bluuebunny/crossref_metadata_2025 huggingface dataset:
Automated Long-Term Monitoring of Parallel Microfluidic Operations Applying a Machine Vision-Assisted Positioning Method
Authors: Yip Hon Ming , Li John C. S. , Xie Kai , Cui Xin , Prasad Agrim , Gao Qiannan , Leung Chi Chiu , Lam Raymond H. W.
Published: July 2014

As microfluidics has been applied extensively in many cell and biochemical applications, monitoring the related processes is an important requirement. In this work, we design and fabricate a high-throughput microfluidic device which contains 32 microchambers to perform automated parallel microfluidic operations and monitoring on an automated stage of a microscope. Images are captured at multiple spots on the device during the operations for monitoring samples in microchambers in parallel; yet the device positions may vary at different time points throughout operations as the device moves back and forth on a motorized microscopic stage. Here, we report an image-based positioning strategy to realign the chamber position before every recording of microscopic image. We fabricate alignment marks at defined locations next to the chambers in the microfluidic device as reference positions. We also develop image processing algorithms to recognize the chamber positions in real-time, followed by realigning the chambers to their preset positions in the captured images. We perform experiments to validate and characterize the device functionality and the automated realignment operation. Together, this microfluidic realignment strategy can be a platform technology to achieve precise positioning of multiple chambers for general microfluidic applications requiring long-term parallel monitoring of cell and biochemical activities.
Wide Distribution of Virulence Genes amongEnterococcus faeciumandEnterococcus faecalisClinical Isolates
Authors: Soheili Sara , Ghafourian Sobhan , Sekawi Zamberi , Neela Vasanthakumari , Sadeghifard Nourkhoda , Ramli Ramliza , Hamat Rukman Awang
Published: July 2014

Enterococcus, a Gram-positive facultative anaerobic cocci belonging to the lactic acid bacteria of the phylum Firmicutes, is known to be able to resist a wide range of hostile conditions such as different pH levels, high concentration of NaCl (6.5%), and the extended temperatures between 5°C and 65°C. Despite being the third most common nosocomial pathogen, our understanding on its virulence factors is still poorly understood. The current study was aimed to determine the prevalence of different virulence genes inEnterococcus faecalisandEnterococcus faecium. For this purpose, 79 clinical isolates of Malaysian enterococci were evaluated for the presence of virulence genes.pilB, fms8, efaAfm, andsgrAgenes are prevalent in all clinical isolates. In conclusion, the pathogenicity ofE. faecalisandE. faeciumcould be associated with different virulence factors and these genes are widely distributed among the enterococcal species.
Dissipativity Analysis of Descriptor Systems Using Image Space Characterization
Authors: Qiao Liang , Zhang Qingling , Liu Wanquan
Published: July 2014

In this paper, we analyze the dissipativity for descriptor systems with impulsive behavior based on image space analysis. First, a new image space is used to characterize state responses for descriptor systems. Based on such characterization and an integral property of delta function, a new necessary and sufficient condition for the dissipativity of descriptor systems is derived using the linear matrix inequality (LMI) approach. Also, some of the earlier related results on dissipativity for linear systems are investigated in the framework proposed in this paper. Finally, two examples are given to show the validity of the derived results.
A Multiband Printed Log-Periodic Dipole Array for Wireless Communications
Authors: Casula Giovanni Andrea , Maxia Paolo
Published: July 2014

A multiband printed Log-periodic dipole array (LPDA) antenna for wireless communications is presented. The antenna has been designed starting from Carrel’s theory, optimized using CST Microwave Studio 2012, and then realized. The comparison between simulated and measured results shows that the proposed antenna can be used for wireless communications both in the S (2.4–3 GHz) and in the C (5.2–5.8 GHz) frequency bands, with very good input matching and a satisfactory end-fire radiation pattern. Moreover, it has a compact size, is very easy to realize, and presents an excellent out-of-band rejection, without the use of stop-band filters, thus avoiding interference out of its operating frequency band.
Iterative Mixture Component Pruning Algorithm for Gaussian Mixture PHD Filter
Authors: Yan Xiaoxi
Published: July 2014

As far as the increasing number of mixture components in the Gaussian mixture PHD filter is concerned, an iterative mixture component pruning algorithm is proposed. The pruning algorithm is based on maximizing the posterior probability density of the mixture weights. The entropy distribution of the mixture weights is adopted as the prior distribution of mixture component parameters. The iterative update formulations of the mixture weights are derived by Lagrange multiplier and Lambert W function. Mixture components, whose weights become negative during iterative procedure, are pruned by setting corresponding mixture weights to zeros. In addition, multiple mixture components with similar parameters describing the same PHD peak can be merged into one mixture component in the algorithm. Simulation results show that the proposed iterative mixture component pruning algorithm is superior to the typical pruning algorithm based on thresholds.
Histogram Estimation for Optimal Filter Skyline Query Processing in Wireless Sensor Networks
Authors: Wang Haixiang , Zheng Jiping , Song Baoli , Wang Yongge
Published: July 2014

The skyline query processing technique plays an increasingly important role for multicriteria decision making applications in wireless sensor networks. The technique of saving energy to prolong the lifetime of sensor nodes is one of the dominating challenges to resource-constrained wireless sensor networks. In this paper, we propose an energy-efficient skyline query processing algorithm, called the histogram filter based algorithm (HFA), to efficiently retrieve skyline results from a sensor network. First, we use historical data at the base station to construct histograms for further estimating the probability density distributions of the sensor data. Second, the dominance probability of each tuple is computed based on the histograms, and the optimal tuple which has the largest possibility of dominance/filtering capability is obtained using in-network aggregation approach. After that, the base station broadcasts the optimized tuple as the global filter to each sensor node. Then, the tuples which do not satisfy the skyline query semantics are discarded to avoid unnecessary data transmissions. An extensive experimental study demonstrates that the proposed HFA algorithm performs more efficiently than existing algorithms on reducing data transmissions during skyline query processing, which saves the energy and prolongs the lifetime of wireless sensor networks.
Updating Finite Element Model of a Wind Turbine Blade Section Using Experimental Modal Analysis Results
Authors: Luczak Marcin , Manzato Simone , Peeters Bart , Branner Kim , Berring Peter , Kahsin Maciej
Published: July 2014

This paper presents selected results and aspects of the multidisciplinary and interdisciplinary research oriented for the experimental and numerical study of the structural dynamics of a bend-twist coupled full scale section of a wind turbine blade structure. The main goal of the conducted research is to validate finite element model of the modified wind turbine blade section mounted in the flexible support structure accordingly to the experimental results. Bend-twist coupling was implemented by adding angled unidirectional layers on the suction and pressure side of the blade. Dynamic test and simulations were performed on a section of a full scale wind turbine blade provided by Vestas Wind Systems A/S. The numerical results are compared to the experimental measurements and the discrepancies are assessed by natural frequency difference and modal assurance criterion. Based on sensitivity analysis, set of model parameters was selected for the model updating process. Design of experiment and response surface method was implemented to find values of model parameters yielding results closest to the experimental. The updated finite element model is producing results more consistent with the measurement outcomes.
Diverse Functions of Secretory Phospholipases A2
Authors: Shridas Preetha , Webb Nancy R.
Published: July 2014

Phospholipase A2enzymes (PLA2s) catalyze the hydrolysis of glycerophospholipids at their sn-2 position releasing free fatty acids and lysophospholipids. Mammalian PLA2s are classified into several categories of which important groups include secreted PLA2s (sPLA2s) and cytosolic PLA2s (cPLA2s) that are calcium-dependent for their catalytic activity and calcium-independent cytosolic PLA2s (iPLA2s). Platelet-activating factor acetylhydrolases (PAF-AHs), lysosomal PLA2s, and adipose-specific PLA2also belong to the class of PLA2s. Generally, cPLA2enzymes are believed to play a major role in the metabolism of arachidonic acid, the iPLA2family to membrane homeostasis and energy metabolism, and the sPLA2family to various biological processes. The focus of this review is on recent research developments in the sPLA2field. sPLA2s are secreted enzymes with low molecular weight (with the exception of GIII sPLA2), Ca2+-requiring enzymes with a His-Asp catalytic dyad. Ten enzymatically active sPLA2s and one devoid of enzymatic activity have been identified in mammals. Some of these sPLA2s are potent in arachidonic acid release from cellular phospholipids for the biosynthesis of eicosanoids, especially during inflammation. Individual sPLA2enzymes exhibit unique tissue and cellular localizations and specific enzymatic properties, suggesting their distinct biological roles. Recent studies indicate that sPLA2s are involved in diverse pathophysiological functions and for most part act nonredundantly.
Comparison of the Effects of Low Volume Prilocaine and Alkalinized Prilocaine for the Regional Intravenous Anesthesia Technique in Hand and Wrist Surgery
Authors: Kapusuz Ozlem , Argun Guldeniz , Arikan Murat , Toğral Guray , Basarir Aysun , Kadiogullari Nihal
Published: July 2014

Aim. Comparing the effectivity of prilocaine and prilocaine alkalinized with 8.4% NaHCO3in terms of sensory and motor block onset and termination durations in RIVA technique considering patients’ satisfaction and tolerance with application of tourniquet undergoing hand-wrist surgery.Materials and Methods. 64 patients were randomised into two groups. First group (Group P) was administered prilocaine and second group (Group PN) was administered prilocaine + %8.4 NaHCO3. Sensory and motor block onset and termination times and onset of tourniquet pain were recorded.Results. No significant difference was found between the two groups in terms of onset and termination of sensory block and the onset of motor block. The duration of the motor block was longer in Group PN than in Group P(P<0.05). Tourniquet pain was more intense in Group P(P=0.036). In Group PN, the use of additional drugs was recorded at a lower rate and patients’ satisfaction was higher than Group P.Conclusion. In the present study, it was established that alkalinization of prilocaine had no effect on the duration of sensory block and it prolonged the duration of motor block, increased patients’ satisfaction, and decreased tourniquet pain. It is our suggestion that future studies should be carried out on the issue by using different volumes.
Analysis of EEG Signals Related to Artists and Nonartists during Visual Perception, Mental Imagery, and Rest Using Approximate Entropy
Authors: Shourie Nasrin , Firoozabadi Mohammad , Badie Kambiz
Published: July 2014

In this paper, differences between multichannel EEG signals of artists and nonartists were analyzed during visual perception and mental imagery of some paintings and at resting condition using approximate entropy (ApEn). It was found that ApEn is significantly higher for artists during the visual perception and the mental imagery in the frontal lobe, suggesting that artists process more information during these conditions. It was also observed that ApEn decreases for the two groups during the visual perception due to increasing mental load; however, their variation patterns are different. This difference may be used for measuring progress in novice artists. In addition, it was found that ApEn is significantly lower during the visual perception than the mental imagery in some of the channels, suggesting that visual perception task requires more cerebral efforts.
Effects of Inorganic Fillers on the Thermal and Mechanical Properties of Poly(lactic acid)
Authors: Liu Xingxun , Wang Tongxin , Chow Laurence C. , Yang Mingshu , Mitchell James W.
Published: July 2014

Addition of filler to polylactic acid (PLA) may affect its crystallization behavior and mechanical properties. The effects of talc and hydroxyapatite (HA) on the thermal and mechanical properties of two types of PLA (one amorphous and one semicrystalline) have been investigated. The composites were prepared by melt blending followed by injection molding. The molecular weight, morphology, mechanical properties, and thermal properties have been characterized by gel permeation chromatography (GPC), scanning electron microscope (SEM), instron tensile tester, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and dynamic mechanical analysis (DMA). It was found that the melting blending led to homogeneous distribution of the inorganic filler within the PLA matrix but decreased the molecular weight of PLA. Regarding the filler, addition of talc increased the crystallinity of PLA, but HA decreased the crystallinity of PLA. The tensile strength of the composites depended on the crystallinity of PLA and the interfacial properties between PLA and the filler, but both talc and HA filler increased the toughness of PLA.
Light-Output Enhancement of GaN-Based Light-Emitting Diodes with Three-Dimensional Backside Reflectors Patterned by Microscale Cone Array
Authors: Huang Huamao , Hu Jinyong , Wang Hong
Published: July 2014

Three-dimensional (3D) backside reflector, compared with flat reflectors, can improve the probability of finding the escape cone for reflecting lights and thus enhance the light-extraction efficiency (LEE) for GaN-based light-emitting diode (LED) chips. A triangle-lattice of microscale SiO2cone array followed by a 16-pair Ti3O5/SiO2distributed Bragg reflector (16-DBR) was proposed to be attached on the backside of sapphire substrate, and the light-output enhancement was demonstrated by numerical simulation and experiments. The LED chips with flat reflectors or 3D reflectors were simulated using Monte Carlo ray tracing method. It is shown that the LEE increases as the reflectivity of backside reflector increases, and the light-output can be significantly improved by 3D reflectors compared to flat counterparts. It can also be observed that the LEE decreases as the refractive index of the cone material increases. The 3D 16-DBR patterned by microscale SiO2cone array benefits large enhancement of LEE. This microscale pattern was prepared by standard photolithography and wet-etching technique. Measurement results show that the 3D 16-DBR can provide 12.1% enhancement of wall-plug efficiency, which is consistent with the simulated value of 11.73% for the enhancement of LEE.
Viscosity Approximation Methods with Errors and Strong Convergence Theorems for a Common Point of Pseudocontractive and Monotone Mappings: Solutions of Variational Inequality Problems
Authors: Tang Yan
Published: July 2014

We introduce two proximal iterative algorithms with errors which converge strongly to the common solution of certain variational inequality problems for a finite family of pseudocontractive mappings and a finite family of monotone mappings. The strong convergence theorems are obtained under some mild conditions. Our theorems extend and unify some of the results that have been proposed for this class of nonlinear mappings.
Current and Future Intraoperative Imaging Strategies to Increase Radical Resection Rates in Pancreatic Cancer Surgery
Authors: Handgraaf Henricus J. M. , Boonstra Martin C. , Van Erkel Arian R. , Bonsing Bert A. , Putter Hein , Van De Velde Cornelis J. H. , Vahrmeijer Alexander L. , Mieog J. Sven D.
Published: July 2014

Prognosis of patients with pancreatic cancer is poor. Even the small minority that undergoes resection with curative intent has low 5-year survival rates. This may partly be explained by the high number of irradical resections, which results in local recurrence and impaired overall survival. Currently, ultrasonography is used during surgery for resectability assessment and frozen-section analysis is used for assessment of resection margins in order to decrease the number of irradical resections. The introduction of minimal invasive techniques in pancreatic surgery has deprived surgeons from direct tactile information. To improve intraoperative assessment of pancreatic tumor extension, enhanced or novel intraoperative imaging technologies accurately visualizing and delineating cancer cells are necessary. Emerging modalities are intraoperative near-infrared fluorescence imaging and freehand nuclear imaging using tumor-specific targeted contrast agents. In this review, we performed a meta-analysis of the literature on laparoscopic ultrasonography and we summarized and discussed current and future intraoperative imaging modalities and their potential for improved tumor demarcation during pancreatic surgery.
REALFLOW: Reliable Real-Time Flooding-Based Routing Protocol for Industrial Wireless Sensor Networks
Authors: Yu Kan , Pang Zhibo , Gidlund Mikael , Åkerberg Johan , Björkman Mats
Published: July 2014

Wireless technologies have been increasingly applied in industrial automation systems due to flexible installation, mobility, and cost reduction. Unlike traditional wireless sensor networks (WSNs), industrial wireless sensor networks (IWSNs), when expanding from wireless monitoring to wireless control, have more stringent requirements on reliability, real-time performance, and robustness in a number of industrial applications. Successive transmission failures or deadline misses in these applications may severely degrade the control quality and result in serious economic losses and safety problems. Therefore, when deploying IWSNs in harsh industrial environments, to achieve reliable and deterministic end-to-end transmissions is critically important. In this paper, we explain the primary challenges of designing appropriate routing protocols and present a reliable real-time flooding-based routing protocol for IWSNs (REALFLOW). Instead of traditional routing tables, related node lists are generated in a simple distributed manner, serving for packet forwarding. A controlled flooding mechanism is applied to improve both reliability and real-time performance. A seamless transition in the event of topology change can be achieved by REALFLOW. Performance evaluations via simulations verify that significant improvements of reliability, real-time performance, and network recovery time can be achieved by REALFLOW, compared with traditional routing protocols.
Developing Dynamic Digital Image Correlation Technique to Monitor Structural Damage of Old Buildings under External Excitation
Authors: Shih Ming-Hsiang , Sung Wen-Pei
Published: July 2014

The capacity of buildings to resist external excitation is an important factor to consider for the structural design of buildings. When subject to external excitation, a building may suffer a certain degree of damages, and its residual capacity to resist external excitation cannot be evaluated. In this research, dynamic digital image correlation method combined with parameter evaluation available in system identification is used to evaluate the structural capacity to resist external excitation. The results reveal possible building latent safety problems so that timely structural reinforcement or dismantling of the building can be initiated to alleviate further damages. The results of experiments using the proposed method conform to the results obtained using the conventional method, but this method is more convenient and rapid than the latter in the subsequent procedure of data processing. If only the frequency change is used, the damages suffered by the building can be detected, but the damage location is not revealed. The interstory drift mode shape (IDMS) based on the characteristic of story drift has higher sensitivity than the approximate story damage index (ADSI) method based on modal frequency and vibration type; however, both indices can be used to determine the degree and location of building damages.
Similarity of Fibroglandular Breast Tissue Content Measured from Magnetic Resonance and Mammographic Images and by a Mathematical Algorithm
Authors: Nayeem Fatima , Ju Hyunsu , Brunder Donald G. , Nagamani Manubai , Anderson Karl E. , Khamapirad Tuenchit , Lu Lee-Jane W.
Published: July 2014

Women with high breast density (BD) have a 4- to 6-fold greater risk for breast cancer than women with low BD. We found that BD can be easily computed from a mathematical algorithm using routine mammographic imaging data or by a curve-fitting algorithm using fat and nonfat suppression magnetic resonance imaging (MRI) data. These BD measures in a strictly defined group of premenopausal women providing both mammographic and breast MRI images were predicted as well by the same set of strong predictor variables as were measures from a published laborious histogram segmentation method and a full field digital mammographic unit in multivariate regression models. We also found that the number of completed pregnancies, C-reactive protein, aspartate aminotransferase, and progesterone were more strongly associated with amounts of glandular tissue than adipose tissue, while fat body mass, alanine aminotransferase, and insulin like growth factor-II appear to be more associated with the amount of breast adipose tissue. Our results show that methods of breast imaging and modalities for estimating the amount of glandular tissue have no effects on the strength of these predictors of BD. Thus, the more convenient mathematical algorithm and the safer MRI protocols may facilitate prospective measurements of BD.
Improvement of Ocean State Estimation by Assimilating Mapped Argo Drift Data
Authors: Masuda Shuhei , Sugiura Nozomi , Osafune Satoshi , Doi Toshimasa
Published: July 2014

We investigated the impact of assimilating a mapped dataset of subsurface ocean currents into an ocean state estimation. We carried out two global ocean state estimations from 2000 to 2007 using the K7 four-dimensional variational data synthesis system, one of which included an additional map of climatological geostrophic currents estimated from the global set of Argo floats. We assessed the representativeness of the volume transport in the two exercises. The assimilation of Argo ocean current data at only one level, 1000 dbar depth, had subtle impacts on the estimated volume transports, which were strongest in the subtropical North Pacific. The corrections at 10°N, where the impact was most notable, arose through the nearly complete offset of wind stress curl by the data synthesis system in conjunction with the first mode baroclinic Rossby wave adjustment. Our results imply that subsurface current data can be effective for improving the estimation of global oceanic circulation by a data synthesis.
Load Balanced Routing for Lifetime Maximization in Mobile Wireless Sensor Networks
Authors: Khalid Saifullah , Masood Ashraf , Hussain Faisal Bashir , Abbas Haider , Ghafoor Abdul
Published: July 2014

Challenge of efficient protocol design for energy constrained wireless sensor networks is addressed through application specific cross-layer designs. This design approach along with strong design assumptions limits application of protocols in universal scenarios and affects their practicality. With proliferation of embedded mobile sensors in consumer devices, a changed application paradigm requires generic protocols capable of managing greater device heterogeneousness and mobility. In this paper, we propose a novel lifetime maximization protocol for mobile sensor networks with uncontrolled mobility considering residual energy, traffic load, and mobility of a node. The protocol being generic is equally applicable to heterogeneous, homogenous, static, and mobile sensor networks. It can handle event driven as well as continuous traffic flow applications. Simulation results show that proposed scheme outperforms minimum hop routing and greedy forwarding in terms of network lifetime, data packet latency, and load balance while maintaining comparable throughput.
Onk-Gamma andk-Beta Distributions and Moment Generating Functions
Authors: Rahman Gauhar , Mubeen Shahid , Rehman Abdur , Naz Mammona
Published: July 2014

The main objective of the present paper is to definek-gamma andk-beta distributions and moments generating function for the said distributions in terms of a new parameterk>0. Also, the authors prove some properties of these newly defined distributions.
Combined SFK/mTOR Inhibition Prevents Rapamycin-Induced Feedback Activation of AKT and Elicits Efficient Tumor Regression
Authors: Yori Jennifer L. , Lozada Kristen L. , Seachrist Darcie D. , Mosley Jonathan D. , Abdul-Karim Fadi W. , Booth Christine N. , Flask Chris A. , Keri Ruth A.
Published: July 2014

Resistance to receptor tyrosine kinase (RTK) blockade in breast cancer is often mediated by activation of bypass pathways that sustain growth. Src and mammalian target of rapamycin (mTOR) are two intrinsic targets that are downstream of most RTKs. To date, limited clinical efficacy has been observed with either Src or mTOR inhibitors when used as single agents. Resistance to mTOR inhibitors is associated with loss of negative feedback regulation, resulting in phosphorylation and activation of AKT. Herein, we describe a novel role for Src in contributing to rapalog-induced AKT activation. We found that dual activation of Src and the mTOR pathway occurs in nearly half of all breast cancers, suggesting potential cross-talk. As expected, rapamycin inhibition of mTOR results in feedback activation of AKT in breast cancer cell lines. Addition of the Src/c-Abl inhibitor, dasatinib, completely blocks this feedback activation, confirming convergence between Src and the mTOR pathway. Analysis in vivo revealed that dual Src and mTOR inhibition is highly effective in two mouse models of breast cancer. In a luminal disease model, combined dasatinib and rapamycin is more effective at inducing regression than either single agent. Furthermore, the combination of dasatinib and rapamycin delays tumor recurrence following the cessation of treatment. In a model of human EGFR-2–positive (HER2+) disease, dasatinib alone is ineffective, but potentiates the efficacy of rapamycin. These data suggest that combining mTOR and Src inhibitors may provide a new approach for treating multiple breast cancer subtypes that may circumvent resistance to targeted RTK therapies. Cancer Res; 74(17); 4762–71. ©2014 AACR.
A Randomized Phase II Presurgical Trial of Transdermal 4-Hydroxytamoxifen Gel versus Oral Tamoxifen in Women with Ductal Carcinoma In Situ of the Breast
Authors: Lee Oukseub , Page Katherine , Ivancic David , Helenowski Irene , Parini Vamsi , Sullivan Megan E. , Margenthaler Julie A. , Chatterton Robert T. , Jovanovic Borko , Dunn Barbara K. , Heckman-Stoddard Brandy M. , Foster Kathleen , Muzzio Miguel , Shklovskaya Julia , Skripkauskas Silvia , Kulesza Piotr , Green David , Hansen Nora M. , Bethke Kevin P. , Jeruss Jacqueline S. , Bergan Raymond , Khan Seema A.
Published: July 2014

Purpose: Local transdermal therapy to the breast may achieve effective target-organ drug delivery, while diminishing systemic effects. We conducted a randomized, double-blind, placebo-controlled phase II trial comparing transdermal 4-hydroxytamoxifen gel (4-OHT) to oral tamoxifen (oral-T) in women with ductal carcinoma in situ (DCIS).

Methods: Twenty-seven pre- and postmenopausal women were randomized to 4-OHT (4 mg/day) or oral-T (20 mg/day) for 6 to 10 weeks before surgery. Plasma, nipple aspirate fluid, and breast adipose tissue concentrations of tamoxifen and its major metabolites were determined by liquid chromatography/tandem mass spectrometry. The primary endpoint was Ki67 labeling in DCIS lesions, measured by immunohistochemistry. In plasma, insulin-like growth factor-1 (IGFI), sex hormone–binding globulin (SHBG), and coagulation protein concentrations were determined.

Results: Posttherapy Ki67 decreased by 3.4% in the 4-OHT and 5.1% in the oral-T group (P ≤ 0.03 in both, between-group P = 0. 99). Mean plasma 4-OHT was 0.2 and 1.1 ng/mL in 4-OHT and oral groups, respectively (P = 0.0003), whereas mean breast adipose tissue concentrations of 4-OHT were 5.8 ng/g in the 4-OHT group and 5.4 ng/g in the oral group (P = 0.88). There were significant increases in plasma SHBG, factor VIII, and von Willebrand factor and a significant decrease in plasma IGFI with oral-T, but not with 4-OHT. The incidence of hot flashes was similar in both groups.

Conclusions: The antiproliferative effect of 4-OHT gel applied to breast skin was similar to that of oral-T, but effects on endocrine and coagulation parameters were reduced. These findings support the further evaluation of local transdermal therapy for DCIS and breast cancer prevention. Clin Cancer Res; 20(14); 3672–82. ©2014 AACR.
Phenotypic and Functional Activation of Hyporesponsive KIRnegNKG2Aneg Human NK-Cell Precursors Requires IL12p70 Provided by Poly(I:C)-Matured Monocyte-Derived Dendritic Cells
Authors: Curran Shane A. , Romano Emanuela , Kennedy Michael G. , Hsu Katharine C. , Young James W.
Published: July 2014

A functionally responsive natural killer (NK)–cell repertoire requires the acquisition of inhibitory NKG2A and killer immunoglobulin-like receptors (KIR) through pathways that remain undefined. Functional donor NK cells expressing KIRs for non-self class I MHC ligands contribute to a positive outcome after allogeneic hematopoietic stem cell transplantation (alloHSCT) by targeting HLA-matched recipient leukemic cells. Insofar as circulating donor conventional dendritic cells (DC) reconstitute with comparable kinetics with donor NK cells after alloHSCT, we used hyporesponsive KIRnegNKG2Aneg precursor cells to evaluate how specific DC subtypes generate a functionally active NK-cell repertoire. Both monocyte-derived DCs (moDC) and Langerhans-type DCs (LC) induce KIRnegNKG2Aneg precursor cells to express the inhibitory receptors NKG2A and KIR, without requiring cell proliferation. Poly(I:C)-matured moDCs significantly augmented the expression of NKG2A, but not KIR, in an IL12p70-dependent manner. Although all DC-stimulated KIRnegNKG2Aneg cells were able to acquire cytolytic activity against class I MHC-negative targets, the ability to secrete IFNγ was restricted to cells that were stimulated by IL12p70-producing, poly(I:C)-matured moDCs. This critical ability of poly(I:C)-matured moDCs to provide IL12p70 to developing KIRnegNKG2Aneg precursors results in a dominant, multifunctional, NKG2Apos NK-cell population that is capable of both cytolysis and IFNγ production. Poly(I:C)-matured moDCs are, therefore, the most effective conventional DC subtype for generating a functionally competent NK-cell repertoire by an IL12p70-dependent mechanism. Cancer Immunol Res; 2(10); 1000–10. ©2014 AACR.
Accelerated Reepithelialization by Triterpenes: Proof of Concept in the Healing of Surgical Skin Lesions
Authors: Metelmann Hans-Robert , Brandner Johanna M. , Schumann Hauke , Bross Felix , Fimmers Rolf , BFttger Kerstin , Scheffler Armin , Podmelle Fred
Published: July 2014

The acceleration of wound healing is a major surgical concern. A triterpene extract from birch bark (Betulae cortex) experimentally enhances keratinocyte differentiation in vitro and accelerates wound healing ex vivo. We conducted an open, blind-evaluated, controlled, prospective, randomized (1:1) phase II clinical trial in patients requiring split-thickness skin graft transplantation at two university hospitals in Germany. Donor sites on the upper legs were covered with a moist silicone-coated dressing. Oleogel-S10 ointment containing 10% birch bark extract was randomly applied to the distal or proximal half of the wound, with the other half serving as an intraindividual control, for 14 days after the skin graft surgery. The primary efficacy variable was faster reepithelialization as determined from macrophotographs by independent, blinded experts. Twenty-four patients were randomized and completed the trial. After the 14-day test period, the planned interim analysis revealed a highly significant (p < 0.0001) superiority of Oleogel-S10 in the primary efficacy variable and the trial was terminated early due to ethical concerns. The treatment side was also better reepithelialized and more similar to normal skin after 3 months. In conclusion, Oleogel-S10 significantly accelerated reepithelialization at split-thickness skin graft donor sites. Treatment with Oleogel-S10 was safe and well tolerated. i 2014 S. Karger AG, Basel
Future Perspective: Immunomodulatory Therapy for Autoimmune Hepatitis
Authors: Sebode Marcial , Lohse Ansgar W.
Published: July 2014

In the last two decades, more and more light has been shed on the immunologic pathogenesis of autoimmune liver diseases, notably autoimmune hepatitis (AIH). An immunologic dysbalance with proinflammatory immune responses dominating over hepatic tolerance seems to be part of AIH pathogenesis. In detail, an impairment of regulatory T cells (Treg) is suspected. If this holds true and reduced Treg numbers or their function are pathogenic for AIH, this offers the option of cellular or immunomodulatory therapy. However, the exact immunological role of Treg in AIH still needs to be clarified before cellular therapy is promising for patients.
Treatment of Hepatocellular Carcinoma
Authors: Liccioni Alexandre , Reig Maria , Bruix Jordi
Published: July 2014

Hepatocellular carcinoma (HCC) is a highly prevalent and lethal neoplasia. Several studies have shown that HCC is the main cause of death in patients with cirrhosis. A better knowledge of the natural history of the tumor and the development of staging systems has allowed to refine the prognosis of the patients. The Barcelona Clinic Liver Cancer system (BCLC) has become the preferred staging system since it takes into account the tumor characteristics, the degree of liver impairment and the physical performance. It has been endorsed by several scientific associations and research consortia as it does not just define prognosis, but, more interestingly, it links staging with prognosis assessment and treatment recommendation. Curative therapies such as resection, transplantation and ablation can improve survival in patients diagnosed at an early HCC stage and may offer a long-term cure with overall survival that may exceed 70% at 5 years. Patients with intermediate stage HCC benefit from chemoembolization and proper selection of candidates permits a 50% survival at 3-4 years. Finally, patients diagnosed at an advanced stage benefit from sorafenib, an oral available, multikinase inhibitor with antiangiogenic and antiproliferative effects. Current research efforts are aimed at further refining prognosis prediction through molecular profiling and enhanced clinical characterization. At the same time, better knowledge of the molecular mechanisms of cancer should result in a further improvement of the current life expectancy of patients.
IgG4-Associated Cholangitis
Authors: Beuers Ulrich , Maillette de Buy Wenniger Lucas J. , Doorenspleet Marieke , Hubers Lowiek , Verheij Joanne , van Gulik Thomas , van de Graaf Stan F.J. , de Vries Niek
Published: July 2014

IgG4-associated cholangitis (IAC) is the hepatobiliary manifestation of immunoglobulin G4-related disease (IgG4-RD), a systemic fibroinflammatory disorder with a wide variety of clinical presentations and organ manifestations. IgG4-RD predominantly affects the hepatobiliary tract (IAC) and pancreas (autoimmune pancreatitis) and mimics hepatobiliary, pancreatic and other malignancies. Patients typically are 60-80 years old and 80-85% are male. They often present with painless obstructive jaundice and organ swelling that can be mistaken for pancreatic or bile duct cancer, as well as primary or secondary sclerosing cholangitis. An accurate diagnostic marker is lacking and extensive surgery for presumed malignant hepatobiliary or pancreatic disease leads to the diagnosis of IgG4-RD in 1 of 3 patients. Early effective immunosuppressive treatment is often missed. The pathogenesis of IgG4-RD has been enigmatic. We recently identified dominant IgG4+ B-cell receptor clones in blood and tissue of patients with IAC, but not in healthy or disease controls, and hypothesized that specific B-cell responses are pivotal to the pathogenesis of IAC and IgG4-RD. Analysis of our Amsterdam cohort and blinded extramural validation of the Oxford cohort of patients with IgG4-RD disclosed a remarkable association with ‘blue-collar work'. Thus, long-term exposure to solvents and other organic agents might predispose to IgG4-RD.
Evidence-Based Treatment of Primary Biliary Cirrhosis
Authors: Poupon Raoul
Published: July 2014

The natural history of primary biliary cirrhosis (PBC) has improved greatly during the past two decades because of its diagnosis at earlier stages and the widespread use of ursodeoxycholic acid as first-line treatment. As a result, far fewer patients require liver transplantation and patients diagnosed with early-stage disease appear to have a normal life expectancy. The evidence-based treatment of PBC is reviewed here. The challenge of designing and executing high-quality clinical trials as well as lessons from past clinical trials are discussed. The rationales for the use of budesonide and new investigational therapies (PPAR and FXR agonists) as well as their therapeutic potential in light of recent available data are also reviewed. An algorithm of the management of PBC patients responding or not to ursodeoxycholic acid is proposed.
Therapeutic Role of Bile Acids and Nuclear Receptor Agonists in Fibrosing Cholangiopathies
Authors: Trauner Michael , Halilbasic Emina , Kazemi-Shirazi Lili , Kienbacher Christian , Staufer Katharina , Traussnigg Stefan , Hofer Harald
Published: July 2014

Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) result in progressive fibrosis of the biliary tract and ultimately cirrhosis of the liver. Since the etiology and pathogenesis of these fibrosing cholangiopathies are still poorly understood, therapeutic options are rather limited at present. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and established standard treatment for PBC, but its role for medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid, a side chain-shortened C23 homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g. obeticholic acid) which currently undergo clinical development for fibrosing cholangiopathies such as PBC and PSC. Other nuclear receptors such as vitamin D receptor and fatty acid-activated peroxisome proliferator-activated receptors are also of considerable interest. This review article is a summary of an overview talk given at Falk Symposium 191 on Advances in Pathogenesis and Treatment of Liver Diseases held in London, October 3-4, 2013, and summarizes the recent progress with novel therapeutic bile acids and bile acid derivatives as novel therapies for fibrosing cholangiopathies such as PBC and PSC.
The HCV Life Cycle: In vitro Tissue Culture Systems and Therapeutic Targets
Authors: Gerold Gisa , Pietschmann Thomas
Published: July 2014

Hepatitis C virus (HCV) is a highly variable plus-strand RNA virus of the family Flaviviridae. Viral strains are grouped into six epidemiologically relevant genotypes that differ from each other by more than 30% at the nucleotide level. The variability of HCV allows immune evasion and facilitates persistence. It is also a substantial challenge for the development of specific antiviral therapies effective across all HCV genotypes and for prevention of drug resistance. Novel HCV cell culture models were instrumental for identification and profiling of therapeutic strategies. Concurrently, these models revealed numerous host factors critical for HCV propagation, some of which have emerged as targets for antiviral therapy. It is generally assumed that the use of host factors is conserved among HCV isolates and genotypes. Additionally, the barrier to viral resistance is thought to be high when interfering with host factors. Therefore, current drug development includes both targeting of viral factors but also of host factors essential for virus replication. In fact, some of these host-targeting agents, for instance inhibitors of cyclophilin A, have advanced to late stage clinical trials. Here, we highlight currently available cell culture systems for HCV, review the most prominent host-targeting strategies against hepatitis C and critically discuss opportunities and risks associated with host-targeting antiviral strategies.
Host Factor-Targeted Hepatitis B Virus Therapies
Authors: Gehring Adam , Bertoletti Antonio , Tavis John E.
Published: July 2014

In this review we will focus on host factors known to impact hepatitis B virus (HBV) replication as current or potential targets for therapeutic intervention. Some immunotherapeutic strategies will be discussed because they have the potential to activate interferon-mediated clearance of HBV, but attention will also be paid to host machinery and proteins that silence covalently closed circular DNA, destabilize viral RNA, or disrupt entry and trafficking of HBV virions. Many of these are in the early stages of development, but may represent novel avenues to reduce HBV burden when combined with nucleos(t)ide analogues.
Mechanisms of Hepatitis B Virus Resistance Development
Authors: Warner Nadia , Locarnini Stephen
Published: July 2014

Hepatitis B virus (HBV) resistance to nucleos(t)ide analogue (NA) therapy is essentially structure specific, with each NA falling within three main structural groups. Resistance to each of these is characterized by specific mutations in the reverse transcriptase domains of the HBV polymerase, and may be associated with compensatory mutations which can increase replication. HBV polymerase is considered to have a traditional ‘right-handed' structural conformation, and each of the resistance mutations is predicted to cause a specific structural change of the polymerase, thereby preventing incorporation of NA into replicating DNA. The selection of resistance occurs at different rates for each NA, and is affected by the high mutational rate of HBV and the ability of the drug to suppress viral replication. Some mutations or combinations of mutations may be associated with multidrug resistance, limiting treatment options. In contrast to most other viruses, resistance in HBV is confounded by the overlapping surface gene, the major NA-resistant mutations also altering the surface proteins in most cases, potentially altering virus secretion and neutralization, which may pose a public health threat in the future.
Interferon Therapy of Chronic Hepatitis B
Authors: Brunetto Maurizia Rossana , Bonino Ferruccio
Published: July 2014

Chronic hepatitis B (CHB) results from the inability of the host's immune system to control viral replication. Interferon-α (IFN-α) therapy can convert CHB into inactive hepatitis B virus (HBV) infection in 20-30% of the treated patients. In spite of the low response rate, IFN-α therapy has the advantage of having a limited duration and being effective even after therapy, as demonstrated by a much higher incidence of HBsAg clearance in responders to IFN-α than in naturally occurring inactive HBsAg carriers. IFN-α has multiple antiviral, antiproliferative, and immunomodulatory activities and targets: cellular genes (IFN-stimulated genes) activating different pathways of antiviral defense in infected and noninfected cells, HBV replication blocking the RNA-containing core particle formation and accelerating their decay, degrading pregenomic RNA, and modulating the nuclear viral minichromosome (covalently closed circular DNA) activity by targeting its epigenetic regulation and both innate and adaptive immune response. The interference of viral heterogeneity and genetic polymorphisms of the host on IFN-α susceptibility is under investigation. Only a better understanding of the complex interplay between the different activities of IFN-α would warrant the amelioration of current therapeutic strategies and the design of new therapeutic approaches. The study of on-treatment dynamics of HBV infection by means of combined quantitative monitoring of serum HBV DNA and HBsAg warrant tailoring treatment at the single-patient level and can help to make treatment more cost-effective by using the different combinations of currently available antivirals, including IFN, more appropriately. Integrated molecular and clinical knowledge in a systems medicine fashion is mandatory to further improve antiviral therapy in CHB.
Tegumentary Leishmaniasis: A Diagnostic Approach Considering Aspects of the Cytological Examination
Authors: de Mello Cintia Xavier , de Morais Luan Hugolino , Schubach Armando de Oliveira , Madeira Fátima
Published: July 2014

Objective: To elaborate figures that highlight the microscopic appearance of amastigote forms of the genus Leishmania and other structures subject to confusion during the routine of the direct examination of tegumentary leishmaniasis (TL). Study Design: We reviewed imprint and scraping slides previously prepared from patients with a definite diagnosis. Smear examinations were performed with an immersion objective (×1,000) selecting structures of interest for photodocumentation and elaboration of the illustrations. Results: We elaborated two 13 × 17 cm figures containing photomicrographs of amastigote forms with typical and atypical morphology of Leishmania parasites and other microorganisms, mainly fungi in the yeast-like phase and bacteria which could be confused with amastigote forms during the direct examination. Conclusions: The production of material like we show here is important and should be encouraged because of the need for constant training of professionals working in the area of TL diagnosis.