bluuebunny/crossref_metadata_2025 huggingface dataset:
IONIZATION IN A 1-DIMENSIONAL DIPOLE MODEL
Authors: COSTIN O. , LEBOWITZ J. L. , STUCCHIO C.
Published: August 2008

We study the evolution of a one-dimensional model atom with δ-function binding potential, subjected to a dipole radiation field E(t)x with E(t) a 2π/ω-periodic real-valued function. We prove that when E(t) is a trigonometric polynomial, complete ionization occurs, i.e. the probability of finding the electron in any fixed region goes to zero as t → ∞.

For ψ(x, t = 0) compactly supported and general periodic fields, we decompose ψ(x, t) into uniquely defined resonance terms and a remainder. Each resonance is 2π/ω periodic in time and behaves like the exponentially growing Green's function near x = ±∞. The remainder is given by an asymptotic power series in t-1/2 with coefficients varying with x.
MODIFICATION OF WETTING PROPERTIES OF PMMA BY IMMERSION PLASMA ION IMPLANTATION
Authors: MIREAULT N. , ROSS G. G.
Published: August 2008

Advancing and receding contact angles below 5° have been obtained on PMMA surfaces with the implantation of argon and oxygen ions. The ion implantations were performed by means of the Immersion Plasma Ion Implantation (IPII) technique, a hybrid between ion beams and immersion plasmas. Characterization of treated PMMA surfaces by means of XPS and its combination with chemical derivatization (CD-XPS) have revealed the depletion of oxygen and the creation of dangling bonds, together with the formation of new chemical functions such as –OOH , –COOH and C = C . These observations provide a good explanation for the strong increase of the wetting properties of the PMMA surfaces.
SURFACE-ACTIVE AND PERFORMANCE PROPERTIES OF CATIONIC IMIDAZOLINIUM SURFACTANTS BASED ON DIFFERENT FATTY ACIDS
Authors: BAJPAI DIVYA , TYAGI V. K.
Published: August 2008

Imidazoline surfactants belong to the category of cationic surfactants. Cationic surfactants are often quaternary nitrogen salts and are widely used both in nonaqueous systems and in applications such as textile softeners, dispersants, and emulsifiers. This study describes the surface-active properties of cationic imidazolinium surfactants synthesized from different fatty acids. Their laundry performance in combination with nonionic surfactants like detergency, foaming property, softening property, rewettability etc., is also emphasized.
STUDY OF PULSE ON PULSED NANOCRYSTALLINE PLASMA ELECTROLYTIC CARBONITRIDING ON THE NANOSTRUCTURE OF COMPOUND LAYER
Authors: ALIOFKHAZRAEI MAHMOOD , AHANGARANI SHAHROKH , ROUHAGHDAM ALIREZA SABOUR
Published: August 2008

Surface hardening of commercially pure titanium by using pulse on pulsed nanocrystalline plasma electrolytic carbonitriding has been studied in this investigation. Coating process has been performed on Triethanolamine-based electrolyte by cooling bath. Nanostructure of obtained compound layer was examined with figure analysis of SEM nanographs. The effects of process variables, i.e., Triethanolamine concentration, electrical conductivity of electrolyte, applied voltage, and treatment time, have been experimentally studied. Statistical methods were used to achieve the optimum size of nanocrystals. Finally the contribution percentage of effective factors of pulsed current was revealed and confirmation run show the validity of obtained results.
CHARACTERIZATION OF SURFACE COMPOSITION AND MICROSTRUCTURE OF H13 STEEL IMPLANTED BY Ti IONS USING MASKING IMPLANTATION PROCEDURE
Authors: YANG J. H. , LI S. , CHENG M. F. , LUO X. D.
Published: August 2008

Ti and C ions extracted from a metal vapor vacuum arc ion source (MEVVA) were implanted into H13 steel using a masking procedure to ensure reproducible conditions for testing and subsequent analysis. An optical interference microscope and pin-on-disc apparatus investigated the wear and friction characteristics of the steel. The Ti concentration depth profile from Rutherford backscattering spectroscopy was compared with that calculated by a TRIDYN code. It was observed by grazing-angle X-ray diffraction and transmission electron microscopy that carbide of Ti appeared in the doped region. The concentration depth profile and microstructure analysis can serve to illuminate the wear resistance improvement mechanisms of the Ti -implanted steel.
SURFACE PHONON AND CONFINED PHONON POLARITONS IN WURTIZTE NITRIDE THIN-FILM STRUCTURES
Authors: ZHANG L.
Published: August 2008

The polar phonon polariton modes in a wurtzite thin-film structure have been theoretically investigated in the present paper. It has been confirmed that there are two types of phonon polariton modes, i.e., the surface phonon polariton (SPP) modes and the confined phonon polariton (CPP) modes in wurtzite thin-film systems. The frequency ranges of the SPP and CPP modes have been discussed in detail. The dispersive equations for the two types of polarition modes are also deduced. Numerical calculations on a GaN thin-film structure reveal that, for a given free wavenumber kt in x-direction, there are two branches of SPP modes in general. The width of the wurtizte thin film has important influence on the dispersive properties of the polariton modes, especially the width d is small. Our calculated result agrees well with the recent experimental observation in GaN thin-film system. Furthermore, we confirm that the SPP modes observed (at about the frequency of 700 cm-1) is the low-frequency SPP modes. The CPP modes appear in two frequency ranges of [ωzT, GaN ,ωtT, GaN ] and [ωzL, GaN ,ωtL, GaN ]. There are infinite branches of CPP modes in each range. The low-frequency branch, in contrast to the high-frequency branch, is more dispersive. Moreover, the dispersion of lower-order CPP modes is more obvious than that of higher-order CPP ones. At last, the distribution properties of the electric field components Ex(z) for the SPP and CPP modes are discussed and analyzed. It is found that Ex(z) are either symmetrical, or antisymmetrical. The electric field components [Formula: see text] for SPP modes are mainly localized at the surfaces. The distribution properties of electric field components [Formula: see text] are quite analogous to the behaviors of bound electronic states in confined quantum systems. In terms of these features, the CPP modes in the GaN thin film structures are distinguished and labeled.
THE SENSE OF SCENTS
Authors: THAVANESWARAN SHANTI
Published: August 2008

The scientific study of fragrances brings together many different facets of chemistry, and is an excellent illustration of the importance of chemistry in our daily lives. This article briefly describes the history of fragrance chemistry, from its origins in natural product isolation, to the improved technologies of synthetic chemistry and the analytical methods used to determine fragrance composition. The biological basis of smell and molecular recognition is explored, including examples and applications of fragrant compounds from five different fragrance families.
q-ANALOGUES OF WILSON'S THEOREM
Authors: CHAPMAN ROBIN , PAN HAO
Published: August 2008

We give q-analogues of Wilson's theorem for the primes congruent to 1 and 3 modulo 4, respectively. Also q-analogues of two congruences due to Mordell and Chowla are established.
A PROBLEM OF ERDÖS, SZÖSZ AND TURÁN CONCERNING DIOPHANTINE APPROXIMATIONS
Authors: BOCA FLORIN P.
Published: August 2008

For A > 0 and c > 1, let S(N, A, c) denote the set of those numbers θ ∈ ]0,1[ which satisfy [Formula: see text] for some coprime integers a and b with N < b ≤ cN. The problem of the existence and computation of the limit f(A, c) of the Lebesgue measure of S(N, A, c) as N → ∞ was raised by Erdös, Szüsz and Turán [3]. This limit has been shown to exist by Kesten and Sós [5] using a probabilistic argument and explicitly computed when Ac ≤ 1 by Kesten [4]. We give a complete solution proving directly the existence of this limit and identifying it in all cases.
An adaptive automatically tuning intrusion detection system
Authors: Yu Zhenwei , Tsai Jeffrey J. P. , Weigert Thomas
Published: August 2008

An intrusion detection system (IDS) is a security layer to detect ongoing intrusive activities in computer systems and networks. Current IDS have two main problems: The first problem is that typically so many alarms are generated as to overwhelm the system operator, many of these being false alarms. The second problem is that continuous tuning of the intrusion detection model is required in order to maintain sufficient performance due to the dynamically changing nature of the monitored system. This manual tuning process relies on the system operators to work out the updated tuning solution and to integrate it into the detection model.

In this article, we present an automatically tuning intrusion detection system, which controls the number of alarms output to the system operator and tunes the detection model on the fly according to feedback provided by the system operator when false predictions are identified. This system adapts its behavior (i) by throttling the volume of alarms output to the operator in response to the ability of the operator to respond to these alarms, and (ii) by deciding how aggressively the detection model should be tuned based on the accuracy of earlier predictions. We evaluated our system using the KDDCup'99 intrusion detection dataset. Our results show that an adaptive, automatically tuning intrustion detection system will be both practical and efficient.
A survey of autonomic computing—degrees, models, and applications
Authors: Huebscher Markus C. , McCann Julie A.
Published: August 2008

Autonomic Computing is a concept that brings together many fields of computing with the purpose of creating computing systems that self-manage. In its early days it was criticised as being a “hype topic” or a rebadging of some Multi Agent Systems work. In this survey, we hope to show that this was not indeed ‘hype’ and that, though it draws on much work already carried out by the Computer Science and Control communities, its innovation is strong and lies in its robust application to the specific self-management of computing systems. To this end, we first provide an introduction to the motivation and concepts of autonomic computing and describe some research that has been seen as seminal in influencing a large proportion of early work. Taking the components of an established reference model in turn, we discuss the works that have provided significant contributions to that area. We then look at larger scaled systems that compose autonomic systems illustrating the hierarchical nature of their architectures. Autonomicity is not a well defined subject and as such different systems adhere to different degrees of Autonomicity, therefore we cross-slice the body of work in terms of these degrees. From this we list the key applications of autonomic computing and discuss the research work that is missing and what we believe the community should be considering.
Towards achieving fairness in the Linux scheduler
Authors: Wong Chee Siang , Tan Ian , Kumari Rosalind Deena , Wey Fun
Published: August 2008

The Operating System scheduler is designed to allocate the CPU resources appropriately to all processes. The Linux Completely Fair Scheduler (CFS) design ensures fairness among tasks using the thread fair scheduling algorithm. This algorithm ensures allocation of resources based on the number of threads in the system and not within executing programs. This can lead to fairness issue in a multi-threaded environment as the Linux scheduler tends to favor programs with higher number of threads. We illustrate the issue of fairness through experimental evaluation thus exposing the weakness of the current allocation scheme where software developers could take advantage by spawning many additional threads in order to obtain more CPU resources. A novel algorithm is proposed as a solution towards achieving better fairness in the Linux scheduler. The algorithm is based on weight readjustment of the threads created in the same process to significantly reduce the unfair allocation of CPU resources in multi-threaded environments. The algorithm was implemented and evaluated. It demonstrated promising results towards solving the raised fairness issue. We conclude this paper highlighting the limitations of the proposed approach and the future work in the stated direction.
CUBIC
Authors: Ha Sangtae , Rhee Injong , Xu Lisong
Published: August 2008

CUBIC is a congestion control protocol for TCP (transmission control protocol) and the current default TCP algorithm in Linux. The protocol modifies the linear window growth function of existing TCP standards to be a cubic function in order to improve the scalability of TCP over fast and long distance networks. It also achieves more equitable bandwidth allocations among flows with different RTTs (round trip times) by making the window growth to be independent of RTT -- thus those flows grow their congestion window at the same rate. During steady state, CUBIC increases the window size aggressively when the window is far from the saturation point, and the slowly when it is close to the saturation point. This feature allows CUBIC to be very scalable when the bandwidth and delay product of the network is large, and at the same time, be highly stable and also fair to standard TCP flows. The implementation of CUBIC in Linux has gone through several upgrades. This paper documents its design, implementation, performance and evolution as the default TCP algorithm of Linux.
Practical techniques for purging deleted data using liveness information
Authors: Boutcher David , Chandra Abhishek
Published: August 2008

The layered design of the Linux operating system hides the
liveness
of file system data from the underlying block layers. This lack of liveness information prevents the storage system from discarding blocks deleted by the file system, often resulting in poor utilization, security problems, inefficient caching, and migration overheads. In this paper, we define a generic "purge" operation that can be used by a file system to pass liveness information to the block layer with minimal changes in the layer interfaces, allowing the storage system to discard deleted data. We present three approaches for implementing such a purge operation: direct call, zero blocks, and flagged writes, each of which differs in their architectural complexity and potential performance overhead. We evaluate the feasibility of these techniques through a reference implementation of a dynamically resizable copy on write (COW) data store in User Mode Linux (UML). Performance results obtained from this reference implementation show that all these techniques can achieve significant storage savings with a reasonable execution time overhead. At the same time, our results indicate that while the direct call approach has the best performance, the zero block approach provides the best compromise in terms of performance overhead and its semantic and architectural simplicity. Overall, our results demonstrate that passing liveness information across the file system-block layer interface with minimal changes is not only feasible but practical.
Virtual servers and checkpoint/restart in mainstream Linux
Authors: Bhattiprolu Sukadev , Biederman Eric W. , Hallyn Serge , Lezcano Daniel
Published: August 2008

Virtual private servers and application checkpoint and restart are two advanced operating system features which place different but related requirements on the way kernel-provided resources are accessed by userspace. In Linux, kernel resources, such as process IDs and SYSV shared messages, have traditionally been identified using global tables. Since 2005, these tables have gradually been transformed into per-process namespaces in order to support both resource availability on application restart and virtual private server functionality. Due to inherent differences in the resources themselves, the semantics of namespace cloning differ for many of the resources. This paper describes the existing and proposed namespaces as well as their uses.
Prolonged administration of a dithiol antioxidant protects against ventricular remodeling due to ischemia-reperfusion in mice
Authors: Ambler S. Kelly , Hodges Yvonne K. , Jones Gayle M. , Long Carlin S. , Horwitz Lawrence D.
Published: August 2008

The prolonged production of reactive oxygen species due to ischemia-reperfusion (I/R) is a potential cause of the pathological remodeling that frequently precedes heart failure. We tested the ability of a potent dithiol antioxidant, bucillamine, to protect against the long-term consequences of I/R injury in a murine model of myocardial infarction. After transiently occluding the left anterior descending coronary artery for 30 min, saline or bucillamine (10 μg/g body wt) was injected intravenously as a bolus within the first 5 min of reperfusion. The antioxidant treatment continued with daily subcutaneous injections for 4 wk. There were no differences in infarct sizes between bucillamine- and saline-treated animals. After 4 wk of reperfusion, cardiac hypertrophy was decreased by bucillamine treatment (ventricular weight-to-body weight ratios: I/R + saline, 4.5 ± 0.2 mg/g vs. I/R + bucillamine, 4.2 ± 0.1 mg/g; means ± SE; P < 0.05). Additionally, the hearts of bucillamine-treated mice had improved contractile function (echocardiographic measurement of fractional shortening) relative to saline controls: I/R + saline, 32 ± 3%, versus I/R + bucillamine, 41 ± 4% ( P < 0.05). Finally, I/R-induced injury in the saline-treated mice was accompanied by a fetal pattern of gene expression determined by ribonuclease protection assay that was consistent with pathological cardiac hypertrophy and remodeling [increased atrial natriuretic peptide, β-myosin heavy chain (MHC), skeletal α-actin; decreased sarco(endo)plasmic reticulum Ca2+ ATPase 2a, and α-MHC-to-β-MHC ratio]. These changes in gene expression were significantly attenuated by bucillamine. Therefore, treatment with a dithiol antioxidant for 4 wk after I/R preserved ventricular function and prevented the abnormal pattern of gene expression associated with pathological cardiac remodeling.
An Intracellular Renin-Angiotensin System in Neurons: Fact, Hypothesis, or Fantasy
Authors: Grobe Justin L. , Xu Di , Sigmund Curt D.
Published: August 2008

The renin-angiotensin system in the brain acts to regulate a number of physiological processes. Evidence suggests that angiotensin peptides may act as neurotransmitters, although their biosynthetic pathways are poorly understood. We review evidence for neuronal production of angiotensin peptides and hypothesize that angiotensin may be synthesized intracellularly in neurons.
Potassium Channels Keep Mobile Cells on the Go
Authors: Schwab Albrecht , Hanley Peter , Fabian Anke , Stock Christian
Published: August 2008

Cell motility is a prerequisite for the creation of new life, and it is required for maintaining the integrity of an organism. Under pathological conditions, “too much” motility may cause premature death. Studies over the past few years have revealed that ion channels are essential for cell motility. This review highlights the importance of K+channels in regulating cell motility.
Predicting Clinical Outcome through Molecular Profiling in Stage III Melanoma
Authors: John Thomas , Black Michael A. , Toro Tumi T. , Leader Debbie , Gedye Craig A. , Davis Ian D. , Guilford Parry J. , Cebon Jonathan S.
Published: August 2008

Purpose: Patients with macroscopic stage III melanoma represent a heterogeneous cohort with average 5-year overall survival rates of <30%. With current algorithms, it is not possible to predict which patients will achieve longer-term survival. We hypothesized that molecular profiling could be used to identify prognostic groups within patients with stage III melanoma while also providing a greater understanding of the biological programs underpinning these differences.

Experimental Design: Lymph node sections from 29 patients with stage IIIB and IIIC melanoma, with divergent clinical outcome including 16 “poor-prognosis” and 13 “good-prognosis” patients as defined by time to tumor progression, were subjected to molecular profiling using oligonucleotide arrays as an initial training set. Twenty-one differentially expressed genes were validated using quantitative PCR and the 15 genes with strongest cross-platform correlation were used to develop two predictive scores, which were applied to two independent validation sets of 10 and 14 stage III tumor samples.

Results: Supervised analysis using differentially expressed genes was able to differentiate the prognostic groups in the training set. The developed predictive scores correlated directly with clinical outcome. When the predictive scores were applied to the two independent validation sets, clinical outcome was accurately predicted in 90% and 85% of patients, respectively.

Conclusion: We describe a gene expression profile that is capable of distinguishing clinical outcomes in a previously homogeneous group of stage III melanoma patients.
Effect of Rapamycin Alone and in Combination with Sorafenib in an Orthotopic Model of Human Hepatocellular Carcinoma
Authors: Wang Zheng , Zhou Jian , Fan Jia , Qiu Shuang-Jian , Yu Yao , Huang Xiao-Wu , Tang Zhao-You
Published: August 2008

Purpose: Novel therapeutic strategies are needed to prevent the tumor recurrence or metastasis after liver transplantation for hepatocellular carcinoma (HCC). This study was to investigate the effect of rapamycin, alone and in combination with sorafenib, on HCC in vivo.

Experimental Design: Xenograft of a highly metastatic human HCC tumor (LCI-D20) was used to evaluate primary tumor growth and lung metastasis after treatment with rapamycin alone or in combination with sorafenib. Tumor cell proliferation was determined by Ki-67 immunostaining. To detect tumor cell apoptosis, the terminal deoxynucleotidyl-transferase–mediated dUTP nick-end labeling assay was used. Tumor angiogenesis was investigated by using a monoclonal anti-CD31 antibody. A vascular endothelial growth factor ELISA kit was used to measure vascular endothelial growth factor protein levels in the mice serum.

Results: Rapamycin, alone and in combination with sorafenib, strongly inhibited primary tumor growth and lung metastases in LCI-D20 model. Furthermore, the combination therapy significantly enhanced the effect of antitumor on primary tumor growth compared with single treatment with either rapamycin (P < 0.001) or sorafenib (P < 0.001). Rapamycin alone inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Nevertheless, the combination therapy showed a significant inhibition of tumor cell proliferation (P < 0.05). Additionally, the combination therapy also further enhanced suppression of tumor cell angiogenesis compared with rapamycin treatment (P < 0.01). However, the induction of apoptosis in combination therapy group was not significantly higher than in the rapamycin-treated group (P > 0.05).

Conclusions: The combination therapy of rapamycin and sorafenib could be a new and promising therapeutic approach to the treatment of HCC and prevention of HCC recurrence after liver transplantation.
Vascular Endothelial Growth Factor Receptor-1 Contributes to Resistance to Anti–Epidermal Growth Factor Receptor Drugs in Human Cancer Cells
Authors: Bianco Roberto , Rosa Roberta , Damiano Vincenzo , Daniele Gennaro , Gelardi Teresa , Garofalo Sonia , Tarallo Valeria , De Falco Sandro , Melisi Davide , Benelli Roberto , Albini Adriana , Ryan Anderson , Ciardiello Fortunato , Tortora Giampaolo
Published: August 2008

Purpose: The resistance to selective EGFR inhibitors involves the activation of alternative signaling pathways, and Akt activation and VEGF induction have been described in EGFR inhibitor–resistant tumors. Combined inhibition of EGFR and other signaling proteins has become a successful therapeutic approach, stimulating the search for further determinants of resistance as basis for novel therapeutic strategies.

Experimental Design: We established human cancer cell lines with various degrees of EGFR expression and sensitivity to EGFR inhibitors and analyzed signal transducers under the control of EGFR-dependent and EGFR-independent pathways.

Results: Multitargeted inhibitor vandetanib (ZD6474) inhibited the growth and the phosphorylation of Akt and its effector p70S6 kinase in both wild-type and EGFR inhibitor–resistant human colon, prostate, and breast cancer cells. We found that the resistant cell lines exhibit, as common feature, VEGFR-1/Flt-1 overexpression, increased secretion of VEGF and placental growth factor, and augmented migration capabilities and that vandetanib is able to antagonize them. Accordingly, a new kinase assay revealed that in addition to VEGF receptor (VEGFR)-2, RET, and EGFR, vandetanib efficiently inhibits also VEGFR-1. The contribution of VEGFR-1 to the resistant phenotype was further supported by the demonstration that VEGFR-1 silencing in resistant cells restored sensitivity to anti-EGFR drugs and impaired migration capabilities, whereas exogenous VEGFR-1 overexpression in wild-type cells conferred resistance to these agents.

Conclusions: This study shows that VEGFR-1 contributes to anti-EGFR drug resistance in different human cancer cells. Moreover, vandetanib inhibits VEGFR-1 activation, cell proliferation, and migration, suggesting its potential utility in patients resistant to EGFR inhibitors.
Phenotype and Functional Characterization of Long-term gp100-Specific Memory CD8+ T Cells in Disease-Free Melanoma Patients Before and After Boosting Immunization
Authors: Walker Edwin B. , Haley Daniel , Petrausch Ulf , Floyd Kevin , Miller William , Sanjuan Nelson , Alvord Greg , Fox Bernard A. , Urba Walter J.
Published: August 2008

Purpose: Effective cancer vaccines must both drive a strong CTL response and sustain long-term memory T cells capable of rapid recall responses to tumor antigens. We sought to characterize the phenotype and function of gp100 peptide-specific memory CD8+ T cells in melanoma patients after primary gp100209-2M immunization and assess the anamnestic response to boosting immunization.

Experimental Design: Eight-color flow cytometry analysis of gp100-specific CD8+ T cells was done on peripheral blood mononuclear cells collected shortly after the primary vaccine regimen, 12 to 24 months after primary vaccination, and after boosting immunization. The anamnestic response was assessed by comparing the frequency of circulating gp100-specific T cells before and after boosting. Gp100 peptide-induced in vitro functional avidity and proliferation responses and melanoma-stimulated T-cell CD107 mobilization were compared for cells from all three time points for multiple patients.

Results: The frequency of circulating gp100-specific memory CD8+ T cells was comparable with cytomegalovirus-specific and FLU-specific T cells in the same patients, and the cells exhibited anamnestic proliferation after boosting. Their phenotypes were not unique, and individual patients exhibited one of two distinct phenotype signatures that were homologous to either cytomegalovirus-specific or FLU-specific memory T cells. Gp100-specific memory T cells showed some properties of competent memory T cells, such as heightened in vitro peptide-stimulated proliferation and increase in central memory (TCM) differentiation when compared with T-cell responses measured after the primary vaccine regimen. However, they did not acquire enhanced functional avidity usually associated with competent memory T-cell maturation.

Conclusions: Although vaccination with class I–restricted melanoma peptides alone can break tolerance to self-tumor antigens, it did not induce fully competent memory CD8+ T cells—even in disease-free patients. Data presented suggest other vaccine strategies will be required to induce functionally robust long-term memory T cells.
Midkine Enhances Soft-Tissue Sarcoma Growth: A Possible Novel Therapeutic Target
Authors: Jin Zeming , Lahat Guy , Korchin Borys , Nguyen Theresa , Zhu Quan-Sheng , Wang Xuemei , Lazar Alexander J. , Trent Jonathan , Pollock Raphael E. , Lev Dina
Published: August 2008

Purpose: New therapeutic targets for soft-tissue sarcoma (STS) treatment are critically needed. Midkine (MK), a multifunctional cytokine, is expressed during midgestation but is highly restricted in normal adult tissues. Renewed MK expression was shown in several malignancies where protumorigenic properties were described. We evaluated the expression and function of MK in STS.

Experimental Design: Immunohistochemistry, reverse transcription-PCR, and Western blotting (WB) evaluated MK expression in human STS tissues and cell lines. WB and flow cytometry analyzed MK receptor expression. Cell growth assays evaluated the effect of MK on STS cell growth, and WB assessed MK downstream signaling. MK knock-in and knockout experiments further evaluated MK function. The growth of parental versus MK-transfected human fibrosarcoma cells was studied in vivo.

Results: MK was found to be overexpressed in a variety of human STS histologies. Using a rhabdomyosarcoma (RMS) tissue microarray, cytoplasmic and nuclear MK was identified; nuclear MK expression was significantly increased in metastases. Similarly, several STS cell lines expressed and secreted MK; RMS cells exhibited nuclear MK. STS cells also expressed the MK receptors protein tyrosine phosphatase ζ and lipoprotein receptor-related protein. MK significantly enhanced STS cell growth potentially via the Src and extracellular signal-regulated kinase pathways. STS cells stably transfected with MK exhibited increased growth in vitro and in vivo. MK-expressing human STS xenografts showed increased tumor-associated vasculature. Furthermore, MK knockdown resulted in decreased STS cell growth, especially in RMS cells.

Conclusion: MK enhances STS tumor growth; our results support further investigation of MK and its receptors as therapeutic targets for human STS.
Prognostic Effect of Epithelial and Stromal Lymphocyte Infiltration in Non–Small Cell Lung Cancer
Authors: Al-Shibli Khalid I. , Donnem Tom , Al-Saad Samer , Persson Magnus , Bremnes Roy M. , Busund Lill-Tove
Published: August 2008

Purpose: The major value of prognostic markers in potentially curable non-small cell lung cancer (NSCLC) should be to guide therapy after surgical resection. In this regard, the patients' immune status at the time of resection may be important and also measurable. The immune system has paradoxical roles during cancer development. However, the prognostic significance of tumor-infiltrating lymphocytes is controversial. The aim of this study is to elucidate the prognostic significance of epithelial and stromal lymphocyte infiltration in NSCLC.

Experimental Design: Tissue microarrays from 335 resected NSCLC, stage I to IIIA were constructed from duplicate cores of viable and representative neoplastic epithelial and stromal areas. Immunohistochemistry was used to evaluate the epithelial and stromal CD4+, CD8+, and CD20+ lymphocytes.

Results: In univariate analyses, increasing numbers of epithelial CD8+ (P = 0.023), stromal CD8+ (P = 0.002), epithelial CD20+ (P = 0.023), stromal CD20+ (P < 0.001), and stromal CD4+ (P < 0.001) lymphocytes correlated significantly with an improved disease-specific survival. No such relation was noted for epithelial CD4+ cells. Furthermore, a low level of stromal CD8+ lymphocyte infiltration was associated with an increased incidence of angiolymphatic invasion (P = 0.032). In multivariate analyses, a high number of stromal CD8+ (P = 0.043) and CD4+ (P = 0.002) cells were independent positive prognostic factors for disease-specific survival.

Conclusions: High densities of CD4+ and CD8+ lymphocytes in the stroma are independent positive prognostic indicators for resected NSCLC patients. This may suggest that these cells are mediating a strong antitumor immune response in NSCLC.
Deletion of 1p32-p36 Is the Most Frequent Genetic Change and Poor Prognostic Marker in Adenoid Cystic Carcinoma of the Salivary Glands
Authors: Rao Pulivarthi H. , Roberts Diana , Zhao Yi-Jue , Bell Diana , Harris Charles P. , Weber Randal S. , El-Naggar Adel K.
Published: August 2008

Purpose: Adenoid cystic carcinoma (ACC) is a relatively uncommon salivary gland malignancy known for its protean phenotypic features and pernicious clinical behavior. Currently, no effective therapy is available for patients with advanced nonresectable, recurrent, and/or metastatic disease. The purpose of this study is to identify prognostic factors other than tumor stage that can be used to predict the outcome of the patients with ACC.

Experimental Design: We used comparative genomic hybridization (CGH) to identify copy number aberrations in 53 primary ACCs. Array CGH and fluorescence in situ hybridization analysis was used to validate CGH results on selected cases. We correlated these copy number aberrations with clinicopathologic factors using Pearson's χ2 or by the two-tailed Fisher exact test. The disease-specific survival and disease-free intervals were generated by the Kaplan-Meier product limit method.

Results: Chromosomal losses (n = 134) were more frequent than gains (n = 74). The most frequent genetic change was the loss of 1p32-p36 in 44% of the cases followed by 6q23-q27, and 12q12-q14. The most frequently gained chromosomal regions were 8 and 18. Of the chromosomal aberrations, loss of 1p32-p36 was the only abnormality significantly associated with patient's outcome.

Conclusions: This study, for the first time, identifies loss of 1p32-p36 as a significant aberration in ACC. Molecular characterization of 1p32-36 region using the available genomic technologies may lead to the identification of new genes critical to the development of novel therapeutic targets for this disease copy number aberration.
Vandetanib Inhibits Growth of Adenoid Cystic Carcinoma in an Orthotopic Nude Mouse Model
Authors: Choi Sungweon , Sano Daisuke , Cheung Melvina , Zhao Mei , Jasser Samar A. , Ryan Anderson J. , Mao Li , Chen Wan-Tao , El-Naggar Adel K. , Myers Jeffrey N.
Published: August 2008

Purpose: Adenoid cystic carcinoma (ACC) can often be controlled with surgery and postoperative adjuvant radiotherapy but is also characterized by late local recurrence and distant metastasis. No effective systemic therapeutic agents have been found to alter the natural history of ACC. Therefore, new therapeutic approaches are needed. In this study, we evaluated whether vandetanib (Zactima), a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinases, had antitumor efficacy in vitro and in an orthotopic nude mouse model of human ACC.

Experimental Design: The in vitro effects of vandetanib were assessed in three ACC cell lines on cell growth, apoptosis, and VEGFR-2 and EGFR phosphorylation levels. The in vivo antitumor activity of vandetanib was examined in nude mice bearing parotid gland ACC tumors. The mice were treated for 4 weeks with vandetanib (50 mg/kg/d) or placebo (control). Tumors were resected at necropsy, and immunohistochemical and immunofluorescence staining were done.

Results: In vitro, vandetanib caused dose-dependent inhibition of VEGFR-2 and EGFR phosphorylation in ACC cells. Vandetanib also inhibited the cell proliferation and induced their dose-dependent apoptosis. In vivo, mice in the vandetanib group had tumor volumes significantly lower than those in the control group (P < 0.01). In addition, immunohistochemical staining showed a decrease in microvessel density and an increase in apoptosis of both tumor cells and endothelial cells within the tumor xenografts.

Conclusion: These results suggest that vandetanib inhibits the growth of ACC in vitro and in vivo, making it a promising novel agent for the treatment of ACC.
Checkpoint Kinase 1 Down-Regulation by an Inducible Small Interfering RNA Expression System Sensitized In vivo Tumors to Treatment with 5-Fluorouracil
Authors: Ganzinelli Monica , Carrassa Laura , Crippa Francesca , Tavecchio Michele , Broggini Massimo , Damia Giovanna
Published: August 2008

Purpose: After DNA damage, checkpoints pathways are activated in the cells to halt the cell cycle, thus ensuring repair or inducing cell death. To better investigate the role of checkpoint kinase 1 (Chk1) in cellular response to different anticancer agents, Chk1 was knocked down in HCT-116 cell line and in its p53-deficient subline by using small interfering RNAs (siRNA).

Experimental Design: Chk1 was abrogated by transient transfection of specific siRNA against it, and stable tetracycline-inducible Chk1 siRNA clones were obtained transfecting cells with a plasmid expressing two siRNA against Chk1. The validated inducible system was then translated in an in vivo setting by transplanting the inducible clones in nude mice.

Results: Transient Chk1 down-regulation sensitized HCT-116 cells, p53−/− more than the p53 wild-type counterpart, to DNA-damaging agents 5-fluorouracil (5-FU), doxorubicin, and etoposide treatments, with no modification of Taxol and PS341 cytotoxic activities. Inhibition of Chk1 protein levels in inducible clones on induction with doxycycline correlated with an increased cisplatin and 5-FU activity. Such effect was more evident in a p53-deficient background. These clones were transplanted in nude mice and a clear Chk1 down-regulation was shown in tumor samples of mice given tetracycline in the drinking water by immunohistochemical detection of Chk1 protein. More importantly, an increased 5-FU antitumor activity was found in tumors with the double Chk1 and p53 silencing.

Conclusions: These findings corroborate the fact that Chk1 protein is a molecular target to be inhibited in tumors with a defective G1 checkpoint to increase the selectivity of anticancer treatments.
Production and Perception of Temporal Patterns in Native and Non-Native Speech
Authors: Bent Tessa , Bradlow Ann R. , Smith Bruce L.
Published: August 2008

Two experiments examined production and perception of English temporal patterns by native and non-native participants. Experiment 1 indicated that native and non-native (L1 = Chinese) talkers differed significantly in their production of one English duration pattern (i.e., vowel lengthening before voiced versus voice-less consonants) but not another (i.e., tense versus lax vowels). Experiment 2 tested native and non-native listener identification of words that differed in voicing of the final consonant by the native and non-native talkers whose productions were substantially different in experiment 1. Results indicated that differences in native and non-native intelligibility may be partially explained by temporal pat-tern differences in vowel duration although other cues such as presence of stop releases and burst duration may also contribute. Additionally, speech intelligibility depends on shared phonetic knowledge between talkers and listeners rather than only on accuracy relative to idealized production norms.
Safety of Topical Methimazole for the Treatment of Melasma
Authors: Kasraee B. , Safaee Ardekani G.H. , Parhizgar A. , Handjani F. , Omrani G.R. , Samani M. , Nikbakhsh M. , Tanideh N. , Eshraghian A. , Sorg O. , Saurat J.H.
Published: August 2008

Methimazole is an oral antithyroid compound that exhibits a skin-depigmenting effect when used topically. However, the effect of topical methimazole on thyroid function has not been reported. This study was aimed at assessing the safety of topical methimazole used to treat pigmented lesions, without affecting thyroid hormones due to systemic delivery. The pharmacokinetics of methimazole, either applied in the form of a 5% topical formulation to facial skin or taken orally in the form of a 5-mg tablet by 6 volunteers, were determined. In addition, the effect of long-term topical applications of 5% methimazole on the function of the thyroid gland in 20 patients with epidermal melasma was determined following 6 weeks of once-daily application. Cutaneous adverse effects of topical methimazole were determined. From 15 min up to 24 h after application, methimazole was undetectable in the serum of the individuals receiving single topical methimazole dosing. Methimazole, however, was detected in serum after 15 min of oral administration and remained detectable in serum up to 24 h after administration. Long-term topical methimazole applications in melasma patients did not induce any significant changes in serum TSH, free thyroxine and free triiodothyronine levels. Topical methimazole was well tolerated by the patients and did not induce any significant cutaneous side effects. Present data together with the previously shown non-cytotoxic and non-mutagenic characteristics of methimazole indicate that this agent could be considered as a safe skin-depigmenting compound for topical treatment of skin hyperpigmentary disorders in humans.
Skin Tolerance of a New Bath Oil Containing St. John’s Wort Extract
Authors: Reuter J. , Huyke C. , Scheuvens H. , Ploch M. , Neumann K. , Jakob T. , Schempp C.M.
Published: August 2008

Background: Dry and atopic skin requires skin care with lipid-rich emollients and moisturizing bath or shower oils. However, it has been shown recently that some bath oils may even impair the skin barrier. Objective: To investigate the skin-irritating potential of a new bath oil containing a lipophilic St. John’s wort (Hypericum perforatum) extract. Methods: In this single-center, randomized, double-blind, prospective study, 3 bath oils together with positive and negative controls were applied under occlusion on test areas on the volar forearms of 18 volunteers (visit 1). After 24 h, the tapes were removed, and the test areas were evaluated by a visual score and the instrumental measurement of skin erythema and transepidermal water loss (TEWL) using a Mexameter and a Tewameter (visit 2). The test substances were applied a second time, and the measurements were performed after another 24 h (visit 3). Results: The positive control, 1% vol/vol sodium lauryl sulfate (SLS), caused a significant increase in skin erythema and TEWL. In contrast, distilled water as a negative control did not influence these parameters. The new bath oil containing St. John’s wort extract and 1 of the other 2 commercial products were not different from the water control. The third bath oil displayed a skin-irritating effect similar to SLS. Conclusion: The results of this study confirm the different skin-irritating potential of bath oils and demonstrate good skin tolerance of the new bath oil containing St. John‘s wort extract.
Stereopsis and Color Vision Impairment in Patients with Right Extrastriate Cerebral Lesions
Authors: Koh Seong-Beom , Kim Byung-Jo , Lee Jongyun , Suh Sang-il , Kim Tack-Koon , Kim Seung-Hyun
Published: August 2008

Background and Aim: The extrastriate cortex is a visual processing structure beyond the striate cortex. This region contains cells that differ in selectivity for different features of stimuli such as color, motion and stereopsis. We studied stereopsis and color vision in patients with right extrastriate cerebral lesions. Methods: Patients with right extrastriate cerebral lesions determined by MRI were recruited among consecutive inpatients. Patients with cognitive impairment (Mini Mental Status Examination score <24) were excluded. An ophthalmologist performed cortical visual testing: visual acuity, stereopsis, color vision and strabismus within 1 week after the insult. Results: Cortical visual testing was performed in 12 patients. Among the patients studied, 11 demonstrated abnormalities: reduced stereoacuity (8/12), color vision abnormalities (7/12). Seven patients showed complex cortical visual abnormalities. However, only 2 patients complained of subjective clinical symptoms. The MRI lesions in patients with disturbance of stereopsis were located in the dorsal occipitoparietal area and the ventral occipitotemporal area. Color vision abnormalities corresponded to lesions in the ventral occipitotemporal area. Conclusions: Patients with lesions in the right extrastriate cortex tend to have disturbance of stereopsis and color vision abnormalities, even in the absence of visual complaints.
Outcome of Bilateral Subthalamic Nucleus Stimulation in the Treatment of Parkinson’s Disease: Correlation with Intra-Operative Multi-Unit Recordings but Not with the Type of Anaesthesia
Authors: Lefaucheur Jean-Pascal , Gurruchaga Jean-Marc , Pollin Bernard , von Raison Florian , Mohsen Nabil , Shin Masahiro , Ménard-Lefaucheur Isabelle , Oshino Satoru , Kishima Haruhiko , Fénelon Gilles , Rémy Philippe , Cesaro Pierre , Gabriel Inana , Brugières Pierre , Keravel Yves , Nguyen Jean-Paul
Published: August 2008

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) gained general acceptance in the treatment of Parkinson’s disease (PD). Objective: To study the clinical outcome and the predicting factors of efficacy of chronic STN stimulation, while DBS electrodes were implanted under local or general anaesthesia with intra-operative electrophysiological guidance based on multi-unit recordings. Methods: We included a large single-centre cohort of 54 patients with advanced PD (mean age: 59 years; disease duration: 14 years). Clinical evaluation was performed by the Unified Parkinson’s Disease Rating Scale (UPDRS) before and 1 year after surgical placement of DBS electrodes. Results: In the on-stimulation and off-medication condition, the UPDRS part III score was reduced by 56% compared to the off-stimulation condition or pre-operative off-drug score. In the on-stimulation and on-medication condition, this score was reduced by 73%. The severity of motor fluctuations and dyskinesia (UPDRS part IV) and the activities of daily living (UPDRS part II) were reduced by 65 and 80%, respectively, in the on-stimulation/on-medication condition compared to the pre-operative baseline. The daily dose of antiparkinsonian treatment was diminished by 72%. Among the various pre- and intra-operative data, the most important predictive factor for clinical efficacy of STN stimulation was the length of hyperactivity along the best track observed in intra-operative multi-unit recordings. Other predictive factors included age, disease duration and pre-operative levodopa responsiveness or baseline off-drug values of the Hoehn and Yahr and UPDRS part III scores. In contrast, the type of anaesthesia (local vs. general) did not significantly influence the clinical outcome. Conclusion: The present results are in the average of previously published results, but they have been obtained from a large single-centre cohort of patients with important reductions in the daily dose of antiparkinsonian drugs. This study confirmed the efficacy of the STN-DBS technique and emphasized the value of an original intra-operative electrophysiological approach based on multi-unit and not single-unit quantified recordings. This method allows DBS electrode implantation to be safely performed under general anaesthesia without lessening the rate of efficacy of the procedure.