENT HIGHER-ORDER NONLINEAR SCHRÖDINGER EQUATION IN OPTICAL FIBERS USING SYMBOLIC COMPUTATION
Authors: MENG XIANG-HUA , SUN ZHI-YUAN , ZHANG CHUN-YI , TIAN BO
Published: April 2011

In this paper, a generalized variable-coefficient nonlinear Schrödinger equation with higher-order and gain/loss effects which can be used to describe the femtosecond pulse propagation is analytically investigated via symbolic computation. Under sets of coefficient constraints, such an equation is transformed into a completely integrable constant-coefficient higher-order nonlinear Schrödinger equation. Furthermore, through the transformation, the dark one- and two-soliton solutions for the generalized variable-coefficient higher-order nonlinear Schrödinger equation are derived by means of the bilinear method.
A LATTICE BGK MODEL FOR SIMULATING SOLITARY WAVES OF THE COMBINED KdV–MKDV EQUATION
Authors: MA CHANGFENG
Published: April 2011

A lattice BGK model for simulating solitary waves of the combined KdV–MKDV equation, ut+αuux-βu2ux+δuxxx= 0, is established. The tunable parameters in Chapman–Enskog expansion of the local equilibrium distribution function are determined by the coefficient of the combined KdV–MKDV equation. Simulating results fit close in with the theoretical results.
PROPERTIES OF RESONANCE TRANSMISSION THROUGH A SEMICONDUCTOR DOUBLE-WELL STRUCTURE WITH SPIN-ORBIT COUPLING
Authors: LI CHUN-LEI , WANG XIAO-MING , ZHANG PENG
Published: April 2011

In this paper, we investigate effects of the Dresselhaus spin-orbit coupling, inter-well coupling, and external bias on the dynamics of resonance tunneling through a semiconductor double-well structure. Based on the transfer matrix technique and the single band effective-mass approximation method, the numerical results demonstrate that the transmission peaks of the spin-up and spin-down electrons split due to the Dresselhaus spin-orbit coupling in the double-well structure. As the in-plane wave vector and external electric field increase, the split becomes farther apart. There is a prominent difference between the lifetime of the quasibound energy level for different spin-polarized electrons. The spin-dependent tunneling time is obtained using the time-dependent Schrödinger equation.
DESIGN AND ANALYSIS OF A NOVEL LOW PDP FULL ADDER CELL
Authors: GHADIRY M. H. , A'AIN ABU KHARI , NADI S. M.
Published: April 2011

This paper, presents a new full-swing low power high performance full adder circuit in CMOS technology. It benefits from a full swing XOR-XNOR module with no feedback transistors, which decreases delay and power consumption. In addition, high driving capability of COUT module and low PDP design of SUM module contribute to more PDP reduction in cascaded mode. In order to have accurate analysis, the new circuit along with several well-known full adders from literature have been modeled and compared with CADENCE. Comparison consists of power consumption, performance, PDP, and area. Results show that there are improvements in both power consumption and performance. This design trades area with low PDP.
SYNTHESIS OF LINEAR VCOs: THE STATE-VARIABLE APPROACH
Authors: GUPTA S. S. , BHASKAR D. R. , SENANI R. , SINGH A. K.
Published: April 2011

The paper presents a systematic approach of synthesizing sinusoidal linear VCOs (i.e., an oscillator providing linear tuning law of the type f0∝ VCbetween the oscillation frequency f0and an external control voltage VC). In view of recent interest on current feedback operational amplifier (CFOA)-based oscillators, the proposed methodology has been demonstrated by deriving a class of linear VCOs employing CFOAs and analog multipliers (AM). The workability of the new VCOs has been established by experimental results of the circuits implemented with commercially available AD844 type CFOAs and AD534 type AMs.
GENERATION OF CFOA, CCII AND DVCC BASED OSCILLATORS FROM PASSIVE RLC FILTER
Authors: SOLIMAN AHMED M.
Published: April 2011

In a recent paper the link between the Op Amp-based two integrator loop oscillators and current feedback operational amplifier (CFOA)-based oscillators is detected and clearly explained. It was found that one of the grounded capacitor two CFOA two integrator loop oscillators, however, was not related directly to any of the Op Amp oscillators. In this paper the origin of the two CFOA grounded capacitor oscillator is found to be the passive second-order low-pass filter. It is also found that the differential voltage current conveyor (DVCC) grounded passive element oscillator is generated from the same passive second-order low-pass filter. A new family of grounded capacitor oscillators using current conveyors (CCII) and inverting current conveyors (ICCII) which includes sixteen members is introduced. A second new family of grounded passive elements oscillators using CCII and ICCII which includes eight members is also introduced. A discussion and a comparison with some of the previously reported CCII oscillator circuits is also given at the end of the paper.
A NEW SWITCHED OPAMP APPROACH FOR IMPROVING THE OPERATION OF AUTO-RESET SWITCHED-CAPACITOR FILTERS
Authors: RASHTIAN MOHAMMAD , HASHEMIPOUR OMID , NAVI KEIVAN , JALALI ALI
Published: April 2011

In this paper, a new switched opamp is presented in order to improve the operation of auto-zeroed switched capacitor circuit. This approach results in a considerable reduction in power consumption and a moderate speed improvement. Based on the above improvement, a second-order band-pass filter with a center frequency of 833 kHz and quality factor of 8 is realized and compared with previous works. The proposed switched opamp is also utilized in the structure of a novel z to -z2block for the design of pseudo two-path band-pass filters. A second-order pseudo two-path band-pass filter with the same specification of the previous work is designed, simulated, and compared.
BIFURCATION ANALYSIS IN A PWM CURRENT-CONTROLLED H-BRIDGE INVERTER
Authors: ASAHARA HIROYUKI , KOUSAKA TAKUJI
Published: April 2011

This paper introduces the complete bifurcation analysis in a PWM current-controlled H-Bridge inverter in a wide parameter space. First, we briefly explain the behavior of the waveform in the circuit in terms of the switched dynamical system. Then, the consecutive waveform during the duration of the clock interval is exactly discretized, and the return map is defined for the rigorous analysis. Using the map, we derive the one- and two-dimensional bifurcation diagrams, and discuss the specific property of each bifurcation phenomena in the circuit.
COMPARISON-BASED CONDITIONAL DIAGNOSABILITY ON THE CLASS OF HYPERCUBE-LIKE NETWORKS
Authors: HSU GUO-HUANG , CHIANG CHIEH-FENG , TAN JIMMY J. M.
Published: April 2011

For system diagnosis, Lai et al.16 introduced a new measurement, called the conditional diagnosability, by adding a condition that no faulty set contains all the neighbors of any vertex in a network. Taking the hypercube as the target, Lai et al.16 (respectively, Hsu et al.13) estimated the PMC-based19 (respectively, the comparison-based18) conditional diagnosability as about four (respectively, three) times larger than the original diagnosability. In this paper, we extend the concept of conditional diagnosability to the generalized version of hypercubes, the class of hypercube-like networks. We prove that the conditional diagnosability of an n-dimensional hypercube-like network HLn is 3n - 5 under the comparison diagnosis model, for n ≥ 5.
A REVIEW OF EJECTOR TECHNOLOGY FOR REFRIGERATION APPLICATIONS
Authors: LITTLE ADRIENNE B. , GARIMELLA SRINIVAS
Published: April 2011

This paper provides a comprehensive review of ejector technology for refrigeration applications, combining an understanding of basic fluid flow fundamentals within the ejector with application in cycle-level development. An ejector is a passive device that requires no external mechanical input or moving parts. A high-velocity motive stream produces a low-pressure region into which a suction flow is entrained, resulting in a pressure rise of the suction flow and mixing between the two streams to provide a pumping effect. The first part of this review addresses the progression from experiment-based analytical models to computational modeling of the ejector itself from the early 1950s to 2009. Included is an assessment of the most recent work in CFD modeling, and an exploration into what is needed to develop these models further. Suggestions for future research include better modeling of shock phenomena and the effects of two-phase flow in ejectors. The second part of this review focuses on ejector applications in refrigeration cycles with special emphasis on the vapor-jet refrigeration cycle. Important connections are made between ejector component and system level studies, an understanding of which would enable improvement of system level performance to the extent where they could be used in some niche applications instead of conventional refrigeration systems.
HEAT AND MOISTURE TRANSFER CHARACTERISTICS OF A PLATE-TYPE ENTHALPY EXCHANGER MADE OF PAPER
Authors: LEE EUL-JONG , KIM NAE-HYUN , SONG GIL-SUB , LEE JUNG-PYO
Published: April 2011

In this study, heat and moisture transfer data of an enthalpy exchanger were obtained varying the indoor and outdoor condition systematically. At the same time, equilibrium water content ratios of the membrane were measured. It is shown that equilibrium water content ratio of the membrane increases with the increase of relative humidity. The effect of temperature on equilibrium water content ratio, however, is rather complex. It decreases with the increase of temperature to a certain value, and then increases with further increase of temperature. Moisture transfer effectiveness of the enthalpy exchanger is also affected by relative humidity and temperature. Heat transfer effectiveness, however, is independent of relative humidity and temperature. Moisture transfer effectiveness of the enthalpy exchanger was successfully correlated by equilibrium water content ratio of the membrane.
Role of Binders in High Temperature PEMFC Electrode
Authors: Park J. O. , Kwon K. , Cho M. D. , Hong S.-G. , Kim T. Y. , Yoo D. Y.
Published: April 2011

Several different binders for high temperature proton exchange membrane fuel cell (PEMFC) were tested to investigate the effects of binder properties on cell performance. The cell voltage values measured with electrodes with PTFE binders are compared to that obtained with electrode with PBI or polyurethane binders. The electrodes that used PBI and polyurethane binders showed Tafel slopes of 87 mV/decade, and the values were lower than the Tafel slope measured from Teflon containing electrodes which showed the Tafel slope value of 100 mV/decade. Pt utilization also showed dependence on the kind of binders used in the electrodes. When PTFE or polyurethane binder was used, Pt utilization of 15% was measured. The PBI binder was found to reduce Pt utilization, and 10% of catalyst utilization was measured. The changes in Tafel slope, Pt utilization, ηohm affected cell performance, and it was found that the electrodes with polyurethane binder showed the highest cell voltage among the tested binders with the cell voltage of 0.619V @ 0.2 A/cm2. Binder properties also affected cell life time. By increasing Teflon content in the electrode, it was possible to operate cells for a longer period.
The physiological basis of complementary and alternative medicines for polycystic ovary syndrome
Authors: Raja-Khan Nazia , Stener-Victorin Elisabet , Wu XiaoKe , Legro Richard S.
Published: April 2011

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is characterized by chronic hyperandrogenic anovulation leading to symptoms of hirsutism, acne, irregular menses, and infertility. Multiple metabolic and cardiovascular risk factors are associated with PCOS, including insulin resistance, obesity, type 2 diabetes, hypertension, inflammation, and subclinical atherosclerosis. However, current treatments for PCOS are only moderately effective at controlling symptoms and preventing complications. This article describes how the physiological effects of major complementary and alternative medicine (CAM) treatments could reduce the severity of PCOS and its complications. Acupuncture reduces hyperandrogenism and improves menstrual frequency in PCOS. Acupuncture's clinical effects are mediated via activation of somatic afferent nerves innervating the skin and muscle, which, via modulation of the activity in the somatic and autonomic nervous system, may modulate endocrine and metabolic functions in PCOS. Chinese herbal medicines and dietary supplements may also exert beneficial physiological effects in PCOS, but there is minimal evidence that these CAM treatments are safe and effective. Mindfulness has not been investigated in PCOS, but it has been shown to reduce psychological distress and exert positive effects on the central and autonomic nervous systems, hypothalamic-pituitary-adrenal axis, and immune system, leading to reductions in blood pressure, glucose, and inflammation. In conclusion, CAM treatments may have beneficial endocrine, cardiometabolic, and reproductive effects in PCOS. However, most studies of CAM treatments for PCOS are small, nonrandomized, or uncontrolled. Future well-designed studies are needed to further evaluate the safety, effectiveness, and mechanisms of CAM treatments for PCOS.
Response variability to high rates of electric stimulation in retinal ganglion cells
Authors: Cai Changsi , Ren Qiushi , Desai Neal J. , Rizzo Joseph F. , Fried Shelley I.
Published: April 2011

To improve the quality of prosthetic vision, it is important to understand how retinal neurons respond to electric stimulation. Previous studies present conflicting reports as to the maximum rate at which retinal ganglion cells can “follow” pulse trains, i.e., generate one spike for each pulse of the train. In the present study, we measured the response of 5 different types of rabbit retinal ganglion cells to pulse trains of 100–700 Hz. Surprisingly, we found significant heterogeneity in the ability of different types to follow pulse trains. For example, brisk transient (BT) ganglion cells could reliably follow pulse rates up to 600 pulses per second (PPS). In contrast, other types could not even follow rates of 200 PPS. There was additional heterogeneity in the response patterns across those types that could not follow high-rate trains. For example, some types generated action potentials in response to approximately every other pulse, whereas other types generated one spike per pulse for a few consecutive pulses and then did not generate any spikes in response to the next few pulses. Interestingly, in the types that could not follow high-rate trains, we found a second type of response: many pulses of the train elicited a biphasic waveform with an amplitude much smaller than that of standard action potentials. This small waveform was often observed following every pulse for which a standard spike was not elicited. A possible origin of the small waveform and its implication for effective retinal stimulation are discussed.
Genetic influences on survival time after severe hemorrhage in inbred rat strains
Authors: Klemcke Harold G. , Joe Bina , Calderon Mariam L. , Rose Rajiv , Oh Thomas , Aden James , Ryan Kathy L.
Published: April 2011

To find a genetic basis for differential ability to survive severe hemorrhage, we previously showed eightfold differences in survival times among inbred rat strains. We assumed that rat strains had similar normalized blood volumes (NBV; ml/100 g body wt). As NBV might vary among strains and constitute one genetic variable affecting survival time to hemorrhage, in experiment 1 of the current studies we first measured total blood volumes and calculated NBV in specific inbred rat strains (Brown Norway/Medical College of Wisconsin, BN; Dark Agouti, DA; Fawn Hooded Hypertensive, FHH; Lewis, LEW; and Dahl Salt-Sensitive, SS) previously found to be divergent in survival time. NBV differed by 20% ( P < 0.01; BN > SS > FHH = LEW = DA) and had a heritability (h2) of 0.56. Hence, differential survival times in our previously published study might reflect strain-dependent differences in NBV. Then studies were conducted wherein rats were catheterized and, ∼24 h later, 47% of their blood volume was removed; these rats were observed for a maximum of 4 h. In experiment 2, blood volumes were measured the day prior to hemorrhage. Percent survival and survival time did not differ among strains. To obviate possible confounding effects of blood volume determination, in experiment 3 the average NBV for each strain was used to determine hemorrhage volumes. Percent survival ( P < 0.01) and survival times ( P < 0.001) were different with DA demonstrating the best (62.5%, 190 ± 29 min) and BN the worst (0%, 52 ± 5 min) survival responses. These data indicate that both blood volume and survival time after hemorrhage in rats are heritable quantitative traits, and continue to suggest that genetic assessment of these phenotypes might lead to novel therapeutics to improve survival to hemorrhage.
Observations on Forced Colony Emigration inParachartergus fraternus(Hymenoptera: Vespidae: Epiponini): New Nest Site Marked with Sprayed Venom
Authors: Mateus Sidnei
Published: April 2011

Five cases of colony emigration induced by removal of nest envelope and combs and a single one by manipulation are described. The disturbance was followed by defensive patterns, buzz running, and adult dispersion. An odor trail created by abdomen dragging, probably depositing venom or Dufour's gland secretions, connected the original nest to the newly selected nesting place and guided the emigration. The substrate of the selected nesting place is intensely sprayed with venom prior to emigration, and this chemical cue marked the emigration end point. The colony moves to the new site in a diffuse cloud with no temporary clusters formed along the odor trail. At the original nest, scouts performed rapid gaster dragging and intense mouth contacts stimulating inactive individuals to depart. Males were unable to follow the swarm. Individual scouts switched between different behavioral tasks before and after colony emigration. Pulp collected from the old nest was reused at the new nest site.
Micro- and Nano-Air Vehicles: State of the Art
Authors: Petricca Luca , Ohlckers Per , Grinde Christopher
Published: April 2011

Micro- and nano air vehicles are defined as “extremely small and ultra-lightweight air vehicle systems” with a maximum wingspan length of 15 cm and a weight less than 20 grams. Here, we provide a review of the current state of the art and identify the challenges of design and fabrication. Different configurations are evaluated, such as fixed wings, rotary wings, and flapping wings. The main advantages and drawbacks for each typology are identified and discussed. Special attention is given to rotary-wing vehicles (helicopter concept); including a review of their main structures, such as the airframe, energy storage, controls, and communications systems. In addition, a review of relevant sensors is also included. Examples of existing and future systems are also included. Micro- and nano-vehicles with rotary wings and rechargeable batteries are dominating. The flight times of current systems are typically around 1 hour or less due to the limited energy storage capabilities of the used rechargeable batteries. Fuel cells and ultra capacitors are promising alternative energy supply technologies for the future. Technology improvements, mainly based on micro- and nanotechnologies, are expected to continue in an evolutionary way to improve the capabilities of future micro- and nano air vehicles, giving improved flight times and payload capabilities.
The Role of Mirk Kinase in Sarcomas
Authors: Friedman Eileen
Published: April 2011

Targeting the tyrosine kinase KIT in gastrointestinal stromal tumors has led to improved treatment. Other kinases might serve as therapeutic targets in the more common forms of sarcoma. The kinase Mirk/dyrk1B is highly expressed in the vast majority of osteosarcomas and rhabdomyosarcomas and mediates their growth, as depletion of Mirk led to tumor cell apoptosis. Mirk is known to increase the expression of a series of antioxidant genes, which scavenge reactive oxygen species (ROS) within various tumor cells, mediating their survival. As a result, depleting Mirk led to increased levels of damaging ROS. Tumor cells depleted of Mirk were also sensitized to low levels of chemotherapeutic drugs that increase ROS levels. In contrast, Mirk expression is quite low in most normal cells, and Mirk depletion or embryonic knockout of Mirk did not detectably affect cell survival. Thus targeting Mirk for intervention in sarcomas might spare most normal tissues.
The Characterization and Hydrogen Production from Water Decomposition with Methanol in a Semi-Batch Type Reactor Using In, P-TiO2s
Authors: Kim Joonwoo , Kim Hae-Ri , Choung Suk-Jin
Published: April 2011

The photocatalytic production of hydrogen from water using solar energy is potentially a clean and renewable source for hydrogen fuel. This study examines the production of hydrogen over In, P-TiO2s photocatalysts. 1 mol% In-TiO2and P-TiO2were produced using the solvothermal method and were treated at 500 and 800∘C to obtain anatase and rutile structure, respectively. The photocatalysts were characterized by X-ray diffraction, photoluminescence spectra, X-ray spectroscopy, UV-visible spectroscopy, and scanning electron microscopy. The production of H2from methanol photodecomposition was greater over the rutile structure than over the anatase structure of TiO2. Moreover, the amount of hydrogen was enhanced over In-TiO2and P-TiO2compared to that over pure TiO2; the production increased by about 30%. The structural effect and the addition of In, P have significant influence on the H2production from methanol/water decomposition.
Adaptive Control of Chaos in Chua′s Circuit
Authors: Guo Weiping , Liu Diantong
Published: April 2011

A feedback control method and an adaptive feedback control method are proposed for Chua′s circuit chaos system, which is a simple 3D autonomous system. The asymptotical stability is proven with Lyapunov theory for both of the proposed methods, and the system can be dragged to one of its three unstable equilibrium points respectively. Simulation results show that the proposed methods are valid, and control performance is improved through introducing adaptive technology.
Asia Oceania Guidelines for the Implementation of Programs for Cervical Cancer Prevention and Control
Authors: Ngan Hextan Y. S. , Garland Suzanne M. , Bhatla Neerja , Pagliusi Sonia R. , Chan Karen K. L. , Cheung Annie N. Y. , Chu Tang-Yuan , Domingo Efren J. , Qiao You Lin , Park Jong Sup , Tay Eng Hseon , Supakarapongkul Wisit
Published: April 2011

This paper aims to provide evidence-based recommendations for health professionals, to develop a comprehensive cervical cancer program for a clinic, a community, or a country. Ensuring access to healthcare is the responsibility of all societies, and the Asia Oceania Research Organisation in Genital Infections and Neoplasia (AOGIN) is committed to working collaboratively with governments and health professionals to facilitate prevention programs, to protect girls and women from cervical cancer, a disease that globally affects 500,000 and kills nearly 300,000 women annually, just over half of whom are in the Asia Oceania region. We share the vision that a comprehensive program of vaccination, screening, and treatment should be made accessible to all girls and women in the world. The primary purpose of these guidelines is to provide information on scientific evidence on the different modalities and approaches of cervical cancer prevention programs, for high resource and low resource settings. The secondary purpose is to provide an overview of the current situation of cervical cancer control and prevention in various Asian Oceania countries: their views of an ideal program, identified obstacles, and suggestions to overcome them are discussed.
Brainstorm: A User-Friendly Application for MEG/EEG Analysis
Authors: Tadel François , Baillet Sylvain , Mosher John C. , Pantazis Dimitrios , Leahy Richard M.
Published: April 2011

Brainstorm is a collaborative open-source application dedicated to magnetoencephalography (MEG) and electroencephalography (EEG) data visualization and processing, with an emphasis on cortical source estimation techniques and their integration with anatomical magnetic resonance imaging (MRI) data. The primary objective of the software is to connect MEG/EEG neuroscience investigators with both the best-established and cutting-edge methods through a simple and intuitive graphical user interface (GUI).
Humanized Bone Marrow Mouse Model as a Preclinical Tool to Assess Therapy-Mediated Hematotoxicity
Authors: Cai Shanbao , Wang Haiyan , Bailey Barbara , Ernstberger Aaron , Juliar Beth E. , Sinn Anthony L. , Chan Rebecca J. , Jones David R. , Mayo Lindsey D. , Baluyut Arthur R , Goebel W Scott , Pollok Karen E
Published: April 2011

Purpose: Preclinical in vivo studies can help guide the selection of agents and regimens for clinical testing. However, one of the challenges in screening anticancer therapies is the assessment of off-target human toxicity. There is a need for in vivo models that can simulate efficacy and toxicities of promising therapeutic regimens. For example, hematopoietic cells of human origin are particularly sensitive to a variety of chemotherapeutic regimens, but in vivo models to assess potential toxicities have not been developed. In this study, a xenograft model containing humanized bone marrow is utilized as an in vivo assay to monitor hematotoxicity.

Experimental Design: A proof-of-concept, temozolomide-based regimen was developed that inhibits tumor xenograft growth. This regimen was selected for testing because it has been previously shown to cause myelosuppression in mice and humans. The dose-intensive regimen was administered to NOD.Cg-PrkdcscidIL2rgtm1Wjl/Sz (NOD/SCID/γchainnull), reconstituted with human hematopoietic cells, and the impact of treatment on human hematopoiesis was evaluated.

Results: The dose-intensive regimen resulted in significant decreases in growth of human glioblastoma xenografts. When this regimen was administered to mice containing humanized bone marrow, flow cytometric analyses indicated that the human bone marrow cells were significantly more sensitive to treatment than the murine bone marrow cells and that the regimen was highly toxic to human-derived hematopoietic cells of all lineages (progenitor, lymphoid, and myeloid).

Conclusions: The humanized bone marrow xenograft model described has the potential to be used as a platform for monitoring the impact of anticancer therapies on human hematopoiesis and could lead to subsequent refinement of therapies prior to clinical evaluation. Clin Cancer Res; 17(8); 2195–206. ©2011 AACR.
Polymorphisms in the Endothelin-1 and Endothelin A Receptor Genes and Survival in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma
Authors: Wen Yue-Feng , Qi Bin , Liu Huai , Mo Hao-Yuan , Chen Qiu-Yan , Li Juan , Huang Pei-Yu , Ye Yan-Fang , Zhang Ying , Deng Man-Quan , Guo Xiang , Hong Ming-Huang , Cao Ka-Jia , Mai Hai-Qiang
Published: April 2011

Purpose: We aimed to investigate the prognostic role of endothelin-1 (EDN1) and endothelin A receptor (EDNRA) gene polymorphisms in patients with locoregionally advanced nasopharyngeal carcinoma (NPC).

Experimental Design: Two hundred three consecutive patients with locoregionally advanced NPC were enrolled. Seven potentially functional polymorphisms in the EDN1 and EDNRA genes were determined by ligase detection reaction-PCR method from prospectively collected blood samples. The influence of the genetic polymorphisms on patient overall survival (OS) was analyzed using Cox proportional hazards model, Kaplan–Meier method, and the log-rank test.

Results: The 5-year OS in patients with EDNRA/H323H TT, TC, and CC genotypes were 81.3%, 62.1%, and 75.0%, respectively (P = 0.004). Patients carrying the heterozygous (TC) or homozygous variant (CC) genotype in EDNRA/H323H were combined for analysis, which revealed that the 5-year OS in patients with TC/CC genotypes was significantly lower than those with the wild-type TT genotype (63.2% vs. 81.3%; P = 0.002). Multivariate analysis showed that EDNRA/H323H polymorphism (HR: 1.95; 95% CI: 1.18–3.23; P = 0.009) and N classification (HR: 1.35; 95% CI: 1.03–1.79; P = 0.03) were independent significant prognostic factors for OS in patients with locoregionally advanced NPC. In contrast, the EDN1 polymorphisms revealed no prognostic value.

Conclusions: The EDNRA/H323H polymorphism was a novel and independent prognostic marker for patients with locoregionally advanced NPC. The analysis of EDNRA/H323H polymorphism may help identify patient subgroups at high risk for poor disease outcome. Clin Cancer Res; 17(8); 2451–8. ©2011 AACR.
Plasma Markers for Identifying Patients with Metastatic Melanoma
Authors: Kluger Harriet M. , Hoyt Kathleen , Bacchiocchi Antonella , Mayer Tina , Kirsch Jonathan , Kluger Yuval , Sznol Mario , Ariyan Stephan , Molinaro Annette , Halaban Ruth
Published: April 2011

Purpose: With the rising incidence of melanoma, more patients are undergoing surveillance for disease recurrence. Our purpose was to study levels of proteins that might be secreted in the blood of patients with metastatic melanoma that can be used for monitoring these individuals.

Methods: Genome-wide gene expression data were used to identify abundantly expressed genes in melanoma cells that encode for proteins likely to be present in the blood of cancer patients, based on high expression levels in tumors. ELISA assays were employed to measure proteins in plasma of 216 individuals; 108 metastatic melanoma patients and 108 age- and gender-matched patients with resected stage I/II disease split into equal-sized training and test cohorts.

Results: Levels of seven markers, CEACAM (carcinoembryonic antigen–related cell adhesion molecule), ICAM-1 (intercellular adhesion molecule 1), osteopontin, MIA (melanoma inhibitory activity), GDF-15 (growth differentiation factor 15), TIMP-1 (tissue inhibitor of metalloproteinase 1), and S100B, were higher in patients with unresected stage IV disease than in patients with resected stage I/II disease. About 81% of the stage I/II patients in the training set had no marker elevation, whereas 69% of the stage IV patients had elevation of at least one marker (P < 0.0001). Receiver operating characteristic curves for the markers in combination in these two patient populations had an area under curve (AUC) of 0.79 in the training set and 0.8 in the test set. A CART (Classification and Regression Trees) model developed in the training set further improved the AUC in the test set to 0.898.

Conclusions: Plasma markers, particularly when assessed in combination, can be used to monitor patients for disease recurrence and can compliment currently used lactate dehydrogenase and imaging studies; prospective validation is warranted. Clin Cancer Res; 17(8); 2417–25. ©2011 AACR.
Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma
Authors: Piguet Anne-Christine , Saar Bettina , Hlushchuk Ruslan , St-Pierre Marie V. , McSheehy Paul M.J. , Radojevic Vesna , Afthinos Maresa , Terracciano Luigi , Djonov Valentin , Dufour Jean-François
Published: April 2011

Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2×/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI quantified tumor volumes. Erk1/2, 4E-BP1, and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85%, and 55%, relative to controls, in everolimus, the combination, and sequential groups, respectively (P < 0.01). Survival was longest in the combination group (P < 0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (P < 0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib, and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib. Mol Cancer Ther; 10(6); 1007–17. ©2011 AACR.
Trastuzumab Regulates IGFBP-2 and IGFBP-3 to Mediate Growth Inhibition: Implications for the Development of Predictive Biomarkers for Trastuzumab Resistance
Authors: Dokmanovic Milos , Shen Yi , Bonacci Tabetha M. , Hirsch Dianne S. , Wu Wen Jin
Published: April 2011

Activation of insulin-like growth factor-I receptor (IGF-IR) signaling is an important mechanism for trastuzumab resistance. IGF-binding proteins (IGFBP) modulate IGF-IR signaling and play important roles in the control of breast cancer progression. In this article, we report that trastuzumab treatment enhances the expression and secretion of IGFBP-3 in SKBR3 cells, a trastuzumab-sensitive breast cancer cell line, and that this upregulation of IGFBP-3 induced by trastuzumab correlates with trastuzumab-mediated growth inhibition. We describe a new role for IGFBP-3 in the regulation of IGF-I–mediated cross-talk between IGF-IR and ErbB2 signaling pathways. In particular, treatment of SKBR3 cells with recombinant IGFBP-3 blocks IGF-I–induced activation of IGF-IR and ErbB2, and stable expression of IGFBP-3 inhibits SKBR3 cell growth. We find an inverse relationship in the levels of secreted IGFBP-3 such that high levels of IGFBP-3 are associated with trastuzumab-sensitive breast cancer cells (SKBR3 and BT-474), whereas low levels of IGFBP-3 are found in trastuzumab-resistant cells (clone 3 and JIMT-1). In contrast to IGFBP-3, the secretion and expression of IGFBP-2 are upregulated in trastuzumab-resistant SKBR3 cells. Furthermore, we show that IGFBP-2 stimulates activation of ErbB2 and that trastuzumab reduces IGFBP-2–stimulated ErbB2 activation. Based on our data, we propose a novel mechanism of action whereby trastuzumab enhances the expression and secretion of IGFBP-3, which interferes with IGF-I–mediated mitogenic signaling via autocrine and paracrine mechanisms and reduces IGFBP-2–induced ErbB2 activation to mediate growth inhibition. Changes in secretion profiles of IGFBP-2 and IGFBP-3 in trastuzumab-sensitive and trastuzumab-resistant cells may promote the development of IGFBP-2 and IGFBP-3 as predictive biomarkers for trastuzumab resistance. Mol Cancer Ther; 10(6); 917–28. ©2011 AACR.
Maternal Smoking, Obesity and Male Fetal Sex Predispose to a Large Nuchal Translucency Thickness in Healthy Fetuses
Authors: Rode L. , Ekelund C. , Pedersen N.G. , Wøjdemann K.R. , Christiansen M. , Sundberg K. , Tabor A.
Published: April 2011

Objectives: Our aim was to evaluate the effect of fetal sex, smoking and body mass index (BMI) on nuchal translucency (NT). Methods: We analyzed data from 7,357 women with a normal singleton live birth outcome with information on smoking, BMI and sex of the infant. NT measurements were converted to multiples of the median (MoMNT) using a previously reported linear regression analysis. Results: The odds ratio (OR) for MoMNT >95th centile was 1.5 (95% CI 1.2–1.9) for smokers compared to nonsmokers and 1.4 (95% CI 1.1–1.7) for male fetuses compared to female fetuses. Obese women (BMI ≧30) had an increased OR for a large NT of 1.7 (95% CI 1.2–2.6) compared to normal weight women. Obese smokers carrying a male fetus had an OR of 4.2 (95% CI 1.7–10.1) of a MoMNT >95th centile compared to normal weight nonsmoking women with a female fetus. The effects of smoking, obesity status and fetal sex were independent of each other. Conclusions: Smoking, obesity and male sex are associated to a MoMNT >95th centile. This may affect screening performance and entail unnecessary anxiety in these women. Further investigations, including fetuses with adverse outcome, are needed.
Hemimegalencephaly: 2D, 3D Ultrasound and MRI Correlation
Authors: Romero X.C. , Molina F.S. , Pastor E. , Amaya F.
Published: April 2011

Background: Hemimegalencephaly (HMC) is a disorder associated with enlarged and dysplastic hamartomatous overgrowth of all or part of the one cerebral hemisphere that can be isolated or associated with other syndromes. In the normal development of the brain it is important to bear in mind that there are two main processes: firstly the development of the hemispheres and the corpus callosum, and secondly the cortical formation with proliferation, migration and organization of the cortex, which occurs mostly between 12 and 20 weeks of gestation. Case Report: We present a 22-week-old fetus with macrocephaly depending on HMC and emphasize the possibility of an early ultrasound diagnosis, the correlation in the diagnosis between 2D and 3D ultrasound, and the use of magnetic resonance imaging as an imaging method for a more precise diagnosis of neuronal migration anomalies. Conclusion: The diagnosis of HMC is possible at the time of the anomaly scan. The use and correlation with other diagnostic tools provide essential information for parent counseling in these complex cases.
Can a 15-mm Cervical Length Cutoff Discriminate between Low and High Risk of Preterm Delivery in Women with Threatened Preterm Labor?
Authors: Wulff Camilla B. , Ekelund Charlotte K. , Hedegaard Morten , Tabor Ann
Published: April 2011

Objectives: To investigate if a cervical length (CL) cutoff of 15 mm is relevant to use in women with threatened preterm labor. Methods: From 2006 to 2009, 146 women with singleton pregnancies were admitted with threatened preterm labor between 23 and 33+6 weeks of gestation at Copenhagen University Hospital. Transvaginal sonographic measurement of CL was carried out on admission. Outcome measures were spontaneous delivery within 48 h, within 7 days and delivery before 34 weeks according to a CL cutoff of 15 mm. Results: CL was <15 mm in 36 women (24.7%) and ≧15 mm in 110 women (75.3%). Spontaneous delivery occurred within 48 h or 7 days of presentation and before 34 weeks in 25, 38.9 and 50.0% of women with CL <15 mm and 3.6, 9.1 and 11.8% of women with CL ≧15 mm, respectively. The 15-mm CL cutoff had a sensitivity, false positive rate and negative predictive value for delivery within 48 h of 69.0, 20.3 and 96.4%, and within 7 days of 58.3, 18.1 and 90.9%. Women with CL <15 mm had odds of delivery within 7 days of 6.4 (95% CI 2.5–16.2). Conclusion: Although a 15-mm CL defines a group of women at high risk of spontaneous preterm delivery, 10 out of 110 women (9.1%) with a CL ≧15 mm deliver within 7 days.
Turning the Pyramid of Prenatal Care
Authors: Nicolaides Kypros H.
Published: April 2011

The current approach to prenatal care, which involves visits at 16, 24, 28, 30, 32, 34 and 36 weeks and then weekly until delivery, was established 80 years ago. The high concentration of visits in the third trimester implies, firstly, that most complications occur at this late stage of pregnancy and, secondly, that most adverse outcomes are unpredictable during the first or even second trimester. This review presents evidence that many pregnancy complications can now be predicted at an integrated first hospital visit at 11–13 weeks by combining data from maternal characteristics and history with findings of biophysical and biochemical tests. It is therefore proposed that the traditional pyramid of care should be inverted with the main emphasis placed in the first rather than third trimester of pregnancy.
Effects of Peroxisome Proliferator-Activated Receptors, Dietary Fat Intakes and Gene–Diet Interactions on Peak Particle Diameters of Low-Density Lipoproteins
Authors: Bouchard-Mercier Annie , Godin Gaston , Lamarche Benoît , Pérusse Louis , Vohl Marie-Claude
Published: April 2011

The risk of cardiovascular diseases (CVDs) is modulated by gene–diet interactions. The objective of this study was to examine whether gene–diet interactions affect peak particle diameters (PPD) of low-density lipoprotein (LDL). Methods: The study included 674 participants. A food frequency questionnaire was administered to obtain dietary information. LDL-PPD was determined by non-denaturing 2–16% polyacrylamide gradient gel electrophoresis. Peroxisome proliferator-activated receptor (PPAR) gene polymorphisms PPARα L162V (rs1800206), PPARγ P12A (rs1801282) and PPARδ –87T→C (rs2016520) were determined by PCR-RFLP. Results: Among carriers of thePPARα L162V polymorphism, gene–diet interaction effects on LDL-PPD were observed with saturated fat (p = 0.0005) and total dietary fat (p = 0.006). Among PPARα V162 carriers, subjects with higher saturated fat intakes had smaller LDL-PPD than those with lower intakes (254.23 ± 2.74 vs. 256.21 ± 2.61 Å, respectively, p = 0.007). Among subjects homozygous for the PPARα L162 allele, those with higher saturated fat intakes had larger LDL-PPD than those with lower saturated fat intakes (255.86 ± 2.66 vs. 255.05 ± 2.65 Å, respectively, p = 0.01). Gene–diet interactions were also found for PPARγ P12A polymorphism with saturated fat intake (p = 0.04) and for PPARδ –87T→C with the polyunsaturated/saturated fat ratio (p = 0.0013). Conclusions: These results stress that dietary factors should be included in studies determining the effect of different polymorphisms on CVD risk factors.
Risk of Cerebral Angiography in Patients with Symptomatic Intracranial Atherosclerotic Stenosis
Authors: Cloft Harry J. , Lynn Michael J. , Feldmann Edward , Chimowitz Marc ,   for the WASID Study Group
Published: April 2011

Background: A well-defined rate of adverse events following cerebral angiography in patients with symptomatic intracranial atherosclerosis would be useful to physicians making decisions regarding imaging and treatment of these patients. We report the adverse events associated with angiography in patients who underwent single-vessel cerebral angiography as part of the study protocol in the Warfarin-Aspirin for Symptomatic Intracranial Arterial Stenosis trial. Methods: Single-vessel cerebral angiography was performed to specifically define the degree of stenosis in 196 patients suspected of having intracranial atherosclerotic stenosis on noninvasive tests. Adverse events that occurred within 24 h of cerebral angiography were reported by the sites performing the angiography. Results: Overall, neurological adverse events occurred in 4 patients (2.0%; 95% CI: 0.6–5.1%), and nonneurological adverse events occurred in 12 patients (6.1%; 95% CI: 3.2–10.5%). All of the neurological adverse events were transient. Conclusions: The risk of permanent neurological adverse events associated with single-vessel cerebral angiography in patients with symptomatic intracranial atherosclerosis is relatively low. The quantification of the risk of cerebral angiography in patients with intracranial atherosclerosis provides useful information to consider when evaluating noninvasive imaging techniques for their relative value.