bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of beam efficiency through the patient‐specific collimator on secondary neutron dose equivalent in double scattering and uniform scanning modes of proton therapy
Authors: Hecksel D. , Anferov V. , Fitzek M. , Shahnazi K.
Published: June 2010

Purpose

Conventional proton therapy facilities use double scattering nozzles, which are optimized for delivery of a few fixed field sizes. Similarly, uniform scanning nozzles are commissioned for a limited number of field sizes. However, cases invariably occur where the treatment field is significantly different from these fixed field sizes. The purpose of this work was to determine the impact of the radiation field conformity to the patient‐specific collimator on the secondary neutron dose equivalent.

Methods

Using a WENDI‐II neutron detector, the authors experimentally investigated how the neutron dose equivalent at a particular point of interest varied with different collimator sizes, while the beam spreading was kept constant. The measurements were performed for different modes of dose delivery in proton therapy, all of which are available at the Midwest Proton Radiotherapy Institute (MPRI): Double scattering, uniform scanning delivering rectangular fields, and uniform scanning delivering circular fields. The authors also studied how the neutron dose equivalent changes when one changes the amplitudes of the scanned field for a fixed collimator size.

Results

The secondary neutron dose equivalent was found to decrease linearly with the collimator area for all methods of dose delivery. The relative values of the neutron dose equivalent for a collimator with a 5 cm diameter opening using 88 MeV protons were 1.0 for the double scattering field, 0.76 for rectangular uniform field, and 0.6 for the circular uniform field. Furthermore, when a single circle wobbling was optimized for delivery of a uniform field 5 cm in diameter, the secondary neutron dose equivalent was reduced by a factor of 6 compared to the double scattering nozzle. Additionally, when the collimator size was kept constant, the neutron dose equivalent at the given point of interest increased linearly with the area of the scanned proton beam.

Conclusions

The results of these experiments suggest that the patient‐specific collimator is a significant contributor to the secondary neutron dose equivalent to a distant organ at risk. Improving conformity of the radiation field to the patient‐specific collimator can significantly reduce secondary neutron dose equivalent to the patient. Therefore, it is important to increase the number of available generic field sizes in double scattering systems as well as in uniform scanning nozzles.
MapCHECK used for rotational IMRT measurements: Step‐and‐shoot, Tomotherapy, RapidArc
Authors: Jursinic Paul A. , Sharma Renu , Reuter Jim
Published: June 2010

Purpose

To measure patient‐specific‐QA dose distributions with a 2D array of diodes, the MapCHECK, for the dose delivered, with step‐and‐shoot and rotational IMRT.

Methods

Two MapCHECKs were used that had different styles of diode connection. These MapCHECKs were used in their original manufactured configuration and in a modified configuration. The modification made in the clinic consists of filling air gaps with sheets of Lucite that had custom‐machined slots for the diodes and by adding pieces of copper to offset the intrinsic asymmetry of the diodes. The MapCHECKs were housed in a tight‐fitting phantom fabricated from solid water. Measurements were made on IMRT treatment plans delivered with Varian linear accelerators with step‐and‐shoot and RapidArc methods, and a TomoTherapy machine with helical delivery. Patient plans and QA plans were developed with the XiO, Eclipse, and TomoTherapy planning systems. All MapCHECK data were analyzed with its commercially available software.

Results

Kilovoltage CT imaging of the MapCHECK in its phantom has streak artifacts from high atomic number components. These artifacts must be corrected in order to obtain accurate calculation of dose. The original MapCHECK is found to have an angular dependence of ±20%. A modification of the MapCHECK has been made that reduces the angular dependence to ±2%. Proper compensation for attenuation by the treatment couch is also necessary for accurate results. The modified MapCHECK has been successfully used for doing patient‐specific QA for IMRT treatments delivered with step‐and‐shoot, TomoTherapy, and RapidArc methods. Treatment plans that require large amounts of fluence from the 90° and 270° directions have significantly better QA measurements when made with modified MapCHECKs.

Conclusions

When properly modified, the MapCHECK response becomes isotropic. It can then be used for patient‐specific QA measurements for IMRT treatments delivered with step‐and‐shoot and rotational techniques such as helical Tomotherapy and RapidArc.
kVCT, MVCT, and hybrid CT image studies—Treatment planning and dose delivery equivalence on helical tomotherapy
Authors: Martin Spencer , Yartsev Slav
Published: June 2010

Purpose

To determine the equivalence of radiation therapy treatment planning and delivery for various imaging options on helical tomotherapy.

Methods

Seven treatment plans using identical anatomy and planning parameters were created based on the following CT studies: Standard kilovoltage CT (kVCT); 2, 4, and 6 mm spacing megavoltage CT (MVCT); and 2, 4, and 6 mm hybrid MVCT/kVCT studies. In addition, two kVCT based plans were created to explore the effect of the choice of dose calculation grid for optimization. Calculated and measured dose distributions were compared via volumetric and dosimetric analysis at the planning stage, point dose measurements with ion chamber, along with EDR2 film data for gamma function analysis for distance to agreement of 3 mm and dose differences of 3%, 5%, and 7% using both the commercially available “cheese” phantom and the new QUASAR Verification (QVer) phantom.

Results

Plans created for each imaging option showed residual error increasing as image slice spacing increased and critical structure size decreased. With the exception of the low dose area in hybrid studies, point dose measurements were within the calculated/measured dose acceptance criteria of 5% on both the QVer and cheese phantoms. Gamma analysis for the original kVCT plan delivery showed an average of and of dose pixels passing kVCT study treatment and delivery quality assurance procedures, respectively. The QVer phantom allows for delivery quality assurance with simultaneous use of two films and more convenient gamma function assessment but shows some measurement discrepancy up to 10% compared to the cheese phantom.

Conclusions

The kVCT, MVCT, and kVCT/MVCT hybrid studies showed considerable agreement at both planning and delivery stages. The choice of calculation grid is more important when dealing with smaller anatomical structures.
Microwaves create larger ablations than radiofrequency when controlled for power in ex vivo tissue
Authors: Andreano A. , Huang Yu , Meloni M. Franca , Lee Fred T. , Brace Christopher
Published: June 2010

Purpose

To compare ablation zones created with equal amounts of 2.45 GHz microwave and 480 kHz radiofrequency (RF) energy inex vivo liver and lung.

Methods

A total of 38 ablations were performed inex vivo liver and lung for 10 min each. Nineteen RF ablations (nine liver, ten lung) were performed with a 480 kHz system (200 W max, impedance‐based pulsing) and cooled electrode while measuring the average RF power applied. Nineteen microwave ablations (nine liver, ten lung) were then created using a cooled triaxial antenna to deliver 2.45 GHz at the same power level as in RF experiments. Ablation zones were then sectioned and measured for minimum, maximum and mean diameters, and circularity. Measurements were compared using ‐tests, with indicating statistical significance.

Results

Mean diameters of microwave ablations were greater than RF ablations in both liver and lung ( vs in liver; vs in lungs; all comparisons). There was no significant difference in the mean power applied during microwave or RF ablations in either organ ( vs in liver, ; vs in lung, ).

Conclusions

Using a single cooled applicator, microwave energy at 2.45 GHz produces larger ablations than an equivalent amount of 480 kHz RF energy in normal liver and lung. This was more apparent in lung, likely due to the high baseline impedance which limits RF, but not microwave power delivery.
Quantized Anomalous Hall Effect in Magnetic Topological Insulators
Authors: Yu Rui , Zhang Wei , Zhang Hai-Jun , Zhang Shou-Cheng , Dai Xi , Fang Zhong
Published: June 2010

Quantum Anomalous Hall Effect

In addition to the Hall effect, which appears as a voltage change in conductors in response to an external magnetic field, ferromagnets exhibit the anomalous Hall effect, which is often proportional to their magnetization and independent of the presence of the magnetic field. This effect, first observed more than a century ago, has not been realized in its quantized form.

Yu
et al.

(p.
61
, published online 3 June) propose a realization of a quantum anomalous Hall system by magnetically doping thin films of three-dimensional topological insulators and calculate the effects of various dopants and film thicknesses. The resulting insulators are predicted to have long-range ferromagnetic order, potentially joining dilute magnetic semiconductors as candidates for spintronic applications.
An Autophagy-Enhancing Drug Promotes Degradation of Mutant α
1
-Antitrypsin Z and Reduces Hepatic Fibrosis
Authors: Hidvegi Tunda , Ewing Michael , Hale Pamela , Dippold Christine , Beckett Caroline , Kemp Carolyn , Maurice Nicholas , Mukherjee Amitava , Goldbach Christina , Watkins Simon , Michalopoulos George , Perlmutter David H.
Published: June 2010

Correcting a Liver Problem

The classical form of α
1
-antitrypsin (AT) deficiency is caused by a point mutation that alters the folding and causes intracellular aggregation of AT—an abundant liver-derived plasma glycoprotein. AT deficiency is the most common genetic cause of liver disease in childhood and can also lead to cirrhosis and/or hepatocellular carcinoma in adulthood. Carbamazepine is a drug known to be well tolerated in humans that enhances the intracellular degradation process known as autophagy. Now,

Hidvegi
et al.

(p.
229
, published online June 3; see the Perspective by

Sifers

) show that carbamazepine can reduce the severity of liver disease in a mouse model of AT deficiency by enhancing the degradation of misfolded accumulated AT.
The Landscape of
C. elegans
3′UTRs
Authors: Mangone Marco , Manoharan Arun Prasad , Thierry-Mieg Danielle , Thierry-Mieg Jean , Han Ting , Mackowiak Sebastian D. , Mis Emily , Zegar Charles , Gutwein Michelle R. , Khivansara Vishal , Attie Oliver , Chen Kevin , Salehi-Ashtiani Kourosh , Vidal Marc , Harkins Timothy T. , Bouffard Pascal , Suzuki Yutaka , Sugano Sumio , Kohara Yuji , Rajewsky Nikolaus , Piano Fabio , Gunsalus Kristin C. , Kim John K.
Published: June 2010

A New Look at Old Data

Although the full genome of
Caenorhabditis elegans
has been available for over 10 years, only a portion of the full-length messenger RNAs (mRNAs) and their expression through development has been analyzed. By combining multiple methods, involving a careful reannotation of existing data sets, sequencing of poly-A captured RNAs from multiple developmental stages, as well as cloning and deep sequencing of a subset of genes,

Mangone
et al.

(p.
432
, published online 3 June) defined ∼26,000 distinct mRNA three-prime untranslated regions (3′UTRs) for ∼85% of the protein-coding genes. Most
C. elegans
genes have more than one 3′UTR, arising through different mechanisms including trans-splicing–coupled cleavage and polyadenylation. The work highlights the importance of the 3'UTRs in the regulation of mRNA stability and translation.
Surface light-induced drift, including number flux and heat flux, in flat-plate and circular-cylindrical geometries
Authors: Goodman Frank O.
Published: June 2010

With standard forms of the approximate Maxwell–Boltzmann rate equations, some of the author’s previous work is used to obtain exact results for the gas particle velocity distribution functions for the general case of laser excitation function, and, for use in calculations of the fluxes, a very simple effective distribution function is derived. The work is confined to the limit of low radiation absorption by the gas and to the limit of large Knudsen number. Where possible, the exact results for the fluxes are compared with recent corresponding approximate results of Chermyaninov, Chernyak, Khinkina, and Vilisova (CCKV), with interesting conclusions. The results allow useful assessment of approximation schemes such as those in CCKV.
Investigations of the spin Hamiltonian parameters for the cubic Mn2+ centers in ZnX (X = S, Se, Te) and CdTe
Authors: Wang Xue-Feng , Wu Shao-Yi , Li Li-Li , Zhang Shan-Xiang
Published: June 2010

The spin Hamiltonian parameters (g factors and the hyperfine structure constants) for the cubic Mn2+ centers in ZnX (X = S, Se, Te) and CdTe are investigated theoretically using the perturbation formulas of these parameters for a tetrahedral 3d5 cluster containing both the crystal-field and charge-transfer contributions. The relevant molecular orbital coefficients are uniformly determined from the cluster approach, and the calculated spin Hamiltonian parameters are in good agreement with the observed values. The g-shifts of the g factors related to the pure spin value gs (≈ 2.0023) arising from the charge transfer contributions are opposite (positive) in sign and much larger in magnitude than those from the crystal field contributions. On the other hand, the contributions from the charge-transfer mechanism to the hyperfine structure constants are the same in sign and about 20%–30% in magnitude of those from the crystal-field mechanism. The importance of the charge transfer contributions increases significantly with the increase of the covalency and the spin–orbit coupling coefficient of the ligand, i.e., S2− < Se2− < Te2−.
Nonlinear vibration of rectangular atomic force microscope cantilevers by considering the Hertzian contact theory
Authors: Sadeghi Ali , Zohoor Hassan
Published: June 2010

The nonlinear flexural vibration for a rectangular atomic force microscope cantilever is investigated by using Timoshenko beam theory. In this paper, the normal and tangential tip–sample interaction forces are found from a Hertzian contact model and the effects of the contact position, normal and lateral contact stiffness, tip height, thickness of the beam, and the angle between the cantilever and the sample surface on the nonlinear frequency to linear frequency ratio are studied. The differential quadrature method is employed to solve the nonlinear differential equations of motion. The results show that softening behavior is seen for most cases and by increasing the normal contact stiffness, the frequency ratio increases for the first mode, but for the second mode, the situation is reversed. The nonlinear-frequency to linear-frequency ratio increases by increasing the Timoshenko beam parameter, but decreases by increasing the contact position for constant amplitude for the first and second modes. For the first mode, the frequency ratio decreases by increasing both of the lateral contact stiffness and the tip height, but increases by increasing the angle α between the cantilever and sample surface.
BRAIDED STATISTICS FROM ABELIAN TWIST IN κ-MINKOWSKI SPACETIME
Authors: KIM HYEONG-CHAN , LEE YOUNGONE , RIM CHAIHO
Published: June 2010

κ-deformed commutation relation between quantum operators is constructed via Abelian twist deformation in κ-Minkowski spacetime. The commutation relation is written in terms of universal R-matrix satisfying braided statistics. The equal-time commutator function vanishes in this framework.
SEMI-SUPERVISED DYNAMIC CLASSIFICATION FOR INTRUSION DETECTION
Authors: KOOCHAKZADEH NEGAR , KIANMEHR KEIVAN , JIDA JAMAL , LEE ILTAE , ALHAJJ REDA , ROKNE JON
Published: June 2010

In this paper, a new framework to build an adaptive classifier is introduced. At first, a clustering algorithm, Density-Based Spatial Clustering of Applications with Noise (DBSCAN) is applied to a set of sample data to form initial set of clusters. The clusters are represented as classes. Using support vector machine (SVM), a classifier model is generated. In real world application, data comes in continuously. Therefore, if the model does not learn from the new data, the model may not perform as well with the new data especially when the model's training data is different from the test data. The new framework proposed in this paper rebuilds the classifier model using selected data from test data set to improve the accuracy of the model. A case study on intrusion detection data set has been performed to evaluate our methodology. The result shows that this approach lead to have more accurate classification models over time.
INTEGRATING MULTIMEDIA SEMANTIC CONTENT ANALYSIS OF YOUTUBE VIDEOS WITH HURRICANE WIND ANALYSIS FOR PUBLIC SITUATION AWARENESS AND OUTREACH
Authors: RAVITZ GUY , SHYU MEI-LING , POWELL MARK D.
Published: June 2010

Natural disasters, such as hurricanes, have had an enormous social and economical impact on society in the United State and around the world for many years. With the goal of preventing, diverting, or weakening the destructive forces of tropical cyclones, the preparedness of the public plays a major role in the magnitude of inflicted damage due to these storms. Acknowledging the captivating power of social networking and Web 2.0 over society, we present a prototype system which integrates meteorological data along with user generated content with the aim of improving public response by increasing their situational awareness due to such natural threats. The proposed system aggregates storm track and wind analysis data from the existing H*Wind system along with videos taken from YouTube and presents it to the user in Google Earth. A content-based concept detection mechanism is used to evaluate the relevance of the extracted YouTube videos to the storm of interest. The proposed system demonstrates the potential public benefit resulting from the integration of the areas of multimedia content analysis, Web 2.0, and meteorology.
ATTENTIONAL OBJECT DETECTION WITH AN ACTIVE MULTI-FOCAL VISION SYSTEM
Authors: XU TINGTING , ZHANG TIANGUANG , KÜHNLENZ KOLJA , BUSS MARTIN
Published: June 2010

A biologically inspired foveated attention system in an object detection scenario is proposed. Bottom-up attention uses wide-angle stereo camera data to select a sequence of fixation points. Successive snapshots of high foveal resolution using a telephoto camera enable highly accurate object recognition based on SIFT algorithm. Top-down information is incrementally estimated and integrated using a Kalman-filter, enabling parameter adaptation to changing environments due to robot locomotion. In the experimental evaluation, all the target objects were detected in different backgrounds. Significant improvements in flexibility and efficiency are achieved.
MOTION GENERATION FOR THE UPPER BODY OF HUMANOID ROBOT
Authors: XING DENGPENG , SU JIANBO
Published: June 2010

This paper aims at the guarantee of yaw moment requirement for the ZMP convention. In order to compensate for the yaw moment of whole body during motion, we present two motion generation methods for the upper body of the humanoid robot. The ground reactive torque and the effect of arms swinging on whole body locomotion are analyzed. Therefore trunk spinning and arms swinging methods are planned to improve the robot motion stability, based on compensating for the yaw moment. These two methods are further compared with each other from the viewpoint of energy consumption. The performance and the feasibility of the proposed methods are evaluated by the simulation results.
Inhibition of acinar apoptosis occurs during acute pancreatitis in the human homologue ΔF508 cystic fibrosis mouse
Authors: DiMagno Matthew J. , Lee Sae-Hong , Owyang Chung , Zhou Shi-yi
Published: June 2010

Previously, we found that the University of North Carolina cystic fibrosis (UNC-CF) mouse had more severe experimental acute pancreatitis (AP) than wild-type (WT) mice characterized by exuberant pancreatic inflammation and impaired acinar apoptosis. Because exon 10 CFTR gene mutations exhibit different phenotypes in tissues such as the mouse lung, we tested the hypothesis that ΔF508-CF mice also develop severe AP associated with an antiapoptotic acinar phenotype, which requires indirect effects of the extracellular milieu. We used cerulein hyperstimulation models of AP. More severe pancreatitis occurred in cerulein-injected ΔF508-CF vs. WT mice based on histological severity ( P < 0.01) and greater neutrophil sequestration [ P < 0.0001; confirmed by myeloperoxidase activity ( P < 0.005)]. In dispersed acini cerulein-evoked necrosis was greater in ΔF508-CF acini compared with WT ( P < 0.05) and in WT acini pretreated with CFTRinh-172 compared with vehicle ( P < 0.05). Cerulein-injected ΔF508-CF vs. WT mice had less apoptosis based on poly(ADP-ribose) polymerase (PARP) cleavage ( P < 0.005), absent DNA laddering, and reduced terminal deoxynucleotidyltransferase biotin-dUTP nick end labeling (TUNEL) staining ( P < 0.005). Unexpectedly, caspase-3 activation was greater in ΔF508-CF vs. WT acini at baseline ( P < 0.05) and during AP ( P < 0.0001). Downstream, ΔF508-CF pancreas overexpressed the X-linked inhibitor of apoptosis compared with WT ( P < 0.005). In summary, the ΔF508-CF mutation, similar to the UNC-CF “null” mutation, causes severe AP characterized by an exuberant inflammatory response and impaired acinar apoptosis. Enhanced acinar necrosis in ΔF508-CF occurs independently of extracellular milieu and correlates with loss of CFTR-Cl conductance. Although both exon 10 models of CF inhibit acinar apoptosis execution, the ΔF508-CF mouse differs by increasing apoptosis signaling. Impaired transduction of increased apoptosis signaling in ΔF508-CF acini may be biologically relevant to the pathogenesis of AP associated with CFTR mutations.
Spleen tyrosine kinase inhibition prevents tissue damage after ischemia-reperfusion
Authors: Pamuk Omer Nuri , Lapchak Peter H. , Rani Poonam , Pine Polly , Dalle Lucca Jurandir J. , Tsokos George C.
Published: June 2010

Reperfusion injury to tissue following an ischemic event occurs as a consequence of an acute inflammatory response that can cause significant morbidity and mortality. Components of both the innate (complement, immunoglobulin, monocytes, and neutrophils) and adaptive (B and T lymphocytes) immune systems have been demonstrated to mediate tissue injury. Spleen tyrosine kinase (Syk) is responsible for membrane-mediated signaling in various cell types including B lymphocytes, macrophages, and T cells. We investigated the ability of a small drug Syk inhibitor, R788, to protect mice against mesenteric ischemia-reperfusion (I/R)-induced local (intestine) and remote lung injury. Mice were fed with chow containing a Syk inhibitor for 6 days before the performance of intestinal I/R, which resulted in silencing of the expression of the active phosphorylated Syk. Syk inhibition significantly suppressed both local and remote lung injury. The beneficial effect was associated with reduced IgM and complement 3 deposition in the tissues and significant reduction of polymorphonuclear cell infiltration. Our data place Syk upstream of events leading to the binding of natural antibodies to the ischemia-conditioned tissues and urge the consideration of the use of Syk inhibitors in the prevention or improvement of tissue injury of organs exposed to ischemia or hypoperfusion.
Heat stroke: Role of the systemic inflammatory response
Authors: Leon Lisa R. , Helwig Bryan G.
Published: June 2010

Heat stroke is a life-threatening illness that is characterized clinically by central nervous system dysfunction, including delirium, seizures, or coma and severe hyperthermia. Rapid cooling and support of multi-organ function are the most effective clinical treatments, but many patients experience permanent neurological impairments or death despite these efforts. The highest incidence of heat stroke deaths occurs in very young or elderly individuals during summer heat waves, with ∼200 deaths per year in the United States. Young, fit individuals may experience exertional heat stroke while performing strenuous physical activity in temperate or hot climates. Factors that predispose to heat stroke collapse include pre-existing illness, cardiovascular disease, drug use, and poor fitness level. For decades the magnitude of the hyperthermic response in heat stroke patients was considered the primary determinant of morbidity and mortality. However, recent clinical and experimental evidence suggests a complex interplay between heat cytotoxicity, coagulation, and the systemic inflammatory response syndrome (SIRS) that ensues following damage to the gut and other organs. Cytokines are immune modulators that have been implicated as adverse mediators of the SIRS, but recent data suggest a protective role for these proteins in the resolution of inflammation. Multi-organ system failure is the ultimate cause of mortality, and recent experimental data indicate that current clinical markers of heat stroke recovery may not adequately reflect heat stroke recovery in all cases. Currently heat stroke is a more preventable than treatable condition, and novel therapeutics are required to improve patient outcome.
CYP3A4 Genetic Polymorphism Influences Repaglinide’s Pharmacokinetics
Authors: Ruzilawati A.B. , Gan S.H.
Published: June 2010

Aim: To investigate the effects of CYP3A4 and CYP2C8 enzymes on repaglinide’s pharmacokinetics in healthy Malaysian subjects. Methods: Subjects (n = 121) received oral repaglinide (4 mg). Blood samples were taken at 0, 30, 60, 120, 180 and 240 min and serum concentrations of repaglinide were determined using high-performance liquid chromatography. Subjects were also genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for CYP3A4*4, *5 and*18 and by an allele-specific multiplex PCR for CYP2C8*2, *3, *4 and *5 alleles. Results: The allele frequencies of CYP2C8*1, *2, *3, *4 and *5 were 95.04, 0.40, 0.40, 0 and 4.13%, respectively. The frequencies of the CYP3A4*1, *4, *5 and *18 alleles were 97.93, 0, 0 and 2.07%, respectively. CYP2C8 and CYP3A4 genotypes were not significantly associated with repaglinide’s blood glucose-lowering effect. However, the CYP3A4 genotype significantly influenced some of repaglinide’s pharmacokinetics, where the mean elimination rate constant was 44.0% lower (p = 0.04) and the mean half-life was 33.8% higher (p = 0.04) in subjects with the CYP3A4*1/*18 genotype as compared to those with the normal CYP3A4*1/*1 genotype. This result confirms that CYP3A4 plays a large role in metabolizing repaglinide. Conclusion: Genetic polymorphisms of CYP3A4, specifically CYP3A4*18, play a major role in contributing to the interindividual variability in repaglinide’s pharmacokinetics.
Analysis of Signal Transduction Pathways Involved in Anti-CD30 mAb-Induced Human Eosinophil Apoptosis
Authors: Matsumoto Kenji , Terakawa Maki , Fukuda Shuhei , Saito Hirohisa
Published: June 2010

Background: Activation of cell surface CD30 by immobilized anti-CD30 monoclonal antibodies (mAbs) induces extremely rapid and intense apoptosis in human eosinophils in vitro. This anti-CD30 mAb-induced eosinophil apoptosis was inhibited by the addition of inhibitors of p38 and ERK1/2 mitogen-activated protein kinases (MAPKs). However, the signal transduction pathways other than for MAPKs remain unclear. In the present study, we tried to clarify the molecules involved in the induction of apoptosis after cross-linking of CD30. Methods: Purified human eosinophils were suspended in Iscove’s minimal essential medium supplemented with 10% FCS and 1 ng/ml IL-5 and then cultured for 4 h in plates precoated with anti-CD30 mAb (clone Ber-H8) in the presence or absence of various signal transduction inhibitors. Eosinophil apoptosis was assessed using annexin V and flow cytometry. Results: The addition of inhibitors of caspase-3, caspase-8, pan-caspases, nuclear factor ĸB and protein kinase C at reasonable concentrations did not alter anti-CD30 mAb-induced eosinophil apoptosis in vitro. However, apoptosis was inhibited by phosphatidylinositol 3-kinase (PI3K) inhibitors: wortmannin at very high concentrations (>1 µM) significantly and LY294002 at a reasonable concentration partially inhibited that apoptosis. Conclusions: Anti-CD30 mAb-induced eosinophil apoptosis is likely to be mediated mainly through MAPKs and partially through PI3K, but independent of caspase activation. Downstream signaling molecules of MAPK activation in eosinophils have to be clarified in future studies.
Selective Down-Regulation of Th2 Cytokines by C-Terminal Binding Protein 2 in Human T Cells
Authors: Kitamura Fujiko , Kitamura Noriko , Mori Akio , Tatsumi Hideki , Nemoto Soichi , Miyoshi Hiroyuki , Miyatake Shoichiro , Hiroi Takachika , Kaminuma Osamu
Published: June 2010

Background: Among several C-terminal binding proteins (CtBPs), friend of GATA (FOG) has been implicated in the down-regulation of GATA-3-mediated Th2 cell differentiation. Here we investigated the role of CtBP2 in Th1 and Th2 cytokine expression in human T cells. Methods: CtBP2 was introduced into human peripheral CD4+ T cells by a lentiviral transduction system. Subsequently, the expression of Th1 and Th2 cytokine mRNA was determined by quantitative real-time RT-PCR. Results: CtBP2 significantly suppressed stimulation-induced expression of IL-4, IL-5 and IL-13 in human T cells. However, IFN-γ expression was not affected by the introduction of CtBP2. Conclusion: CtBP2 selectively down-regulates Th2 cytokines, therefore it is a potential target for the treatment of allergic diseases.
Prolonged Culture of Mast Cells with High-Glucose Medium Enhances the FcεRI-Mediated Degranulation Response and Leukotriene C4 Production
Authors: Kitahata Yuko , Nunomura Satoshi , Terui Tadashi , Ra Chisei
Published: June 2010

Background: Mast cell-released chemical mediators such as histamine, leukotriene (LT) C4 and prostaglandin (PG) D2 lead to the onset of allergic disorders. ATP provided from glycolysis is essential for histamine release and LTC4 secretion from mast cells upon FcΕRI cross-linking, indicating that glucose is a primary environmental factor for mast cell activation. In this study, we investigated whether increases in concentrations of glucose in culture media affect the activation of bone marrow-derived mouse mast cells (BMMCs) upon FcΕRI cross-linking. Methods: BMMCs were cultured in RPMI-1640 supplemented with varying concentrations (5.5, 11, 16.5, 22, 27.5 and 33 mM) of D-glucose for 3 h, or 1, 3 or 7 days. D-Mannitol was added to the medium containing 5.5 mMD-glucose for osmotic control. After culturing, these cells were sensitized with anti-TNP IgE and then stimulated with TNP-BSA. Results: We found that long-term culture (7 days) of BMMCs with 33 mMD-glucose increases the FcΕRI-dependent release of β-hexosaminidase and LTC4 without affecting surface expression levels of FcΕRI, intracellular ATP levels or calcium signaling. Biochemical analyses demonstrated that FcΕRI-dependent phosphorylation of cytosolic phospholipase A2 (cPLA2) at the Ser505 residue was significantly increased by culturing with 33 mM glucose. Conclusions: Taken together, our data suggest that glucose can augment FcΕRI-mediated mast cell activation, particularly the degranulation response and LTC4 secretion after prolonged culture of mast cells with high-glucose medium. Moreover, it is suggested that increased phosphorylation of cPLA2 at the Ser505 residue contributes to the enhancement of LTC4 secretion.
Salbutamol Modulates the Balance of Th1 and Th2 Cytokines by Mononuclear Cells from Allergic Asthmatics
Authors: Yamaguchi Takefumi , Soma Tomoyuki , Takaku Yotaro , Nakagome Kazuyuki , Hagiwara Koichi , Kanazawa Minoru , Nagata Makoto
Published: June 2010

Background: There is evidence that excessive use of inhalational β2-agonists induces the deterioration of asthma. Although the exact mechanism of this remains to be elucidated, overuse of β2-agonists may impair the Th1/Th2 balance in asthmatic airways. The aim of the present study was to evaluate whether salbutamol, a representative inhalational β2-agonist, modifies the production of Th1- and Th2-type cytokines by mononuclear cells separated from patients with asthma and healthy volunteers. Methods: Peripheral blood mononuclear cells (PBMCs) obtained from 8 healthy volunteers and 10 patients with mild persistent asthma allergic to house dust mites were treated with either salbutamol or medium alone. PBMCs were then stimulated with either medium alone, house dust mite (Dermatophagoides farina, Df) allergen or a combination of ionomycin plus phorbol 12-myristate 13-acetate ester (PMA). Concentrations of IFN-γ, IL-13, TNF-α and RANTES in the cell supernatants were measured using ELISA. Results: In PBMCs from healthy volunteers, salbutamol did not modify IFN-γ production, but increased the spontaneous production of IL-13. In contrast, salbutamol significantly inhibited the spontaneous and ionomycin- plus PMA-stimulated production of IFN-γ by PBMCs from asthmatics. Salbutamol significantly enhanced both spontaneous and Df-induced production of IL-13 by PBMCs from asthmatics. Salbutamol did not modify the production of TNF-α. Finally, salbutamol enhanced the production of RANTES induced by Df allergen in asthmatics. Conclusions: Salbutamol inhibits IFN-γ and enhances IL-13 production by PBMCs from asthmatics. These effects would promote a Th1/Th2 imbalance in the airways and may therefore contribute to the deterioration of asthma.
Changes in Airway Inflammation and Hyperresponsiveness after Inhaled Corticosteroid Cessation in Allergic Asthma
Authors: Takaku Yotaro , Nakagome Kazuyuki , Kobayashi Takehito , Yamaguchi Takefumi , Nishihara Fuyumi , Soma Tomoyuki , Hagiwara Koichi , Kanazawa Minoru , Nagata Makoto
Published: June 2010

Background: Most patients with asthma are currently controlled by pharmacotherapeutic means such as inhaled corticosteroid (ICS). However, whether ICS actually induces remission of asthma remains unknown. The present study evaluates changes in airway inflammation and hyperresponsiveness in adult patients with asthma after stopping ICS. Methods: We enrolled 11 patients with allergic asthma (7 males and 4 females; mean age, 52.3 years) who had been asymptomatic and had no exacerbation by low-dose ICS. Airway hyperresponsiveness (AHR) was assessed using methacholine challenge, and induced sputum was evaluated before and every 3 months after ICS cessation during the 1-year follow-up. Results: Among the 11 asthmatics, AHR increased in 10 (90.9%) and asthma clinically relapsed in 4 (36.4%) within 1 year of ICS cessation. AHR increased in all 7 asthmatics that were sensitized to Dermatophagoides farinae and asthma clinically relapsed in 4 (57.1%) of them. Furthermore, eosinophil numbers and IL-4 concentrations in the sputum significantly increased after ICS cessation. Conclusions: Remission with normal airway response to methacholine (no AHR) might be rare in adult patients with allergic asthma, and sensitization to house dust mites appears to play an important role in relapse. Therefore, ICS cessation should be carefully considered in patients sensitive to house dust mites. Serial determination of eosinophil counts or IL-4 concentrations in sputum might be appropriate for monitoring and preventing asthma relapse in adults.
Strain-Specific Phenotypes of Airway Inflammation and Bronchial Hyperresponsiveness Induced by Epicutaneous Allergen Sensitization in BALB/c and C57BL/6 Mice
Authors: Kodama Motohiro , Asano Koichiro , Oguma Tsuyoshi , Kagawa Shizuko , Tomomatsu Katsuyoshi , Wakaki Misa , Takihara Takahisa , Ueda Soichiro , Ohmori Nao , Ogura Hiromi , Miyata Jun , Tanaka Kyuto , Kamiishi Nobufumi , Fukunaga Koichi , Sayama Koichi , Ikeda Eiji , Miyasho Taku , Ishizaka Akitoshi
Published: June 2010

Background: Allergen sensitization through a disrupted skin barrier appears to play a prominent role in the development of atopic diseases, including allergic asthma. The role of the genetic background in immunological and physiological phenotypes induced by epicutaneous sensitization is undetermined. Methods: BALB/c and C57BL/6 mice were sensitized either epicutaneously by patch application of ovalbumin (OVA) or systemically by intraperitoneal injection of OVA with alum before exposure to aerosolized OVA. The concentrations of OVA-specific immunoglobulin in serum and cytokines in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay. The severity of airway inflammation was evaluated by cell counts in BALF, and bronchial responsiveness to methacholine was measured by the flexiVent system. Results: The production of OVA-specific IgG1 and IgE was greater in the epicutaneously sensitized BALB/c than C57BL/6 mice. In contrast, both eosinophilic airway inflammation and bronchial responsiveness to methacholine were more prominent in the C57BL/6 than in the BALB/c mice. The concentrations of interleukin-4 increased significantly in the BALF from C57BL/6 mice only. No between-strain differences were observed after intraperitoneal sensitization. Conclusions: The C57BL/6 mouse is a more appropriate model than the BALB/c mouse to study the relationship between skin barrier dysfunction and the pathogenesis of allergic asthma.
Eosinophils Are Required for the Induction of Bronchial Hyperresponsiveness in a Th Transfer Model of BALB/c Background
Authors: Ohtomo Takayuki , Kaminuma Osamu , Yamada Junji , Kitamura Noriko , Abe Akemi , Kobayashi Noriaki , Suko Matsunobu , Mori Akio
Published: June 2010

Background: Helper T (Th) cells are deeply involved in the pathophysiology of bronchial asthma, such as eosinophilic inflammation, bronchial hyperresponsiveness (BHR), airflow limitation and remodeling. It is still unclear whether Th cells contribute to BHR independently of eosinophilic inflammation. The double GATA (dblGATA) site is a high-affinity GATA-binding site in the GATA-1 promoter. dblGATA site-deficient (ΔdblGATA) mice lack eosinophils. Method: Ovalbumin (OVA)-reactive Th clones were transferred into ΔdblGATA and wild-type (WT) mice of BALB/c background. The number of eosinophils in the bronchoalveolar lavage fluid (BALF) and bronchial responsiveness to methacholine were examined after OVA challenge. Results: The number of BALF eosinophils was significantly increased in WT mice, but not detectable in ΔdblGATA mice. BHR was also induced in WT mice, but significantly attenuated in ΔdblGATA mice. Conclusion: Eosinophils are involved in T-cell-mediated BHR.
The Pathophysiological Roles of PI3Ks and Therapeutic Potential of Selective Inhibitors in Allergic Inflammation
Authors: Takeda Masahide , Ito Wataru , Tanabe Masako , Ueki Shigeharu , Kihara Junko , Kato Hikari , Tanigai Tomomi , Kayaba Hiroyuki , Sasaki Takehiko , Chihara Junichi
Published: June 2010

Phosphoinositide 3-kinases (PI3Ks) are known to be involved in a variety of cellular responses such as cell survival, proliferation, differentiation and cell migration. Recently, PI3Ks have been associated with the pathogenesis of asthma because various immune cells regulate allergic responses. Among the three classes of PI3Ks, the roles of PI3Kγ and PI3Kδ in allergic responses have attracted particular attention. In a previous report, allergic airway hyperresponsiveness (AHR), inflammation and airway remodeling in an ovalbumin-induced asthma model were decreased in PI3Kγ-deficient mice compared with wild-type mice. In addition, AHR and inflammation were attenuated by administration of a selective PI3Kδ inhibitor in a murine model of asthma. These results indicate that PI3Kγ and PI3Kδ may be new therapeutic targets for asthma. However, PI3Kγ and PI3Kδ may differ in terms of the mechanism of regulation. In this review, we focus on the roles of PI3Kγ and PI3Kδ in the pathogenesis of asthma and discuss the mechanistic differences between PI3Kγ and PI3Kδ.
FIP1L1/PDGFRα-Associated Systemic Mastocytosis
Authors: Yamada Yoshiyuki , Cancelas Jose A.
Published: June 2010

Since the identification of the FIP1L1/PDGFRA fusion gene as a pathogenic cause of the hypereosinophilic syndrome (HES), the importance of the molecular classification of HES leading to the diagnosis of chronic eosinophilic leukemia (CEL) has been recognized. As a result, a new category, ‘myeloid and lymphoid neoplasm with eosinophilia and abnormalities in PDGFRA, PDGFRB or FGFR1’, has recently been added to the new WHO criteria for myeloid neoplasms. FIP1L1/PDGFRα-positive disorders are characterized by clonal hypereosinophilia, multiple organ dysfunctions due to eosinophil infiltration, systemic mastocytosis (SM) and a dramatic response to treatment with imatinib mesylate. A murine HES/CEL model by the introduction of FIP1L1/PDGFRα and IL-5 overexpression also shows SM, representing patients with FIP1L1/PDGFRα-positive HES/CEL/SM. The murine model and the in vitro development system of FIP1L1/PDGFRα-positive mast cells revealed the interaction between FIP1L1/PDGFRα, IL-5 and stem cell factor in the development of HES/CEL/SM. Current findings of FIP1L1/PDGFRα-positive HES/CEL are reviewed focusing on aberrant mast cell development leading to SM.
Effects of Silibinin, Inhibitor of CYP3A4 and P-Glycoprotein in vitro, on the Pharmacokinetics of Paclitaxel after Oral and Intravenous Administration in Rats
Authors: Lee Chong-Ki , Choi Jun-Shik
Published: June 2010

Silibinin, a flavonoid, is an inhibitor of P-glycoprotein (P-gp)-mediated efflux transporters, and its oxidative metabolism is catalyzed by CYP3A4. The purpose of this study was to investigate the effect of oral silibinin on the bioavailability and pharmacokinetics of orally and intravenously administered paclitaxel in rats. The pharmacokinetic parameters of paclitaxel were determined in rats after oral (40 mg/kg) or intravenous (4 mg/kg) administration in the presence and absence of silibinin (0.5, 2.5 or 10 mg/kg). The effect of silibinin on the P-gp as well as CYP3A4 activity was also evaluated. Silibinin inhibited CYP3A4 enzyme activity with an IC50 of 1.8 µmol/l. In addition, silibinin significantly inhibited P-gp activity. Compared to the control group, silibinin significantly (p < 0.05 by 2.5 mg/kg, p < 0.01 by 10 mg/kg) increased the area under the plasma concentration-time curve (65.8–101.7% higher) of oral paclitaxel. Silibinin also significantly increased (p < 0.05 by 2.5 mg/kg, 31.0% higher; p < 0.01 by 10 mg/kg, 52.9% higher) the peak plasma concentration of paclitaxel. Consequently, the absolute bioavailability of paclitaxel was increased by silibinin compared to that in the control group, and the relative bioavailability of oral paclitaxel was increased 1.15- to 2.02-fold. The intravenous pharmacokinetics of paclitaxel were not affected by the concurrent use of silibinin in contrast to the oral administration of paclitaxel. Accordingly, the enhanced oral bioavailability in the presence of silibinin could mainly be due to the increased intestinal absorption of paclitaxel via P-gp inhibition.
Insect-Foraging in Captive Owl Monkeys (Aotus nancymaae)
Authors: Wolovich Christy K. , Rivera Jeanette , Evans Sian
Published: June 2010

Whereas the diets of diurnal primate species vary greatly, almost all nocturnal primate species consume insects. Insect-foraging has been described in nocturnal prosimians but has not been investigated in owl monkeys (Aotus spp.). We studied 35 captive owl monkeys (Aotus nancymaae) in order to describe their foraging behavior and to determine if there were any age or sex differences in their ability to capture insect prey. Because owl monkeys cooperate in parental care and in food-sharing, we expected social interactions involving insect prey. We found that owl monkeys most often snatched flying insects from the air and immobilized crawling insects against a substrate using their hands. Immatures and adult female owl monkeys attempted to capture prey significantly more often than did adult males; however, there was no difference in the proportion of attempts that resulted in capture. Social interactions involving prey appeared similar to those with provisioned food, but possessors of prey resisted begging attempts more so than did possessors of other food. Owl monkeys attempted to capture prey often (mean = 9.5 ± 5.8 attempts/h), and we speculate that the protein and lipid content of captured prey is important for meeting the metabolic demands for growth and reproduction.
X-Linked Ichthyosis along with Recessive Dystrophic Epidermolysis Bullosa in the Same Patient
Authors: Hernández-Martín A. , Cuadrado-Corrales N. , Ciria-Abad S. , Arias-Palomo D. , Mascaró-Galy J.M. , Escámez M.J. , García M. , Del Río M. , Torrelo A. , González-Sarmiento R.
Published: June 2010

X-linked ichthyosis (XLI) is a relatively common keratinization disorder which is caused, in the vast majority of cases, by a total deletion of the sulfatase steroid (STS) gene. Dystrophic epidermolysis bullosa (DEB) is a scarring form of epidermolysis bullosa of either autosomal recessive or dominant inheritance secondary to collagen VII gene mutations. We report the first case of a patient with both XLI and DEB in whom a partial deletion of the STS gene and a recessive point mutation in COL7A1 were demonstrated.
Non-Platinum-Based First-Line Followed by Platinum-Based Second-Line Chemotherapy or the Reverse Sequence in Patients with Advanced Non-Small Cell Lung Cancer: A Retrospective Analysis by the Lung Cancer Group of the Hellenic Oncology Research Group
Authors: Agelaki Sofia , Hatzidaki Dora , Kotsakis Athanasios , Papakotoulas Pavlos , Polyzos Aris , Ziras Nikolaos , Gioulbasanis Ioannis , Karampeazis Athanasios , Agelidou Athina , Tsiafaki Xanthi , Chandrinos Vassilis , Lerikou Maria , Georgoulias Vassilis
Published: June 2010

Background: Non-platinum-containing regimens have been proposed as alternatives to platinum-based doublets in the first-line treatment of patients with non-small cell lung cancer (NSCLC). However, conflicting results about their equivalence have been reported. Methods: We reviewed the records of patients enrolled in randomized controlled first-line trials conducted by the Hellenic Oncology Research Group from February 1997 to September 2006. The outcome of patients treated with first-line non-platinum-based chemotherapy who received platinum-based chemotherapy upon progression (cohort A) or platinum-based first-line chemotherapy followed by non-platinum-containing second-line chemotherapy (cohort B) was retrospectively analyzed. Results: Two-hundred and sixty-seven patients were identified in cohort A, and 123 in cohort B. Median follow-up time was 12.5 and 15.7 months for cohorts A and B. A significantly higher response rate and time to tumor progression (TTP) was recorded for patients treated with platinum-based compared to those receiving non-platinum-based first-line chemotherapy (45.5 vs. 21.3%, p < 0.0001 and 5.8 vs. 3.1 months, p= 0.002, respectively). Platinum-based regimens administered as second-line treatment resulted in a 13.1% response rate. TTP for second-line chemotherapy did not differ significantly between the two cohorts. Median overall survival was 13.3 and 15.7 months for cohorts A and B (p = 0.538). Conclusion: Both sequences resulted in similar efficacy in terms of overall survival. Encouraging median survival was achieved for selected patients with NSCLC who received both first- and second-line chemotherapy.